Q4 2020 Alnylam Pharmaceuticals Inc Earnings Call

Yeah.

Operator: Ladies and gentlemen, thank you for standing by, and welcome to the Alnylam Pharmaceuticals conference call to discuss fourth quarter and full year 2020 financial results. There will be a question and answer session to follow. Please be advised that this call is being taped at the company's request. I would now like to turn the call over to the company.

Ladies and gentlemen, thank you for standing by and welcome to the Al Nylon Pharmaceuticals conference call to discuss fourth quarter and full year 2020 financial result, there will be a question and answer session to follow please be advised that this call is being taped at the company's request I would now like to turn the call.

All over to the company.

Christine Regan Lindenboom: Good morning, I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are John Maragnori, Chief Executive Officer, Tolga Tanguler, Chief Commercial Officer, Akshay Vaishnaw, President of R&D, Jeff Poulton, Chief Financial Officer, and Yvonne Greenstreet, President and Chief Operating Officer. In addition, Andy Wurth, Senior Vice President, Head of the U.S. Business, is on the line and available for Q&A.

Good morning, I'm, Christine Lindbloom senior Vice President of Investor Relations and corporate communications at on Island.

With me today on the phone are John <unk>, Chief Executive Officer until the Cannula, Chief Commercial officer Akshay based on our President of R&D, Jeff Felton, Chief Financial Officer, and Yvonne Greenstreet, President and Chief Operating Officer. In addition, Andy worth of senior Vice President head of the U S business is on the line and available for Q&A for those of.

Christine Regan Lindenboom: For those of you participating via conference call, the accompanying slides can be accessed by going to the events section of the investor page of our website, investors.alnylam.com slash events. During today's call, as outlined in slide two, John will provide some introductory remarks and provide general context. Togol will provide an update on our global commercial progress, Akshay will review recent clinical and preclinical updates, Jeff will review our financials, and Yvonne will provide a brief summary of upcoming milestones before opening the call to your questions.

Are you participating via conference call. The accompanying slides can be accessed by going to the events section of the Investor page of our website and the Doctor thought on the island Dotcom Washington.

During today's call as outlined on slide two John will provide some introductory remarks and provide general context total.

We'll provide an update on our global commercial progress.

Akshay will review review of recent clinical and preclinical updates.

I view, our financial and the bond will provide a brief summary of upcoming milestones before opening the call to your questions.

Christine Regan Lindenboom: I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor Provision under the Private Securities Litigation Reform Act of 1995. However, actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent quarterly report on file with the SEC. In addition, any forward-looking statements represent our views only 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'd like to turn the call over to John. Okay?

I would like to remind you that this call will contain 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.

Actual results may differ materially from those indicated by these forward looking statements as a result of various important factors, including those discussed in our most recently quarterly report on file with the SEC. In addition, any forward looking statements represent our views only as the day of this recording and should not be relied upon as representing our views as of any subsequent date, we specifically disclaim any.

On to update such statements with that I'd like to turn the call over to John John.

John Maragnori: Thanks Christine and thank you everyone for joining the call today. Despite the challenges we all faced in 2020 with the COVID-19 pandemic, Alnylam had one of its strongest years ever as a successful global commercial organization with a highly productive R&D platform. We delivered on our commercial expansion, growing top-line product revenues by over 100%, driven by strong continued execution for Ampatro and Givlari. We continue to advance the pipeline, which includes programs across both rare and common disease populations, and we remain focused on financial discipline to help us reach our goal of achieving a self-sustainable financial profile.

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

Challenges, we all faced in 2020 with the COVID-19 pandemic L. Myeloma had one of its strongest year ever at the successful global commercial organization with a highly productive R&D platform.

We delivered on our commercial expansion growing top line product revenues by over 100% driven by strong continued execution for our Petro and give Laurie.

We continue to advance the pipeline, which includes programs across both rare and common disease populations.

And we remain focused on financial discipline to help us reach our goal of achieving of self sustainable financial profile.

John Maragnori: Underscoring the success of 2020, we started the year with two products, six approvals, and access in 14 countries. We then ended the year with 4 products, 15 approvals, and access in 41 countries. This includes the approvals of Oxlumo in the EU and the US and, together with our partners at Novartis, Lectio in the EU.

Underscoring the success of 'twenty 'twenty, we started the year with two products six approvals and the axis in 14 countries.

We then ended 2020 with four products 15 approvals and access in 41 countries. This includes the approvals of box Lou MAU in the EU and the U S and together with our partners at Novartis like the O in the EU.

John Maragnori: We are very proud to have ended 2020 exceeding our Alnylam 2020 goals that we boldly set forth back in 2015. We're now excited to have announced our new five-year strategy and goals with Alnylam P to the 5th by 2025. Alnylam P to the 5th by 25 is aimed at fulfilling Alnylam's aspirations and potential of becoming one of the most successful biotech companies ever with transformative medicines in both rare and common diseases for patients around the world supported by additional growth through life expansion, a robust and high yielding pipeline of first and or best in class product candidates from our organic product engine and exceptional financial performance with over 40% revenue CAGR to year-end 2025 and sustainable profitability achieved within the period.

We are very proud to avenge of twenty-twenty exceeding our L. Myeloma twenty-twenty goals that we boldly said for back in 2015.

We're now excited to of Enel started new five year strategy and goals without violent piece of the fifth by 'twenty five.

L mile of Peter the fifth by 'twenty five is aimed at fulfilling all of <unk> aspirations and the potential of becoming one of the most successful biotech companies ever with transformative medicines in both rare and common diseases for patients around the world supported by additional growth through label expansion.

Our robust and high yielding pipeline of first <unk> best in class of product candidates from the organic product engine and exceptional financial performance with over 40% revenue CAGR through year end 2025 kind of sustainable profitability achieved within the period.

John Maragnori: Without a doubt, this is an exciting new chapter for Alma. Akshay will review our recent R&D progress in just a moment, but an important highlight in the recent period is the positive pipeline results from our Helios A phase 3 study of Futrisiran. Importantly, we believe that Futrisiran can significantly expand our opportunity in HATTR amyloidosis with polyneuropathy, positioning alnylam for continued growth in our ATTR franchise, even before our expected expansion in the wild-type ATTR cardiomyopathy setting, assuming favorable clinical results and approval.

Without a doubt this is an exciting new chapter for all of them.

Akshay will review our recent R&D progress in just a moment, but an important the highlight in the recent period as the positive topline results from our Helios a phase III study of the Treece ran the importantly, we believe that the tree surround can significantly expand our opportunity and the <unk> amyloidosis with Polyneuropathy.

<unk> L mile of with continued growth in our ATT our franchise, even before our expected expansion in the wild type <unk> cardiomyopathy, setting the assuming favorable clinical results and approvals.

John Maragnori: Now, for a review of our commercial and medical affairs progress, it's my pleasure to welcome Tolga Tanguler to his first Alnylam earnings call. Tolga joined Alnylam recently as our chief commercial officer, following roles at Alexion and Pfizer in both rare and common disease franchises, and we're excited about the future of our global commercial efforts under his leadership. With that, let me turn the call over to Tolga. Okay?

Now for a review of our commercial and medical Affairs progress. It's my pleasure to welcome Tolga tangle or two is first on lot of the earnings call. It's all good joined on my all of them recently as our Chief commercial officer. Following the roles that Alexia on adviser in both rare and common disease franchises and we're excited about the future of arc.

Commercial efforts under his leadership with that let me turn the call over to toga toga.

Tolga Tanguler: Thanks, John, and good morning, everyone. I appreciate the warm welcome and couldn't be more excited to join the Alnylam team.

Thanks, John and good morning, everyone I appreciate the warm welcome and couldn't be more excited to join the on island team.

Tolga Tanguler: Let's get started with a review of our commercial performance. For Ompetro, we achieved $90.4 million in global net product revenues in the fourth quarter, representing approximately 10% quarter-on-quarter growth compared with Q3, and we achieved $306.1 million in global Ompetro revenues for the full year 2020. As of December 31st, approximately 1350 patients were on commercial on-patron treatment worldwide. In the U.S., we continue to see strength in demand with just over 10% growth, and we saw patient compliance remain at pre-COVID levels.

It started with the review of our commercial performance.

Four on Petro, we achieved $90.4 million in global net product revenues in the fourth quarter, representing approximately <unk> 10 per cent quarter on quarter growth compared with Q3, and we achieved $306.1 million and global on Petro revenues for the full year two.

On 'twenty.

As of December 31st approximately 1300 50 patients were on commercial on Patrick treatment worldwide.

In the U S. We continued to see strength in demand with just over 10% growth and we saw of patient compliance remain at pre COVID-19 levels.

Tolga Tanguler: In the U.S., we also continue to see a steady rate of concomitant use of Ompatro to treat HA-TTR polyneuropathy along with the use of TTR stabilizers in mixed phenotype patients as the HA-TTR diagnosis rates continue to increase due to, we believe, the wider availability of PYP scans.

In the U S. We also continue to see a steady rate of concomitant use of on Petro to treat H E. T. T. R. Polyneuropathy along with the use of T. T. R. Stabilizers in mixed phenotype patients as the H E. T T. Our diagnosis rates continue to increase due to.

We believe why do the availability of Typ's cats.

Tolga Tanguler: We believe our leadership with regard to access is also notable, with over 98% of U.S. lives covered. Turning to the rest of the world, we made very encouraging progress with Ompatro in the fourth quarter, with $47.3 million in revenue from ex-US markets. Market access has now been achieved in over 20 countries, and we recently received regulatory approval in Taiwan. As we have noted, an important ongoing dynamic observed at XUS is patient switching from stabilized, which we believe is attributable to the potential to halt or reverse polyneuropathy manifestations of the disease with Ompetra, and this represents more than 50% of new Ompetra patients outside the U.S. Our customer-facing medical affairs team also remains committed to As of January, 33,912 samples have been submitted, out of which 1,952 have tested positive for a pathogenic TTR mutation.

We believe our leadership with regards to access. It is also notable with over 98 per cent of U S lives covered.

Turning to the rest of the World, we made very encouraging progress with on Petro in the fourth quarter with $47 $3 million in revenue from ex U S markets.

Market access has now been achieved in over 20 countries and we recently received regulatory approval in Taiwan.

As we have noted an important ongoing dynamic observed ex U S is patient switching from stabilizers, which we believe is attributable to the potential to halt or reverse polyneuropathy manifestations of the disease with the on Petro and this represents more than 50 per cent of.

New on Petro of patients outside the U S.

Our customer facing medical affairs team also remains committed to addressing the challenge of.

Raising disease awareness and improving diagnosis of H E. T. T are on low doses, including with all of the Island Act or third party genetic screening initiative in the U S, Canada and Brazil.

As of January 33912 samples have been submitted submitted out of which 1952 have tested positive for the pathogenic T. T. R mutation.

Tolga Tanguler: We are encouraged by the recovery in testing volumes we've seen in recent months, and we believe this trend will continue. We have also seen continued strength in PYP scans being performed, another leading indicator of new patient growth. In 2021, we expect steady and continued growth for Ompatro, driven mostly by new patient findings, with some additional geographic expansion. Moving on to Givlare. We achieved $22.1 million in global net product revenues in the 4th quarter, representing 33% quarter-on-quarter growth compared to Q3, and we achieved $55.1 million in global Givlari revenues for the full year 2020. As of December 31st...

We are encouraged by the recovery in testing volumes, we've seen in recent months and we believe this trend will continue.

We have also seen continued strength in <unk> scans being performed and other leading indicator for new patient growth.

In 2021, we expect steady and continued growth for on Petro driven mostly by new patient findings with some additional geographic expansion.

Moving on to give Laurie.

We achieved 21 22.1 million in global net product revenues in the fourth quarter, representing 33 per cent quarter on quarter of growth compared to Q3.

And we achieved $55 $1 million in global give Laurie revenues for the full year 2020.

As of December 31st approximately 200 patients were on commercial give laurie treatments worldwide.

Tolga Tanguler: Approximately 200 patients are on commercial divlari treatment worldwide. Our progress with patient access in the U.S. has been strong, having now finalized over ten value-based agreements, or VBAs, including the first state-level VBA with MassHealth for Medicaid. We now have confirmed access for 94% of covered U.S. lives. We have not experienced any payer headwinds with GiveLari to date, and we're pleased to see the majority of plans adopt medical policies without restrictions on the number of baseline attacks. The Simia region saw great progress as well, with notable strength from our launch in Germany, as well as ATU's supply in France, finalization of reimbursement in Italy, and name patient sales in other countries

Our progress with patient access in the U S has been strong having now finalized over 10 value based agreements or vba's, including first state level the be a with net held for Medicaid.

We now have confirmed the access for 94 per cent of covered the U S. Lives, we have not experienced any payer headwinds, we'd give laurie to date and we're pleased to see the majority of of plans.

The medical policies without restrictions to the number of baseline attacks.

This EMEA region, so great progress as well with notable strength from our launch in Germany, as well as a to use supply in France finalization of reimbursement in Italy.

And named patient sales in other countries.

Tolga Tanguler: We also look forward to the completion of the ongoing review of our NDA in Japan, which was submitted in September and is expected to be launched in mid 2021. In 2021, we expect steady and continued growth for Gill Larry, driven by geographic expansion, along with new patient findings. Finally, we're excited with the progress of our third launch, Oxluma, the brand name for LumiSeren. 2021 will be the first full year of marketing for this new medicine from Alnylam, and we're pleased to see strong early demand.

We also look forward to completion of the ongoing review of our NDA in Japan.

Which was submitted in September and is expected to be launched in mid 2021.

In 'twenty and 'twenty, one we expect steady and continued growth forgive Laurie driven by geographic expansion, along with new patient findings.

Finally, we're excited with the progress so far third launch of Slo-mo the brand name for Loomis around.

2021 will be the first full year of launch for this new medicines from our island and we're pleased to see strong early demand.

Tolga Tanguler: Since receiving approval in the U.S. and EU in November 2020 and launching in December, we have received eight starter forms as of year-end and achieved global net product revenues for the fourth quarter of approximately $0.3 million. Representing Encouraging Early Patient Demand in Europe As with our other launches, and guided by our patient access philosophy, we are hard at work making sure the patients who need Oxlumo are able to access it. We're pleased with progress being made with payers in the US and EU in establishing DBAs, including patient need adjustment and prevalence-based adjustment features.

Since receiving approval in the U S and EU in November 2020, and launching in December we have received eight start forms as of year end and achieved global net product revenues for the fourth quarter of approximately $3 million.

Representing encouraging early patient demand in Europe.

As we the other is with our other launches and guided by our patient access philosophy, we are hard at work, making sure the patients who need of Slo-mo are able to access it.

We're pleased with progress being made with payers in the U S and EU in.

In establishing the base, including patient needs.

Net adjustment and prevalence based adjustment features.

Tolga Tanguler: Our teams are now actively engaged with the physician and patient advocacy communities, leveraging capabilities we've strengthened over the past year and delivering success even in the challenging virtual environment of an ongoing pandemic. In conclusion, the fourth quarter highlighted the broad capabilities of our operation, which supported the continued growth of Ompetra, the ongoing adoption of Givlari, and the initial launch of Oxlumos. And looking back at the full year, I'm so impressed by the team's resilience in the face of unprecedented challenges to meet the needs of patients and continue driving awareness, uptake, and growth. With that, I will now turn it over to Akshay to review our recent R&D and pipeline progress. Okay, Akshay?

Our teams are now actively engaged with the physician and patient advocacy communities leveraging capabilities, we've strengthened over the past year delivering success, even in the challenging virtual environment of an ongoing pandemic.

In conclusion, the fourth quarter highlighted the broad capabilities of our operations, which supported the continued growth of on Petro the ongoing adoption of give Laurie and the initial launch for <unk>.

And looking back at the full year I'm. So impressed by the team's resilience in the face of unprecedented challenges to meet the needs of patients and continue driving awareness uptake and growth.

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

Akshay K. Vaishnaw: Thanks, Tolga, and good morning, everyone. I'll start with our efforts in at-term amyloidosis, where we're advancing our two product candidates, Patisserin and Butrisserin. While Donpatro is currently approved in multiple markets around the world to treat the polyneuropathy associated with her 3ATG amyloidosis, we're committed to expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild-type at-type amyloidosis patients. To this end, we're conducting the Apollo B phase three study.

Thanks, Paul and good morning, everyone.

I'll start with our efforts in a T. J amyloidosis, we're advancing our two product candidates <unk> and Boutris Ron.

Most of them on Patria is currently approved in multiple markets around the world to treat the polyneuropathy associated with her true <unk> amyloidosis.

Committed to expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild type 80 times low doses patients.

To this end we are conducting the Apollo B phase III study.

Akshay K. Vaishnaw: We continue to enroll patients in Apollo B and continue to expect completion of enrollment in early 2021, which would put us on track for top-line readout in mid-22. We're also advancing Vutrisran, which is delivered by a quarterly subcutaneous injection and is also in development for AT-Tamloidosis. Here we're conducting two phase three studies. The first phase 3 study is Helios A, which is evaluating Butrysran in HAT thromboidosis patients with polyneuropathy. Just last month, we announced positive, top-line, nine-month results from the study, demonstrating very impressive efficacy and encouraging safety with a once-quarterly subcutaneous injection of Butrysran, specifically. It was found that the primary and both secondary endpoints measured at nine months.

We continue to enroll patients in Apollo B and continue to expect completion of enrollment in early 2021, which would put us on track for topline readout in mid 'twenty two.

We're also advancing the interest ran which is delivered by quarterly subcutaneous injection and he's also on development for each family of doses.

Yeah, we are conducting two phase III studies the.

The first phase III studies, Helios, a which is evaluating the interest rent and <unk> family doses patients with Polyneuropathy.

Just last month, we announced positive topline nine months results from the study demonstrating very impressive efficacy and encouraging safety with a once quarterly subcutaneous injection of interest right.

Specifically, which was around met the primary and secondary endpoints measured at nine months.

Akshay K. Vaishnaw: As compared with the historical placebo control from the Apollo study, Boutros-Rand achieved a highly significant improvement in neuropathy impairment as measured by the MNIST plus 7 assessment. Also, Boutros-Rand showed improvements in the Norfolk QOL and Gates Speed Sector endpoints compared with historical placebos. Additionally, Boutris around demonstrated improvements in neuropathy impairment and quality of life relative to baseline, confirming that RNAi therapeutics can achieve reversal of polyneuropathy disease manifestations commensurate with what we've observed with patisserin in the APOLLO study.

As compared with the historical placebo control from the Apollo study, which was ran achieved of highly significant improvement in neuropathy impairment as measured by the end of this plus seven assessment.

So interest around showed improvements in the north of QL and gait speed sector, the endpoints compared with the historical placebo.

Additionally, butros around demonstrated improvements in Europe, the impairment on quality of life relative to baseline.

Firming that RNA therapeutics can achieve reversal of the neuro polyneuropathy disease manifestations commensurate with what we've observed the T <unk> in the Apollo study.

Akshay K. Vaishnaw: We also observed significant effects on the 9-month cardiac endpoint of NT-PRO-BNP and additional cardiac data being collected as part of the 18-month endpoint, which we plan to report later in the year, trying to demonstrate an encouraging safety and tolerability profile. There were two study discontinuations, or 1.6%, due to adverse events that led to death in the vitreous surround arm by month 9, neither of which was considered related to the study drugs.

We also observe significantly of things on the nine months cardiac endpoint of empty per BNP and additional cardiac data being collected as part of the 18 month endpoint, which we plan to report later in the year.

Which was around demonstrated an encouraging safety and tolerability profile.

The <unk> two study discontinuation of one 6% due to adverse events that led to that kind of interest right now by month nine.

Each of which was considered related to study drug.

Akshay K. Vaishnaw: There were two SAEs deemed related to Futrisran, dyslipidemia, and an E. coli UTI. A's occurring in more than 10% of patients receiving putrescent include diarrhea, pain in the extremities, fall, and urinary tract infection. These events are common in the disease itself and occurred at a similar rate or lower than observed in the historical placebo comparator group. Injection site reactions were reported in five patients, or 4.1%, and were all mild and transient. There were no clinically significant changes in liver function.

The TSA he's deemed related to the interest ran dyslipidemia of Nicolai UTI.

As of occurring in more than 10 percentage of patients receiving for true surround include diarrhea paint on the extremities full and urine tract infections.

These events are common in the.

These itself and occurred at a similar rate will lower the observed in the historical placebo comparator group.

The injection site reactions were reported in five patients of four 1% of all mild and transient.

Two of no clinically significant changes in liver function tests.

Akshay K. Vaishnaw: With these positive results in hand, we plan to file our NDA in early 2021 and aim to bring our fifth RNAi therapeutic to market in early 2022, assuming regulatory approval. And, as we've mentioned, what's exciting about Food Tree Surround is the opportunity to expand our overall market share, particularly to treat polyneuropathy in mixed phenotype patients. The second phase 3 vitricillin study is Helios B, which has been conducted in hereditary and wild-type at-term leuidosis patients with cardiomyopathy, and this study is actively enrolling patients.

With these positive results in hand, we plan to file our NDA in early 2021 and aimed to bring our fifth RNA therapeutic to market in early 'twenty 'twenty, two assuming regulatory approval.

And as we've mentioned what's the.

Citing about food treatment is the opportunity of expanding our overall market share, particularly to treat polyneuropathy in mixed phenotype patients.

The second phase III with Tricia on studies, Helios, B, which is being conducted in inherited and wild type <unk> amyloidosis patients with cardiomyopathy and the study is actively enrolling.

Akshay K. Vaishnaw: Finally, in addition to Helios A and B, we're also evaluating a once-every-six-month dosing regimen for Butresran, and we expect to initiate our study of this regimen in early 2021. Also, later in 2021, we plan to start the Helios-C study of Utrisran for the prevention of manifestations of AT2 amyloidosis. I'll now turn to progress with Oxaluma, our RNAi therapeutic recently approved in the EU and US as the first treatment for primary hyperoxalurea type 1, or PH1.

Finally in addition to Helios, a and B. We're also evaluating of once every six month dosing regimen for Butros ran.

We expect to initiate a study of this regimen in early 2021.

Also later in 'twenty 'twenty, one we plan to start the Helios a study of Richardson for the true.

Revenge of manifestations of <unk> amyloidosis.

I'll now turn to progress with Oxiclean. The RNA therapeutic recently approved in the EU and U S. As the first treatment for primary Hyperoxaluria type one Oh ph one.

Akshay K. Vaishnaw: We continue to evaluate the safety and efficacy of oxaluminum in the ongoing Illuminate C Phase III clinical trial in PH1 patients of all ages with more severe renal impairment, including patients on dialysis, once enrollment has been completed.

We continue to evaluate the safety of them because of your folks leaving them in the ongoing Loopnet UC phase III clinical trial, Inc.

<unk> patients of all ages with more severe renal impairment, including patients on dialysis.

Enrollment has been completed and we expect data in 2021.

Akshay K. Vaishnaw: We expect data in 2021. Together, the Illuminate studies comprise a comprehensive clinical development program intended to demonstrate safety and efficacy of Oxlumo across the full spectrum of patients diagnosed with PH1. We're also excited to initiate a phase 2 study later in the year evaluating Lumasran for the treatment of recurrent renal stones, which could really expand the overall opportunity. As you know, we have two additional late-stage programs that are in development with partners.

Together the illuminate studies comprise of comprehensive clinical development program intended to demonstrate safety and efficacy of <unk> across the full spectrum of patients diagnosed with ph one.

We're also excited to initiate the phase II study later in the year evaluating <unk> for the treatment of recurrent renal stones, which could really expand the overall opportunity.

As you know we have two additional late stage programs that are in development with partners.

Akshay K. Vaishnaw: These include Lectvio or Inclisran, partnered with Novartis, which was approved last year in the EU for the treatment of adults with hypercholesterolemia or mixed dyslipidemia. Lecvio marks the first RNAi therapeutic approved for a common disease and has the potential to be a blockbuster product for our partner Novartis. On top of approval in the EU, Vartis has completed 10 additional filings globally.

These include leg for you are interest in closer on partnered with the volunteers, which was approved last year in the EU for the treatment of adults with hypercholesterolemia or mixed dyslipidemia.

Latvia amongst the first RNA therapeutic approved from common disease and has the potential to be of blockbuster product for our partner Novartis.

On top of approval in the EU Novartis has completed 10 additional filings globally.

Akshay K. Vaishnaw: As has been communicated previously, Novartis received a CRL from the FDA due to unresolved facility inspection-related conditions at a third-party manufacturing facility in Europe. The FDA has not raised any concerns related to the efficacy or safety of Inclisran, and Novartis plans to submit its response in Q2 or Q3 2021. We're confident Novartis will do everything it can to accelerate this process. Our late-stage programs also include Fitusran in development for haemophilia A or B with or without inhibitors partnered with Sanofi. Produced around his boundary valuation in the Phase 3 Atlas Program.

As has been communicated previously novartis received the CRM <unk> from the FDA due to unresolved facility inspection related conditions out of third party manufacturing facility in Europe.

The FDA has not raised any concerns related to the efficacy or safety of English ran on Novartis plans to submit its response in Q2 Q3 2021.

The confident Novartis will do everything we can to accelerate this process.

On late stage programs also include free to surround in development for hemophilia, a or b with or without inhibitors partnered with Sanofi.

<unk> is under evaluation of the Phase III Atlas program, where.

Akshay K. Vaishnaw: We're pleased to report that dosing has been resumed in the ATLAS Phase 3 studies and that previous reports of thromboembolic events were associated with a high level of antithrombin reduction to less than 10% of normal. Sanofi will now evaluate a once every two months 50 milligram dosing regimen for Fitusran that can be titrated up in frequency to once monthly and in dose to 80 milligrams depending We believe this tailored approach will optimize patient safety and will also provide further differentiation versus other subcutaneous options which are given once weekly. Furthermore, Sanofi has announced that Fitusra has recently received FastTrack designation.

We're pleased to report the dosing has been resumed and the Atlas Phase III studies and the previous reports of thromboembolic events were associated with the high level of antithrombin reduction to less than 10% of normal.

Sanofi will now evaluate of once every two months the 50 milligram dosing regimens of <unk> that can be titrated up in frequency to once monthly and in dose of 80 milligrams, depending on the antithrombin levels achieved.

We believe this tailored approach will optimize patient safety I'm going to also provide further differentiation versus other subcutaneous options, which are given the once weekly.

Excitingly sign of he has announced that for the Tucson recently received fast track designation.

Akshay K. Vaishnaw: Now, in addition to our late-stage clinical programs, we believe we've also been making great progress with our early and mid-stage programs. One of the exciting parts of our story now is the expansion of RNAi therapeutics beyond rare diseases into prevalent disease opportunities. We believe now is the time to address many unmet needs in common disease settings such as hypertension, NASH, gout, and diabetes, amongst others, and that the pharmacological properties of RNAi therapeutics provide the foundation for success. Program 5 potentially is a great example.

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

One of the exciting parts of our story now is the expansion of RNA on therapeutics beyond rare diseases into prevalence of these opportunities.

We believe now is the time to address many unmet needs in common disease settings, such as hypertension, Nash gout and diabetes amongst others.

The pharmacological properties of RNA Therapeutics provides the foundation for success.

On a program potentially the Great example.

Akshay K. Vaishnaw: LNAGT is our investigational RNAi therapeutic targeting the genetically validated target angiotensinogen for the treatment of hypertension. We're now transitioning to the start of our Cardio 1 and Cardio 2 Phase 2 studies, which will start in mid-2021, and these studies will evaluate LNAGT as monotherapy and also in combination with RAS inhibitors in about a thousand patients with uncontrolled hypertension. We also have a promising development program, ALN HSD, for the treatment of NASH in phase one in partnership with Regeneron.

<unk> is our investigation of RNA therapeutic target the genetically validated target and your 10 citizen for the.

The treatment of hypertension.

We're now transitioning to the start of the cardio one in cardiac two phase II studies, which will start in mid 2021.

And the studies will evaluate <unk> as monotherapy and also in combination with RAF inhibitors, and about 1000 patients with uncontrolled hypertension.

We also have a promising development program on HST for the treatment of Nash in phase one in partnership with Regeneron.

Akshay K. Vaishnaw: In addition, we continue to make strong progress on our many preclinical RNAi therapeutic opportunities beyond the liver. Today, we're advancing over 25 preclinical programs with delivery in four tissues: liver, CNS, eye, and lung. These programs span rare and common diseases, are supported by human genetics, and are poised to be first and or best-in-class medicines. Notably, we continue to advance our CNS and Ocular efforts with Regeneron, and our LNAPP program remains on track for a CTA filing in mid-2021.

In addition, we continued to make strong progress on on many preclinical RNA therapeutic opportunities beyond the liver.

Today, we are advancing of of 25 preclinical programs with delivery and for tissues liver.

Yes, hi, and lung.

Program spend rare and common diseases of supported by human genetics and are poised to be first and of best in class medicines.

Notably we continued to advance of CNS and ocular effort with Regeneron and our <unk> program remains on track for a Cta filing in mid 2021.

Akshay K. Vaishnaw: Overall, we expect to deliver 2 to 4 new INDs per annum in the near term and aim to achieve 4 plus INDs per annum by the end of 2025. In summary, we see this as a truly remarkable time for Alnylam and RNAi. I couldn't be more excited about our continued progress in bringing transformative medicines to patients, and our Alnylam P to the fifth times 25 strategy highlights the impact we're now positioned to make for the future of medicine. With that, I now turn it over to Jeff to review our financial results. Jeff.

Overall, we expect.

We expect to deliver two to four new ind's per annum in the near term and aim to achieve full plus ind's per annum by the end of 2025.

In summary, we see this as a truly remarkable time for on island and RNA on.

I couldnt be more excited about our continued progress in bringing transformative medicines to patients and are on island piece of the five times 25 strategy highlights the impact we are now positioned to make for the future of medicine.

With that let me now turn it over to Jeff to review our financial results Jeff.

Jeff Poulton: Thanks Akshay and good morning everyone. 2020 was an unprecedented year that underscored Alnylam's strong commercial capabilities and operational excellence as we delivered robust top-line growth while managing disciplined investment across our business. After commenting on our fourth quarter and full year 2020 results, I will also provide our financial guidance for 2021. Tolga highlighted U.S. sales of Onpatro increased 10% versus Q3 2020 and were impacted by the following. Patient demand increased 13% driven by the addition of new patients on therapy, with patient compliance remaining consistent with Q3 when we returned to pre-pandemic levels. However, inventory de-stocking during the quarter, compared with modest stocking in Q3, reduced reported growth during the quarter.

Thanks, Akshay and good morning, everyone 2020 was an unprecedented year that underscores on the island strong commercial capabilities and operational excellence as we delivered robust topline growth, while managing disciplined investment across our business.

After commenting on our fourth quarter and full year 2020 results I will also provide our financial guidance for 2021.

As told the highlighted U S sales of on Petro increased 10% versus Q3, 2020 and were impacted by the following.

Patient demand increased 13% driven by the addition of new patients on therapy with patient compliance remaining consistent with Q3, when we return to pre pandemic levels.

Inventory destocking during the quarter compared with modest stocking in Q3 reduced reported growth during the quarter.

Jeff Poulton: We ended the quarter with just over one week of inventory in the channel in the U.S. We're really pleased with the continued strength in our U.S. results, two consecutive quarters of double-digit growth following a pandemic-challenged Q2 and with Q4 sales representing the highest level since launch, and in our international market. Unpatril performance remains strong with growth of 9% versus Q3 2020, primarily driven by increased patient demand broadly across Europe and Japan. Additionally, there was a modest benefit from inventory stocking in Japan at year end.

We ended the quarter with just over one week of inventory in the channel in the U S.

We're really pleased with the continued strength in our U S results with two consecutive quarters of double digit growth. Following the pandemic challenge Q2, and with Q4 sales representing the highest level since launch.

On our international markets on Petro performance remained strong with growth of 9% versus Q3, 2020, primarily driven by increased patient demand broadly across Europe and Japan.

Additionally, there was a modest benefit from inventory stocking in Japan at yearend.

Jeff Poulton: Turning to our results for Gibralari, we had a strong fourth quarter, generating $22.1 million in global net revenue, representing 33% growth compared to the third quarter of 2020. Revenue in Europe during 2020, as expected, was primarily generated from two markets, Germany and France. As we saw with Onpatro in year two of its commercialization, as we secure pricing and reimbursement, we anticipate additional markets for Giblari coming online across Europe and Asia in 2021.

Turning to our results for give Laurie we had a strong fourth quarter generating $22 1 million of global net revenue, representing 33% growth compared to the third quarter of 2020.

Revenue in Europe. During 2020 as expected was primarily generated from two markets, Germany, and France as we saw with on Petro in year two of its commercialization as we secure pricing and reimbursement, we anticipate additional markets forgive Laurie coming on line across Europe and Asia in 2021.

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

Jeff Poulton: Turning now to a summary of our full P&L results for the quarter and full year. Total product sales for 2020 were approximately $362 million, which was more than double 2019, with Unpathro delivering more than 80% growth versus 2019, and Giblari contributing $55 million in its initial launch year. Net revenue from collaborations for the fourth quarter was $50.7 million, primarily due to revenue recognized from Arvir and Regeneron collaborations and a $15 million increase around a milestone from Novartis following the December EU approval of Lectio.

Total product sales for 2020 were approximately $362 million, which were more than double 2019 with on path flow delivering more than 80% growth versus 2019, and get blurry contributing $55 million in its initial launch here.

Net revenue from collaborations for the fourth quarter was $50 7 million, primarily due to revenue recognized from our <unk> and regeneron collaborations and of $15 million increase surround milestone from Novartis. Following the December EU approval of <unk>.

Gross margin as a percentage of total revenue was 86% for the quarter up from 83% in Q4 2019, primarily due to an on Petro inventory write off that occurred in Q4 2019.

Jeff Poulton: Gross margin as a percentage of total revenue was 86% for the quarter, up from 83% in Q4 2019, primarily due to an Ompatro inventory write-off that occurred in Q4 2019. Our non-GAAP R&D expenses in the fourth quarter of 2020 decreased compared to the same period in 2019, primarily due to Q4 2019 having a high level of expenses associated with clinical material manufactured for future clinical trials. Our non-GAAP SG&A expenses increased in the fourth quarter of 2020 compared to the same period in 2019, primarily due to increased investment in commercial and medical affairs activities to support the ongoing launches of Onpatro and Giblari and the launch preparation activities for Oxlumo.

Our non-GAAP R&D expenses in the fourth quarter 2020 decreased compared to the same period in 2019, primarily due to Q4 2019, having a high level of expense associated with clinical material manufactured for future clinical trials.

Our non-GAAP SG&A expenses increased in the fourth quarter of 2020 compared to the same period in 2019, primarily due to increased investment in commercial and medical affairs activities to support the ongoing launches of on Petro and give Laurie and the launch preparation activities for <unk>.

Our combined non-GAAP R&D and SG&A expenses were $1 $63 million in 2020, representing 11% growth versus 2019, which was significantly lower than the growth in combined non-GAAP R&D and SG&A expense in 2019, which was 31%.

As I have noted on several occasions over the last year. This more moderate level of Opex growth is one of the key levers supporting our path towards profitability.

Jeff Poulton: Our combined non-GAAP R&D and SG&A expenses were $1,063,000,000 in 2020, representing 11% growth versus 2019, which is significantly lower than the growth in combined non-GAAP R&D and SG&A expenses in 2019, which was 31%. As I have noted on several occasions over the last year, this more moderate level of OpEx growth is one of the key levers supporting our path toward profitability. Our non-GAAP operating loss for the quarter decreased by approximately $82 million compared to the same period in 2019, driven by strong top-line growth and flat non-GAAP combined R&D and SG&A expenses.

Our non-GAAP operating loss for the quarter decreased by approximately $82 million compared with the same period in 2019, driven by strong top line growth and flat non-GAAP combined R&D and SG&A expense.

The full year non-GAAP operating loss ended at approximately $649 million, which is $116 million favorable to our full year 2019, non-GAAP operating loss consistent with our past guidance. The 2019 would be our peak loss year.

We ended the year with cash cash equivalents and marketable securities of approximately $1 9 billion up from $1 5 billion at the end of 2019 cash.

Cash was favorably impacted in 2020 by the $2 billion Blackstone strategic financing collaboration that we announced in Q2, which contributed approximately $800 million in financing this year, including $200 million in Q4 related to the initial drawdown of the debt facility with GSO Blackstone credit arm.

Jeff Poulton: Our full-year non-GAAP operating loss ended at approximately $649 million, which is $116 million favorable to our full-year 2019 non-GAAP operating loss, consistent with our past guidance that 2019 would be our peak loss year. We ended the year with cash, cash equivalents, and marketable securities of approximately $1.9 billion, up from $1.5 billion at the end of 2019. Cash was favorably impacted in 2020 by the $2 billion Blackstone strategic financing collaboration that we announced in Q2, which contributed approximately $800 million in financing this year, including $200 million in Q4 related to the initial drawdown of the debt facility with GSO, Blackstone's credit arm.

Now turning to our financial guidance for 2021.

With net product revenues, we are now transitioning to providing combined at net product revenue guidance for on Petro give Laurie and ox Lou Moe.

We anticipate combined net product revenue for these three products will be between 610 $660 million with the midpoint, representing more than 75% growth compared to 2020.

We treat the ran approval is not expected until early 2022. So it was not factored into our guidance for product revenues this year.

It is also worth noting that our guidance reflects the uncertainty related to the COVID-19, pandemic, which should decrease over time as the vaccine rollout progresses around the world.

Jeff Poulton: Now turning to our financial guidance for 2021. Starting with Net Product Revenues, we are now transitioning to providing combined Net Product Revenue guidance for Onpatro, Givlari, and Oxlumo. We anticipate combined net product revenues for these three products will be between $610 and $660 million, with the midpoint representing more than 75% growth compared to 2020. Nutriserine approval is not expected until early 2022, so it is not factored into our guidance for product revenues this year.

Our guidance for net revenue from collaborations and royalties in the range between 150 and $200 million with the midpoint of the range representing more than 30% growth from 2020.

Growth in 2021 is expected to come primarily from our collaboration with Regeneron and royalties and milestones from <unk>.

Our guidance for combined non-GAAP, R&D and SG&A expense as a range between $1 billion $175 million and $1 $275 million the midpoint of the guidance range represents a projected 15% increase compared with 2020.

We anticipate SG&A growth will be modest as we generate operating leverage from our existing commercial infrastructure to support our three commercial products.

Jeff Poulton: It is also worth noting that our guidance reflects the uncertainty related to the COVID-19 pandemic, which should decrease over time as the vaccine rollout progresses around the world. Guidance for net revenue from collaborations and royalties is a range between $150 million and $200 million, with the midpoint of the range representing more than 30% growth from 2020. Growth in 2021 is expected to come primarily from our collaboration with Regeneron and royalties and milestones from Lectvio.

We expect the higher rate of growth for R&D driven by investments in our two phase III ATR cardiomyopathy studies, Apollo B and Helios B as well as the initiation of two robust phase II studies in our <unk> program for hypertension.

Finally achievement of the top one of non-GAAP operating expense guidance. We have provided today for 2021 will deliver another year of improvement in our non-GAAP operating loss as we continued to make progress on our path to delivering sustainable profitability.

With that I'll now turn the call over to move on to review our goals for 2021 Gabon.

Jeff Poulton: Our guidance for combined non-GAAP R&D and SG&A expense is a range between $1,175,000,000 and $1,275,000,000. The midpoint of the guidance range represents a projected 15% increase compared with 2020. We anticipate SG&A growth will be modest as we generate operating leverage from our existing commercial infrastructure to support our three commercial products. We expect a higher rate of growth for R&D driven by investments in our two phase three ATTR cardiomyopathy studies, Apollo B and Helios B, as well as the initiation of two robust phase two studies in our AGT program for hypertension.

The bond.

Thanks, Jeff and Hello, everyone.

2021 is shaping up to be a productive year for on the island as we embark on a new five year sort of.

Germany outlines the Ireland piece of the first times 25 guidance.

But as John says we plan to continue on a global commercialization of on Patrick give Laurie.

We look forward to major market approvals in Japan, So give laurie on Brazil for three months.

We plan to continue advancing with Tcl franchise credit growth.

The ongoing atti cardiomyopathy study.

The <unk>, we expect to complete enrollment in the Apollo B study out of this year.

So the tree surround enrollment is ongoing in the Helios B study.

Following the heat against a positive top line results, we look forward the filing an NDA representing nine months results.

Jeff Poulton: Finally, achievement of the top line and non-GAAP operating expense guidance we have provided today for 2021 will deliver another year of improvement in our non-GAAP operating loss as we continue to make progress on our path to delivering sustainable profitability. With that, I'll now turn the call over to Yvonne to review our goals for 2021.

And in April.

In 2021.

We also plan to report additional data on the 18 month endpoint, which include the larger number of exploratory cardiac endpoint measures.

We expect to start studying our biannual dose regimen of retreat zone.

Yvonne L. Greenstreet: Thanks Jeff and hello everyone. 2021 is shaping up to be a productive year for Alnylam as we embark on a new five-year chapter of our journey outlined in our own piece of FIFSTIMES 25 guidance. For starters, we plan to continue our global commercialization of Onpatro, Givlari, and Oxluma. We look forward to major market approvals in Japan for Givlari and Brazil for Oxluma. We plan to continue advancing our TTR franchise program and the ongoing ATTR cardiomyopathy study. For Patisaran, we expect to complete enrolment in the Apollo B study early this year.

Early 2021.

So the mass around the.

Illuminate the phase III study is expected to have top line results midyear.

Look forward to initiating the cardio one.

Two phase III studies for AI, and AGC and hypertension.

And of course, we're excited about what's on our partners have in the store. This year Novartis will be executing on the initial launch some of that clear and aiming for the U S approval on.

<unk> will be advancing the Tucson, and the Atlas Phase III program.

Finally, you can expect additional data readout the mile pipeline during the course of the year.

2021 marks the start of the next chapter from the items with sight set on a new five vehicles become one of the most successful companies in the industry.

Yvonne L. Greenstreet: Patrice Rance, Enrollment is Ongoing in the HEDIS-B Study; I'm following the HEDIS-A positive top-line results. We look forward to filing an NDA and presenting nine-month results at AAN in April 2021. We also plan to report additional data on the 18-month end, which includes a larger number of exploratory cardiac endpoint measures, and expect to start studying our biannual dose with Ruth Rees-Rand in early 2021. For Lumasaran, the Illuminate-C Phase 3 study is expected to have top-line results mid-year, and we look forward to initiating the Cardio I and II Phase 2 studies for ALM, AGT And, of course, we're excited about what our partners have in store this year. Novartis will be executing on the initial launch of Leclerc and aiming for U.S. approval.

We are eager to deliver on this ambition and look forward to updating you throughout the year.

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

Thank you Yvonne operator, we will now open the call for your questions to the style then we'd like to ask you to limit yourself to one question each and then get back on the queue. If you have any additional question.

As a reminder to ask a question you will need the press star one on your telephone to withdraw your question press the pound key please standby, while we compile the Q&A roster.

Our first question comes from the line of David Lebowitz of Morgan Stanley. Your line is now open.

Yvonne L. Greenstreet: And Sanofi will be advancing to 2SRAM in the Atlas Phase III program. Finally, you can expect additional data readouts from our pipeline during the course of the year. 2021 marks the start of the next chapter for Alnylam, with sights set on our new five-year goal to become one of the most successful companies in the industry.

Thank you for taking my question when you look at Duke of Larry.

The performance thus far.

It seems to be doing quite well has this caused you to number one reevaluate what the size of the market is for <unk> in general.

And does it change the way you look at markets for for these types of diseases.

Christine Regan Lindenboom: We're eager to deliver on this ambition and look forward to updating you throughout the year. Let me now turn it back to Christine to coordinate our Q&A session. Thank you, Christine.

And what you think of what the ultimate opportunity for the east for ph one per <unk>.

Syria and other diseases of the central might be.

Operator: Thank you, Yvonne. Operator, we will now open the call for your questions. To those dialed in, we'd like to ask you to limit yourself to one question each and then get back in the queue if you have any additional questions. As a reminder, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A list.

Thank you David David I think that was your David.

It's a good question, obviously give laurie was really off to a good start ahead of very strong year.

Its first full year of launch last year, and we look forward to to its launch into a continued launch in 2021.

And we do expect continued growth in 'twenty, one driven not only by new patient finding but significant geographic expansion.

Operator: Our first question comes from the line of David Lebowitz from Morgan Stanley. Your line is now open. Thank you for taking my question. When you look at the Gavlari performance thus far, it seems to be doing quite well. Has this caused you to, number one, re-evaluate what the size should be?

We will be occurring by virtue of PNR.

And also approvals, we expect in major markets like Japan in 2021.

Unknown Speaker: Akshay Desai, Weinong Guo, Alnylam Pharmaceuticals Inc.

Let me turn it over to <unk> and.

John Maragnori: Thank you, David. I think that was you, David.

And Andy Orth, maybe to comment further let's start with toga anything to add to that.

Tolga Tanguler: I think it's a good question. Obviously, Givlari was really off to a good start. It had a very strong year, its first full year of launch last year, and we look forward to its launch and continued launch in 2021. And we do expect continued growth in 21, driven not only by new patient finding but significant geographic expansion that will be occurring by virtue of P&R and also approvals we expect in major markets like Japan in 2021.

Thanks, John and Hi, David Good morning, No John essentially I mean, it's good to be recognized with a good strong performance of give laurie, especially during a pandemic era that says a lot about the the capabilities of the organization on how we've been able to launch this both in the U S and ex U S and to your point, we do anticipate.

On the approval in Japan.

So overall I think the trends are good.

So a good sign off the value of the medicine debt provides to these patients that have not been per.

Tolga Tanguler: Let me turn it over to Tolga and Andy Orth, maybe to comment further. Let's start with Tolga. Anything to add to that? Tolga Tanguler, Unknown Attendee, Huidong Wang

Properly treated.

Andy anything to add to that.

Yes, I would just add that we continue to be really excited about the opportunity. We still think this is of half a billion dollar opportunity for the company globally and the learnings we're gaining here as we go through 2020 will hopefully allow us to accelerate that as we get into 'twenty, one and 'twenty two.

Tolga Tanguler: Thanks, John. And hi, David. Good morning.

Tolga Tanguler: No, John, essentially, I mean, it's good to be recognized for a good, strong performance of Givlari, especially during a pandemic era. That says a lot about the capabilities of the organization and how we've been able to launch this, both in the US and beyond. And to your point, we do anticipate approval in Japan. So overall, I think the trends are good. It's also a good sign of the value of the medicine that provides treatment to these patients that have not been properly treated.

Alright. Thank you David does that answer your question.

Thank you thanks for taking my questions great.

Thank you. Our next question comes from the line of Joe Albi Beatty from Citi. Your line is now open.

Hi, Thanks for taking the question I'm sure.

Could you share of any insight into the ability to have combination therapy in ctr with any competing drugs on the U S and how that compares with ex U S markets.

Yes, that's sort of.

Andy Wurth: Andy, anything to add to that?

Great question of very important one and one that defines an important part of the dynamics of the on Petro.

Andy Wurth: I would just add that we continue to be really excited about the opportunity and still think this is a half a billion dollar opportunity for the company.

Execution and market dynamics.

Unknown Speaker: Transcribed by https://otter.ai

<unk> in the U S and rest of World. So why don't we go the toga to add some more color on that question.

David N. Lebowitz: Right. Thank you. David, does that answer your question?

David N. Lebowitz: Thank you. Thanks for taking my question. Great.

Unknown Speaker: Great

Yes would you be able to repeat the question again I wasn't quite sure. If you were asking about the sort of the concomitant use.

Operator: Thank you. Our next question comes from the line of Joel Beattie from Citi. Your line is now open. Hi, thanks for taking the question. I'm curious, could you share any insight into the ability to have combination therapy and NTTR with any competing drugs in the U.S. and how that compares with ex-U.S. markets?

Yes, contaminant use of on Petro with computing GTR agents.

Is that different than the U S vs ex U S.

No. It is it is different what we see in the U S. In particular is that theres about 20% to 25% of the utilization of current on Petro of patients are actually also on <unk>.

Unknown Speaker: Yeah, that's a great question, a very important one, and one that defines, you know, an important part of the dynamics of the patro execution and market dynamics in the U.S. and the rest of the world. So why don't we go to Tolga to add some more color to that question?

We do see that.

In ex U S. We tend to see.

A much rep.

<unk> switch from the TTM stabilizers to silences the.

And that's why we've experienced however in some markets. We also see some minor level of.

Tolga Tanguler: Yeah, would you be able to repeat the question again? I wasn't quite sure if you were asking about the sort of concomitant use.

Concomitant use as well when it comes to both of.

Using a stabilizer of the silencer.

Operator: Yeah, you can terminate use of Onpetro with computing TTR agents.

And just and just to emphasize the point.

Obviously the use of on Patrick is for the treatment of the Polyneuropathy that exists in these patients which is where it's indicated. So these are hereditary <unk> patients that have polyneuropathy and likely have a mixed phenotype, which is why they may be getting both drugs.

Tolga Tanguler: Unknown Speaker Right. No, it isn't. It is different. What we see in the U.S., in particular, is that about 20-25% of the utilization of current Onpatra patients are actually also on tefamidase. We do see that. However, in the ex-U.S., we tend to see a much faster switch from TTR stabilizers to silencers. That's what we've experienced. However, in some markets, we also see some minor levels of concomitant use as well when it comes to both using a stabilizer and a silencer.

Absolutely yes.

Great. Thank you.

Thank you. Our next question comes from the line of solving Richter from Goldman Sachs. Your line is now open.

Good morning, Thanks for taking my question I'm, just curious if we're going to see an interim analysis here on the Helios B.

John Maragnori: And just to emphasize the point, you know, obviously, the use of Ampatro is for the treatment of the polyneuropathy that exists in these patients, which is where it's indicated. So these are hereditary ATTR patients that have polyneuropathy and likely have a mixed phenotype, which is why they may be getting both drugs. Absolutely.

When we can expect that in and what we should expect to see.

Yeah, Great Great question, Sylvain, So just as a reminder, and I'm on.

And I hand, this over to Akshay on the second but as a reminder, Helios b is our randomized double blind placebo controlled study of the tree Saran compared to placebo on top of the standard of care for the treatment of of <unk> amyloidosis with cardiomyopathy. So that includes both hereditary as well as <unk>.

Unknown Speaker: Great, thank you.

Operator: Our next question comes from the line of Salveen Richter from Goldman Sachs. Your line is now open. Good morning, thanks for taking my question. I'm just curious if we're going to see an interim analysis here on Helios B and when we can expect that, and what we should expect to see.

Disease, the study is enrolling quite well.

We are going to be enrolling throughout 'twenty, one, but we're really pleased with how well the enrollment is going but your point about interim analysis, let's turn it over to Akshay.

Unknown Speaker: Yeah, a great question, Salveen.

Yes, thanks Sylvain so.

John Maragnori: So, just as a reminder, and I'm going to hand this over to Akshay in a second, but as a reminder, Helios-B is our randomized, double-blind, placebo-controlled study of Vutrese-Saran compared to placebo on top of standard of care for the treatment of ATTR amyloidosis with cardiomyopathy, so that includes both hereditary as well as wild- You know, we're going to be enrolling throughout 21, but we're really pleased with how well the enrollment is going. But your point about interim analysis, let's turn it over to Akshay.

I think we have a wonderful option during the interim analysis in the Helios B.

The number of approaches we can consider but importantly, we wanted to use the old data elements to inform that interim analysis.

We have data from the original parties from the Apollo study itself.

Data from Helios, a nine month stage.

In patients with mixed <unk> disease with cardiomyopathy, those rates 40 day until BNP, which we've shared showing improvement in BNP.

And we're going to get 18 months days later in the year that will encompass.

Not just the BNP and Echo data that's on the technician scan data.

Akshay K. Vaishnaw: Yeah, thanks, Salveen. So, you know, I think we have a wonderful opportunity to do an interim analysis on Helios B. There are a number of approaches we can consider, but importantly, we want to use all the data elements to inform that interim analysis. And most importantly, next year, as we've just discussed, we'll get Apollo B data on the six-minute walk distance. And so these are the elements that will go into our thinking. There are lots of options. We're excited about it, and we will update you when we have finalized the approach.

And also tend to be towards sales and other elements. So that there's a lot of data that's coming that continue to inform us about the potential for RNA based approaches <unk> cardiomyopathy and most importantly next year as we've just guided will get Apollo B data on the six minute walk distance and so these are the needs of the elements that will go into our thing.

King.

Lots of options, we're excited about it and we will update you.

When we have finalized the approach.

Unknown Speaker: Great. Does that answer your question, Salveen?

Great does that answer your question on solving.

Unknown Speaker: Thank you. It's excellent.

Yes, Thank you <unk>.

Unknown Speaker: Excellent

Operator: Thank you. Our next question comes from the line of Paul Matteis from Steeple. Your line is now open.

Excellent.

Thank you. Our next question comes from the line of Paul <unk> from Stifel. Your line is now open.

Paul Matteis: Great, thank you very much for taking my question. I want to ask just a broader pipeline question. You know, last year, AGT really came into the forefront. If you had to pick one of your earlier programs that you featured at R&D Day or in the CNS pipeline that you don't think is being discussed right now but might be at the forefront of the conversation by the end of this year or early next, which would you pick?

Great. Thanks, so much for taking my question.

I wanted to ask just the broader pipeline one last year ADT really came into the forefront. If you were to pick one of your earlier programs that feature to R&D day or are in the CNS pipeline that you don't think it's discuss right now, but it might be at the forefront of the conversation by the end of the tier early next which would you pick and then one piece of that.

I'm a little surprised you guys don't have anything of neuromuscular given the amount of funding Thats gone into conjugation approaches there are there any is there.

Paul Matteis: And then one piece of that, you know, I'm a little surprised you guys don't have anything in neuromuscular given the amount of funding that's gone into conjugation approaches there. Are there any, is that at all of interest to you with RNAi? Thanks a lot.

And all of interest of you with RNA on thanks a lot.

Great questions, Paul So I'm going to.

I'm going to give you my view and then we'll go to Akshay and then we'll go to have on so you get three different perspectives on it.

John Maragnori: Okay, great questions, Paul. So I'm going to give you my view, and then we'll go to Akshay, and then we'll go to Yvonne. So you get three different perspectives on that.

And then and then we'll come back on Akshay will address the question on neuromuscular.

Look from my perspective.

Our program on our pipeline that debt.

John Maragnori: And then we'll come back, and Akshay will address the question on neuromuscular. Look, from my perspective, a program in our pipeline that I think will get a lot of attention this year is ALNAPP. That's our RNAi therapeutic targeting the amyloid precursor protein. It's our first CNS program. It's really going to be a defining moment for extrahepatic delivery of RNAi therapeutics, and we're leading the way on the translation of this remarkable technology for the treatment of neurodegenerative diseases where there's just enormous unmet need. And so I think that's going to be a landmark program for the field and for Alnylam and for the future of our pipeline. So that's my pick. Let's go to Akshay next.

No.

I think we will get a lot of attention. This year is ale on ATP.

That's our <unk> therapeutic targeting amyloid precursor protein.

Our first CNS program.

It's really going to be a defining moment for extra hepatic delivery of <unk> therapeutics, and we're leading the way on the translation of this this remarkable technology for the treatment of neuro degenerative diseases.

Where there is just enormous unmet need and so I think thats going to be of landmark program for the field and for our myeloma and for the future of our pipeline. So that's my that's my pick let's go to Akshay next.

Akshay K. Vaishnaw: I was going to pick that. Okay, I'll pick something.

I was going to pick that okay I'll pick something.

Akshay K. Vaishnaw: I think we, Paul, we have the benefit of many, many interesting targets we're addressing to address high unmet medical needs. You know, I trained as a rheumatologist. The XDH program, which we featured at R&D Day, will address gout. Gout is a hugely prevalent global disorder. Not only is it a rheumatologic disorder, but it can impact kidneys and kidney function. So, a very, very important disease, and one that's rapidly increasing in incidence, by the way.

I think we pull we have the benefit of many many interesting targets, we're addressing two reported the to address.

High unmet medical need.

I trained as the rheumatologist.

The H program, which we featured at R&D day will address GAAP gout is a hugely prevalent of global disorder.

The only that of Rubens logic disorder, but an impact of the kidneys and kidney function.

Very very important disease, and one that is rapidly increasing in incidence by the way. So we would love to make a debt that the animal data are very encouraging we can get out of 95% knockdown of target XDA H.

Akshay K. Vaishnaw: So, we would love to make a dent there. The animal data are very encouraging. We can get over 95% knockdown at the target XTH, with over 50% reduction in peripheral blood urate levels. It'll be interesting, you know, based on phase one, which I think will be very informative, and we can achieve a lot with that phase one to figure out how to position the device exactly and help the most patients. But, as part of our, you know, broadening into common diseases, that's another element beyond AGT and the NASH programs like HSD. John's talked about APP and Alzheimer's. So, I'd pick the XTH program. Yvonne.

The over 50% of reduction in peripheral blood <unk> levels.

Just being based on the phase, one, which I think will be very informative and we can achieve of law without phase one to figure out how to position of exactly and help the most patients but as part of our broadening into common disease. That's another element of beyond <unk> in the Nash programs like HFC, John has talked about <unk> outside the us so.

Pick the ex stage program Avon.

I have on.

Okay, well I'm going to pick the HBV program for for three reasons.

The one HBV is a.

Yvonne L. Greenstreet: Yvonne

Enormous opportunity, it's a disease that afflicts close to 300 million people around the world. So incredibly important second reason is I think the encouraging data that we pass them on phase II study with the one log reduction in HB Seth.

Yvonne L. Greenstreet: Okay, well, I'm going to pick the HPV program for three reasons. You know, one, HPV is an enormous opportunity. It's a disease that afflicts, you know, close to 300 million people around the world. So incredibly important.

This antigen and obviously.

Yvonne L. Greenstreet: The second reason is, I think, the encouraging data that we've had from our phase two study with a one and a half log reduction in HP surface antigen. And obviously, in partnership with VAER, that's now being studied in combination, and I think it has the opportunity to effect a functional cure for these patients, which would be absolutely tremendous. And then the third reason is the fact that we have a 50-50 free opt-in right prior to Phase 3. So I think this could start to become a program that we spend a little bit more time talking about as the year goes on.

Partnership with fed Thats not being studied in <unk>.

Combination.

And I think has the opportunity to effects functional cure for these patients which would be absolutely tremendous and then the third reason is the fact that we have the 50 53 offset and the right process to phase III. So I think this could start some kind of the program that we spend on.

A bit more time talking about houses the.

As the it goes on.

And we're encouraged.

Two two by the progress of beer has been making and I'm sure there'll be quite of bit of new data. This year on that program.

Akshay K. Vaishnaw: Absolutely, and you know we're encouraged by the progress that Vera has been making, and I'm sure there'll be quite a bit of new data this year on that program. So Akshay, do you want to handle the neuromuscular question?

So akshay do you want to handle the neuromuscular question, yes.

Yes, Paul.

Sure.

I think we are doing a good amount of work actually neuromuscular disease.

We do think about it the.

Front and center, we've got all of that work in HIV engine of amyloidosis Polyneuropathy there is price.

Akshay K. Vaishnaw: Yeah, Paul.

Akshay K. Vaishnaw: So, I mean, I think we are doing a good amount of work in neuromuscular disease. You know, if we think about it, the front and center, we've got all that work in HHTG amyloidosis, the polyneuropathy there is a. Petro is approved, of course, for the hereditary polyneuropathy in ATTR. So that's one area.

Neuropathy and squarely of neuromuscular disorder.

Of course as impactful in the hereditary situation increasingly we hear about neuropathy in wild type and I think that'll be an important area to think about as well.

On Patrick is approved of course for the hereditary Polyneuropathy ATT ATT.

So that's one area of week, we're going to do is for the Helio C, which we intend to kick off later in the year with the interest around to prevent.

Akshay K. Vaishnaw: We, you know, we're going to do a study of Helios C, which we intend to kick off later in the year with Butrisseran to prevent the onset of this syndrome, HIT triamyloidosis. More to come on that. And, you know, separately, we've got programs in ALS. There are a number of genetically validated targets in ALS that people are familiar with, SOD1, C9-ORF, and others, and that's under the basket of programs with Regeneron, where we collaborate, so that's another neuromuscular disorder caused by Regeneron.

The onset of the syndrome, <unk> amyloidosis moving to come on that.

And separately we've got.

The programs in ILS, the number of genetically validated target in.

The people are familiar with salt ones on the wharf and others.

And that's some of the basket.

Programs with Regeneron, where we collaborate.

So that's another of neuromuscular disorder of course with Regeneron, We're also pursuing myasthenia gravis.

Akshay K. Vaishnaw: but I can assure you there are programs ongoing in other disorders, including common inherited peripheral neuropathy, for example, which we're interested in. So there's lots going on in neuromuscular disease, and I think we're pretty excited about the progress we've made and certainly the dent we've made in HAT-terminal aidosis polyneuropathy.

With the some dis round and the C finance reported because that would map so more details on those the regeneron collaborative programs to come on shortly during the year actually.

And beyond that we have.

Doing working lots of additional neuromuscular disorders of the research and preclinical stage.

That we don't necessarily share until the data mature enough to discuss but I can assure you.

There are programs ongoing in the other disorders, including.

Commonly inherited proof of neuropathy for example, we're interested in the lots going on in neuromuscular disease, and I think we're pretty excited about the progress we've made and certainly the debt we've made in <unk> amyloidosis polyneuropathy.

Paul Matteis: Thanks Akshay. Paul, does that answer your question?

Unknown Speaker: Yep, thank you. All right, great.

Thanks, Akshay Pall of the Cynosure question.

Unknown Speaker: All right. Great.

Operator: Thank you. Our next question comes from the line of Tazeen Ahmad from Bangalore, America. Your line is now open. Hi guys, good morning.

Yep, Thank you alright, great.

Thank you. Our next question comes from the line of <unk> from Bank of America. Your line is now open.

Hi, guys. Good morning, Thank you for taking my question.

Tazeen Ahmad: Thank you for taking my question. I wanted to get your thoughts on how you think the ATTR market in general is developing. Do you have a better sense of how much of the addressable patients have been diagnosed and how the stabilizers are helping to develop that market? Thanks.

One of you get your thoughts on.

How you think the ATP on market in general is the Dallas thing do you have a better sense of how much of being adjusted the patients have been diagnosed.

And how the stabilizers are helping to develop that market.

John Maragnori: Well, that's a great question, Tazeen, and let me kick it off by saying that we have a multi-product, multi-year perspective on the broader ATTR franchise at Alnylam, a franchise where we aim to be the leader across the industry, helping patients with the medicines and the innovation we bring forward. Obviously, today, we are approved with one product for the treatment of the polyneuropathy of hereditary ATTR amyloidosis. Onpatro is off to a terrific start.

Well that's of Great question <unk>.

Let me, let me kick it off by saying that we have a multi product multi year perspective on the broader ATR franchise at all myeloma.

Franchise, where we aim to be the leader.

Across the industry, helping patients with the medicines of the innovation, we bring forward. Obviously today, we are approved with one product for the treatment of the Polyneuropathy of hereditary <unk> amyloidosis.

<unk> is off to a terrific start it is the market leading product for treating polyneuropathy.

John Maragnori: It is the market-leading product for treating polyneuropathy in this disease, and we're really pleased with the performance that we've seen. We expect continued growth in the polyneuropathy segment for Onpatro alone. At the same time, we just recently reported positive phase three data with Helios A, which will open up the opportunity for Vutrisiran, a once-quarterly sub-Q drug that, with additional work, we believe we can make a once-every-six-monthly sub-Q drug. And we should expect approval next year for HATTR polyneuropathy, which we believe will expand the polyneuropathy opportunity beyond even Onpatro.

With this disease and we're really pleased with the performance that we've seen we expect continued growth on the Polyneuropathy segment for our Petro alone at the same time, we just recently reported positive phase III data with the Helios, a which will open up the opportunity for vitry surround a once quarterly subcutaneous <unk>, which with additional.

Work, we believe we can make it of once or once every six monthly sub.

<unk> drug.

And we should expect approval next year in <unk>, Polyneuropathy, which we believe will expand the polyneuropathy opportunity beyond deepen on Petro and then of course as Akshay mentioned a minute ago, we opened up the door with the Apollo B study mid next year, assuming positive data.

John Maragnori: And then, of course, as Akshay mentioned a minute ago, we open up the door with the Apollo B study mid-next year, assuming positive data, for cardiomyopathy, both wild-type and hereditary. So this is really a multi-year growth opportunity for the innovation that we're bringing forward for the treatment of this disease. Toga, do you want to comment a little bit further, Andy, and you as well, in terms of how we see this evolving over time?

<unk>.

With cardiomyopathy, both wild type of hereditary. So this is really a multi year growth opportunity for for the innovation that we're bringing forward for the treatment of this disease.

Total debt do you want to comment a little bit further Andy you as well in terms of how we see this evolving over time.

Tolga Tanguler: No, I think, John, you said it very nicely. We certainly see this category evolving as time goes by, and as John indicated, obviously, we now have one indication with Ompatro that is the leader in the silencer market for polyneuropathy. But we know that there is almost a tale of two cities.

I think John you said it very nicely, we certainly see this category.

The evolving as the time goes by and as John indicated obviously, we now have.

The one indication where the on Petro that's becoming that is the leader in the in the silencer market for Polyneuropathy.

But we know that.

There are a tale of two cities almost you have the polyneuropathy, that's more of a rare disease with lesser prevalence.

Tolga Tanguler: You have the polyneuropathy that's more of a rare disease with a lesser prevalence given the hereditary condition. And then, obviously, there's the wild type that we certainly don't have the indication for yet with cardiomyopathy. But the diagnosis of that is probably going through the same route, which is really an inexpensive PYP scan. That access, having that access, has significantly increased our ability to be able to diagnose more polyneuropathy patients. And if Helios A as well as Apollo B were to succeed, we certainly would be able to take advantage of much larger cardiomyopathy segments.

Given the hereditary condition and then obviously, there's the wild type that we certainly don't have the indication yet with cardiomyopathy, but the diagnostics of debt is probably going through the same route which is really in it.

On the expensive piece of Ken.

Debt access having debt access has significantly increased our ability to be able to diagnose diagnose more polyneuropathy patients and if <unk>.

<unk>.

Sorry.

A as well as the Apollo B, if they were to succeed.

We certainly will be able to take advantage of much larger cardiomyopathy segments. So from an alliance perspective.

Tolga Tanguler: So from an Alliance perspective, what we're already demonstrating with Onpatro and its leadership in polyneuropathy, I think is a great signal for us to be able to actually define how we're going to be able to play in this current segment as well as be able to provide the right medicine for other segments if our products were to be approved. Andy?

We're already demonstrating with on Petro and its leadership in Polyneuropathy I think is of great signal for us to be able to actually the define how we're going to be able to play in in this current segment as well as be able to provide the right medicine for other signals if our products were to be approved Andy.

Tolga Tanguler: Yeah, and just to add, the hereditary and the wild type markets are in the very early stages of their growth for what we expect them to be. And that's going to have

Yes, and just to add.

The hereditary and the wild type of markets are in the very early stages of their growth for what we expect them to be.

And that's going to happen over the next one to five to 10 years and as John and told the highlighted our portfolio that we're going to bring to bear here puts us in an excellent position. So we're really pretty excited about it.

Unknown Speaker: ...

Unknown Speaker: Unknown Speaker for 10 years and as John Antle

Andy Wurth: Again, Tolga highlighted that our portfolio that we're going to bring to bear here puts us in an excellent position, so we're really pretty excited about it.

John Maragnori: And, you know, Tazeen, I agree with everything that Tolga and Andy just said. I have often made the analogy of where the ATTR marketplace will go over time to what happened with multiple sclerosis and, you know, with many products, many mechanisms of action, you know, and obviously major patient impact at the end of the day, along with obviously significant revenue and overall value of that market. So I think you will see that materializing in a way that will accommodate multiple opportunities for patients at the end of the day, and Alnylam is going to be a major leader in this space.

And <unk> I agree with everything the toga, Andy just said I have often made the analogy.

Of where the ATR marketplace will go over time to what happened with multiple sclerosis, and with many products.

Many mechanisms of action.

And obviously major patient impact at the end of the day, along with obviously significant revenue and overall value of that market. So I think you will see that materializing in a way that will accommodate multiple.

<unk> opportunities for patients at the end of the day and <unk> is going to be of major leader in the space.

Unknown Speaker: Okay, thank you. Thank you.

Okay. Thank you. Thank you.

Operator: Thank you.

Ritu Baral: Thank you. Our next question comes from the line of Ritu Baral from Cowen. Your line is now open. Hey guys, thanks for taking the question. I'm going to be up front. It does have a couple different parts, but it's all about Patra performance, which continues to be really great.

Thank you. Our next question comes from the line of Ritu <unk> from Cowen. Your line is now open.

Hey, guys. Thanks for taking the question.

I'm going to be upfront. It does have a couple of different parts, but it's all on on Patrick of performance.

Which continues to be really strong.

Unknown Speaker: One, you know, how much does home infusion present a tailwind to what we've seen over, especially in Q4? And long term, can you maintain coverage of home infusion? Are you planning on potentially expanding the sales effort with the VitruSaran approval in early 2022? And then, lastly, is there just any color on Apollo C? Akshay, you sort of threw it out there, prevention of symptoms. But anything else you can say about that?

One.

How much does home infusion present of tailwind to what we've seen over especially of the Q4 long term can you maybe.

Maintain coverage of home infusion.

Are you planning on potentially expanding the sales effort with the true Saran.

Approval in early 2022, and then lastly, just any color on on a policy Akshay you sort of threw it out there prevention of symptoms, but.

Anything else you can say about that.

Unknown Speaker: Okay, so let's, why don't we, Akshay, why don't you quickly answer the HELIOS-C question and then we'll go, we'll give Tolga and Andy some time to reflect on the Alpatra questions, and we'll go to them. So, Akshay.

Okay. So let's.

Why don't we.

Why don't you quickly answer the Helios <unk> question and then we'll go we'll give a total debt Andrew some time to reflect on the on Patrick questions and we will go to them. So.

Akshay K. Vaishnaw: Sure. You know, Ritu, when we looked at the original Apollo data, it was very clear that potent, significant reduction of TTR, 80% or so, you know, was associated with remarkable outcomes for the polyneuropathy and for the cardiac aspects in those with mixed disease. You know, the drug was labeled for the treatment of polyneuropathy of HATTL, which is right and proper. But as we looked at the detailed data, patients with very early disease, with lesser disease burden, did very well, and all their MNISC scores went down to single digits or very close to zero.

Sure.

When we looked at the reason the Apollo data it was very clear of that.

Potent significant reduction of TTS, 80% of it.

It was associated with remarkable outcomes of the Polyneuropathy and for the <unk>.

Cardiac aspects in those with mixed disease, we think.

And.

No.

The drug was labeled for the treatment of the Polyneuropathy of <unk>, which is right and proper, but as we looked at the detailed day to patients with very early disease with less of disease burden.

Did very well on the empty schools went down to single digits. So very close to zero and that led to the hypothesis that what if we could give the drug even before the overt onset of disease in patients with.

Akshay K. Vaishnaw: And that led to the hypothesis that what if we could give the drug even before the overt onset of disease in patients with, you know, very low or maybe no evident polyneuropathy, and can we prevent the onset of symptomatic disease?

Very low maybe no evidence of Polyneuropathy and can we prevent the onset of symptomatic disease and I think we feel very optimistic about that similarly, we now know that patients are being diagnosed the oil being identified as having.

Akshay K. Vaishnaw: And I think we feel very optimistic about that. Similarly, you know, we now know that patients are being diagnosed or being identified as having TTR deposits in their heart before the onset, by technician scan, of clinical disease. And so, you know, it's a very reasonable hypothesis, and one with a high likelihood of success, that if we can turn the tap off and substantially reduce TTR levels, we can substantially reduce the occurrence of this disease and prevent its onset.

<unk> deposits in the heart before the onset because by technetium scan before the onset of clinical disease and so it's a very reasonable hypothesis and I think one with the high likelihood of success for the if we can turn the tap off and substantially reduce <unk> levels that we can we can substantially reduce the current as of this disease and prevent as home sales.

Akshay K. Vaishnaw: So that's what we're working on now. We intend to start that study, which we'll call Helios-C with Vutrisiran later in the year, the subcutaneous injectable once every six months or so, and more details to follow. But I think it's a very, very exciting hypothesis. And how often do we get a chance to try and help patients by, you know, preventing the onset of disease?

That's what we're working on now we intend to start that study, which will call heal youll see with interest around later in the year cutaneous injectable once every six months of.

And more details to follow but I think the very very exciting hypothesis on how often in the rare disease do we get a chance to.

Try and help patients by preventing the onset of disease.

Tolga Tanguler: Great. And let's go to Tolga first on the commercial questions about Ompatro and then Boutrice Seran and the sales effort. Tolga.

Great and lets go to told the first on on the commercial questions on on Petro and.

And then blue tree surrounded the sales effort toga sure. Thanks John.

Tolga Tanguler: Sure. Thanks, John. A great question.

Question and Youre right. We are very pleased with the growth of and Petro quarter over quarter, and certainly that will be it will be driven by continuous patient finding.

Tolga Tanguler: And you're right, we are very pleased with the growth of Ampatro quarter over quarter, and certainly that will be driven by continuous patient finding. And if appropriate, switch outs from the patient's current treatments. Now in regards to patient access, obviously, with the pandemic, what we've seen is a good steady increase in patients being able to access home infusion, particularly in the United States and Europe. Those rates have gone up.

And if appropriate.

On the switch on.

Outs from the patients current treatments now in regards to.

Patient access obviously with.

With the pandemic, what we've seen is a good steady increase of patients be able to access home infusion.

Particularly in the United States and Europe those rates.

Have gone up.

Tolga Tanguler: But we also believe that patients have been actually able to, as well as healthcare systems being able to quickly pivot and provide alternative care sites for patients, as well as provide easy access to infusion clinics. So we're pleased that we have the ability to either redirect those patients to alternative site care or provide the home infusion network that we have available, particularly in the US and Europe. That's certainly a tailwind.

But we also believe that patients have been actually able to as well as the healthcare systems of being able to Cui.

Quickly pivot and provides alternative care sites for patients as well as providing easy access to infusion infusion clinics. So we're pleased that we have the ability to be able to either redirect those patients to alternatives.

<unk> cares or provide the home infusion.

The network that we have available principally in the U S and Europe.

That's certainly a tailwind and we actually of frankly have not seen.

Tolga Tanguler: And we actually, frankly, have not seen any impact on our compliance rates. Therefore, you know, the pandemic didn't really impact current patient retention and compliance rates at all. And again, we have those services available. The second part of your question in regards to how we would see the expansion, obviously, when the cardiomyopathy indication is received, obviously, that's something we are always exploring and making sure that we have the ability to be able to communicate effectively to healthcare professionals about earlier indications. But that's something we obviously need to continue to plan for. Let me turn it over to Andy if he has anything to add. Yep.

Any impact on our compliance rates therefore, the pandemic.

It didn't really impact.

The the current patient retention and compliance rates at all and again, we have those services available. The second part of your question in regards to how would we see.

The expansion obviously when the.

The cardiomyopathy indication has received obviously that's something we are always exploring and making sure that we have the ability to be able to communicate.

Effectively to health care professionals about earlier indications, but that's something obviously, we need to continue to plan for.

Let me turn it over to Andy if he has anything to add.

Andy Wurth: Yep, thanks. Thanks, Tolga.

Yeah. Thanks, Thanks, Paul.

Andy Wurth: And I think you got it right on the home infusion, Ritu. We've got that essentially, quote unquote, running smoothly and maxed out on our commercially insured patients and where they choose. Many are taking advantage of that. And then on the Medicare side, obviously, the rule that was passed last year isn't exactly the favorite of hospitals in some positions, but we've been able to take advantage of that where we can. I will say our ability to get folks infused at, you know, the common locations, infusion centers, hospitals, et cetera, is great. And many patients, frankly,

You got it right on the on the home infusion of <unk>, we've got that essentially the quote unquote running.

Running smoothly and maxed out on our commercially insured patients and where they choose many of our taking advantage of it.

And then on the Medicare side obviously.

On the rule that was passed last year isn't exactly the favorite of hospitals and some physicians, but we've been able to take advantage of that where we can I will say.

Our ability to get folks infused at the.

The the common locations of infusion centers hospitals et cetera is great in many patients frankly choose that.

Sort of preference.

Unknown Speaker: [inaudible]

For the social dynamic or are they just don't want somebody on their house.

Unknown Speaker: Ritu, was your question on Helios A in Neuropathy or Helios B in Cardiomyopathy? Yes, it actually was on Helios.

And on the second one was your question on Helios, a and the neuropathy or Helios B in cardiomyopathy.

It actually was actually was for for Helios day I'm, just wondering if you're planning any commercial expansion.

Unknown Speaker: [inaudible] You got it, got it. And as you know, right, right, overlapping labels with on Patro. And while we're not exactly releasing any plans on that front, you know, we love the promotional efforts we've got out there today and are really excited about what Helios A is going to bring to our portfolio.

She asked for richer surrounded FEP even before.

Cardiomyopathy labels might come on line.

You got it got it and as you know right of right overlapping labels with on Petro and while we're not exactly releasing any plans on that front.

Ritu Baral: Okay, good. Thank you, Ritu. We should move on to the next question, I think.

We love the.

The promotional efforts we've got out there today and are really excited about what Helios, a is going to bring bring to our portfolio.

Operator: Thank you. Our next question comes from the line of Anupam Rama from J.P. Morgan. Your line is now open. Good morning, this is Tess on the call for Anupam.

Great. Okay. Good. Thank you Ritu, we should move on to the next question I think.

Thank you. Our next question comes from the line of on <unk> Rama from J P. Morgan. Your line is now open.

Unknown Speaker: Thanks for taking our question. As you consider the launch dynamics between Gavlari and Oxluma, what are the similarities and differences worth considering here? And then, the second part of the question is on Gavlari. Anything more granular you can provide on your assumptions around 2021 US versus rest of world growth in 2021 versus 2020? Thanks so much, guys.

Okay.

Good morning, Jason pass on the call.

All of Ronny Thanks for taking our question.

General launch dynamics between Gulf Laurie will Matt.

What are the similarities and differences.

Worse, considering here and then second part of the question.

Of Laurie.

The more granular you can provide on your assumptions around 2021.

Versus the rest of world growth in 'twenty, one versus 2020, thanks, so much guidance.

John Maragnori: Okay, thank you, Taz. Those are great questions.

Thank you test those are great questions obviously.

John Maragnori: Obviously, I think we covered Giblari as an introduction earlier. You know, we're excited about this year as being the second full year of launch for that important medicine. And then, in the case of Oxlumo, which only got approved in November of last year for the treatment of primary hyperoxyluria, this will be the first full year of launch, so that's an exciting milestone. So let's go to Tolga to answer this great question.

I think we covered give laurie as an introduction earlier.

We're excited about this year as being the second full year of <unk>.

Of launch for that important medicine, and then in the case of <unk>, which only got approved in November of last year for the treatment of primary Hyperoxaluria. This will be the first full year of launch. So that's an exciting milestone so let's go to tolga to answer this.

Great question.

Tolga Tanguler: Sure. Thanks, John. Yeah, I mean, look, if you look at both of those products and what they're really addressing, both diseases are highly rare, and both diseases are highly devastating. And as John indicated, we had an excellent full year of launch with GiveLary during a pandemic. And we've been able to capitalize on a lot of patients that have been waiting for this therapy. And we look, we're probably going to be looking at the same type of dynamic with Oxlumo, with obviously a relevant number of patients across the world. Therefore, you know, from a business model perspective, the condition that those patients are in, we expect a very similar uptake when it comes to Oxlumo.

Sure. Thanks, John.

Yes, I mean look if you look at those both of those products and what they are really addressing.

Both of these are highly rare.

And both diseases of our highly devastating.

And.

As John indicated we had an excellent full year of launch would give laurie during a pandemic and we've been able to capitalize on a lot of patients that have been waiting for this therapy.

And we look.

We're probably going to be looking at the same type of dynamic with docs luma with obviously the relevant prevalent the number of patients across the world.

Therefore.

From a business model perspective, the condition that the those patients are in.

We expect the very similar uptake when it comes to Oklahoma.

Tolga Tanguler: Great, and Andy... I mean, John, if... I would just... Oh, let Andy go. But I was just going to add, I guess, one of the main differences here is that...

Yeah.

Great and Andy on this.

And the guidelines is going to add I guess one of the main difference here is that.

Oxnard was going to be treating of lots of pediatric patients and I hope this evening.

Andy Wurth: Akshay Desai, Weinong Guo, Alnylam Pharmaceuticals Inc. But yeah, the only thing I would add here is the level of excitement we are seeing right now in the PH1 communities, physicians, patients, patient advocacy groups, etc. It is just incredible and, frankly, matches the levels that we saw with Givlari a year ago. So we're off to a really, really good start. And as Yvonne mentioned here, this is, you know,

Different population that needs to be addressed but sorry, Andy.

The U.

Yes, the only thing I would add here is the level of excitement we are seeing right now and the th one communities physicians patients patient advocacy groups et cetera.

Is just incredible and frankly matches that of we saw would give laurie a year ago. So we're off to a really really good start and as Ivan mentioned here. This is.

Andy Wurth: A more so pediatric population than we saw with Gidlari, clearly.

More so of pediatric population than we saw on with good Laurie clearly.

Unknown Speaker: Terrific. So I think we have time for one more question.

Terrific. So I think we have time for one more question.

Operator: Thank you. Our next question comes from Gena Wang from Barclays. Your line is now open.

Thank you. Our next question comes from the line of Gena Wang from Barclays. Your line is now open.

Gena Wang: Thank you for taking my questions. So I have one big picture question. For Alnylam, we know, no doubt, Alnylam is a clear leader in the AI space. And you've done so much work identifying the best targets and the candidates, and some have already come to fruition. Will you be willing to leverage this knowledge to other technology platforms, such as gene editing? Since we could see some synergy there.

Thank you for taking my questions. So on.

I have a one big picture questions.

I would now and we know on no doubt.

Now he has a clear leader Inc.

On the AI space and you've done so much of work identifying the best targets on the Kennedy Center of some already come to fruition would you be willing to leverage this knowledge to the other technology platform, such as gene editing space and he thinks we could see some synergy there.

John Maragnori: Yeah, thanks, Gena. I mean, look, we are excited about the many, many prospects we have with R&AI for the foreseeable future. We have a ton of wood to chop with this science and this technology, and the type of innovation that we can bring forward is really boundless. Now, you know, we're always going to look at other types of technologies and how they might complement what we're doing, especially in areas where we have a commercial presence where we might want to, you know, obviously think about ways to strengthen and expand our leadership beyond maybe just an R&AI-based approach.

Yes, Thanks, Gena I mean look we are <unk>.

Excited about the many many prospects we have with arent AI for the foreseeable future we have a ton of wood to chop with the science in this technology and the type of innovation that we can bring forward.

Really is boundless now we're always going to look at it.

Other types of technologies and how they might complement what we're doing especially for especially in areas, where we have a commercial presence where we might want to.

Obviously think about ways to strengthen and expand our leadership beyond maybe just on R&D I based approach. So we will certainly look at that but in terms of product engines to speak of what we have in front of US right. Now is just boundless from from the number of opportunities in.

John Maragnori: So we'll certainly look at that. But in terms of, you know, product engines to speak of, what we have in front of us right now is just boundless in terms of the number of opportunities. And, you know, we're very flush with things. Let me turn it over to Yvonne also to provide some additional color on that question as well. Yvonne?

We're very flush with the with things, let me turn it over to Yvonne also to provide some additional color on that question as well.

John Maragnori: Yeah, no, that's, that's great, John. And yes, no, we do keep a, you know, careful watch on what's going on outside Alnylam as well, for sure.

John.

So on great John and.

Yes, we do keep cash.

Careful watch on whats going on outside on the items as well for sure.

Yvonne L. Greenstreet: You know, I think I have one additional point to make on gene editing because that's probably where you were going. I think, you know, whilst this approach has a lot of potential for patients, I think, you know, it is still in the very early stages of clinical development, and there's a lot that we need to learn. About, you know, long-term durability and efficacy and safety, etc. So, you know, we continue to stay engaged and be aware of what's going on. But, as John says, we have an awful lot to do with, you know, what we have in our hands at the moment.

I think one additional point to make on on.

On gene editing, because thats, probably where you would go and I think Ross.

No.

This approach track of lots of potential for patients I think it is still on the very early stages of cash.

Clinical development that sort of drop that we need to learn about long term durability of efficacy and safety et cetera.

We continue to stay engaged and be aware of what's going on but as John says, we have an awful lot to do with.

What we have on our hands at the moment.

Yvonne L. Greenstreet: Terrific. Thank you, Yvonne. Agree. So, I think that's the last question, right Christine?

Terrific.

Thank you Yvonne agree.

So.

I think that's the last question right Christine.

Christine Regan Lindenboom: Okay, good. All right. So, let me let me, then just close.

Correct. Okay. Good alright, So let me let me then just close I want to thank everybody for joining us on the call. We're obviously very pleased with our results for the fourth quarter and.

John Maragnori: I want to thank everybody for joining us on the call. We're obviously very pleased with our results for the fourth quarter, and what we did in 2020 was a remarkable year despite the headwinds from COVID-19. But we're now on a new chapter with Alnylam P to the fifth by 25, aiming to build the top five companies in market capitalization over the next five years with remarkable science and technology and innovation. So, thank you all and have a great day. Bye bye now.

And what we did in 2020 was a remarkable year. Despite the headwinds from COVID-19, but we're now on a new chapter with our Mylan Pete of the fit by 'twenty five.

Aiming to build the top five company in market capitalization over the next five years with the.

Remarkable science and technology and innovation. So thank you all of that have a great day Bye bye now.

Operator: Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.

Okay.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating you may now disconnect.

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