Q1 2021 Alnylam Pharmaceuticals Inc Earnings Call

Operator: Thank you for standing by, and welcome to the Alnylam Pharmaceuticals first quarter 2021 earnings conference call. At this time, all participants are in listen only mode.

Thank you for Sydney by and welcome to the on Island Pharmaceuticals first quarter 2021 earnings Conference call. At this time all participants are in listen only mode. After the speaker's presentation. There will be a question and answer session to ask a question. During the session you will need to press star one on your telephone as a reminder, today's program is being recorded.

Operator: After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star one on your telephone. As a reminder, today's program is being recorded. And now, I'd like to introduce your host for today, Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications. Please go ahead.

And now I'd like to introduce your host for today's program Christine didn't Bloom Senior Vice President of Investor Relations and corporate Communications. Please go ahead.

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. For those of you participating via conference call, the accompanying slides can be accessed by going to the events section of the investors page of our website, investors.alnylam.com slash events. During today's call, as outlined in slide two, John will provide some introductory remarks and general context.

Good morning, I'm, Christine Linda Bilmes Senior Vice President of Investor Relations on corporate Communications that on island with me today on the phone are John Barrington, Ori <unk> Chief Executive Officer.

And as our Chief commercial Officer, Akshay base now President of R&D, Jeff Poulton, Chief Financial Officer, NEP on Greene Street, President and Chief operating Officer.

It doesn't you participating via conference call. The accompanying slides can be accessed by going to the events section of the investors page of our website.

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

Christine Regan Lindenboom: Togo will provide an update on our global commercial progress. Aksha will review recent clinical and pre-clinical updates, and Jesse will review our financials.

Well it will provide an update on our global commercial progress.

With the recent clinical and preclinical updates.

Kathy will review our financial on.

Christine Regan Lindenboom: And Yvonne will provide a brief summary of upcoming milestones before opening the call to your questions. I'd 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 Faith Harper provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent annual report on file with the SEC.

On the bond will provide a brief summary of upcoming milestones before opening the call to your questions.

I'd like to remind you that this call will contain remarks concerning on that on 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 1995.

Actual results may differ materially from those indicated by these forward looking statements as a result of various important factors, including those discussed in our most recent annual report on file with the SEC.

Christine Regan Lindenboom: In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'd like to turn the call over to John.

In addition, any forward looking statements represent our views only as of day. This recording and should not be alive PON as representing our views as of any subsequent date.

Specifically disclaims any obligation 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. 2021 is off to a great start for Alnylam, with four approved RNAi therapeutics now helping patients around the world, and more in our pipeline poised to do the same in the coming years. To start, our teams delivered steady, ongoing commercial execution and continued revenue growth, including 13% quarterly growth for Ampatro in our first triple-digit revenue quarter and an impressive initial uptake for Oxlumo in its first full quarter on the market.

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

2021 is off to a great start or L. Marvell with four approved Arnie I therapeutics now helping patients around the world and more on our pipeline poised to do the same in the coming years.

To start our teams delivered steady ongoing commercial execution and continued revenue growth, including 13% quarterly growth or on Petro with our first triple digit revenue quarter.

And an impressive initial uptake for ox lube oil in its first full quarter on the market.

John Maragnori: On the pipeline side, the full positive results from the Helios A phase 3 study of Buttrey Saran were presented last week, and we announced that we have filed an NDA for Buttrey Saran with the FDA, bringing us a step closer to the potential approval of this important asset in our TTR franchise.

On the pipeline side, the full positive results from the Helios a phase III study on who treats rent were presented last week, we announced that we have filed an NDA for butare surround with the F. D. A brings us a step closer to the potential approval of this important asset in our T T. Our franchise.

We're also excited to have announced today that we expect the Helios B study arbitrary saran in a T T. Our patients with cardiomyopathy to complete enrollment later this year earlier than previously anticipated.

John Maragnori: We're also excited to have announced today that we expect the Helios B study of Tresoran in ATTR patients with cardiomyopathy to complete enrollment later this year, earlier than previously anticipated. Regarding our broader corporate strategy, we announced in January a new set of five-year goals, Alnylam P to the 5th by 25, highlighting a bold vision for Alnylam with transformative medicines in both rare and common diseases for patients around the world, supported by additional growth through label expansion, a robust and high-yielding pipeline of first and or best-in-class product candidates from our organic product engine, exceptional financial At Alnylam, we continue to be guided by our Challenge Accepted philosophy, which underpins our commitment to tackling unprecedented and complex challenges, taking courageous action, and using our business as a force of good.

Regarding our broader corporate strategy, we announced in January a new set of five year goals L. Biola, Peter the fifth by 'twenty five highlighting a bold vision for L. Myeloma with transformative medicines at both rare and common diseases for patients around the world supported by additional growth through label.

Expansion, a robust and high yielding pipeline of burst <unk> best in class product candidates from our organic product engine exceptional financial performance with over 40% revenue CAGR through year end 2025, and sustainable non-GAAP profitability achieved within.

On the period.

And on myeloma, we continue to be guided by our challenge accepted philosophy, which underpins our commitment to tackling unprecedented and complex challenges taken courageous action and using our business as a force of good.

John Maragnori: As a result, we are extremely proud to release this quarter our first corporate responsibility summary, which includes scientific pioneers, corporate leaders, and global citizens. Alnylam has long been committed to using our business as a force of good, beyond our core mission of developing innovative medicine. If you haven't already, I encourage you to visit our website to review the exciting progress and commitments we've made. So with that, I should now turn the call over to Tolga for a review of our commercial performance. Tolga?

As a result, we are extremely proud to have released this quarter, our first corporate responsibility summary.

Scientific pioneers corporate leaders and global citizens.

Ireland has long been committed to using our business as a force of good beyond our core vision of developing innovative medicines.

You haven't already I encourage you to visit our website to review the exciting progress progress and commitments we've made.

So with that I'll turn now turn the call over to <unk> for a review of our commercial performance Olga.

Tolga Tanguler: Thanks, John, and good morning, everyone. Let's get started with a review of our commercial performance in the first quarter. In Q1, despite COVID headwinds, particularly in the U.S., we were able to achieve strong results. For Ompatra, we achieved $102 million in global net product revenues in the first quarter, and we ended the quarter with over 1,500 patients on commercial treatment. In the U.S., we continue to see progress on many fronts, including steady and continuous growth in patients, as well as notable growth in new prescribers across specialties who are seeing patients with HATTR polyneuropathy.

Thanks, John and good morning, everyone.

Let's get started with a review of our commercial performance from the first quarter Inc.

Q1, despite COVID-19 headwinds, particularly in the U S. We were able to achieve strong results.

Four on Petro, we achieved $102 million in global net product revenues in the first quarter.

And we ended the quarter with over 500 patients on commercial treatment.

In the U S. We continue to see progress on many fronts, including steady on continuous growth in patients as well as notable growth in new prescribers across specialties seeing patients with H I G. G Artful neuropathy.

Tolga Tanguler: Adherence to treatment remains stable at pre-COVID levels, and we continue to observe a trend of HCP choice in the concomitant use of Ampetra to treat polyneuropathy, along with the use of a TTR stabilizer for cardiomyopathy in mixed phenotype HATTR amyloidosis patients.

It's used to treat loans remained stable at pre COVID-19 levels, and we continue to observe it strength of HCP choice in concomitant use off on Petro to treat polyneuropathy along with the use of our ctr stabilizer for cardiomyopathy and mixed phenotype.

<unk> amyloidosis patients.

Tolga Tanguler: Much of our continuous growth in El Patro revenue is driven by increased HATTR diagnosis rates, which we believe is due to wider availability of PYP scans. Access is another important highlight, with confirmed access to Ompatro for over 98% of covered lives. With regard to the rest of the world,

On some of our continuous growth and on Petro revenue is driven by increased Hh ETR diagnosis rates, which we believe is due to wider availability of few IP scans.

Excess it's another important highlight with cold from access to on Petro for over 98% of covered lives.

Okay.

With regard to the rest of the world.

Tolga Tanguler: Market access has now been achieved in over 30 countries worldwide, including additional global expansion with the achievement of regulatory approval in Taiwan. In 2021, we expect steady and continued growth for Ompetro, driven mostly by new patient findings. Moving to GiveLary, we achieved $25 million in global net product revenues in the first quarter, and as of March 31st, we had 225 patients worldwide on commercial therapy. Relative to where we ended 2020 and after significant strength in the initial launch quarters, Q1 of this year was softer than anticipated in terms of Gildari's new patient acquisition, likely due to reduced patient flow through the healthcare system in the U.S. due to COVID However, we did observe a notable uptick in March toward the end of the quarter, and patient compliance remained strong at over 90%.

Market access has now been achieved in over 30 countries worldwide, including additional global expansion with achievement of regulatory approval in Taiwan.

In 2021, we expect steady and continued growth we're on Petro driven mostly by new patient finding.

Moving to give Laurie.

We achieved $25 million in global net product revenues in the first quarter.

And as of March 31st we think 225 patients worldwide on commercial therapy.

Relative to where we ended 2020 and after significant strength initial launch quarters.

Q1 of this year was softer than anticipated in terms of <unk> new patient at.

Likely due to reduce patient flow through the health care system in the U S due to COVID-19.

However, we did observe a notable uptick in march towards the end of the quarter.

On patient compliance remains strong at over 90%.

Tolga Tanguler: So we continue to be optimistic about steady and continuous growth for Givlari for the rest of the year and beyond, especially with geographic expansion from expected pricing and reimbursement in multiple European countries. In the U.S., we continue to make strong progress in establishing VBAs for GiveLari with over 10 finalized to date with commercial payers and confirmed access for over 98% of covered U.S. lives with no pushback or headwinds. In terms of prescribers, we observed ongoing expansion of the base, including new riders with a significant number of prescriptions coming from community centers in addition to those coming out of centers of expertise.

So we continue to be optimistic about steady on continuous growth for <unk> for the rest of the year and be on.

Especially with geographic expansion from expected pricing and reimbursement in multiple European countries.

In the U S. We continued to make strong progress in establishing DBA forgive Laurie with over 10 finalized to date with commercial Payors and confirmed excess for over 98% of covered U S lives with no prospect or headwinds.

In terms of prescribers, we observed ongoing expansion of the base, including new riders with a significant number of prescriptions coming from community centers and in addition to those coming out of centers of excellence.

Tolga Tanguler: As noted earlier, geographic expansion around the world will be a driver for GiveLari this year, and we continue to make great progress with market access efforts across the Simia region. This includes our recent launch in Italy. We've also received approval in Switzerland, and we believe our Japan JNDA review is on track for approval mid-year. Moving to Oxluma, we're thrilled with the strong initial demand observed in its first full quarter of launch. We achieved $9 million in global net product revenues in the first quarter.

As noted earlier geographic expansion around the world will be a driver for give Laurie this year and we continue to make great progress with market access efforts across the CMEA region.

This includes our recent launch in Italy.

We've also received approval in Switzerland, and we believe our Japan J NDA review is on track for approval mid year.

Moving talk Shlomo.

We're thrilled with the strong initial demand observed in its first full quarter of launch.

We achieved non millions of dollars in global net product revenues in the first quarter.

Tolga Tanguler: Of course, with this being our first full quarter of Oxfam alone, we also benefited from the loading dose portion of the overall treatment regimen. We also received over 30 starter forms in the U.S. since launch and attained approximately 50 patients on commercial oxlomoid treatment in the U.S. and EU as of March 31st. Our market access efforts are progressing very well for Oxfam, with over five DBAs finalized to date with commercial payers and confirmed access already for about two-thirds of covered U.S. lives.

Of course with this being our first full quarter of axiom will launch.

We're also benefited from the loading dose portion of the overall treatment regimen.

We also received over 30 start forms in the U S. Since launch and attained approximately 50 patients on commercial Shlomo treatment in the U S and EU as of March 31st.

Our market access efforts are progressing very well four of them all.

With over five EBITDA finalize the date with commercial Payors and confirm axis already or about two thirds of covered U S lives.

Tolga Tanguler: Globally, we continue to make strong progress across the Semiya region with a recent launch in Germany, ATU supply in France, and named patient sales in other countries. At this early stage of launch, we're very pleased to see broad utilization of Oxluma across age groups and EGFR categories. We're encouraged by the initial uptake in both the pediatric and adult patient segments, and we think this bodes well for the long-term potential of Oxlum

Globally, we continue to make strong progress across the senior region with a recent launch in Germany.

<unk> supply in France, and named patient sales in other countries.

So early stage of launch we're very pleased to see broad utilization of looks little low across age groups and Egfr category.

We're encouraged by the initial uptake in both the pediatric and adult patient segments, and we think this bodes well for the long term potential of Occidental.

Tolga Tanguler: In conclusion, we believe 2021 is off to a great start as we continue to achieve steady growth across our wholly owned commercial portfolio. With that, I will now turn it over to Akshay to review our recent R&D and pipeline progress.

In conclusion, we believe 2021 is off to a great start as we continue to achieve steady growth across our wholly owned commercial portfolio.

With that I.

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 ATTR amyloidosis, where we're advancing our two product candidates, Patisserin and Vutrisserin. With Patisserand, we're committed to expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild-type A-T-tramyloidosis patients. To this end, we're conducting the Apollo B Phase 3 study.

Thanks, Tom and good morning, everyone I'll start with our efforts in Atg on amyloidosis, where we are advancing on two product candidates <unk> and <unk>.

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

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

Akshay K. Vaishnaw: We continue to enroll patients in Apollo B and continue to expect completion of the enrollment in early 2021, which would put us on track for a top-line readout in mid-2022. We're also advancing Vutrisran, which is delivered by a quarterly subcutaneous injection. Here, we're conducting two phase three studies. The first is Helios A, evaluating Butrysran in HAT for amyloidosis patients with Just over a week ago at the American Academy of Neurology conference, we presented our positive full nine month results, which I'll briefly recap here. On the primary endpoint of change in MNIST plus seven from baseline 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 a top line readout in mid 2022.

We're also advancing Boutris ran which is delivered by quarterly subcutaneous injection.

Here, we are conducting two phase III studies.

The first is helio say evaluating boutris, Ron in amyloidosis patients with Polyneuropathy <unk> amyloidosis patients with Polyneuropathy.

Just over a week ago at the American Academy of Neurology Conference, we presented a positive full nine months results, which I'll briefly recap here.

On the primary endpoint of change in M&A, plus seven from baseline at nine months.

Akshay K. Vaishnaw: Mutriceram treatment resulted in a 17 point mean treatment benefit relative to the external placebo group from the Apollo phase 3 study of Mutriceram. The effect was highly significant, indicating robustness of the treatment effect. Also, the mean change in MNIST plus 7 relative to baseline was a negative value indicating improvement, providing evidence that, like pitiseran, pitiseran not only halts neuropathy progression but also achieves reversal of neuropathy symptoms relative to baseline in the majority of patients in this pivotal trial.

<unk> treatment resulted in a 17 point mean treatment benefit relative to the external placebo group from the Apollo Phase III study expertise from.

The effect was highly significant indicating robustness of the treatment effect.

So the main change in <unk>, plus seven relative to baseline was at negative value, indicating improvement providing evidence that like <unk>.

Tricia on not only halt neuropathy progression, but also achieve reversal of neuropathy symptoms relative to baseline in the majority of patients in a pivotal trial.

Akshay K. Vaishnaw: As to the key secondary end point, change in Norfolk quality of life score at 9 months relative to baseline, Patricia and treated patients demonstrated a mean improvement in quality of life relative to the external placebo arm. Another important secondary endpoint, the 10-meter walk test measuring gait speed, was stable in the vitreous surround arm at month 9 relative to baseline, compared to demonstrated worsening in gait speed from baseline for the external placebo group.

As to the key secondary endpoint is change in Norfolk quality of life score at nine months relative to baseline.

Chris or untreated patients demonstrate to the mean improvement in quality of life relative to the excellent placebo on another.

Another important secondary endpoint the 10 meter walk test measuring gait speed was stable in the vitro Suriname at months behind relative to baseline compared to demonstrate with an <unk> <unk> beat from baseline for the external placebo group.

Akshay K. Vaishnaw: We also analyzed the exploratory endpoint of NT-proBNP, a marker of cardiac stress. The external placebo group showed an increase or worsening in anti-proBNP levels over nine months. Levels of this marker in the vitreous sarin group were stable over nine months and did not decline, supporting further evaluation of vitreous sarin effects on cardiomyopathy manifestations of disease. Importantly, Boutros-Rham demonstrated an encouraging safety and tolerability profile. There were no drug-related discontinuations or deaths.

We also analyze the exploratory endpoint of empty pro BNP, a marker of cardiac stress.

Well I'll say external placebo group showed an increase of worsening in NT pro BNP levels over nine months levels of this market and the interest on group was stable over nine months from did not decline supporting further evaluation of the troops are on effects on cardiomyopathy manifestation of disease.

Importantly, <unk> demonstrated an encouraging safety and tolerability profile.

There were no drug related discontinuation so that it.

Akshay K. Vaishnaw: There were two serious adverse events (SAEs) deemed related to vitrexran by the study investigator consisting of dyslipidemia and an E. coli urinary tract infection. Treatment-emergent adverse events occurring in 10% or more of patients receiving butresirine include diarrhea, pain in the extremity, fall, and urinary tract infections, each occurring at a similar or lower rate compared with the external placebo group in Apollo. Injection site reactions were reported in 5 uterus-ran patients, or 4.1%, and were all mild and transient.

There were two serious adverse events, where I say he's deemed relate deemed related to <unk> by the study investigator consisting of Dyslipidemia and an E coli urinary tract infection.

Treatment emergent adverse events occurring and 10% on more of patients receiving <unk> included diarrhea paid an extremity full and urine tract infections, each occurring at a similar or lower rate compared with the excellent placebo group in Apollo.

Injection site reactions were reported in five butros around patients or four 1%.

And were all mild and transient.

Akshay K. Vaishnaw: We're thrilled with these results and have now filed our NDA with the FDA for the treatment of HAT in amyloidosis patients with polyneuropathy and look forward to reporting top-line results from the 18-month analysis in late 2021, which will also further characterize Futrisaran's impact on exploratory cardiac endpoints. The second phase 3 vitreous study is Helios B, being conducted in hereditary and wild type A tetraamnoylosis patients with cardiomyopathy.

We're thrilled with these results and have now filed our NDA with the FDA for the treatment of <unk> amyloidosis patients with Polyneuropathy.

Look forward to reporting topline results from the 18 months of analysis in late 2021, which will also further characterize future surrounds impact on exploratory cardiac endpoints.

The second phase III <unk> studies Helios B b.

Being conducted in hereditary and wild type <unk> amyloidosis patients with cardiomyopathy.

Akshay K. Vaishnaw: As John noted, we announced today that due to the strong pace of enrolment in the study, we now expect complete enrolment in late 2021, well ahead of our prior expectations. Lastly, for vitreous RAN, we plan to initiate our study of a biannual dosing regimen for vitreous RAN in the coming weeks. Let's now move on to Lumasran, our RNAi therapeutic recently approved in the EU and U.S. as the first treatment for primary hyperoxylurea type 1, or PH1.

As John noted, we announced today that due to the strong pace of enrolment in this study we now expect to complete enrollment in late 2021, well ahead of our prior expectations.

Lastly from Richard's ran.

On to initiate a study of our biannual dosing regimen from Richard's Ryan in the coming weeks.

Let's now move on to new mass ran our RNA therapeutic recently approved in the EU and U S. As the first treatment from primary Hyperoxaluria type one ph one.

Akshay K. Vaishnaw: Here, we continue to dose PH1 patients with advanced renal disease in the fully enrolled Illuminate C Phase 3 study and remain on track to report top-line results in mid-2021. As you know, we have two additional late stage programs that are in development with partners. This includes Lexio or Inclisran, partnered with Novartis, which was approved last year in the EU for the treatment of adults with hypercholesterolemia or mixed dyslipidemia. Lexio marks the first RNAi therapeutic approved for a widespread condition.

Yeah, we continue to dose ph one in patients with advanced renal disease in a fully enrolled illuminate C phase III study and remain on track to report top line results in mid 2021.

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

<unk> <unk> from cliffs ran partnered with Novartis, which was approved last year in the EU for the treatment of adults with hypercholesterolemia or mixed dyslipidemia.

Nexium amongst the first RNA on my therapeutic approved from a prevalent condition.

Akshay K. Vaishnaw: 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 that Novartis will do everything it can to accelerate this process. Our late stage programs also include two surrounding departments for A or B with or without inhibitors partnered with Sanofi. Sanofi mentioned this week that all the health authorities relevant to the program have approved re-dosing of Fetustran, and a majority of patients have resumed dosing.

Novartis received as TRL 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 English ran on Novartis plans to submit its response in Q2 Q3 2021.

We're confident that Novartis will do everything we can to accelerate this process.

Our late stage programs also include from Tucson development for hemophilia, a or b with or without inhibitors partnered with Sanofi.

Sorry, if you mentioned this week that all health authorities relevant to the program have improved re dosing for Tucson.

The majority of patients have resumed dosing.

Akshay K. Vaishnaw: They intend to share data from initial pivotal trials and medical conferences later this year or early next year. Furthermore, following interactions with the FDA, Sanofi is planning for a U.S. submission in the second half of 2022, once data for the revised dose regimen are available. 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.

I intend to share data from initial pivotal trials at medical conferences later this year and on early next year.

Furthermore, following interactions with the FDA Sanofi is planning for U S submission in the second half of 2022, one statement from the revised dose regimen are available.

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 part sales story now is the expansion of RNA therapeutics beyond rare diseases into prevalent disease opportunities.

Akshay K. Vaishnaw: 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 we believe the pharmacological properties of RNAi therapeutics provide the foundation for success. Our program for hypertension is a great example. LNAGT is our investigational RNA mice therapeutic targeting the genetically validated target angiotensinogen for the treatment of hypertension. We reported additional interim results from the Phase 1 study a couple of weeks ago in which patients treated with single doses of LNAGT at 100 mg or higher experienced durable reductions in serum AGT of more than 90% through 12 weeks. Additionally, reductions in 24-hour systolic blood pressure of more than 15 mmHg were achieved with LNAGT as monotherapy. ALNAGT has also been shown to be generally well tolerated.

We believe now is the time to address many unmet needs in common disease, setting such as hypertension, Nash count and diabetes amongst others and we believe the pharmacological properties of RNA Therapeutics provides the foundation for success.

Program Protection is a great example.

<unk> is our investigational <unk> therapeutic targeting genetically validated target angiotensin engine for the treatment of hypertension.

We reported additional interim results from the Phase one study a couple of weeks back and which patients treated with single doses of <unk> 100 milligrams, Ohio experienced durable reductions in serum HGT of more than 90% through 12 weeks.

Reductions in 24 hour systolic blood pressure on more than 15 millimeters of Mercury were achieved with the M&A.

As monotherapy.

And on AZT low session to be generally well tolerated.

Akshay K. Vaishnaw: These durable pharmacologic effects may support tonic control of blood pressure with once quarterly and potentially biannual dosing, and we look forward to advancing LNA-GT into our phase two cardiac program planned to be initiated in mid 2021. Moving on, we're also advancing LNHSD in collaboration with our partner, Parthasar Regeneron, for the treatment of NASH. We believe that RNAi-mediated knockdown of HSD17B13 will phenocopy the genetic loss-of-function findings, reducing hepatic inflammation, injury, and fibrosis in NASH patients.

These durable pharmacologic effects may support tonic control of blood pressure with once quarterly and potentially biannual dosing and we look forward to advancing <unk> into phase two cardiac program planned to be initiated in mid 2021.

Moving on we're also advancing and in HST in collaboration with our partner partners at Regeneron for the treatment of Nash.

We believe that RNA <unk> mediated knockdown of HST 17, visa team will pheno copied the genetic loss of function findings, reducing hepatic inflammation injury and fibrosis and Nash patients.

Akshay K. Vaishnaw: Enrolment and dosing continue in the Phase 1 study of LNHSD, and we also continue to make good progress on our many preclinical RNAi therapeutic opportunities beyond the liver. Notably, we continue to advance our CNS and ocular efforts with Regeneron. Our LNAPP program remains on track for a CTA filing in mid-2021, becoming the first RNAi therapeutic for CNS disease to start clinical testing. And with that, let me now turn it over to Jeff to review our financial results. Thank you, Jeff.

Enrollment and dosing continues in the phase one study of add on.

On HST.

We also continue to make good progress on our many preclinical RNA therapeutic opportunities beyond the liver, notably we continue to advance our CNS and ocular effort with regeneron.

Our <unk> program remains on track from a Cta filing in mid 2021, becoming the first on Eric Therapeutics for CNS disease to stop clinical testing.

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

Jeff Poulton: Thanks, Akshay, and good morning, everyone. I'm pleased to be presenting Alnylam's Q1 2021 financial results. As Tolga highlighted, it was another very strong quarter of commercial execution with excellent results. Turning to our results first for Antatro, we generated $102 million in net revenue for the quarter, representing 13% growth from the fourth quarter of 2019 and 53% growth compared with Q1 2020. This marks the third consecutive quarter of double-digit, quarter-on-quarter growth following one quarter of flattened growth we experienced during the onset of the pandemic in Q2 of last year. U.S. On Patrot sales increased 15% versus Q4 2020 and were primarily impacted by the following.

Thanks, Akshay and good morning, everyone.

Im pleased to be presenting on <unk> Q1, 2021 financial results.

Hold on highlighted it was another very strong quarter on commercial execution with excellent results.

Turning to our results for a strong cash flow, we generated $102 million in net revenue for the quarter, representing 13% growth from the fourth quarter of 2020, and 53% growth compared with Q1 2020.

This marks the third consecutive quarter of double digit quarter on quarter growth.

Following one quarter of flattened growth, we experienced during the onset of the pandemic from Q2 of last year.

U S on patio sales increased 15% versus Q4, 2020 and were primarily impacted by the following.

Jeff Poulton: Approximate 4% increase in demand driven by the addition of new patients on therapy. An increase in inventory in the distribution channel, with inventory increasing from approximately one week at the end of 2020 to approximately two weeks at the end of Q1, and a lower level of gross to net deductions in the third quarter compared with Q4 2020. Consistent with full year 2020, we expect gross to net deductions will remain in the mid 20s globally for Impatro in 2021, and our international markets on Patria performance remain strong with growth of 11% versus Q4 2020, primarily driven by increased patient demand in our five major markets in Europe, while results in Japan were unfavorably impacted by a reduction of inventory at a distributor during Q1.

An approximate 4% increase in demand driven by the addition of new patients on therapy.

An increase of inventory in the distribution channel with inventory increasing from approximately one week at the end of 2020 to approximately two weeks at the end of Q1.

And a lower level of gross to net deductions in the third quarter compared with Q4 2020.

Consistent with full year 2020, we expect gross to net deductions will remain in the mid twenty's globally on Petro in 2021.

In our international markets on Patrick performance remained strong with growth of 11% versus Q4, 2020, primarily driven by increased patient demand and our five major markets in Europe.

Results in Japan were unfavorably impacted by a reduction of inventory at our distributor during Q1.

Turning to our results for give Laurie we generated $24 7 million in net revenue in Q1, representing 11% growth compared to the fourth quarter of 2020, driven by ongoing launches in the U S and Europe.

Jeff Poulton: Turning to our results for Givlari, we generated $24.7 million in net revenue in Q1, representing 11% growth compared to the fourth quarter of 2020, driven by ongoing launches in the U.S. and Europe. However, reported results in the U.S. were unfavorably impacted by an increase in gross to net sales deductions in Q1 compared with Q4. For Doxolumo, we had a strong first full quarter of sales, generating $9.1 million in net revenue in the quarter.

Reported results in the U S were unfavorably impacted by an increase from gross to net sales deductions in Q1 compared with Q4.

With <unk>, we had a strong first full quarter of sales generating $9 1 million and net revenue in the quarter.

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

Total combined product sales in the first quarter were $135 8 million, representing 89% growth versus Q1 2020.

Jeff Poulton: Turning now to a summary of our full P&L results for the quarter. Total combined product sales in the first quarter were $135.8 million, representing 89% growth versus Q1 2020. Net revenue from collaborations for the quarter was $41.8 million, a significant increase from Q1 last year, primarily due to revenue recognized from our Regeneron collaboration. Gross margin on total revenues was 83% for the quarter, down from 87% in Q1 2020, primarily due to lower margins on collaboration revenues in the quarter. combined non-GAAP R&D and SB&A expenses for the quarter increased modestly at 6% versus Q1 2020.

Net revenue from collaborations for the quarter was $41 8 million a significant increase from Q1 last year, primarily due to revenue recognized from our regeneron collaboration.

Gross margin on total revenue was 83% for the quarter down from 87% in Q1 2020, primarily due to lower margins on cloud collaboration revenues in the quarter.

Our combined non-GAAP R&D and SG&A expenses for the quarter increased modestly at 6% versus Q1 2020.

Key drivers of the increase were additional R&D investment in advancing our late stage pipeline programs and increased SG&A investments to support launch of <unk>.

Our non-GAAP operating loss for the quarter decreased by approximately $45 million versus the same period in 2020, driven by strong topline growth and moderate growth on operating expenses.

Jeff Poulton: Key drivers of the increase were additional R&D investment in advancing our late-stage pipeline programs and increased SB&A investment to support the launch of Oxluma. Our non-GAAP operating loss for the quarter decreased by approximately $45 million versus the same period in 2020, driven by strong top-line growth and moderate growth in operating revenue.

Q1 also represents the fifth consecutive quarter that we've delivered an improvement in our non-GAAP operating loss clearly signals the path we're on towards profitability.

Lastly, turning to our financial guidance following our strong Q1 results. We remain confident in our full year outlook and are reiterating financial guidance. We provided on our Q4 results call in February.

Starting with net product revenue, we anticipate combined net product revenues for our three commercialized products will be between 610 $660 million.

Jeff Poulton: Q1 also represents the fifth consecutive quarter that we've delivered an improvement in our non-GAAP operating loss and clearly signals the path we're on toward profitability. Lastly, turning to our financial guidance. Following our strong Q1 results, we remain confident in our full-year outlook and are reiterating the financial guidance we provided on our Q4 results call in February. Starting with Net Product Revenues, we anticipate combined Net Product Revenues for our three commercialized products will be between $610 and $660 million.

Our guidance for net revenue from collaborations on loyalty is a range between $150 and $200 million.

And our guidance for combined non-GAAP, R&D and SG&A expenses as a range between $1 billion $175 million and $1 $275 million.

With that I will now turn the call over to move on to review our upcoming milestones of on.

Thanks Jack.

One.

We've already achieved important milestones in 2021 and as we look ahead. There are plenty of calculus cute on the next 12 to 24 months.

Within our <unk> franchise, we expect to complete enrollment in the phase III Apollo B study expertise from added this year setting up top line results in mid 2022.

Jeff Poulton: Our guidance for net revenue from collaborations and royalty is a range between $150 and $200 million, and our guidance for combined non-GAAP R&D and SG&A expenses is a range between $1,175,000,000 and $1,275,000,000. With that, I'll now turn the call over to Yvonne to review our upcoming milestones.

With <unk>, we're on track to initiate data generation for bi annual dosing regimen in mid 2021 for the data in 2021 my presentation of 18 months top line results from TTS, a natural you've announced the day. We can look forward to completion of enrollments on Helios B later this year.

To give Laurie you look for what's an important regulatory milestone with its potential to people in Japan midyear.

Yvonne L. Greenstreet: Thanks, Jeff, and hello, everyone. We've already achieved important milestones in 2021, and as we look ahead, there are plenty of catalysts queued up for the next 12 to 24 months. Firstly, within our TTR franchise, we expect a complete enrollment in the Phase 3 Apollo-B study of the T-SRAM early this year, setting up top-line results in mid-2022. With Ritree Saran, we're on track to initiate data generation for a biannual dosing regimen in mid-2021, followed later in 2021 by presentation of 18-month top-line results in Helios A.

Turning to ex Newmont, we anticipate an approval in Brazil in mid 2021.

From an clinical milestones will also include top line results from the phase III.

T study in mid 2021, as well as the initiation of the phase III study for recurrent renal stones in late 2021.

This phase II study will be important for lifecycle management spoke three months with the potential.

<unk> to significantly expand the overall opportunity.

Our early and mid stage pipeline has lots in store as well.

<unk> enrollments from dosing continues in the phase II monotherapy study in Iga nephropathy.

Yvonne L. Greenstreet: And as we've announced today, we can look forward to completion of enrollment in Helios B later this year. For Giblari, we look forward to an important regulatory milestone with its potential approval in Japan mid-year. Turning to Oxlumo, we anticipate approval in Brazil in mid-2021. Upcoming clinical milestones will also include top-line results in the Phase III Illuminate C study in mid-2021, as well as initiating a Phase II study for recurrent renal stones in late 2021. This Phase 2 study will be important for the life-cycle management of Oxlumo, with the potential to significantly expand the overall opportunity.

Dosing continues in the phase one combo study with closing on that in collaboration with Regeneron.

On partnerships continued to enroll into AI in HBV.

In the phase II combo trial with Pegylated interferon Alpha.

And as I said, our partners continues to advance well Seth surrounds the AAC deficiency liver disease.

<unk> is on track to enter phase III midyear with the stance of the cardiac program in hypertension.

We're very excited about the planned filing in mid 2021 of our fast CNN Cta for alien ATP.

A potential initial CNS proof of concept data in 2022.

Yvonne L. Greenstreet: Our early and mid-stage pipeline has lots in store as well. Since MD-SARAN, enrollment and dosing have continued in the Phase II Monotherapy Study in IgA Nephropathy, and dosing has continued in the Phase I Combo Study with Cozumel MAP in collaboration with Regeneron. Our partners at FAIR continue to enroll dose AIM-HBbO2 in a Phase 2 combo trial with pegylated interferon alpha, and at Dyserna, our partners continue to advance Valseseran for AAT deficiency liver disease. ALNAGT is on track to enter phase 2 mid-year with the start of the cardio program in hypertension.

So needless to say on non <unk> have much to look forward to in the coming quarters as we.

We execute on these key cuts on the.

Across our pipeline on platform in the first quarter months with strong songs with regard to our on island Pizza Fifth times 25 goals outlined in January.

Now turn it back to Christine to coordinate on Q&A session Christine.

Thank you Yvonne operator, we will now open the call for your questions.

Eldon, we would like to ask you to limit yourself to one question each and then get back on the queue. If you have additional question.

Yvonne L. Greenstreet: And we're very excited about the planned filing in mid-2021 of our first CNS CPA for AIN APP. This sets us up for potential initial CNS proof-of-concept data in 2022. So needless to say, Alnylam has much to look forward to in the coming quarters as we execute on these key catalysts across our pipeline and platform, and the first quarter marks a strong start with regard to our Alnylam P5x25 goals outlined in January.

Certainly ladies and gentlemen, if you have a question at this time. Please press Star then one on your Touchtone telephone. If your question has been answered and you'd like to remove yourself from the queue. Please press the pound key our first question comes from the line of <unk> from Bank of America. Your question. Please.

Hi, Good morning, guys. Thanks, so much for taking my question on.

Good news on the enrollment rate for Helios B I, just wanted to get a little bit of color. If you could provide any on.

Christine Regan Lindenboom: 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 those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have additional questions. Certainly, ladies and gentlemen, if you have a question at this time, please press star, then one on your touchtone telephone. If your question has been answered and you'd like to remove yourself from the queue, please press the pound key. Our first question comes from the line of Tazeen Ahmad from Bank of America. Your question, please.

Why do you think it was able to it is enrolling faster than you previously anticipated and does that give you a better sense of when we could see the data at least at the topline level readout. Thank you.

Okay.

Thank you Zane and we're also very excited about the progress on on Helios B.

It really it really is supported by the enthusiasm in the community for who treats Iran is a once quarterly sub Q medicine for <unk>.

<unk> amyloidosis with cardiomyopathy, which is what we're evaluating at that phase III study.

Operator: Hi, good morning, guys. Thanks so much for taking my question. Good news on the enrollment rate for Helios B. I just wanted to get a little bit of color if you could provide any on why you think it was able to; it is enrolling faster than you previously anticipated. And does that give you a better sense of when we could see the data, at least at the top line level readout? Thank you.

So really really good and obviously there is an opportunity for biannual dosing as well.

Pending those results so.

Let me turn it over to Akshay to comment really on his perspectives on that Akshay.

Yes, just building on what you said John.

First and foremost I'd say the outstanding work of our clinical operations team, particularly during these very stressful and remark on COVID-19 period.

John Maragnori: Thank you, Tazeen, and we're also very excited about the progress on Helios-B. I think it really is supported by the enthusiasm in the community for Futrisiran as a once-quarterly sub-2 medicine for ATTR amyloidosis with cardiomyopathy, which is what we're evaluating in that Phase 3 study. So really, really good, and obviously, there's an opportunity for biannual dosing as well, pending those results. So let me turn it over to Akshay to comment really on his perspectives on that. Akshay

I think it's also a testament on global reach in TTS space work and HFC time, low doses with Polyneuropathy many of the investigators.

We know because they work in both diseases <unk> the ITT on cardiomyopathy.

And I think they're very excited about the possibility of our drugs in wild type detailed cardiomyopathy.

And then of course with our global reach we have gone into many sites with no access to.

Akshay K. Vaishnaw: Yeah, just building on what you said, John, first and foremost, I'd say the outstanding work of our clinical operations team, particularly during this very stressful and remarkable COVID period. I think it's also a testament to our global reach in the TTR space through our work in HAT Tyramboidosis with polyneuropathy. Many of the investigators we know because they work in both diseases, HATTR and ATTR cardiomyopathy.

Proved drugs like to families for example.

One type TTM in cardiomyopathy.

And so people are very motivated to help study.

Both on pantry amounts of interest revenue in that setting so.

With that revenue in house assets from I think there is a tremendous therapeutic rationale for our agents and those diseases and.

Wonderful collaboration with investigators and sites.

Akshay K. Vaishnaw: And I think they're very excited about the possibility of our drugs in wild-type TTR cardiomyopathy. And then, of course, you know, with our global reach, we've gone to many sites where there's no access to approved drugs like tefamidase, for example, for wild-type TTR cardiomyopathy. And so people are very motivated to help study both Patro and Boutrisran in that setting.

And so to your question about timing for results.

We're not giving any guidance at this point it would be premature to do that but we are planning an interim analysis and we are planning on discussions with regulators to locked on exactly what the design would be of that.

That interim analysis and when we have more clarity on that we can provide it to you at that time, otherwise you probably remember that the Helios B study has a 30 month endpoint. So the without the interim analysis that would go 30 months.

Akshay K. Vaishnaw: I'm delighted with our own in-house efforts, and I think there's a tremendous therapeutic rationale for our agents in those diseases and wonderful collaboration with the investigators. And Tazeen, to your question about timing for results, you know, we're not giving any guidance at this point. It would be premature to do that.

The point of Av.

Enrollment being completed.

Okay. Thanks, John.

Thank you. Our next question comes from the line of Maury Raycroft from Jefferies. Your question. Please.

John Maragnori: But we are planning an interim analysis, and we are planning discussions with regulators to lock down exactly what the design of that interim analysis would be. And when we have more clarity on that, we can provide it to you at that time. Otherwise, you probably remember that the Helios B study has a 30-month end. So, you know, without the interim analysis, it would go 30 months past the point when enrollment was completed.

Hi, good morning, everyone and congrats on the update today.

Just wondering if you could provide a breakdown on on how many on hydro patients are on concurrent use with stabilizers.

Any specifics on switches as well.

Yes, let me, let me hand, it over to the toga on debt.

And he can give you some framing around what we see in the U S. On what we see on the rest of World, which is which is very important there, but just before I hand, it over obviously the and in all cases, the use of our Petro is for the treatment on the Polyneuropathy.

Operator: Okay, thanks, John. Thank you. Our next question comes from the line of Maury Raycroft from Jefferies. Hi, good morning, everyone. I'm just wondering if you could provide a breakdown on how many people are on Patreon.

In the hereditary ATR disease.

Tolga Tanguler: Yeah, let me hand it over to Tolga on that, and he can give you some context around what we see in the U.S. and what we see in the rest of the world, which is very important there. But just before I hand it over, obviously, in all cases, the use of Onpatio is for the treatment of polyneuropathy in the hereditary ATTR disease, so that's an important reminder as well. Tolga, do you want to go ahead and comment on some of these market dynamics that we have observed?

So that's an important reminder, as well total debt you want to go ahead and comment on some of these dynamic market dynamics that we observed share.

Sure John Thank you and Hi, Morey.

Yes, so as John indicated we are obviously indicated toward polyneuropathy, which actually makes the difference between different geographies.

As you May know.

On Petro is one of the the only other stabilizes then there's no sorry.

Tolga Tanguler: Sure, John, and thank you, and hi, Maury. Yeah, so as John indicated, we are obviously indicated for polyneuropathy, which actually makes the difference between different geographies. As you may know, Onpatro is one of the only other stabilizers, sorry, silencers, and there's no stabilizer indicated for polyneuropathy in the U.S.

Sorry, Tyler and Theres no stabilizer indicators for Polyneuropathy in the U S. There, we do see fluid mixed phenotype patients for <unk>.

And those numbers remain.

About 20% right now with the concomitant use of.

Tolga Tanguler: There We do see mixed phenotype patients for HATTR, and those numbers remain about 20% right now with the concomitant use of a stabilizer for the cardiomyopathy treatment, which was not indicated. In Europe and Japan, we are indicated with another, a stabilizer, and as a silencer, I must say, we're very encouraged by the switches for those patients that are progressing potentially with the stabilizers, and there we do see the benefit of silencers, and the contribution of switches in both Japan and major European markets remains a very significant contributor to our growth. Board, does that answer your question?

Elfa stay.

Stabilizer for the cardiomyopathy, III treatments, which were not indicated.

In Europe and Japan.

We are indicated with another.

With a stabilizer and as a silo I must say.

We're very encouraged by the switches for those patients that are progressing.

Potentially with the stabilizers and there we do see day benefit of <unk>.

<unk> and <unk>.

The contribution of switches in both in Japan, and major European markets remain a very significant contributor of our growth.

John or does that answer your question yes.

Tolga Tanguler: Yeah, very, very helpful. And maybe just as a follow-up, based on the combo use trend, just checking if you're thinking about or having conversations with Fye. Akshay Desai, Huidong Wang, Konstantinos Biliouris, William Pickering, Alnylam Pharmaceuticals Inc., Akshay Desai, Weinong Guo, Alnylam Pharmaceuticals Inc., Yeah, Tolga. Yeah, I mean, first of all, having multiple players in this devastating condition is a very good thing for the patient, and even though we're not We certainly believe those protocols should include genetic testing, which then further establishes the condition in polyneuropathy and mixed phenotype patients.

Yes, yes, very very helpful and maybe just as a.

Follow up.

Based on the combo use trend that youre seeing just checking if youre thinking about or having conversations with Pfizer.

Potentially collaborate on scanning or diagnosing or maybe even leveraging the combo commercially as you think about reaching the broader cardiomyopathy opportunity.

Yes toga.

Yes, I mean look first of all.

Multiple players in this devastating condition is a very good thing for the patients.

<unk>.

Even though we're not collaborating with Pfizer I think if you look at the protocol development in major U S centers with the advent of these.

Treatment is.

Certainly is helping we certainly believe.

Those protocols should include genetic testing, which then further.

Establishes the condition for Polyneuropathy on mixed phenotype patients. So while we're not indirect communication or collaboration I can tell you. We're all aiming for those patients to get diagnosed as quickly as possible, which we know it takes anywhere between five to 10 years and can cause.

Tolga Tanguler: So while we're not in direct communication or collaboration, I can tell you we're all aiming for those patients to get diagnosed as quickly as possible, which takes anywhere between 5 to 10 years and can cause mortality and morbidity. So again, we're moving in the right direction, in the same direction, but there's no specific collaborative action between the two companies. Got it. Very helpful. Thank you. Thanks for watching Explore E! Our next question comes from the line of Alethia Young from Canterbury, Seattle.

Mortality and morbidity so.

Again, we're moving in the right direction in the same direction, but there's no specific collaborative.

Between the two companies.

Got it very helpful. Thank you very much.

Thanks, Laurie thank you.

Next question comes from the line of Alicia Yap from Cantor Fitzgerald. Your question. Please.

Operator: Your question, please. Um, and congrats on all the products. I wanted to talk in particular about, um, Diplori and the trends that you're seeing. It seems like if I'm reading this chart, I'm a little bit colorblind, I think, but, you know, you saw, like, 7 million plus in sales, ex-U.S. and 1.4 in the U.S., and I just wanted to talk a little bit about how you think about growth trends in the United I saw that you had the ATU in France. I'm assuming you booked that thing.

And congrats on all the time that I wanted to talk on particular about the glory and the trends that you're seeing it seems like if I'm reading on the chart on Olympic color on why I think but.

Like 7 million plus in sales ex U S and one four in the U S. I just wanted to talk a little bit about how you're thinking about growth trends in the United States.

And kind of the trends that youre seeing their unique and distinct obviously relative to ex U S. I saw that you had the Apu in France on that that May give us that.

Yeah, Let me I'll hand, it over to Targa and maybe Jeff on what to say a few things, but let me just let me just comment obviously with give Laurie. We are we are very excited about where this product is going on with the impact it's having on patients with acute hepatic porphyria is really is really profound and very impressive.

John Maragnori: Yeah, let me I'll hand it over to Tolga, and maybe Jeff will want to say a few things. But let me just let me just comment, obviously, on Givlari. We are very excited about where this product is going. I mean, the impact it's having on patients with acute hepatic porphyria is really, really profound and very impressive. And so we are really pleased with the help that we're providing patients with this terrible disorder.

And so we are we are really pleased with the help of will providing patients with this terrible disorder.

A big part of the growth story for give Laurie this year is going to be geographic expansion with pricing and reimbursement achieved in many European countries.

John Maragnori: You know, a big part of the growth story for Givlari this year is going to be geographic expansion with pricing and reimbursement achieved in many European countries because right now it's really big. You've been driven from Germany and our APU in France. So we do expect growth coming from geographic expansion, along with new patient finding growth as well. But Tolga, do you want to comment more broadly and Jeff as well? Absolutely. Don't tell me.

Trees, because right now, it's really largely been driven from Germany, and our Apu in France.

So we do expect growth coming from geographic expansion, along with new patient finding growth as well, but toga do you want to comment more broadly and Jeff as well.

John.

But actually I was asked about windows I actually.

Oh.

Oh, Okay, alright, sorry about that okay, alright, well thanks for the correction yeah, no look ex level had a had a fantastic first quarter.

John Maragnori: But actually, I was asked about Blue Mose. I actually misspoke. Oh. Okay, sorry. Sorry, my bad. Okay. All right. Well, thanks for the correction. Yeah, no, look, Oxflamo had a fantastic first quarter of launch.

Of launch, we're really really pleased with that and.

Obviously, it's approved in both Europe, Europe, and the U S and was first approved in Europe, which is.

Which is terrific.

And it's off to a great start Pogo do you want to comment a little bit on some of that dynamic.

John Maragnori: We're really, really pleased with that. And obviously, it's approved in both Europe and the US and was first approved in Europe, which is terrific and it's off to a great start. Tolga, do you want to comment a little bit on some of that dynamic? Yeah, I was all ready and geared up for Giblari.

Was already four geared up for give Lori I'm going to switch from your theater absolutely listen.

Zoom obviously.

And.

Is there another is treating another devastating condition.

We greatly benefited from early access patients in Europe.

Tolga Tanguler: I'm going to switch gears here, absolutely. Listen, Oxluma obviously and is another very effective treatment for another devastating condition. We greatly benefited from early access patients in Europe, and the majority of our early access program patients were in Europe. Therefore, these treating physicians electing to continue with commercial therapy, which frankly went rather smoothly, is the reason why we see a good uptake in Europe. The U.S. had fewer EAP patients and therefore less to convert, but given over 30 start forms in the U.S., we're very confident that the U.S. will be a key driver of Oxluma growth.

And majority of our early access program patients were in Europe. Therefore.

These treating physicians electing to continue with the commercial therapy, and frankly weighted rather smoothly is the reason why we see a good uptick in Europe, USA fewer EAP patients and therefore less to convert but given over 30 start forms in the U S.

We're very confident that the U S will be a key driver of <unk> growth.

Im also really encourage the fact that we're on.

Attracting.

Patients that are being treated are both pediatric and adults.

And broad EGF category with a broad VEGF category. So that's also really encouraging and last but not least.

Tolga Tanguler: I'm also really encouraged by the fact that we're... Attracting patients that are being treated are both pediatric and adults and in the broad EGRF category. So that's also really encouraging. And last but not least, we've already achieved two-thirds access in the U.S. universe with payers, and our value-based agreements driving clearly easy, smooth access. So again, it's too soon for us to be concerned about the U.S., and, in fact, I'm really encouraged with what we're seeing with the patient start forms, which are over 30 right now, already this last quarter.

We've been able to already.

Two thirds.

Access so on.

On the U S universe.

With Payors and our value based agreements driving.

Clearly.

It's from the taxes, so again, it's too soon for us to.

To be concerned about USA on in fact on I'm really encouraged with what we're seeing with the patient start forms which is over 30 right now already this last quarter.

Tolga Tanguler: Awesome, thank you. Thanks, Alethea. Thank you. Our next question comes from the line. It's Salveen Richter from Goldman Sachs. Your question...

Awesome. Thank you.

Thanks Alicia.

Thank you. Our next question comes from the line of <unk> Richter from Goldman Sachs. Your question. Please.

Operator: Hi, thank you so much for taking our question. This is Sonia on behalf of Salveen.

Great. Thank you so much for taking our question. This is sonya on for Celgene can you help frame expectations into the Apollo B trial in particular wondering what would be considered clinically meaningful and how we should think about potential read through to your Thanksgiving day trial.

Akshay K. Vaishnaw: Could you help frame expectations for the Apollo B trial? In particular, we're wondering what would be considered clinically meaningful and how we should think about potential read-through to the Helios B trial. Thank you.

Yeah.

Akshay K. Vaishnaw: Yeah, thanks, Sonia. Just as a reminder, I'll hand it over to Akshay, but just as a reminder, Apollo B is our randomized double-blind placebo-controlled study of Petitseran in wild-type and hereditary ATTR patients with cardiomyopathy. So this is the opportunity to potentially expand our Petitseran opportunity into that broader segment. And so, Akshay, do you want to comment a little bit on how we view success in that study? Yeah, the primary endpoint in Apollo B is the six minute walk distance, which is a clinically validated measure in the disease and is, you know, intuitively clinically meaningful because patients with cardiomyopathies, any form of heart failure, struggle with exercise and exercise tolerance.

Yes, Thanks, Sonya just as a reminder, I'll hand, it over to Akshay, but just as a reminder, Apollo b is our randomized double blind placebo controlled study of <unk> in wild type and hereditary ATR pace.

Patients with cardiomyopathy. So this is the opportunity to potentially expand.

R T surround opportunity.

To that broader segment.

And so akshay do you want to comment a little bit on how we view.

Success in that study.

Yes.

The primary endpoint in Apollo B is six minute walk distance, which is a clinically validated measure in.

In the disease on these.

Intuitively clinically meaningful patients with cardiomyopathy is any form of heart failure.

With exercise in exercise tolerance.

Akshay K. Vaishnaw: So you know, being able to walk significantly better relative to the control arm is going to be very important to demonstrate that. And so the primary endpoint, in and of itself, will be very clinically meaningful. Beyond that, we will get a lot of additional data from that study. Of course, we'll be looking at hospitalization rates and mortality, but the study is not powered for that.

Are you able to significantly better relative to the control arm is going to be very important to demonstrate that.

And so that the.

The primary end point in and of itself will be very clinically meaningful.

Beyond that we will get a lot of additional data from that study of course, we'll be looking at hospitalization rates mortality.

Study is not powered for that but it will of course be important to see what trends. We're seeing there and in addition to that a host of Biomarkers and other endpoints such as BNP.

Akshay K. Vaishnaw: But it will, of course, be important to see what trends we're seeing there. And, you know, in addition to that, a host of biomarkers and other endpoints, such as BNP, such as echocardiogram changes, and technetium and the like. Now, the reason why we feel excited about that whole package and the likelihood of success is that if you go back to the original Apollo study with Patrice Rannan and HATTR with polyneuropathy, in the cardiac patients within that study, or patients that had significant cardiac disease, I should say, we saw, you know, very encouraging findings.

Such as echocardiogram changes.

And the technician in the light now the reason why we feel excited about that whole package on the likelihood of success is that if you go back to the original Apollo study with <unk> and <unk> with Polyneuropathy.

In the cardiac patients within that study on patients that have significant cardiac disease I should say.

So very encouraging findings.

So.

To walk test stabilize.

Relative to placebo rate deteriorated from.

<unk>, we sold the BNP was favorable slightly down relative to placebo non study bmp's an important cardiac biomarker echocardiogram showed reduction in the left ventricular wall thickness.

Akshay K. Vaishnaw: We saw, you know, that the 10 meter walk test stabilized, relative to placebo, very deteriorated. Dramatically, we saw that BNP was stable or slightly down relative to placebo in that study. BNP is an important cardiac biomarker. The echocardiogram showed a reduction in left ventricular wall thickness.

And then subsequent to that other groups have demonstrated good academic groups such as the <unk> group in London on publish this.

I see diminution on technetium scan evidence for regression of amyloid in the hospital without my cardiac MRI based on stabilization of six minute walk distance and now on Patrick treated.

Akshay K. Vaishnaw: And then subsequent to that, other groups have demonstrated, academic groups, such as the Gilmore Group in London, and they published this, that they saw diminution on technetium scan with evidence for regression of amyloid in the heart. They also saw that by cardiac MRI. And they saw stabilization of six-minute walk distance in their on-patro treated HATTR cardiomyopathy patients.

<unk> funded biopsy patients.

These are all very encouraging.

Findings to us that support.

On the likelihood of success with the Apollo B.

And then finally.

With mortality and hospitalization itself post hoc analyses from the original Apollo study demonstrate.

Akshay K. Vaishnaw: These are all very encouraging findings for us that support the likelihood of success with Apollo-V. And then finally, you know. With mortality and hospitalization itself, post-hoc analyses from the original Apollo study did demonstrate significant differences. Now, they're post-hoc, and we should be very mindful of that. But again, an encouraging finding. So, in totality, I think the therapeutic rationale is very strong, both for Apollo B and also for Voutrisran in Helios B, where, of course, the study's larger in its power to detect mortality and hospitalization changes, and that's the primary readout.

Significant difference now that post hall, and we should be very mindful.

But again, an encouraging findings in totality.

I think the therapeutic rationale on very strong both for Apollo B and also for <unk> and Helios B. We have of course. The study is larger and is powered to detect.

Mortality and hospitalization changes and Thats the primary readout.

So I think if Apollo is positive which.

You the reasons why we're excited we've been very encouraged by.

Patients for Helios B as a result, and should speed the interim analysis and so forth of Helios B.

Yes, I'll just add.

To that that obviously wolf, we're expecting data from Apollo B middle of 'twenty. Two we do we are on track to complete enrollment in early 'twenty. One so just in the next period and then we expect to have data from Apollo B in mid 'twenty. Two so that is going to be obviously an important data.

Akshay K. Vaishnaw: And so, you know, I think if Apollo B is positive, which I've given you the reasons why we're excited, we're then very encouraged by the implications for Helios B as a result, and should speed the interim analysis and so forth of Helios. Yeah, and I'll just add to that that obviously we'll be expecting data from Apollo B in the middle of 22. We do. We're on track to complete enrollment in early 21.

Out sometime mid next year.

John Maragnori: So just in the next, you know, period, and then we expect to have data from Apollo B in mid-22. So that is going to be, obviously, an important data readout sometime in mid-23. Thank you so much.

Thank you.

Thank you. Our next question comes from the line of David <unk> from Morgan Stanley. Your question. Please.

You very much for taking my question.

If there is when there is an interim analysis for Apollo B.

Operator: Our next question comes from the line of David Lebowitz from Morgan Stanley. Your question, please. Thank you very much. If there is, I mean when there is an interim analysis for Apollo, what type of analysis will actually be, and is there a possibility that that allows for an earlier, I guess, regulatory submission, or is it really, you just should assume 30.

What type of analysis will actually be conducted and is there a possibility that that interim analysis can produce the results that that allows for an earlier.

I guess.

<unk> submission or is it really just should assume 30 months as the only route to a submission.

David N. Lebowitz: Yeah, David, thanks for that question. I'll hand it over to Akshay, and maybe Yvonne wants to comment as well. But I mean, the purpose of doing the interim analysis would be to potentially bring vitrecerin to the market ahead of the final result, which would read out at 30 months. And so that certainly is the intent of the interim analysis to shorten that time. So that is why we're doing it. Akshay, Yvonne, any more to add to that?

Yes, David Thanks for that question I'll hand, it over to Akshay, maybe a volume lots of comments as well, but I mean, the purpose for doing the interim analysis would be to potentially bring vitry saran to the market ahead of the final results, which would read out it at 30 months and so that.

That certainly is the intent of the interim analysis to shorten that that time.

So that is why we're doing debt.

Akshay.

On any more to add to that.

John Maragnori: No, not really. I think you covered it, John. I think if Apollo B is positive, then that would certainly be very exciting for anticipating the results from Helios B.

No not really I think you've covered it John I think if Apollo is positive then that would certainly be very exciting for anticipating the results from Helios B that would accelerate the interim analysis gives us great insight into the kind of relevant interim analysis to do and the motivation would be to Kevin Richardson on to patients faster.

Akshay K. Vaishnaw: That would accelerate the interim analysis, giving great insight into the kind of relevant interim analysis to do. And the motivation would be to get Rutrisone to patients faster with that IA. Yeah, Yvonne.

With that high.

Yes on.

Yes.

Yvonne L. Greenstreet: No, that's great. I think that's covered it. I mean, the only thing I would say, David, is just bear in mind that we have not yet resolved the design of the interim analysis with the regulatory authorities. We have, you know, in the original protocol specified that there would be an interim analysis, or there could be an interim analysis, but the final design of that would need to be aligned with regulators, which is an important step. Does that include the timing of the announcement? Absolutely, the design and the timing and what the endpoint would exactly be would be determined in alignment with regulators.

No that's great I think Ken I think that covered it.

I mean, the only thing I would say David is just bear in mind that we have not yet resolved the design of the interim analysis with the regulatory authorities.

<unk>.

We have in the original protocol.

Pesified that there would be an interim analysis from that could be an interim analysis of the final design of that would need to be aligned on with regulators, which is an important step.

Does that include the timing of the analysis.

Absolutely the design and the timing and what the endpoint would exactly be all of those elements would be.

Pained in alignment with regulators absolutely.

Yvonne L. Greenstreet: Absolutely. Excellent. Thank you for taking my question. Thanks, David.

Excellent. Thank you for taking my question.

Thanks, David.

Operator: Thank you. Our next question comes from the line of Gena Wang from Barclays. Your question, please. Thank you for taking my questions. I have one regarding value-based payment. Just wondering, now that you have three drugs; all have value-based reimbursement. So I'm just wondering, what is the real world implementation, and based on current experience, roughly what percentage of patients do you need to actually adjust the payment or value due to lack of access?

Thank you. Our next question comes from the line of Gena Wang from Barclays. Your question. Please.

Thank you for taking my questions I have one regarding the value based.

Our payments just wondering now you have three drugs.

Is it value based debt investments.

So just wondering what is the real wood implementation and based on current experience roughly what percentage of patients you need to actually a cash pay.

<unk>.

On value due to lack of efficacy.

Operator: Yeah, well, Gena, let me just start on that really important question and then maybe turn it over to Jeff to sort of address, you know, how that's been handled in the real world. But let me start by saying that we're really proud of our proactive approach with value-based agreements with payers. You know, certainly in the US commercial market, but we've also done some elements of that in Europe as well.

Yeah, well Gino let me just start.

On that really important question and then maybe turn it over to Jeff to sort of address.

Uh huh.

How how that's been handled on the real world, but let me start by saying that we're really proud of our proactive approach with value based on agreements with payers.

Certainly in the U S commercial market. We've also done some element of that in Europe as well.

John Maragnori: And I think the results speak for themselves. I mean, because the benefit of these shared arrangements with the payer community has been one in which they view Alnylam as being, you know, proactive and open-minded about value. It has changed the dialogue away from price into a discussion or a recognition of value.

And I think the results speak for themselves because the benefit of these.

Shared arrangements with the payer community has been one in which they view <unk> as being.

On proactive.

On an open minded about value.

It has changed the dialogue away from price into a discussion or a recognition of value.

John Maragnori: We've been very innovative in that, and, of course, the result has been essentially no payer headwinds in the US market and very broad access that we've been able to achieve for patients. So it is something which we're especially proud of. And we, we, you know, hopefully, you know, can demonstrate the innovation of this from a commercial perspective, similar to the innovation we've always had as an R&D organization. So with that, Jeff, do you want to comment on some of the real world color on those DBAs?

Been very innovative on that and of course. The result has been essentially no payer headwinds in the U S market and very broad access that we've been able to achieve for patients. So it is something which.

We're especially proud of and we hopefully.

Can can demonstrate the innovation on.

On this from a commercial perspective similar to the innovation. We've always had is on the R&D organization. So with that Jeff do you want to comment on some of the real world color, Yes on both CBS.

John Maragnori: Yeah, happy to. And I'll, Gene, I'll speak to you on Patro. Obviously, that's the product that's been on the market the longest, so we have the most experience there. And I will say that the deductions that we're paying associated with the DBAs that have been signed with commercial payers are extremely modest at this point.

Yeah happy to on all gene I'll speak to on Patrick obviously, thats the product thats been on the market. The longest that we have the most experience there and I will say that.

The the deductions that were pain associated with the BBA is that had been signed the commercial payers are extremely modest at this point and that's because the product is working well so we're not having to make payments from.

Jeff Poulton: And that's because the product's working well. So, you know, we're not having to make payments for patients that are discontinuing due to an unsatisfactory experience with the product. So extremely modest, again, I would say in terms of the impact on the deductions that we're paying.

For patients that are discontinuing due to unsatisfactory experience with the product. So extremely modest again I would say in terms of of the impact on the deductions that were paying.

Jeff Poulton: And I think the one, the one, you know, index of that that we report out from time to time, Gena, as you know, is the adherence rate being so high with the product, which really speaks to how well the product is performing in the patient community. I think it's fair to say generally consistent with our clinical experience with, you know, Patricia Ran and the Apollo, and if I can add anything to add, Yeah, Yeah, Yeah, I mean, it's you and Jeff I mentioned.

And I think the one the one index of that that you debt. We report out from time to time gene as you know is the adherence rate being so high with the product, which really speaks to the to how well the product is performing and the patient community I think it's fair to say generally consistent with our clinical experience with <unk>.

Surrounded the Apollo study.

And if I can add anything to add yes, yes, yes.

As Jeff mentioned.

Tolga Tanguler: The outcomes of our products and their efficacy are really a testament that these VBAs are working in favor of the patient and payers as well as us. So it's really a win-win-win situation. And one should also keep in mind that as we design these VBAs, the ASP risk is really minimized, and we're certainly not seeing that at this moment. And if it were to occur, it certainly is minimized in the way we formulate our VBAs.

On the outcomes of our product and its efficacy is really a testament that these <unk> are working in favor of the patient as payers as well as us. So it is really a win win win situation.

And one should also.

Keeping in mind debt as we designed these ppas.

ASP is really minimized and we're certainly not seeing that at this moment and if it were to occur. It certainly is minimizing the way we formulate our VBA. So we certainly do not anticipate any long term negative impact on our revenues.

Tolga Tanguler: So we certainly do not anticipate any long-term negative impact on our revenue. Thank you very much. Does that answer your question, Gina? Yes, very helpful. Thank you. Thank you. Our next question comes from Tidjane Chattopadhyay from Guggenheim Securities. Your question, please. Are you on mute, Deepchit?

Thank you very much does that answer your question Gena, yes.

Yes very helpful. Thank you.

Okay.

Thank you. Our next question comes from the line of chatter Patty from Guggenheim Securities. Your question. Please.

Are you on mute.

Operator: Sorry, yes, I was on mute. I thought so. Sorry. This is Aaron on for DevJet. So congrats on the progress. The Ampetra launch looks like it's going very well. Can you tell us what proportion of patients being treated in the U.S. also have concomitant cardiomyopathy versus polyneuropathy alone? And maybe elaborate on the ramp in diagnosed patients in ATTR. Uh, sure. I mean, we answered the first question earlier.

Sorry, Yes, I was on mute.

I thought so.

This is eric on for that debt.

So congrats on the progress.

On Petro launch it looks like its going very well.

Can you tell us what proportion of patients being treated in the U S. Also have concomitant cardiomyopathy vs Polyneuropathy alone and maybe elaborate on the ramp and diagnose patients from <unk>.

Thanks.

Sure I mean, we exited the first question earlier, you made out of her day answer, but we can do it again no problem toga do you want to handle both of those questions yes.

Tolga Tanguler: You may not have heard the answer, but we can do it again. No problem. Uh, Tolga, do you want to handle both of those questions?

Tolga Tanguler: Yeah, absolutely. The first question, obviously, is, first of all, let's be clear, our objective is to make sure that we get to treat as many patients with polyneuropathy as possible. In some cases, physicians identify these patients with mixed phenotypes, and in those instances, we obviously help support patients to make sure they get access to our medicine if they are on another treatment with a concomitant therapy. We're pleased with what we're seeing, and obviously, in Europe and Japan, we don't have this phenomenon, and we tend to build our business with switches. And obviously, net naive patients, which again, we see great progress. Can you repeat the second question?

Yes, absolutely.

The first question. Obviously is first of all let's be clear our objective is to make sure that we get to treat as many patients with polyneuropathy condition as possible in some cases physicians.

<unk> these patients with mixed phenotype and in those instances, we obviously help support patients to make sure they get access to our medicine, if they were on on.

Treatment with a concomitant therapy.

We're pleased with what we're seeing.

And obviously in Europe, and Japan, we don't have this.

Phenomena.

And we tend to build on our business with the switches.

And obviously net new <unk> patients.

Patients, which again, we see a great progress.

Can you repeat the second question.

Tolga Tanguler: Just about the ramp in diagnosed patients in ATTR, how that's increasing. Yeah, again, I think, you know, a rising tide lifts all boats. So we do see a great expansion of protocol development in centers of excellence. We see a good referral network with community centers. As you may know, the PYPs, scintigraphy scans, are really helping. And these scans are relatively cheap, inexpensive, and very accessible.

Just about the ramp and diagnose patients and ADT or how that's inc.

Yeah, again, I think rising tide.

It's all boats, so we do see.

<unk> expansion of protocol development and centers of excellence, we see a good referral network with community centers.

As you May know the eyepiece scintigraphy scans are really helping.

And these scans are relatively.

Cheap inexpensive and very accessible so we see more and more sensors are.

Tolga Tanguler: So we see more and more centers diagnosing these patients, and then we do see a good uptake of our genetic testing program, Alnylam Act, as well. In fact, the last two, three months of the first quarter, we've seen our highest number of genetic testing. So right now, up to now, we've tested about 36,000 patients that are suspected of HATTR. And we received a relatively high yield out of these, about 6%. Eventually, over 2,000 patients were diagnosed with the genetic mutation.

Diagnosing these patients and then we do see.

A good uptake of our <unk>.

I think testing program on <unk> as well and in fact the last.

Two to three months of the first quarter, we've seen our highest number of genetic testing. So right now up to now we've tested about 36.

The patients that are suspected of.

Hey, TCR and we received a relatively high yield out of these about 6% over 2000 patients were diagnosed.

John.

On the genetic mutation.

Tolga Tanguler: So that's going really well, and we're very encouraged by both the increase in PYP scans, as well as systems taking advantage of genetic testing, along with the Alnylam Act. Did that answer your question?

So that's going really well and we're very encouraged by both the increase of <unk> <unk> as well as.

As well as system, taking advantage of genetic testing along with algorithm acts.

Does that answer your question.

Operator: Yeah, that's great. Thank you. Thanks Aaron.

Yeah, that's great. Thank you.

Thanks, Eric.

Operator: Thank you. Our next question comes from the line of Paul Matteis from Stifel. Your question, please. Great, thanks so much.

Thank you. Our next question comes from the line of polymer teeth from Stifel. Your question. Please.

Great. Thanks, so much I wanted to ask one more question about Apollo B and that's really.

Paul Matteis: I wanted to ask one more question about Apollo B, and that's really, you know, how do you think we could end up comparing these data to the typhaminus data? If we go back to Apollo A, I remember, John, you kind of talked about ahead of those data, a goal to stabilize the disease or even reverse it, and that would be unequivocally better than typhaminus. Do you think the six-minute walk test data from Apollo B is going to be directly comparable to what we have from typhaminus in this population, and what would be the caveats in the comparison?

How do you think we could end up comparing these data to the to standard of state. If we go back to Apollo way are remember John you're kind of talking about ahead of those data on our goal to stabilize disease or even reverse it and that would be unequivocally better than to standard US do you think the six minute walk test data from Apollo B youre going to be directly comparable to what we happen to be.

They are on this in this population six minute walk and what would be the caveat semi comparison. Thanks.

Paul Matteis: Well, Paul, I'll just start, and then I'm sure Akshay will want to chime in. But, you know, in general, of course, comparisons between studies are something that you have to always take with a grain of salt. There are formal ways of doing it, which may be done by people, but ultimately, it is, you know, fraught with caveats, to say the least.

Well, Paul I'll, just start and then I'm sure Akshay.

Want to chime in but.

In general of course comparisons between studies.

That you have to always take with a grain of salt there are formal ways of doing it.

Which may be done by people, but ultimately it is it is fraught with caveat.

John Maragnori: Akshay, do you want to comment a little bit on that further? Yeah, I mean, let me just reiterate what you just said because I think it's so important what you just said that, you know, Pfizer colleagues, their investigators did wonderful work. And, you know, they speak to the value of their results and the implication that direct comparisons are not, really. Now, having said all of that, at a very high level, I think what all of us would like to see in this space, patients, investigators, and all of us investigating drugs is that we'd like to halt the course of this terrible disease, cardiomyopathy, in these patients.

They lease Akshay do you want to comment a little bit on that further.

Yes, I mean, let.

Let me just reiterate because I think it's so important to what you just said.

Pfizer colleagues.

Investigators did wonderful work.

They should speak to the value of their results and the implications.

Direct comparisons on not.

Not pilot greatly now having said all of that add on.

On a very high level I think what all of us would like to see in this space patients investigators on all of us investigating drugs as we'd like to hold the course of this terrible disease cardiomyopathy in these patients on looking at the published find the data with our families.

John Maragnori: And looking at the published Pfizer data with families, I think it's fair to say that that drug obviously has a significant impact on mortality and hospitalization. It's a six-minute walk distance, but the overall feeling is that it's just slowing down the rate of deterioration. And what if we could just sort of halt the disease in its tracks, stabilize these parameters like a six-minute walk distance, which is what we very much look forward to doing and showing with Apollo B. The work of Gilmore et al., which I cited earlier, in a study of 20-something HAT-Tyramyloidosis patients, where they looked at the cardiomyopathy aspect, showed stabilization compared to historic

It's fair to say the drug obviously has significant.

Impact on mortality and hospitalization and six minute walk distance, but the overall feeling is that it.

Slowing down the rate of deterioration and what if we could just sort of help the disease and extract stabilize these parameters like six minute walk distance, which is what we very much look forward to doing.

And sharing with Apollo B.

The work of Gilmore tile, which I cited earlier.

The company.

Timely doses patients where they looked at the cardiomyopathy aspects showed stabilization compared to historic controls now that's sustained.

Akshay K. Vaishnaw: Now, you know, that's a single-arm study compared to historic control, but that's encouraging, you know. And everything keeps pointing to the idea that we could stabilize. Recently, with Butresran in Helios A, we showed stabilization of BMP versus deterioration of the placebo. We'd seen that previously with Patisaran in the original Apollo study. So I think direct comparisons are very fraught for all sorts of reasons. But I think we'll have a similar population on Apollo B. So it'd be a valid population to think about the value of the drug.

The last study comparing to is on control, but thats encouraging.

And everything keeps pointing to the idea that we could stabilize recently with butros around in Hayley I'll say, we showed stabilization of BNP vs deterioration that placebo, we'd seen that previously been producer on the original Apollo study so.

Think direct comparisons on very fraud for some reasons I think we will have a similar population in Apollo b. So it would be a valid population to think about the value of the drug.

Akshay K. Vaishnaw: And, you know, our goal is to show stabilization of the primary endpoint sex network. Does that answer your question, Paul? Totally. Thank you. Thanks, Paul. Thank you. Our next question comes from the line of Ritu Baral from Gowan. Your question, please.

Our goal is to show stabilization on the primary endpoint six minute walk distance.

Does that answer your question Paul.

Total it thank you.

Thanks, Paul.

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

Operator: Hi guys, thanks for taking the questions. A quick one on the timing of the potential Helios B interim. Am I sort of reading between the lines, right?

Hi, guys. Thanks for taking the questions.

Quick one on the timing of the potential feeling SP interim.

And my my sort of reading between the lines right guidance you have to meet with FDA before you decide on the interim to get there Brian.

Ritu Baral: Guys, you have to meet with FDA before you decide on the interim to get their buy-in, and you want the top line Apollo B data ahead of that discussion. Would that necessarily put that FDA discussion in the second half of 2022?

And that you want the topline Apollo B data ahead of that discussion would that necessarily put that FDA discussion in the second half of 2022.

John Maragnori: Well, okay, so first of all, it's the FDA and also other regulators that have important input on a matter like this, like the EMA. So it's not just the FDA.

Well.

Okay. So first of all it's the FDA and also other regulators.

On an important input here on a matter like this like the EMA.

So it's not just the FDA, but we saw.

John Maragnori: But we certainly think the timing of it will probably naturally occur; the timing of that interim analysis will probably naturally occur after we have visibility on Apollo B results. Right? But the design of the interim, our plan would be to try to, You know, focus on what that is sooner that we have the readout from Apollo B. Akshay, anything to add, Akshay, from your perspective on that? No, I just want to, with our announcement today of Helios B enrollment completion by the end of the year, looking very likely now, you know, we didn't have that line of sight, but we have that now, so the timing looks very, very conducive that we'll have the Apollo B data by the middle of next year, and of course, by that time, the Helios B study is fully enrolled, the patients have been on the drug Okay.

Certainly the timing of it will probably naturally occur the timing of that interim analysis will probably naturally occur. After we have visibility on Apollo b results right.

But the.

The design of the interim our plan would be to try to.

Focus on what that is sooner that we have the readout from Apollo B.

Akshay anything.

Anything to add Akshay from your perspective on that.

No I just wanted to with our announcement today on the Helios B enrollment completion by the end of the year Luca.

Looking very likely now.

We didn't have that line of sight, we have that announce the timing looks very.

On.

Conducive to have the Apollo B data.

Middle of next year.

By that time, the Helios B studies fully enrolled the patients have been on drug or placebo for a sufficient length of time and so it naturally leads to a very well structured and planned after that for Helios b.

Akshay K. Vaishnaw: Okay, and that would mean that when Helios V enrolls at a completion around the end of 2022, most of those patients will have been on for 12 months or more. Do you think that that's adequate powering for an event-based trial based on your internal modeling of what TTR knockdown?

Okay and that would.

Yes.

Helios B enrolls on completion around end of 2022.

First of those patients will have been on fire.

12 months or more do you think that that's adequate powering from event based trial based on your internal modeling a flat.

TCR knockdown.

Ritu Baral: Well, let's, let's, I think, go ahead, Akshay. Yeah, no, I think Ritu said Helios would be enrollment completion end of 2022. We're just saying today that it should be by the end of 2021, based on our line of sight now. So, yes, the end of 22 would be about 12 months. Yes, you're right. As for the exact details of that, I think we're going to work through that, and we'll share it with you.

Okay.

Well.

I think go ahead actually yes.

Helios B enrollment of completion end of 2022.

We just saw.

Saying today, but it should be by the end of 2021 based on our line of sight now.

So yeah.

Yes end of 'twenty, two would be about 12 months, yes, youre right.

The exact details on that.

I think we're going to work through that a little share in due course.

Okay fair enough I'll keep on telling you about that.

Very quick question, just as far as we think about that on Patrick at the end of the year. What is your line of sight on potential roll offs on.

Akshay K. Vaishnaw: Okay, fair enough. I'll keep bugging you about that. But last very quick question, just as far as we think about it, on the top charts at the end of the year, what is your line of sight on potential roll-offs of home administration allowances during the COVID pandemic that may be ending over the course of

On the administration.

Allowances during the COVID-19 pandemic that may be angle, Okay of course, the fifth year on what impact could that have on tap trials do you think.

Yes, Tony do you want to answer that yes.

Look at the end of the day.

A lot of.

Payers and specialty pharmacies are offering home infusion services, our Payor our patient services program also does a phenomenal job with.

Ritu Baral: over the course of this year, and what impact could that have on Onpetro? Yeah, Tolga, do you want to answer that? Yeah, Look, at the end of the day, many... Payers and specialty pharmacies are offering home infusion services. Our patient services program also does a phenomenal job with and ....................

Site of care and accommodating different.

The routes of the way that those patients will be administered we've seen a good steady uptake even prior to the depend.

It depends on it gives what is during the pandemic so.

The allowance as well their goods, whereas the main driver I believe for our ability to be able to accommodate those patients that are in need in Europe, we've seen an uptake from 9%, 10% all the way up to 30% of home care.

As well as in the U S. We doubled.

Tolga Tanguler: Got it. And as far as you know, there's no particular time when Medicaid home infusion is ending sometime in 2020.

The amount of patients, but it still represents about one fifth of our patients that are getting home care. So we're not.

Broadly expose the type of services, we provide will continue so we really don't see that as a distractor off the performance that we have.

Ritu Baral: that I'm not aware of. I wouldn't be able to speak to that. We've not heard anything for two one. We've not heard anything yet.

Yeah.

Got it and then as far as you know, there's no particular time debt.

Medical home infusion.

On the sometime in 2021 temporary allowances debt on that I'm, not aware I wouldn't be able to speak to that.

We've not heard anything Chris day, one we've not heard anything on that Ritu.

Tolga Tanguler: Got it. Very helpful. Thank you. Thank you.

Got it very helpful. Thank you.

Operator: Thank you. And our final question for today comes from the line, Eric David Jacob from UPS. Your question, please. Hi everyone, this is Jon on behalf of Naveen.

Thank you.

Thank you and on a final question for today comes from the line of airplanes that Jacob from UBS. Your question. Please.

Hi, everyone. This is John on for Devine, We wanted to go back to Helios, a and win that.

Eric Green: We wanted to go back to Helios A, and we noticed that the severe AE rates were a lot lower for Vutri versus for Patro, and we were just curious if there was any color you could provide on that. Yeah, Akshay, do you want to answer that question? This is looking at the and and and the comparison was to the small on pacho arm in the study, I believe, is what you're referring to. Akshay, do you want to comment on that?

Pat.

Severe AE rates were a lot lower for retreat vs.

First is on patch grow and we were just curious if there is any color you can provide on that.

Yeah Akshay do you want to answer that question. This is looking at the.

And the comparison was to the smaller patch O arm in the study I believe is what you're referring to Akshay do you want to comment on that.

Akshay K. Vaishnaw: Yeah, I mean, I think we're very happy about the encoding safety data for Boutrous-Rand in Helios A, as we are with, you know, GALNAC sub-q conjugates overall. As to, you know, direct comparison there, I think that the Boutrous-Rand arm is very small. And really, it's not an apple to apple comparison when the data are so skewed that way in terms of sample size. So I don't think I'd overly conclude anything, as we were discussing earlier, on PATRO.

Yes, I mean I.

We're very happy about the encouraging safety data with Vinci surrounding the Helios a.

As we are with <unk> overall as to direct comparison I think the police right on is very small and.

Really it's not on an apples to apples comparison when the.

NATO skewed that way in terms of sample size.

I think on overly conclude anything as we were discussing earlier on Patrick's day.

Akshay K. Vaishnaw: The overall safety profile relative to placebo, the most robust test for that, of course, was the original Apollo study; the data looked very encouraging and favorable for PATRE in terms of safety, and in the real world, as evidenced by the retention of the drug and you know, the comfort investigators feel with it, patients feel with it; we're very encouraged that the real world safety and experience are as good as it was in the original Apollo study. So that's a real testament to how it's serving John. And, you know, and, and, and, John. The lower SAE rate in the vitreceram arm relative to external placebo, we believe is related to the fact that patients on placebo are probably experiencing disease progression and AEs, that, that, that underscores that.

<unk> safety profile relative to placebo.

The most robust test on from that of course was the reason.

On the Apollo study.

The data looks very encouraging favorable on Patriot in terms of safety and in the real world as evidenced by the retention on drug and.

The comfort investigators patients feel with it we're very encouraged with real world safety and experience is as good as it was.

The original Apollo study, so thats, a real testament to serving patients.

And.

And.

On the lower <unk>.

E rate on that which we share <unk> relative to external placebo. We believe is related to the fact that debt patients on placebo are probably experiencing disease progression.

He's debt that underscores that.

Akshay K. Vaishnaw: So, you know, that's certainly, you know, our belief based on that data. The other, I mean, just from a mechanical viewpoint, if you see a patient every three weeks for an intravenous infusion, you're more likely to hear about a headache or, you know, whatever other intercurrent events are going on in their lives, as it does for all of us. And it may or may not be an adverse event; it may or may not, you know, be irrelevant. So, you know, with the vitreous handling once quarterly, you're just not going to be asking the patient the same questions with the same frequency. But in either case, if something was of significance, it would emerge.

So that's certainly.

Our belief based on those data.

Yes, I mean, just from a mechanical viewpoint, if you see a patient every three weeks for an intravenous infusion you'll more likely to hear about our had equal what it from there.

In the current events going on in their lives as it does for all of US I mean, it may or may not be an adverse event it may or may not.

Be of relevance.

The interest on being ones quarterly.

You're just not going to be asking the patient the same questions with the same frequency, but in either case, if something was on significantly it would emerge.

Akshay K. Vaishnaw: And as you said, the overall safety profile for vitreous hand does look very encouraging. That's very helpful. Thank you. Thank you. Thank you, John. Well, well, listen, thank you, everyone, for joining us on the call today. Obviously, we're really pleased with our first quarter results in 2021. It was a strong quarter for commercial execution. And we also had excellent progress across our pipeline programs, and we're really pleased this quarter to have announced our P to the fifth by 25 strategy, which we're obviously very, very excited about.

And as you said the overall.

Safety profile for Butros on Doug look very encouraging.

Yes.

That's very helpful. Thank you.

Thank you. Thank you John.

Well listen thank you everyone for joining us on the call today, obviously, we're really pleased with our first quarter results from 2021. It was a strong quarter for commercial execution and we also had excellent progress across our pipeline programs.

And we're really pleased this quarter to have announced our PBT by 25 strategy, which were obviously very very excited about so we look forward to talking to you in subsequent calls and wish everyone.

John Maragnori: So we look forward to talking to you on subsequent calls and wish everyone a wonderful rest of the day and hope everybody stays safe as well. Bye bye now. Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.

On a wonderful rest of day.

And hope everybody stays safe as well bye bye now.

Thank you, ladies and gentlemen to participation in today's conference. This does conclude the program you may now disconnect good day.

Operator: BF-WATCH TV 2021

Okay.

Okay.

Moving forward.

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