Alnylam Pharmaceuticals - Earnings Call - Q1 2021

Transcript

Operator (participant)

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. 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's program, Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications. Please go ahead.

Christine Lindenboom (SVP of Investor Relations and Corporate Communications)

Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are John Maraganore, 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/events. During today's call, as outlined in slide two, John will provide some introductory remarks in general context. Tolga will provide an update on our global commercial progress. Akshay will review recent clinical and preclinical updates. Jeff will review our financials. And Yvonne will provide a brief summary of upcoming milestones before opening the call to your questions.

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 Safe Harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent annual report on file with the SEC. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'd like to turn the call over to John. John?

John Maraganore (CEO)

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 ONPATTRO with our first triple-digit revenue quarter and an impressive initial uptake for OXLUMO in its first full quarter on the market. On the pipeline side, the full positive results from the HELIOS-A phase III study of vutrisiran were presented last week, and we announced that we have filed an NDA for vutrisiran with the FDA, bringing us a step closer to the potential approval of this important asset in our TTR franchise.

We're also excited to have announced today that we expect the HELIOS-B study of vutrisiran 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 P5x25 by 2025, 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 performance with over 40% revenue CAGR through year-end 2025, and sustainable non-GAAP profitability achieved within the period. 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.

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

Tolga Tanguler (Chief Commercial Officer)

Thanks, John, and good morning, everyone. Let's get started with a review of our commercial performance from the first quarter. In Q1, despite COVID headwinds, particularly in the U.S., we were able to achieve strong results. For ONPATTRO, 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 seeing patients with hATTR polyneuropathy. Adherence to treatment remains stable at pre-COVID levels, and we continue to observe a trend of HCP choice in concomitant use of ONPATTRO to treat polyneuropathy, along with the use of a TTR stabilizer for cardiomyopathy in mixed phenotype hATTR amyloidosis patients.

Much of our continuous growth in ONPATTRO 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 ONPATTRO for over 98% of covered lives. With regard to the rest of the world, 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 for ONPATTRO, driven mostly by new patient findings. Moving to GIVLAARI, we achieved $25 million in global net product revenues in the first quarter, and as of March 31st, we attained 225 patients worldwide on commercial therapy.

Relative to where we ended 2020 and after significant strength in initial launch quarters, Q1 of this year was softer than anticipated in terms of GIVLAARI new patient adds, 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%. So we continue to be optimistic about steady and continuous growth for GIVLAARI 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 GIVLAARI 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 writers with a significant number of prescriptions coming from community centers, in addition to those coming out of centers of excellence. As noted earlier, geographic expansion around the world will be a driver for GIVLAARI this year, and we continue to make great progress with market access efforts across the CEMEA 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 to OXLUMO, 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. Of course, with this being our first full quarter of OXLUMO 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 OXLUMO treatment in the U.S. and E.U. as of March 31st. Our market access efforts are progressing very well for OXLUMO, with over five VBAs finalized to date with commercial payers and confirmed access already for about two-thirds of covered U.S. lives. Globally, we continue to make strong progress across the CEMEA 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 OXLUMO 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 OXLUMO.

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. Akshay?

Akshay Vaishnaw (President of R&D)

Thanks, Tolga, and good morning, everyone. I'll start with our efforts in ATTR amyloidosis, where we're advancing our two product candidates, patisiran and vutrisiran. With patisiran, we're committed to expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild-type ATTR amyloidosis patients. To this end, we're conducting the APOLLO-B phase III study. 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 vutrisiran, which is delivered by a quarterly subcutaneous injection. Here, we're conducting two phase III studies. The first is HELIOS-A evaluating vutrisiran in hATTR amyloidosis patients with polyneuropathy. 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 changing mNIS+7 from baseline at nine months, vutrisiran treatment resulted in a 17-point mean treatment benefit relative to the external placebo group from the APOLLO phase III study of patisiran. The effect was highly significant, indicating robustness of the treatment effect. Also, the mean change in mNIS+7 relative to baseline was a negative value, indicating improvement, providing evidence that, like patisiran, vutrisiran not only halts neuropathy progression but also achieved reversal of neuropathy symptoms relative to baseline in the majority of patients in its pivotal trial. As to the key secondary endpoint, change in Norfolk quality of life score at nine months relative to baseline, vutrisiran-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 vutrisiran arm at month nine relative to baseline, compared to demonstrated worsening in gait speed from baseline for the external placebo group. We also analyzed the exploratory endpoint of NT-proBNP, a marker of cardiac stress. While the external placebo group showed an increase or worsening in NT-proBNP levels over nine months, levels of this marker in the vutrisiran group were stable over nine months and did not decline, supporting further evaluation of vutrisiran effects on cardiomyopathy manifestations of disease. Importantly, vutrisiran demonstrated an encouraging safety and tolerability profile. There were no drug-related discontinuations or deaths. There were two serious adverse events or SAEs deemed related to vutrisiran 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 vutrisiran included diarrhea, pain in 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 five vutrisiran patients, or 4.1%, and were all mild and transient. We're thrilled with these results and have now filed our NDA with the FDA for the treatment of hATTR 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 vutrisiran's impact on exploratory cardiac endpoints. The second phase III vutrisiran study is HELIOS-B, being conducted in hereditary and wild-type ATTR amyloidosis patients with cardiomyopathy.

As John noted, we announced today that due to the strong pace of enrollment in the study, we now expect complete enrollment in late 2021, well ahead of our prior expectations. Lastly, for vutrisiran, we plan to initiate our study of a biannual dosing regimen for vutrisiran in the coming weeks. Let's now move on to lumasiran, our RNAi therapeutic recently approved in the EU and US as the first treatment for primary hyperoxaluria type 1, or PH1. Here, we continue to dose PH1 patients with advanced renal disease in the 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. This includes Leqvio, or inclisiran, partnered with Novartis, which was approved last year in the EU for the treatment of adults with hypercholesterolemia or mixed dyslipidemia.

Leqvio marks the first RNAi therapeutic approved for a prevalent condition. 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 inclisiran, 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 fitusiran in development for hemophilia A or B with or without inhibitors, partnered with Sanofi. Sanofi mentioned this week that all health authorities relevant to the program have approved redosing of fitusiran, and the majority of patients have resumed dosing. They intend to share data from initial pivotal trials at medical conferences later this year and/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 have also been making great progress with our early and mid-stage programs. One of the exciting parts of our story now is the expansion of RNAi therapeutics beyond rare diseases into prevalent disease opportunities. We believe now is the time to address many unmet needs in common disease settings such as hypertension, NASH, gout, and diabetes, amongst others, and we believe the pharmacological properties of RNAi therapeutics provide the foundation for success. Our program for hypertension is a great example. ALN-AGT is our investigational RNAi 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 back, in which patients treated with single doses of ALN-AGT at 100 milligrams or higher experienced durable reductions in serum AGT of more than 90% through 12 weeks. Reductions in 24-hour systolic blood pressure of more than 15 millimeters of mercury were achieved with ALN-AGT as monotherapy. ALN-AGT was also shown to be generally well tolerated. These durable pharmacological effects may support tonic control of blood pressure with once-quarterly and potentially biannual dosing, and we look forward to advancing ALN-AGT into our phase II cardiac program planned to be initiated in mid-2021. Moving on, we're also advancing ALN-HSD in collaboration with our partners at 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.

Enrollment and dosing continues in the phase I study of ALN-HSD. 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 ALN-APP 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. Jeff?

Jeff Poulton (CFO)

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 ONPATTRO, 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 in Q2 of last year. U.S. ONPATTRO sales increased 15% versus Q4 2020 and were primarily impacted by the following: 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-20s% globally for ONPATTRO in 2021.

In our international markets, ONPATTRO performance remains strong, with growth of 11% versus Q4 2020, primarily driven by increased patient demand in our five major markets in Europe. Results in Japan were unfavorably impacted by reduction of inventory at our distributor during Q1. Turning to our results for GIVLAARI, 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. Reported results in the US were unfavorably impacted by an increase in gross to net sales deductions in Q1 compared with Q4. With OXLUMO, we had a strong first full quarter of sales, generating $9.1 million in 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.

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. 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 investment to support the launch of OXLUMO. 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 expenses. 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 towards 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 million-$660 million. Our guidance for net revenue from collaborations and royalty is a range between $150 million-$200 million. And our guidance for combined non-GAAP R&D and SG&A expenses is a range between $1.175 billion-$1.275 billion. With that, I'll now turn the call over to Yvonne to review our upcoming milestones. Yvonne?

Yvonne Greenstreet (COO)

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 to complete enrollment in the phase III APOLLO-B study of fitusiran early this year, setting up top-line results in mid-2022. With fitusiran, 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. And as we've announced today, we can look forward to completion of enrollment in HELIOS-B later this year. For GIVLAARI, we look forward to an important regulatory milestone with its potential approval in Japan mid-year. Turning to OXLUMO, we anticipate an 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 initiation of a phase II study for recurrent renal stones in late 2021. This phase II study will be important for life cycle management of OXLUMO, with the potential to significantly expand the overall opportunity. Our early and mid-stage pipeline has lots in store as well. For Cemdisiran, enrollment and dosing continues in the phase II monotherapy study in IgA nephropathy, and dosing continues in the phase I combo study with pozelimab in collaboration with Regeneron. Our partners at Vir continue to enroll and dose ALN-HBV02 in a phase II combo trial with pegylated interferon alpha. And at Dicerna, our partners continue to advance belcesiran for AAT deficiency liver disease. ALN-AGT is on track to enter phase II mid-year with the start of the cardio program in hypertension.

We're very excited about the planned filing in mid-2021 of our first CNS CTA for ALN-APP. This sets us up for potential initial CNS proof-of-concept data in 2022. 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. Let me now turn it back to Christine to coordinate our Q&A session. Christine?

Christine Lindenboom (SVP of Investor Relations and Corporate Communications)

Thank you, Yvonne. Operator, we will now open the call for your questions. For those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have additional questions.

Operator (participant)

Certainly. Ladies and gentlemen, if you have a question at this time, please press star then one on your touch-tone 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.

Tazeen Ahmad (Analyst)

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.

John Maraganore (CEO)

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 vutrisiran as a once-quarterly sub-Q medicine for ATTR amyloidosis with cardiomyopathy, which is what we're evaluating in that phase III 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?

Akshay Vaishnaw (President of R&D)

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 hATTR amyloidosis with polyneuropathy. Many of the investigators we know because they work in both diseases, hATTR and the ATTR cardiomyopathy. And I think they're very excited about the possibility of our drugs in wild-type TTR cardiomyopathy. And then, of course, with our global reach, we've gone to many sites where there's no access to approved drugs, like tafamidis, for example, for wild-type TTR cardiomyopathy. And so people are very motivated to help study both ONPATTRO and fitusiran in that setting.

So 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 on the sites.

John Maraganore (CEO)

Tazeen, 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 lock down exactly what the design would be of 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 without the interim analysis, it would go 30 months past the point of enrollment being completed.

Tazeen Ahmad (Analyst)

Okay. Thanks, John.

Operator (participant)

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

Maury Raycroft (Analyst)

Hi, good morning, everyone, and congrats on the update today. Just wondering if you can provide a breakdown on how many ONPATTRO patients are on concurrent use with stabilizers and any specifics on switches as well?

John Maraganore (CEO)

Yeah. Let me hand it over to Tolga on that, and he can give you some framing 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 ONPATTRO is for the treatment of the 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 observe?

Tolga Tanguler (Chief Commercial Officer)

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, ONPATTRO is one of the only other stabilizers, and there's no, sorry, silencers, and there's no stabilizer indicated for polyneuropathy in the U.S. There, we do see mixed phenotype patients for hATTR, and those numbers remain about 20% right now with the concomitant use of another stabilizer for the cardiomyopathy treatment, which were not indicated. In Europe and Japan, we are indicated with 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 both in Japan and major European markets remain a very significant contributor of our growth. John?

John Maraganore (CEO)

Maury, does that answer your question?

Maury Raycroft (Analyst)

Yes. Yeah, very helpful. And maybe just as a follow-up, based on the combo use trend that you're seeing, just checking if you're thinking about or having conversations with Pfizer to potentially collaborate on scanning or diagnosing or maybe even leveraging the combo commercially as you think about reaching the broader cardiomyopathy opportunity?

John Maraganore (CEO)

Yeah. Tolga?

Tolga Tanguler (Chief Commercial Officer)

Yeah. I mean, look, first of all, having multiple players in this devastating condition is a very good thing for the patients. And 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 treatments, it certainly is helping. We certainly believe those protocols should include genetic testing, which then further establishes the condition for polyneuropathy and mixed phenotype patients. 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 we know it takes anywhere between five 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.

Maury Raycroft (Analyst)

Got it. Very helpful. Thank you very much.

John Maraganore (CEO)

Thanks, Maury.

Operator (participant)

Thank you. Our next question comes from the line of Alethia Young from Cantor Fitzgerald. Your question, please.

Alethia Young (Large Cap Biotech Analyst)

Congrats from all the fans. I wanted to talk in particular about GIVLAARI and the trends that you're seeing. It seems like if I'm reading the chart, I'm a little bit colorful, I think. But you saw $7 million plus in sales XUS and $1.4 million 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 you're seeing that are unique and distinct, obviously relative to XUS. I saw that you had the ATU in France. I'm assuming you booked that. Thanks.

John Maraganore (CEO)

Yeah. I'll hand it over to Tolga, and maybe Jeff will want to say a few things. But let me just comment, obviously, with GIVLAARI. 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 profound and very impressive. And so we are really pleased with the help that we're providing patients with this terrible disorder. A big part of the growth story for GIVLAARI this year is going to be geographic expansion with pricing and reimbursement achieved in many European countries because right now, it's really largely been driven from Germany and our ATU 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?

Tolga Tanguler (Chief Commercial Officer)

Absolutely.

Alethia Young (Large Cap Biotech Analyst)

Okay. Don't tell me. But actually, I was asking about OXLUMO. I actually misspoke. I apologize.

John Maraganore (CEO)

Oh. Oh, okay. Sorry.

Alethia Young (Large Cap Biotech Analyst)

Sorry, my bad.

John Maraganore (CEO)

Okay. All right. Thanks for the correction. Yeah. No, look, OXLUMO had a fantastic first quarter of launch. We're really pleased with that. Obviously, it's approved in both Europe and the U.S. and was first approved in Europe, which is terrific. It's off to a great start. Tolga, do you want to comment a little bit on some of that dynamic?

Tolga Tanguler (Chief Commercial Officer)

Yeah. I was all geared up for GIVLAARI. I'm going to switch gears here. Absolutely. Listen, OXLUMO, obviously, is another very, it's treating 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 the commercial therapy and, frankly, went rather smoothly is the reason why we see a good uptake in Europe. 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 OXLUMO growth. I'm also really encouraged by the fact that we're attracting the patients that are being treated, both pediatric and adult, and broad eGFR categories. So that's also really encouraging.

And last but not least, we've been able to already achieve two-thirds access on 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 is over 30 right now already this last quarter.

Alethia Young (Large Cap Biotech Analyst)

Awesome. Thank you.

John Maraganore (CEO)

Thanks, Alethea.

Operator (participant)

Thank you. Our next question comes from Salveen Richter from Goldman Sachs. Your question, please.

Hi. Thank you so much for taking our question. This is Sonja on for Salveen. Could you help frame expectations into 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.

John Maraganore (CEO)

Yeah. Thanks, Sonja. 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 vutrisiran in wild-type and hereditary ATTR patients with cardiomyopathy. So this is the opportunity to potentially expand our vutrisiran opportunity into that broader segment. And so, Akshay, do you want to comment a little bit on how we view success in that study?

Akshay Vaishnaw (President of R&D)

Yeah. The primary endpoint in APOLLO-B is 6-minute walk distance, which is a clinically validated measure in the disease and is intuitively clinically meaningful. Patients with cardiomyopathies, any form of heart failure, struggle with exercise and exercise tolerance. So 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. The study is not powered for that, but it'll, 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, 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 patisiran and hATTR with polyneuropathy, in the cardiac patients within that study or patients that had significant cardiac disease, I should say, we saw very encouraging findings. We saw that 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. Echocardiogram showed reduction in the left ventricular wall thickness. And then subsequent to that, other groups have demonstrated, academic groups such as the Gillmore Group in London, and they published this. They see diminution on technetium scan with evidence for regression of amyloid in the heart. They also saw that by cardiac MRI.

They saw stabilization of six-minute walk distance in their ONPATTRO-treated hATTR cardiomyopathy patients. These are all very encouraging findings to us that support the likelihood of success with APOLLO-B. And then finally, with mortality and hospitalization itself, post-hoc analyses from the original APOLLO study did demonstrate a significant difference. 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 vutrisiran in HELIOS-B, where, of course, the study is larger and is powered to detect mortality and hospitalization changes, and that's the primary readout.

And so, 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-B.

John Maraganore (CEO)

Yeah. And I'll just add to that that obviously, we're expecting data from APOLLO-B middle 2022. We're on track to complete enrollment in early 2021, so just in the next period. And then we expect to have data from APOLLO-B in mid 2022. So that is going to be obviously an important data readout sometime mid next year.

Thank you so much.

Operator (participant)

Thank you. Our next question comes from the line of David Lebowitz from Morgan Stanley. Your question, please.

David Lebowitz (Senior Research Analyst)

Thank you very much for taking my question. If there is, I mean, when there is an interim analysis for APOLLO-B, what type of analysis will actually be conducted, and is there a possibility that that interim analysis can produce a result that allows for an earlier, I guess, regulatory submission, or is it really we just should assume 30 months is the only route to a submission?

John Maraganore (CEO)

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 for doing the interim analysis would be to potentially bring vutrisiran to the market ahead of the final result, which would readout 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?

Akshay Vaishnaw (President of R&D)

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 results from Helios B. That would accelerate the interim analysis. It gives great insight into the kind of relevant interim analysis to do. And the motivation would be to get vutrisiran to patients faster with that IA.

John Maraganore (CEO)

Yeah. Yvonne?

Yvonne Greenstreet (COO)

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

John Maraganore (CEO)

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 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 on with regulators, which is an important step.

David Lebowitz (Senior Research Analyst)

Does that include the timing of the analysis?

John Maraganore (CEO)

Absolutely. The design and the timing and what the endpoint would exactly be, all those elements would be obtained in alignment with regulators. Absolutely.

David Lebowitz (Senior Research Analyst)

Excellent. Thank you for taking my question.

John Maraganore (CEO)

Thanks, David.

Operator (participant)

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

Gena Wang (Managing Director and Biotech Equity Research)

Thank you for taking my questions. I have one regarding the value-based payment. Just wondering, now you have three drugs, all have a value-based reimbursement. So just wondering, what is the real-world implementation? And based on current experience, roughly what percentage of patients you need to actually adjust the payment or value due to lack of efficacy?

John Maraganore (CEO)

Yeah. Well, Gena, let me just start on that really important question and then maybe turn it over to Jeff to sort of address 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. Certainly, in the U.S. commercial market, we've also done some element of that in Europe as well. 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 proactive and open-minded about value. It has changed the dialogue away from price into a discussion or a recognition of value. We've been very innovative on that.

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 demonstrate the innovation on 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 VBAs?

Jeff Poulton (CFO)

Yeah. Happy to. Gena, I'll speak to ONPATTRO. 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 VBAs that have been signed with commercial payers are extremely modest at this point. And that's because the product's working well. So 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.

John Maraganore (CEO)

I think the one index of that that we report on 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 fitusiran and the APOLLO study.

Tolga Tanguler (Chief Commercial Officer)

And if I can add.

John Maraganore (CEO)

Oh, anything to add? Yeah.

Tolga Tanguler (Chief Commercial Officer)

Yeah. Yeah. I mean, as you and Jeff mentioned, the outcomes of our products and its efficacy is 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, 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 VBA. So we certainly do not anticipate any long-term negative impact on our revenues.

Gena Wang (Managing Director and Biotech Equity Research)

Thank you very much.

John Maraganore (CEO)

Does that answer your question, Gena?

Gena Wang (Managing Director and Biotech Equity Research)

Yes. Very helpful. Thank you.

John Maraganore (CEO)

Thank you.

Operator (participant)

Thank you. Our next question comes from the line of Debjit Chattopadhyay from Guggenheim Securities. Your question, please.

John Maraganore (CEO)

Are you on mute, Debjit?

Sorry. Yes, I was on mute.

I thought so.

Sorry. This is Aaron on for Debjit. So congrats on the progress. The ONPATTRO 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? Thanks.

Sure. I mean, we answered the first question earlier. You may not have heard the answer, but we can do it again. No problem. Tolga, do you want to handle both of those questions?

Tolga Tanguler (Chief Commercial Officer)

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 condition as possible. In some cases, physicians identify 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 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 the switches. And obviously, net naive patients, which, again, we see a great progress. Can you repeat the second question?

Just about the ramp in diagnosed patients in ATTR, how that's increasing.

Yeah. Yeah. Again, I think 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 PYP scintigraphy scans are really helping. And these scans are relatively cheap, inexpensive, and very accessible. 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've received a relatively high yield out of these, about 6%. Over 2,000 patients were diagnosed with the genetic mutation. So that's going really well.

We're very encouraged by both the increase of PYP scans as well as system taking advantage of genetic testing along with Alnylam Act. Did that answer your question?

Yeah. That's great. Thank you.

John Maraganore (CEO)

Thanks, Aaron.

Operator (participant)

Thank you. Our next question comes from the line of Paul Matteis from Stifel. Your question, please.

Paul Matteis (Managing Director and Head of Therapeutics Research)

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

John Maraganore (CEO)

Paul, I'll just start, and then I'm sure Akshay will want to chime in. In general, of course, comparisons between studies is 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 fraught with caveats, to say the least. Akshay, do you want to comment a little bit on that further?

Akshay Vaishnaw (President of R&D)

Yeah. I mean, let me just reiterate because I think it's so important what you just said that Pfizer colleagues, their investigators did wonderful work, and they should speak to the value of their results and the implication. Direct comparisons are not valid, 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 we'd like to halt the course of this terrible disease, cardiomyopathy, in these patients. And looking at the published Pfizer data with tafamidis, I think it's fair to say that that drug obviously has significant impact on mortality and hospitalization and 6-minute walk distance. But the overall feeling is that it's just slowing down the rate of deterioration.

What if we could just sort of halt the disease and arrest, stabilize these parameters like six-minute walk distance, which is what we very much look forward to doing and showing with APOLLO-B. The work of Gillmore et al., which I cited earlier, study of 20-something hATTR amyloidosis patients where they looked at the cardiomyopathy aspect, showed stabilization compared to historic control. Now, that's a single-arm study comparing to historic control, but that's encouraging. Everything keeps pointing to the idea that we could stabilize. Recently, with vutrisiran and HELIOS-A, we showed stabilization of NT-proBNP versus deterioration of the placebo. We'd seen that previously with vutrisiran in the original APOLLO study. I think direct comparisons are very fraught for all sorts of reasons.

I think we'll have a similar population in APOLLO-B, so it would be a valid population to think about the value of the drug. And our goal is to show stabilization of the primary endpoint, 6-minute walk distance.

John Maraganore (CEO)

Does that answer your question, Paul?

Paul Matteis (Managing Director and Head of Therapeutics Research)

Totally. Thank you.

John Maraganore (CEO)

Thanks, Paul.

Operator (participant)

Thank you. Our next question comes from the line of Ritu Baral from Cowen. Your question, please.

Ritu Baral (Managing Director and Senior Biotechnology Analyst)

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? Guys, you have to meet with FDA before you decide on the interim to get their buy-in, and that 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?

John Maraganore (CEO)

Okay. So first of all, it's the FDA and also other regulators that have an important input here on a matter like this, like the EMA. So it's not just the FDA. But 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 design of the interim, our plan would be to try to focus on what that is sooner than we have the readout from APOLLO-B. Akshay, anything?

Anything to add, Akshay, from your perspective on that?

Akshay Vaishnaw (President of R&D)

No. I just want to, with our announcement today of HELIOS-B enrollment completion by the end of the year, looking very likely now. We didn't have that line of sight. We have that now. So the timing looks very conducive that we'll have the APOLLO-B data middle of next year. And of course, by that time, the HELIOS-B study is fully enrolled. The patients have been on drug or placebo for a sufficient length of time, so it naturally leads to a very well-structured and planned IA after that for HELIOS-B.

Ritu Baral (Managing Director and Senior Biotechnology Analyst)

Okay. And if HELIOS-B enrollment 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 might result in?

John Maraganore (CEO)

Go ahead, Akshay.

Akshay Vaishnaw (President of R&D)

Yeah. No, I think we just said HELIOS-B 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, end of 2022 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 in due course, Ritu.

Ritu Baral (Managing Director and Senior Biotechnology Analyst)

Okay. Fair enough. I'll keep bugging you about that. But last very quick question, just as far as we think about ONPATTRO to 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 this year? And what impact could that have on ONPATTRO, do you think?

John Maraganore (CEO)

Yeah. Tolga, do you want to answer that?

Tolga Tanguler (Chief Commercial Officer)

Yeah. Look, at the end of the day, a lot of payers and specialty pharmacies are offering home infusion services. Our patient services program also does a phenomenal job with site of care and accommodating different routes of the way those patients will be administered. We've seen a good steady uptake even prior to the pandemic as well as during the pandemic. So those allowances, while they're good, were 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% home care. As well as in the U.S., we doubled the amount of patients, but it still represents about one-fifth of our patients that are getting home care. So we're not broadly exposed. The type of services we provide will continue.

So we really don't see that as a detractor of the performance that we have in this business.

Ritu Baral (Managing Director and Senior Biotechnology Analyst)

Got it. And as far as you know, there's no particular time that Medicaid home infusion is ending sometime in 2021, those temporary allowances?

Tolga Tanguler (Chief Commercial Officer)

That I'm not aware. I wouldn't be able to speak to that.

John Maraganore (CEO)

We've not heard anything on that, Ritu.

Ritu Baral (Managing Director and Senior Biotechnology Analyst)

Got it. Very helpful. Thank you.

John Maraganore (CEO)

Thank you.

Operator (participant)

Thank you. And our final question for today comes from the line of Navin Jacob from UBS. Your question, please.

Hi everyone. This is Jon on for Navin. We wanted to go back to HELIOS-A, and we knew that the severe AE rates were a lot lower for vutrisiran versus ONPATTRO. And we were just curious if there was any color you could provide on that.

John Maraganore (CEO)

Yeah. Akshay, do you want to answer that question? This is looking at the, and the comparison was to the small ONPATTRO arm in the study, I believe, is what you're referring to. Akshay, do you want to comment on that?

Akshay Vaishnaw (President of R&D)

Yeah. I mean, I think we're very happy about the encouraging safety data with vutrisiran and HELIOS-A as we are with our GalNAc siRNA conjugates overall. As to direct comparison there, I think that the TTR arm's very small, and really, it's not an apples-to-apples 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, ONPATTRO, 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 in favor of ONPATTRO in terms of safety. And in the real world, as evidenced by the retention on drug and the comfort investigators feel with it, patients feel with it, we're very encouraged that the real-world safety and experience is as good as it was in the original APOLLO study.

So that's a real testament to how it's serving patients.

John Maraganore (CEO)

John, the lower SAE rate in the vutrisiran arm relative to external placebo, we believe, is related to the fact that patients on placebo are probably experiencing disease progression, AEs, that underscores that. So that's certainly our belief based on those data.

Akshay Vaishnaw (President of R&D)

Yeah. 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 whatever other intercurrent event is 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 be of relevance. So with the vutrisiran being 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. And as you said, the overall safety profile for vutrisiran does look very encouraging.

That's very helpful. Thank you.

Thank you.

John Maraganore (CEO)

Thank you, Jon. 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 P5x25 strategy, which we're obviously very, very excited about, so we look forward to talking to you in subsequent calls and wish everyone a wonderful rest of the day and hope everybody stays safe as well. Bye-bye now.

Operator (participant)

Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.