Q4 2023 Alnylam Pharmaceuticals Inc Earnings Call

February 15, 2024

Operator: Today's conference is being recorded. I would now like to hand the conference call over to the company.

Is being recorded I would now like to hand, the conference call over to the company.

Christine Regan Lindenboom: Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Pushkal Garg, Chief Medical Officer and Jeff Poulton, Chief Financial Officer. Also on the line and available for Q&A is Akshay Vaishnaw, Chief Innovation Officer. For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, investors.alnylam.com/events.

Speaker Change: Good morning, I'm, Christine Linda Bell Senior Vice President of Investor Relations Corporate Communications that on island with me today are Yvonne Greenstreet, Chief Executive Officer until the Tengiz, Our Chief commercial officer, what's called Garg, Chief Medical Officer, and Jeff Burton Chief Financial Officer.

Speaker Change: On the line and available for Q&A is Akshay. This now chief Innovation Officer.

Speaker Change: For those of you participating via conference call. The accompanying slides can be accessed by going to the events section of the investors page of our website investor thought on island Dotcom, Washington.

Christine Regan Lindenboom: During today's call, as outlined in slide two, Yvonne will offer some introductory remarks and provide general context. Tolga will provide an update on our global commercial progress, Pushkal will review pipeline updates and clinical progress and Jeff will review our financials and guidance, followed by a summary of upcoming milestones before we open the call for your questions. I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe, proper provision of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent periodic report on file with the SEC. In addition, any forward-looking statement represent our views only up to the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'll turn it over to Yvonne. Yvonne?

During today's call, as outlined in slide two, Yvonne will offer some introductory remarks and provide general context. Tolga will provide an update on our global commercial progress, Pushkal will review pipeline updates and clinical progress and Jeff will review our financials and guidance, followed by a summary of upcoming milestones before we open the call for your questions. I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe, proper provision of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent periodic report on file with the SEC. In addition, any forward-looking statement represent our views only up to the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements.

Speaker Change: During today's call as outlined in slide two of onward offer some introductory remarks and provide general context total will provide an update on our global commercial progress.

Speaker Change: Scott will review pipeline updates and clinical progress and Jeff will review, our financials and guidance followed by a summary of upcoming milestones before we open the call for your question.

I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe, proper provision of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent periodic report on file with the SEC. In addition, any forward-looking statement represent our views only up to the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements.

Speaker Change: I would like to remind you that this call will contain remarks concerning on islands future expectations plans and prospects, which constitute forward looking statements for the purposes of the safe Harbor provision of the private Securities Litigation Reform Act of 90 to 95.

Speaker Change: Actual results may differ materially from those indicated by these forward looking statements as a result of various important factors.

Speaker Change: Putting those discussed in our most recent periodic reports on file with the FCC. In addition, any forward looking statements represent our views only as of the date of this reporting it should not be relied upon as representing our views as of any subsequent date, we specifically disclaim any obligation to update such statements with that I'll turn the call over to Yvonne.

With that, I'll turn it over to Yvonne. Yvonne?

Yvonne L. Greenstreet: Thanks, Christine and thank you, everyone, for joining the call today. Alnylam made great strides in 2023, delivering strong progress across all areas of our business. This includes a robust product growth for our four wholly-owned commercial medicines, delivering $1.24 billion in global net product revenues and hitting the remarkable milestone of over 5,000 patients now on an Alnylam commercial RNAi Therapeutic. We also extended our leadership on RNAi, including the first-ever demonstration of RNAi-mediated target gene silencing of a human brain and pre-clinical data showing for the first-time, delivery of RNAi Therapeutics for adipose and muscle tissues. ZILEBESIRAN also made exciting progress for hypertension, with encouraging results in the KARDIA-1 Phase II study. Together with ZILEBESIRAN, we strengthened our business for the future through business development with a landmark collaboration with Roche.

Yvonne L. Greenstreet: Thanks, Christine and thank you, everyone, for joining the call today.

Yvonne L. Greenstreet: Thanks, Christine and thank you everyone for joining the call today.

Alnylam made great strides in 2023, delivering strong progress across all areas of our business. This includes a robust product growth for our four wholly-owned commercial medicines, delivering $1.24 billion in global net product revenues and hitting the remarkable milestone of over 5,000 patients now on an Alnylam commercial RNAi Therapeutic. We also extended our leadership on RNAi, including the first-ever demonstration of RNAi-mediated target gene silencing of a human brain and pre-clinical data showing for the first-time, delivery of RNAi Therapeutics for adipose and muscle tissues. ZILEBESIRAN also made exciting progress for hypertension, with encouraging results in the KARDIA-1 Phase II study. Together with ZILEBESIRAN, we strengthened our business for the future through business development with a landmark collaboration with Roche.

Yvonne L. Greenstreet: I'm not a made great strides in 2023, delivering strong progress across all areas of our business. This includes the robust product grid draw for wholly owned commercial medicines, delivering 124 billion in global net product revenues and fixing the remarkable milestone.

Yvonne Greenstreet: 5000 patients now on an hour niland commercial RNA therapeutic.

We also extended our leadership on RNAi, including the first-ever demonstration of RNAi-mediated target gene silencing of a human brain and pre-clinical data showing for the first-time, delivery of RNAi Therapeutics for adipose and muscle tissues. ZILEBESIRAN also made exciting progress for hypertension, with encouraging results in the KARDIA-1 Phase II study. Together with ZILEBESIRAN, we strengthened our business for the future through business development with a landmark collaboration with Roche.

Yvonne Greenstreet: <unk> also extended our leadership in R&D, including the first ever demonstration of RNA <unk> mediated target gene silencing of the human grade and preclinical data sharing for the first time delivery of RNA therapeutics adipose and muscle tissues.

<unk> also made exciting progress for hypertension with encouraging results in the cardio <unk> phase II studies further with Dolby surround we strengthened our business for the future with business development with a landmark collaboration depressed.

Yvonne L. Greenstreet: Looking forward, we're excited to continue this progress in 2024, delivering continued commercial execution, notable clinical trial readouts and advancing programs across all stages of developments. As you're aware, a key clinical milestone anticipated this year is the readout from our HELIOS-B Phase III study of VUTRISIRAN in patients with ATTR amyloidosis with cardiomyopathy. As we indicated in our press release this morning, we're announcing a few updates to the analysis plan that we believe will enhance the study, enable the best demonstration of VUTRISIRAN's impact across the entirety of the patient population and support a strong and competitive label. Pushkar will walk through these updates in detail later in the call.

Looking forward, we're excited to continue this progress in 2024, delivering continued commercial execution, notable clinical trial readouts and advancing programs across all stages of developments. As you're aware, a key clinical milestone anticipated this year is the readout from our HELIOS-B Phase III study of VUTRISIRAN in patients with ATTR amyloidosis with cardiomyopathy.

Yvonne Greenstreet: Looking forward. We're excited to continue this progress in 2024, delivering continued commercial execution notable clinical trial, readouts and advancing programs across all stages of development.

Yvonne Greenstreet: As you are aware a key critical milestone anticipated. This year is the readout from our Helios B phase III study of <unk> in patients with <unk> amyloidosis with cardiomyopathy.

As we indicated in our press release this morning, we're announcing a few updates to the analysis plan that we believe will enhance the study, enable the best demonstration of VUTRISIRAN's impact across the entirety of the patient population and support a strong and competitive label. Pushkar will walk through these updates in detail later in the call.

Yvonne Greenstreet: As we indicated in our press release. This morning, we are announcing a few updates to the analysis plan that we believe will enhance the study enable the best demonstration of <unk> impact across the entirety of the patient population and support a strong and competitive label Cusco walk through these updates detail later in the call.

Yvonne L. Greenstreet: We believe all of this puts us on track with our Alnylam P5x25 goals, making Alnylam a top-tier biotech, developing and commercializing transformative medicines for patients around the world with rare and prevalent diseases, driven by a high-yielding pipeline of first and/or best-in-class product candidates from our organic product engine -- all while delivering exceptional financial results. With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga?

We believe all of this puts us on track with our Alnylam P5x25 goals, making Alnylam a top-tier biotech, developing and commercializing transformative medicines for patients around the world with rare and prevalent diseases, driven by a high-yielding pipeline of first and/or best-in-class product candidates from our organic product engine -- all while delivering exceptional financial results.

We believe all of this puts us on track with our nylon piece of it by 'twenty five goals, making it an item a top tier biotech developing and commercializing transformative medicines for patients around the world with Ron and prevalent diseases, driven by high yielding pipeline of first and best in class product candidates from our organic product engine.

Talk: All while delivering exceptional financial results with that let me now turn the call over to talk up for a review of our commercial performance saga.

With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga?

Tolga: Thanks, Yvonne and good morning, everyone. Q4 was another strong quarter for our commercial portfolio, with both our TTR franchise and our Ultra Rare franchise delivering growth in excess of 30% compared with Q4 2022. Total net product revenues grew 32% in the 4th quarter versus prior year or 30% at a constant exchange rate, as we continue to steadily increase the number of patients on each of our therapies. Let me now turn to a summary of our 4th quarter TTR performance. Our TTR franchise achieved $254 million in global net product revenues, representing a 10% increase compared with the 3rd quarter and 33% growth compared with the 4th quarter of 2022.

Tolga Tanguler: Thanks, Yvonne and good morning, everyone.

Q4 was another strong quarter for our commercial portfolio, with both our TTR franchise and our Ultra Rare franchise delivering growth in excess of 30% compared with Q4 2022. Total net product revenues grew 32% in the 4th quarter versus prior year or 30% at a constant exchange rate, as we continue to steadily increase the number of patients on each of our therapies. Let me now turn to a summary of our 4th quarter TTR performance. Our TTR franchise achieved $254 million in global net product revenues, representing a 10% increase compared with the 3rd quarter and 33% growth compared with the 4th quarter of 2022.

Talk Up: Thanks, Steven and good morning, everyone.

Talk Up: Q4 was another strong quarter for our commercial portfolio.

Talk Up: With both our TCR franchise, and our ultra rare franchise delivering growth in excess of 30% compared with Q4 2022.

Talk Up: Total net product revenues grew 32% in the fourth quarter versus prior year or 30% at a constant exchange rate as we continue to steadily increase the number of patients on each of our therapies.

Speaker Change: Let me now turn to a summary of our fourth quarter Ctr performance.

Speaker Change: Our teacher, our franchise achieved $254 million in global net product revenues, representing a 10% increase compared with the third quarter and 33% growth compared with the fourth quarter of 2022.

Tolga: At the end of the 4th quarter, more than 4,060 patients were on commercial ONPATTRO or AMVUTTRA treatment worldwide, up from over 3,790 patients at the end of the 3rd quarter, representing 7% quarterly patient growth. Now, let me provide highlights of our U.S. and International TTR performance. In the U.S., combined sales of ONPATTRO and AMVUTTRA increased by 5% compared with the 3rd quarter and a robust 38% year-over-year, driven by AMVUTTRA's launch. The U.S. quarter-over-quarter growth was primarily driven by an increase in demand, resulting from the strength of ongoing AMVUTTRA patient uptake, more than offsetting a decrease in ONPATTRO patients switching to AMVUTTRA.

Speaker Change: At the end of the fourth quarter more than 4060 patients who are on commercial on petro or ample truck treatments worldwide up from over 30 790 patients at the end of the third quarter, representing 7% quarterly patient growth.

Speaker Change: Now, let me provide highlights of our U S and international TCR performance.

Speaker Change: In the U S combined sales of our Petro and how much of the increased by 5% compared with the third quarter and a robust 38% year over year driven by our <unk> launch.

Tolga: The U.S. quarter-over-quarter growth was primarily driven by an increase in demand resulting from the strength of ongoing Onbutra patient uptake more than offsetting a decrease in on-patron patients switching to Onbutra. At the end of the fourth quarter, more than 85% of U.S. HATTR polyneuropathy patients are now on Amutra, a testament to its clearly differentiated market-leading profile, including rapid knockdown, reversal of polyneuropathy manifestations, well-established safety profile with thousands of patient years of experience, along with only four times a year administration. We also continue to progress on increasing our prescriber base, which has grown over 50% since Ambuter was launched in the third quarter of 2022. While we've been able to facilitate the development of a multidisciplinary center approach for the treatment of HATTR pulmonary neuropathy, driven primarily by cardiologists and neurologists in these centers, Now, let me turn to our international markets, where the TTR franchise growth increased by 18% compared with the third quarter and a strong 28% year over year. The quarter-over-quarter growth was driven by the following.

The U.S. quarter-over-quarter growth was primarily driven by an increase in demand resulting from the strength of ongoing Onbutra patient uptake more than offsetting a decrease in on-patron patients switching to Onbutra.

Speaker Change: The U S quarter over quarter growth was primarily driven by an increase in demand, resulting from the strength of ongoing <unk> patient uptake more than offsetting a decrease in our petro patients switching to ultra.

At the end of the 4th quarter, more than 85% of U.S. hATTR polyneuropathy patients are now on AMVUTTRA, a testament to its clearly differentiated, market-leading profile including rapid knockdown, reversal of polyneuropathy manifestations, well-established safety profile with thousands of patient years of experience, along with only four times a year administration. We also continue to progress on increasing our prescriber base, which has grown over 50% since AMVUTTRA was launched in the 3rd quarter of 2022; while we've been able to facilitate the development of multi-disciplinary center approach for the treatment of hATTR polyneuropathy, driven primarily by cardiologists and neurologists in these centers. Now, let me turn to our International markets, where the TTR franchise growth increased by 18%, compared with the 3rd quarter and a strong 28% year over year. The quarter-over-quarter growth was driven by the following:

Speaker Change: At the end of the fourth quarter more than 85% of U S. <unk> neuropathy patients are now on a mood truck a testament to its clearly differentiated market, leading profile, including rapid knockdown reversal of Polyneuropathy manifestations, well established safety profile with <unk>.

Speaker Change: <unk> of patient years of experience at.

Speaker Change: Along with only four types of your administration.

Speaker Change: We also continue to progress on increasing our prescriber base, which has grown over 50% since <unk> was launched in the third quarter of 2022.

Speaker Change: While we've been able to facilitate the development of multi disciplined et cetera approach for the treatment of <unk> Polyneuropathy, driven primarily by cardiologists and neurologists in these centers.

Now, let me turn to our International markets, where the TTR franchise growth increased by 18%, compared with the 3rd quarter and a strong 28% year over year. The quarter-over-quarter growth was driven by the following: Demand growth driven by Almutra's performance, including recent launches in Spain and Italy, and continued strong Onpetra performance in markets where Almutra is not yet available, and improvement in gross net deductions in the quarter following price reductions in Q3, primarily in Germany, that were highlighted in our Q3 poll. Lastly, consistent with our prior years, growth in the fourth quarter was also favorably impacted by increased inventories in Japan and the timing of orders in various partner markets. In summary, Amutra, with its market-leading profile, is now available and reimbursed in all major markets across the US, Canada, Europe, and Japan, driving robust patient and revenue growth in 2023, and we believe we are well positioned for future growth. Moving to our ultra-rare franchise... Gibralar in Oxlumo delivered $92 million in combined product sales during the fourth quarter, representing an 11% increase compared with the third quarter and a solid 30% growth compared with the fourth quarter of 2022.

Speaker Change: Now, let me turn to our international markets, where the GTR franchise growth increased by 18% compared with the third quarter and a strong 28% year over year.

Speaker Change: The quarter over quarter growth was driven by the following.

Tolga: Demand growth driven by Almutra's performance, including recent launches in Spain and Italy, and continued strong Onpetra performance in markets where Almutra is not yet available, and improvement in gross net deductions in the quarter following price reductions in Q3, primarily in Germany, that were highlighted in our Q3 poll. Lastly, consistent with our prior years, growth in the fourth quarter was also favorably impacted by increased inventories in Japan and the timing of orders in various partner markets. In summary, Amutra, with its market-leading profile, is now available and reimbursed in all major markets across the US, Canada, Europe, and Japan, driving robust patient and revenue growth in 2023, and we believe we are well positioned for future growth. Moving to our ultra-rare franchise... Gibralar in Oxlumo delivered $92 million in combined product sales during the fourth quarter, representing an 11% increase compared with the third quarter and a solid 30% growth compared with the fourth quarter of 2022.

Speaker Change: Demand growth driven by our <unk> performance, including recent launches in Spain, and Italy and continued strong loan Petro performance in markets, where I would say is not yet available.

Speaker Change: An improvement in gross to net deductions in the quarter following price reductions in Q3, primarily in Germany that were highlighted on our Q3 call lastly, consistent with our prior years growth in the fourth quarter was also favorably impacted by increased inventories in Japan, and the timing of orders in various partner Mark.

Lastly, consistent with our prior years, growth in the 4th quarter was also favorably impacted by increased inventories in Japan and the timing of orders in various partner markets. In summary, AMVUTTRA, with its market-leading profile, is now available and reimbursed in all major markets across the U.S., Canada, Europe and Japan, driving robust patient and revenue growth in 2023 and we believe we are well positioned for future growth. Moving to our Ultra Rare franchise, GIVLAARI and OXLUMO delivered $92 million in combined product sales during the 4th quarter, representing an 11% increase compared with the 3rd quarter and a solid 30% growth compared with the 4th quarter of 2022.

That's.

Speaker Change: In summary, I would throw out with its market leading profile is now available and reimbursed in all major markets across the U S, Canada, Europe, and Japan, driving robust patient and revenue growth in 2023, and we believe we are well positioned for future growth.

Speaker Change: Moving to our alternate air franchise.

Speaker Change: <unk> delivered $92 million in combined product sales during the fourth quarter, representing an 11% increase compared with the third quarter and a solid 30% growth compared with the fourth quarter of 2022.

Tolga: We ended the quarter with more than 1,080 patients on our two Ultra Rare products, with approximately 650 patients on GIVLAARI and approximately 430 patients on OXLUMO, representing an 8% combined quarterly growth in patients on our Ultra Rare products compared with the 3rd quarter of 2023. For GIVLAARI, product sales increased by 10% in Q4 compared with the 3rd quarter, with the following regional dynamics: a 7% increase in the U.S., primarily driven by a higher net price achieved in the quarter due to favorable gross to net adjustments; a 16% increase in our international markets, driven by continued demand growth, timing of orders in partner markets and favorable growth to net adjustments.

Speaker Change: We ended the quarter with more than 1080 patients on our tool to air products with approximately 650 patients don't give laurie and approximately 430 patients on ox luma, representing an 8% combined quarterly growth in patients on our ultra air products compared with the third quarter of.

Speaker Change: 2023.

Speaker Change: Forgive Laurie product sales increased by 10% in Q4 compared with the third quarter with the following regional dynamics, a 7% increase in U S, primarily driven by a higher net price achieved in the quarter due to favorable gross to net adjustments.

Speaker Change: A 16% increase in our international markets driven by continued demand growth timing of orders and partner markets and favorable gross to net adjustments.

Pushkal: For OXLUMO, well-positioned as the market-leading therapy in PH1, we delivered a robust 14% increase in product sales compared with the 3rd quarter, which was driven by the following: a 9% increase in the U.S. driven by demand growth; a 16% increase in our International markets, driven by increased demand and the timing of orders in our partner markets. In conclusion, we're very pleased with the results in the 4th quarter with both our TTR and Ultra Rare franchises, which delivered strong growth in patients on therapy during the quarter, as well as robust year-over-year growth in revenues with both franchises delivering 30% or greater growth versus the 4th quarter of 2022. We are well-positioned as we enter 2024 to continue delivering our medicines to more patients in need around the world. Now, with that, I will turn it over to Pushkal to review our recent R&D and pipeline progress. Pushkal?

For OXLUMO, well-positioned as the market-leading therapy in PH1, we delivered a robust 14% increase in product sales compared with the 3rd quarter, which was driven by the following: a 9% increase in the U.S. driven by demand growth; a 16% increase in our International markets, driven by increased demand and the timing of orders in our partner markets. In conclusion, we're very pleased with the results in the 4th quarter with both our TTR and Ultra Rare franchises, which delivered strong growth in patients on therapy during the quarter, as well as robust year-over-year growth in revenues with both franchises delivering 30% or greater growth versus the 4th quarter of 2022. We are well-positioned as we enter 2024 to continue delivering our medicines to more patients in need around the world.

Speaker Change: <unk> well positioned as the market leading therapy in ph, one we delivered a robust 14% increase in product sales compared with the third quarter, which was driven by the following.

Speaker Change: A 9% increase in the U S driven by demand growth, a 16% increase in our international markets driven by increased demand and the timing of orders and our partner markets.

In conclusion, we're very pleased with the results in the 4th quarter with both our TTR and Ultra Rare franchises, which delivered strong growth in patients on therapy during the quarter, as well as robust year-over-year growth in revenues with both franchises delivering 30% or greater growth versus the 4th quarter of 2022. We are well-positioned as we enter 2024 to continue delivering our medicines to more patients in need around the world.

Speaker Change: In conclusion, we're very pleased with the results in the fourth quarter with both our Ctr and also rare franchises, which delivered strong growth in patients on therapy during the quarter as well as robust year over year growth in revenues with both franchises, delivering 30% or greater growth versus the fourth quarter.

Speaker Change: <unk> of 2022.

Speaker Change: We are well positioned as we enter 2024 to continue delivering our medicines to more patients in need around the world.

Now, with that, I will turn it over to Pushkal to review our recent R&D and pipeline progress. Pushkal?

Speaker Change: Now with that I will turn it over to push call to review, our recent R&D and pipeline progress Pushcart. Thank.

Pushkal: Thank you, Tolga and good morning, everyone. I'm going to begin with some important updates that we're announcing this morning regarding Helios. As you know, HELOS-B is an outcome study being conducted to expand the label for Ambutra to include the treatment of cardiomyopathy in patients with hereditary and wild-type ATTR amyloidosis. Today, Onpatra and Ambucha are approved to treat polyneuropathy in patients with hereditary ATTR amyloidosis, which has an estimated prevalence of 25,000 to 30,000 patients worldwide.

Pushkal Garg: Thank you, Tolga and good morning, everyone.

Pushcart: Thank you Tom and good morning, everyone I'm going to begin with some important updates that we're announcing this morning regarding Helios b.

I'm going to begin with some important updates that we're announcing this morning regarding HELIOS-B. As you know, HELIOS-B is an outcome study being conducted to expand the label for AMVUTTRA to include the treatment of cardiomyopathy in patients with hereditary and wild-type ATTR amyloidosis. Today, ONPATTRO and AMVUTTRA are approved to treat polyneuropathy in patients with hereditary ATTR amyloidosis, with an estimated prevalence of 25,000 to 30,000 patients worldwide. Assuming successful results from the HELIOS-B study and regulatory approval, we expect to expand into a market approximately 10 times larger, with a global prevalence greater than 300,000 patients.

Pushcart: As you know <unk> is an outcome study being conducted to expand the label for <unk> to include the treatment of cardiomyopathy in patients with hereditary and wild type <unk> amyloidosis.

Pushcart: Today on petroleum Bouchara approved to treat polyneuropathy in patients with hereditary <unk> amyloidosis with an estimated prevalence of 25% to 30000 patients worldwide.

Pushkal: Assuming successful results from the HELIOS-B study and regulatory approval, we expect to expand into a market approximately 10 times larger, with a global prevalence greater than 300,000 patients. And furthermore, we're committed to continuing to innovate for patients with this disease as we advance ALN-TTRscO4, another medicine that can deliver rapid knockdown with the potential for greater efficacy and once-annual dosing through clinical development. Moreover, as illustrated in this graphic for the United States, we expect this already sizable market to continue to grow substantially in the coming years due to increasing disease awareness, earlier diagnosis and the availability of new treatments. Thus, given these dynamics, we are laser-focused on bringing our industry-leading portfolio of potentially transformative therapeutics to ATTR-CM patients and being leaders in this important growth category.

Assuming successful results from the HELIOS-B study and regulatory approval, we expect to expand into a market approximately 10 times larger, with a global prevalence greater than 300,000 patients. And furthermore, we're committed to continuing to innovate for patients with this disease as we advance ALN-TTRscO4, another medicine that can deliver rapid knockdown with the potential for greater efficacy and once-annual dosing through clinical development.

Assuming successful results from the HELIOS-B study and regulatory approval, we expect to expand into a market approximately 10 times larger, with a global prevalence greater than 300,000 patients.

Pushcart: Assuming successful results from the Helios B study and regulatory approval, we expect to expand into a market approximately 10 times larger with the global prevalence is greater than 300000 patients and Furthermore, we're committed to continuing to innovate for patients with this disease as we advanced <unk> for another medicine that can deliver rapid knockdown with.

And furthermore, we're committed to continuing to innovate for patients with this disease as we advance ALN-TTRscO4, another medicine that can deliver rapid knockdown with the potential for greater efficacy and once-annual dosing through clinical development. Moreover, as illustrated in this graphic for the United States, we expect this already sizable market to continue to grow substantially in the coming years due to increasing disease awareness, earlier diagnosis and the availability of new treatments. Thus, given these dynamics, we are laser-focused on bringing our industry-leading portfolio of potentially transformative therapeutics to ATTR-CM patients and being leaders in this important growth category.

Pushcart: The potential for greater efficacy and once annual dosing through clinical development.

Moreover, as illustrated in this graphic for the United States, we expect this already sizable market to continue to grow substantially in the coming years due to increasing disease awareness, earlier diagnosis and the availability of new treatments. Thus, given these dynamics, we are laser-focused on bringing our industry-leading portfolio of potentially transformative therapeutics to ATTR-CM patients and being leaders in this important growth category.

Pushcart: Moreover, as illustrated in this graphic for the United States. We expect this already sizable market to continue to grow substantially in the coming years due to increasing disease awareness earlier diagnosis and the availability of new treatments. Thus given these dynamics, we are laser focused on bringing our industry leading portfolio of potentially transformative therapeutics.

Pushcart: To <unk> cm patients and being leaders in this important growth category.

Pushkal: Now, as we previously highlighted, between now and TAFAMIDIS's loss of exclusivity anticipated in late 2028, we expect the market to be primarily monotherapy driven given the cumulative costs of combination therapy. Our research with payers has confirmed that they plan to restrict combination use given that it would drive a substantially higher cost. And even today, where TAFAMIDIS and AMVUTTRA have non-overlapping labels, about 90% of commercial plans restrict combination use. More importantly, we've seen very limited instances in which two branded rare disease products are used in combination, regardless of the therapeutic area.

Pushcart: As we previously highlighted between now and two family. This loss of exclusivity anticipated in late 2028, we expect the market to be primarily monotherapy driven given.

Pushcart: Given the cumulative cost of combination therapy.

Pushcart: Our research with payers has confirmed that they plan to restrict combination use given that it would drive a substantially higher cost.

Pushcart: And even today with <unk> and <unk> have non overlapping labels about 90% of commercial plans restrict combination use.

Pushcart: More importantly, we've seen very limited instances in which two branded rare disease products are used in combination regardless of the therapeutic area.

Pushkal: Assuming positive data from HELIOS-B and regulatory approval, we anticipate that VUTRISIRAN has the potential product profile -- including compelling efficacy, safety and a quarterly sub-Q dosing regimen -- to become primarily a first-line treatment for newly diagnosed ATTR-CM patients and a switch therapy for those who experience disease progression with stabilizers and to be combined with a stabilizer in those limited situations where payers support access. Once TAFAMIDIS goes generic and again, pending the label, we believe that combination therapy will become more common. With this backdrop in mind, let's now turn to HELIOS-B, why we're confident it's poised for success and the endpoint refinements that we're announcing today. The reasons for our continued confidence are summarized here. The impact of TTR silencing with an RNAi therapeutic on cardiomyopathy was demonstrated in the 12-month Apollo B study.

Assuming positive data from HELIOS-B and regulatory approval, we anticipate that VUTRISIRAN has the potential product profile -- including compelling efficacy, safety and a quarterly sub-Q dosing regimen -- to become primarily a first-line treatment for newly diagnosed ATTR-CM patients and a switch therapy for those who experience disease progression with stabilizers and to be combined with a stabilizer in those limited situations where payers support access. Once TAFAMIDIS goes generic and again, pending the label, we believe that combination therapy will become more common.

Assuming positive data from Helios, B and regulatory approval, we anticipate that <unk> has the potential product profile, including compelling efficacy safety and a quarterly sub Q dosing regimen to become primarily a first line treatment for newly diagnosed <unk> patients and a switch therapy for those who experienced disease.

Pushcart: Progression with stabilizers and to be combined with a stabilizer in those limited situations where payers support access.

Pushcart: Once the payment is going generic and again pending the label, we believe that combination therapy will become more common.

With this backdrop in mind, let's now turn to HELIOS-B, why we're confident it's poised for success and the endpoint refinements that we're announcing today. The reasons for our continued confidence are summarized here. The impact of TTR silencing with an RNAi Therapeutic on cardiomyopathy was demonstrated in the 12-month APOLLO-B study. We believe these data are exceedingly informative and support the potential for VUTRISIRAN to demonstrate an outcomes benefit in HELIOS-B on functional outcomes such as 6-minute walk test as well as quality of life, we saw evidence of disease stabilization over time. We also saw a profound impact on NT-proBNP and troponin, which are highly validated indicators of disease severity and prognosis. These four parameters, all of which showed the greatest magnitude of effect in the monotherapy setting, are important predictors of cardiovascular outcomes which we would expect to manifest in a larger and longer study like HELIOS-B. And accordingly, as we shared at AHA last November, we were encouraged to see a favorable trend in mortality that separated beginning as early as nine months and continued to expand over 24 months. While not powered for mortality, the hazard ratio at 24 months was 0.67, favoring the T-strand and benefits were seen in both the monotherapy and combination settings.

Pushcart: With this backdrop in mind lets now turn to Helios B why we're confident it's poised for success and the endpoint refinements that we're announcing today.

Pushcart: The reasons for our continued confidence are summarized here the impact of TCR silencing with an RNA therapeutic on cardiomyopathy was demonstrated in the 12 months of Apollo B study.

Pushkal: We believe these data are exceedingly informative and support the potential for RetreSARAN to demonstrate an outcomes benefit in Helios B. On functional outcomes such as the 6-minute walk test as well as quality of life, we saw evidence of disease stabilization over time. We also saw a profound impact on antiprobian petroponin, which is a highly validated indicator of disease severity and prognosis. These four parameters, all of which showed the greatest magnitude of effect in the monotherapy setting, are important predictors of cardiovascular outcomes, which we would expect to manifest in a larger and longer study like Helios B. And accordingly, as we shared at AHA last November, we were encouraged to see a favorable trend in mortality that separated beginning as early as nine months and continued to expand over 24 months. While not powered for mortality, the hazard ratio at 24 months was 0.67, favoring the T-strand, and benefits were seen in both the monotherapy and combination settings.

We believe these data are exceedingly informative and support the potential for <unk> to demonstrate an outcomes benefit in Helios b.

On functional outcomes, such as six minute walk test as well as quality of life. We saw evidence of disease stabilization over time. We also saw a profound impact on NT pro BNP proponent, which are highly validated indicators of the severity and prognosis.

We also saw a profound impact on NT-proBNP and troponin, which are highly validated indicators of disease severity and prognosis. These four parameters, all of which showed the greatest magnitude of effect in the monotherapy setting, are important predictors of cardiovascular outcomes which we would expect to manifest in a larger and longer study like HELIOS-B. And accordingly, as we shared at AHA last November, we were encouraged to see a favorable trend in mortality that separated beginning as early as nine months and continued to expand over 24 months. While not powered for mortality, the hazard ratio at 24 months was 0.67, favoring the T-strand and benefits were seen in both the monotherapy and combination settings.

We also saw a profound impact on NT-proBNP and troponin, which are highly validated indicators of disease severity and prognosis.

These four parameters, all of which showed the greatest magnitude of effect in the monotherapy setting, are important predictors of cardiovascular outcomes which we would expect to manifest in a larger and longer study like HELIOS-B. And accordingly, as we shared at AHA last November, we were encouraged to see a favorable trend in mortality that separated beginning as early as nine months and continued to expand over 24 months. While not powered for mortality, the hazard ratio at 24 months was 0.67, favoring the T-strand and the benefits were seen in both the monotherapy and combination settings. We find these data very compelling, as while APOLLO-B was too short and too small to establish an outcomes benefit, an impact on mortality appeared to occur earlier than seen in other ATTR-CM studies to date, was durable and, in fact, grew over time despite crossover of all patients to active treatment at 12 months.

Pushcart: These four parameters all of which showed the greatest magnitude of effect in the monotherapy setting are important predictors of cardiovascular outcomes, which we would expect to manifest in a larger and longer study like Helios b.

Pushcart: And accordingly, as we shared at IHA last November we were encouraged to see a favorable trend in mortality that separated beginning as early as nine months and continuing to expand over 24 months.

While not powered for mortality, the hazard ratio at 24 months was 0.67, favoring the T-strand and the benefits were seen in both the monotherapy and combination settings. We find these data very compelling, as while APOLLO-B was too short and too small to establish an outcomes benefit, an impact on mortality appeared to occur earlier than seen in other ATTR-CM studies to date, was durable and, in fact, grew over time despite crossover of all patients to active treatment at 12 months.

While not powered for mortality, the hazard ratio at 24 months was 0.67, favoring the T-strand and the benefits were seen in both the monotherapy and combination settings.

Pushcart: While not powered for mortality the hazard ratio at 24 months with 0.67 favoring the <unk> and the benefits were seen in both the monotherapy and combination settings.

We find these data very compelling, as while APOLLO-B was too short and too small to establish an outcomes benefit, an impact on mortality appeared to occur earlier than seen in other ATTR-CM studies to date, was durable and, in fact, grew over time despite crossover of all patients to active treatment at 12 months. Now, moving on to HELIOS-B itself, the study is designed and powered to deliver outcomes and it is twice as large and three times as long as APOLLO-B. Previous studies have shown that intervention in ATTR cardiomyopathy most benefits patients with NYHA Class I and II and the HELIOS-B study is enriched specifically for these patients, as they're most likely to show the largest treatment effect. And HELIOS-B provides the longest follow-up of any study conducted in ATTR cardiomyopathy to date.

Pushkal: We find these data very compelling, as while APOLLO-B was too short and too small to establish an outcomes benefit, an impact on mortality appeared to occur earlier than seen in other ATTR-CM studies to date, was durable and, in fact, grew over time despite crossover of all patients to active treatment at 12 months. Now, moving on to HELIOS-B itself, the study is designed and powered to deliver outcomes and it is twice as large and three times as long as APOLLO-B. Previous studies have shown that intervention in ATTR cardiomyopathy most benefits patients with NYHA Class I and II and the HELIOS-B study is enriched specifically for these patients, as they're most likely to show the largest treatment effect. And HELIOS-B provides the longest follow-up of any study conducted in ATTR cardiomyopathy to date. The study was conservatively powered at the outset, with additional tailwinds that include over-enrollment by 10% and TAFAMIDIS baseline and drop-in rates that are below the expectations we used to power the study. In fact, the TAFAMIDIS rates at baseline were 40%, substantially less than the 50% we'd assumed when powering the study.

Pushcart: We find these data are very compelling as well Apollo B was too short and too small to establishing outcomes benefit and impact on mortality appeared to occur earlier than seen in other <unk> studies to date with durable and in fact grew over time, despite crossover of all patients to active treatment at 12 months.

Now, moving on to HELIOS-B itself, the study is designed and powered to deliver outcomes and it is twice as large and three times as long as APOLLO-B. Previous studies have shown that intervention in ATTR cardiomyopathy most benefits patients with NYHA Class I and II and the HELIOS-B study is enriched specifically for these patients, as they're most likely to show the largest treatment effect. And HELIOS-B provides the longest follow-up of any study conducted in ATTR cardiomyopathy to date. The study was conservatively powered at the outset, with additional tailwinds that include over-enrollment by 10% and TAFAMIDIS baseline and drop-in rates that are below the expectations we used to power the study. In fact, the TAFAMIDIS rates at baseline were 40%, substantially less than the 50% we'd assumed when powering the study.

Pushcart: Now moving onto Helios B itself. The study is designed and powered to deliver outcomes and is twice as large and three times as long as Apollo B.

Previous studies have shown that intervention in ATTR cardiomyopathy most benefits patients with NYHA Class I and II and the HELIOS-B study is enriched specifically for these patients, as they're most likely to show the largest treatment effect. And HELIOS-B provides the longest follow-up of any study conducted in ATTR cardiomyopathy to date.

Pushcart: Previous studies have shown that intervention in <unk> cardiomyopathy, most benefits patients with NY HLA class, one and two and the Helios B study is enriched specifically for these patients as they most likely to show the largest treatment effect.

Pushcart: And Helios B provides the longest follow up of any study conducted in <unk> cardiomyopathy to date.

The study was conservatively powered at the outset, with additional tailwinds that include over-enrollment by 10% and TAFAMIDIS baseline and drop-in rates that are below the expectations we used to power the study. In fact, the TAFAMIDIS rates at baseline were 40%, substantially less than the 50% we'd assumed when powering the study. So, putting all this together, we have several key takeaways. First is, existing plan restrictions and prior precedents suggest that for the next several years, the market is expected to be primarily monotherapy driven. And second, we have data from APOLLO-B that demonstrates substantial effects on multiple endpoints that provide evidence of a differentiated profile with disease stabilization, along with evidence of an early emerging benefit in mortality. And finally, and as expected, the treatment effect in APOLLO-B was shown to be largest in the monotherapy population, which was the dominant population in the study and best-suited to demonstrate the treatment benefits of PATISIRAN.

Pushcart: That he was considerably powered at the outset with additional tailwind that include over enrollment by 10% and to parameters baseline and drop in rates that are below the expectations. We used to power. This study.

Pushcart: In fact, the <unk> rates at baseline were 40% substantially less than the 50% we had assumed when powering the study.

Pushkal: So putting all this together, we have several key takeaways. First, existing plan restrictions and prior precedents suggest that for the next several years, the market is expected to be primarily monotherapy driven. And second, we have data from Apollo B that demonstrates substantial effects on multiple endpoints that provide evidence of a differentiated profile with disease stabilization, along with evidence of an early emerging benefit in mortality. And finally, and as expected, the treatment effect in Apollo B was shown to be largest in the monotherapy population, which was the dominant population in the study and best suited to demonstrate the treatment benefits of Patisse.

Pushcart: So putting all this together we have several key takeaways.

Pushcart: First is <unk> existing plan restrictions in prior precedent suggest that for the next several years the market is expected to be primarily monotherapy driven and.

And second, we have data from APOLLO-B that demonstrates substantial effects on multiple endpoints that provide evidence of a differentiated profile with disease stabilization, along with evidence of an early emerging benefit in mortality. And finally, and as expected, the treatment effect in APOLLO-B was shown to be largest in the monotherapy population, which was the dominant population in the study and best-suited to demonstrate the treatment benefits of PATISIRAN.

Pushcart: And second we have data from Apollo b that demonstrate substantial effects on multiple endpoints that provide evidence of a differentiated profile with disease stabilization along with evidence of an early emerging benefit mortality and finally and as expected the treatment effect in Apollo B was shown to be largest in the monotherapy population, which was the dominant pop.

Pushcart: <unk> study and best suited to demonstrate the treatment benefits of <unk>.

Pushkal: Today, we are announcing enhancements to the HELIOS-B statistical plan to optimize the study for success and a strong and competitive label. These changes are informed by insights from the APOLLO-B data and emerging data from the field. With these optimizations, we remain focused on clinical outcomes of death and hospitalization, which are critical to all stakeholders. We plan to evaluate this in the overall population, as well as the monotherapy population, which is expected to have the largest treatment effect and best demonstrate the drug's true impact. We also are focusing the secondary endpoint structure on critical clinical elements that highlight the drug's potentially differentiated profile and its benefits on stabilization of this progressive disease. And we are enhancing the overall statistical powering of the study by incorporating up to an additional three months of event collection at the tailend of the study period. The most critical period and firmly establishing HELIOS-B as the longest placebo-controlled study conducted to date in ATTR-CM. Let me review the key changes one by one.

Today, we are announcing enhancements to the HELIOS-B statistical plan to optimize the study for success and a strong and competitive label. These changes are informed by insights from the APOLLO-B data and emerging data from the field. With these optimizations, we remain focused on clinical outcomes of death and hospitalization, which are critical to all stakeholders. We plan to evaluate this in the overall population, as well as the monotherapy population, which is expected to have the largest treatment effect and best demonstrate the drug's true impact. We also are focusing the secondary endpoint structure on critical clinical elements that highlight the drug's potentially differentiated profile and its benefits on stabilization of this progressive disease. And we are enhancing the overall statistical powering of the study by incorporating up to an additional three months of event collection at the tailend of the study period, the most critical period and firmly establishing HELIOS-B as the longest placebo-controlled study conducted to date in ATTR-CM.

Pushcart: Today, we are announcing enhancements to the Helios B statistical plan to optimize the study for success and a strong and competitive label.

Pushcart: These changes are informed by the insights from the Apollo data and emerging data from the field.

Pushcart: With these optimizations, we remain focused on clinical outcomes of death, and hospitalization, which are critical to all stakeholders. The plan to evaluate this in the overall population as well as the monotherapy population, which is expected to have the largest treatment effect and best demonstrate the drug's true impact.

We also are focusing the secondary endpoint structure on critical clinical elements that highlight the drugs potentially differentiated profile and its benefits benefits on stabilization of this progressive disease and.

We also are focusing the secondary endpoint structure on critical clinical elements that highlight the drug's potentially differentiated profile and its benefits on stabilization of this progressive disease. And we are enhancing the overall statistical powering of the study by incorporating up to an additional three months of event collection at the tailend of the study period, the most critical period and firmly establishing HELIOS-B as the longest placebo-controlled study conducted to date in ATTR-CM.

Pushcart: And we're enhancing the overall statistical powering of the study by incorporating up to an additional three months of event collection at the tail end of the study period.

Pushcart: The most critical period and firmly establishing Helios b is the longest placebo controlled study conducted to date and ATT RCM.

Let me review the key changes one by one. First, we're sharing today that we are increasing the minimum follow-up in the study from 30 to 33 months, with variable follow-up to 36 months. This adds up to three months of event collection for the patients who enrolled later in the study, thereby providing greater statistical power. With these changes, approximately 60% of patients remaining on study will have greater follow-up, with about 20% or a third more having follow-up all the way out to month 36. This is an important change as these three additional months of observation constitute a short but meaningful prolongation during the critical late part of the study, which is when we expect to see the greatest number of outcome events happening in the placebo arm. As a result, this enhancement leads to greater study power, as we know that survival curves typically diverge more and more over time, a phenomenon that was seen in the 24-month APOLLO-B data as well.

Pushcart: Okay.

Speaker Change: Let me review the key changes one by one.

Pushkal: First, we're sharing today that we're increasing the minimum follow-up in the study from 30 to 33 months, with variable follow-up to 36 months. This adds up to three months of event collection for the patients who enrolled later in the study, thereby providing greater statistical power. With these changes, approximately 60% of patients remaining on study will have greater follow-up, with about 20% or a third more having follow-up all the way out to month 36. This is an important change as these three additional months of observation constitute a short but meaningful prolongation during the critical late part of the study, which is when we expect to see the greatest number of outcome events happening in the placebo arm. As a result, this enhancement leads to greater study power, as we know that survival curves typically diverge more and more over time. And this is a phenomenon that was seen in the 24-month Apollo B data as well.

Speaker Change: First we're sharing today that we're increasing the minimum follow up in the study from 30 to 33 months with variable follow up to 36 months. This adds up to three months of event collection for the patients who enrolled later in the study they have provided thereby providing greater statistical power.

Speaker Change: With these changes approximately 60% of patients remaining on study will have greater follow up.

Speaker Change: With about 20% or a third more having follow up all the way out to month 36. This is an important change as these three additional months of observation constituted short, but meaningful prolongation. During the critical late part of the study which is when we expect to see the greatest number of outcome events happening in the placebo arm.

This is an important change as these three additional months of observation constitute a short but meaningful prolongation during the critical late part of the study, which is when we expect to see the greatest number of outcome events happening in the placebo arm. As a result, this enhancement leads to greater study power, as we know that survival curves typically diverge more and more over time, a phenomenon that was seen in the 24-month APOLLO-B data as well.

Speaker Change: As a result, this enhancement leads to greater scale study power as we know that survival curves typically diverge more and more over time.

Speaker Change: Phenomenon that was seen in the 24 month, Apollo B data as well.

Pushkal: Second, we're modifying the methodology used to analyze the primary endpoint. The primary outcome measure remains the composite of all-cause mortality in recurrent cardiovascular events. This will now be tested in parallel in two populations, the overall population and the monotherapy population -- that is, the subgroup of patients not on TAFAMIDIS's baseline. We're maintaining the analysis in the overall population, which has the largest sample size and an opportunity to show a broad effect across the full patient spectrum. We're confident that there is a combo effect, as demonstrated by the fact that the overall population remains the primary endpoint. In parallel, we're elevating an analysis of the composite in the monotherapy population, which constitutes the majority of the study population at 60%. Additionally, analysis in the monotherapy population allows us to demonstrate the true impact of VUTRISIRAN as a standalone treatment, providing a data set that will be particularly relevant to patients, prescribers and others, as it closely aligns with where we see the treatment landscape over the next several years. It's important to note that these are not co-primary endpoints; rather, the primary endpoint will be tested in parallel in both populations, such that if each p-value is less than or equal to 0.05, then statistical significance can be claimed for both.

Second, we're modifying the methodology used to analyze the primary endpoint. The primary outcome measure remains the composite of all-cause mortality in recurrent cardiovascular events. This will now be tested in parallel in two populations, the overall population and the monotherapy population -- that is, the subgroup of patients not on TAFAMIDIS's baseline. We're maintaining the analysis in the overall population, which has the largest sample size and an opportunity to show a broad effect across the full patient spectrum.

Speaker Change: Second we're modifying the methodology used to analyze the primary endpoint. The primary outcome measure remains the composite of all cause mortality and recurrent cardiovascular events. This will now be tested in parallel in two populations. The overall population and the monotherapy population that is the subgroup of patients not on <unk>.

Speaker Change: That's the baseline.

Speaker Change: We're maintaining the analysis in the overall population, which is the largest sample size and an opportunity to show a broad effect across the full patient spectrum.

We're confident that there is a combo effect, as demonstrated by the fact that the overall population remains the primary endpoint. In parallel, we're elevating an analysis of the composite in the monotherapy population, which constitutes the majority of the study population at 60%. Additionally, analysis in the monotherapy population allows us to demonstrate the true impact of VUTRISIRAN as a standalone treatment, providing a data set that will be particularly relevant to patients, prescribers and others, as it closely aligns with where we see the treatment landscape over the next several years. It's important to note that these are not co-primary endpoints; rather, the primary endpoint will be tested in parallel in both populations, such that if each p-value is less than or equal to 0.05, then statistical significance can be claimed for both.

Speaker Change: We're confident that there is a combo effect as demonstrated by the fact that the overall population remains in the primary endpoint.

Speaker Change: In parallel we are elevating an analysis of the composite in the monotherapy population, which constitutes the majority of the study population at 60%. Additionally analysis in the monotherapy population allows us to demonstrate the true impact of <unk> as a standalone treatment, providing a data set that will be particularly relevant to patients prescribers and others is it.

Speaker Change: Closely aligns with where we see the treatment landscape over the next several years.

It's important to note that these are not co-primary endpoints; rather, the primary endpoint will be tested in parallel in both populations, such that if each p-value is less than or equal to 0.05, then statistical significance can be claimed for both. Alternatively, the study will be declared a positive study if either of the p-values for the two analyses is less than or equal to 0.025. Thus, the study will be deemed positive if both or either of the analyses achieve the predefined criteria for statistical significance. Based on our assumptions, as informed by APOLLO--B and other studies as well as the conduct and execution of HELIOS-B, we remain confident about HELIOS-B and its ability to deliver a positive result. Finally, we've streamlined the secondary endpoints.

Speaker Change: It is important to note that these are not co primary endpoints, rather primary endpoint will be tested in parallel in both populations such that if each P value is less than or equal to 0.5 and statistical significance can be claimed for bolt. Alternatively. The study will be declared a positive study either of the P values for the two two <unk>.

Pushkal: Alternatively, the study will be declared a positive study if either of the p-values for the two analyses is less than or equal to 0.025. The study will be deemed positive if both or either of the analyses achieve the predefined criteria for statistical significance. Based on our assumptions, as informed by APAHLO-B and other studies, as well as the conduct and execution of Helios-B, we remain confident about Helios-B and its ability to deliver a positive result. Finally, we've streamlined the secondary endpoints.

Speaker Change: <unk> is less than or equal to 0.5. The study will be deemed positive with both or either of the analyses achieved a predefined criteria for statistical significance.

Speaker Change: Based on our assumptions as it as informed by Apollo B and other studies.

Speaker Change: As well as the conduct and execution of Helios B, we remain confident about <unk> and its ability to deliver a positive result.

Finally, we've streamlined the secondary endpoints. Specifically, the structure now includes six-minute walk tests, KCCQ OS, all-cause mortality and change from baseline and NYHA class. These endpoints are considered clinically meaningful and will help to demonstrate the impact of VUTRISIRAN on disease stabilization and including them as formal secondary endpoints, enables them to potentially be included in the label and support differentiation in the marketplace. Based on the three optimizations I've just outlined, here is the updated study design. I do want to note that the changes I've shared today were made after consultation with the FDA and other health authorities, who were supportive of this approach, particularly as it relates to the handling of the primary endpoint. With the three-month extension and the overall study duration we are sharing today, the top-line results are now expected in late June or early July. At that time, we plan to provide key values on the primary and secondary endpoints, as well as key details regarding safety. We also expect to provide some high-level information on subgroups, including patients on baseline TAFAMIDIS. Full results are expected to be presented at a scientific congress soon thereafter.

Speaker Change: Finally, we've streamlined the secondary endpoints specifically the structure now includes six minute walk test Casey Qos, all cause mortality and change from baseline in NY HLA class. These endpoints are considered clinically meaningful and will help to demonstrate the impact of <unk> on disease stabilization and including.

Pushkal: Specifically, the structure now includes six-minute walk tests, KCCQ, OOS, all-cause mortality, and change from baseline and NYHA. These endpoints are considered clinically meaningful and will help to demonstrate the impact of vitreous sarin on disease stabilization, and including them as formal secondary endpoints enables them to potentially be included in the label and support differentiation in the marketplace. Based on the three optimizations I've just outlined, here is the updated study design.

Speaker Change: [noise] them as formal secondary endpoints enabled them to potentially be included in the label and support differentiation in the marketplace.

Speaker Change: Based on the three optimizations I've just outlined here is the updated study design.

Pushkal: I do want to note that the changes I've shared today were made after consultation with the FDA and other health authorities, who were supportive of this approach, particularly as it relates to the handling of the primary endpoint. With the three-month extension and the overall study duration we are sharing today, the top-line results are now expected in late June or early July. At that time, we plan to provide key values on the primary and secondary endpoints, as well as key details regarding safety. We also expect to provide some high-level information on subgroups, including patients on baseline defamatory agents. Full results are expected to be presented at a scientific congress soon thereafter.

Speaker Change: Do want to note that the changes I've shared today were made after consultation with the FDA and other health authorities are supportive of this approach, particularly as it relates to the handling of the primary endpoint.

With the three-month extension and the overall study duration we are sharing today, the top-line results are now expected in late June or early July. At that time, we plan to provide key values on the primary and secondary endpoints, as well as key details regarding safety. We also expect to provide some high-level information on subgroups, including patients on baseline TAFAMIDIS. Full results are expected to be presented at a scientific congress soon thereafter. Assuming positive results from HEIIOS-B, we expect to submit a supplemental NDA to the FDA in late 2024. We're confident that the study updates I've just reviewed, refinements to endpoints and extension of the blinded study period, further enhance the power of the study and our confidence that HELIOS-B will deliver a positive result. Assuming positive data and regulatory approval, we believe that VUTRISIRAN will be well-positioned to serve patients with ATTR cardiomyopathy, addressing unmet needs with the potential for a highly competitive, market-leading profile, including a unique mechanism of action that works upstream of protein production and enables rapid knockdown of TTR, an impactful clinical profile with the potential to reduce mortality of CV hospitalizations and help be an [inaudible] decline in functional capacity and quality of life, an attractive quarterly dosing schedule that aligns with physician visits, supports strong adherence and provides the flexibility of in-office or at-home dose administration and favorable payer dynamics, where coverage under Medicare Part B is expected to result in the majority of patients having zero out-of-pocket costs and where we also expect payers to favor monotherapy use for the next several years.

Speaker Change: With a three month extension in the overall study duration, we are sharing today. The topline results are now expected in late June or early July.

Speaker Change: At that time, we plan to provide P values on the primary and secondary endpoints as well as key details regarding safety.

Speaker Change: We also expect to provide some high level information on subgroups, including patients on baseline to families.

Speaker Change: Full results are expected to be presented at a scientific Congress soon thereafter.

Pushkal: Assuming positive results from Helios B, we expect to submit a supplemental NDA to the FDA in late 2024. We're confident that the study updates I've just reviewed, refinements to endpoints and extension of the blinded study period, further enhance the power of the study and our confidence that Helios B will deliver a positive result. Assuming positive data and regulatory approval, we believe that Tristran will be well positioned to serve patients with ATTR cardiomyopathy, addressing unmet needs with the potential for a highly competitive, market-leading profile, including a unique mechanism of action that works upstream of protein production and enables rapid knockdown of TTR, an impactful clinical profile with the potential to reduce mortality and CV hospitalizations and help be an extra decline in functional capacity and quality of life, an attractive quarterly dosing schedule that aligns with physician visits, supports strong adherence, and provides the flexibility of in-office or at-home dose administration, and favorable payer dynamics, where coverage under Medicare Part B is expected to result in the majority of patients having zero out-of-pocket costs and where we also expect payers to favor monotherapy use for the next several years. It was a pleasure.

Speaker Change: Assuming positive results from Helios B, we expect to submit a supplemental NDA to the FDA in late 2024.

We're confident that the study updates I've just reviewed, refinements to endpoints and extension of the blinded study period, further enhance the power of the study and our confidence that HELIOS-B will deliver a positive result. Assuming positive data and regulatory approval, we believe that VUTRISIRAN will be well-positioned to serve patients with ATTR cardiomyopathy, addressing unmet needs with the potential for a highly competitive, market-leading profile, including a unique mechanism of action that works upstream of protein production and enables rapid knockdown of TTR; an impactful clinical profile with the potential to reduce mortality of CV hospitalizations and help be an [inaudible] decline in functional capacity and quality of life; an attractive quarterly dosing schedule that aligns with physician visits, supports strong adherence and provides the flexibility of in-office or at-home dose administration and favorable payer dynamics, where coverage under Medicare Part B is expected to result in the majority of patients having zero out-of-pocket costs and where we also expect payers to favor monotherapy use for the next several years.

Speaker Change: We're confident that the study updates I've just reviewed refinements to endpoints and extension of the blinded study period further enhance the power of the study and are confident that Helios B will deliver a positive result, assuming positive data and regulatory approval. We believe that <unk> will be well positioned to serve patients with <unk> cardiomyopathy addressing unmet.

Assuming positive data and regulatory approval, we believe that VUTRISIRAN will be well-positioned to serve patients with ATTR cardiomyopathy, addressing unmet needs with the potential for a highly competitive, market-leading profile, including a unique mechanism of action that works upstream of protein production and enables rapid knockdown of TTR; an impactful clinical profile with the potential to reduce mortality of CV hospitalizations and help be an [inaudible] decline in functional capacity and quality of life; an attractive quarterly dosing schedule that aligns with physician visits, supports strong adherence and provides the flexibility of in-office or at-home dose administration and favorable payer dynamics, where coverage under Medicare Part B is expected to result in the majority of patients having zero out-of-pocket costs and where we also expect payers to favor monotherapy use for the next several years.

Assuming positive data and regulatory approval, we believe that VUTRISIRAN will be well-positioned to serve patients with ATTR cardiomyopathy, addressing unmet needs with the potential for a highly competitive, market-leading profile, including a unique mechanism of action that works upstream of protein production and enables rapid knockdown of TTR, an impactful clinical profile with the potential to reduce mortality of CV hospitalizations and help be an [inaudible] decline in functional capacity and quality of life, an attractive quarterly dosing schedule that aligns with physician visits, supports strong adherence and provides the flexibility of in-office or at-home dose administration and favorable payer dynamics, where coverage under Medicare Part B is expected to result in the majority of patients having zero out-of-pocket costs and where we also expect payers to favor monotherapy use for the next several years.

Speaker Change: <unk> with the potential for a highly competitive market, leading profile, including a unique mechanism of action that works upstream of protein production and enables rapid knockdown of GTR and impactful clinical profile with the potential to reduce mortality and CV hospitalizations, and hoping extra will decline and functional capacity and quality of life and attractive.

Quarterly dosing schedule that aligns with physician visits support strong adherence and provides the flexibility of inoffice or at home dose administration and favorable payer dynamics for coverage under Medicare part B is expected to result in the majority of patients having zero out of pocket costs, and where we also expect payers to favor monotherapy use for the next several.

Pushkal: We look forward to sharing top-line results from HELIOS-B in the late June to early July timeframe, bringing this transformative medicine one step closer to patients. Let me now turn to some recent and exciting developments with ALN-APP, in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy. The early clinical data from this program continue to be very encouraging. At CTAD, we presented data showing that single doses of ALN-APP achieved sustained pharmacodynamic activity up to 10 months after administration, with marked reductions in A beta 42 and A beta 40, amyloid fragments implicated in Alzheimer's disease and CAA respectively, as well as an encouraging safety profile.

Speaker Change: Years.

Speaker Change: We look forward to sharing top line results from Helios B in the late June early July timeframe, bringing this transformative medicine, one step closer to patients.

Speaker Change: Let me now turn to some recent and exciting developments with <unk> in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy.

Speaker Change: The early clinical data from this program continue to be very encouraging at <unk>, we presented data showing that single doses of <unk> achieved sustained pharmacodynamic activity up to 10 months. After administration with marked reductions in EBITDA 42 in a beta 40, amyloid fragrance implicated in Alzheimer's disease and Caa respectively.

Speaker Change: As well as an encouraging safety profile.

Pushkal: As we announced in our press release today, we are very pleased to share that the FDA has provided clearance to initiate the multi-dose Part B of the Phase I study in the United States. This decision came after we submitted additional non-clinical data as well as emerging clinical data from the ongoing Phase I study. The FDA has confirmed that multiple dosing in the Phase 1 study may proceed at doses as high as 180mg every 6 months, while a partial clinical hold remains for doses that are higher or more frequent than that. We're delighted by the FDA's decision and are encouraged that we will be able to proceed in Phase I with multiple doses at levels up to and even exceeding all the dose levels that we plan to test in Part B of the study, based on the high and sustained levels of knockdown that we've already seen with single doses of 75mg in Part A. Let me now move on to highlight recent progress across the rest of the pipeline. For ZILEBESIRAN, we presented the KARDIA Phase II results, which demonstrated over 16 millimeters of placebo-adjusted reduction in 24-hour mean systolic blood pressure at three months after a single dose, with an encouraging safety and tolerability profile.

As we announced in our press release today, we are very pleased to share that the FDA has provided clearance to initiate the multi-dose Part B of the Phase I study in the United States. This decision came after we submitted additional non-clinical data as well as emerging clinical data from the ongoing Phase I study. The FDA has confirmed that multiple dosing in the Phase I study may proceed at doses as high as 180mg every 6 months, while a partial clinical hold remains for doses that are higher or more frequent than that. We're delighted by the FDA's decision and are encouraged that we will be able to proceed in Phase I with multiple doses at levels up to and even exceeding all the dose levels that we plan to test in Part B of the study, based on the high and sustained levels of knockdown that we've already seen with single doses of 75mg in Part A. Let me now move on to highlight recent progress across the rest of the pipeline.

Speaker Change: As we announced in our press release today, we are very pleased to share that the FDA has provided clearance to initiate the multi dose part b of the phase one study in the United States.

Speaker Change: This decision came after we submitted additional non clinical data as well as emerging clinical data from the ongoing phase one study.

Speaker Change: The FDA has confirmed that multiple dosing in the phase. One study may proceed at doses as high as 180 milligrams every six months.

Speaker Change: While a partial clinical hold remains for doses that are higher or more frequent than that.

Pushkal: While a partial clinical hold remains for doses that are higher or more frequent than that. We're delighted by the FDA's decision and are encouraged that we will be able to proceed in Phase 1 with multiple doses at levels up to and even exceeding all the dose levels that we plan to test in Part B of the study, based on the high and sustained levels of knockdown that we've already seen with single doses of 75 milligrams in Part A. Let me now move on to recent to highlight recent progress across the rest of the pipe. For Zalbisaran, we presented the Cardio Phase II results, which demonstrated over 16 millimeters of placebo-adjusted reduction in 24-hour mean systolic blood pressure at three months after a single dose with an encouraging safety and tolerability profile.

Speaker Change: We're delighted by the Fda's decision and are encouraged that we will be able to proceed in phase one with multiple doses at levels up to and even exceeding all the dose levels that we plan to test in part B of the study based on the high and sustained levels of knockdown that we've already seen with single doses of <unk> 75 milligrams in part a.

We're delighted by the FDA's decision and are encouraged that we will be able to proceed in Phase I with multiple doses at levels up to and even exceeding all the dose levels that we plan to test in Part B of the study, based on the high and sustained levels of knockdown that we've already seen with single doses of 75mg in Part A. Let me now move on to highlight recent progress across the rest of the pipeline. For ZILEBESIRAN, we presented the KARDIA Phase II results, which demonstrated over 16 millimeters of placebo-adjusted reduction in 24-hour mean systolic blood pressure at three months after a single dose, with an encouraging safety and tolerability profile.

Speaker Change: Let me now move on to recent to highlight recent progress across the rest of the pipeline for.

Speaker Change: <unk>, we presented the cardiac phase II results, which demonstrated over 16 millimeters for placebo adjusted reduction in 24 hour mean systolic blood pressure at three months after a single dose with an encouraging safety and tolerability profile on.

For ZILEBESIRAN, we presented the KARDIA Phase II results, which demonstrated over 16 millimeters of placebo-adjusted reduction in 24-hour mean systolic blood pressure at three months after a single dose, with an encouraging safety and tolerability profile. On ALN-TTRsc04, we recently shared single-dose data that showed deep and rapid knockdown with mean serum TTR reduction up to 97%, with durability supporting the potential for annual dosing. We also announced positive initial results from the Phase I study of ALN-KHK, with robust target engagement and encouraging safety that supported continued development as a novel treatment for type 2 diabetes. And wrapping up on the pipeline, we announced several exciting updates from our research portfolio at our R&D day, including progress with extrahepatic delivery of RNAi to muscle and adipose, compelling new targets in areas of high unmet need and advancement of RNAi into oncology, with a Phase I study for ALN-BCAT in hepatocellular carcinoma on track to initiate early this year. And this progress is accelerating as we plan to file proprietary INDs for 9 programs by the end of 2025 against targets in the liver, CNF, muscle and adipose. We include partnered programs.

On <unk>, we recently shared single dose data, which showed deep and rapid knockdown with mean serum ctr reduction up to 97% with.

With durability supporting the potential for annual dosing.

Speaker Change: We also announced positive initial results from the phase one study of <unk> K with robust targeted robust target engagement and encouraging safety that supported continued development as a novel treatment for type two diabetes.

Pushkal: On ALM TTR SCO4, we recently shared single-dose data that showed deep and rapid knockdown with mean serum TTR reduction up to 97%, with Durability Supporting the Potential for Annual Dose. We also announced positive initial results from the Phase 1 study of ALNKH-K with robust target engagement and encouraging safety that supported continued development as a novel treatment for type 2 diabetes. And wrapping up on the pipeline, we announced several exciting updates from our research portfolio at our R&D day, including progress with extra hepatic delivery of RNAi to muscle and adipose, compelling new targets in areas of high unmet need, and advancement of RNAi into oncology, with a Phase I study for ALN-BCAT in Patasailor carcinoma on track to initiate early this year. And this progress is We include partnered programs.

Speaker Change: And wrapping up on the pipeline, we announced several exciting updates from our research portfolio at our R&D day, including progress with extra hepatic delivery of RNA to muscle and adipose compelling new targets in areas of high unmet need and advancement of <unk> and oncology with a phase one study for <unk> <unk> to <unk> carcinoma on track to Ines.

And wrapping up on the pipeline, we announced several exciting updates from our research portfolio at our R&D day, including progress with extrahepatic delivery of RNAi to muscle and adipose, compelling new targets in areas of high unmet need and advancement of RNAi into oncology, with a Phase I study for ALN-BCAT in hepatocellular carcinoma on track to initiate early this year. And this progress is accelerating as we plan to file proprietary INDs for 9 programs by the end of 2025 against targets in the liver, CNF, muscle and adipose. We include partnered programs, we anticipate 15 new INDs by the end of 2025, representing a doubling of the Alnylam clinical pipeline by the end of next year. This remarkable and unique pace of innovation puts us in a great position to have a robust, self-sustainable pipeline that can deliver meaningful impact to patients across multiple disease areas.

Speaker Change: <unk> early this year.

Speaker Change: And this progress is accelerating as we plan to file proprietary IND for.

Speaker Change: For nine programs by the end of 2025 against targets in the liver CNS muscle and adipose. If we include partnered programs. We anticipate 15, new <unk> by the end of 2025, representing a doubling of the on island clinical pipeline by the end of next year. This remarkable and unique pace of innovation puts us in a great position.

Speaker Change: <unk> to have a robust self sustainable pipeline that can deliver meaningful impact to patients across multiple disease areas.

Speaker Change: And with that let me now turn it over to Jeff to review, our financial results and upcoming milestones Jeff.

We include partnered programs, we anticipate 15 new INDs by the end of 2025, representing a doubling of the Alnylam clinical pipeline by the end of next year. This remarkable and unique pace of innovation puts us in a great position to have a robust, self-sustainable pipeline that can deliver meaningful impact to patients across multiple disease areas.

Jeff Burton: Thanks push call. Good morning, everyone I am pleased to be presenting our <unk> full year 2023 financial results and providing our financial guidance for 2024.

Pushkal: We anticipate 15 new INDs by the end of 2025, representing a doubling of the Alnylam clinical pipeline by the end of next year. This remarkable and unique pace of innovation puts us in a great position to have a robust, self-sustainable pipeline that can deliver meaningful impact to patients across multiple disease areas. And with that, I now turn it over to Jeff to review our financial results and upcoming milestones.

Jeff Burton: Starting with a summary of our P&L results for the full year total product revenues for 2023 for $1 billion to $4 billion or 39% growth versus 2022, with both our ctr and ultra rare franchises reporting strong growth of 35% or greater for the full year.

And with that, let me now turn it over to Jeff to review our financial results and upcoming milestones.

Jeff: Thanks, Pushkal. Good morning, everyone. I'm pleased to be presenting Alnylam's full year 2023 financial results and providing our financial guidance for 2024. Starting with a summary of our P&L results for the full year, total product revenues for 2023 were $1.24 billion, or 39% growth versus 2022, with both our TTR and Ultra Rare franchises reporting strong growth of 35% or greater for the full year. The full-year net revenue from collaborations was $546 million, representing more than a four-fold increase compared with 2022, with the increase being primarily driven by revenue recognized under our co-development and co-commercialization collaboration with Roche, as executed in July 2023. Gross margin on product sales was 78% for the full year, representing a 6% decrease compared with 2022, primarily due to increased excess and obsolete charges due to canceling manufacturing commitments and the impairment of Onpatro inventory that had been manufactured for future demand associated with the ATTR cardiomyopathy indication for Patisseran, for which we did not receive regulatory approval, in addition to a higher royalty rate payable on net sales of Ambutra.

Jeffrey Poulton: Thanks, Pushkal. Good morning, everyone.

I'm pleased to be presenting Alnylam's full year 2023 financial results and providing our financial guidance for 2024. Starting with a summary of our P&L results for the full year, total product revenues for 2023 were $1.24 billion or 39% growth versus 2022, with both our TTR and Ultra Rare franchises reporting strong growth of 35% or greater for the full year. The full-year net revenue from collaborations was $546 million, representing more than a four-fold increase compared with 2022, with the increase being primarily driven by revenue recognized under our co-development and co-commercialization collaboration with Roche, as executed in July 2023. Gross margin on product sales was 78% for the full year, representing a 6% decrease compared with 2022, primarily due to increased excess and obsolete charges due to canceling manufacturing commitments and the impairment of ONPATTRO inventory that had been manufactured for future demand associated with the ATTR cardiomyopathy indication for PATISIRAN, for which we did not receive regulatory approval, in addition to a higher royalty rate payable on net sales of AMVUTTRA.

Jeff Burton: For the full year net revenue from collaborations was $546 million representing more than a four fold increase compared with 2022 with the increase being primarily driven by revenue recognized under our co development and co commercialization collaboration with Roche as executed in July 2023.

Jeff Burton: Gross margin on product sales was 78% for the full year, representing a 6% decrease compared with 2022, primarily due to increased excess and obsolete charges due to canceling manufacturing commitments and the impairment on Petro inventory that had been manufactured for future demand associated with the ATR.

Jeff Burton: On behalf of the indication for <unk> for which we did not receive regulatory approval. In addition to a higher royalty rate payable on net sales of <unk>.

Gross margin on product sales was 78% for the full year, representing a 6% decrease compared with 2022, primarily due to increased excess and obsolete charges due to canceling manufacturing commitments and the impairment of ONPATTRO inventory that had been manufactured for future demand associated with the ATTR cardiomyopathy indication for PATISIRAN -- for which we did not receive regulatory approval in addition to a higher royalty rate payable on net sales of AMVUTTRA. Our non-GAAP R&D expenses increased 15% for the full year, primarily related to increased headcount and infrastructure-related costs to support our growing pipeline and increased clinical costs driven by KARDIA-I and KARDIA-II, two of our Phase II studies in support of our ZILEBESIRAN hypertension program. Our non-GAAP SG&A expenses increased 6% for the full year, lower than in prior years, as we seek to increase the operating leverage associated with our existing commercial and corporate infrastructure.

Jeff Burton: Our non-GAAP R&D expenses increased 15% for the full year, primarily related to increased head count and infrastructure related costs to support our growing pipeline and increased clinical costs driven by cardio one in cardiac two two of our phase III studies in support of our <unk> hypertension program.

Jeff Burton: Our non-GAAP SG&A expenses increased 6% for the full year lower than in prior years as we seek to increase the operating leverage associated with our existing commercial and corporate infrastructure.

Our non-GAAP R&D expenses increased 15% for the full year, primarily related to increased headcount and infrastructure-related costs to support our growing pipeline and increased clinical costs driven by KARDIA-I and KARDIA-II, two of our Phase II studies in support of our ZILEBESIRAN hypertension program. Our non-GAAP SG&A expenses increased 6% for the full year, lower than in prior years, as we seek to increase the operating leverage associated with our existing commercial and corporate infrastructure. The 6% increase for the year was primarily driven by increased headcount, related costs and other investments supporting our strategic growth, including the global launch of AMVUTTRA. Our non-GAAP operating loss for 2023 was $60 million, representing a nearly $500 million improvement compared with 2022, primarily driven by strong top-line results both in product sales as well as revenue from collaborations, as I previously highlighted. Delivering non-GAAP operating profit by the end of 2025 remains a key focus for the organization per our P5x25 goals.

Jeff: Our non-GAAP R&D expenses increased 15% for the full year, primarily related to increased headcount and infrastructure-related costs to support our growing pipeline and increased clinical costs driven by Cardia I and Cardia II, two of our Phase II studies in support of our Zolbisoran hypertension program. Our non-GAAP SG&A expenses increased 6% for the full year, lower than in prior years as we seek to increase the operating leverage associated with our existing commercial and corporate infrastructure.

Jeff Burton: A 6% increase for the year was primarily driven by increased head count related costs and other investments supporting our strategic growth, including the global launch of emblem trucks.

Jeff Burton: Our non-GAAP operating loss from 2023 was $60 million, representing nearly $500 million improvement compared with 2022, primarily driven by strong topline results both in product sales as well as revenue from collaborations as I previously highlighted delivering non-GAAP operating profit by the end of 2025 remains a.

Jeff: The 6% increase for the year was primarily driven by increased headcount, related costs, and other investments supporting our strategic growth, including the global launch of M-Boot Truck. Our non-GAAP operating loss for 2023 was $60 million, representing a nearly $500 million improvement compared with 2022, primarily driven by strong top-line results, both in product sales as well as revenue from collaborations, as I previously highlighted. Delivering non-GAAP operating profit by the end of 2025 remains a key focus for the organization per our P to the 5th by 25 goals. Finally, we ended the year with cash, cash equivalents, and marketable securities of $2.4 billion, compared to $2.2 billion at the end of 2022, with the increase primarily related to the $310 million upfront payment from our Zalbisaran co-development and co-commercialization collaboration with Roche, We continue to believe our current cash balance is sufficient to bridge us to a self-sustainable financial profile.

The 6% increase for the year was primarily driven by increased headcount, related costs, and other investments supporting our strategic growth, including the global launch of M-Boot Truck.

The 6% increase for the year was primarily driven by increased headcount, related costs and other investments supporting our strategic growth, including the global launch of AMVUTTRA. Our non-GAAP operating loss for 2023 was $60 million, representing a nearly $500 million improvement compared with 2022, primarily driven by strong top-line results both in product sales as well as revenue from collaborations, as I previously highlighted. Delivering non-GAAP operating profit by the end of 2025 remains a key focus for the organization per our P5x25 goals.

<unk> focus for the organization for our piece of the fifth by 'twenty five goals.

Finally, we ended the year with cash cash equivalents in marketable securities of $2 4 billion compared to $2 2 billion at the end of 2022 with the increase primarily related to the $310 million upfront payment from <unk> co development co commercialization collaboration with Roche $100 million from Regeneron for achievement.

Our non-GAAP operating loss for 2023 was $60 million, representing a nearly $500 million improvement compared with 2022, primarily driven by strong top-line results both in product sales as well as revenue from collaborations, as I previously highlighted. Delivering non-GAAP operating profit by the end of 2025 remains a key focus for the organization per our P5x25 goals. Finally, we ended the year with cash, cash equivalents and marketable securities of $2.4 billion, compared to $2.2 billion at the end of 2022, with the increase primarily related to the $310 million upfront payment from our ZILEBESIRAN co-development and co-commercialization collaboration with Roche. $100 million from Regeneron for achievement of the ALN-APP Proof of Principle milestone and approximately $150 million from a [inaudible] option exercises, offset by our operating loss for the year. We continue to believe our current cash balance is sufficient to bridge us to a self-sustainable financial profile.

Jeff Burton: Of the.

Jeff Burton: Proof of principle milestone and approximately $150 million from employee option exercises offset by our operating loss for the year.

Finally, we ended the year with cash, cash equivalents and marketable securities of $2.4 billion, compared to $2.2 billion at the end of 2022, with the increase primarily related to the $310 million upfront payment from our ZILEBESIRAN co-development and co-commercialization collaboration with Roche; $100 million from Regeneron for achievement of the ALN-APP Proof of Principle milestone and approximately $150 million from a [inaudible] option exercises, offset by our operating loss for the year. We continue to believe our current cash balance is sufficient to bridge us to a self-sustainable financial profile.

Jeff Burton: Continue to believe our current cash balance is sufficient to bridges to a self sustainable financial profile.

Speaker Change: Now I'd like to turn to our financial guidance for 2024.

Speaker Change: Starting with net product revenues, we are providing combined net product revenue guidance from Petro and Boutris give Laurie <unk> our guidance assumes foreign exchange rates as of January 31, 2024, which are noted in the footnote on our guidance slide.

Speaker Change: We anticipate combined net product revenues for these four products will be between one four and $1 5 billion corresponding to a 13% to 21% broker growth rate at January 31, FX rates.

Jeff: Now, I'd like to turn to our financial guidance for 2024. Starting with net product revenues, we are providing combined net product revenue guidance for ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO. Our guidance assumes foreign exchange rates as of January 31, 2024, which are noted in the footnote on our guidance slide. We anticipate combined net product revenues for these four products will be between $1.4 and $1.5 billion, corresponding to a 13% to 21% growth rate at January 31st FX rates. Consistent with 2023, we are providing constant exchange rate growth guidance for our net product revenues, with a projected range of 13% to 21% as well, highlighting no current difference between our guidance using January 31st FX rates and 2023 constant exchange rates. The collaboration and royalty revenue guidance is $325 to $425 million.

Now, I'd like to turn to our financial guidance for 2024. Starting with net product revenues, we are providing combined net product revenue guidance for ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO. Our guidance assumes foreign exchange rates as of January 31, 2024, which are noted in the footnote on our guidance slide. We anticipate combined net product revenues for these four products will be between $1.4 and $1.5 billion, corresponding to a 13% to 21% growth rate at January 31st FX rates. Consistent with 2023, we are providing constant exchange rate growth guidance for our net product revenues, with a projected range of 13% to 21% as well, highlighting no current difference between our guidance using January 31st FX rates and 2023 constant exchange rates.

Speaker Change: Consistent with 2023, we are providing constant exchange rate growth guidance for our net product revenues with a projected range of 13% to 20, 21% as well highlighting no current difference between our guidance using January 31, FX rates in 2023 constant exchange rates.

Speaker Change: Collaboration and royalty revenue guidance is $325 million to $425 million, we anticipate that collaboration revenue associated with our partnerships with Roche and Regeneron and <unk> royalties from Novartis will drive the majority of our collaboration and royalty revenue in 2024.

Speaker Change: Our guidance for combined non-GAAP, R&D and SG&A expenses as a range between $1 675, and one 775 billion with the midpoint of the guidance range, representing 9% growth versus 2023.

Speaker Change: Growth highlights for R&D expense in 2024 include increased clinical investment and our resolve these saran Trs <unk> and <unk> programs as well as growth in pre DC and IND, enabling efforts across our preclinical portfolio as we continue to invest in creating new organic growth opportunities for the future.

The collaboration and royalty revenue guidance is $325 to $425 million. We anticipate that collaboration revenue associated with our partnerships with Roche and Regeneron and LEQVIO royalties from Novartis, will drive the majority of our collaboration and royalty revenue in 2024. Our guidance for combined non-GAAP R&D and SG&A expenses is a range between $1.675 and $1.775 billion, with the midpoint of the guidance range representing 9% growth versus 2023. Growth highlights for R&D expense in 2024 include increased clinical investment in our ZILEBESIRAN, TTRsc04 and APP programs, as well as growth in pre-DC and IND-enabling efforts across our pre-clinical portfolio as we continue to invest in creating new, organic growth opportunities for the future. As a reminder, reimbursement from partners for R&D OpEx for some partner programs highlighted by ZILEBESIRAN is accounted for as collaboration revenue. Growth highlights for SG&A expense in 2024 include increased medical and commercial investment as we prepare for the potential launch of VUTRISIRAN in the U.S. for ATTR amyloidosis with cardiomyopathy. Let me now turn from financials and discuss some key goals and upcoming milestones slated for early 2024. We will, of course, be executing on global commercialization of our products ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO.

Jeff: We anticipate that collaboration revenue associated with our partnerships with Roche and Regeneron and Lectvio royalties from Novartis will drive the majority of our collaboration and royalty revenue in 2024. Our guidance for combined non-GAAP R&D and SG&A expenses is a range between $1.675 and $1.775 billion, with the midpoint of the guidance range representing 9% growth versus 2023. Growth highlights for R&D expense in 2024 include increased clinical investment in our Zalpysiran, TTRS-Co4, and APP programs, as well as growth in pre-DC and IND-enabling efforts across our preclinical portfolio as we continue to invest in creating new organic growth opportunities for the future. As a reminder, reimbursement from partners for R&D OPEX for some partner programs highlighted by Zalpysiran is accounted for as collaboration revenue.

Speaker Change: As a reminder, reimbursed from partners for R&D Opex for some partnered programs highlighted by <unk> is accounted for as collaboration revenue.

Speaker Change: Growth highlights for SG&A expense in 2024 include increased medical and commercial investment as we prepare for the potential launch of <unk> in the U S for ATT <unk> amyloidosis with cardiomyopathy.

Growth highlights for R&D expense in 2024 include increased clinical investment in our ZILEBESIRAN, TTRsc04 and APP programs, as well as growth in pre-DC and IND-enabling efforts across our pre-clinical portfolio as we continue to invest in creating new, organic growth opportunities for the future. As a reminder, reimbursement from partners for R&D OpEx for some partner programs highlighted by ZILEBESIRAN is accounted for as collaboration revenue. Growth highlights for SG&A expense in 2024 include increased medical and commercial investment as we prepare for the potential launch of VUTRISIRAN in the U.S. for ATTR amyloidosis with cardiomyopathy.

Speaker Change: Let me now turn from financials and discuss some key goals and upcoming milestones slated for early 2024.

Speaker Change: We will of course be executing on global commercialization of our products on Petro and food truck give Laurie <unk>.

Speaker Change: We also intend to report topline results from the cardio to phase II study of <unk> as well as initiate the cardiac III multi agent combo study.

Speaker Change: We also expect three other trial initiations in early 2024, including a phase two study of <unk> in patients with cerebral amyloid angiopathy part.

Jeff: Growth highlights for SG&A expense in 2024 include increased medical and commercial investment as we prepare for the potential launch of Lutreceran in the U.S. for ATTR amyloidosis with cardiomyopics. Let me now turn from financials and discuss some key goals and upcoming milestones slated for early 2024. We will, of course, be executing on the global commercialization of our products on Patro and Vutra, Givlari, and Oxlumo.

Speaker Change: Part B of the Phase one study of <unk> in type two diabetes and a phase one study of <unk> and <unk> cellular carcinoma.

Let me now turn from financials and discuss some key goals and upcoming milestones slated for early 2024. We will, of course, be executing on global commercialization of our products ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO. We also intend to report top-line results from the CARDIA II Phase II study of Zolbisiran, as well as initiate the CARDIA III Multi-Agent Combo Study. We also expect three other trial initiations in early 2024, including a phase two study of ALNAPP in patients with cerebral amyloid angiopathy. Part B of the Phase I study of ALN-KHK and Type II diabetes and a Phase I study of ALN-BCAT and hepatocellular carcinoma And as Pushcall previously noted, we expect to report top-line results from the Helios B Phase III study of Lutriceran in late June or early July. Let me now turn it back to Christine to coordinate our Q&A session.

Let me now turn from financials and discuss some key goals and upcoming milestones slated for early 2024. We will, of course, be executing on global commercialization of our products ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO. We also intend to report top-line results from the KARDIA-2 Phase II study of ZILEBESIRAN, as well as initiate the KARDIA-3 multi-agent combo study. We also expect three other trial initiations in early 2024, including a Phase II study of ALN-APP in patients with cerebral amyloid angiopathy, Part B of the Phase I study of ALN-KHK and Type II diabetes and a Phase I study of ALN-BCAT in hepatocellular carcinoma. And as Pushkal previously noted, we expect to report top-line results from the HELIOS-B Phase III study of VUTRISIRAN in late June or early July.

Speaker Change: And as push called previously noted we expect to report topline results from the Helios B Phase III study of <unk> in late June or early July.

Speaker Change: Let me now turn it back to Christine to coordinate our Q&A session pristine.

Christine: Operator, we can now open the call to questions to those dialed in we would like to ask you to limit yourself to one question each and then get back in the queue. If you have additional question.

Jeff: We also intend to report top-line results from the CARDIA II Phase II study of Zolbisiran, as well as initiate the CARDIA III Multi-Agent Combo Study. We also expect three other trial initiations in early 2024, including a phase two study of ALNAPP in patients with cerebral amyloid angiopathy. Part B of the Phase I study of ALN-KHK and Type II diabetes and a Phase I study of ALN-BCAT and hepatocellular carcinoma

Christine: Thank you as a reminder to ask a question. Please press star one one on your telephone and wait for your name to be announced.

Christine: Draw. Your question. Please press Star one one again please.

Christine: Please standby, while we compile the Q&A roster.

Jeff: And as Pushcall previously noted, we expect to report top-line results from the Helios B Phase III study of Lutriceran in late June or early July. Let me now turn it back to Christine to coordinate our Q&A session.

Christine: Our first question comes from the line of Rich <unk> from TD.

Rich: Good morning, guys. Thanks for taking my question.

Rich: Quick question on the updated stats analysis.

Let me now turn it back to Christine to coordinate our Q&A session. Christine?

Rich: Makes a lot of sense.

Christine Regan Lindenboom: Thank you, Jeff. Operator, we can now open the call to questions. To those dialed in we would like to ask you to limit yourself to one question each and get back in the queue if you have additional questions. Thank you. As a reminder, to ask a question, please press star one on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Stand by while we compile the Q&A roster. Our first question comes from the line of Ritu Baral from TD. Good morning, guys.

Christine Regan Lindenboom: Thank you, Jeff. Operator, we can now open the call to questions. To those dialed in, we would like to ask you to limit yourself to one question each and get back in the queue if you have additional questions.

Rich: I'm wondering about a certain scenario that is outlined on slide 18 versus some of the proceedings.

Rich: The Apollo the AD com.

Rich: <unk> succeed on the monotherapy population with a P value of point or two five only.

Thank you. As a reminder, to ask a question, please press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Ritu Baral from TD. Good morning, guys.

Operator: Thank you. As a reminder, to ask a question, please press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. Please stand by while we compile the Q&A roster.

Rich: Hi.

Rich: Feedback.

Rich: Just given the importance placed on combination therapy.

Our first question comes from the line of Ritu Baral from TD.

Rich: A benefit.

Rich: From prior proceedings.

Ritu Baral: Good morning, guys. Thanks for taking the question. Question on the updated stats analysis, makes a lot of sense but I'm wondering about a certain scenario that is outlined on slide 18 versus some of the proceedings of the APOLLO-B adcoms. If you succeed on the monotherapy population with a p-value of 0.025 only, what has FDA feedback been on this, just given the importance placed on combination therapy and lack of benefit from the prior proceedings and could that lead to a more restrictive label for the drug for second line or something, based on your interactions on the SAP -- on this final SAP. Thanks. Thanks, Ritu. That's a great question.

Ritu Baral: Good morning, guys. Thanks for taking the question. Question on the updated stats analysis, makes a lot of sense but I'm wondering about a certain scenario that is outlined on slide 18 versus some of the proceedings of the APOLLO-B AdComs. If you succeed on the monotherapy population with a p-value of 0.025 only, what has FDA feedback been on this, just given the importance placed on combination therapy and lack of benefit from the prior proceedings? And could that lead to a more restrictive label for the drug for second line or something, based on your interactions on the SAP -- on this final SAP? Thanks.

Rich: Could that lead to.

Ritu Baral: Thanks for taking the question. Question on the updated stats analysis. A lot of sense, but I'm wondering about a certain scenario that is outlined on slide 18 versus some of the proceedings of the Apollo B adcoms. If you succeed in the monotherapy population with a p-value of 0.025, only, you know, what has FDA feedback been on this, just given the importance placed on combination therapy and lack of benefit from the prior proceedings? And, you know, could that lead to a more restrictive label for the drug for a second line or something? based on your interactions on the SAP, on this final SAP. Thanks. Thanks, Ritu. That's a great question.

Rich: More restrictive label for the drug.

Rich: Of course second line or something.

Rich: Based on our interactions on the walk.

Rich: Okay.

Speaker Change: Thanks Richard.

Speaker Change: Great question I, just wanted to kind of underscore that.

Speaker Change: Really confident.

Speaker Change: On the potential effects of <unk> will deliver on cardiovascular outcomes in center <unk> with already well designed and executed to deliver these results and the changes that we're announcing today.

Speaker Change: Enhance an already robust study given how important this study is for patients and.

Speaker Change: For all nine of them and clearly as <unk> said, we we consulted with the FDA.

Thanks, Ritu. That's a great question. And I just want to kind of underscore that we're really confident in the potential effects that VUTRI will deliver on cardiovascular outcomes and that HELIOS-B was already well-designed and executed to deliver these results. The changes that we're announcing today enhance an already robust study, given how important the study is for patients and for Alnylam. And clearly, as Pushkal said, we consulted with the FDA as we made these changes. It's important to note that this is a study that is focused on outcomes and it's outcomes that are most important to physicians, patients and payers. And that's very different from a scenario where you're assessing endpoints, like, six-minute walk test and KCCQ. Really, if we're able to deliver the primary endpoints as we've described, we're confident that this will be a study that should be approved by health authorities. But, happy for Pushkal to add any additional comments to that.

Yvonne L. Greenstreet: Thanks, Ritu. That's a great question. And I just want to kind of underscore that we're really confident in the potential effects that VUTRI will deliver on cardiovascular outcomes and that HELIOS-B was already well-designed and executed to deliver these results. The changes that we're announcing today enhance an already robust study, given how important the study is for patients and for Alnylam. And clearly, as Pushkal said, we consulted with the FDA as we made these changes.

Yvonne L. Greenstreet: And I just want to kind of underscore that we're, you know, really confident in the potential effects that BOOT3 will deliver on study after outcomes and that Helios B was already well designed and executed to deliver these results. And the changes that we're announcing today enhance an already robust study, given, you know, how important the study is for patients and for Alnylam. And clearly, as Kushkal said, we consulted with the FDA as we made these changes. It's important to note that this is a study that is focused on outcomes, and it's outcomes that are most important to physicians, patients, and payers. And, you know, that's very different from a scenario where you're assessing, you know, endpoints, like the six minute walk test and the KCCQ. Really, if we're able to deliver the primary endpoints, as we described, we're confident that this will be a study that should be approved by health authorities. But, you know, I would be happy for Kushkal to add any additional comments to that.

Speaker Change: As we made these changes.

Speaker Change: To note that the study that is focused on outcomes and its outcomes that are most important to physicians patients and.

Speaker Change: Payors.

Speaker Change: And.

Speaker Change: That's very different from a scenario assessing.

Speaker Change: Endpoints like like six minute walk test.

Speaker Change: <unk> really if we're able to deliver the primary endpoints as we've described.

It's important to note that this is a study that is focused on outcomes and it's outcomes that are most important to physicians, patients and payers. And that's very different from a scenario where you're assessing endpoints, like, six-minute walk test and KCCQ. Really, if we're able to deliver the primary endpoints as we've described, we're confident that this will be a study that should be approved by health authorities. But, happy for Pushkal to add any additional comments to that.

Speaker Change: We're confident that this will be.

Speaker Change: That should be approved.

Speaker Change: By health authorities.

Speaker Change: For <unk> to add any additional comments that no I think Ivan you've really covered it Rick too I think we remain focused on both the overall population and what we're doing today is highlighting that based on all the learnings from Apollo B.

Speaker Change: And in terms of delivering a strong and competitive label and aligning with what is where we see the market being for the next several years that we've elevated our analysis of the monotherapy group vendors.

Speaker Change: As I mentioned as Ivan has highlighted we've.

Pushkal Garg: No. I think, Yvonne, you've really covered it. Ritu, I think we remain focused on both the overall population and what we're doing today is highlighting that, based on all the learnings from APOLLO-B and in terms of delivering a strong and competitive label and aligning with where we see the market being for the next several years, that we've elevated our analysis of the monotherapy group. And as I mentioned, as Yvonne has highlighted, we've made these adjustments after consultation with FDA and other health authorities. And so, we think that will support an approvable package.

Speaker Change: These adjustments after consultation with FDA and other health authorities and so we think that will support.

Speaker Change: An approvable package.

Speaker Change: Thank you.

Speaker Change: Thank you one moment for our next question.

Speaker Change: Yeah.

Speaker Change: Our next question comes from the line of Paul Matteo <unk> from Stifel.

Paul Matteis: Hey, Thanks for taking my question I appreciate it I totally agree to that these changes at base makes sense, but I think my main question is why now.

Paul Matteis: Feels like when that study started we all knew that 33 months is better than 30.

Paul Matteis: Your drug alone would probably have a bigger effect size alone.

Paul Matteis: Thank you. Thank you. One moment for our next question. Our next question comes from the line of Paul Matteis from Stifel. Hey, thanks for taking my question. I appreciate it.

Ritu Baral: Thank you.

Thank you. One moment for our next question. Our next question comes from the line of Paul Matteis from Stifel. Hey, thanks for taking my question. I appreciate it.

Operator: Thank you. One moment for our next question. Our next question comes from the line of Paul Matteis from Stifel.

Paul Matteis: <unk> size that could be a little bit dilutive by <unk> <unk>. So.

Paul Matteis: Hey, thanks for taking my question, I appreciate it. I totally agree with Ritu that these changes at face value make sense but I think my main question is why now? It feels like when this study started, we all knew that 33 months is better than 30, that your drug alone would probably have a bigger effect size alone than effect size that could be a little bit diluted by TAFAMIDIS. So, what changed? What have you seen in the blinded data? Is there something that's more nuanced here that's leading you to make these changes and accepting the fact that there's going to be a small delay versus initial guidance? Thank you.

Paul Matteis: What changed.

Paul Matteis: What are you seeing in the blinded data is there something thats more nuance here, that's leading you to make these changes.

Paul Matteis: I totally agree with Ritu that these changes at face value make sense, but I think my main question is why now? It feels like when this study started, we all knew that 33 months was better than 30, that your drug alone would probably have a bigger effect size alone than effects that could be a little bit diluted by tefamidin. What changed?

Speaker Change: And accepting the fact that theres going to be a small delay versus initial guidance. Thank you.

Speaker Change: Thanks for that Thats, a great question look I mean, these changes were primarily.

Speaker Change: No.

Yvonne L. Greenstreet: What have you seen in the blinded data? Is there something that's more nuanced here that's leading you to make these changes and accept the fact that there's going to be a small delay versus initial guidance? Thanks.

Speaker Change: Influenced by earnings from Apollo B and unimportant to note not just the 12 month data for the open label extension data at 24 months and beyond.

Speaker Change: And these states that have already informed.

Speaker Change: Constants that we've announced today and I think for US it's important to make sure we had as much information.

Yvonne L. Greenstreet: Thanks, Paul, that's a great question. Look, I mean, these changes were primarily influenced by learnings from APOLLO-B. And important to note, not just the 12-month data but the open-label extension data at 24 months and beyond. And these data have really informed the enhancements that we've announced today. And I think for us, it's important to make sure we have as much information as we possibly could prior to making any changes before database lock. And also, as Pushkal emphasized, to make sure that we consulted with the FDA and other health authorities and that takes time. I think we're in this sweet spot, if you like, between really understanding all the data that we're going to have prior to database lock. And obviously, database lock, beyond which it's not possible to make changes. Yeah, I think, building on what you said, Yvonne, Paul, I think, look, it makes sense for us to have the maximum amount of information before we make changes to an analysis plan, as we're announcing today. These are not changes in the operational conduct of the study; they're to the analytic plan. And again, it makes the most sense to have as much information that's come out of Apollo B. We've gotten, you know, we were in a very fortunate position to run that study and get all the information that we did out of that study on a variety of endpoints, to have that extended follow-up, and then to have the opportunity to align with health authorities. In the long-term Apollo B data, are you seeing a more pronounced monotherapy effect versus an effect on typhamidus on outcomes and typhamidus-treated patients on outcomes endpoints? Is that part of the nuance here?

Speaker Change: As we possibly could products or making any changes.

Speaker Change: <unk> also.

Speaker Change: As <unk> emphasized to make sure that we can.

Speaker Change: Consulted with the FDA and other health authorities and that takes time. So I think I think we are in this sweet spots. If you like between really understanding all the data that we're going to have prior to database lock on opposite database lock beyond which is not possible to make changes.

And also, as Pushkal emphasized, to make sure that we consulted with the FDA and other health authorities and that takes time. I think we're in this sweet spot, if you like, between really understanding all the data that we're going to have prior to database lock. And obviously, database lock, beyond which it's not possible to make changes.

Speaker Change: Yes, I think.

Speaker Change: Building on what you said Yvonne Paul I think look it makes sense for us to have the maximum amount of information before we make changes to an analysis plan.

Yvonne L. Greenstreet: So I think we're in this sweet spot, if you like, between really understanding all the data that we're going to have prior to database lock and, obviously, database lock, beyond which it's not possible to make changes. Yeah, I think, building on what you said, Yvonne, Paul, I think, look, it makes sense for us to have the maximum amount of information before we make changes to an analysis plan, as we're announcing today. These are not changes in the operational conduct of the study; they're to the analytic plan. And again, it makes the most sense to have as much information that's come out of Apollo B. We've gotten, you know, we were in a very fortunate position to run that study and get all the information that we did out of that study on a variety of endpoints, to have that extended follow-up, and then to have the opportunity to align with health authorities. In the long-term Apollo B data, are you seeing a more pronounced monotherapy effect versus an effect on typhamidus on outcomes and typhamidus-treated patients on outcomes endpoints? Is that part of the nuance here?

Speaker Change: We're announcing today you do not changes in the operational conduct of the study there to the analytic plan.

Speaker Change: It makes most sense to have as much information.

Speaker Change: Let's come out of Apollo B, we've got we're in a very fortunate position to run that study and gotten all the information that we did out of that study in a variety of endpoints to have that extended follow up and then to have the opportunity to align with health authorities.

Yeah. I think, building on what you said, Yvonne, Paul, it makes sense for us to have the maximum amount of information before we make changes to an analysis plan, as we're announcing today. These are not changes in the operational conduct of the study; they are to the analytic plan. And, again, it makes the most sense to have as much information that's come out of APOLLO-B. We've gotten -- we were in a very fortunate position to run that study and gotten all the information that we did out of that study on a variety of endpoints, to have that extended follow-up and then to have the opportunity to align with health authorities. In the long-term APOLLO-B data, are you seeing a more pronounced monotherapy effect versus an effect on typhamidus on outcomes and typhamidus-treated patients on outcomes endpoints? Is that part of the nuance here?

Pushkal Garg: Yeah. I think, building on what you said, Yvonne, Paul, it makes sense for us to have the maximum amount of information before we make changes to an analysis plan, as we're announcing today. These are not changes in the operational conduct of the study; they are to the analytic plan. And, again, it makes the most sense to have as much information that's come out of APOLLO-B. We've gotten -- we were in a very fortunate position to run that study and gotten all the information that we did out of that study on a variety of endpoints, to have that extended follow-up and then to have the opportunity to align with health authorities.

Speaker Change: In the long term Apollo data are you seeing a more pronounced monotherapy effect versus an effect on <unk> on outcomes and so payments treated patients on outcomes endpoints of that part of the nuance here.

Speaker Change: Paul what I'd say is that what we've seen in the long term data and we presented some data last last fall at the AD Com and then I think in <unk> H FSA.

Speaker Change: Really encouraging to us in both populations frankly as it relates to outcomes right. If you look in the monotherapy group, what we've seen was really sizeable effects on a variety of endpoints as I highlighted in my.

authorities. In the long-term APOLLO-B data, are you seeing a more pronounced monotherapy effect versus an effect on typhamidus on outcomes and typhamidus-treated patients on outcomes endpoints? Is that part of the nuance here?

authorities.

Paul Matteis: In the long-term APOLLO-B data, are you seeing a more pronounced monotherapy effect versus an effect on TAFAMIDIS on outcomes and TAFAMIDIS-treated patients on outcomes endpoints? Is that part of the nuance here?

Speaker Change: Opening remarks on a variety of endpoints that predict outcomes.

And we saw a mortality separation.

Speaker Change: <unk>.

Speaker Change: And as we've looked also in the combination group over time.

Paul Matteis: You know, Paul, what I'd say is that what we've seen in the long-term data -- and we presented some data last fall at the AdCom and then, I think, at HFSA -- are really encouraging to us, in both populations, frankly, as it relates to outcomes, right? If you look at the monotherapy group, what we've seen was really sizable effects on a variety of endpoints as I highlighted in my opening remarks, on a variety of endpoints that predict outcomes. And we saw mortality separation. And as we've looked also in the combination group over time, what we saw was favorable effects on outcomes there as well. And so, I think both of this just builds into our confidence but I think, certainly what we're seeing in monotherapy -- and, again, this is not just APOLLO-B. When we look back at the original APOLLO study, when we look at HELIOS-A, all of this really highlights a very compelling effect. When you look at that overall hazard ratio for mortality, it was .67 at 24 months in the overall population. So, we have a lot of confidence in what we're seeing here and we think these refinements to the analysis plan will only optimize the study for success in getting a strong and competitive label. Yeah, let me just jump in as well, Paul. This actually, you know, I think if we stand back and look, just to put some numbers on what Pushkar just mentioned, in Apollo itself, the hazard ratio for mortality was 0.53.

You know, Paul, what I'd say is that what we've seen in the long-term data -- and we presented some data last fall at the AdCom and then, I think, at HFSA -- are really encouraging to us, in both populations, frankly, as it relates to outcomes, right? If you look at the monotherapy group, what we've seen was really sizable effects on a variety of endpoints as I highlighted in my opening remarks, on a variety of endpoints that predict outcomes. And we saw mortality separation. And as we've looked also in the combination group over time, what we saw was favorable effects on outcomes there as well. And so, I think both of this just builds into our confidence but I think, certainly what we're seeing in monotherapy -- and, again, this is not just APOLLO-B. When we look back at the original APOLLO study, when we look at HELIOS-A, all of this really highlights a very compelling effect. When you look at that overall hazard ratio for mortality, it was .67 at 24 months in the overall population. So, we have a lot of confidence in what we're seeing here and we think these refinements to the analysis plan will only optimize the study for success in getting a strong and competitive label.

Pushkal Garg: You know, Paul, what I'd say is that what we've seen in the long-term data -- and we presented some data last fall at the AdCom and then, I think, at HFSA -- are really encouraging to us, in both populations, frankly, as it relates to outcomes, right? If you look at the monotherapy group, what we've seen was really sizable effects on a variety of endpoints as I highlighted in my opening remarks, on a variety of endpoints that predict outcomes. And we saw mortality separation. And as we've looked also in the combination group over time, what we saw was favorable effects on outcomes there as well.

Speaker Change: We saw was favorable effects on outcomes there as well.

Speaker Change: And so I think both of this builds into our confidence, but I think certainly what we're seeing in monotherapy and again. This is not just a follow up is when we look back at the original Apollo study when we look at helium say all of this really highlights a very compelling effect. When you look at that overall hazard ratio for mortality was <unk> 67 or 24 months.

Speaker Change: In the overall population so we have a lot of confidence in what we're seeing here and.

Speaker Change: And we think these refinements to the analysis plan will only optimize the study for success in getting a strong and competitive label, Yes, Let me just jump in as well pull this oxide.

And so, I think both of this just builds into our confidence but I think, certainly what we're seeing in monotherapy -- and, again, this is not just APOLLO-B. When we look back at the original APOLLO study, when we look at HELIOS-A, all of this really highlights a very compelling effect. When you look at that overall hazard ratio for mortality, it was 0.67 at 24 months in the overall population. So, we have a lot of confidence in what we're seeing here and we think these refinements to the analysis plan will only optimize the study for success in getting a strong and competitive label.

Speaker Change: If we stand back and look just to put some numbers to work with <unk> as mentioned in our polo itself that hazard ratio for mortality was five three.

Paul Matteis: When you look at that overall hazard ratio for mortality, it was.67 at 24 months in the overall population. So we have a lot of confidence in what we're seeing here, and we think these refinements to the analysis plan will only optimize the study for success in getting a strong and competitive label. Yeah, let me just jump in as well, Paul. This actually, you know, I think if we stand back and look, just to put some numbers on what Pushkar just mentioned, in Apollo itself, the hazard ratio for mortality was 0.53.

Speaker Change: And that showed up as early as six months and then the costar et separating.

Speaker Change: And Apollo B.

Speaker Change: Hazard ratio from <unk>, 36, or 12 months.

Speaker Change: Within the.

Speaker Change: Monotherapy as well as the tablet farms.

Speaker Change: Type two sound one.

Speaker Change: Is <unk> 67, as he said at 24 months.

Yeah. Let me just jump in as well, Paul. This is Akshay. I think if we stand back and look -- just to put some numbers to what Pushkal just mentioned -- in APOLLO itself, the hazard ratio for mortality was 0.53. And that showed up as early as six months and then the curve started separating. In APOLLO-B, the hazard ratio for mortality is 0.36 at 12 months, both in the monotherapy as well as the TAFAMIDIS arms. [inaudible] PATISIRAN one is 0.67, as you said, at 24 months. This is now -- APOLLO-B, a study that's half the size and changes showing up at nine months and continuing to separate since then. So, I think the changes we've made today, I'm glad you agree, are wise. And a three-month addition to further increase the robustness of the encouraging data we already see from APOLLO and APOLLO-B, I think just further consolidates that we anticipate a positive study and we're confident about that. And today's changes just further attest to our confidence in our approach. So, I'll leave it at that but I hope that makes sense. Thanks. Akshay. That's great.

Akshay K. Vaishnaw: Yeah. Let me just jump in as well, Paul. This is Akshay. I think if we stand back and look -- just to put some numbers to what Pushkal just mentioned -- in APOLLO itself, the hazard ratio for mortality was 0.53. And that showed up as early as six months and then the curve started separating. In APOLLO-B, the hazard ratio for mortality is 0.36 at 12 months, both in the monotherapy as well as the TAFAMIDIS arms. [inaudible] PATISIRAN one is 0.67, as you said, at 24 months. This is now -- APOLLO-B, a study that's half the size and changes showing up at nine months and continuing to separate since then.

This is now Apollo B study that's half the size.

Speaker Change: And.

Speaker Change: China is showing up at nine months and continue to separate since then so I think the changes we've made today I'm glad you agree a wise and a three month edition to further increase the robustness of the encouraging data, we already see from Apollo and Apollo B I think just further consolidates that we anticipate a positive study that we're confident about that.

Akshay K. Vaishnaw: And that showed up as early as six months, and then the curve started separating. In Apollo B, you know, the hazard ratio for mortality is 0.36 at 12 months, both in monotherapy as well as the defibrillator farms produce around one is 0.67, as you said, at 24 months. And this is now, apparently, a study that's half the size, and changes showing up at nine months and continuing to separate since then. So I think the changes we've made today, I'm glad you agree, are wise. And a three month addition to further increase the robustness of the encouraging data we already see from Apollo and Apollo B just further consolidates that we anticipate a positive study. And we're confident about that.

Speaker Change: And today's changes to further test.

Speaker Change: Now approach so I'll leave it at that but I hope that makes sense.

Speaker Change: Thanks, Ashley Thats, great. We will have our next question.

Speaker Change: Thank you one moment for our next question.

So, I think the changes we've made today, I'm glad you agree, are wise. And a three-month addition to further increase the robustness of the encouraging data we already see from APOLLO and APOLLO-B, I think just further consolidates that we anticipate a positive study and we're confident about that. And today's changes just further attest to our confidence in our approach. So, I'll leave it at that but I hope that makes sense. Thanks.

Speaker Change: Okay.

Speaker Change: Our next question comes from the line of Ellie Merle from UBS.

Ellie Merle: Hey, guys. Thanks for taking the question.

Ellie Merle: Can you just elaborate a bit more on the changes you're dead on the secondary endpoint analysis, specifically what the hierarchy.

Ellie Merle: Streamline secondary endpoint analysis and.

Akshay K. Vaishnaw: And today's changes just further attest to our confidence in our approach. So I'll leave it at that, but I hope that makes sense. Thanks, Akshay. That's great.

Ellie Merle: What this does for the powering of key secondaries like mortality.

Ellie Merle: And your latest expectation for what we could see on.

Yvonne L. Greenstreet: Thanks, Akshay. That's great. We'll have the next question.

Operator: We'll have the next question. Thank you. One moment for our next question....

We'll have the next question.

Ellie Merle: On the mortality.

Ellie Merle: Particularly in the monotherapy arm.

Operator: Thank you. One moment for our next question. Our next question comes from the line of Ellie Merle from UBS.

Speaker Change: Yes, no that's a great question Ed.

Ellie Merle: Our next question comes from the line of Ellie Merle from UBS. Hey guys, thanks for taking the question. Can you just elaborate a bit more on the changes you did to the secondary endpoint analysis, specifically what the hierarchy is of this, you know, streamlined secondary endpoint analysis, and what this does for the powering of key secondaries like mortality, and your latest expectation for what we could see on the mortality secondary, particularly in the monotherapy arm? Thanks. Yeah, no, that's a great question, Eddie.

Our next question comes from the line of Ellie Merle from UBS.

Speaker Change: Note that we took with efficiency streamline with secondary endpoints, so because we really want to focus on the most.

Hey guys, thanks for taking the question. Can you just elaborate a bit more on the changes you did to the secondary endpoint analysis, specifically what the hierarchy is of this, you know, streamlined secondary endpoint analysis, and what this does for the powering of key secondaries like mortality, and your latest expectation for what we could see on the mortality secondary, particularly in the monotherapy arm? Thanks. Yeah, no, that's a great question, Eddie.

Ellie Merle: Hey guys, thanks for taking the question. Can you just elaborate a bit more on the changes you did on the secondary endpoint analysis, specifically, what the hierarchy is of this streamlined secondary endpoint analysis and what this does for the powering of key secondaries, like mortality? And your latest expectation for what we could see on the mortality secondary, particularly in the monotherapy arm? Thanks.

Speaker Change: Clinically important.

Speaker Change: Endpoints to support differentiation, we've seen evidence of disease stabilization and this doesn't appear to be true.

Speaker Change: As evidenced generators with stabilizes.

Speaker Change: We've really been thoughtful about what are the endpoints that focus on important clinical.

Yeah. No, that's a great question, Ellie and as you noted, we took the decision to streamline the secondary endpoints because we really want to focus on the most clinically important endpoints that support differentiation. We've seen evidence of disease stabilization and this doesn't appear to be true of evidence generated with stabilizers. So, we've really been thoughtful about what are the endpoints that focus on important clinical learnings and have, therefore, removed some of the endpoints from the hierarchical structure. But, obviously, we'll be looking at all those data as exploratory endpoints. But Pushkal, perhaps you could just go through a little bit of the specific changes that we've made to the secondary endpoints? Yeah, absolutely.

Yvonne L. Greenstreet: Yeah. No, that's a great question, Ellie and as you noted, we took the decision to streamline the secondary endpoints because we really want to focus on the most clinically important endpoints that support differentiation. We've seen evidence of disease stabilization and this doesn't appear to be true of evidence generated with stabilizers. So, we've really been thoughtful about what are the endpoints that focus on important clinical learnings and have, therefore, removed some of the endpoints from the hierarchical structure. But, obviously, we'll be looking at all those data as exploratory endpoints. But Pushkal, perhaps you could just go through a little bit of the specific changes that we've made to the secondary endpoints?

Speaker Change: Learnings and have therefore.

Pushkal: And, you know, as you noted, we took the decision to streamline the secondary endpoints because we really want to focus on the most clinically important endpoints that support differentiation. We've seen evidence of disease stabilization, and this doesn't appear to be true of evidence generated with stabilizers. So, you know, we've really been thoughtful about what the endpoints that focus on important clinical learnings are and have therefore, you know, removed some of the endpoints from the hierarchical structure. But obviously, we'll be looking at all those data points as exploratory endpoints. But Pushkar, perhaps you could just go through, you know, a little bit of the specific changes that we've made to the secondary endpoints. Yeah, absolutely.

Speaker Change: Remove some of the endpoints from the.

Speaker Change: From the hierarchical structure, but obviously, we'll be looking at all this data is exploratory endpoints, but perhaps you could just go through.

Speaker Change: Little bit of specific changes that we've made to the secondary endpoints yeah, absolutely. So what we've done is obviously the primary as we've talked about remains a focus on outcomes of depth and recurrent CV events that we'll be looking at in two populations than going down.

So, we've really been thoughtful about what are the endpoints that focus on important clinical learnings and have, therefore, removed some of the endpoints from the hierarchical structure. But, obviously, we'll be looking at all those data as exploratory endpoints. But Pushkal, perhaps you could just go through a little bit of the specific changes that we've made to the secondary endpoints?

Speaker Change: Put six minute walk test and Casey Q next we think we have ample power for those and we think those are great endpoints based on what we learned from Apollo B to really demonstrate what we seem to see be seeing as in terms of differentiated profile, whereas patients on an RNA therapeutic appear to have disease stabilization over an extended period of time.

Pushkal Garg: Yeah, absolutely. So Ellie, what we've done is -- obviously, the primary, as we've talked about, remains a focus on outcomes of death and recurrent CV events that we'll be looking at in two populations. Then going down, we put the six-minute walk test and KCCQ next. We think we have ample power for those and we think those are great endpoints based on what we learned from APOLLO-B, to really demonstrate what we seem to be seeing in terms of a differentiated profile whereas patients on an RNAi Therapeutic appear to have disease stabilization over an extended period of time. And while no head-to-head, it looks very different than the progressive decline that we've seen now in two pivotal trials with stabilizer therapies. And so, we look forward to hopefully seeing those patterns emerge again in HELIOS-B.

Pushkal: So Ellie, what we've done is obviously the primary focus, as we've talked about, remains a focus on outcomes of death and recurrent CV events that we'll be looking at in two populations. Then going down, you know, we put the six minute walk test in KCCQ next. We think we have ample power for those, and we think those are great endpoints based on what we learned from Apollo B to really demonstrate what we seem to be seeing in terms of a differentiated profile, whereas patients on an RNAi therapeutic appear to have disease stabilization over an extended period of time. And while not head to head, it looks very different than the progressive decline that we've seen now in two pivotal trials with stabilizer therapies. And so we look forward to hopefully seeing those patterns emerge again in Helios B.

Speaker Change: And while no head to head looks very different than the progressive decline that we've seen now in two pivotal trials with stabilizer therapies and so we look forward to hopefully seeing those patterns emerge again in Helios b.

Speaker Change: Third endpoint is all cause mortality, obviously, that's a higher bar.

Speaker Change: Then the primary endpoint.

Speaker Change: But again based on what we're seeing and while the study was primarily powered for the composite.

Speaker Change: It's important to be able to demonstrate to look for all cause mortality.

Speaker Change: And so we'll be testing that formally in the in the secondary endpoint structure.

Speaker Change: And last we've added an endpoint of NY HLA class.

And while no head-to-head, it looks very different than the progressive decline that we've seen now in two pivotal trials with stabilizer therapies. And so, we look forward to hopefully seeing those patterns emerge again in HELIOS-B.

Speaker Change: Because we saw some very encouraging data emerging out of Apollo b.

Speaker Change: That suggested it again consistent with an emerging profile that this class of drugs can actually delay disease progression and and stabilize the disease that we may see benefits on Nyj class and we think all of those are clinically important.

Pushkal: The third endpoint is all-cause mortality. Obviously, that's a higher bar than the primary endpoint but, again, based on what we're seeing and while the study is primarily powered for the composite, we think it's important to be able to demonstrate to look for all-cause mortality. And so, we'll be testing that formally in the secondary endpoint structure. And last, we've added an endpoint of NYHA class because we saw some very encouraging data emerging out of APOLLO-B that suggested that, again, consistent with an emerging profile, that this class of drugs can actually delay disease progression and stabilize the disease that we may see benefits in NYHA class. And we think all of those are clinically important, differentiating factors that we want to make sure that we look at with the potential to include them in the label and differentiate in the marketplace.

The third endpoint is all-cause mortality. Obviously, that's a higher bar than the primary endpoint but, again, based on what we're seeing and while the study is primarily powered for the composite, we think it's important to be able to demonstrate to look for all-cause mortality. And so, we'll be testing that formally in the secondary endpoint structure.

Speaker Change: Differentiating factors that that may that we want to make sure that we look at with the potential to include them in the label and differentiate in the marketplace.

Speaker Change: Yes.

And last, we've added an endpoint of NYHA class because we saw some very encouraging data emerging out of APOLLO-B that suggested that, again, consistent with an emerging profile, that this class of drugs can actually delay disease progression and stabilize the disease that we may see benefits in NYHA class. And we think all of those are clinically important, differentiating factors that we want to make sure that we look at with the potential to include them in the label and differentiate in the marketplace.

Speaker Change: Building off that last point and pushed coal I think you went through the different end points very carefully.

Speaker Change: From our perspective, we're focusing on the most stringent outcomes, whether it's mortality hospitalization quality of life neocart cessation of mortality.

Speaker Change: This is what matters to us it will show the true impact of this drug and its both matters to patients and doctors and ultimately we hope to get this into the label and you'll note that we've avoided putting things like BNP and other endpoints, which we could have predicted but we want to focus on the strongest outcomes I hope that's a surrogate for the confidence we feel in what we can.

Akshay K. Vaishnaw: Yeah. And just building on that last point, Pushkal, I think you went through the different endpoints very carefully. From our perspective, we're focusing on the most stringent outcomes. Whether it's mortality, hospitalization, quality of life, post-hospitalization or post-mortality, this is what matters to us. It'll show the true impact of this drug and it's what matters to patients and doctors. And ultimately, we hope to get this into the label. And you know that we've avoided putting things like BNP and other endpoints which we could have put i, but we want to focus on the strongest outcomes. And I hope that's a surrogate for the confidence we feel in what we can achieve with VITRUSIRAN. So, I'll leave it at that. Thanks. Thanks, Akshay.

Speaker Change: <unk> so.

Speaker Change: I'll leave it at that.

Speaker Change: Thanks. Thanks.

Speaker Change: Next question please.

Speaker Change: Thank you one moment far next question.

Seth Coast: Our next question comes from the line of Coast, Seth <unk> from BMO capital markets.

And ultimately, we hope to get this into the label. And you know that we've avoided putting things like BNP and other endpoints which we could have put in but we want to focus on the strongest outcomes. And I hope that's a surrogate for the confidence we feel in what we can achieve with VITRUSIRAN. So, I'll leave it at that.

Seth Coast: Hello, everyone. Thanks for taking our questions.

Seth Coast: One question from us on the <unk>, so far Helios B looking back at the Aqua Amit. This trial. We are wondering whether there was any information that into any doubt last year that that helped you decide on the changes you are making and may be looking for what how do these changes that youre, making.

Thanks. Thanks, Akshay.

Ellie Merle: Thanks.

Yvonne L. Greenstreet: Thanks, Akshay. Next question, please.

Seth Coast: <unk> position on boots.

Operator: Next question, please. Thank you. One moment for our next question. Our next question comes from the line of Kostas Bilouris from BMO Capital Markets. Hello, everyone. Thanks for taking our questions. One question from us on the changes to Helios B.

Next question, please.

Seth Coast: Compare to Epsilon data Sandwich is editing out next year and also has a well pilot Italian thank you.

Thank you. One moment for our next question. Our next question comes from the line of Kostas Bilouris from BMO Capital Markets. Hello, everyone. Thanks for taking our questions. One question from us on the changes to Helios B.

Operator: Thank you. One moment for our next question. Our next question comes from the line of Kostas Biliouris from BMO Capital Markets.

Speaker Change: Okay, if I, if I heard you correctly.

Hello, everyone. Thanks for taking our questions. One question from us on the changes to HELIOS-B. Looking back at the Acquiramidis trial, we are wondering whether there was any information in the readout last year that helped you decide on the changes you are making, and maybe looking forward, how do these changes that you are making help you position Ambutra compared to Eplon Dersin, which is read out next year and also has a well-powered trial? Thank you. Okay, if I understand you correctly, I'm trying to understand, you know, whether there's any information from the Akramadu study that influenced these changes, maybe Pushkar, if you can take that question. And then there was a second question around how these changes influenced our views on the commercial opportunity and Tolga, you know; it would be great if you would take that question. Christopher?

Kostas Biliouris: Hello, everyone. Thanks for taking our questions. One question from us on the changes of HELIOS-B. Looking back at the ACORAMIDIS trial, we are wondering whether there was any information there in the readout last year that helped you decide on the changes you are making? And maybe looking forward, how do these changes that you are making help you position AMVUTTRA compared to EPLONTERSEN, which is reading out next year and also has a well-powered trial? Thank you.

Speaker Change: I'm trying to understand.

Speaker Change: Are there any information.

Speaker Change: Calamitous study that influenced these changes may be pushed quite a few can take that question and then there was the second question around how did these changes influence.

Gbola Amusa: Looking back at the Acquiramidis trial, we are wondering whether there was any information in the readout last year that helped you decide on the changes you are making, and maybe looking forward, how do these changes that you are making help you position Ambutra compared to Eplon Dersin, which is read out next year and also has a well-powered trial? Thank you. Okay, if I understand you correctly, I'm trying to understand, you know, whether there's any information from the Akramadu study that influenced these changes, maybe Pushkar, if you can take that question. And then there was a second question around how these changes influenced our views on the commercial opportunity and Tolga, you know; it would be great if you would take that question. Christopher?

Speaker Change: Fees on the commercial opportunity and toga.

Speaker Change: It would be great. If you would take that question. So Frisco sure customers I think look I think what was.

Frisco: A couple of things that we took away from looking at the attribute data that we've talked about in the past I think first and foremost I think it's important to note that study as well as Apollo b for that matter enrolled patients in our contemporary era, where we know patients are being diagnosed earlier in their disease through noninvasive means as opposed to what was done in the original attract trial and what.

Yvonne L. Greenstreet: Okay. If I heard you correctly, Kostas, you're trying to understand whether there's any information from the ACORAMIDIS study that influenced these changes? Maybe, Pushkal, if you can take that question. And then there was a second question around how do these changes influence our views on the commercial opportunity. And Tolga, it would be great if you would take that question. So, Pushkal?

Frisco: It showed is that patients in those earlier stages of disease can continue through events.

Frisco: As a precipitous rate if theyre not treated and then an effective therapy can show a benefit on top of that second of all it also showed sort of.

Pushkal: Sure. Kostas, I think, look -- a couple of things that we took away from looking at the attribute data that we've talked about in the past. First and foremost, I think it's important to note that study -- as well as APOLLO-B, for that matter -- enrolled patients in a contemporary era where we know patients are being diagnosed earlier in their disease through non-invasive means, as opposed to what was done in the original TRACK trial. And what it showed is that patients in those earlier stages of disease can continue to go through events at a precipitous rate if they're not treated and then an effective therapy can show a benefit on top of that. Second of all, it also showed -- confirming what was seen in the original TRACK study that patients with earlier stage of disease, like NYHA Class I and II, appeared to have the largest magnitude of effect. And three, as we've seen in lots of different outcomes trials -- not just in this disease -- but the longer exposure leads to greater separation of curves. And so, all of those things were learnings that we learned and the patients on stabilizers continued to decline month by month, in terms of functional ability and quality of life, on average.

Pushkal Garg: Sure. Kostas, I think, look -- a couple of things that we took away from looking at the attribute data that we've talked about in the past. First and foremost, I think it's important to note that study -- as well as APOLLO-B, for that matter -- enrolled patients in a contemporary era where we know patients are being diagnosed earlier in their disease through non-invasive means, as opposed to what was done in the original TRACK trial. And what it showed is that patients in those earlier stages of disease can continue to go through events at a precipitous rate if they're not treated and then an effective therapy can show a benefit on top of that.

Frisco: Confirming what was seen in the original attract study that patients with earlier stages of disease like Nyj class, one and two appear to have the largest magnitude of effect right.

Frisco: And three as we've seen in lots of different outcomes trials not just in this disease, but but right.

Second of all, it also showed -- confirming what was seen in the original TRACK study that patients with earlier stage of disease, like NYHA Class I and II, appeared to have the largest magnitude of effect. And three, as we've seen in lots of different outcomes trials -- not just in this disease -- but the longer exposure leads to greater separation of curves. And so, all of those things were learnings that we learned and the patients on stabilizers continued to decline month by month, in terms of functional ability and quality of life, on average.

Frisco: The longer exposure leads to greater separation of curves right and so all of those things worth <unk>.

Frisco: <unk> that we learned in that patients with on stabilizers continue to decline.

Frisco: Month by month in terms of functional ability and quality of life and so on average and so I think.

Pushkal: I think all of those are aspects that we looked at, again, and sort of helped inform some of the choices we made. In particular, but most importantly, it was the APOLLO-B results as well. As we looked at them -- again, no head-to-head studies but we see a contrast in terms of the profile that's emerging here, these classes of medicines and the endpoints and refinements we made really to use the opportunity to extend the double-blind period so that we can increase study power, to optimize the study endpoints, the primary endpoint structure, to allow us to elevate the monotherapy and include secondary endpoints that can elaborate on some of those potential points of differentiation and disease stabilization that these other data sets seems to suggest. Thanks, Pushkal. Great answer. Tolga?

I think all of those are aspects that we looked at, again, and sort of helped inform some of the choices we made. In particular, but most importantly, it was the APOLLO-B results as well. As we looked at them -- again, no head-to-head studies but we see a contrast in terms of the profile that's emerging here, these classes of medicines and the endpoints and refinements we made really to use the opportunity to extend the double-blind period so that we can increase study power, to optimize the study endpoints, the primary endpoint structure, to allow us to elevate the monotherapy and include secondary endpoints that can elaborate on some of those potential points of differentiation and disease stabilization that these other data sets seems to suggest.

Frisco: All of those are aspects that we looked at again and sort of where and to help inform some of the choices. We made in particular, but most importantly, it was the Apollo <unk> results as well as we look at them again, no head to head studies, but we see a contrast in terms of the profile. That's emerging here of these classes of medicines and the <unk>.

Frisco: <unk> and refinements, we made really too.

Frisco: Use the opportunity to extend the double blind period. So that we can increase study power to optimize the study endpoints. The primary endpoint structure to allow us to elevate the monotherapy and includes secondary endpoints that can elaborate on some of those potential points of differentiation and disease stabilization that these other datasets seem to.

Yvonne L. Greenstreet: Thanks, Pushkal. Great answer. Tolga?

Tolga Tanguler: Yeah. I mean, as Pushkal indicated, these analytical enhancements obviously makes us very confident in HELIOS-B's ability to show added benefit on VUTRI on top of TAF, as well as demonstrating the value of VUTRISIRAN in a pure placebo. Now, HELIOS-B really empowers us to position AMVUTTRA in a very unique way, both in first-line utilization as well as on the switch with TAFAMIDIS until EPLONTERSEN comes into market. Couple of key, I think, attributes that we really need to highlight is the rapid knockdown and sustained knockdown of disease-causing protein is very unique to AMVUTTRA. Along with clear outcomes benefits in total population as well as in mono, halting the decline in functional capacity and quality of life, demonstrated years of safety -- which we have already established with our colonoscopy indication -- attractive sub-quarterly dosing and also, limited co-pay burden in patients. These are really going to be unique for AMVUTTRA, which we believe is going to position us a year before potentially even EPLON coming into the marketplace. Yeah, no, that's great.

Speaker Change: Suggests <unk> great job.

Speaker Change: Yes.

Speaker Change: <unk> indicated these analytical enhancements, obviously makes us very confident in giving us visibility to show added benefit on <unk> on top of tap as well as obviously demonstrating the value of which was thread and a pure placebo now Helios b.

Speaker Change: Really empowers us to position <unk> in a very unique way.

Speaker Change: Both in first line utilization.

Speaker Change: As well as on the switch with the Fabulous until <unk> comes to market.

Speaker Change: A couple of key attributes that we really need to highlight is the rapid knockdown and sustained knockdown of disease, causing protein is very unique to our.

Along with clear outcomes benefits in total population as well as in mono, halting the decline in functional capacity and quality of life, demonstrated years of safety -- which we have already established with our colonoscopy indication -- attractive sub-quarterly dosing and also, limited co-pay burden in patients. These are really going to be unique for AMVUTTRA, which we believe is going to position us a year before potentially even EPLON coming into the marketplace.

Yvonne L. Greenstreet: Along with clear outcomes benefits in the total population as well as in mono, halting the decline in functional capacity and quality of life, demonstrated years of safety, which we have already established with our colonoscopy indication, attractively sub-quarterly dosing, and also limited co-pay burden in patients, these are really going to be unique for Amutra, which we believe is going to position us a year before potentially even Eflon comes into the marketplace Yeah, no, that's great.

Speaker Change: Our mantra.

Speaker Change: <unk>.

Speaker Change: Along with clear outcomes benefit in total population as well as in mono halting the decline and functional capacity and quality of life.

Speaker Change: Demonstrated use of safety, which we have already established with <unk>.

Speaker Change: The key indication.

Speaker Change: Attractively sub quarterly dosing and also.

Limited copay burden in patients. These are really going to be unique for <unk>, which we believe is going to position us a year before.

Speaker Change: Essentially even epsilon coming into the marketplace.

Yeah. No, that's great. And just to add, this is in the context of a market that is growing really rapidly and a market where we know that patients who are on current treatments continue to progress. So, with the profile that Tolga's described, we think we're in a really good position to drive broad commercial uptake of AMVUTTRA. Obviously, assuming positive results from HELIOS-B and approval. And both are first line, as Tolga described, but also switch from stabilizers. We've shown how AMVUTTRA has led to a significant switch in the polyneuropathy market and we anticipate we'll see the same in cardiomyopathy as well, with positive data. So, I think the changes that we've made continue to support our confidence in the profile of AMVUTTRA and the potential that will be delivered in the cardiomyopathy market. Next question, please. Thank you.

Yvonne L. Greenstreet: Yeah. No, that's great. And just to add, this is in the context of a market that is growing really rapidly and a market where we know that patients who are on current treatments continue to progress. So, with the profile that Tolga's described, we think we're in a really good position to drive broad commercial uptake of AMVUTTRA. Obviously, assuming positive results from HELIOS-B and approval.

Operator: And just to add, this is in the context of a market that is growing really rapidly and a market where we know that patients who are on current treatments continue to progress. So with the profile that Tolga's described, we think we're in a really good position to drive broad commercial uptake of Amutra, obviously assuming positive results from HDSV and approval. And, you know, both in the first line, as Tolga described, but also switch from stabilizers.

Speaker Change: That's great and just to add this is in the context of <unk>.

Speaker Change: Market that is growing really rapidly and our market WAF.

Speaker Change: We know that.

Speaker Change: Patients who are on current.

Speaker Change: <unk> continued to progress so with a profile that <unk> described we think we're in a really good position to drive in a broad commercial uptake.

Speaker Change: And which obviously assuming positive results from <unk>.

Speaker Change: <unk>.

Speaker Change: An approval and.

Speaker Change: Both in first line as focus described but also switched from stabilized as we've shown.

And both are first line, as Tolga described, but also switch from stabilizers. We've shown how AMVUTTRA has led to a significant switch in the polyneuropathy market and we anticipate we'll see the same in cardiomyopathy as well, with positive data. So, I think the changes that we've made continue to support our confidence in the profile of AMVUTTRA and the potential that will be delivered in the cardiomyopathy market. Next question, please.

David N. Lebowitz: We've shown, you know, how Amutra has led to a significant switch in the polyneuropathy market, and we anticipate we'll see the same in cardiomyopathy as well, with positive data. So, I think the changes that we've made, I think, continue to support our confidence in the profile of, you know, Ambuter and, you know, the potential that will be delivered in cardiomyopathy. Next question, please. Thank you.

Speaker Change: How.

Speaker Change: <unk> has led to a significant switch in the Polyneuropathy.

Speaker Change: Markets in <unk>.

Speaker Change: We anticipate we'll see the same in cardiomyopathy as well with positive data.

Speaker Change: So I think.

Speaker Change: The changes that we've made I think continue to support our confidence in the profile.

Speaker Change: In our <unk> and.

Speaker Change: The potential.

Speaker Change: That will be delivered in the cardiomyopathy market.

Speaker Change: Next question.

Thank you. One moment for our next question, and our next question comes from the line of David Lebowitz from Citi. Thank you very much for taking my question. In terms of the primary readout, I know historically you've released P values as part of the update, will you be sticking to that plan, or are there additional data points you might be able to offer in the top line to allow for some level of differentiation between Ambutra and the other therapies and just kind of attached to that? When you look, since you're targeting really the front line here with your new analysis plan, what do you actually need in your mind to In the study, to be able to unseat the famine is on the front line.

Operator: Thank you. One moment for our next question. And our next question comes from the line of David Lebowitz from Citi.

Yvonne L. Greenstreet: One moment for our next question, and our next question comes from the line of David Lebowitz from Citi. Thank you very much for taking my question. In terms of the primary readout, I know historically you've released P values as part of the update, will you be sticking to that plan, or are there additional data points you might be able to offer in the top line to allow for some level of differentiation between Ambutra and the other therapies and just kind of attached to that? When you look, since you're targeting really the front line here with your new analysis plan, what do you actually need in your mind to In the study, to be able to unseat the famine is on the front line.

Speaker Change: Thank you one moment far next question.

Speaker Change: Yes.

David N. Lebowitz: Thank you very much for taking my question. In terms of the primary readout, I know, historically, you've released p-values as part of the update -- will you be sticking to that plan or is there additional data points you might be able to offer in the top-line to allow for some level of differentiation between AMVUTTRA and the other therapies? And just kind of attached to that, when you look to see -- you're targeting, really, the front line here with your new analysis plan, what do you actually need, in your mind, to achieve in the study to be able to unseat TAFAMIDIS in the front line? I mean, given that the trials are quite different and it's not necessarily going to be easy to compare on a head-to-head basis. Thank you.

Speaker Change: Our next question comes from the line of David Lebowitz from Citi.

David N. Lebowitz: Thank you very much for taking my question in terms of the primary readout.

David N. Lebowitz: I know historically you've.

David N. Lebowitz: Released P values as part of the update.

David N. Lebowitz: Will you be sticking to that plan or is there additional data points you might be able to offer in the topline to allow for some level of differentiation between.

David N. Lebowitz: And <unk> and the other therapies and just.

Kind of attached to that.

David N. Lebowitz: When you look since youre targeting really the frontline here with your new analysis plan, what do you actually need in your mind to achieve.

In this study to be able to unseat to families in the frontline I mean, given that the trials are quite different and it's not necessarily going to be able to be easy to compare on a head to head basis. Thank you.

Tolga: I mean, given that the trials are quite different and it's not necessarily going to be easy to compare on a head-to-head basis. Thank you. Yeah, so just briefly, first question: we'll do what we normally do, and we'll share, you know, key values on the primary endpoints and key secondary endpoints, as well as some qualitative assessments of safety. We will also present information on subgroups, such as the dramatist subgroups.

I mean, given that the trials are quite different and it's not necessarily going to be easy to compare on a head-to-head basis. Thank you.

Yeah. So just briefly, first question, we'll do what we normally do and we'll share p-values on the primary endpoints and key secondary endpoints, as well as some qualitative assessments on safety. We will also present information on subgroups, such as the TAFAMIDIS subgroup. So, I hope that answers that question for you. Tolga, if you could just very briefly respond to David's commercial question. Right. Look, we have extensive research that suggests physicians believe 75% of their patients on a stabilizer continue to progress or experience inadequate treatment, which indicates to us that there's a significant remaining unmet need and a sizable potential to switch to onboard drugs. And particularly prior to the Tefamidis LOE, when payers are already implementing restrictions on combo use, and as Yvonne indicated, we actually already had that great experience starting with Ompatra first, and now with Almutra in ex-US markets, where we actually did compete with great data. Great

Yvonne L. Greenstreet: Yeah. So just briefly, first question, we'll do what we normally do and we'll share p-values on the primary endpoints and key secondary endpoints, as well as some qualitative assessments on safety. We will also present information on subgroups, such as the TAFAMIDIS subgroup. So, I hope that answers that question for you. Tolga, if you could just very briefly respond to David's commercial question.

Speaker Change: Yes, just briefly first question.

Speaker Change: Well, we'll we'll do what we normally do in SaaS.

Speaker Change: In a P values on the primary endpoints and key secondary endpoints as well as some qualitative assessment on safety. We will also present information on our.

Jessica Fye: I hope that answers that question for you, Tolga. If you could just very briefly respond to David's commercial question, Right, look, we have extensive research that suggests physicians believe 75% of their patients on a stabilizer continue to progress or experience inadequate treatment, which indicates to us that there's a significant remaining unmet need and a sizable potential to switch to onboard drugs. And particularly prior to the Tefamidis LOE, when payers are already implementing restrictions on combo use, and as Yvonne indicated, we actually already had that great experience starting with Ompatra first, and now with Almutra in ex-US markets, where we actually did compete with great data. Great

Speaker Change: Subgroups statistical parameters subgroups I hope that answers that question for you.

Speaker Change: If you could just be just very briefly this fall.

Right. Look, we have extensive research that suggests physicians believe 75% of their patients on a stabilizer continue to progress or experience inadequate treatment, which indicates to us that there's a significant remaining unmet need and a sizable potential to switch to AMVUTTRA. And, particularly, prior to the TAFAMIDIS LOE, when payers are implementing already restrictions on combo use. And as Yvonne indicated, we have actually already that great experience starting with ONPATTRO first and now with AMVUTTRA in ex-US markets, where we actually [inaudible] with great data. Great.

Tolga Tanguler: Right. Look, we have extensive research that suggests physicians believe 75% of their patients on a stabilizer continue to progress or experience inadequate treatment, which indicates to us that there's a significant remaining unmet need and a sizable potential to switch to AMVUTTRA. And, particularly, prior to the TAFAMIDIS LOE, when payers are implementing already restrictions on combo use. And as Yvonne indicated, we have actually already that great experience starting with ONPATTRO first and now with AMVUTTRA in ex-US markets, where we actually [inaudible] with great data.

Speaker Change: Crush a question right. We have extensive research that says it suggests physicians believe 75% of their patients on a stabilizer continued to progress.

Speaker Change: Our experience inadequate treatment, which indicates to us that there is a significant remaining unmet need and a sizable potential to switched on with truck.

Speaker Change: And particularly.

Speaker Change: Prior to the Fabulous Louie when the payers are implementing already restrictions on combo use and as <unk> indicated we have actually already that great experience, starting with <unk> and now with <unk> in ex U S markets, where we exited opiates.

Speaker Change: With the great data Great next question. Please.

Yvonne L. Greenstreet: Great. Next question, please.

Pushkal: Next question, please. Thank you. One moment for our next question. Our next question comes from the line of Jessica Fye from J.P. Morgan. Hey, good morning.

Next question, please.

Thank you. One moment for our next question. Our next question comes from the line of Jessica Fye from J.P. Morgan. Hey, good morning.

Operator: Thank you. One moment for our next question. Our next question comes from the line of Jessica Fye from J.P. Morgan.

Speaker Change: Thank you one moment far next question.

Speaker Change: Our next question comes from the line of Jessica Fye from Jpmorgan.

Hey, good morning. Thanks for taking my question. Another one on Helios B. Recognizing that the comparison is going to be versus placebo, what do you want to see in terms of how the event rate in the monotherapy Ambutra patients looks relative to the monotherapy to thamudus. Yeah, Jessica, thanks for the question.

Jessica Fye: Hey, good morning. Thanks for taking my question. Another one on HELIOS-B, recognizing that the comparison is going to be versus placebo, what do you want to see in terms of how the event rate in the monotherapy AMVUTTRA patients looks relative to the monotherapy TAFAMIDIS patients?

Jessica Fye: Thanks for taking my question. Another one on Helios B. Recognizing that the comparison is going to be versus placebo, what do you want to see in terms of how the event rate in the monotherapy Ambutra patients looks relative to the monotherapy to thamudus. Yeah, Jessica, thanks for the question.

Jessica Fye: Hey, good morning, Thanks for taking my question another one on Helios B and.

Jessica Fye: Recognizing that the comparison is going to be versus placebo. What do you want to see in terms of how the event rate in the mono therapy and future patients.

Jessica Fye: Relative to the mono therapy to <unk> patients.

Yeah. Jessica, thanks for the question. Look, I think it's important to note that this was not a head-to-head study, looking at AMVUTTRA versus TAFAMIDIS. This is a study looking at AMVUTTRA or VUTRISIRAN versus placebo, where a proportion of the patients -- 40% -- are on background TAFAMIDIS. And so really, the comparisons are VUTRI to placebo in those two situations and, as we've said, the primary analysis we'll be looking at this in the two populations, the blended population overall as well as the monotherapy population. Thanks for your question, Jessica. Next question. Thank you.

Pushkal Garg: Yeah. Jessica, thanks for the question. Look, I think it's important to note that this was not a head-to-head study, looking at AMVUTTRA versus TAFAMIDIS. This is a study looking at AMVUTTRA or VUTRISIRAN versus placebo, where a proportion of the patients -- 40% -- are on background TAFAMIDIS. And so really, the comparisons are VUTRI to placebo in those two situations and, as we've said, the primary analysis we'll be looking at this in the two populations, the blended population overall as well as the monotherapy population.

Speaker Change: Yes, Jessica.

Luca Isi: Look, I think it's important to note that this was not a head-to-head study looking at ambutra versus tefamidus. This is a study looking at ambutra or butrecerin versus placebo, where a proportion of the patients, 40%, are on a background tefamidus. And so really, the comparisons are butre to placebo in those two situations. And as we've said, the primary analysis will be looking at this in the two populations, the blended population overall, as well as the monotherapy population. Thanks for your question, Jessica. Next question. Thank you.

Jessica Fye: Thanks for the question look.

Jessica Fye: I think it's important to note. This was not a head to head study looking at <unk> versus <unk>. This is a study looking at <unk> or <unk>.

Jessica Fye: <unk> versus placebo, where a proportion of the patients 40% are on backlog.

Jessica Fye: Our background to parameters and so really the comparisons are a gucci to placebo in those two situations and as we've said the primary analysis will be looking at this in the two populations the blended population of overall as well as the monotherapy population.

Thanks for your question, Jessica. Next question. Thank you.

Yvonne L. Greenstreet: Thanks for your question, Jessica. Next question.

Speaker Change: Thanks for your question Jessica next question.

Operator: Thank you. One moment for our next question. Our next question comes from the line of Luca Issi from RBC Capital.

Pushkal: One moment for our next question. Our next question comes from the line of Luca Isi from RBC Capital. Oh great, thanks so much for... Yeah, yeah, thank you so much for taking my question. Steve Pushkal, actually, if I may, circling back on a prior question, maybe ask a little more directly.

One moment for our next question. Our next question comes from the line of Luca Isi from RBC Capital.

Speaker Change: One moment for our next question.

Speaker Change: Our next question comes from the line of Luca <unk> from RBC capital.

Luca Issi: Oh great, thanks so much for [inaudible]. Thank you so much for taking my question. [inaudible] Pushkal actually, if I may, circling back on a prior question, maybe ask a little more directly. Is this informed by blinded event rates tracking below your expectation? And then, maybe separately, is this considered a formal protocol amendment? And if so, will you incur any statistical penalties for changing the trial so late in the game? Any call there is much appreciated. Thanks so much.

Luca: Oh, great. Thanks, so much.

Luca: Yes, yes. Thank you so much for taking my question.

So actually if I may circling back on a prior question maybe ask it a little more directly.

Luca Isi: Is this informed by blinded event rates tracking below your expectation? And then, maybe separately, is this considered a formal protocol amendment? And if so, will you incur any statistical penalties for changing the trial so late in the game? Any call there would be much appreciated. Thanks so much.

Luca: For by blinded event trades tracking below your expectation.

Luca: And then maybe separately is this considered a formal protocol amendment and if so will you incur any statistical penalties for changing the trial. So late in the game and you call very much appreciate it. Thanks so much.

Pushkal: Yeah. Luca, let me take your second point first. There's no change to the operational conduct of the study. This is just a change in the statistical analysis plan and we outlined in the slides, really, how the statistics around the primary endpoint are going to be analyzed. So, there's no statistical penalty for that at all. It's just a change to the analytic plan that we've talked about. So, no, not at all. And with regards to the first question, trying to highlight -- the changes are really driven by what we've seen with APOLLO-B over two plus years. And the patterns that we're seeing there and our heightened confidence in terms of the impact of this class of medicines on this disease and what we can do to further optimize the study and set it up well for a strong and competitive label. Of course we have, as we've said before, teams that are looking at the blinded data. Primarily, to ensure excellent study conduct and execution, make sure the right patients are enrolled, make sure that the data are clean, make sure that we've got complete capture of all the events, et cetera. And, of course, they're looking at event rates, et cetera. But we're not going to be sharing dribs and drabs of the data and that's not the driver here. Those types of events rates are extremely variable, it's subject to a lot of variability and interpretation. If I told you we had a very high event rate, you might say, 'well, that's because -- that's great. The placebo event patients are accruing events'. Or you might say, 'wow, the drug's not working'. Or conversely, if we have a low event rate, that might indicate that, oh, you know, we haven't enrolled the right patients or maybe the drug's working remarkably well. So, the primary drivers here are what we understand about science, biology and prior precedent from clinical medicine and clinical trials. And that's the driver.

Pushkal Garg: Yeah. Luca, let me take your second point first. There's no change to the operational conduct of the study. This is just a change in the statistical analysis plan and we outlined in the slides, really, how the statistics around the primary endpoint are going to be analyzed. So, there's no statistical penalty for that at all. It's just a change to the analytic plan that we've talked about. So, no, not at all. And with regards to the first question, trying to highlight -- the changes are really driven by what we've seen with APOLLO-B over two plus years. And the patterns that we're seeing there and our heightened confidence in terms of the impact of this class of medicines on this disease and what we can do to further optimize the study and set it up well for a strong and competitive label.

Speaker Change: Yes, Luca let me let me take your second 0.1st there is no change to the operational conduct those data. This is just a change in the statistical analysis plan and we outlined in the slides really how the statistics around the primary endpoint are going to be analyzed so theres no statistical penalty for that at all it's just a change to the.

Pushkal: It's just a change to the analysis plan that we've talked about. So, no, not at all. And with regard to the first question, I think it's trying to highlight the changes are really driven by what we've seen with Apollo B over two plus years and the patterns that we're seeing there and our heightened confidence in terms of the impact of this class of medicines on this disease and what we can do to further optimize the study and set it up well for a strong and competitive label. Of course, we have, as we've said before, teams that are Make sure that the right patients are enrolled. Also, make sure that the data are clean.

Luca: Analytic plan that we've talked about so no not at all and with regard to the first question I think has tried to highlight the.

And with regards to the first question, trying to highlight -- the changes are really driven by what we've seen with APOLLO-B over two plus years. And the patterns that we're seeing there and our heightened confidence in terms of the impact of this class of medicines on this disease and what we can do to further optimize the study and set it up well for a strong and competitive label. Of course we have, as we've said before, teams that are looking at the blinded data. Primarily, to ensure excellent study conduct and execution, make sure the right patients are enrolled, make sure that the data are clean, make sure that we've got complete capture of all the events, et cetera. And, of course, they're looking at event rates, et cetera. But we're not going to be sharing dribs and drabs of the data and that's not the driver here. Those types of events rates are extremely variable, it's subject to a lot of variability and interpretation. If I told you we had a very high event rate, you might say, 'well, that's because -- that's great. The placebo event patients are accruing events'. Or you might say, 'wow, the drug's not working'. Or conversely, if we have a low event rate, that might indicate that, oh, you know, we haven't enrolled the right patients or maybe the drug's working remarkably well. So, the primary drivers here are what we understand about science, biology and prior precedent from clinical medicine and clinical trials. And that's the driver.

Luca: The changes are really driven by what we've seen with Apollo b over two plus years and the patterns that we're seeing there and our heightened confidence in terms of the impact of this class of medicines on this disease and what we can do.

Of course we have, as we've said before, teams that are looking at the blinded data. Primarily, to ensure excellent study conduct and execution, make sure the right patients are enrolled, make sure that the data are clean, make sure that we've got complete capture of all the events, et cetera. And, of course, they're looking at event rates, et cetera. But we're not going to be sharing dribs and drabs of the data and that's not the driver here. Those types of events rates are extremely variable, it's subject to a lot of variability and interpretation. If I told you we had a very high event rate, you might say, 'well, that's because -- that's great. The placebo event patients are accruing events'. Or you might say, 'wow, the drug's not working'. Or conversely, if we have a low event rate, that might indicate that, oh, you know, we haven't enrolled the right patients or maybe the drug's working remarkably well. So, the primary drivers here are what we understand about science, biology and prior precedent from clinical medicine and clinical trials. And that's the driver.

Luca: To further optimize the study.

Luca: Set it up well for a strong and competitive label of course, we have as we've said before have teams that are looking at.

Luca: The blinded data primarily to ensure excellent study conduct and execution make sure. The right patients are enrolled make sure that the data are clean make sure that we've got complete capture of all the events et cetera and of course, they are looking at event rates et cetera, but we're not going be sharing dribs and drabs, the data and thats not the driver here.

Pushkal: Make sure that we've got complete capture of all the events, etc. And, of course, they're looking at event rates, etc. But we're not going to be sharing dribs and drabs of the data, and that's not the driver here.

Pushkal: You know, those types of events rates are extremely variable. It's subject to a lot of variability and interpretation. If I told you we had a very high event rate, you might say, well, that's because that's great. The placebo event patients are accruing events. Or you might say, wow, the drug's not working.

Luca: Those types of events rates are extremely variable are subject to a lot of variability in interpretation. If I told you. We had a very high event rate you might say well thats because thats great. The placebo patients are accruing events or you might say, while the drug is not working or Conversely, if we have a low event rate that might indicate that.

If I told you we had a very high event rate, you might say, 'well, that's because -- that's great. The placebo event patients are accruing events'. Or you might say, 'wow, the drug's not working'. Or conversely, if we have a low event rate, that might indicate that, oh, you know, we haven't enrolled the right patients or maybe the drug's working remarkably well. So, the primary drivers here are what we understand about science, biology and prior precedent from clinical medicine and clinical trials. And that's the driver.

Pushkal: Or conversely, if we have a low event rate, that might indicate that, oh, you know, we haven't enrolled the right patients or maybe the drug's working remarkably well. So the primary drivers here are what we understand about science, biology, and prior precedent from clinical medicine and clinical trials. And that's the driver.

Luca: We don't we haven't enrolled the right patients or maybe the drug's working remarkably well. So the primary drivers here are what we understand about science biology, and prior precedent from from clinical medicine, and clinical trials and Thats. The driver. Okay. Let me just add protocol.

Akshay K. Vaishnaw: Let me just add, Pushkal. I think we all got to stand back a little bit, it's obviously in our line of interest -- for patients and for everybody concerned -- to show definitive outcomes for VUTRISIRAN. If there had been mass panic at Alnylam that the study design was wrong or too small or too short, there are many changes we could have made and we could have made them well in advance. We have reiterated our confidence over and over again in the study, [inaudible] I've outlined today -- deep insights from APOLLO-B, understanding the landscape. And what you see today is a three-month extension for the last patient. giving a reasonable amount of additional data, just further enhance the robustness of what we're going to share with the world come June and July. So, I think it's well worth it. It reiterates our confidence in this study and we haven't fundamentally changed the design to a 1,500 or 2,000 patient study for five years. If we were panicked, you would have seen those things some time ago. Others have done what they've done, you've seen what we've done. And on the backdrop of the scientific edifice we've built with the TTR mechanism in APOLLO, in APOLLO-B, I think we should have the confidence. Thanks, Akshay. Great. Next question. Thank you. One moment for our next question. Our next question comes from the line of Salveen Richter from Goldman Sachs. Good afternoon.

Let me just add, Pushkal. I think we all got to stand back a little bit, it's obviously in our line of interest -- for patients and for everybody concerned -- to show definitive outcomes for VUTRISIRAN. If there had been mass panic at Alnylam that the study design was wrong or too small or too short, there are many changes we could have made and we could have made them well in advance. We have reiterated our confidence over and over again in the study, [inaudible] I've outlined today -- deep insights from APOLLO-B, understanding the landscape. And what you see today is a three-month extension for the last patient. giving a reasonable amount of additional data, just further enhance the robustness of what we're going to share with the world come June and July. So, I think it's well worth it. It reiterates our confidence in this study and we haven't fundamentally changed the design to a 1,500 or 2,000 patient study for five years. If we were panicked, you would have seen those things some time ago. Others have done what they've done, you've seen what we've done. And on the backdrop of the scientific edifice we've built with the TTR mechanism in APOLLO, in APOLLO-B, I think we should have the confidence. Thanks, Akshay.

Luca: We won't go to spend back a little bit it's obviously in our dialogues interests for patients and for everybody concerned to show definitive outcome for <unk>.

Luca: <unk> had been mass panic at all now that the study design is wrong too small too short there are many changes we could have made and we could've made them well in advance we have reiterated our confidence over and over again in this study.

Luca: I have outlined today deep insights from Apollo B.

Luca: Understanding the landscape and what you see today is a three month extension for the last patient, giving a reasonable amount of additional data just further enhance the robustness of what we're going to share with the world come June July So I think it's well worth it it reiterates our confidence in this study and we haven't fundamental.

And what you see today is a three-month extension for the last patient. giving a reasonable amount of additional data, just further enhance the robustness of what we're going to share with the world come June and July. So, I think it's well worth it. It reiterates our confidence in this study and we haven't fundamentally changed the design to a 1,500 or 2,000 patient study for five years. If we were panicked, you would have seen those things some time ago. Others have done what they've done, you've seen what we've done. And on the backdrop of the scientific edifice we've built with the TTR mechanism in APOLLO, in APOLLO-B, I think we should have the confidence.

Luca: We changed that design to a 1500 or 2000 patient study for five years.

Luca: If we were panicked you would've seen those things sometime ago, others have done what they've done you've seen what we've done and on the backdrop of the scientific edifice, we've built with the <unk> mechanism and Apollo and Apollo B I think we should have the confidence.

Akshay K. Vaishnaw: And on the backdrop of the scientific edifice we've built with the TTR mechanism in Apollo, in Apollo B, I think we should have confidence. Thanks, Akshay. Great. Next question. Thank you. One moment for our next question. Our next question comes from the line of Salveen Richter from Goldman Sachs. Good afternoon.

Speaker Change: Thanks Akshay.

Speaker Change: Great next question.

Speaker Change: Thank you <unk>.

Yvonne L. Greenstreet: Thanks, Akshay. Great. Next question.

Great. Next question. Thank you. One moment for our next question. Our next question comes from the line of Salveen Richter from Goldman Sachs. Good afternoon.

Great. Next question.

Speaker Change: One moment for our next question.

Thank you. One moment for our next question. Our next question comes from the line of Salveen Richter from Goldman Sachs. Good afternoon.

Operator: Thank you. One moment for our next question. Our next question comes from the line of Salveen Richter from Goldman Sachs.

Our next question comes from the line of Salvia Richter from Goldman Sachs.

Good afternoon, thanks for taking my question. How much of a differential does extending the duration by three months provide instead of conducting the primary analysis at 36 months for all patients? I'm asking this in the context of recently announced studies in the field that have flexible duration of up to 48 months or based on events. So, just any clarity there. And secondly, does the monotherapy analysis heighten the need to show significance on all-cause mortality alone, just given tasks on label benefit for front-line use? Oscar, are you good to take this?

Salveen Richter: Good afternoon, thanks for taking my question. How much of a differential does extending the duration by three months provide instead of conducting the primary analysis at 36 months for all patients? I'm asking this in the context of recently announced studies in the field that have flexible duration of up to 48 months or based on events. So, just any clarity there. And secondly, does the monotherapy analysis heighten the need to show significance on all-cause mortality alone, just given tasks on label benefit for front-line use?

Salveen Richter: Thanks for taking my question. How much of a differential does extending the duration by three months provide instead of conducting the primary analysis at 36 months for all patients? I'm asking this in the context of recently announced studies in the field that have flexible duration up to 48 months or based on events, so just any clarity there. Secondly, does the monotherapy analysis heighten the need to show significance on all-cause mortality alone, just given tasks on label benefit for front-line use? Oscar, are you good to take this?

Salvia Richter: Good afternoon, Thanks for taking my question.

Salvia Richter: How much of a differentiator differentiable says extending the duration by three months provide instead of conducting the primary analysis at 36 months for all patients.

Salvia Richter: Asking this in the context of recently announced studies in the field that our second quarter and up to 48 months.

Salvia Richter: Or based on events. So just any clarity there and then secondly does the mono therapy analysis heightened the need to show significance on all cause mortality alone just given tasks on label benefits for frontline use.

Pushkal, are you good to take this? Yeah, absolutely. So, Salveen, look, I think what we've done here is we think meaningfully add to the duration of the study or the experience in the study at the tail end. And what we've done is actually for patients who are on the back of the study, which is where the most, you know, the greatest events accrue in the placebo arm and where you see the curves diverge, we've added exposure. It turns out that 60% of patients will actually have additional exposure in the study, and about a third of those 20% more will actually complete all the way out to 36 months, which is when patients roll over into open-label And so we really and we think that that critical addition, frankly, is a no brainer for us. And it's an important way to further add to study power.

Yvonne L. Greenstreet: Pushkal, are you good to take this?

Pushkal Garg: Yeah, absolutely. So Salveen, look, I think what we've done here is meaningfully add to the duration of the study or the experience in the study in the tailend. And what we've done is actually for patients who are on the back of the study, which is where the most -- the greatest events accrue in the placebo arm and where you see the curves diverge, we've added exposure. It turns out that 60% of patients will actually have additional exposure in the study and about a third of those, 20% more, will actually complete all the way up to 36 months -- which is when patients roll over into open-label extension. And so, we really -- and we think that that critical addition, frankly, becomes a no-brainer for us. And it's an important way to further add to study power. So, that's why that was done. And again, based on all the trends we've seen in APOLLO-B, which where we started to see separation as we've highlighted much, much earlier, we think this is a great enhancement that we were able to institute in the study.

Pushkal: Yeah, absolutely. So, Salveen, look, I think what we've done here is we think meaningfully add to the duration of the study or the experience in the study at the tail end. And what we've done is actually for patients who are on the back of the study, which is where the most, you know, the greatest events accrue in the placebo arm and where you see the curves diverge, we've added exposure. It turns out that 60% of patients will actually have additional exposure in the study, and about a third of those 20% more will actually complete all the way out to 36 months, which is when patients roll over into open-label And so we really and we think that that critical addition, frankly, is a no brainer for us. And it's an important way to further add to study power.

Salvia Richter: Scott.

Scott: Yes, absolutely. So <unk> look I think what we've done here is we think meaningfully add.

Scott: To the duration of the study or the experience in the study and the tail end and what we've done is actually for patients who are on the back of the steady which is where the.

Scott: Greatest events accrue in the placebo arm and where you see the curse diverged. We've added exposure it turns out that 60% of patients will actually have additional exposure in the study.

Scott: About a third of those 20% more will actually complete all the way up to 36 months, which is when patients rollover into open label extension and so we really and we think that that critical edition frankly becomes a no brainer for us and it's an important way to further add to study power and so that's why that was done.

And so, we really -- and we think that that critical addition, frankly, becomes a no-brainer for us. And it's an important way to further add to study power. So, that's why that was done. And again, based on all the trends we've seen in APOLLO-B, which where we started to see separation as we've highlighted much, much earlier, we think this is a great enhancement that we were able to institute in the study.

Pushkal: So, that's why that was done. And again, based on all the trends we've seen in APOLLO-B, which where we started to see separation as we've highlighted much, much earlier, we think this is a great enhancement that we were able to institute in the study. With regard to your question around monotherapy and all-cause mortality, look, I think it's really important to just remember that in cardiovascular disease, we have about 40 or 50 years of doing outcome studies. And they typically focus on Mase-type endpoints, which include death and hospitalization. And the reason that that's been the focus and accepted by regulators and by the clinical community is because, in general, those events all go hand in hand. Hospitalization events predict mortality better than doing mortality alone. Studies typically tend to be inefficient. They're too large and too long.

So, that's why that was done. And again, based on all the trends we've seen in APOLLO-B, which where we started to see separation as we've highlighted much, much earlier, we think this is a great enhancement that we were able to institute in the study.

Scott: And again based on the trends, we've seen in Apollo B, which where we started to see separation as we've highlighted much much earlier.

Scott: We think this is a great enhancement that we were able to institute in the study with regard to your question around monotherapy and all cause mortality look I think it's really important to just remember that in cardiovascular disease. We have about 40 or 50 years of doing outcome studies and they typically focus on mace type of endpoints.

With regard to your question around monotherapy and all-cause mortality -- look, I think it's really important to just remember that in cardiovascular disease, we have about 40 or 50 years of doing outcome studies. And they typically focus on MACE-type of endpoints, which include death and hospitalization. And the reason that that's been the focus and accepted by regulators and by the clinical community is because, in general, those events all go hand-in-hand. Hospitalization events predict mortality and doing mortality alone studies typically tend to be inefficient. They're too large and too long and we need to get therapy to patients. So, we've designed a study that is focused on death and hospitalization and we expect to show a positive result in that study. As well as, we will of course, have the breakdown of events under those two and we expect them on a consistent manner, which is what you would expect to see based on the biology and precedent in almost every other cardiovascular outcomes trial that's been done. Next question. Thank you. One moment for our next question. Our next question comes from the line of Gena Wang from Barclays. Thank you for taking my questions. I have two very quick questions.

Scott: Which include death, and hospitalization and the reason that that's been the focus and accepted by regulators and by the clinical community is because in general those events. All go hand in hand, hospitalization events predict mortality and doing mortality alone studies typically are tend to be inefficient. They are too large and too.

Pushkal: And we need to get treatments to patients. So we've designed a study that is focused on death and hospitalization, and we expect to show a positive result in that study, as well as the breakdown of events under those two, and we expect them to go in a consistent manner, which is what you would expect to see based on the biology and precedent in almost every other cardiovascular outcomes trial that's been done. Next question. Thank you. One moment for our next question. Our next question comes from the line of Gena Wang from Barclays. Thank you for taking my questions. I have two very quick questions.

Scott: Long and we need to get the therapy to patients. So we've designed a study that is.

So, we've designed a study that is focused on death and hospitalization and we expect to show a positive result in that study. As well as, we will of course, have the breakdown of events under those two and we expect them on a consistent manner, which is what you would expect to see based on the biology and precedent in almost every other cardiovascular outcomes trial that's been done.

Scott: Focused on death and hospitalization.

Scott: And we expect to show a positive result in that study as well as we will of course have the breakdown of events under those two and we expect them to come on a consistent manner, which is what you would expect to see based on the biology and precedent in almost every other cardiovascular outcomes trial that's been done.

Scott: Yeah.

Speaker Change: Next question.

Speaker Change: Thank you one moment far next question.

Next question. Thank you. One moment for our next question. Our next question comes from the line of Gena Wang from Barclays. Thank you for taking my questions. I have two very quick questions.

Yvonne L. Greenstreet: Next question.

Thank you. One moment for our next question. Our next question comes from the line of Gena Wang from Barclays. Thank you for taking my questions. I have two very quick questions.

Operator: Thank you. One moment for our next question. Our next question comes from the line of Gena Wang from Barclays.

Speaker Change: Our next question comes from the line of Gena Wang from Barclays.

Gena Wang: Thank you for taking my questions. I have two very quick questions. One is for the 60%, the monotherapy subgroup. For your stats analysis or assumption, do you assume most of the TAFAMIDIS droppings will be in the placebo arm? And my second question, just want to double check my math is correct and that's based on slide 17, you said 60% of patients remaining on study will have a greater follow-up and 20% more patients will have follow-up to full 36 months. So, my calculation will be 40% plus 20%, that equals 60% of the patients that will reach full 36 months. Just want to make sure that my math is correct.

Gena Wang: Thank you for taking my questions I have two very quick questions. One is that for the 60% mono therapy subgroup.

Gena Wang: One is for the 60%, the monotherapy subgroup. For your stats analysis or assumption, do you assume most of the typhatomous droppings will be in the placebo arm? And my second question, just want to double check my math is correct, and that's based on slide 17.

Gena Wang: For your stats analysis.

Do you assume most of that to Fathomless droppings would be in the placebo arm and my second question just wanted to double check My math is correct and Thats based on Slide 17, you said, 60% of the patients remaining on study we will have a greater follow up 20% more patients will have follow up to 430.

Pushkal: You said 60% of patients remaining on study will have a greater follow-up, and 20% more patients will have follow-up to full 36 months. So my calculation will be 40% plus 20%, that equals 60% of the patients that will reach full 36 months. Just want to make sure that my math is correct.

Gena Wang: Six months, so my calculation will be 40% plus 20% that equals <unk>.

Gena Wang: <unk> prefer.

Gena Wang: The patient that will reach 436 months just wanted to make sure.

Gena Wang: My math is correct.

Pushkal: Yeah. So Gena, in terms of your questions, as we've said, our cap drop in rates are lower than we expected when we designed the study. So, we're very encouraged by that. That represents another tailwind that supports the success and the powering of the study. I can't get into any more specifics other than that but to tell you that we're encouraged by those data. In terms of the additional follow-up, maybe what I can clarify is, those are changes relative to what the study looked like when it was a 30 to 36 month follow-up study. And so, what we're saying is -- and, of course, what we're focusing on are patients who remain on study. Throughout the study, we've had patients, for example, who have passed away because of their disease, et cetera. And so what we're saying is that, in the patients who remain in the study, approximately 60% of them will have some extension of their follow-up in the study. And roughly a third of those, or 20% additional, would get to the full 36 months. So, I hope that clarifies. Great.

Yeah. So Gena, in terms of your questions, as we've said, our cap drop in rates are lower than we expected when we designed the study. We're very encouraged by that, that represents another tailwind that supports the success and the powering of the study. I can't get into any more specifics other than that but to tell you that we're encouraged by those data. In terms of the additional follow-up, maybe what I can clarify is, those are changes relative to what the study looked like when it was a 30 to 36-month follow-up study. And so, what we're saying is -- and, of course, what we're focusing on are patients who remain on study. Throughout the study, we've had patients, for example, who have passed away because of their disease, et cetera. And so what we're saying is that, in the patients who remain in the study, approximately 60% of them will have some extension of their follow-up in the study. And roughly a third of those, or 20% additional, would get to the full 36 months. So, I hope that clarifies.

Pushkal Garg: Yeah. So Gena, in terms of your questions, as we've said, our cap drop in rates are lower than we expected when we designed the study. We're very encouraged by that, that represents another tailwind that supports the success and the powering of the study. I can't get into any more specifics other than that but to tell you that we're encouraged by those data. In terms of the additional follow-up, maybe what I can clarify is, those are changes relative to what the study looked like when it was a 30 to 36-month follow-up study.

Speaker Change: Yeah. So in terms of your questions.

Speaker Change: The.

Speaker Change: As we've said our tap drop in rates are lower than we expected obviously when we designed the study. So we're very encouraged by that that represents another tailwind that supports the success and the powering of the study.

Speaker Change: And.

Speaker Change: And so I can't get into any more specifics other than that but to tell you that.

Pushkal: But to tell you that that's, that's, you know, we're encouraged by those data. In terms of the additional follow-up, maybe what I can clarify is those are changes relative to what the study looked like when it was a 30 to 36 month follow-up study. And so what we're saying is, and of course, what we're focusing on are patients who remain on study.

Speaker Change: We're encouraged by those data in terms of the.

Speaker Change: The additional follow up maybe what I can clarify those are changes relative to what this study look like when it was a 30% to 36 month follow up study and so what we're saying is and of course, what we're focusing on those patients who remain on study throughout the study. We've had patients for example, who have passed away because of their disease et cetera.

And so, what we're saying is -- and, of course, what we're focusing on are patients who remain on study. Throughout the study, we've had patients, for example, who have passed away because of their disease, et cetera. And so what we're saying is that, in the patients who remain in the study, approximately 60% of them will have some extension of their follow-up in the study. And roughly a third of those, or 20% additional, would get to the full 36 months. So, I hope that clarifies.

Pushkal: Throughout the study, we've had patients, for example, who have passed away because of their disease, etc. And so what we're saying is that in the patients who remain in the study, approximately 60% of them will have some extension of their follow-up in the study. And we believe in roughly a third of those, or 20%.

Speaker Change: And so what we're saying is that in the patients who remain on study approximately 60% of them will have some extension of their follow up in this study and roughly a third of those are 20%.

Pushkal: Additional, we'll get to the full 36. So I hope that clarifies things. Rates.

Speaker Change: Additional we will get to the full 24 36 months, so I hope that clarified.

Yvonne L. Greenstreet: Great. Okay, next question.

Operator: Okay. Next question. Thank you. Please take a moment for our next question. Our next question comes from Maury Raycroft from Jeffrey's, Hi, thanks for taking my question. With the new STATS plan and the latest conversations with regulators, can you talk more at this point about what the minimum delta and the composite endpoint is that you need to achieve to be STAT-SIG for monotherapy and combo therapy? And in the top line update, can you commit to reporting when you first hit STAT-SIG on the separation of the curves so we get a sense of kinetics versus competitor drugs? Yeah, Maury. I think what I would say is a couple things. First of all, I think, you know, I think it's widely accepted that death and hospitalization are incredibly clinically relevant endpoints, and so there's no sort of minimum threshold there.

Okay. Next question.

Thank you. Please take a moment for our next question. Our next question comes from Maury Raycroft from Jeffrey's, Hi, thanks for taking my question. With the new STATS plan and the latest conversations with regulators, can you talk more at this point about what the minimum delta and the composite endpoint is that you need to achieve to be STAT-SIG for monotherapy and combo therapy? And in the top line update, can you commit to reporting when you first hit STAT-SIG on the separation of the curves so we get a sense of kinetics versus competitor drugs? Yeah, Maury. I think what I would say is a couple things. First of all, I think, you know, I think it's widely accepted that death and hospitalization are incredibly clinically relevant endpoints, and so there's no sort of minimum threshold there.

Operator: Thank you. Please take a moment for our next question. Our next question comes from Maury Raycroft from Jefferies,

Speaker Change: Okay.

Speaker Change: Next question.

Speaker Change: Thank you.

Speaker Change: One moment far next question.

Hi, thanks for taking my question. With the new STATS plan and the latest conversations with regulators, can you talk more at this point about what the minimum delta and the composite endpoint is that you need to achieve to be STAT-SIG for monotherapy and combo therapy? And in the top line update, can you commit to reporting when you first hit STAT-SIG on the separation of the curves so we get a sense of kinetics versus competitor drugs? Yeah, Maury. I think what I would say is a couple things. First of all, I think, you know, I think it's widely accepted that death and hospitalization are incredibly clinically relevant endpoints, and so there's no sort of minimum threshold there.

Maury Raycroft: Hi, thanks for taking my question. With the new stats plan and the latest conversations with regulators, can you talk more at this point about what the minimum delta and the composite endpoint is that you need to achieve to be stat sig for monotherapy and combo therapy? And in the top-line update, can you commit to reporting when you first hit stat sig on the separation of the curves so we get a sense of kinetics versus competitor drugs?

Our next question comes from the line of Maury Raycroft from Jefferies.

Maury Raycroft: Hi, Thanks for taking my question.

Maury Raycroft: With the new stats plan and the latest conversations with regulators can you talk more at this point on what the minimum of Delta in the composite endpoint is that you need to achieve to be stat, Sig for monotherapy and combo therapy and in the top line update can you commit to reporting when you first hit stat Sig on the separation of the curves. So we get a sense of <unk>.

Yeah. Maury, I think what I would say is a couple of -- first of all, I think it's widely accepted that death and hospitalization are incredibly clinically-relevant endpoints and so, there's no sort of minimum threshold there. Obviously, there's always benefit and risk but in general, any benefit in terms of death and hospitalization is considered clinically significant and is very different than scenarios of looking at NT-proBNP or six-minute walk test or things like that. And as we've said, what we're committing to in the top-line results, is we will provide p-values on the primary and secondary endpoints, we will provide a statement on safety and we will provide information on relevant subgroups, including the TAF subgroup. And of course, we will be providing a lot more data, as is our custom. We tend to be quite transparent with our data at scientific congresses, et cetera, thereafter.

Pushkal Garg: Yeah. Maury, I think what I would say is a couple of -- first of all, I think it's widely accepted that death and hospitalization are incredibly clinically-relevant endpoints and so, there's no sort of minimum threshold there. Obviously, there's always benefit and risk but in general, any benefit in terms of death and hospitalization is considered clinically significant and is very different than scenarios of looking at NT-proBNP or six-minute walk test or things like that.

<unk> versus competitor drugs.

Speaker Change: Yes, Maury I think what I would say is a couple things first of all I think I think it's widely accepted that death and hospitalization are incredibly clinically relevant endpoints in there. So there's no sort of minimum threshold. There obviously, there's always benefit risk, but in the general any benefit in terms of death and hospitalization.

Maury Raycroft: Obviously, there's always benefit and risk, but in general, any benefit in terms of death and hospitalization is considered clinically significant, and is very different than scenarios of looking at NT ProBNP or the six minute walk test, or things like that. And as we've said, you know, what we're committing to in the primary and secondary endpoints, we will provide P values on the primary and secondary endpoints, we will provide a statement on safety, and we will provide information on relevant subgroups, including the TAP subgroup. And, of course, we will be providing a lot more data, as is our custom. We tend to be quite transparent with our data at scientific congresses, et cetera, thereafter.

Speaker Change: <unk> is considered clinically significant.

Speaker Change: Very different in scenarios of looking at NT Pro BNP or six minute walk test or things like that and as we've said.

And as we've said, what we're committing to in the top-line results, is we will provide p-values on the primary and secondary endpoints, we will provide a statement on safety and we will provide information on relevant subgroups, including the TAF subgroup. And of course, we will be providing a lot more data, as is our custom. We tend to be quite transparent with our data at scientific congresses, et cetera, thereafter.

What we're committing to in the primary and the topline results as we will provide P values on the primary and secondary endpoints, we will provide a statement on safety and we will make we will provide information on relevant subgroups, including the tap subgroup.

Speaker Change: And of course, we will be providing.

Speaker Change: A lot more data as our customer where we tend to be quite transparent with our data at.

Speaker Change: At scientific Congresses et cetera thereafter.

Maury Raycroft: And as to the kinetics of the effects of either PATISIRAN or VUTISIRAN, for that matter, it's quite clear that the onset appears to be much more rapid than has been seen in other trials with other drugs. So for example, in the original APOLLO with PATISIRAN, by six months you're seeing the separation -- post-hoc analysis -- but you were seeing a bit of separation in mortality and hospitalization. The same was true in APOLLO-B, emerging at nine months. Now, you look at recent studies in the ATTR-CM space; it's nothing like that. And my points are mortality are further attested to by the time separation for the 3, 5, 6-minute walk distance or KCCQ, Which also promptly occurred within the first few months of the study. So...

And as to the kinetics of the effects of either PATISIRAN or VUTISIRAN, for that matter, it's quite clear that the onset appears to be much more rapid than has been seen in other trials with other drugs. So for example, in the original APOLLO with PATISIRAN, by six months you're seeing the separation -- post-hoc analysis -- but you were seeing a bit of separation in mortality and hospitalization. The same was true in APOLLO-B, emerging at nine months. Now, you look at recent studies in the ATTR-CM space; it's nothing like that. And my points are mortality are further attested to by the time separation for the 3, 5, 6-minute walk distance or KCCQ, Which also promptly occurred within the first few months of the study. So, I think, not just the magnitude effect but the kinetics of how our drugs work by depleting the pathogenic protein -- which, certainly, in the peripheral neuropathy setting seems to be a very potent way to treat the disease -- will undoubtedly show the impact, ultimately, towards [inaudible].

Speaker Change: And as to the kinetics of the effects of it.

Speaker Change: <unk> for that matter, it's quite clear that the onset is appears to be much more rapid than has been seen with other trials with other drugs. So for example in the original Apollo with Tucson by six months, you're seeing the separation post hoc analyses, but you will see government separation in mortality and hospitalization.

Speaker Change: The same was true in a polar be emerging at nine months. When you look at recent studies in the <unk> space is nothing like that and my point about mortality of further testing to try the time separation for between six minute walk distance, Okay, CQ, which also promptly occurred within the first few months of the study so.

Pushkal: Now, you look at recent studies in the ATTRCM space; it's nothing like that. And my points about mortality are further attested to by the time separation for the 356-minute walk distance, or KCCQ, which also promptly occurred within the first, you know, few months of the study. So...

Now, you look at recent studies in the ATTR-CM space; it's nothing like that. And my points are mortality are further attested to by the time separation for the 3, 5, 6-minute walk distance or KCCQ, Which also promptly occurred within the first few months of the study. So, I think, not just the magnitude effect but the kinetics of how our drugs work by depleting the pathogenic protein -- which, certainly, in the peripheral neuropathy setting seems to be a very potent way to treat the disease -- will undoubtedly show the impact, ultimately, towards [inaudible].

So, I think, not just the magnitude effect but the kinetics of how our drugs work by depleting the pathogenic protein -- which, certainly, in the peripheral neuropathy setting seems to be a very potent way to treat the disease -- will undoubtedly show the impact, ultimately, towards [inaudible]. Great, thank you. Thank you. Please take a moment for our next question. Our next question comes from the line of Mike Olds from Morgan Stanley. Good morning, thanks for taking the question. Maybe just one on Apollo B.

Akshay K. Vaishnaw: I think, you know, not just the magnitude effect but the kinetics of how our drugs work by depleting the pathogenic protein, which certainly in the peripheral neuropathy setting seems to be a very potent way to treat the disease, will undoubtedly show the impact. I think, you know, ultimately it is towards preclinical. Great, thank you. Thank you. Please take a moment for our next question. Our next question comes from the line of Mike Olds from Morgan Stanley. Good morning, thanks for taking the question. Maybe just one on Apollo B.

Speaker Change: Not just the magnitude of effect that the kinetics of how our drugs work by depleting the pathogenic protein, which certainly in the peripheral neuropathy <unk> seems to be very potent way to treat the disease.

Speaker Change: Absolutely show the impact I think ultimately it will speed towards the cardiomyopathy.

Speaker Change: Great. Thank you Nick.

Great, thank you. Thank you. Please take a moment for our next question. Our next question comes from the line of Mike Olds from Morgan Stanley. Good morning, thanks for taking the question. Maybe just one on Apollo B.

Maury Raycroft: Great, thank you.

Nick: Thank you.

Thank you. Please take a moment for our next question. Our next question comes from the line of Mike Olds from Morgan Stanley. Good morning, thanks for taking the question. Maybe just one on Apollo B.

Operator: Thank you. One moment for our next question. Our next question comes from the line of Mike Ulz from Morgan Stanley.

Speaker Change: One moment for our next question.

Speaker Change: Our next question comes from the line of Michael <unk> from Morgan Stanley.

Michael Ulz: Good morning, thanks for taking the question. Maybe just one on APOLLO-B. You highlighted the AMVUTTRA monotherapy arm did better than the combination of arm of AMVUTTRA and TAFAMIDIS -- I think you highlighted that back at the R&D day. But just curious, what's the rationale or the mechanism or reason why the combo performs worse than the monotherapy arm? Thanks.

Good morning, Thanks for taking the question.

Michael: Maybe just one on Apollo B.

Mike Olds: You highlighted that the Ambutra monotherapy arm did better than the combination of arms of amfutra and defaminist. And I think you highlighted that back at the R&D day. But just curious, what's the rationale or the mechanism or reason why the combo performs worse?

Michael: Highlighted the <unk> monotherapy arm.

Michael: Did better than the combination arm of <unk> and to feminists and I think you highlighted that back at the R&D day, but just curious what's the rationale or the mechanism or reason why the combo performs worse than the monotherapy arm.

Mike Olds: Yeah. Mike, maybe just to clarify a couple points, right? I think, first of all, what we're saying is that when we look at the monotherapy data, you're looking at the effects of one drug and certainly, comparing that to placebo. And so, those placebo patients tend to decline and it gives the cleanest perspective on the impact that your drug is having. And what we've seen out of APOLLO-B, Mike, was really quite potent, substantial effects on the four key powered endpoints that we looked at in that study -- six-minute walk test, KCCQ, NT-proBNP and troponin, that were sizable and durable. We also saw benefits on mortality, as we've been talking about. Some people have brought up some of the data around time-to-event and the recurrent CV events and I would just point out that one, it's one endpoint out of all, so I think you'd have to kind of question why that would be the case and if that makes any clinical or biological sense. Moreover, when we look at those data, actually, the lack of apparent separation was due to a few early events that happened in the PATISIRAN arm in the first three months. And if you look beyond three months -- in the first three months, the drug is just starting to take effect. Beyond three months, we actually see good separation even in the monotherapy group, even on outcomes and recurrent CV events, specifically. So, I think all of that bodes very well. And as it relates to combination, as we've said all along, we're very encouraged. But certainly, just like you see in blood pressure medicines or other things, when you start to combine effective therapeutics together with different mechanisms of action, it can change the magnitude of the effect that you might detect. But everything that we're seeing coming out of APOLLO-B suggests that there will be an effect there and it's most visibly seen in the outcomes data that we talked about in that study. Yeah. And, of course, we have a much larger study with EDSB, and a longer study. A larger and longer study. Absolutely.

Yeah. Mike, maybe just to clarify a couple points, right? I think, first of all, what we're saying is that when we look at the monotherapy data, you're looking at the effects of one drug and certainly, comparing that to placebo. And so, those placebo patients tend to decline and it gives the cleanest perspective on the impact that your drug is having. And what we've seen out of APOLLO-B, Mike, was really quite potent, substantial effects on the four key powered endpoints that we looked at in that study -- six-minute walk test, KCCQ, NT-proBNP and troponin, that were sizable and durable. We also saw benefits on mortality, as we've been talking about. Some people have brought up some of the data around time-to-event and the recurrent CV events and I would just point out that one, it's one endpoint out of all, so I think you'd have to kind of question why that would be the case and if that makes any clinical or biological sense. Moreover, when we look at those data, actually, the lack of apparent separation was due to a few early events that happened in the PATISIRAN arm in the first three months. And if you look beyond three months -- in the first three months, the drug is just starting to take effect. Beyond three months, we actually see good separation even in the monotherapy group, even on outcomes and recurrent CV events, specifically. So, I think all of that bodes very well. And as it relates to combination, as we've said all along, we're very encouraged. But certainly, just like you see in blood pressure medicines or other things, when you start to combine effective therapeutics together with different mechanisms of action, it can change the magnitude of the effect that you might detect. But everything that we're seeing coming out of APOLLO-B suggests that there will be an effect there and it's most visibly seen in the outcomes data that we talked about in that study.

Pushkal Garg: Yeah. Mike, maybe just to clarify a couple points, right? I think, first of all, what we're saying is that when we look at the monotherapy data, you're looking at the effects of one drug and certainly, comparing that to placebo. And so, those placebo patients tend to decline and it gives the cleanest perspective on the impact that your drug is having. And what we've seen out of APOLLO-B, Mike, was really quite potent, substantial effects on the four key powered endpoints that we looked at in that study -- six-minute walk test, KCCQ, NT-proBNP and troponin, that were sizable and durable.

Speaker Change: Yes, Mike maybe just to clarify a couple of points right I think first of all.

Mike: What we're saying is that we when we look at the monotherapy data.

Mike: Its youre looking at the effects of a effect of one drug and certainly comparing that to placebo and so those placebo patients.

Mike: Tend to decline.

Mike: And it gives the cleanest.

Our perspective on the impact that your drug is having right and what we've seen out of Apollo B, Mike was really quite potent substantial effects on the four key powered endpoints that we looked at in that study six minute walk test <unk> empty pro BNP and troponin that were sizable and durable.

Pushkal: And what we've seen out of Apollo B, Mike, was really quite potent, substantial effects on the four key powered endpoints that we looked at in that study, the six minute walk test, KCCQ, NT Pro BNP, and troponin that were sizable and durable. We also saw benefits on mortality, as we've been talking about. You know, some people have brought up some of the data around time-to-event and recurrent CV events. And I would just, you know, point out that, one, it's just one endpoint out of all. So I think you'd have to kind of question why that would be the case and if that makes any clinical or biological sense. Moreover, when we look at those data, actually, the lack of apparent separation was due to a few early events that happened in the Petitstrand arm in the first three months.

We also saw benefits on mortality, as we've been talking about. Some people have brought up some of the data around time-to-event and the recurrent CV events and I would just point out that one, it's one endpoint out of all, so I think you'd have to kind of question why that would be the case and if that makes any clinical or biological sense. Moreover, when we look at those data, actually, the lack of apparent separation was due to a few early events that happened in the PATISIRAN arm in the first three months. And if you look beyond three months -- in the first three months, the drug is just starting to take effect. Beyond three months, we actually see good separation even in the monotherapy group, even on outcomes and recurrent CV events, specifically. So, I think all of that bodes very well. And as it relates to combination, as we've said all along, we're very encouraged. But certainly, just like you see in blood pressure medicines or other things, when you start to combine effective therapeutics together with different mechanisms of action, it can change the magnitude of the effect that you might detect. But everything that we're seeing coming out of APOLLO-B suggests that there will be an effect there and it's most visibly seen in the outcomes data that we talked about in that study.

Mike: We also saw benefits on mortality as we've been talking about.

Mike: Some people have brought up some of the data around time to event or in the recurrent CV events and I would just point out that one it's one endpoint out of all so I think you'd have to kind of question why that wouldn't be the case.

Mike: And if that makes any clinical or biologics. Moreover, when we look at those data actually the lack of apparent separation was due to a few early event that happened in the <unk> arm in the first three months and if you look beyond three months.

Pushkal: And if you look beyond three months, you know, in the first three months, the drug is just starting to take effect. Beyond three months, we actually see good separation, even in the monotherapy group, even on outcomes and recurrent CV events specifically. So I think all of that bodes very well. And as it relates to combination, as we've said all along, we're very encouraged. But certainly, just like you see in blood pressure medicines or other things, when you start to combine effective therapeutics together with different mechanisms of action, it can change the magnitude of the effect that you might detect.

So, I think all of that bodes very well. And as it relates to combination, as we've said all along, we're very encouraged. But certainly, just like you see in blood pressure medicines or other things, when you start to combine effective therapeutics together with different mechanisms of action, it can change the magnitude of the effect that you might detect. But everything that we're seeing coming out of APOLLO-B suggests that there will be an effect there and it's most visibly seen in the outcomes data that we talked about in that study.

Mike: And the first three months of the drug is just starting to take effect beyond three months, we actually see good separation, even the monotherapy group, even on outcomes and recurrent CV events, specifically, so I think all of that bodes very well and as it relates to combination as we've said all along we're very encouraged but certainly just like you see in blood pressure medicines or other things when you start to combine effective therapy.

Mike: <unk> together with different mechanisms of action. It can change the magnitude of effect that you might detect but everything that we're seeing coming out of Apollo B suggests that there will be an effect there and it's most visibly seen by the outcomes data that we talked about in that study.

Pushkal: But everything that we're seeing coming out of ApolloB suggests that there will be an effect there, and it's most visibly seen in the outcomes data that we talked about in that study. Yeah, and of course, we have a much larger study with EDSB, and a longer study. A larger and longer study. Absolutely.

Yeah. And, of course, we have a much larger study with EDSB, and a longer study. A larger and longer study. Absolutely.

Yvonne L. Greenstreet: Yeah. And [inaudible] we have a much larger study with HELIOS-B. And a longer study.

Mike: It's a much larger study with <unk> and some of our larger and longer studies absolutely yes.

A larger and longer study. Absolutely.

Pushkal Garg: A larger and longer study.

Yvonne L. Greenstreet: Absolutely.

Akshay K. Vaishnaw: In reference to that larger and longer study that is our friend here, a friend for the patients and physicians, ultimately, in showing a positive outcome. Just before this call, you and I were looking at the ACORAMIDIS data. If they looked at month 18, ACORAMIDIS was faring worse than placebo for mortality. So, you know, looking at the wrong time point in a study that's smaller can really lead you astray. And so, APOLLO-B was highly informative but it's not surprising that one or two of the endpoints didn't line up where the vast majority did. And, ultimately, our friend is the largest, longest study that's ever been conducted and will shortly be completed in ATTR-CM and that's HELIOS-B. So, I think getting too over-indexed on one endpoint that went in the wrong direction, you have to be careful about that. You can be easily mislead.

Mike: In reference to that larger loan with study that is our friend here for the patients and physicians ultimately ensuring a positive outcome.

Mike: Just before this focused on looking at their parameter space if.

Mike: If they looked at month 18, a permanent was faring worse than placebo.

Mike: But mortality.

Mike: So.

Mike: Looking at the wrong time point in a study that smaller.

And so, APOLLO-B was highly informative but it's not surprising that one or two of the endpoints didn't line up where the vast majority did. And, ultimately, our friend is the largest, longest study that's ever been conducted and will shortly be completed in ATTR-CM and that's HELIOS-B. So, I think getting too over-indexed on one endpoint that went in the wrong direction, you have to be careful about that. You can be easily mislead.

Mike: Can really lead you astray, so our policy was highly informative but.

But one or two of you haven't always been lineup with a vast majority bid and ultimately offer and is the largest longest study that's ever been conducted and will shortly be completed ATP LCM and that Cvs piece. So I think.

Mike: Getting to over index on one endpoint that went in the wrong direction.

Mike: You have to be careful about that and the easily misled.

Operator: Good. I think we've got time for one more question. One last question. Thank you. Our last question comes from the line of William Pickering from Bernstein. Hi.

Yvonne L. Greenstreet: Good. I think we've got time for one more question. One last question.

Speaker Change: Good I think we've got time for one more question one last question.

Operator: Thank you. Our last question comes from the line of William Pickering from Bernstein.

Speaker Change: Thank you.

Speaker Change: Our last question.

Speaker Change: Comes from the line of William Pickering from Bernstein.

William Pickering: Hi, thank you for taking my question. What is the powering of the study with respect to the overall population at the 0.025 significance level? Like, I think a lot of the changes make sense but you've also said in the past, that the study is not powered for stat sig and monotherapy. So, if that doesn't hit, are you then in a more difficult position than you were before the stats plan change? Thank you.

William Pickering: Hi, Thank you for taking my question.

William Pickering: What is the powering of the study with respect to the overall population at that point <unk> five significant level like I think a lot of the changes makes sense, but you've also said in the past that the study is not powered for.

William Pickering: Stat Sig in mono therapy. So if that doesn't hit are you then in like a more difficult position than you were before the stats plan change. Thank you.

Pushkal: Thank you. Yeah. Well, no. I think, what I would take away from today is that the changes we make, really -- we've actually enhanced the overall statistical power of the study. By adding extra follow-up for those patients at the tailend of the study who may have studied, we think we've added -- we certainly have added statistical power there. And the way that we've constructed this endpoint, which again remains focused on the most critical endpoint which is outcomes, we were able to look now at the full totality of the population, 660 plus patients in the combination -- in the overall. As well as, the way I think about it, an enriched population of the monotherapy patients who we expect to have the largest treatment effect and the purest demonstration of what VUTRISIRIN can accomplish in this and do in this disease. And so, we really think we've -- that's really what we've done here. We don't think that we've, in any way, made it harder.

Thank you.

Yeah. Well, no. I think, what I would take away from today is that the changes we make, really -- we've actually enhanced the overall statistical power of the study. By adding extra follow-up for those patients at the tailend of the study who may have studied, we think we've added -- we certainly have added statistical power there. And the way that we've constructed this endpoint, which again remains focused on the most critical endpoint which is outcomes, we were able to look now at the full totality of the population, 660 plus patients in the combination -- in the overall. As well as, the way I think about it, an enriched population of the monotherapy patients who we expect to have the largest treatment effect and the purest demonstration of what VUTRISIRIN can accomplish in this and do in this disease. And so, we really think we've -- that's really what we've done here. We don't think that we've, in any way, made it harder. We think that we've actually made the study better and aligned it with where, as Tolga's highlighted, where we think the market's going to be for the next several years. I think that's great. I think we need to bring the call to a close. I'd like to thank everybody for joining us today. Like I said, we're really pleased with the execution. We delivered in 2023 and we're looking forward to keeping on with our 2024 goals on our path to becoming a top-tier biotech company.

Pushkal Garg: Yeah. Well, no. I think, what I would take away from today is that the changes we make, really -- we've actually enhanced the overall statistical power of the study. By adding extra follow-up for those patients at the tailend of the study who may have studied, we think we've added -- we certainly have added statistical power there. And the way that we've constructed this endpoint, which again remains focused on the most critical endpoint which is outcomes, we were able to look now at the full totality of the population, 660 plus patients in the combination -- in the overall.

Speaker Change: Yes, well no I think.

Speaker Change: What I would take away from today is that the changes we make really we think we've actually enhanced the overall statistical power of the study.

Speaker Change: By adding.

Speaker Change: Extra follow up.

Speaker Change: For those patients at the tail end of the study who remain on study. We think we've added we certainly have added statistical power there and the way that we've constructed this endpoint, which again remains focused on the most critical endpoint which is outcomes.

Speaker Change: We were allowed to we were able to look now and the whole totality of the population of 660 plus patients.

As well as, the way I think about it, an enriched population of the monotherapy patients who we expect to have the largest treatment effect and the purest demonstration of what VUTRISIRIN can accomplish in this and do in this disease. And so, we really think we've -- that's really what we've done here. We don't think that we've, in any way, made it harder. We think that we've actually made the study better and aligned it with where, as Tolga's highlighted, where we think the market's going to be for the next several years.

Speaker Change: And the combination and the overall as well as in.

Speaker Change: The way I think about an enriched population.

Speaker Change: The monotherapy patients, who we expect to be.

Speaker Change: Have the largest treatment effect and the purest demonstration of what Patrice shrank in accomplishing this in due in this disease and so we really think we've.

Speaker Change: That's really the.

Speaker Change: What we've done here and so we don't think that we have in any way made it harder we think that we've actually made the study better aligned it where as Tony has highlighted where we think the market is going to be for the next several years absolutely thats great.

Pushkal: We think that we've actually made the study better and aligned it with where, as Tolga's highlighted, we think the market's going to be for the next several years. I think that's great. I think we need to bring this call to a close. I'd like to thank everybody for joining us today. Like I said, we're really pleased with the execution. We delivered in 2023, and we're looking forward to keeping on with our 2024 goals on our path to becoming a top-tier biotech company.

Yvonne L. Greenstreet: I think that's great. I think we need to bring the call to a close. I'd like to thank everybody for joining us today. Like I said, we're really pleased with the execution. We delivered in 2023 and we're looking forward to keeping on with our 2024 goals on our path to becoming a top-tier biotech company. So, thank you all and have a great day.

Speaker Change: Okay.

Speaker Change: I think we need to bring in the quarter I close I'd like to thank everybody for joining us today.

Speaker Change: We're really pleased with the execution because it's effectively three alright, okay perfect sitting on offline for any <unk>.

Speaker Change: It's something that top tier asset.

Yvonne L. Greenstreet: So, thank you all and have a great day. Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.

So, thank you all and have a great day.

Speaker Change: Company. So thank you all and have a great day.

Operator: Thank you. This concludes today's conference call. Thank you for participating, you may now disconnect.

Speaker Change: Oh.

Speaker Change: Thank you. This concludes goodbye rinse call. Thank you for participating you may now disconnect.

Speaker Change: Yes.

Speaker Change: Yeah.

Speaker Change: Okay.

Speaker Change: Yes.

Speaker Change: Okay.

Q4 2023 Alnylam Pharmaceuticals Inc Earnings Call

Request a DemoDemo

ALNY

Alnylam Pharmaceuticals

Earnings