Q3 2021 Alnylam Pharmaceuticals Inc Earnings Call

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Operator: Ladies and gentlemen, thank you for standing by, and welcome to the Arnal Pharmaceuticals Q3-2020 calls. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you need to press Star 1 on your telephone. If you require any further assistance, please press Star Zero. I would not like to turn the caller over to the company. You may begin.

Ladies and gentlemen, thank you for standing by and books, the Enel and Pharmaceuticals Q3, 2021 earnings call. At this time all participants are in a listen only mode. After the speaker's presentation there'll be a question and answer session to ask a question during the session need to press star one on your telephone if you require any further assistance. Please press star zero I would now like to turn the call over to the company you may begin.

Christine Regan Lindenboom: Good morning. I'm Christine Lyndoom, Senior Vice President of Investor Relations and Corporate Communications at El Nileum. With me today on the phone are John Meriginori, Chief Executive Officer, Tulgatangular, Chief Commercial Officer, Oxi Vashnav, President of R&D, Jeff Pulton, Chief Financial Officer, and, on Green Street, President and Chief Operating Officer. For those of you participating in a conference call, the accompanying slides can be accessed by going to the event section of the Investors page of our website, Investors.lnilm.com slash event.

Good morning, I'm, Christine Lindenberg, Senior Vice President of Investor Relations and corporate Communications at an island with me today on the phone are John American oriented Executive officer until the tanker Lara Chief Commercial Officer Akshay. That's now president of R&D, Castleton, Chief Financial Officer, Yvonne Greenstreet, President and Chief operating Officer.

Sure.

Are 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 thought on island Dotcom flash events.

Christine Regan Lindenboom: During today's call, which is outlined in slide two, John will provide some introductory remarks, provide some general context, and discuss the planned leadership transition. Avon will provide some remarks on the leadership transition plans. Tova will provide an update on our global commercial progress. Oksha will review recent clinical and pre-clinical updates, including the new positive top-line results of the 18-month endpoints of the Helios A study of Utrea

During today's call as outlined in slide two John will provide some introductory remarks provide some general context and discuss the planned leadership transition avant who will provide some remarks on the leadership transition plan 12, I will provide an update on our global commercial progress Akshay will review recent clinical and preclinical updates, including the new posit.

Topline results of the 18 month end points that the Helios a study of Blue tree Saran, Jeff will review our financials and then provide a brief summary of upcoming milestones before opening the call to your questions.

Christine Regan Lindenboom: Jeff will review our financials and then provide a brief summary of upcoming milestones before opening the call to your questions. I would like to remind you that this call contains remarks concerning Elanelam'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. 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.

I would like to remind you that this call contains remarks concerning on the 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 1995 actual results may differ materially from those indicated by these forward looking statements as a result of various important factors, including those discussed in our <unk>.

Most recently quarterly report on file with the SEC. In addition, any forward looking statements 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 with that I will turn the call over to John.

Christine Regan Lindenboom: In addition, any forward-looking statements 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. With that, I will turn the call over to John.

John Meriginori: Thanks, Christine, and thank you everyone for joining the call today. In the third quarter of this recent period, we made continued progress bringing our commercial R&I therapeutics to patients around the world. We advanced our clinical pipeline of over a dozen potential transformative medicine programs, and we delivered on the promise of sustainable innovation with RNII, with our industry-leading platform and our pre-clinical effort. Of course, a highlight for the period was the positive top line 18-month results from the Heliose Phase Restart study of Vutrisaran that we announced just yesterday. And Akshay will review those results very shortly.

Thanks, Christine and thank you everyone for joining the call today in the third quarter and recent period, we made continued progress, bringing our commercial Arnie <unk> therapeutics to patients around the world, We advanced our clinical pipeline of over a dozen potential transformative medicine programs and we delivered on the promise of sustainable innovation.

With Arnie I with our industry, leading platform and our preclinical efforts of course, a highlight for the period was the positive top line 18 month results from the Helios a phase III start the study of <unk> that we announced just yesterday and Akshay will review those results very shortly.

John Meriginori: As we announced this morning, after much thoughtful consideration and planning, I've decided that this is the right time to begin a smooth transition of leadership at El Nilo. Additionally, I have decided that this is the time for me to begin a new chapter in my career of yet again pushing the bounds of biomedical innovation by helping entrepreneurs and companies advance new modalities to improve the lives of patients. I couldn't be more pleased that Yvonne Green Street has agreed to help lead El Nilem in a planned transition that will occur at the end of this year.

As we announced this morning after much thoughtful consideration in planning harvest.

Sided that this is the right time to begin a smooth transition of leadership at El myeloma.

I've decided that this is the time for me to begin a new chapter in my career of yet again, pushing the bounds of biomedical innovation by helping entrepreneurs and companies advanced new modalities to improve the lives of patients.

I couldn't be more pleased that Yvonne Greenstreet has agreed to help lead all while I'm in a planned transition that will occur at the end of this year of course I am so honored to have had the opportunity to build on myeloma over the last month.

John Meriginori: Of course, I am so honored to have had the opportunity to build El Nilem over the last night. 19 years, RNAI therapeutics to patients around the world. I am so proud of what we've accomplished, and I'm so thankful for the opportunity to have worked with our past and present El Nilem team to build this incredibly special company. I have no doubt that El Nylon will continue to soar in the years to come, helping patients with its transformative science and medicine.

19 years, being Arnie <unk> therapeutics to patients around the world.

I am so proud of what we've accomplished and I'm. So thankful for the opportunity to have worked with our past and present all myeloma team to build this incredibly special company.

I have no doubt that all Mylan will continue to soar in the years to come helping patients with its transformative science and medicine.

Yvonne L. Greenstreet: So with that, let me turn it over to Yvon to make some remarks as well. Thank you, John, and good morning, everyone. We've been so fortunate as our Nileum to have had your tremendous leadership, John, over these last 19 years.

So with that let me turn it over to Yvonne to make some remarks as well Ivan.

Thank you John and good morning, everyone. We've been so fortunate to some items have had your tremendous leadership on over these last 19 years and I know I speak for the entire online item team in thanking you for your commitment passion and excellence has been the architect and the inspiration.

Yvonne L. Greenstreet: team in thanking you for your commitment, passion, and excellence. You have been the architect and the inspiration behind our success to this stage, and I'm so grateful that you have given me the opportunity to advance Al-Nyadam in its next exciting chapter, and I couldn't be more excited about our Nilems prospects

<unk> success to this stage and I'm, so grateful that you've given me the opportunity to advance one item and its next exciting chapter.

And I couldn't be more excited about on items prospects going forward with an island Pizza first times 25. This is a clear roadmap for delivering RNA therapeutics to help patients around the world and deliver value to our shareholders and in the coming year, we expect to bring our fifth R&D.

Yvonne L. Greenstreet: to help patients around the world and deliver value to our shareholders, and in the coming year, we expect to bring

Yvonne L. Greenstreet: our fifth RNAI Therapeutic to Market and potentially expand our TTR franchise opportunity significantly, we expect steady and continued growth of our three directly marketed products with excellence in our commercial performance while also advancing sustainable innovation from our organic product engine, including our

<unk> therapeutic to market and potentially expand our TTS franchise opportunities significantly.

We expect steady and continued growth of our three directly marketed products with excellence in our commercial performance, while also advancing sustainable innovation from our organic product engine, including our first extra hepatic program.

Yvonne L. Greenstreet: including our first extra hepatic production.

Yvonne L. Greenstreet: These are very bright days for Al-Nilum, and I really encourage you to join us at our upcoming R&D day on November the 19th to hear some of our exciting new progress. With that, let me now turn the call over to Tolga for a view of our commercial performance. Thank you.

These are very bright days for all nine of them and I really encourage you to join us at our upcoming R&D day on November 19th. So he has been with exciting new progress with that let me now turn the call over to Targa for review of our commercial performance toga.

Tolga Tanguler: Thank you, Yvonne, and good morning, everyone. We're pleased with our third quarter performance, particularly with Ompatro, but also with our two ultra-rare medicines, Givari and Oxumo, where we're still in the launch phases and seeing some continued impact from the pandemic, particularly with Givari. For Opatro, we achieved $120 million in global net product revenues, representing approximately 6% quarter-on-quarter growth compared with the second quarter. We ended the quarter with over 1875 patients on commercial treatment.

Ivan and good morning, everyone. We're pleased with our third quarter performance, particularly with the on Petro, but also with our two ultra rare medicines.

Laurean Oaks limo, where we're still in launch phases and seeing some continued impact from the pandemic, particularly therefore give laurie.

Foreign Petro, we achieved $120 million in global net product revenues, representing approximately 6% quarter on quarter growth compared with the second quarter.

We ended the quarter with over 1800 75 patients on commercial treatment.

Tolga Tanguler: In the US, we continue to see strength on many fronts, including 12% growth in demand and notable growth in new prescribers. We have also continued to see encouraging signs of the healthcare system reopening. As an example, we've also seen an uptick in face-to-face interactions between our field team and HCPs in the third quarter, resulting in the second highest number of start forms for Ompatro in the U.S.

In the U S. We continue to see strength on many fronts, including 12% growth in demand and notable growth in new prescribers.

We have also continued to see encouraging signs so if the health care system reopening as an example, we've also seen an uptick in face to face interactions between our field team and H C piece in the third quarter, resulting in the second highest number of start forms were on Petro in the U S in any quarter since <unk>.

Launch first.

Tolga Tanguler: Further, patient diagnosis is evolving well, with continued growth in the use of PYP scans, which is often the start of the patient journey toward HATTR Polyopathy Diagnosis. Treatment compliance has returned to pre-COVID levels and remains stable at over 90%, a remarkable result for an infused medicine. We also have confirmed access to over 98% of covered US lives with no payer headwind. Now, with regard to the rest of the world, market access has been achieved in over 30 countries worldwide.

Further patient diagnosis is evolving well with continued growth in the use of <unk>, which is also in the start of the patient journey towards <unk> Polyneuropathy diagnosis.

Treatment compliance has returned to pre COVID-19 levels and remained stable at over 90% a remarkable result, foreign infused medicine.

We also have confirmed access over 98% of covered U S lives with no payer headwinds.

Now with regard to the rest of the world market access has been achieved in over 30 countries worldwide and notable highlight in Q3 was the achievement of pricing and reimbursement in Ireland, which is a country with endemic disease due to the $2 68 mutation. We're also observing a good balance of first line use.

Tolga Tanguler: A notable highlight in Q3 was the achievement of pricing and reimbursement in Ireland, which is a country with endemic disease due to the T60A mutation. We're also observing a good balance of first-line use and switches from other products, including stabilizers, in the rest of world markets. Moving to Gibblog.

And switches from other products, including stabilizers in rest of world markets.

Moving to give Laurie.

Tolga Tanguler: We continue to execute on this product launch, having achieved $32 million in global net product revenues in the third quarter, representing approximately 4% quarter-on-quarter growth compared with Q2. As of September 30th, we had over 300 patients worldwide on commercial therapy. We observed a steady quarter-on-quarter patient growth rate of over 10%, driven primarily by geographic expansion, and we're optimistic that Givlar will continue to perform well over time. In the US, we continue to make strong progress toward establishing value-based agreements with over 10 finalized to date with commercial payers.

We've continued to execute on this product's launch having achieved $32 million in global net product revenues in the third quarter.

Representing approximately 4% quarter on quarter growth compared with Q2.

As of September 30th we attained over 300 patients worldwide on commercial therapy.

We observed a steady quarter on quarter patient growth rate of over 10% driven primarily by geographic expansion.

And we are optimistic give laurie will continue to perform well over time.

In the U S. We continued to make strong progress towards establishing value based agreements with over 10 finalize to date with commercial payers. We also have confirmed access for over 94% of covered U S lives with no pushback or headwinds.

Tolga Tanguler: We also have confirmed access for over 94% of covered US lives with no pushback or head. We continue to make great progress with market access efforts outside of the US, with recent launches in Japan and Spain, and achievement of pricing and reimbursement in the UK and France. Moving now to Okslomo, which is also still in the launch phase. We achieved $15 million in global net product revenues in the third quarter, which represented a decrease of approximately 9% from Q2 revenues.

We continue to make great progress with market access efforts outside of the U S. With recent launches in Japan, and Spain, and achievement of pricing and reimbursement in the U K and France.

Moving now to <unk>, which is also still in the launch phase reached.

We achieved $50 million in global net product revenues in the third quarter, which represented a decrease of approximately 9% from Q2 revenues revenues. This decrease reflects the transition of the initial bolus of commercial patients from their monthly loading doses to their quarterly maintenance dose.

Tolga Tanguler: This degree reflects the transition of the initial bolus of commercial patients from their monthly loading doses to their quarterly maintenance doses, as we previously highlighted as a dynamic expected to following launch. As of September 30th, we attained over 120 patients on commercial oxymot treatment globally, representing approximately 25 patient growth versus Q2. We believe this demonstrates that notwithstanding the decline in revenues during the quarter, Oksumos' fundamental growth remains strong.

<unk>.

As we previously highlighted as a dynamic expected to following launch.

As of September 30th we obtained over 120 patients on commercial looks somewhat treatment globally, representing over approximately 25 patient growth versus Q2.

We believe this demonstrates that notwithstanding the decrease in revenues during the quarter of slow most fundamental growth remained strong our market access efforts are also progressing well now with over 10, Dba's finalize the date with commercial Payors and confirmed access or over 85.

Tolga Tanguler: Our market access efforts are also progressing well. Now with over 10 VBAs finalized to date with commercial payers, and confirmed access to over 85% of covered US lives with no payer head. Geographic expansion of Oksluma is moving along steadily with two important launches underway in Germany and France, supported by timely execution of the transitions to commercial drugs for patients previously treated through early access programs. In the Simea region, we continue to be pleased by the broad utilization of Hoxlomo across age groups and EGFR categories at this early stage of the launch.

A set of covered U S lives with no payer headwinds.

Geographic expansion of books luminaries moving along steadily with two important launches underway in Germany, and France supported by timely execution of the transition to commercial drugs for patients previously treated through early access programs.

In the EMEA region, we continue to be pleased by the broad utilization of Vogue slo-mo across age groups any GFR categories. At this early stage of the launch.

Tolga Tanguler: In conclusion, we are very pleased with our third quarter commercial results, with strong Petro performance and continued launch execution on Givlari and Ops Luma. With that, I will now turn it over to Akshay to review our recent R&D and pipeline progress.

In conclusion, we are very pleased with our third quarter commercial results with strong loan Petro performed and continued launch execution, all give laurie and Auxilium.

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

Akshay K. Vaishnaw: Thanks, Holger, and good morning, everyone. I'll start with our efforts in ATTR amyosis, where we're advancing two clinical stage product candidates, Petiran and Vutriseran. While Sondpatre is currently approved in multiple markets around the world, it is not yet approved to treat the associated HAT ptoidosis. We're committed to expanding the product label for the treatment of cardiomyopathy in both hereditary and wild type ATT amyloidosis patients. To this end, we're conducting the Apollo B phase three study, which is fully enrolled with over 300 patients and where we expect to report top-line results in mid-2020.

I'll start with our efforts in <unk> amyloidosis, where we are advancing two clinical stage product candidates. The piece ran in Boutris Ron.

Also on Patrick is currently approved in multiple markets around the world.

Well to treat <unk> amyloidosis.

We're committed to expanding the product's label for the treatment of cardiomyopathy, both hereditary and wild type ATT amyloidosis patients.

To this end, we're conducting the Apollo B phase III study, which is fully enrolled with over 300 patients and where we expect to report top line results in mid 2022.

Akshay K. Vaishnaw: We're also advancing Vucrisaran, which is delivered by a quarterly subcutaneous injection and is also in development for AETa amyosis. Here, we are conducting two phase three studies. The first is Heliosei, evaluating Vutriaran in HAT for Amaloidosis patients with polyneuropy. Earlier this year, we presented positive nine-month results from the study, which showed that the study met its primary and secondary endpoints at nine months. These data formed the basis for our regulatory submissions to both the FDA and EMA.

We're also advancing Boutris ran which is delivered by quarterly subcutaneous injection and is also in development for a teacher amyloidosis.

We are conducting two phase III studies.

First is helios, a evaluating boutris around in <unk> amyloidosis patients with Polyneuropathy.

Earlier this year, we presented positive nine month results from the study which showed that the study met its primary and secondary endpoints at nine months.

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

Akshay K. Vaishnaw: The FDA has accepted the submission and assigned a Purdue date to Vutris around April 14, 2022, and the EMA has validated our MAA submission. Patients dozing on Helios A continued past the nine-month mark, and yesterday we were happy to report positive top-line results from the 18-month time point of the Helios A study, which I will now review. Please note that we plan to present the full 18-month results from the study at a medical congress in early 2022, and as such, we'll need to limit our discussion to the top line results only.

The FDA has accepted the submission and assigned a <unk> date to Boutris round of April 14 2022.

And the EMA has validated our MAA submission.

Patient dosing in Helios, a continued past the nine month, Mark and yesterday, we were happy to report positive topline results from the 18 month time point of the Helios, a study, which I will now review.

Please note that we plan to present the full 18 month results from this study at a medical Congress in early 2022, and as such we will need to limit our discussion to the topline results only.

Akshay K. Vaishnaw: These results mark an important step in bringing Vitrisran, a low dose once quarterly and potentially biannual, subcutaneously administered therapy to patients living with HAT phthalmloidosis with polyneuropsy, as well as progressing our efforts to build an industry-leading franchise of medicines for the treatment of these patients. As a reminder, Heliose is a randomized open-label study in patients with heretry 80 char The study enrolled 164 patients who were randomized 3 to 1 to receive Butryceran at a dose of 25 milligrams administered subcutaneously once every three months or Peticerand administered intravenously once every three weeks at a dose of 0.3 micrograms per kick.

These results Mark an important step in bringing Boutris ran a low dose once quarterly and potentially biannual subcutaneously administered therapy to patients living with H I T family doses with Polyneuropathy as well as progressing our efforts to build an industry leading franchise of medicines for the treatment of these patients.

As a reminder, Helios a is a randomized open label study in patients with hereditary <unk> amyloidosis with Polyneuropathy.

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.

Surround administered intravenously. Once every three weeks at a dose of <unk> three Meg per kg.

Akshay K. Vaishnaw: The primary endpoint was measured at nine months and was the change from baseline in the MNus plus 7 neuropathy impairment score as compared to the external placebo group from the Apollo Phase 3 study. We're delighted to report today that Heli met all secondary endpoints measured at 18 months, including statistically significant improvements in progression of neuropsy as measured by the MNIS Plus 7 score, quality of life, gate speed, nutritional status, and overall disability relative to the placebo data from the Apollo Phase 3 study of Petitran.

The primary endpoint was measured at nine months and was the change from baseline in the <unk> plus seven neuropathy impairment score as compared to the external placebo group from the Apollo Phase III study.

We are delighted to report today that the.

Helios a met all secondary endpoints measured at 18 months, including statistically significant improvements in progression of neuropathy as measured by the <unk> plus seven school quality of life gait speed nutritional status and overall disability relative to the placebo data from the Apollo Phase III study for <unk>.

Akshay K. Vaishnaw: The final secondary endpoint reduction in serum TTR levels with Vutrisran demonstrated no-in superiority relative to the within study Patisran arm as expected. These results build on the positive nine-month uterouserine data we shared earlier this year and demonstrate that the reduction in neurological improvement and improvement in quality of life in patients with HAT to amyloidosis seen at nine months is maintained at 18 months.

The final sector endpoint reduction in serum <unk> levels with Boutris ran demonstrated non inferiority relative to that within study parties right out as expected.

These results build on the positive nine months interest around data, we shared earlier this year and demonstrated that the reduction of neurological improvement and improvement in quality of life in patients with H I T traveler doses seen at nine months is maintained at 18 months.

Akshay K. Vaishnaw: Furthermore, at 18 months, Putreceran-treated patients showed quantitative improvement across a variety of exploratory endpoints evaluated in both the intent-to-treat population as well as a pre-specified cardiac population. Improvements were seen in a number of exploratory endpoints, including the biomarker NP ProbNP, a measure of cardiac stress, and certain echocardiographic parameters relative to the external placebo group. Other echocardiographic endpoints showed trends toward improvement but did not reach significance due to the small sample size.

Furthermore, at 18 months Butros around treated patients showed quantitative improvement across a variety of exploratory endpoints evaluated both the intent to treat population as well as a prespecified cardiac subpopulation.

<unk> was seen in a number of exploratory endpoints, including the biomarker NT Pro BNP.

A measure of cardiac stress and sudden echocardiographic parameters relative to the external placebo group.

Other echocardiographic endpoints showed trends towards improvement did not reach significance due to the small sample size.

Akshay K. Vaishnaw: Finally, in a cohort of 48 patients, treatment with Vutris RAND was associated with an improvement in technetium uptake, that is, reduced tracer uptake, in the heart relative to baseline in a majority of patients. This is the largest study conducted to date using imaging to characterize the impact of a TTR silencer on cardiac amyloid.

Finally in a cohort of 48 patients treatment with Butros ran was associated with an improvement in technetium uptake that is reduced tracer uptake in the hot relative to baseline and a majority of patients.

This is the largest study conducted to date using imaging to characterize the impact of a TTS islands.

On cardiac amyloid.

Akshay K. Vaishnaw: Whilst it's important to recognize that these are exploratory data, and that these patients had predominantly polyneuropathy, we believe these results are very encouraging with respect to providing potential evidence for reduced cardiac amyloid burden with vitriss around treatment. Trisoran's potential impact on cardiac manifestations of the disease is currently being studied in the Helios B trial. Let's now review the safety results during the 18-month treatment period. The Trisand demonstrated an encouraging safety and tolerability profile.

Also it's important to recognize that these are exploratory data that these patients had predominantly polyneuropathy. We believe these results are very encouraging with respect to providing potential evidence for reduced cardiac amyloid burden with Richard's around treatment.

The truth surrounds potential impact on cardiac manifestations of the disease is currently being studied in the Helios B trial.

Let's now review the safety results during the 18 month treatment period.

<unk> demonstrated an encouraging safety and tolerability profile stuff.

Akshay K. Vaishnaw: Study discontinuations occurred in three patients for 2.5% and were due to adverse events in the Vutrisaran arm by month 18. The single new discontinuation since month 9 was an event of cardiac failure, failure considered unrelated to study drugs by the investigator. By month 18, there were two deaths, neither of which were considered related to study drugs.

Study discontinuation occurred in three patients or two 5% and were due to adverse events in the Butros Butros ran out by months 18.

The single New discontinuation since month mine wasn't event of cardiac failure failure considered unrelated to study drug by the investigator.

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

Akshay K. Vaishnaw: There were two serious adverse events deemed related to Vutris Rand by the study investigator, consisting of dyslipidemia and a urinary tract infection. Deaths and related essays all occurred by month nine and have been previously reported. Treatment emergent adverse events occurring in 10% or more of the patients included fall, diarrhea, pain in the extremities, peripheral edema, arthralgia, dizziness, urinary tract infections. 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. Injection site reactions were reported in five patients 4.1% and were all mild and transient. There were no hepatic safety concerns.

There were two serious adverse events deemed related to retrieve surrounded by the study investigator consisting of Dyslipidemia and a urinary tract infection.

<unk> and related SAE is all occurred by month nine and have been previously reported.

Treatment emergent adverse events occurring 10% or more of the Ah patients included full diarrhea painting extremity peripheral edema arthralgia business urinary tract infections with the exception of painting extremity trials year. Each of these events occurred at a similar level.

As compared with the external placebo.

Injection site reactions were reported in five patients or four 1% and were all mild and transient hepatic safety concerns and.

Akshay K. Vaishnaw: In summary, Vutri-Sran has demonstrated an encouraging efficacy and safety profile in Helios A through 18 months. Moreover, within the realm of reproducing clinical trial data, we're delighted to see the extent to which Heliol-A results with Vutris-Ran recapitulate the Apollo data with Paticeran. As previously noted, the other phase three Vutrisran study is Helios B, which is our ongoing phase three cardiac outcome study with Vutrisran in hereditary and wild type 802 amylidosis patients with caribularis, patients with caribularase.

In summary, <unk> has demonstrated encouraging efficacy and safety profile in Hayley I'll say through 18 months. Moreover, within the realm of reproducing clinical trial data. We are delighted to see the extent to which Helios a result, with vitry surround recapitulate, the Apollo data with Patese Ryan.

As previously noted the other phase III <unk> studies, Helios, B, which is our ongoing phase III cardiac outcome study with Boutris ran in hereditary and wild type <unk> amyloidosis patients with cardiomyopathy we.

Akshay K. Vaishnaw: We were excited in the third quarter to complete enrollment in the study with over 600 patients well ahead of schedule due to strong enrollment demand. Beyond Petitran and Vutrisran, the newest addition to our ATTR Amloidosis franchise is the preclinical program, ALN TTRS, CO4. Using our ICAREA platform, we've generated a new TTR targeting SIRNA, ALN TTR, CO4, that we believe could support an annual dosing regimen with greater 90% TTR knockdown. LNTTERO4, the plan is to enter clinical development with an I&D filing at or around year end 2020. Let's now move on to Lumassaran, our RNA therapeutic approved late last year in the EU and US as the first treatment for primary hyperoxyl urea type 1 or pH1.

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

Beyond Patese ran Boutris ran the newest addition to our <unk> amyloidosis franchise is a preclinical program <unk> for.

Using our carrier platform, we've generated a new T J targeting assai RNA antiterrorist, therefore that we believe could support an annual dosing regimen with greater than 90% ETR knockdown.

L. Antiterrorist here for is planned to enter clinical development with an IND filing at or around year end 2022.

Let's now move onto Lemass ran our RNA therapeutic approved late last year in the EU and U S. As the first treatment for primary Hyperoxaluria type one ph one.

Akshay K. Vaishnaw: In the third quarter, we were pleased to announce positive top-results from the Illuminate C Phase 3 study of Lumasaran, and we announced today that we plan to present full results from the study at the American Society of Nephrogy meeting being held next week. We also now intend to submit supplemental regulatory filings with the FDA and EMA in late 2021, with the goal of further strengthening labeling supporting Oxlumo. We're also excited about the potential for Lumas for patients with recurrent renal stones, and later this year, we plan to start a phase two trial to evaluate that potential.

In the third quarter, we were pleased to announced positive topline results from the illuminate C. Phase III study of new mass ran and we announced today that we plan to present full results from this study at the American Society of Nephrology meeting being held next week.

We also now intend to submit supplemental regulatory filings with the FDA and EMA in late 2021 with a goal of further strengthening strengthening the labeling supporting Oklahoma.

We're also excited about the potential new master and for patients with recurrent renal stones and later this year, we plan to start a phase II trial to evaluate that potential.

Akshay K. Vaishnaw: Now, in addition to our late-stage programs, we believe we're also making great progress with our early and mid-stage programs. While Othai can't cover all these programs due to limited time today, one of the exciting parts of our story is the expansion of RNA therapeutics beyond rare diseases into prevalent disease opportunities. Our program for high potential is a great example.

Now in addition to our late stage programs. We believe we're also making great progress without early and mid stage programs.

Having covered all these programs due to limited time today, one of the exciting parts of our story is the expansion of RNA therapeutics beyond rare diseases into prevalent to these opportunities.

Our program hypertension is a great example, because I'll be saran, formerly known as Alan HGT is our investigational <unk> therapeutic targeting genetically validated target angiotensin agent in development for the treatment of hypertension.

Akshay K. Vaishnaw: Zalbicaran, formerly known as ALNAGT, is our investigational RNA therapeutic targeting the genetically validated target angiotensinogen in development for the treatment of hypertension. We look forward to presenting additional clinical results from the Phase 1 study at the American Heart Association meeting later this month, including patients on a low salt diet and in patients receiving co-administration with the conventional RAS inhibitor herb Sartan. We have also recently initiated our Cardia Phase 2 program with Zol B-Beran. The first of the two studies, Cardio 1, is designed to evaluate the efficacy and safety of Zol B-Beran as monotherapy in patients with mild and moderate hypertension; this study is currently enrolling patients.

We look forward to presenting additional clinical results from the phase one study at the American Heart Association meeting later this month, including in patients on a low salt diet in patients receiving co administration of the conventional Ras inhibitor absorbed tab.

We also recently initiated a cardio phase II program Exalt D surround the first of the two studies cardio one is designed to evaluate the efficacy and safety of <unk> as a monotherapy in patients with mild to moderate hypertension. This.

This study is currently enrolling patients in late 2021, we plan on initiating cardio too, which is designed to evaluate the efficacy and safety of the obese or an add on therapy in patients with hypertension, despite treatment with standard of care.

Akshay K. Vaishnaw: In late 2021, we plan on initiating Cardia 2, which is designed to evaluate the efficacy and safety of Zalbicaran as add-on therapy in patients with hypertension, despite treatment with standard of care. We also continue to harness our organic product engine with the goal of achieving sustainable innovation with two to four INDs per year. To this end, we're on track to file a CTA for LNXDH in development for the treatment of gout in late 2021.

We also continue to harness our organic product engine with the goal of achieving sustainable innovation with two to four <unk> per year.

To this to this and we're on track to file a Cta for <unk> XT eight in development for the treatment of count in late 2021.

Akshay K. Vaishnaw: We're also on track to file a CTA for ALNAPP, in development for the treatment of Alzheimer's disease and cerebral amyloid angiopsy, in late 2021. We're very excited about our APP program, as it's the first investigational RNA therapeutic for our CNS platform, which was also featured at the OTS meeting this past month. We believe that our initial human data for L&APP, expected next year, could open the frontiers of RNI therapeutics for many CNS diseases and also herald the potential growth of our broader extra-hepatic efforts.

Also on track to file a Cta for L. N. A P. P in development for the treatment of Alzheimer's disease, and cerebral amyloid Angiopathy and late 2021.

We're very excited about our <unk> program as it is the first investigational RNA therapeutics for our CNS platform, which was also a feature at the Ots meeting this past month.

We believe that our initial human data for Ellen ADP expected next year, if positive could open the frontiers of RNA therapeutics for many CNS diseases and also heralds the potential growth of our broader extra hepatic assets now.

Akshay K. Vaishnaw: Now, in closing and on a personal note, John, thank you for your remarkable leadership over the last 19 years as Al Nilem built a whole new class of medicine, RNI Therapeutics. It has been my great privilege to work with you. You will leave us in a remarkably strong position as we build towards P to the 525 and beyond, my friend. With that, I'll turn it over to Jess.

Now in closing and on a personal note John Thank you for your remarkable leadership over the last 19 years as <unk> built a whole new class of medicines RNA therapeutics.

It has been my great privilege to work with you you will leave us in a remarkably strong position as we build towards pizza with 525 and beyond my friend.

With that I'll turn it over to Jeff Jeff.

Jeff Poulton: Thanks, Akshha. Good morning, everyone. I'm pleased to be presenting our line of LUM's Q3, 2021 financial results, which reflect another quarter of progress on our journey toward building a self-sustainable financial profile aligned with our P to the 5th by 25 goals. Turning to our results, on the first front, Patro, we generated $120 million in net revenue for the quarter, representing 6% growth from the second quarter of 2021 and 46% growth compared with Q3 2020.

Thanks, Akshay and good morning, everyone I.

I am pleased to be presenting our linemen Q3, 2021 financial results, which reflect another quarter of progress on our journey towards building a self sustainable financial profile aligned with our peer did a fifth by 'twenty five goals.

Turning to our results first front Petro we generated $123 million in net revenue for the quarter, representing 6% growth from the second quarter of 2021, and 46% growth compared with Q3 2020.

Jeff Poulton: U.S. Patro sales decreased 2% versus Q2 2021 and were impacted by the following. Demand growth was 12% consistent with Q2, primarily driven by an increase in patients on therapy and greater than 90% patient treatment compliance. Demand growth was offset by inventory de-stocking in Q3, compared with stocking in Q2, representing an approximate 10% headwind to reported Q3 growth and higher gross to net deductions, which negatively impacted reported Q3 growth by approximately 3%.

U S on Petro sales decreased 2% versus Q2, 2021 and more impacted by the following demand growth was 12% consistent with Q2, primarily driven by an increase in patients on therapy and greater than 90% patient treatment compliance.

Growth was offset by inventory Destocking in Q3, compared with stocking in Q2, representing an approximate 10% headwind to reported Q3 growth and higher gross to net deductions, which negatively impacted reported Q Q3 growth by approximately 3%.

Jeff Poulton: And our international markets for Patro performance remains strong with growth of 12% versus Q2 2021, primarily driven by increased patient demand broadly across markets in Europe, Canada, and Japan. Turning to our results for Givari, we generated 31.8 million in net revenue in Q3, representing 4% growth compared to the second quarter of 2021 and 91% growth versus Q3 2020. U.S. Gublari sales were flat versus Q2 2021 and were impacted by the following. Demand growth was 9%, primarily due to an increase in patients on therapy and greater than 90% patient treatment compliance.

In our international markets on Patrick performance remained strong with growth of 12% versus Q2, 2021, primarily driven by increased patient demand broadly across markets in Europe, Canada and Japan.

Turning to our results for give Laurie.

Generated $31 8 million in net revenue in Q3, representing 4% growth compared to the second quarter of 2021, and 91% growth versus Q3 2020.

U S. <unk> sales were flat versus Q2, 2021 and were impacted by the following.

Demand growth was 9% primarily due to an increase in patients on therapy and greater than 90% patient treatment compliance.

Jeff Poulton: Demand growth was offset by inventory de-stocking in Q3 compared with stocking in Q2, negatively impacting Q2, and negatively impacting Q3 reported growth by approximately 8%. With Oxlumo, we generated $14.4 nett revenue in the quarter, representing a 9% decrease compared with Q2.

Demand growth was offset by inventory destocking in Q3, compared with stocking in Q2 negatively impacting Q3 reported growth by approximately 8%.

With ox limo, we generated $14 9 million in net revenue in the quarter, representing a 9% decrease compared with Q2.

Jeff Poulton: As previously mentioned, despite patient growth of approximately 25% in a quarter, fails decreased due to the transition of the initial bolus of commercial patients from monthly loading dose to quarterly maintenance dose regimens. Turning now to a summary of our full P&L results for the quarter, with the following highlights. Total combined product sales in the second quarter were 167 million, representing 68% growth versus Q3 2020.

Toga previously mentioned despite patient growth of approximately 25% in the quarter sales decreased due to the transition of the initial bolus of commercial patients from monthly loading dose to quarterly makes it maintenance dose regiments.

Turning now to a summary of our full P&L results for the quarter with the following highlights.

Total combined product sales in the second quarter were $167 million, representing 68% growth versus Q3 2020.

Jeff Poulton: Net revenue from collaborations for the quarter was $20.1 million, a decrease from Q3 last year, primarily due to less revenue recognized from our collaboration with beer. combined non-GAP R&D expenses for the quarter increased 12% versus Q3 2020. Key drivers of the increase continue to be additional R&D investment in advancing our early, mid, and late stage pipeline programs, and an increased SGNA investment to support our three commercial brands, including the launch

Net revenue from collaborations for the quarter was $20 1 million a decrease from Q3 last year, primarily due to less revenue recognized from our collaboration with Vir.

Our combined non-GAAP R&D and SG&A expenses for the quarter increased 12% versus Q3 2020.

Key drivers of the increase continue to be additional R&D investment and advancing our early mid and late stage pipeline programs and increased SG&A investment to support our three commercial brands, including the launch of excellent mill.

Jeff Poulton: Non-Gap operating loss for the quarter decreased by approximately 20 million versus the same period in 2020, driven by strong topline growth and more moderate growth in operating expenses, continuing our progress towards achieving profitability. Cash, cash equivalents, and marketable securities were 2.3 billion as of September 30th, 2021, compared to $1.9 billion as of December 30th, 2020.

Non-GAAP operating loss for the quarter decreased by approximately $20 million versus the same period in 2020, driven by strong topline growth and more moderate growth in operating expenses continue continuing our progress towards achieving profitability.

Cash cash equivalents in marketable securities were $2 3 billion as of September 32021, compared to $1 9 billion as of December 32020.

Jeff Poulton: Notably, the third quarter included the second $500 million payment from Blackstone for the monetization of 50% of increased RAN royalties. Lastly, turning to our full year 2021 financial guidance, we are reiterating our guidance. For combined product sales, 640 to 665 million, for net revenue from collaborations and royalties, 150 to 200 million, and for non-GAP combined R&D and SGNA expenses, $1,175 million to $1,275 million.

Notably the third quarter included the second $500 million payment from Blackstone for the monetization of 50% of <unk> royalties.

Lastly, turning to our full year 2021 financial guidance, we are reiterating reiterating our guidance for combined product sales $640 million to $665 million.

Net revenue from collaborations and royalties of $150 million to $200 million.

And for non-GAAP, combined R&D, and SG&A expenses $1 billion $175 million to $1 billion $275 million.

Jeff Poulton: Let me now turn to a review of upcoming milestones. We were very excited about the positive 18-month data from Heliosei for HATTR amylidosis. Patients with polyneuropathy and plan to present the full results at a medical conference in early 2022. With Sal B Serran, as Akshay mentioned, we plan to present additional data from the phase one study at the AHA meeting later this month and plan to initiate the Cardia 2 phase two combination study later this year as well.

Let me now turn to a review of upcoming milestones.

We're very excited about the positive 18 month data from Helios say for <unk> amyloidosis patients with Polyneuropathy and plan to present the full results at a medical conference in early 2022.

Wasabi Saran as Akshay mentioned, we plan to present additional data from the phase one study at the IHA meeting later this month and plan to initiate the cardio two phase two combination study later this year as well.

Jeff Poulton: From LaMassarin, we plan to initiate a phase two study for renal stone events in late 2021. This phase two study will be important for life cycle management of Oxlumo, with the potential to enable a phase three trial to significantly expand the overall opportunity. We also intend to submit supplemental regulatory documents with the FDA and the EMA in late 2021 based on the results from the Illuminate C study with the goal of strengthening the labeling supporting Oxlumo and turning to Simdicaran for complement mediated diseases.

From a master and we plan to initiate a phase two study for renal stone events in late 2021. This phase II study will be important for lifecycle management of Oxley mill with the potential to enable a phase III trial to significantly expand the overall opportunity.

We also intend to submit supplemental regulatory filings with the FDA and the EMA in late 2021 based on the results from the illuminate C study with the goal of strengthening the labeling supporting excellent mill.

Turning to some dis ran for complement mediated diseases, our partner Regeneron plans to initiate a phase III study of <unk> and <unk> combination in myasthenia gravis.

Jeff Poulton: Our partner Regeneron plans to initiate a phase three study of Semdiceran and Pozellumab combination in myosthenia gravis. With ALNHSD, as AACHA mentioned, we expect to report initial safety results in healthy volunteers from the Phase 1 study at our upcoming R&D day. We're very excited to file our first CNS-based application for AL&APP in late 2021, setting us up for potential initial clinical proof of concept data in late 2022. And as another step toward expanding our prevalent disease opportunities, we plan to advance ALN, XDH, and development for the treatment of gout toward a CTA filing in late 2021. Let me now turn it back to Christine to coordinate our Q&A session. Okay, Christine? Thank you, Jeff.

With Elan HST as Akshay mentioned, we expect to report initial safety results in healthy volunteers from the phase one study at our upcoming R&D day.

We're very excited to file our first CNS Cta for <unk> in late 2021 studies are setting us up for potential initial clinical proof of concept data in late 2022.

And as another step toward expanding our prevalent disease opportunities, we plan to advance <unk> X D H and development for the treatment of gout toward a cta filing in late 2021.

Christine Regan 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 additional questions.

Operator: Good, ladies and gentlemen, if you have a question or a comment at this time, please press the number farther than one key on your touchtone telephone. Our first question comes from Mori, Roacraft, for Jeff. Hi, good morning, everyone, and congratulations on the updates and the CEO transition to both John and Yvonne. I look forward to next. For my question, for the Helios A data, just wondering if you can contextualize what you have relative to Apollo A, and are there any new observations that could inform how the Apollo B and Helios A studies could read out?

John Meriginori: And I'm just wondering, just checking, based on the data, do you plan to make any supplemental filings for Vatrice? So, Maury, let me start by just thanking you and for your congratulatory comments, but the question here really goes right to Aksh. Aksh, take it away.

Alright comments, but the question here.

He goes right to Akshay akshay taken away Yeah, I'm Maree, obviously, the current data now with Boutris around only further strengthen our belief in the drug debates look outstanding in HHH amyloidosis with poly neuropathy. These new exploratory data with cardiac endpoints are extremely encouraging.

Akshay K. Vaishnaw: Yeah, Maury, obviously, the current data now with Gutrisra only further strengthen our belief in the drug; the data look outstanding in HAT tamloid doses with polyneuropathy. These new exploratory data with the cardiac endpoints are extremely encouraging. We're very excited about the technician scan observations that show reduced uptake of the technetium. And in addition to the previously reported finding at nine months, which we see again at 18 months improvement in pro-BNP, improvement in aspects of the echocardiogram, and these new technician data, I think this all bodes well for the performance of Butris ran in Helios B and strengthens our hypothesis that TTR lowering is an important way to address TTR-related cardiac disorders.

We're very excited about the technician scandal observations that show reduced uptake of the technician and in addition to.

The previously reported finding at nine months with which we see again at 18 months improvement in her BNP improvement in aspects the echocardiogram.

And these new the technician beta I think this all bodes well for the performance of Boutrous ran uhm in Helios B and strengthens our hypothesis that teacher lowering is is an important way to address T. T. R related cardiac disorders, and so Ah confidence in Apollo B of course also goes up significantly.

Akshay K. Vaishnaw: And so our confidence in Apollo B, of course, also goes up significantly because of these observations. So I'll stop there and have to take any other questions. Does that answer your question, Maury? Yes, and just wondering if you do plan on supplementing the vitrits. Yeah, real quickly on that, obviously, for the European filing, we will be including these 18-month data in the European filing. That was agreed to by the ESA. But with the FDA, there's no need for an up in that filing.

Because of these these observations so I'll stop there and have to take any other questions.

Does that answer your question Marty.

Yes, and just wondering if you if you do plan on supplementing the richer certain filing.

Yeah, just real quickly on that obviously the for the European filing we will be including these 18 month data and the European following that was agreed to.

By the.

But with the F D. A there's no needed updating that filing.

Akshay K. Vaishnaw: Got it. Okay, thank you for taking my question. Thanks, Maure. Our next question comes from Gina Wang with Mark.

Got it okay. Thank you for taking my questions.

Thanks Marian.

Our next question comes from Chino Wang with Barclays.

Thank you for taking my questions at <unk>, Congrats on the new profession, and John we were surely Matthew My best wishes to your next journey and I Hope our roads will cross again in the near future. So I have two part question on the a T. T. R franchise for the first one is regarding the Helios.

Operator: Thank you for taking my questions. Yvang, congratulations on the new position. And, John, we will surely miss you. My best wish is for your next journey, and I hope our roads will cross again in the near future.

Yvonne L. Greenstreet: So I have a two-part question on the ATTR franchise. The first one is regarding the Helios A. Just wondering, regarding the 30% cardio subpopulation, you know, based on your definition of the cardio subpopulation, which NYHA class these patients will belong to. And then another short question regarding Apollo B; I understand that patients will be allowed to take a tephanumis at some point in the study. So if there are any set time restrictions before allowing these patients to take tephatomis, and this is referring to the 70% patient population that would not be on tephatomis at the baseline, yeah, thank you.

<unk>.

Just wondering regarding the 30 per cent cardio subpopulation, you know based on your definition on the cardio a population, which in my H a class. These patient belong to and then another show up Flushing regarding Apollo B I understand a patient will be allowed to take her to Falmouth at some point.

In a study so is there any set time restriction before allowing these patients to take a <unk> and this is referring to the 70% patient population that would not be can fathom is on the baseline.

Yeah. Thank you. Thank you Gina Akshay do you want to handle both questions. Yeah. So with respect to Helios a will present the full data gene at an upcoming medical meeting, but suffice it to say.

Akshay K. Vaishnaw: Yeah, thank you, thank you, Gina. Aksha, do you want to handle both questions? Yeah, so with respect to Heliosay, you know, we'll present the full date for Gina at an upcoming medical meeting, but suffice it to say, you know, the vast majority of patients would have a New York Association 1 or 2 level disease. With respect to Apollo B and to Famadis, Pushko, Gag, is with us. Pushka, do you want to comment on that? Sure, thanks, Aksa, Gina. Your question about TAPFRAP drop.

Vast majority of patients would have Neocart Association, one O two level disease with respect to Apollo B and Tafamidis Pushcart God gives me the <unk> you want to comment on that sure. Thanks actually Gina.

Few question about tap drop ins.

Pushkal Garg: In, you know, ethically, patients can drop in or positionally do that, but they're discouraged from doing that in the first 12 months. And our statistical analysis plan also accounts for the potential for drop-ins, so we feel completely about the design of the study and accommodating that. Thank you. Our next question comes from Kazina Med with Bank of America. Good morning, guys. Thank you for taking my questions.

Ethically up patients can drop in a position to do that but they are discouraged from doing that in the first 12 months in our statistical.

Stickle analysis plan also accounts.

For the potential for drop ins Uhm, So we feel about the design of the study and accommodating that.

Thank you.

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

Good morning, Thank you for taking my questions, John and you've been a terrific C. E. L. We most certainly nephew me I say that fast in your future endeavors and look forward to working with design.

Operator: John, you've been a terrific CEO. We will certainly miss you. We wish you the best in your future endeavors and look forward to working with Yvonne. Just a clarification question.

Uhm.

A clarification question are you just going to be joining the scientific advisory Board are you gonna be staying on what the full board of directors.

John Meriginori: Are you just going to be joining the Scientific Advisory Board? Or are you going to be staying on with the full Board of directors? And then, a quick question: how is enrollment progressing in the Cardier one trial? Yeah, thank you, Tizine, thanks for your very warm comments, and you're going to love working with Yvonne. She's nothing short of terrific.

And then a quick question how is enrollment progressing in the cardiac <unk>. Thank you.

Yeah. Thank you Dizzy and thanks for your very warm comments and you're going to love working with Ivan She's she's nothing short of terrific I wouldn't be staying on the scientific advisory board because I cannot.

John Meriginori: I'm going to be staying on the Scientific Advisory Board because I cannot do anything other than love the science of El Milamon and can't wait to continue to be involved with the great science and progress that we're making here in the company. As you can imagine, being on boards for a former CEO is always a competition. thing, and I just think it's a lot better for Avon if I'm not on the board, and I just focus on the science, which I'll do, and I'll torture Akshay instead.

Do anything other than love the science of Alnylam and can't wait to continue to be involved with the great science and progress that we're making here in the company as as you can imagine being on boards for former C. E. O is always a complicated thing and I just think it's a lot better for Yvonne if I am.

Not on the board and I, just focus on the science, which I'll do and I'll torture Akshay. Instead, you live on a good and good place, but no. It's it's a decision that I made because I think it's very difficult for farmers C E O's to stay on board.

John Meriginori: You'll go on in a good place, but no, it's a decision that I made because I think it's very difficult for former CEOs to stay on boards, and obviously, I will participate in the company on the scientific advisory board. But actually, do you want to comment on Cardia? Yeah.

And obviously I will participate in the company on the scientific Advisory Board.

But actually do you want to comment on cardio yeah.

Uhm Cuddyer, one enrollment is going well generally speaking does need and we let the trial progress.

Akshay K. Vaishnaw: Cardia 1 enrollment is going well. You know, generally speaking, Tazine, we let the trial progress and we have a clear line of sight on the last patient in before we give further guidance. But it's going very well. I mean, this is hypertension in over 1.2 billion patients around the world. So it's an eminently enrollable study, and it is going well.

Clear line of sight on the last patient and before we get to set the gardens, but it's getting very well I mean this is hypertension is.

1.2 billion patients around the world.

So it's an eminently enrolls in Rollable study and it is getting well.

Yvonne L. Greenstreet: I mean, if I could just ask,

I mean, if I could just add that I'm I'm looking forward to actually what it's going to be quite a reasonable transition period here I'm not actually taking on the role C. O until January the first next there and I'm sure it will be staying on as an adviser uhm for the.

Yvonne L. Greenstreet: that I'm looking forward to actually what is going to be quite a sort of reasonable transition period here. I'm not actually taking on the role of CEO until January the first next year, and John will be staying on as a little

Yvonne L. Greenstreet: advisor for the, you know, three or so months following that period. So we're going to be seeing quite a lot of each other still, I think, John, for the next period of time.

Three O seven months following that period, so you're going to be seeing quite source of each other so I think.

Period of time.

Yvonne L. Greenstreet: seeing quite off of each other, so I think so on it in the next period of time. I think so.

I think so thanks diseases that answer your question.

Operator: Thanks, DeZine. Does that answer your question? Any more questions?

Yep. Thank you guys.

Operator: Yep, thank you guys. Thank you. Our next question comes from Ted Kentoff on 5%. Great, thank you, and John, my sincere congratulations. I wish you nothing but personal and professional success. It's such a pleasure for a long time.

Thank you.

Our next question comes from Ted cut off with five per Sandler.

Great. Thanks, and calm my sincere congratulations with skim milk and Burke personal one and professional because it's such a pleasure to load card [laughter].

Operator: And a long, congratulations, really exciting transition point for the company. So I wanted to ask a little bit about pipelines in terms of AAP and maybe, again, not to get too much further from the upcoming RD Day, but can you give us a little bit more insight into how you anticipate development of that asset went for? So, Ted, you were coming in and out on which asset with Regeneron specifically?

At the avant congrats it really.

Really kind of transfer support for a company so ordered to ask a little bit or type or in terms of a T. M. Maybe again that <unk> southern from the upcoming R. D day, but can you give us a little bit more insight to how you anticipate developing that set what.

Thanks.

So tell you were coming in and out which asset with regeneron specifically.

John Meriginori: AOLN, APP, oh, fantastic, okay, yeah, no, I mean, let me just start by saying one of the really exciting next frontiers for El Lylem is the broader extra-hypatic delivery opportunities, and you'll hear a lot about that at our upcoming R&D day, and I think you're going to be really pleased with what you hear. And, of course, the program that's pushing that frontier is ALNAPP, which targets amyloid precursor protein, and we are really excited that the I and D should be filed, or CTA, in this case, will be filed by the end of the year.

M a O M a P P.

A P. P O fantastic Okay, Yeah, no I mean, let me just start by saying.

One of the really exciting next frontier is four alnylam is the broader extra hepatic delivery opportunities and you'll hear a lot about that at our upcoming R&D day, and I think you're gonna be really pleased.

With with what you're here.

And of course the program, that's pushing that frontier is Allen a P P, which targets amyloid precursor protein and we are we are really excited that the <unk> should be filed or CPA. In this case will be filed by the end of the year and we do expect to have human data next year.

John Meriginori: And we do expect to have human data next year from that program, which will be really important because if we can reproduce the, you know, 70, 80% lowering of APP and beta fragments that we've observed so durably in the primate, that would be a major milestone for the entire field and, frankly, for the treatment of neurodegenerative diseases in the future. So we really look forward to that. Now, specifically on the development plans, maybe I can point it over to Pushko to maybe make some high-level comments. Push-gole.

From that program, which will be really important because if we can reproduce the.

70, 80% lowering of of ADP and a bit of a data fragments that we've observed so durably and the primate that would be a major milestone for the entire field and frankly for the treatment of neurodegenerative diseases in the future.

So we really look forward to that now.

Specifically on the development plans.

Maybe I can pointed over to postpone to maybe make some high level comments pushball sure. Thanks John.

Pushkal Garg: Sure. Thanks, John. So with regard to ALNAPP, as ACHHA mentioned in his comments, we're going to be filing the I&D later this year to take that molecule forward to have broad applicability across, you know, if it meets its proof of concepts, as John highlighted, Alzheimer's disease, as well as another very, very disabling and fatal condition, cerebral amyloid angiopathy, both of which APP has been strongly implicated in

So with regard K on a P. P. As actually mentioned in his comments were gonna be filing. The Indy later this year to take that molecule afford it has I think it has brought applicability across.

If it meets as proof of concept is John highlighted in Alzheimer's disease as well as another very very disabling in favourable condition strubel amyloid angiopathy, both of which <unk> has been strongly implicated in.

Pushkal Garg: The initial study that we're planning to do will be opening the I&D in NCT and CTA in early onset Alzheimer's disease, which is a well-characterized population of patients with severe unmet need. And then based on the result. There, where we will be looking initially for safety, tolerability, as well as pharmacologic activity, we'll be able to branch into a broader phase two and three program in those two diseases. That's our plan. Does that answer your question, Ted?

The initial study that we're planning to do will be opening the I N D.

N C T. A in early onset Alzheimer's disease, which is Ah well characterized population of patients with severe unmet need and then based on the results there where we will be looking initially for safety tolerability as well as pharmacologic activity, we'll be able to branch into a broader please two and three program in those two diseases that.

Our plan.

Does that answer your question Ted Georgia, Thanks, everybody.

Operator: Sure does. Thanks, everybody. Thank you. Our next question comes from Sal Bean Richter with Goldman Sachs. Good morning.

Thank you.

Our next question comes from shopping director with Goldman Sachs.

Good morning, and thanks for taking my questions and John It has been a pleasure working with you you will be missed here in Nevada, congratulations on the new role.

Operator: Thanks for taking my questions, John. It has been a pleasure working with you. You'll be missed here, and Yvonne. Congratulations on the new role.

Operator: In terms of Apollo B and this Tefamadus drop in here, how do you account for this in the statistical plan, just given that patients still have the option to pursue it, notwithstanding discouragement? And then secondly, on the CNS platform, maybe help us understand where you stand in the ability to deliver to that tissue. Yeah, let me have Pushkole answer the Apollo B question, and then Akshay can answer the APP question.

In terms of Apollo B and and this <unk> dropping here how do you account for this ethical plan just given that patients still do that the option to pursue it notwithstanding discouragement and then secondly on the CNS platform, maybe help us understand uhm, just where you stand in the ability to deliver to.

That tissue.

Yeah, well, let me let me have political answer the Apollo be question and then Akshay can answer the the AVP question, but let me just start solving first of all by thanking you for your comments at the beginning of course, but also just reminding you that obviously in the design of both the Helios be animal.

John Meriginori: But let me just start, Selvian, first of all by thanking you for your comments at the beginning, of course, but also just reminding you that, obviously, in the design of both the Helios B and Apollo B studies, we come at this with enormous experience in doing clinical studies in ATTR amyidosis. And we come at this, of course, with a very solid track record, as you know, from our overall clinical development team and designing very robust, typically highly overpowered studies, I might say, as you can note from our traditional P values. So with that as a background, Pushko, do you want to answer Selvian's specific question? Sure. Hi Selvine.

<unk> study.

We come at this with enormous experience and doing clinical studies and a T. T. R amyloidosis and we come at this of course with a with a very solid track record as you know from our our overall clinical development team in designing very robust typically highly overpowered studies I'd say.

As you can note from our traditional P values, so with that as background political do you want to answer Soviet specific question sure I solving.

Pushkal Garg: Look, I think, you know, understand why you're asking your question. Again, as John highlighted, as we designed the study, we were obviously very cognizant of the availability of the ability to defamitis, and the potential for it to drop in.

Look I think.

Understand what you're asking your question again as John highlighted as we design. The study were obviously very cognizant of the availability of Tafamidis and the potential drop in.

Pushkal Garg: There was an allowance for a certain amount of baseline defamidus use on entry into the study, as we talked about, and we modeled out a variety of parameters. The studies do allow for patients to drop in on TAV, particularly guiding after the first year. And as you'll recall in Apollo B, the primary endpoint is a 12-month endpoint of a six-minute lock test.

There wasn't allowance for a certain amount of baseline to families use an entry into the study as we talked about and.

And we modeled out a variety of parameters. The studies do allow for patients to drop in on tap.

Excuse me guiding after the first year and as you'll recall in Apollo be the primary endpoint is a 12 month the endpoint of six minute lock test. The other thing to remember is that as we think about.

Pushkal Garg: The other thing to remember is that as we think about the geographic deployment of this study, we are also aware of where TAF is available to patients. And so through an operational, through the way we operationally manage the study, we can also have some control over the availability of TAF and the potential risks around drop-in. And then also, statistically, we assumed some very conservative assumptions. As John highlighted, we were very thoughtful about how we designed these studies. And so we considered very conservative assumptions in terms of drop-in and made sure that our powering considerations were robust to even the worst case scenarios.

The geographic deployment of this study. We also are aware of where taffe is available to patients and so through an operational through the way we operationally manage the study. We can also have some control about the availability of tap and the potential risks around dropping.

And then also statistically we assume some very conservative assumptions as John highlighted were very thoughtful about how we design. These studies and sweet we considered very conservative assumptions in terms of drop in and made sure that are powering considerations were robust to even the worst case scenario. So we feel very very comfortable with that and then finally our in house.

Pushkal Garg: So we feel very, very comfortable with that. And then finally, our analysis plan also takes into account the potential for drop-ins, and there are analytic methods where we can, for example, detect drop-ins and look at analyses with and without drop-ins, et cetera. And I'll just highlight that we monitor this very closely, as does our DMC, and we feel very, very confident and good that the numbers are, you know, continuing to be low, and we're monitoring that. And we feel very comfortable with the overall conduct of the study. Great. Thank you, Pushkal. Akshay, the question on APP.

This plan also takes into account the potential for drop ins and there are analytic methods, where we can for example sensor drop ins and look at analyses with and without drop ins et cetera.

And I'll you know I'll just highlight that we remain we monitor this very closely as does our D. M C and we feel very very confident and good that the numbers are continued to be low and we're up and we're monitoring that and we feel very comfortable with the overall conduct a study great. Thank you push call Akshay. The question that a P. P.

Akshay K. Vaishnaw: Yeah, so we're very excited about the CNS delivery approaches we have in hand. You know, we shared at OTS that we've got a novel conjugate that's a lipid-based system, C-16, and we've shown, you know, reproducibly, both in small animals, rodents, and in non-human primates, that we get widespread delivery in the central nervous system with potent knockdown, 80% or greater and against multiple targets.

Yeah. So we're very excited about the CNS delivery approaches we have in hand, uhm, we shared it O T S.

We've got a novel called you get selected based systems, He 16 and we've shown.

Reproduceably, both in small animals rodents and in non-human primates that we get widespread delivery in the central nervous system with potent knock down 80% on great durable knockdown of up to a year.

And against multiple targets in these targets we've looked at cell specific market. So we know we get knocked out and then all of the major all types in the nervous system. The neural NASA site microbial cells and you know anatomically the Biodistribution books very encouraging indeed with knock down in deep brain structures, which I know has been a challenge for.

Akshay K. Vaishnaw: And these targets, you know, we've looked at cell-specific markets, so we know we get knocked down in all the major cell types in the nervous system, the neuron, the astrocyte, microgliol cells. And, you know, anatomically, the biodistribution looks very encouraging indeed with knockdown in deep brain structures, which I know has been a challenge for other modalities, cortical structures, cerebell So, you know, with that kind of pre-clinical pharmacology package, one has to be excited.

The modality cortical structures cerebellar stripes isn't the spinal cord, so with that kind of preclinical pharmacology package, one has to be excited and with the full DLNA P. P program, which we discuss just a few minutes ago really is in the vanguard of what's to come in and we look forward to two exciting data from that program.

Akshay K. Vaishnaw: Therefore, the L&APP program, which we discussed just a few minutes ago, really is in the vanguard of what's to come, and we look forward to exciting data from that program in 2022 with biomarker knockdown, hopefully. Our next question comes from Paul Mateuse. Great, thanks so much.

In 2022 with biomarker knock down hopefully.

Thank you.

Our next question comes from Palm of Tasteless Sniffles.

Operator: And I'll echo what everyone else said, John, about working with you and Yvonne. Congratulations. I wanted to ask a few more questions about the transition and why now. And I guess, you know, one thing that I noticed going back to the last quarter press release was that Mike Bonny was named Executive Chair really recently, and it had to do with legal and compliance functions. And I guess I wanted to just kind of understand, is there anything beyond what was disclosed?

Great. Thanks, so much and Oh Echo what everyone else that John about working with you in a van and congratulations.

I wanted to ask a few more questions just about the transition in N Y now and I guess.

One thing that I noticed going back to the last quarter press release, because that might Bonnie was named executive Chair really recently and I had to do with legal and compliance functions and I guess I wanted to just kind of understand is there anything beyond what was disclosed here as it just relates to kind of job.

Operator: here as it just relates to kind of John your vision strategically, the board's vision strategically was there, I guess really just flat out. Was there any kind of disagreement at all on where El Milam is going, or is this purely

Dawn Eurovision Strategically the Board Division strategically was there I guess really just flat out was there any kind of disagreement at all on where on my home, it's going or is this purely just voluntary uhm and you and do you feel like it's the right time and I guess, if you do feel like it's really just the right time why not wait until after Apollo be given how big of a value crew.

Operator: Just voluntary, and you feel like it's the right time, and I guess

Operator: If you do feel like it's really just the right time, why not wait until after Apollo B, given how big of a value-creating event that could be for our model? Thanks, Omar. Paul, thanks for the question and your kind words at the beginning. And let me try to be really clear.

<unk> event that could be for I'm idle. Thanks, so much.

Paul Thanks, Thanks for the question and and your and your kind words, the beginning and let me try to let me try to be really clear. This was my decision I I wanted to get a new chapter I've been running this company for 19 years.

John Meriginori: This was my decision. I want to begin a new chapter. I've been running this company for 19 years. Came here as the founding CEO, $17.5 million post-money valuation, and took it to $25 billion, and obviously, 1,600 employees in 20 countries around the world and for approved medicines.

Came here when there were six employees as the founding C. O 17.5 million dollar post money valuation then took it to 25 billion.

And obviously 1600 employees in 20 countries around the world and four approved medicines. So after a 19 year tenure like that.

John Meriginori: So after a 19-year tenure like that, you know, it's not unreasonable to say, okay, things are really good, things are going great, maybe you don't want to be a running CEO for the next 19 years. And, you know, in terms of timing, yeah, I could have waited until next year. I could have waited until two years. I could have waited until 30 years, but I'd probably be dead.

It's not unreasonable to say OK things are really good things are going great might want to not be running CEO for the next 19 years and you know in terms of timing I could wait until next year I could have waited until two years I could've waited till 30 years, but I'd probably be dead. So at some point you just got to make the.

John Meriginori: So at some point, you just have to make the call about when to make a transition, and I couldn't be more I could be more excited about where the company is right now, and I could be more excited about the fact that Yvonne is here as my successor. I mean, if I waited for a year and Yvonne got lured to go someplace else, I'd have no successor. So I'd have to keep kicking the can down the road.

Call about when to make a transition and I couldn't be more excited about where the company is right now and I couldn't be more excited about the fact that Yvonne is here's my success I mean, if I waited for a year and Yvonne dot lowered to go someplace else I'd have no successor, so I can't keep kicking the can down the road. So the bottom line is this is the right time.

John Meriginori: So the bottom line is this is the right time. There's never a great time, of course, but I think this is the right time. And in terms of value creation, I'm still a major shareholder of the company, and I'm going to stay a major shareholder of the company, and I'm obviously going to benefit from the, in my view, very likely outcome of Apollo B, which I think will be a very defining event for the company. Does that answer your question? I don't know, Yvonne, if you want to say something?

There's never a great time of course, but I think this is the right time and in terms of value creation I'm still a major shareholder of the company and I want to say a major shareholder of the company and I'm, obviously going to benefit from the very in my view very likely outcome of Apollo B, which I think will be a very defining event for the company does that answer your question.

I Dunno Yvonne if you want to say something so I just want to add that.

Yvonne L. Greenstreet: Well, I just want to add that, you know, John and I created a piece of the five times 25 goals together, and as you all know, this lays out the very bold vision that we have for the company, delivering transformative medicine to patients around the world for both rare and more prevalent diseases from our amazing product engine, as well as delivering excellent financial performance. And we put this strategy together, and going forward, I'm fully committed to implementing the strategy.

John and I created the Pizza five times twenty-five goes together and as you. All know this lays out the very bold bit patient that we have the company delivering transformative medicines to patients around the world, but rats and more prevalent diseases from up amazing pull the engine as well as delivering excellent financial performance and we put the strategy together and going forward.

I'm fully committed uhm two progressing the strategy I think it says as well as a road map to guide US with the next chapter and I kind of <unk> clients execute fully against this plan without any loss of momentum.

Yvonne L. Greenstreet: I think it serves as a roadmap to guide us through the next chapter, and I kind of plan to execute fully against this plan without any loss of momentum. Thank you. Yeah, it does.

Thank you Bob.

Operator: If I can just ask one follow-up question, you know, given that Barry left a year ago and John, now you're deciding it's time. Avon, again, congrats. Do you expect the rest of the management team to remain in place? I mean, absolutely, Paul. I mean, we have a very committed team of leaders here in the company, and I have no reason to believe that any changes are going to happen. But we also have a really strong bench.

Yeah, if I can just ask one follow up given that yeah, Barry Barry left a year ago and John now your ear deciding it's time of.

Again, Congrats do you expect the rest of the management team to remain in place.

I mean, absolutely Paul I mean, we have a very committed team of leaders here in the company.

And I have no reason to believe that Eddie <unk>.

Changes are are are going to happen.

But we also have a really strong batch we have a strong group of people that are right underneath these leaders that we have right now.

Operator: You know, we have a strong group of people that are right underneath these leaders that we have right now. And so we are in a very, very strong position as a result of all that, and I have every confidence that this company will continue to perform unbelievably well in the future. No doubt about that in my mind. Great. Thank you again. Thanks, Paul. Our next question.

And so we are in very very strong position as a result of all that and I have every confidence that this company will continue to perform unbelievably well for the future no doubt about it in my mind.

Great. Thank you again.

Thanks, Paul.

Our next question comes from <unk>.

Operator: Thanks for taking the question, everyone. Yvonne, congrats. I'm really looking forward to working with you. And John, we'll miss you, but that lyric opera offer still stands on my part.

Thanks for taking my question, everyone Yvonne Congrats really looking for it.

Working with you and John will Miss you put that lyric offer like lyric opera offer still stands on my part.

Operator: All right, I'm in. Sounds good. I'm in. I'm in. I wanted to ask, you know, without getting you in trouble with maybe ACC, I wanted to ask about the potential technetium data that we're going to be seeing out of Helios A next year and especially how that could be important for differentiation and marketing potentially going forward. I guess one question is, can you walk us through, like, the units of that scan and what a meaningful burden reduction is, and are we going to get that same data out of Apollo B and Helios B?

Alright, I'm in [laughter], Yeah man I wanted to ask without getting you in trouble with maybe a T. C. I wanted to ask about the potential technician data that we're gonna be seeing.

Chelios, a next year and especially how that can be.

<unk> for differentiation and marketing occasionally going forward I guess, one can you walk us through like the unit at that scan and what a meaningful uhm.

Burden reduction and are we going to get that scene.

Apollo B and Helios.

Operator: Okay, so let me have Akshay answer that question. You asked the question about differentiation as well, so I'm going to have Tull explain the way out of that part of it.

Okay, great. So let let me have Akshay answer you asked a question about differentiation as well so I'm gonna I'm Gonna have Togo way out of that part of it let me let me start though is akshay commenting.

John Meriginori: Let me start, though, with Akshay commenting on it without getting into trouble with ACC if that's where we present it. So, ACHHA, go ahead. Yeah, we will have to wait for the full data to share in more detail. But at a high level, what I would say is this is a denser metric evaluation tool where you look at the extent of the tracer optic into the heart. And what we've done with a significant number, actually the largest number of patients in a study of this kind ever, looked at pre- and post-treatment, and we're very encouraged by the fact that the majority show reduction in tracer optic sensitivity with technician.

On the.

Without getting into trouble with takes you see.

If that's where we presented so akshay go ahead yeah.

Two we will have to wait for the full data to sharing more detailed but at a high level of what I would say this is tends to metric evaluation tool. When you look at the extent of tracer uptake into the hot.

And what we've done in a significant number of actually the largest number of patients in the study of this kind ever looked at pre and post treatment and we're very encouraged by the fact that the majority.

So reduction in trace or update with technician.

John Meriginori: Now, you know, if that's not a clinically approvable endpoint today, what we know scientifically is that we're encouraged by this because the data would suggest that this could be potential evidence for reduction in cardiac amyloid, and that, of course, would be very exciting. So we'll share the full data set with you in due course, but, you know, the data can only be supportive and encouraging of what's to come in Apollo B and Helios B and our overall belief that reduction of TTR levels with our drugs, Patisran and Voutrable, hopefully will convert to significant clinical benefit for patients with ATTR chal charymarts. And Toga, do you want to talk a little bit? Oh, sorry, go ahead, Ritou.

Now if that's not a clinically approved blend point today, what we know scientifically that were encouraged by this because the data would suggest that this could be potential evidence, but reduction in cardiac amyloid and that of course would be very exciting.

Well, we'll share the full data set with you and G cause but.

The data can only be supportive and encouraging of what's to come in Apollo B and Helios B and our overall belief that a reduction of TTL levels without drugs Patese rat.

Hopefully will commit significant clinical benefit for patients with a T T I'll cut him off.

They told me that you want to comment a little bit Oh, sorry go ahead, Richard Akshay well those two trials also January technician call for gas.

Akshay K. Vaishnaw: Okay, actually, will those two trials also generate Technician cohort data? Yeah, Technician is an optional assessment in there. Not all patients will have it, and, of course, you know, the availability will vary at sites around the world. But, yes, there'll be some technician data. But, more importantly, I think in those studies, we'll be the clinical endpoints, of course, right, which six-minute walk distance for Apollo B and Mortatian hospitalization for Helios B. Yeah. And, and, Tolga, do you want to comment a little bit on Richard's question around the potential differentiation of these data as it relates to the competitive landscape and so forth? Sure.

Yeah. The technician is an optional assessment and they're not all patients will have it.

And of course, you know the availability will various sites around the world.

But yes, there'll be some technician data more importantly, I think in those studies right. It will be the clinical endpoints of course right, which.

Six and at what distance for Apollo B, and mortality and hospitalization for Helio space.

And Togger do you want to comment a little bit on Rich's question around the potential differentiation of these data as <unk> as it relates to the competitive landscape and so forth sure I mean first of all obviously, we're very pleased with the Onpattro performance and how we've been able to expand our prescriber base.

Tolga Tanguler: I mean, first of all, obviously, we're very pleased with the OMPATRO performance and how we've been able to expand our prescriber base and increase our initial forms. Now, there will be patients and physicians who are waiting and seeing category. And I believe, with the combination of efficacy and safety and once quarterly in the future and possibly semi-annual subcutaneous treatment regimen, along with coupled with the strong commercial capabilities that we have already built, I believe this product will enable us to further expand the franchise that we have already established, especially in markets where increased convenience is needed, for instance, in Japan, where we have limited home infusion availability.

And an increase our start forms now.

There will be patients and physicians, who are wait and then C category and I believe we'd combination of it because of safety and once quarterly in the future and possibly semiannual subcutaneous treatment regimen.

Along with coupled with the strong commercial capabilities that we already built I believe this this product will enable us to to further expand the franchise.

But we already established especially markers where.

Increased convenience forces in Japan, we have limited home infusion availability.

Tolga Tanguler: The switch dynamic will certainly increase, as well as in the EU, where increased convenience could accelerate the switch dynamic from the stabilizer to increase our category share of first line versus other treatment options. I just want to add one point, and that's just to emphasize that, you know, our commercial organization has done a fantastic job, but, you know, we have something like

The switch dynamic, we'll we'll certainly increased as well as in you were increase convenience could accelerate the switch dynamic from the stabilizer to increase increase our category of sure.

First line versus other treatment options.

I'd just like to add one point and that's just to emphasize that you know a commercial organization has done a fantastic job, but we have something like 18 75 patients that are currently on commercial treatment.

Yvonne L. Greenstreet: 1875 patients that are currently on commercial treatment. We have an opportunity that's much, much larger than that. If you look at the patients that would be appropriate for Patra,

We have an opportunity that much much lots of that if you look at the page.

Patients that.

<unk>.

Would be appropriate.

For an petro and hopefully shortly patrice rent you're looking at it over 30000 patients. So we really are at the beginning of the shiny that I think going to just continue to have to pick up steam as as time goes on.

Yvonne L. Greenstreet: and hopefully, short-butre, you're looking at over 30,000 patients. So we really are at the beginning of this journey that's, I think, going to just continue to pick up steam as time goes on. Great. All right, thank you.

Alright, great Thanksgiving is that alright, Thank you Richard.

Our next question comes from only problem Romo with J P. Morgan.

Operator: Our next question comes from Anuponrama with KP Morgan. Hey, so much for taking the question. John, I'm sad to see you go, but it's been really cool to see everything you've built, man. And I wish you the best.

Hey, guys. So much for taking the question John Sad to see you go but it's been really cool to see everything you've built ma'am and wishing you the best Yvonne Congrats and and look forward to seeing you at the conference in January.

Operator: Yvonne, congratulations, and I look forward to seeing you at the conference in January. On Patisse Rand and Apollo B, more of a market research question. What does your market research say about a knockdown agent within every three-week IV regimen and a six-minute walk distance and point? How does that kind of fit in? versus a catamadus, particularly in wild-type cardiomyopsy, where we know they have hospitalizations and mortality type of data.

<unk> Petite shrimp and Apollo be more of a market research question.

What is your market research say about a knockdown agent within every three week Ivy Regiment six minute walk distance and point, how does that fit in versus a tafamidis, particularly in Wildcat cardiomyopathy, where we know they have hospitalizations and mortality type of data. Thanks, so much.

Operator: Thanks so much. Yeah, thanks, Sahnapam, and I will miss you in January, but I'll perhaps be in the audience watching Yvonne. But getting back to your question on differentiation, and specifically the question on how it all plays out, I'll let Toga answer in just a minute.

No. That's it thanks, an apartment and I will Miss you in January but.

Perhaps be the audience watching Yvonne.

But getting back to your question of differentiation.

And specifically the question on how does it all play out I'll, let toga answer in just a minute, but let me just start by saying that obviously.

John Meriginori: But let me just start by saying that, obviously, you know, if we generate positive results out of Apollo B, and if the drug is approved for the wild type and horrendous TTR cardiomyopathy segment, those are, of course, important ifs. We think that the profile of a TTR silencer and the mechanism of action of a TTR silencer will be a valued part of the treatment options that are available for patients with this disease.

What if we generate positive results out of Apollo B and if the drug is approved for the the wild type and hereditary Atti cardiomyopathy segment. Those are of course important if.

We think that the profile of a TCR silence or the mechanism of action of a T. T. R. Silencer will be a valued part of the treatment options that are available for patients with this disease and we certainly believe based on market research. We've done that Toby can comment on that that type of.

John Meriginori: And we certainly believe, based on market research we've done, that Tobin can comment on, that that type of availability, you know, certainly for patients that may be progressing in their ongoing treatment with a stabilizer drug, if they're on a stabilizer drug, that that type of treatment option may be important for the patients, again, assuming positive Apollo B data and positive approval. So that's at least the foundational aspect of it. Talga, do you want to add anything more to that as well? No, John.

Billety.

Certainly for patients that may be progressing.

In their in their ongoing treatment with a with a stabilizer drug if they're if they're auto stabilizer drug.

That type of treatment option may be important for the patients again, assuming positive Apollo be data and positive approval. So that's that's at least the foundational aspect of it target do you wanted to add anything more to that as well.

Tolga Tanguler: I mean, essentially, what we shared earlier as well, based on some of the market research studies we've done, we certainly saw the early indicators of cardiomyopathy or cardiac data, secondary endpoints, tend to be seen very favorably by the cardiologist if the product is obviously approved. And obviously, given the profile of the product, being a quarterly subcutaneous injection, clearly addresses the adherence issue, which, again, would be another important indicator Yeah. Pushko, do you want to comment? Sure. I think this is an important question.

No John I mean, essentially what we shared earlier as well based on some of the market.

Market Research studies, we've done we've certainly seen the early indicators of cardiomyopathy a cardiac.

Data secondary endpoints tend to be seen very favorably by the by by the cardiologist.

If the product is obviously approved and obviously given the profile of the product they're being.

A quarterly subcutaneous injection.

Clearly address is the adherence issue, which again would be we'd be in another important indicator.

Indicator, yeah Bush going to you want to comment sure I think it's important question I think maybe just a couple of points to reiterate around on Patriot and profiled Tafamidis Uhm I think it's important to recognize the patient's onto families. Even coming out of the track study continued to decline in terms of their six minute walk test and so we think there's an opportunity.

Pushkal Garg: I think maybe just a couple of points to reiterate around patro and the profile of defamidus. You know, I think it's important to recognize that patients on tephamidus, even coming out of the tract study, continue to decline in terms of their six-minute walk test. And so we think there's an opportunity, again, based on the data we've seen more broadly with silencing, to potentially have a very The other, you know, point around this, and we're trying to see some evidence of that, while there haven't been head-to-head studies, it was interesting, for example, that there was a recent abstract presented at the EU TTR meeting that looked at technetium scans in patients given to silencer and patients given to famitis.

Again based on the data we've seen more broadly with silencing to potentially have a very differentiated clinical profile.

The other point around this and was trying to see some evidence of that while there haven't been head to head studies. It was interesting for example that there was a recent abstract presented at the E. U T. T. R meeting that looked at technetium scans in patients given the silence certain patients given to families and.

Pushkal Garg: And, you know, Aksche mentioned early on that we've seen evidence of improvements or reduced uptake on technetium scanning with a silencer. In this case, with Vutrizer and in Helios A, in that study, they looked at patients on Patro and saw similar results. And interestingly, in that study with defamidus patients and stabilizer patients, they did not see those kinds of improvements. So again, a small study, an academic study, but I think as we start to look at the totality of data that's emerging on our class of silencers versus stabilizers, we are starting to see differentiation.

Actually I mentioned early on that we've seen evidence of improvements are reduced uptake on technetium Scranton scanning with with a silencer.

In this case with who treats her in and Helio say in that study they looked at patients on patrol and saw similar results and interestingly and that's a with tafamidis patients.

Cable iser patients that they did not see.

Those kinds of improvements so again, a small study academic study, but I think as we start to look at the totality of data that's emerging on our class of on silences versus stabilizes, we are starting to see differentiation and we'll see then when we get the results from Apollo B, how those aloes materialize clinical trial data five.

Pushkal Garg: And we'll see then, when we get the results from Apollo B, how those correlate with clinical trial data. By the way, just to keep the record straight, I was referring to Helios B, not Apollobos, so sorry about the subcontaneous one. No, thanks. Does that answer your question on Obama?

Just to keep the record straight I was referring to helio speed got Apollo. These so sorry about the the subcutaneous.

Thanks does that answer your question out of them.

Operator: Yep. Thanks so much for taking the question. Thank you. Our next question comes from Malifia Young with Cantor.

Yep. Thanks, so much for taking my question. Thank you. Thank you.

Our next question comes from relief you young with catcher.

Operator: Hey, guys, thanks for taking my question. Yvonne, you've been killing it over there, so keep on killing it. Congratulations. And, John, you guys always have a special place in my heart, and it's been great working with you, and one of the first companies I ever covered, so all the best, man. Thank you.

Hey, guys. Thanks for taking my question <unk>, even counted over there okay found count it congrats and John.

Alright have a special place in my heart and it's been great working with you in one of the first companies I ever covered so all the vast man.

Operator: So I guess I want to talk a little bit about the big picture. Like, you know, you guys have a lot of things going on. I'm obviously now starting to branch out to many different indications. So when you look across, like, the next three to five years, I mean, some of these start to potentially come to fruition. And are you looking to kind of build deeper commercial organizations that do more and diversify, or are you kind of thinking about different other strategic ways and things to do things?

So thank you. So so I guess I went out to love it about like Big picture like you know you guys have a lot of things going on I'm, obviously now starting to branch out into many different indications. So then when you look across like the next three to five years I mean, some of these start to come to potentially to fruition are you looking to kind of build deeper commercial organizations that do more and diversify or are you kind of thing.

About different other strategic ways and thanks to do thanks. Thanks.

Operator: Well, it's a terrific question at the end, and, you know, you've always been such a great covering analyst, so it's wonderful to have been one of the first companies you've covered. But I think your question's a really terrific one for Avon.

Well, it's a it's a terrific question all at the end and.

You've always been such a great covering analysts so it's wonderful to have been one of the first companies you've covered but I take your questions are really terrific blood for awhile. So I'm gonna just pass it right over to her yeah. No. That's great I think we're in a really strong position with what we put in place to continue to execute if we look at the.

John Meriginori: So I'm just passing it right over to her. Yeah, I know, that's great. I think we're in a really strong position with what we've put in place to continue to execute. If we look at the opportunities that are ahead of us, they're going to be focused around the, you know, you know, you know, cardiac market for the next few years, obviously.

Opportunities that are ahead of us.

They're going to be focused around that in a cardiac <unk>.

Market for the next few years, obviously hope hopefully we get great dates around sofa, Apollo B and tedious B and then we look forward to <unk>.

Yvonne L. Greenstreet: So hopefully, we get great data out of Apollo B and HedusB, and then we look forward to Zal Bhran for hypertension, which we believe is going to completely rethink the treatment of hypertension.

For hypertension, which we believe is going to completely re imagine the treatment of hypertension, I think we're going to be able to build on this footprint.

Yvonne L. Greenstreet: I think we're going to be able to build on this footprint from a commercial perspective within the company. But clearly, you know, as we go forward with all the opportunities we have, what that gives us is tremendous optionality for thinking about how we want to build the business. We're just incredibly fortunate to be standing on the foundation that John has built over the last 19 years.

From a commercial perspective within the company, but clearly you know as we as we go forward with all the opportunity we have what that gives us is tremendous optionality. The thinking about how you want to build a business, which is incredibly fortunate to be standing on the foundation that John is built over the last.

Yvonne L. Greenstreet: and, you know, you know, you know, you know.

19 years, and I couldn't be more excited about what we have in front of us.

Yvonne L. Greenstreet: out what we have in front of us. Does that answer your question? Yes, and congrats, guys.

Does that answer your question all I do it does and congrats guys.

Operator: It does, and congrats, guys. Thank you.

Thank you.

Operator: Our next question comes from David Leeowitz with Morgan Thalen. Thank you very much for taking my question. Yvonne, congratulations on the new role, and John, it's been great working with you over the years.

Our next question comes from David Leibowitz with mortgage families.

Thank you very much for taking my question Avon Congratulations on the new role and.

<unk>, it's been great working with you over the years.

Operator: Thank you. A quick question on the data from the Vutrisan trial. Would you be able to compare the safety profiles of Ampatro, Vutriseran, and review Saran, the discontinued therapy, as far as similarities and differences across the platforms? Well, let me give you some context, and then maybe, Akshay, you can comment on that. I mean, you know, Rebuseran, of course, is a completely different animal. Early generation STC, galenac conjugate, poorly stable, not very stable, required extremely high doses, and turned out to be not well tolerated in a frail patient population. And obviously, that program was discontinued.

Thank you.

Quick question on the the the data from the victories fan trial would you be able to compare the safety profiles of Onpattro latrice around and review surround that discontinued therapy and as far as similarities and differences across the platforms.

Well, let me let me let me give some context and then maybe Akshay you can you can comment on it I mean reverse around of course is a completely different animal early generation STC gillnet conjugate poorly.

Stable not very stable required extremely high doses and turned out to be not well tolerated in a frail patient population.

And obviously that that program was discontinued.

John Meriginori: You know, I think the big difference between the subcue delivery of Vutriseran versus the IV infused on Patro really comes down to the type of administration that's involved. If you look at subcue injection, we see a low incidence of mild, moderate, generally always reversible type of injection-site reactions with subcue delivered Vutriseran. With intravenously administered Patro, we see a low incidence, you know, roughly 15 or so percent of infusion-related reactions, which are not uncommon with IV-infused drugs as well.

I think the big difference between the Subcu deliberate delivered vitry surround versus the Ivy infused on patrol really comes down to the the type of administration. That's involved if you look at if you look at Subcu injection, we see a low incidence of miles a moderate generally.

Always reversible type of injection site reactions with Subcu delivered which reached ran with intravenously administered onpattro, we see a low incidence roughly 15 or so percent of infusion related reactions.

Which are not uncommon with with Ivy infused drugs as well.

John Meriginori: And so I think that's really the biggest difference between them. Of course, Vitrisaran also does not require pre-medication, which is a nice feature around Vitris-Ren as well. And so, in general, I think those are the main differences. Aksha, do you want to comment any further? No, I think you covered it well, John.

So I think that's really the biggest difference between them of course were Treece ran also does not require pre medication.

Which is a nice feature around Patrice ran as well.

And so in general I think those are the main differences actually do you want to comment any further no I think you've covered it well John uhm or just that the.

Akshay K. Vaishnaw: I would just add that, you know, the safety profile of Vutrisarant looks extremely encouraging on its face and compared to the placebo data from Apollo. And, you know, just as one..., marker of that, I would say, you know, three study discontinuations in a study of this length with over 120, 30 patients on Butruscan is pretty remarkable. I mean, these are very frail sick patients.

The safety profile of which is fine it looks extremely encouraging on its face and comparing to the placebo data from Apollo and just as one.

Mark her off that I would say three study discontinuation.

In a study of this length with over over 120 30 patients on Boutrous on is pretty remarkable these up very frail sick patients.

Akshay K. Vaishnaw: And with the encouraging efficacy data we've discussed today, I think that all adds to a very encouraging benefit-risk profile. Of course, we'll submit these data to regulators, and they will make the final judgment, but we're certainly very encouraged by the overall profile of this drug. Yeah, and I would just add, to wrap it up, that obviously both Vutri Suran and Ompatro, well, in the case of Ompatro, we also have post-marketing data, and we are encouraged by the very consistent post-marketing data as it relates to the study results that we saw in Apollo.

And with the encouraging efficacy data we've discussed today.

I think that all adds to very encouraging benefit risk profile of coastal submit these data to regulate it can be.

The final judgment, but we're suddenly very encouraged by Derek Lowe protocol of this drug.

Yeah, and I would just add to wrap it up that that obviously both.

Patrice ran and on patrol while in the case of an patch or we also have postmarketing data and we are encouraged by the very consistent postmarketing data as it relates to the.

Study results that we saw in Apollo, but then in terms of ongoing clinical studies for both the <unk> and which research and the cardiomyopathy studied the Apollo B and Helios be studies, we have data safety monitoring boards that review the unblinded safety data.

Akshay K. Vaishnaw: But then, in terms of ongoing clinical studies for both BITC-Serand and Vutri-Seran and the cardiomopathy study, the Apollo B and Helios B studies, we have data safety monitoring boards that review the unblinded safety data quarterly. And so far, so good in terms of any definitive support for continuing to move forward. So, you know, that's the landscape, David.

Quarterly and so far so good in terms of any.

Certainly support for continuing to move forward so.

That's the landscape David.

Operator: You know, we've learned a lot over the years in terms of how to make these molecules better and better. And, knock on wood, so far, so good in terms of how that's played out. Thank you very much for that.

We've learned a lot over the years in terms of how to make these molecules better and better and I think I.

Thank God knock on wood, so far so good in terms of how that's played out.

Thank you very much for that if we jump over to <unk> I know that the you were talking about the the bullets patients at the at the beginning who had the loading dose.

Operator: If we jump over to Oxalumo, I know that you were talking about the, the, the, Bullis patients at the beginning who had the loading dose led to the, I guess, the downtick from last quarter. How should we view that factor going forward from this point, and as far as we're mapping out of run rates going forward for the drug? Maybe Tolga and Jeff can take that on. Toga, do you want to start?

Led to the I guess, the downtick from last quarter how.

How should we view that factor going forward from this point.

And as far as a mapping out a run rates going forward for the drug.

And maybe toga and Jeff can can can take that on a target do you want to start I mean look at the end of the day, we were able to grow our patient basis or five per cent and edit now we're at 120 patients.

Tolga Tanguler: I mean, look, at the end of the day, we were able to grow our patient base by 5%, and edit: now we're at 120 patients. The majority of the patients that we've been able to build over time have been coming from either naive patients where you do see this starting to impact them, and as well as early access program patients that already were getting there, starting those prior to the program before they were commercial.

Majority of the patients that we've been able to build overtime has been coming from either naive patients where you do see this starting those impact.

And as well as early access programme patients that.

Already we're getting there starting dose.

Prior to the program that before they were commercial the way I would really think about this as we are expanding geographically, we would still see some level of this impact.

Tolga Tanguler: The way I would really think about this is, as we are expanding geographically, we would still see some level of this impact to a degree based on the markets that are expanding, as well as our continuous performance in the U.S., where we didn't really have a lot of early access program patients. So this dynamic will continue. but maybe not to the magnitude that we currently see at this stage. Jeff, do you have anything else? The only thing I'd add just on top of that is that I think as the scale of the opportunity grows, some of the noise that you see from these dynamics will dissipate.

To a degree based on the markets that we're expanding.

As well as are continuous performance in the U S, where we didn't really have a lot of or the access program patients. So this dynamic will continue but maybe not to the magnitude that we currently see at this stage.

<unk> do you have anything the only thing I would add just on top of that is I think is the scale of the opportunity grows the some of the the noise that you see from these dynamics will dissipate exactly.

Jeff Poulton: Excellent. Thank you very much for taking the time to answer my questions.

Excellent. Thank you very much for taking my questions.

Thank you.

Operator: I will now turn the call back to the company for closing comments. All right, well, thank you everyone for joining this call. This is my last one at El Milam. I want to thank all of you for the support over the last 19 years. We built a remarkable company that's absolutely here to last, and our next chapter has so much promise for patients and our broader stakeholders.

I will now turn the call back to the company for closing comments.

Alright, well. Thank you everyone for joining on this call. This is my my last one at Milo I want to thank all of you for the support over the last 19 years, we built a remarkable company that's absolutely here to last and our next chapter has so much promise for patients and our broader stakeholders. Thank you have a great day.

John Meriginori: Thank you. Have a great day. Ladies and gentlemen, that concludes today's presentation. You may now disconnect. Have a wonderful day.

Hey.

Ladies and gentlemen, so conclude today's presentation you may now disconnect and have a wonderful day.