Q4 2021 Alnylam Pharmaceuticals Inc Earnings Call

Operator: Good day, and thank you for standing by. Welcome to the Alnylam Pharmaceuticals fourth quarter 2021 earnings conference call. At this time, all participants are in listen only mode.

Good day and thank you for standing by welcome to the L Island Pharmaceuticals fourth quarter 2021 earnings Conference call.

At this time, all participants are in listen only mode.

Operator: After the presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star then 1 on your telephone keypad. Please be advised that today's conference may be recorded. If you require operator assistance during the call, please press star then zero.

After the presentation, there will be a question and answer session.

Can I ask a question during the session you'll need to press Star then one on your telephone keypad.

Please be advised today's conference maybe recorded.

If you require operator assistance during the call. Please press Star then zero.

Operator: I'd now like to hand the conference over to Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications. Good morning, I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are Yvonne Greenstreet, Chief Executive Officer, Tolga Tanguler, Chief Commercial Officer, Akshay Vaishnaw, President, and Jeff Poulton, Chief Financial 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 slash events.

Now like to hand, the conference over to Christine lending them Senior Vice President of Investor Relations and corporate communications.

Christine Lindenboom: During today's call, which is outlined in two parts, Avon will deliver introductory remarks and provide some general contacts, Tolga will provide an update on our global commercial progress, Akshay will review our recent clinical and pre-clinical updates, and Jeff will review our financials, including 2022 guidance, followed by a summary of our 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 Harbor Provision under the Private Securities Litigation Reform Act of 1995.

Good morning, I'm, Christine Lindenberg, Senior Vice President of Investor Relations and corporate Communications Battle in Ireland with me today on the phone or Yvonne Greenstreet, Chief Executive officer until the tangle or chief commercial.

Sir Akshay vision, our president and Jeff Poulton Chief Financial 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 web site investors nylon Dotcom flash event.

During today's call as outlined in slide two Yvonne will deliver introductory remarks and provide some general context talk I will provide an update on our global commercial progress Akshay will review, our recent clinical and preclinical updates and Jeff will review, our financials, including 2022 guidance followed by a summary of our upcoming milestones before we open the call for your quest.

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I would like to remind you that this call will contain remarks concerning Alan island's future expectations plans and prospects, which constitute forward looking statements for the purposes of the safe Harbor provision under the private Securities Litigation Reform Act of 1095.

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 recently quarterly report on file with the SEC.

In addition, any forward looking statements rapidly represent our views only as of 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.

Christine Lindenboom: 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 quarterly report on file with the SEC. In addition, any forward-looking statements represent our views only of the day of this recording and should not be relied upon as representing our views as of any subsequent steps of one date. We specifically claim any obligation to update such dates. With that, I'll now turn the call over to Yvonne. Yvonne?

With that I'll now turn the call over to a long goodbye.

Yvonne Greenstreet: Thanks Christine, and thank you everyone for joining the call today. Thank you very much. 2021 was another year of tremendous success at Alnylam, in which we delivered impressive commercial performance and made significant advancements across our broad pipeline of RNAi therapeutics. To start, our commercial products on patro, giflarri, and oxlumeaux so continued growth, primarily due to strong patient demand. In total, we achieved $662 million in net product revenue, representing year-over-year growth of 83%, delivering at the upper end of our guidance.

Thanks, Christine and thank you everyone for joining the call today.

Yvonne Greenstreet: We're also excited about the end of the year with the U.S. approval of the fourth R&I therapeutic discovered by Alnylam, Lexu, which is partnered with Navarroft. We have also advanced our pipeline programs at all stages of development. This includes our TTR franchise, where we recently presented four 18-month results from the Helius A Phase 3 Study of the Trace Ramp. Akshay will review these short lists.

2021 was another year of tremendous success on the island in which we delivered impressive commercial performance and made significant advancements across our broad pipeline of R&D I therapeutics to start a commercial products on Petro give Laurie Anoxia man So continued growth primarily due.

Strong patient demand and.

In total we achieved $662 million and net collected revenue representing year over year growth of 83% delivering at the upper end of our guidance range.

We're also excited to have ended the year with the U S approval of the false RNA therapeutic discovered by all Muslims next year, which is partnered with Novartis.

We also advanced our pipeline programs at all stages of development.

This includes our GTR franchise, where we recently presented full 18 month results from the Helios a phase III study of the triste draw Akshay will review these shortly.

Yvonne Greenstreet: We also completed enrollment in our two provisional phase three studies in ATTR amyloidosis with cardiomyopathy, Apollo B and healing. Furthermore, we advanced our B-SERAN interface too, with the initiation of Cardio One and Cardio Two, representing what we believe to be an opportunity to reimagine the treatment of hypertension. Additionally, we advanced two more prevalent disease programs toward the clinic, including our first CNS program. Looking toward 2022 and beyond, we view a few strategic goals as key potential growth drivers for Alnylam.

We also completed enrollment in our two pivotal phase III studies, and ATT amyloidosis with cardiomyopathy, Apollo B and C to speed.

Furthermore, we advance L P surround into phase II with the initiation of cardio, one and cardio two representing what we believe to be an opportunity to re imagine the treatment of hypertension.

Additionally, we advanced to more prevalent disease programs towards the clinic.

Our first CNS program.

Looking towards 2022 and beyond we'd be.

A few strategic goals as key potential growth drivers for all nine of them.

Yvonne Greenstreet: First is the potential expansion of RTPR franchise, in the near term, with the potential approval of Triceram and the phase 3 reader of the poll to be with Triceram. And over time, as we aim to become the global leader in delivering impactful and highly differentiated, The second key growth driver is our expansion beyond rare diseases into prevalent diseases. And the third growth driver for the company comes from our sustainable innovation, comprised of new platforms and hunts.

It's just the potential expansion of our TCR franchise in the near term with the potential approval of <unk> and the phase III Readouts of Apollo B with Patese Ram and over time as we aim to become the global leader in delivering impactful and highly differentiated medicines to patients.

The second key growth driver is our expansion beyond rare diseases into prevalent diseases.

And the third growth driver for the company comes from our sustainable innovation engine comprised of new platform enhancements opportunities with extra hepatic delivery and our ability to find new genetically validated targets, which offers the potential to drive further pipeline expansion to 2020.

Yvonne Greenstreet: Opportunities with extra-hepathic delivery and our ability to find new genetically validator targets, which offers the potential to drive further pipeline expansion to 2025 and beyond. Based on these opportunities, we believe we are well-positioned to deliver on our Alnylam piece-of-fifth by 25 goals, making Alnylam a top biotech, developing and commercializing transformative medicines for rare and common diseases for patients around the world, driven by a high-yielding pipeline of first- and or best-in-class product candidates from our organic product engine, all while delivering excellent financial results. With that, let me now turn the call over to Tolga for a view of our commercial performance. Tolga?

Five and beyond.

Based on these opportunities we believe we are well positioned to deliver on or all night pizza fifth by 'twenty five goals, making all nine of them are top biotech company, developing and commercializing transformative medicines for rare and common diseases for patients around the world driven by a high yielding pipeline a first Andrew.

First in class product candidates from our organic product engine, all while delivering excellent financial results with that let me now turn the call over to toga for a review of our commercial performance toga.

Tolga Tanguler: Thanks, Yvonne, and good morning everyone! Thanks Yvonne, thanks Yvonne, thanks Yvonne. We're very pleased with our fourth quarter performance. The Donggong Pandemic had a considerable impact on our ability to engage customers via face-to-face interactions; however, our ability to leverage data and analytics for our promotion lips, and improvements in our virtual interaction capabilities have enabled us to finish 21 with significant year-over-year growth. For Patro, we achieved $139 million in global net product revenues in the fourth quarter, representing 15% quarter on quarter growth compared with the third quarter and 53% growth compared with Q4 2020, and we achieved $475 million in global on-patron revenues for the full year.

Thanks, Ivan and good morning, everyone.

We're very pleased with our fourth quarter performance.

Ongoing pandemic had considerable impact on our ability to engage customers via face to face interactions. However, our ability to leverage data and analytics for our promotional efforts.

And improvements in our virtual interaction capabilities have enabled us to finish 'twenty, one with significant year over year growth.

Foreign Petro, we achieved $139 million in global net product revenues in the fourth quarter, representing 15% quarter on quarter growth compared with the third quarter.

And 53% growth compared with Q4 2020.

And we achieved $475 million and global on Petro revenues for the full year.

Tolga Tanguler: As of December 31st, over 2,050 patients were on commercial on-patron treatment worldwide, with patient compliance remaining consistent above 90%. In the U.S., sales of Ompatra increased 17% versus Q3 and were primarily impacted by the following. Patient demand, which increased 4% driven by the addition of new patients on therapy, with patient compliance remaining consistent above 90%, as noted. Inventory Stocking, in the Distribution Channel, during the fourth quarter. Inventory Stocking, in the fourth quarter. Compared with B-stocking in Q3, favorably impacted US reported growth by 15% during the quarter. This was expected given the low level of inventory in the channel at the end of the third quarter.

As of December 31.

Over 2050 patients were on commercial and Patrick treatment worldwide with patient compliance remaining consistent above 90%.

U S sales of on Patrick increased 17% versus Q3.

And were primarily impacted by the following.

Patient demand, which increased 4% driven by the addition of new patients on therapy with complete patient compliance remaining consistent above 90% as noted.

Inventory stocking in the distribution channel during the fourth quarter.

Compared with Destocking in Q3 favorably impacted U S reported growth by 15% during the quarter.

This was expected given the low level of inventory in the channel at the end of the towards quarter.

Tolga Tanguler: We ended the year with approximately two weeks of inventory in the distribution channel, which is at the midpoint of our expectation in our international markets. On paper, fourth quarter performance remains strong, with growth of 14% versus Q3, primarily driven by increased patient demand across Europe, Canada, and Japan, as well as favorability in gross net deductions, positively impacting net pricing for the quarter. We also continue to observe a good balance of first-line use and switches from stabilizers. Moving to Givlari.

We ended the year with approximately two weeks of inventory in the distribution channel, which is at the midpoint of our expectations.

In our international markets.

Petro fourth quarter performance remained strong with growth of 14% versus Q3, primarily driven by increased patient demand broadly across Europe , Canada, and Japan as well as favorable gross to net deductions positively impacting net pricing for the quarter.

We also continued to absorb a good balance of first line use and switches from stabilizers.

Moving to give Laurie.

Tolga Tanguler: We achieved $41 million in Global Net Product Revenues in the fourth quarter, representing 28% quarter-on-quarter growth compared with Q3, and 84% growth versus Q4 2020. And we achieved $128 million in Global Give Lower revenue for the full year. As of December 31st, over 350 patients were on commercial, giving Larry treatment worldwide. We are pleased with this steady ongoing launch of Gilari. In the US, sales of Gilari increased 35% versus Q3, 21, and were primarily impacted by the following.

We achieved $41 million in global net product revenues in the fourth quarter, representing 28% quarter on quarter growth compared with Q3.

And 84% growth versus Q4 2020 and.

And we achieved $128 million in global <unk> revenues for the full year.

As of December 31 over 350 patients were on commercial <unk> treatment worldwide.

We are pleased with the steady ongoing launch of give Laurie in the U S sales of <unk> increased 35% versus Q3, 'twenty, one and were primarily impacted by the following.

Tolga Tanguler: Patient Demand, which increased 8%, driven by an increase in patients on therapy, with patient treatment compliance at over 90%, and an increase in inventory stocking in the quarter, which favorably impacted growth by approximately 21% In addition to a decrease in growth in net sales deductions, which contributed an additional 6% growth. We also continue to make strong progress with value-based agreements, with over 12 finalized to date with commercial payers. In our international markets, Gilari delivered 10% growth in the fourth quarter compared with Q3, with the growth primarily driven by new patient ads in key Western European markets, notably Spain and Italy.

Patient demand, which increased 8% driven by an increase in patients on therapy with patient treatment compliance at over 90% and increase in inventory stocking in the quarter, which favorably impacted growth by approximately 20%.

In addition to a decrease in gross to net sales deductions, which contributed an additional 6% growth.

We also continued to make strong progress with value based agreements with over 12 finalize to date with commercial payers.

In our international markets give Laurie delivered 10% growth in the fourth quarter compared with Q3.

With the growth primarily driven by new patient adds in key western European markets, notably, Spain, and Italy in the U K, we received a positive opinion from nice and look forward to a launch in the U K in early this year.

Tolga Tanguler: In the UK, we received a positive opinion from Nice and look forward to a launch in the UK early this year. Moving now to Oxfam, we achieved $19 million in global net product revenues in the fourth quarter, representing a 29% increase compared with Q3 and ended our first full year since launch with $60 million in global revenues.

Moving now to <unk> Luma, we achieved $19 million in global net product revenues in the fourth quarter, representing a 29% increase compared with Q3 and ended our first full year since launch with $60 million in global revenues.

Tolga Tanguler: As of December 31st, over 140 patients were on commercial oxlomoid treatment worldwide. In the US, sales of Oxluma increased 9% versus Q3 2021, and were primarily impacted by the following. Patient demand increased 15% driven by an increase in patients on therapy and patient treatment at over 90%. However, reported growth was unfavorably impacted by approximately 6% from a decrease in inventory stocking in the distribution channel during the quarter. Additionally, we have finalized 11 DBAs to date with commercial payers. Oxlumogrot in our international markets was 40% during the fourth quarter compared with Q3.

As of December 31 over 140 patients were in commercial or consumer treatment worldwide.

In the U S sales of <unk> increased 9% versus Q3, 2021 and were primarily impacted by the following.

Patient demand increased 15% driven by an increase in patients on therapy and patient treatment compliance at over 90%.

Reported growth was unfavorably impacted by approximately 6% from a decrease in inventory stocking in the distribution channel during the quarter.

Additionally, we have finalized 11 DBA to date with commercial payers.

Okay. So no growth in our two markets was 40% during the fourth quarter compared with Q3 Q.

Tolga Tanguler: Q4 growth benefited from an increase in patients on therapy in our established markets, progress in geographic expansion, and favorability in gross-to-net deductions positively impacting net pricing for the quarters. We also continue to be pleased by the broad utilization of Oxlimo across age groups and EGFR categories. In conclusion, despite the ongoing pandemic, particularly the effects of Omicron since late November of last year, I'm proud of the performance our teams A strong fourth quarter and a strong year across all our three commercial brands, with 83% revenue and growth versus the prior year.

Q4 growth benefited from an increase in patients on therapy in our established markets progress and geographic expansion.

And favorability in gross to net deductions positively impacting net pricing for the quarter.

We also continue to be pleased by the broad utilization of folks to the mall.

Age groups and Egfr categories.

In conclusion, despite the ongoing pandemic, particularly the effects of omicron since late November of last year I'm proud of the performance our teams delivered.

A strong fourth quarter and a strong year across all our three commercial brands with 83% of revenue growth versus the prior year.

Tolga Tanguler: Furthermore, we're excited about the potential upcoming launch of Wutri Serum, which has a PDUFA date of April 14th. If approved, we believe Wutri Serum will offer an important option for the treatment of the polyneuropathy of hereditary transeridine-mediated amnidiosis in adults with its quarterly sub-Q injection dosing regimen and will further strengthen our franchise leadership in this important growth category. With that, I will now turn it over to Akshay to review our recent R&D and pipeline progress. Okay, Akshay?

Furthermore, we're excited about the potential upcoming launch of <unk>, which has a <unk> date of April 14th.

If approved we believe with Tricia will offer an important option for the treatment of the polyneuropathy of hereditary <unk> mediated amyloidosis in adults with its quarterly sub Q injection dosing regimen.

We will further strengthen our franchise leadership in this important growth category.

With that I will now turn it over to Akshay to review, our recent R&D and pipeline progress Akshay.

Akshay Vaishnaw: Thanks, Tolga, and good morning, everyone. I'll start with our efforts in AT&R Amloidosis, where we're advancing two late-stage clinical product candidates, Patisse Ram and Vutris Ram. While Sonpatra is currently approved in multiple markets around the world to treat the polyneuropathy associated with hereditary ATTR amyloidosis, we're committed to expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild-type A ketone amyloidosis patients. To this end, we're conducting the Apollo B Phase 3 study, with which we expect to report top-line results in the middle of this year.

Thanks, Paul and good morning, everyone.

I'll start with our efforts in <unk> amyloidosis, where we are advancing to late stage clinical product candidates <unk> and <unk>.

Also on Patria is currently approved in multiple markets around the world to treat the polyneuropathy associated with hereditary <unk> amyloidosis.

We're committed to expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild type <unk> amyloidosis patients.

To this end we are conducting the Apollo B phase III study with which we expect to report topline results in the middle of this year.

Akshay Vaishnaw: We're also advancing Boutriss ran, which is delivered by a quarterly subcutaneous injection and is also in development for 80-terameloidosis, as one of the newly announced exciting opportunities in Stargart disease. In ATTR, we're conducting two phase three studies. The first is Helios A, evaluating butrystran in HAT terambuloidosis with polyneuropsin.

We're also advancing Boutris, Ryan, which is delivered by quarterly subcutaneous injection and is also in development for <unk> tomo doses as well as the newly announced exciting opportunity install got disease.

In <unk>, we are conducting two phase III studies.

The first two CDO say evaluating vitreous, Ryan and <unk> term loan doses with Polyneuropathy.

Akshay Vaishnaw: In 2021, we presented positive nine-month results from the study, which showed the study met its primary and secondary endpoints of nine months with an acceptable safety profile. These data form the basis for our regulatory submissions to both the FDA and EMA, and we look forward to a potential US approval with the upcoming producer date of April 14, 2022. Additionally, just a few weeks ago, we presented the positive full results, the 18-month-end points from the study. As a reminder, Helios A is a randomized, open-label study in patients with hereditary apithyromyloidosis polyneuropathy.

In 2021, we presented posted nine month results from the study we showed the study met its primary and secondary endpoints at nine months with an acceptable safety profile.

These data form the basis for our regulatory submissions to both the FDA and EMA.

We look forward to potential U S approval with the upcoming producer date of April 14 2022.

Additionally, just a few weeks ago, we presented a poster and full results for the 18 month endpoints from the study.

As a reminder.

<unk> is a randomized open label study in patients with hereditary <unk> amyloidosis polyneuropathy.

Akshay Vaishnaw: The study enrolled 164 patients who were randomized 3-to-1 to receive butresiran at a dose of 25mg administered subcutaneously once every 3 months or patisiran administered intravenously once every 3 weeks at a dose of 0.3mg per kg as a reference.

The study enrolled 164 patients who were randomized three to one to receive Boutris ran at a dose of 25 milligrams administered subcutaneously. Once every three months or <unk> administered intravenously. Once every three weeks dosing zero three make the king as a reference comparator.

Akshay Vaishnaw: To start, serum TTI reduction in the Vitris-Ran group was racked and sustained for a repeat of 18 months. Specifically, Utrisran achieved a mean steady-state serum TTR reduction from baseline of 88%. We're also very pleased to see low interpatient variability in TTR reduction over the time period. As expected, the TTR reduction achieved with vitrexran was statistically non-inferior to that observed in the patisserin reference file.

To stop certainty churn reduction in the <unk> group was rapid and sustained over a period of 18 months.

Specifically <unk> achieved a mean steady state certainteed TR reduction from baseline of 88%.

I'm also very pleased to see lower inter patient variability and teach out reduction over the time period.

As expected the TGI reduction achieved with Richard <unk> was statistically non inferior to that observed in the <unk> Russian song.

Akshay Vaishnaw: This is important, as we would expect that a comparable level of TTR reduction by Putrisran and Putrisran should result in a comparable level of clinical impact. We're delighted that Helios A met all secondary endpoints measured at 18 months, including the statistically significant improvements in neuropathy as measured by the Modified Neuropathy Impairment Score, or MNIST plus 7, quality of life, gait speed, nutritional status, and overall disability relative to external placebo data from the Apollo Phase 3 study of Petit's, Furthermore, at 18 months, Vutristeran also demonstrated improvement compared to external placebo in the ex-Lortry cardiac endpoint NT-ProBNP and trend towards improvement in echocardiographic parameters, as well as improvement compared to baseline in cardiac uptake of technician on scintigraphy imaging, collectively providing evidence to suggest that Vutristeran treatment may potentially result in improvement of cardiac manifestation.

This is important as we would expect a comparable level of Tito reduction by interest ran Mpt's ran should result in a comparable level of clinical impact.

We are delighted that Helios, a met all secondary endpoints measured at 18 months, including the statistically significant improvements in neuropathy as measured by the modified neuropathy impairment score or <unk>, plus seven quality of life gait speed nutritional status and overall disability relative to external placebo data from the Apollo.

Phase III study of <unk>.

Furthermore, at 18 months of interest around also demonstrated improvement compared to external placebo exploratory cardiac endpoint empty pro BNP and trend towards improvement in echocardiographic parameters as well as an improvement compared to baseline in cardiac uptake of technetium on scintigraphy imaging collectively providing evidence.

To suggest that <unk> treatment may potentially result in improvement of cardiac manifestations of disease.

Akshay Vaishnaw: Looking at it in aggregate, and as expected, the treatment effect of vitreous round at 18 months across an array of endpoints is quite similar to that observed with pituitary round. These observations, including especially the exploratory cardiac data, underscore our confidence in the potential of both patisserin and vitricerin in ATT amyloid doses with cardiomyopathy.

Looked at it in aggregate and as expected the treatment effect of nutrition on at 18 months across an array of endpoints is quite similar to that observed with <unk>.

These observations, including especially the exploratory cardiac data underscore our confidence in the potential of both the <unk> inventory surround in <unk> amyloidosis with cardiomyopathy.

Akshay Vaishnaw: This, of course, is being evaluated in the on-game Phase 3 studies, Apollo V with Tiss-Ran and Helios V with Triss-Ran. Let's now review the safety results at 18 months. Vitriciran demonstrated an encouraging safety and tolerability profile. However, by 18 months, three patients on the vitriciran arm, or 2.5%, discontinued the study due to adverse events. A single new discontinuation since month 9 was an event of cardiac failure considered unrelated to study drug by the investigators; by month 18, there were two deaths, neither of which was considered related to the study. There were two serious adverse events deemed related to vitreous strand by the study investigators, consisting of dyslipidemia and urinary tract infection.

This of course is being evaluated in the ongoing phase III studies, Apollo B T <unk> and Helios B with <unk>.

Let's now review the safety results at 18 months, Chris Ryan demonstrated an encouraging safety and Tolerability profile by 18 months three patients on the <unk> ran almost two 5% discontinued the study due to adverse events. The single new discontinuation since many months nine wasn't events of cardiac failure considered unrelated to study drug.

By the investigator by.

By month 18, there with two deaths neither of which was considered relative related to study drug.

With two serious adverse events deemed related to interest earned by the study investigators consisting of Dyslipidemia and urinary tract infection. These.

Akshay Vaishnaw: These deaths and related SAEs all occurred by month 9 and have been previously reported. Treatment emergent adverse events occurring in 10% or more of patients included fall, pain in the extremities, diarrhea, peripheral edema, urinary tract infection, arthralgia, and dizziness. With the exception of pain in the extremities and arthralgia, each of these events occurred at a similar or lower rate as compared with the external placebo. The injection site reactions were reported in 5 patients, or 4.1%, and were all mild and transient. There were no hepatic safety concerns.

These stats and relates to SaaS all occurred by month nine and had been previously reported.

Treatment emergent adverse events occurring at 10% or more of patients included full paint and extremity diarrhea, peripheral edema, urinary tract infection trial jam and business with the exception of pain and extremity and arthralgia. Each of these events occurred at a similar or lower rate as compared with.

External placebo.

Jackson site reactions were reported in five patients or four 1% overall mild and transient.

Hepatic safety concerns.

Akshay Vaishnaw: We're very pleased with the totality of the results and the prophylaxis of vitrexiran that continues to evolve. We believe that, based on these data, vitrexiran, if approved, will present an exciting commercial opportunity, providing attractive treatment options for patients with HAT-2 amyloidosis with polyneuropathy around the world. Of course, this is just the start for Futris-RAN, and we're also conducting another Phase 3 study, Helios-B, which is our ongoing Phase 3 cardiac outcome study with Futris-RAN in hereditary and wild-type A-T tyramyloidosis with cardiomyopathy.

We're very pleased with the totality of the results and the press a lot of interest around that continues to evolve we believe that based on these data Chris Ryan If approved will presented an exciting commercial opportunity, providing an attractive treatment option for patients with <unk> doses with polyneuropathy around the world.

Of course. This is just the start from interest ran and we're also conducting another phase III study Helios B, which is our ongoing phase II cardiac outcomes study with futures ran in hereditary and wild type <unk> amyloidosis with cardiomyopathy.

Akshay Vaishnaw: We're excited to complete enrollment in the third quarter of 2021 with over 600 patients well ahead of schedule due to strong enrollment. Helios B has a 30-month endpoint of all cause mortality and CV events, and we expect the full results in early 2024. The study design includes the potential for an interim analysis, and we will consider the following results from the Apollo B study and engagement with regulatory authorities. As I alluded to earlier,

We were excited to complete enrollment in the third quarter of 2021 with over 600 patients well ahead of schedule due to strong enrollment.

<unk> has a 30 month endpoint of all cause mortality and CV events and we expect the full results in early 2024.

Study design includes the potential for an interim analysis and we will consider this falling results from the Apollo B study and engagement with the regulatory authorities.

As I alluded to earlier.

Akshay Vaishnaw: We also recently announced a promising new near-term opportunity for Vutriceran in Stargardt disease, providing the potential to expand the use of Vutriceran to treat an inherited and progressive ocular disease. Stems from Arilization, which the vitrists ran methods of action via reducing vitamin A, can, in turn, potentially reduce the build-up toxic metabolites in the eye that lead to vision loss in stagop disease

We also recently announced a promising new near term opportunity for Boutris ran in stock out disease, providing the potential to expand the use of <unk> to treat an inherited and progressive ocular disease.

This stems from a realization that the <unk> mechanism of action via reducing vitamin E can in turn potentially reduce the buildup of toxic metabolites in the IDE that lead to vision loss in Stuttgart disease.

Akshay Vaishnaw: We believe this represents an important expansion opportunity for FutraSan in an area of high unmet medical need where no therapies exist today. We intend to start a phase three study in late 2022. In addition to our late-stage clinical programs, we believe we've also been making great progress with our early and mid-stage programs. As we have highlighted for a bit now, a key growth driver for Alnylam is our expansion beyond rare diseases into prevalence. Our program for hypertension is a great example. Zalbitiran, formerly known as LNA-GT, is our investigational RNAi therapeutic targeting the genetically-validated target angiotensinogen in development for the treatment of hypertension.

We believe this represents an important expansion option for future sign in an area of high unmet medical need windows herpes exists today, we intend to start a phase III study in late 2022.

In addition to our late stage clinical programs. We believe we've also been making great progress without early and mid stage programs.

As we've highlighted for a bit now a key growth driver for <unk> is our expansion beyond rare diseases into prevalent disease.

Program for hypertension is a great example, Dolby surround formerly known as <unk> is our investigational <unk> therapeutic targeting the genetically validated target angiotensin agent in development for the treatment of hypertension.

Akshay Vaishnaw: Zolt Bissrand is being evaluated in the phase two cardio program. The first of the two studies, cardio one, is currently enrolling, and it's designed to evaluate the efficacy and safety of Zolt Bissrand as a monotherapy in patients with multiple appetite tensions. The second of these studies, CARDIAC2, was initiated in the fourth quarter and is designed to evaluate the efficacy and safety of Zalbisran as an add-on therapy in patients with hypertension despite treatment with standard of care.

<unk> is being evaluated in the phase II cardiac program. The first of the two studies cardio. One is currently enrolling and is designed to evaluate the efficacy and safety of <unk> as a monotherapy in patients with mild to moderate hypertension.

Second of these studies <unk> two was initiated in the fourth quarter and is designed to evaluate the efficacy and safety of Dolby surround with an add on therapy in patients with hypertension, despite treatment with standard of care.

Akshay Vaishnaw: We also continue to gather data from the ongoing Phase 1 study and recently presented updated data at the American Heart Association Scientific Session. Here, single doses of investigational Zalbisaran resulted in sustained AGT and blood pressure reductions through six months, supporting quarterly and potentially biannual doses. We also observed that blood pressure response to low salt intake under the peak pharmacodynamic effect of Zarbisran was consistent with augmented pharmacology, with no hypotensive adverse events reported.

We also continued to gather data from the ongoing phase one study and recently presented updated data at the American Heart Association scientific sessions here single doses of investigation with Dolby surround resulted in sustained ADT and blood pressure reductions through six months supporting quarterly and potentially biannual dosing.

We also observed that blood pressure response to low sulfur salt intake under the peak Pharmacodynamic effect of <unk> was consistent with augmented pharmacology with no hypotensive cardiac adverse events reported.

Akshay Vaishnaw: Additionally, co-administration with Urbisartan results in additional blood pressure lowering without signals of renal toxicity. Our B-surround was generally well-tolerated with no treatment-related serious adverse events or study withdrawals, supporting continued development. Another key growth driver for Alnylam in the years to come will be our organic product engine driving sustainable innovation. Here, we've made strong progress in the fourth quarter. We moved two programs toward the clinic with recent CTA filings for LNXDH and gout, and, very excitingly, our first CNS program, LNAPP, for the potential treatment of Alzheimer's disease and cerebral amyloid angiopsy.

Additionally, co administration with <unk> resulted in additional blood pressure lowering without signals of renal toxicity.

<unk> was generally well tolerated with no treatment related serious adverse events will study withdrawals supporting continued development.

Another key growth driver for all nine of them in the years to come will be our organic product engine driving sustainable innovation.

Here, we've made strong progress in the fourth quarter, we moved two programs towards the clinic with recent C. J filings for <unk> gallant and very Excitingly, our first CNS program.

For the potential treatment of Alzheimer's disease, and cerebral amyloid angiopathy.

Akshay Vaishnaw: We're thrilled to announce today that the phase one study for LNAPP has now been initiated, and we look forward to starting the phase one trial for LNXD8 early this year. These are just a few highlights amongst the many exciting programs being advanced by our organic research engine, and we look forward to updating you all on this progress throughout the year. With that, let me now turn the call over to Jeff to review our financial results and upcoming milestones. Jeff?

We're thrilled to announce that the phase one study for <unk>.

<unk> has now been initiated and we look forward to starting the phase one trial for add on XT eight early this year.

So is it a few hotlines amongst the many exciting programs programs being advanced by our organic research engine and we look forward to updating you on this progress throughout the year with that let me now turn the call over to Jeff to review our financial results.

Coming milestones Jeff.

Jeff Poulton: Thanks, Akshay. Good morning, everyone. I'm pleased to be presenting Alnylam's Q4 and full year 2021 financial results, which underscore Alnylam's strong commercial capabilities and operational excellence and reflect another impressive quarter of progress on our journey toward building a self-sustainable financial profile, aligned with our P5 by 25 goal. After commenting on our fourth quarter and full year 2021 results, I will also provide our financial guidance for 2022. Turn it now to a summary of our full P&L results for the quarter and full year.

Thanks, Akshay and good morning, everyone I am pleased to be presenting all violence Q4, and full year 2021 financial results, which underscore all mylan strong commercial capabilities and operational excellence and reflect another impressive quarter of progress on our journey towards building a self sustainable financial profile aligned with our piece of that by 'twenty five.

Goals after commenting on our fourth quarter and full year 2021 results I will also provide our financial guidance for 2022.

Jeff Poulton: Total product revenues for 2021 were $662 million, or 83% growth versus 2020, with all three marketed products contributing material year-over-year growth. Net revenue from collaborations for the fourth quarter was approximately $60 million, which included recognition of a $25 million milestone due from Novartis following the December FDA approval of Lectio. Our non-GAAP R&D expenses increased 34% in the fourth quarter of 2021 compared to the same period in 2020, primarily due to an increase in expenses associated with our mid- and late-stage pipelines.

Turning now to a summary of our full P&L results for the quarter and full year.

Total product revenues for 2021 or $662 million or 83% growth versus 2020, with all three marketed products contributing material year over year growth.

Net revenue from collaborations for the fourth quarter was approximately $60 million, which included recognition of a $25 million milestone due from Novartis. Following the December FDA approval of <unk>.

Our non-GAAP R&D expenses increased 34% in the fourth quarter of 2021 compared to the same period in 2020, primarily due to an increase in expenses associated with our mid and late stage pipeline, including investment in.

Jeff Poulton: Including investment in our two Phase II studies for B-Seran and hypertension, Cardia I and Cardia II, and ongoing investment in our two ATTR Phase III studies in cardiomyopathy, Apollo B and Helios B. Our non-GAF SG&A expenses increased 17% in the fourth quarter of 2021 compared to the same period in 2020, primarily due to increased investment in commercial and medical affairs activities to continue supporting Patro and Givlari and the first full year of Oxlumo commercialization, as well as legal expenses associated with the ongoing Department of Justice investigation.

In our two phase III studies for <unk> <unk> in hypertension, Carty, one in cardio too and ongoing investment in our two <unk> phase III studies in cardiomyopathy, Apollo B Helios B.

Our non-GAAP SG&A expenses increased 17% in the fourth quarter of 2021 compared to the same period in 2020, primarily due to increased investment in commercial and medical affairs activities to continue supporting on Petro and give Laurie and the first full year of box limo commercialization.

Well as legal expenses associated with the ongoing department of Justice investigation.

Jeff Poulton: Our non-GAAP R&D and SG&A expenses were approximately $1.2 billion in 2021, representing 16% growth versus 2020, as we continue to advance our pipeline and deliver strong top-line growth while maintaining discipline in how we invest in our operations. Our non-GAF operating loss for 2021 was $528 million, representing a $121 million improvement compared with 2020 as we continue to progress on our journey toward building a self-sustainable financial profile aligned with our P to the fifth by 25 goals. Finally, we ended the year with cash, cash equivalents, and marketable securities of $2.4 billion, compared to $1.9 billion at the end of 2020.

Our non-GAAP R&D and SG&A expenses were approximately $1 $1 2 billion in 2021, representing 16% growth versus 2020, as we continue to advance our pipeline and deliver strong top line growth, while maintaining discipline in how we invest in our operations.

Our non-GAAP operating loss for 2021 was $528 million, representing a $121 million improvement compared with 2020 as we continue to progress on our journey towards building a self sustainable financial profile aligned with our peer set by 'twenty five goals.

Finally, we ended the year with cash cash equivalents and marketable securities of $2 4 billion compared to $1 9 billion at the end of 2020.

Jeff Poulton: The increase was primarily due to receipt of the second $500 million payment from Blackstone associated with monetizing 50% of the future sales of Lectio, $500 million from a drawdown on our credit facility, and more than $200 million from the exercise of employee equity awards, all offset by cash used in our operations to support overall growth. We continue to believe that our current cash balance will bridge us to a financial self-sustainability profile and an enviable position in today's market environment.

The increase was primarily due to receipt of the second $500 million payment from Blackstone associated with monetizing 50% of the future sales of IPO.

$500 million from drawdown on our credit facility and more than $200 million from the exercise of employee equity awards offset by cash used in our operations to support overall growth.

We continue to believe that our current cash balances will bridge us to a financial self sustainability profile and enviable position in today's market environment.

Jeff Poulton: Now turning to our financial guidance for 2022, which does reflect the potential impact of the ongoing pandemic, particularly during the first half of the year. Starting with Net Product Revenues, we are providing combined Net Product Revenue guidance for Onpatro, Givlari, Oxlumo, and Boutriseran, assuming approval by the PDUPA date in April. We anticipate combined net product revenues for these four products will be between $900 million and $1 billion, with the midpoint of the range representing 44% growth compared to 2021. We also anticipate that our Q1 2022 combined product revenues will be down modestly compared with Q4 2021.

Now turning to our financial guidance for 2022, which does reflect the potential impact of the ongoing pandemic, particularly during the first half of the year.

Starting with net product revenues, we are providing combined net product revenue guidance for on Petro give Laurie Shlomo <unk>, assuming approval by the <unk> date in April .

We anticipate combined net product revenues for these four products will be between $900 million and $1 billion with the midpoint of the range, representing 44% growth compared to 2021.

We also anticipate that our Q1 'twenty two.

<unk> product revenues will be down modestly compared with Q4 2021.

Jeff Poulton: While we do expect an increase in patient demand during Q1, driven by an increase in patients on therapy across our products, we expect this will be more than offset by headwinds associated with the stocking, gross to net benefits that occur in Q4, not recurring in Q1. Our guidance for net revenue from collaborations and royalties is a range between $175 and $225 million, with the midpoint of the range representing 10% growth from 2021.

While we do expect any recent.

A recent peak.

During Q1, driven by an increase in patients on therapy across our products. We expect this will be more than offset by headwinds associated with the stocking gross to net benefits that occurred in Q4 not recurring in Q1.

Our guidance for net revenue from collaborations and royalties is a range between 175 and $225 million with the midpoint of the range representing 10% growth from 2021.

Jeff Poulton: Growth in 2022 is expected to come primarily from our collaboration with Regeneron and royalties and milestones from Novartis based on Lectio sales. Our guidance for combined non-GAAP R&B and SG&A expenses is a range between $1.4 and $1.5 billion.

Growth in 2022 is expected to come primarily from our collaboration with Regeneron on royalties and milestones from Novartis based on lithium sales.

Our guidance for combined non-GAAP , R&D and SG&A expenses as a range between one four and $1 5 billion.

Jeff Poulton: The midpoint of the guidance range represents a projected 18% increase compared with 2021. We anticipate SG&A growth will be lower than our growth in R&D in 2022, as we seek to generate operating leverage from our existing commercial infrastructure to support our three current commercial products and a potential launch of all three. We expect a higher rate of growth for R&D, driven by increased investment in Cardia I and Cardia II, our two ongoing Phase II blood-waste strain studies in hypertension, plus increased investment in our preclinical Let me now turn from the financials and discuss some key goals and upcoming milestones for 2022. To start, we plan to continue commercializing our three existing marketed products, Patro, Givlori, and Oxaluma.

Midpoint of the guidance range represents a projected 18% increase compared with 2021.

We anticipate SG&A growth will be lower than our growth in R&D in 2022, as we seek to generate operating leverage from our existing commercial infrastructure to support our three current commercial products and a potential launch of <unk>.

We expect a higher rate of growth for R&D, driven by increased investment in cardio one cardio to our two ongoing phase III <unk> studies in hypertension, plus increased investment in our preclinical portfolio as we continue to drive additional innovative organic growth opportunities.

Let me now turn from financials and discuss some key goals and upcoming milestones in 2022.

To start we plan to continue commercializing our three existing marketed products on tap broker borrowing and ox limo.

Jeff Poulton: We plan to continue advancing our TTR-ACTR franchise. With Patrice Rann, we look forward to the potential approval of the U.S. launch of the fifth RNAi therapeutic with a PDUPA date of April 14th. Approval in the EU is anticipated mid-year, with subsequent launches in key markets to follow, pending finalization of pricing and reimbursement.

We plan to continue advancing our ctr ctr franchise liquid treats ramp we look forward to the potential approval of Europe and U S launch of the fifth RNA therapeutics with a <unk> date of April 14th.

Approval in the EU as anticipated mid year with subsequent launches in key markets to follow pending finalization of pricing and reimbursement.

Jeff Poulton: With Batista in, we look forward to top-line results from the Apollo B Phase III study in mid-2022. Next, we have an exciting readout coming up with some D-SARAN, where we plan to report Phase 2 monotherapy results in IgA nephropathy in early 2022. For Vabisaran, the CARDI-1 trial is expected to complete enrollment in mid-2022.

With <unk>, we look forward to top line results from the Apollo B Phase III study in mid 2022.

Next we have an exciting readout coming up with some dis ran where we plan to report phase II monotherapy results in Iga nephropathy in early 2022.

First of all be Saran that Carty, one trial is expected to complete enrollment in mid 2022.

Jeff Poulton: For ALN HPVO2, partnered with VEER and also known as VEER 2218, we look forward to phase two combination results in the early part of the year. And for ALN-XDH, we're excited to get that phase one study started shortly, with top-line results for both this program and ALN-APP expected in late 2022.

For <unk> HBV <unk> partnered with Vir and also known as the year of $22 18, we look forward to phase II combination results in the early part of the year.

And for <unk>, we're excited to get that Phase. One study started shortly with top line results for both this program in <unk> and APB expected in late 2022.

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

Christine Lindenboom: Thank you, Jeff. Operator, we will now open the call for your 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 any additional questions. Our first question comes from Ritu Baral on Cowan. Hi guys, thanks for taking the question. I wanted to ask, as you think about the VooTree Saran approval and the VooTree Saran label, how should we be thinking about the potential inclusion of cardiac subgroup data within the label?

Thank you Jeff Operator, we will now open the call for your 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 any additional questions.

Our first question comes from <unk> with Cowen.

Christine Lindenboom: And should we expect any additional Helios A cardiac data sets presented at upcoming meetings that could either give us more insight into a potential Apollo B placebo, whether it's Alnylam data, whether it's third-party data, etc.? Thank you.

Hi, guys. Thanks for taking the question.

Ask as you think about the victory ran approval.

<unk> label.

How should we be thinking about potential inclusion.

Published data within the label and should we expect any additional.

Helios.

Cardiac datasets for example upcoming.

Come on.

Give us Martin site.

<unk>.

Apollo placebo.

Whether it's out in Ireland data, whether it's third party data.

Okay.

Yvonne Greenstreet: Thanks for your question, Ritu. I'll just start off by saying that we're really excited about the potential launch of vitreous REM later this year because we really believe that vitreous REM has a compelling proposition, really, with its quarterly subcutaneous regimen allowing patients essentially freedom from their disease. And just one important point that I'd like to make, we do see the launch of vitreous REM as adding to our overall TTR franchise. We don't see it as a net zero-sum game.

Thanks for your question <unk> I'll, just start off by saying that we're really excited about.

<unk> launch of <unk> later this year, because we really believe that <unk> has a compelling proposition really with its quarterly subcutaneous regiment, allowing patients Sn.

Essentially freedom from their disease, and just one point that I'd like to make we do see the launch of the <unk>.

Adding to our referral GTR franchise, we don't see it as a.

Net zero sum game and we also.

Yvonne Greenstreet: And we also recognize that we're still early with respect to accessing HA-TTR patients with polyneuropathy given that Onpatra has been able to secure about 2,050 patients, and there are about 30,000 patients worldwide that are still awaiting treatment. You probably are aware, and I know this for you too, that what we feel so pleased about is that we've been able to essentially replicate with Helius A both the nine months and the 18 months data what we found in Apollo.

Recognize that we're still early with.

With respect to.

Accessing.

<unk> patients with Polyneuropathy.

Given that <unk> been able to secure about 2015 patients and they are about 30000 patients worldwide.

That is still awaiting treatment.

Yvonne Greenstreet: And I think this is an incredible achievement, actually, when you think about these studies being run at different times. And so the patient population was very similar, and the results, you know, as I said, were very consistent between Helios A and Apollo. But perhaps, Akshay, I'll ask you to comment on your views about the cardiac data and, you know, what we can expect there and, you know, what might be on the label. Yeah, no, thanks, Yvonne.

You probably.

No the three to that.

What we feel so pleased about.

Is that we've been able to essentially replicate.

With <unk>.

PDSA, both the nine months and the 18 month data what we found in Apollo and I think this is an incredible achievement actually when you think about these studies being run at different times.

And so that the patient population was very similar in the results.

As I said, it's very consistent between Helios, a and anthropologie, but perhaps exhale and ask you to comment on your views about the.

Cardiac data and what we can expect there.

What might be on the label.

Akshay Vaishnaw: We were obviously very excited about the exploratory cardiac data, whether it's the BNP, the echocardiographic, and those, essentially, as you said, were very similar to what we've seen in Apollo. But most importantly, some new information on technetium scans showing the potential thalamoid mobilization with reduction in uptake in technetium. So that's really exciting new information and again adds to our confidence in our subsequent work in Apollo B and Helios B. So, you know, we continue to feel very good about the potential for both Onpatro, Pituceran, and Butriceran in the cardiac context in those studies.

Yes.

Thanks, Yvonne we were obviously very excited about the exploratory cardiac data whether it's the.

BNP deck cartographic.

Those essentially as you said were very similar to what we've seen the Apollo.

But most importantly, new information on technician scan showing that.

Potential families mobilization with reduction.

And uptake and technician, so that's really exciting new information and again adds to our confidence in our subsequent work in Apollo B Helios B.

So.

We continue to feel very good about the potential for.

Both <unk> and <unk> in the cardiac context in both studies as far as the labels can said, whilst those exploratory data we believe law.

Akshay Vaishnaw: As far as the label's concerned, whilst those exploratory data we believe are exciting and speak a lot about the potential for the drug, you know, Helios A was designed and executed exactly as closely as possible to Apollo, and we expect a very similar label, frankly, to the data that I'm talking about. We've largely shared. You know, there'll be additional data coming out at meetings through the year, further going into the Helios A data set, but to your specific question, I don't know that those data will shed light on the natural history of the cardiomyopathy and the other features you're alluding to, as we look forward to the Apollo B data, which will be at hand all too soon in the middle of the year, actually. You know, I think that's where I'll leave it. Got it. Thank you.

Ting and speak a lot about the potential for the drug.

Helios a was was designed and executed exactly as close as possible to Apollo and we expect a very similar label frankly REIT too.

The data that I'm talking about while we've largely shed, but there'll be additional data.

Coming out at meetings through the year.

Further going into the Helios, a dataset, but to your specific question.

I don't know that those data will shed light on the natural history of the cardiomyopathy and the other features youre alluding to.

As we look forward to the Apollo B data, which will be at handled to sit in the middle of the year actually so.

I think that that satisfy I'll leave it.

Yes.

Got it thank you.

Yvonne Greenstreet: And Richard, just as a reminder, you know, with respect to Helios A, of course, the patient population is HATTR with polyunit. Our next question comes from Gena Wang with Barclays. Thank you for taking my questions. Just one question regarding the guidance assumption. I assume the main driver will be the ATTR franchise.

And Richard just as a reminder.

With respect to <unk> of course, the patient population is.

<unk> with Polyneuropathy.

Yes.

Our next question comes from Gena Wang with Barclays.

Thank you for taking my questions. Just one question regarding the guidance assumption.

Assume the main driver will be the ATT all franchise wondering if you can give a little bit more color.

Yvonne Greenstreet: I'm wondering if you can give a little bit more color regarding the assumption you have for Ampatro and the Vitrus rent for 2020. Yeah, that's a great question, Gena. You know, this is a very important part of our growth opportunity, the TTR franchise. We believe that, you know, we will be the leaders in this area in terms of meeting the needs of all patients with TTR over time. Tolga, perhaps you could speak specifically about how we're thinking about Vutrisran and Onpatrio.

Regarding assumption you have for <unk> for 2022.

Yes.

Great question Janet this is a very important concept.

Our go forward growth opportunity.

TCR franchise, we believe that we will be the leaders in this area in terms of meeting the needs of all patients with TCR overtime.

Talk of perhaps you could you could speak specifically to how we're thinking about.

Patrice ran and on Patrick I know that one of the things that were maybe piece of that is actually is the stickiness that we're seeing with <unk>.

Yvonne Greenstreet: I know that one of the things that we're really pleased about is the stickiness that we're seeing with Onpatrio, with greater than 90% adherence, which is actually remarkable, you know, for therapy that's administered intravenously every three weeks. And as I said before, you know, I think the profile of Vutrisran is particularly compelling.

On Patriot with a greater than 90% adherence, which actually is remarkable.

For a therapy that's administered intravenously.

Three weeks.

I said before.

I think I think the profile of those which we surround is particularly compelling and so I think as I said the important point here is that we see the launch of Patrice ran in Polyneuropathy is growing the overall TCR franchise, and clearly that will continue to grow overtime.

Yvonne Greenstreet: And so I think, as I said, the important point here is that we see the launch of Vutrisran in polyneuropathy as growing the overall TTR franchise. And clearly, that will continue to grow over time, assuming, of course, positive data for both Onpatrio and Vutrisran from Apollo B and Helios B respectively. But perhaps Tolga, you could provide some additional perspectives on how you see Onpatrio. Andrew Treet's round over the course of this.

Assuming of course.

Positive data for both <unk> and for <unk> from from.

Apollo B, and Helios, b, respectively, but perhaps.

Taco you could you could provide some additional perspective on how your steel Patriot.

<unk> over the course of this year.

Tolga Tanguler: Sure, sure. Good morning, everyone. Listen, I think you really made the point around the fact that the guidance we have provided assumes an accelerated growth for our TTR franchise. That's our anchor franchise.

Sure sure good morning, everyone.

Listen I mean, I think you really made the point around the fact that we the guidance we have provided assumes an accelerated growth.

For our TCR franchise, that's our anchor franchise also at the same time, our other ultra rare disease products will certainly be.

Tolga Tanguler: Also, at the same time, our other, you know, ultra-rare disease products will certainly be contributing to that and punching above their weight. When it comes to vitreous strand, Yvonne is spot on. I mean, this is not going to be a zero-sum game.

Contributing to that and punching above their weight.

Tolga Tanguler: We do anticipate a number of patients that may not have been benefiting from Onpatro will certainly find the profile that we have very appealing, subcutaneous, three months, and then subsequently six months. We believe that's going to accelerate the overall growth rate. And also, as she pointed out, we are barely scratching the surface in terms of the number of patients that are being diagnosed and treated. We have 30,000 patients across the world, and a very small number of those are being treated despite the fact that there are three products available out there.

When it comes to surround.

Ivan Ivan is spot on I mean, this is not going to be a zero sum game.

We do anticipate number of patients that may not have been benefiting from on Petro.

Suddenly find the the profile that we have very appealing subcutaneous three month and then subsequently six months, we believe thats going to exited low growth profile and also.

She also pointed out we are barely scratching the surface in terms of the.

The number of patients that are being diagnosed and treated we have 30000 patients across the world and a very small number of those are being treated despite the fact that there are three products available up there so.

Tolga Tanguler: So, with the product profile, if approved for the vitreous strand polyneuropathy indication, we certainly see an accelerated growth in the U.S. after the PDUFA date of April 14th. And then, additionally, we do anticipate two launches in Japan and Germany later in the fourth quarter, which probably will not contribute as much, but it's going to help the momentum. Our next question comes from Kazin Amon with Bank of America. Hi, good morning, and thank you for taking my question. Could I ask you one or Cartier one?

With the product profile, if approved would treat polyneuropathy indication, we certainly see an accelerated growth in the U S. After that.

The 14th.

And then subsequently also we do anticipate two launches.

In Japan in Germany later in the fourth quarter, which probably will not contribute as much but it's going to help the momentum.

<unk>.

Thank you.

Our next question comes from <unk> <unk> with Bank of America.

Tolga Tanguler: You know, you do have your top line result phase two that is due by this year, and as you mentioned, what should we be looking for for what you would consider to be clinically meaningful data there? And, you know, what would be a good comparator on the competitive landscape to kind of judge effectiveness against? Thank you. Yeah, no. Thank you for that question, Tazeena. As I'm sure you all know, we are really very excited about the potential that Zalbi Saran has and addressing, you know, patients with high potential.

Hi, Good morning, and thank you for taking my question.

One on one you do have your top line results phase III better Keith side, this year and as you mentioned.

What should we be looking for for what you would consider to be clinically meaningful data there.

And what would be a good call.

On the competitive landscape to kind of judge effectiveness again thanks.

Tolga Tanguler: And you know, just to remind you, we've already demonstrated what we need to demonstrate from an efficacy perspective for approval in our phase 1 study, not just as a single dose, we're able to effect a blood pressure lowering of between 10 and 20 millimeters of mercury, which is actually tremendous. Clearly, we need to deliver on the two phase 2 studies and then move forward into phase 3. But I think, from my perspective, what's really exciting about Zarbis-Ran is, firstly, the size of the opportunity in a very prevalent population, 1.2 billion people across the world with hypertension, but also the very straightforward path to regulatory approval here. Clearly, Cardio One is a key step along that journey.

Yes, Hello, and thank you for that question to Athene as I'm sure you all know which are really very excited about the potential that <unk> has in addressing.

Patients with hypertension.

Just to remind you what we've already demonstrated.

What we need to demonstrate from an efficacy perspective for an approval and a phase one study. After a single dose we are able to affect blood pressure lowering of between 10 and 20 millimeters of Mercury, which is which is actually tremendous.

Really we need to.

Deliver on the two phase III studies, and then and then and then move forward into phase III, but I think I think I think from my perspective.

What's really.

Kind of exciting about <unk> is firstly.

Yes.

The size of the opportunity in a very prevalent population $1 2 billion people across the world with hypertension, but also the <unk>.

Straightforward path to regulatory approval here and clearly cardio one is a key step along that.

Johnny So I'll ask <unk> now to maybe speak a bit more specifically about.

Yvonne Greenstreet: So I'll ask Akshay now to maybe speak a bit more specifically about what we're looking for with respect to outcomes from Cardio One, and then I will turn it over to Tolga to provide some views on competitiveness. Yeah, great.

What we're looking for.

With respect to outcomes from.

Cardio, one and then I will turn it over to <unk> to provide some views on the competitive landscape.

Akshay Vaishnaw: So, as Yvonne said, I think we should, once again, recall really the very dramatic and impressive results from the phase one study with over 20 millimeters mercury drop in systolic blood pressure, the top dose maintained out through six months. Now, the phase two study will hope to replicate the blood pressure results. We saw in the phase one study that historically, anything above a five millimeter mercury drop in blood pressure seems to be notable, and people would advance those kinds of drugs into further development.

Yeah, great. So as Ivan said I think we should once again recall really the very dramatic and impressive results from the phase one study with over 20 millimeters of Mercury.

Drop in blood systolic blood pressure at the top dose and maintained that through six months now.

The cardio <unk> study, we'll hope to replicate the blood pressure results. We saw in the phase one study historically anything above a five millimeter.

Mercury drop in blood pressure, you seem to be notable and people would advance those kinds of drugs into further development.

We would hope to do better than that based on what I. Just told you now whether we will see exactly what we saw in the phase one study I don't know.

But I'm confident we can do better than that in cardio. One then the five millimeter threshold I just said.

Akshay Vaishnaw: We would hope to do better than that based on what I just told you now. Whether we'll see exactly what we saw in the phase one study, I don't know. But I'm confident we can do better than that. In cardio one, then the five millimeter threshold, I just said, you know, I think the other thing to remember about what's clinically meaningful with the angiotensinogen approach and why it may not be entirely right to just compare it to a blood pressure reduction number is the way blood pressure is being reduced with Zalbisaran.

I think the other thing to remember about whats clinically meaningful.

With the adjutants antigen approach and why it may be sort of not entirely right to just compare it to.

<unk> pressure reduction number is the way blood pressure is being reduced with Dolby surround so yes absolute reduction blood pressure is important but preventing.

Akshay Vaishnaw: So yes, absolutely reducing blood pressure is important, but preventing, you know, fluctuations in blood pressure and having a smooth atomic control of blood pressure is important to patients, and we hope Zalbisaran can do that. We'll get insight into that from cardio one, and, you know, restoring the physiological nighttime dipping that blood pressure patients often lose that will be important. So there's so much more to Zalbisaran than just a starting blood pressure reduction number; the way it's done and the features I talked about as well as the adherence advantages with having a potentially once every three or six month administration of the drug.

Fluctuations in blood pressure on having a smooth atomic control of blood pressure is important to patients and we hope they'll piece Ryan can do that we'll get insight into that from cardio one.

And.

Restoring the physiological nighttime dipping.

Blood pressure patients saw some lose that will be important so there's so much more to zalviso ran than just.

I'll start with blood pressure reduction number is the way it's done.

And the features I talked about as well as the adherence advantages with having a potentially once every three or six months administration of the drug. So I'll stop there lots to look forward to I think in cardio wasn't but toga you want to say something about the landscape.

Tolga Tanguler: So I'll stop there. Lots to look forward to. I think in cardio one, but to talk about, you want to say something about the landscape. Sure. I mean, look, this is clearly a highly genericized class, but this is why I think Alnylam's underlying technology is so exciting because it allows us to really rethink the entire way we actually manage medicine. In spite of the fact that there are easily accessible, genericized products in this category, we still have 40 million Americans that are suffering. How are they related? You know, diseases and the US is spending about a hundred billion dollars a year, according to ACC, on that.

Sure I mean look this is clearly a heightened genericize class, but this is why I think all islands underlying technology.

So exciting that allows us to really rethink the entire.

How to actually manage medicine.

And this despite the fact that there are easily accessible genericize products in this category.

We still have 40 million Americans.

Our suffering.

Pretensive related.

Tolga Tanguler: So I believe from a category perspective, this approach is going to be a tremendous, tremendous benefit to the broader society. And we are obviously, when it comes to different therapy areas, we are obviously ahead of that curve, like nine terms of providing an entire new class of medicine. That's great.

Diseases and the U S is spending about $100 billion. According to ACC for that so I believe from a category perspective.

This approach is going to be a tremendous.

Tremendous benefit to the broader society.

And we are obviously when it comes to different therapy areas. We are obviously ahead of ahead of that curve right now in terms of providing an entirely new class of medicines.

Akshay Vaishnaw: Thanks, Akshay and Tolga. Kazin, did that answer your question? Yeah, thanks for the color, Yvonne.

That's great. Thanks, Oksana Tallgrass has been does that answer your question.

Yes, thanks for the color Gabon.

Thank you.

Yvonne Greenstreet: Thank you. Our next question comes from Palmitate with Stiefel. Great, thanks so much and congratulations on all the progress and getting close to a billion in product revenues, a big milestone. I wanted to ask a question on Apollo B. I guess there's a right or wrong debate in the investor community about the trial design and powering and how to make sense of the bridge buyer result. I guess now that you've digested their data, can you just point us to the one to two reasons why you're confident that on six minute walk tests, you'll see decline for placebo and Apollo B and that you're confident in your powering assumptions? Thanks so much.

Our next question comes from Paul Matteis with Stifel.

Great. Thanks, so much and congratulations on all the progress and getting close to a 1 billion and in product revenues big milestone.

I wanted to ask a question on Apollo B I guess, there is right or wrong debate and the investor community on the trial design and powering and how to make sense of that bridged by our result, I guess now that you've digested their data.

Can you just point us to the one to two reasons why you are confident that on six minute walk test youll see declining for placebo in Apollo B and that you're confident in your powering assumptions. Thanks, so much.

Yvonne Greenstreet: Thank you, Paul. That's a great question. So, look, we're very confident, and we've reiterated this point about our track record in executing studies in the TTR space, and we believe that we have put all the mechanisms and we have the expertise in place to design studies, train the sites, work with vendors, et cetera, to make sure we have delivered the highest quality data. Now, you probably know as much about the bridge buyer data as we do. So, we're not really going to speak to the bridge buyer specifically, but I'll hand it over to Akshay to reprise, you know, our perspectives on apologies.

Thank you Paul that's that's that's a great question.

So.

We're very confident in.

We've reiterated.

This fifth point about track.

<unk> track record in executing studies.

Studies in the TCR.

Space and we believe that that we put all the mechanisms that we have the expertise expertise in place to design studies train the sites work with vendors etcetera to make sure.

We have.

<unk> delivered the highest quality data now.

You probably notice as much about the <unk> data.

As.

We do.

So we're not going to speak to <unk> specifically.

I'll hand, it over to Akshay tab.

Reprise.

Our perspectives on Apollo B.

Yvonne Greenstreet: Yeah, thanks, Yvonne. So, Paul, I mean, I think, yes, you know, the same data as us, but it's hardly, I think we'd all agree, a full explanation of the data, right? We would love a full presentation. There's lots more to understand.

Yeah. Thanks, So Paul I mean I think.

Yes, you know the same data as us, but it is hardly I think we'd all agree a full expectation of the data right. We would love a full presentation. There's lots more to understand so we have partial glimpses I think a variety of different explanations over time have been offered by bridge by our colleagues. That's obviously for them to speak further to that study.

But in a context bias trading effects on six minute walk distance all of these have been mentioned by bridge buyer.

Akshay Vaishnaw: So we have partial glimpses, I think, a variety of different explanations over time have been offered by BridgeBio colleagues. That's obviously for them to speak further about their study. But, you know, context, bias, training effects on the six-minute walk. All of these have been mentioned by BridgeBio leaders. So there is more for them to comment on there.

Leaders, so more for them to comment there. The one thing that struck us about their data at least what's public is that the six minute walk distance didn't seem to perform and yet other parameters BNP and case, you see Q showed exactly or very similar to what high level.

What happened in the attract study at 12 months. So it's hard to reconcile that and I think there are explanations.

Akshay Vaishnaw: The one thing that struck us about their data, at least what's public, is that the six-minute walk distance didn't seem to perform. And yet other parameters, BNP and KCCQ, showed exactly or very similar to what happened in the ATTRACT study at 12 months. So it's hard to reconcile that.

Sort of explanations around trading effects context buys etcetera, it shouldnt be borne in mind because of the three parameters BNP cases, each year in six minute walk distance. The last one would be influenced by those kinds of features.

Akshay Vaishnaw: And I think their explanations, or putative explanations around training effects, context, bias, et cetera, should be borne in mind because of the three parameters, BNP, KCCQ, and six-minute walk distance, the last one would be influenced by those kinds of features. And so, again, that's what we see and say from the outside. More for them to comment than I think we should. For our part, we've worked in this area for over a decade.

And so again, that's what we say see and say from the outside more from them to comment on that.

And I think for our part.

We've worked in this area for over a decade, we have designed studies in the <unk> space is significant phase III studies with replicate data across studies I think the Helios a example.

We were just discussing earlier in the call.

Akshay Vaishnaw: We have designed studies in the TTR spaces, significant phase three studies, and we've replicated data across studies. I think the Helios example, which we were just discussing earlier in the call, when the design of the study execution and the data delivery looks so similar to what happened in Apollo, you know, and Apollo was designed in 2013, or executed in 2013. So it shows that we, I think we take great care. And we know how to test hypotheses in this space very diligently and rigorously.

But the design of the study execution of the data delivery looks so similar to what happened in Apollo.

Akshay Vaishnaw: And so we continue to feel very confident in our Apollo B work and how we've designed it and powered it conservatively to hit the primary endpoint of 16 walk distance, and we'll have the data all too soon, in the middle of the year. This question comes from Alidia Young with Kendra Fitzgerald.

And Apollo was designed in 2013 or executed in 2013. So it shows that we I think we take great care and we know how to test hypotheses in this space.

Diligently and rigorously and so we continue to feel very confident.

In our Apollo B work and how we've designed and powered it.

Conservatively.

To hit the primary endpoint of six minute walk distance.

We'll have the data all too soon middle of the year.

Our next question comes from Alethia Young with Cantor Fitzgerald.

Akshay Vaishnaw: Hey guys, thanks for taking my question and congrats on all the progress on your 2021. I guess I'll just be talking about maybe the trend lines between the T-Seran and the Petri Seran potential approval and launch. I mean, do you expect kind of the ramp speed to be about the same, or do you think T-Seran has the potential to have a faster ramp speed since it's already, you know, people kind of know about the class of drugs and it's a sub-Q thing? Thank you, Alicia. That's a great question. I mean, look, we've been really pleased with the performance of Patro.

Hey, guys. Thanks for taking my question and congrats on all the progress over your ads lately, one I guess just talking about maybe the.

Trend lines between the teaser in trade spend potential approval and launch I mean, do you expect kind of the ramp speed to be about the same or do you think that <unk> has the potential to have a faster ramp statements authority.

About.

The classic jobs, and it's a sub Q.

Yvonne Greenstreet: We've demonstrated steady and continuous growth since the launch in 2018, so we're delighted with the contribution that that has made to patients but also to building our business. You know, look, but Beatrice Ran, you know, just has such a compelling profile given its quarterly sub-Q regimen, hopefully soon to become a six-month-to-do edge, and we do believe that there we have a real opportunity to grow the polyneuropathy market with Vutriseran and then subsequently, assuming positive results from Helios B, you know, cardiomyopathy as well. But Tolga, perhaps I'll hand this question over to you.

Thank you Alicia that that's a great question I mean, we've been really pleased with the performance of <unk>.

Patrick.

<unk> demonstrated steady and continuous growth since the launch in 2018. So we're delighted with the contribution that that is made to patients, but also to building an island.

No.

<unk> just has such a compelling profile given its quarterly sub Q regimen.

Hopefully.

Im soon to become six monthly regimen.

And.

We do believe that we have a real opportunity to.

To grow the Polyneuropathy.

Market with <unk> and then subsequently assuming positive results from Helios B.

Cardiomyopathy as well.

<unk>.

Now I'll hand. This question over to you I mean, how do you see.

Yvonne Greenstreet: I mean, how do you see Vutriseran and Onpatro performing in the market over the next year or so? Right. Thank you for that question and thanks, Yvonne. Look, we were able to grow that franchise by 55% after the third year of its launch.

With <unk> and on Patrick performing in the market.

Over the next over the next year.

We are also.

Right.

Hi, Alicia Thank you for that question. Thanks Yvonne.

Look we were able to grow that franchise at 55% of the third year of its launch so clearly the the progress we made on in terms of growth has been has been good.

Tolga Tanguler: So clearly, the progress we made in terms of growth has been good. Next year, we will continue to obviously grow on Petro with three Serenis in the market. Based on the profile that Yvonne indicated, we would anticipate the source of business we have is essentially mainly coming from academic centers. However, as it is now, the business is evolving more into community centers.

Next year, we will continue to obviously grow on Petro until.

With <unk> in the market based on the profile that Ivan indicated.

We would anticipate the source of business. We have is essentially mainly coming from academic centers is now the business is evolving more into the community centers and I think the profile that <unk> has to offer will be very attractive to those physicians that are looking some.

Tolga Tanguler: And I think the profile that Boutrisan has to offer will be very attractive to those physicians that are looking for some different profiles. And also, particularly in Europe, where the stabilizers are also indicated for polyneuropathy, a good portion of our growth has been coming from stabilizers, which are, as you know, daily oral tablets. Now, instead of having, you know, an infusion without any premedical treatment and three-month subcutaneous injection, clearly is a very attractive profile for those patients that may still be on stabilizers.

Different different profile and also herculean in Europe , where the stabilizers are also indicated for Polyneuropathy a good portion of our growth has been coming from.

Stabilizers, which are as you know daily oral tablets.

Instead of having.

An infusion.

In a pre med and three months subcutaneous injection clearly is a very attractive profile for those patients that may still be on the stabilizer. So overall.

Tolga Tanguler: So, overall, we certainly see modest accelerated growth that we've been able to post versus last year. And we will see that in an accelerated fashion. That's the best way I would be able to describe it to you.

We certainly see a modest accelerated growth there.

We've been able to post.

Versus last year, and we will we will see that in an accelerated fashion.

That's the best way I would be able to describe it to you.

Yvonne Greenstreet: Yeah, Tolga, that's great. So, you know, very excited about the TTR franchise overall. The vitreous surround affords the opportunity for physicians and patients to start treatment earlier in patients with polyneuropathy, and obviously in the US, patients who have the mixed phenotype as well. And then, as Tolga said, you know, potential for earlier switch, just given the much reduced treatment burden of the vitreous surround. So hopefully that's answered your question earlier. It did indeed.

Yes ill talk it that's great.

Very excited about the TCR franchise overall patrice around affords the opportunity.

Physicians and patients to start treatment earlier.

In patients with Polyneuropathy and obviously in the U S.

Patients who have the mixed phenotype as well that has told us that potential for areas, where it's just given them much reduced treatment.

<unk>. So hopefully that's answered your question is yes.

Thank you.

Yvonne Greenstreet: Thank you. The next question comes from Anuparama with JP Morgan. Hey guys, thanks so much for taking the question. I have a quick question on the net product guidance. So what is assumed specifically for OUS growth and sort of geographic expansion driving growth versus deeper penetration in the U.S. and some of your core countries that you kind of outlined in the slides for ONPATRO, Gizlari, and Apsaluma? Thanks so much.

Our next question comes from <unk> Rama with Jpmorgan.

Hey, guys. Thanks, so much for taking the question.

I have a quick question on the net product guidance. So what is the assumed specifically for O U S growth and sort of geographic expansion driving growth versus a deeper penetration in the U S. On some of your core countries that you've kind of outlined in the slides for on Petro give Laurie Shlomo. Thanks, so much.

Yvonne Greenstreet: Thanks Anna-Pam, that's a great question. Look, you know, if you think about the different products, you know, on petro, have been on the market now for three years, less opportunity for geographical expansion because we've actually managed to work our way through the various, you know, pricing reimbursement systems, ex-US, very well, and we have incredibly good coverage in the US as well. You know, Givlari cleared it earlier in its launch, and we see their, you know, continued geographic expansion. Just recently, the NICE approval in the UK speaks to that point.

Thanks, Andrew Pam that set.

Great.

Great question.

Look if you think about the different products.

Patrick.

The market now for three years.

Less opportunity for geographical expansion, because we've actually managed to work our way through the various app.

Pricing and reimbursement systems.

<unk> very well and we have incredibly good coverage in the U S is while it give laurie clearly earlier in its launch and we see that continued geographic expansion. Just recently the nice approval in the U K speaks to that to that point and slim and we're really.

Yvonne Greenstreet: And Oxlumo, we're really, you know, 2021 was our first full year since launch. And I think what we're particularly pleased about there is really broad utilization across all age groups and disease severity, and I think we're benefiting in Europe with respect to Oxlumo with the centers of excellence that you see there, which means the patient's already been diagnosed, as well as being able to transition patients from our expanded access program, and those were dynamics that we clearly didn't have in the US.

2021 was our first full year since launch I think what we're particularly pleased about there it's really broad utilization across all age groups disease severity.

I think we're benefiting in Europe with respect to oxygen.

With the centers of excellence that you see that which meant the patients have already been diagnosed.

As well as being able to transition patients from.

R R.

<unk> access program and dose with dynamics that we clearly didn't.

Half in the U S and as we look forward.

Yvonne Greenstreet: And as we look forward, you know, I think we see continued geographical expansion for the more recently launched products, Givlari and Oxlumo, as well as continued penetration. And from petro, we see, you know, across the world, increased patient demand, and new prescribers. And so we expect to see continued penetration in the US and outside the US. But what I'll do, maybe I'll hand it over to Jeff to provide a little bit more color on how we're thinking about the year ahead. Jeff?

I think we see continued geographical expansion for the more recently.

Launched product skip Lori toxicity as well as continued pent.

Penetration and from Patria, we see across the world.

Increased patient demand new prescribers.

And so we expect to see continued penetration.

In the U S and outside the U S.

What I'll do is maybe I'll hand, it over to Jeff.

To provide a little bit more color on how we're thinking about the year ahead, Jeff.

Jeff Poulton: Thanks, Yvonne. Good question, Anupam. We're not breaking out specific geographic detail, but I think Yvonne outlined the sort of the key elements of what's going to drive our XUS growth. And it really depends on time on the market.

Thanks, Ron.

Good question on Apollo, we're not breaking out specific geographic detail, but I think <unk> outlined the sort of the key elements of what's going to drive our ex U S growth and it really depends on time on the market the longer the products had been on the market.

The more it's about naive patient finding and in the case of our ATR franchise. There is still a big switch element products that had been on the market a shorter amount of time still will benefit from additional geographic expansion. So in this case sakuma will be the one that will benefit the most from that going forward. So hopefully that answers the question.

Jeff Poulton: The longer the products have been on the market, XUS, the more it's about naive patient funding. And in the case of our ATTR franchise, there's still a big switch element. Products that have been on the market for a shorter amount of time still will benefit from additional geographic expansion. So, in this case, Oxlumo will be the one that will benefit the most from that going forward. So hopefully, that answers the question. That's great. Thank you very much, Greg. Yeah, thanks for the additional color. Our next question comes from Salveen Richter with Goldman Sachs. Good morning.

That's correct. So much guys yeah. Thanks for the additional color.

Additional color.

Our next question comes from salvage <unk> Richter with Goldman Sachs.

Yvonne Greenstreet: Thanks for taking my question. So you have two data reads this year in tissue targets outside the liver. Could you just speak to the ALN, APP, and HSD readouts and whether you could establish a proof of concept with these reads and what you're specifically looking for clinically? Yes, thank you for that question, Salveen. Look, I'm particularly excited about the opportunity to extend the power of the R&I platform outside the liver. I think this opens up a whole new horizon for the nine of us.

Good morning, Thanks for taking my question. So you have two data reach this year in tissue targets outside the liver could you just a Q <unk> a P. P. In HST readout and whether you could establish proof of concept with <unk> and what you're specifically looking for clinically.

Yvonne Greenstreet: We think about our growth over the next several years. And as you said, LNAPP, we're very excited to be moving that forward in patients with Alzheimer's disease. HSD is obviously a liver-directed target. I think what we're excited about with HSD is, you know, the size of the national patient population, and therefore this is a much more prevalent disease opportunity.

Yes, thank you for that.

<unk>.

I'm, particularly excited about the opportunity to.

Extend the power of the <unk> platform outside the liver I think this opens up a whole new horizon for an item as we think about our growth over the next several years and as you said.

Alan.

<unk>.

We're very excited to be moving that forward in patients with.

Outside of this disease.

HST is obviously.

They have a direct hit targets I think what we're excited about with respect with HST is.

The size of the Nash patient population and therefore this is a much more.

Prevalent disease opportunity.

Yvonne Greenstreet: So I'm going to hand it over to Akshay to, first of all, just very briefly describe what we're expecting to see out of our LNAPP proof of concept study will be getting clinical data at the end of this year. And then also the ongoing phase one study with HSD and Nash. So actually, it's over to you to maybe address those two programs. Yeah, thanks, Salveen. So with respect to LNHSD, which, in fact, is a liver target therapeutic, and HSD is almost exclusively present in hepatocytes.

So I'm going to hand, it over to to Axeda first of all just very briefly describe what we're expecting to see out of <unk>.

<unk> proof of concept study will be getting clinical data at the end of this year and then also the ongoing phase one study with HST in Nash So akshay over to you to maybe address those two those two programs yeah. Thanks, <unk> so with respect to.

Akshay Vaishnaw: So for NASH, you know, some of the key readouts beyond safety, which is very important, will be, you know, evidence for knockdown. And we're taking biopsies in this study. So you can't detect HSD in circulation, and hopefully the biopsies will support the kind of knockdown we're getting. We're obviously confident in that, given what we've seen with many other liver-directed therapeutics with our gal-nat conjugate system. And, you know, in addition to that, we would welcome seeing changes in transaminases. They're often abnormal in patients with NASH, and some improvements there would be encouraging, of course, as would changes in the biopsy, because we won't get definitive biopsies.

Alan HST, which in fact is the liver targeted therapeutic.

<unk> was exclusively president in hepatocytes.

For Nash you know some of the key Readouts beyond safety of course, which is very important will be.

Evidence of knockdown.

And we are taking biopsies in this study so you can't detect HFC in circulation hopefully the biopsies will support the kind of knockdown, we're getting more confident in that given what we've seen with many other liver directed therapeutics without gallon conjugate system.

And in addition to that we would welcome seeing changes in transaminase as they're often abnormal in patients with Nash and some improvements there would be encouraging of course as would changes in the biopsy because.

We went.

Get definitive biopsies is a small study and a definitive readouts that.

Akshay Vaishnaw: It's a small study and a definitive readout, but some changes in the histological parameters of NASH relating to inflammation and or fibrosis would be exciting to see. But again, you know, small study, short-term treatment, so it would be, frankly, very surprising if we see that, but we would love to see that if we could. So that's for HSD. For APP, CNF-directed therapeutics for Alzheimer's and for cerebral amyloid angiopathy. First and foremost, safety. This is our first foray into the central nervous system with our novel conjugate system for neuronal tissues.

Some changes in the histological parameters of mash relating to inflammation and fibrosis would be exciting to see but again small study short term treatment. So it would be frankly very surprising if we see that but we would love to see that if we could.

So that's for HSV for IPP.

CNS directed therapeutic for Alzheimer's and full circle amyloid Angiopathy first and foremost safety. This is our first foray into the central nervous system with our novel conjugate system.

So for new and old tissues.

Akshay Vaishnaw: And then, beyond safety, we'll be looking for biomarker knockdown to show target engagement. And we'll be looking for changes in those degradation fragments from the proteolytic breakdown of APP, one of which, most importantly, is A-beta itself. So that's what we look forward to from those two studies. But agreed, exciting times, and great to see the power of RNAi going beyond the liver.

And then beyond safety, we will be looking for by Banca knockdown to show target engagement and so a P. P. Amyloid precursor protein generates a host of fragments that are detectable in the cerebrospinal fluid and we will be looking for changes in those.

Degradation fragments from protein intake breakdown of AEP.

One of which most importantly is a beta itself. So that's what we look forward to from those two studies been agreed exciting times and great to see the power of RNA like going beyond the liver.

Akshay Vaishnaw: Thanks, Akshay. And Salveen, of course, we announced today that our Phase 1 study has kicked off with AI and APP. So, you know, we're looking forward to the data that Akshay describes at the end of this year. Terrific progress.

Thanks, Roxanne for being of course, we announced today that the.

Our phase one study has kicked off with <unk>.

Yeah.

Looking forward to that.

Data that assay describes at the end of this year. So terrific progress we're very very pleased.

Thank you.

Yvonne Greenstreet: We're very, very, Our last question comes from Maury Raycroft with Jeffreys. Hi, good morning, congratulations on the progress and thanks for taking my question. I have a question on Apollo B.

Our last question comes from Maury Raycroft with Jefferies.

Maury Raycroft: For the study, you've got 14 sites in the US and then 52 sites XUS listed. Just wondering if you can say what proportion of patients in Apollo B are going to be from the United States versus XUS. And then, as a follow-up, can you talk about sites overlapping between your Apollo B sites and the bridge biosites? Thanks Maury, I think I'm going to pass that question right on to Akshay. Yeah, Samori, I mean, I think, as we've shown before, the performance of our drugs, at least, in our definitive experiences with HATTRPN, both in the shape of the original Apollo study with Piece around and now with Chris around, you know, in the context of HATTRPN out of the show, very similar effects, regardless of geography, frankly, and that's been published; you can go and look at HATTRR, so that So we're looking forward to similar data, consistency of effect, regardless of geography, in a polybion heliosp eventually, regardless of the size split, and with regard to the lack of size.

Hi, good morning, Congrats on the progress and thanks for taking my question.

A question on Apollo B.

For this study you've got 14 sites in the U S. And then 52 sites ex U S listed.

Just wondering if you can say what proportion of patients in Apollo b are going to be from the United States versus ex U S. And then as follow up can you talk about sites overlapping between Euro Apollo B sites in a British bio sites.

Thanks, Maury I think I'm going to pause that.

Question right across two to Akshay.

Yeah, So tomorrow, I mean, I think as.

As we've shown before the performance of our drugs at least in our definitive experiences and <unk>. Both in the shape of the original Apollo study with T Saran and now with Boutris around.

In the context of <unk> capital.

Very similar effects, regardless of geography frankly.

And that's been published you can go and look it up et cetera.

So that's that's important to bear in mind because of the centrality of <unk> to these diseases, whether it's <unk> or other disorders like cardiomyopathy is we believe so.

So we're looking forward to similar data consistency of effect, regardless of geography in Apollo B and Helios B eventually regardless of the site split.

And with regard to a lack of size, we don't get into those details, but because largely we don't know if that's not relevant frankly again because of the strength of our hypothesis. We believe that <unk> silencing approach is the most potent way to address this disease and the consistency of our prior data.

Akshay Vaishnaw: Well, we don't get into those details, but because largely we don't know if it's that relevant, frankly, again, because of the strength of our hypothesis, we believe that TTR philosing approaches are the most potent way to address this disease, and the consistency of our prior data speak to that, and again, the encouraging exposure cardiac data from heliosay just further attest to exciting information we're looking forward to from Apollo But I'll leave it be. Thanks, Thanks. I guess it is.

Speak to that.

Again, the encouraging exploratory cardiac data from Helios a to further task to exciting information, we're looking for from Apollo B later in the year, including.

To remind everybody the potential cut it mobilization that we sold with the technician data infill USA, but I'll leave it there. Thanks Bart.

Thanks.

Yes.

Akshay Vaishnaw: Oh, do you have a follow-up question? Well, maybe a quick follow-up. I guess if there are overlapping sites between the two studies, are you getting first-hand insight into the training effect and bias issues that you've discussed in the text-minute walk tests, and have you been able to mitigate some of those issues? Yeah, the bias issues and the training issues we have reflected commentary from bridge buyer. We don't see any such issue in our studies, either historically or otherwise.

Maybe.

Question.

Maybe a quick follow up I guess, if there are overlapping sites between the two studies are you getting firsthand insight into the training effect and bias issues that you've discussed on six minute walk test and have you been able to mitigate some of those issues.

Akshay Vaishnaw: And with respect to our studies, we take great care in understanding the natural history of these diseases and carefully designing the study, in conservatively powering and designing the statistical approach to the study. And then selecting the right contract research organizations to work with, who have experience with the kinds of end points and managing the kinds of sites we want to work with. And then during the study, diligently following up and making sure sites are performing according to expectations; that's a sophisticated approach.

Yes, the bonds issued in the training issues, we have reflected commentary from bridge buyer.

Don't see any such issue in our studies, either historically or otherwise.

With respect to our studies.

We take great care in understanding the natural history of these diseases in carefully designing this study.

Conservatively powering and designing the statistical approach the study and then selecting the right contract research organizations to work with who have experience with the kinds of endpoints and managing the kinds of sites, we want to work with and then during the study diligently following up and making sure sites are performing per our expectations.

Akshay Vaishnaw: That's one we've heard over a decade; we've done multiple phase three studies, all of which have been positive up until now across a range of drugs, including multiple drugs in the TTR space. But, you know, for bridge buyers, this was their first phase three study, and they would have to answer, you know, how many of those kinds of things were put in place.

That's a sophisticated approach that's one we've heard over a decade, we've done multiple phase III studies, all of which have been positive up until now across a range of drugs, including multiple drugs in the <unk> space.

Akshay Vaishnaw: And they have made the commentary about context bias, training effects, et cetera. So I'll leave it there, Marie. Thanks. Okay, it's very helpful.

Trowbridge buyout. This was their first phase III study.

They would have to answer how many of those kinds of things were put in place and they have made the commentary about context bias training effects etcetera. So I'll leave it there. Thanks.

Very helpful. Thank you.

Operator: Thank you. Thanks, Akshay. Look, and thank you everyone for joining us on this call. 2021 was a remarkable year for Alnylam, and we made significant progress both commercially and scientifically, and we're very excited about 2022, which is shaping up to build further on that as we continue to fire on all cylinders. Thank you, everybody, and have a great year. This concludes today's conference call. Thank you for participating. [Music]

Thanks, Akshay and thank you everyone for joining us on this call two.

2021 was a remarkable year for long island, when we made significant progress both commercially and <unk>.

Typically and we're very excited about 2022, which is shaping up to to build further on that as we continue to fire on all cylinders. Thank you everybody and have a and have a great day.

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

Okay.

[music].

Okay.

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Great.

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