Earnings Call Transcript
Alnylam Pharmaceuticals, Inc. (ALNY)
Earnings Call Transcript - ALNY Q3 2020
Operator, Operator
Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals Conference Call Q3 2020 Earnings Call. Please be advised that this call is being taped at the company's request. I'd now like to turn the call over to the company.
Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications
Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are John Maraganore, Chief Executive Officer; Andy Orth, Senior Vice President and Head of the U.S. business; Akshay Vaishnaw, President of R&D; Jeff Poulton, Chief Financial Officer; and Yvonne Greenstreet, President and Chief Operating Officer. For those participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page on our website, investors.alnylam.com/events. During today's call, as outlined on Slide 2, John will provide some introductory remarks and general context. Andy 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 remind you this call will contain remarks concerning Alnylam's future expectations, plans and prospects that constitute forward-looking statements 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 discussed in our most recent annual and quarterly reports. 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 subsequently. We specifically disclaim any obligation to update such statements. With that, I'd like to turn the call over to John.
John Maraganore, CEO
Thanks, Christine, and thank you, everyone, for joining the call today. We believe the third quarter and recent period highlight the tremendous progress Alnylam has made as a global commercial organization with a highly productive R&D platform. Starting with our commercial execution, we saw strong ONPATTRO and GIVLAARI performance in Q3, which Andy Orth will review momentarily. We have continued confidence for the rest of this year with another upward revision of our ONPATTRO revenue guidance range for 2020 and another beat for GIVLAARI relative to estimates. Akshay will review our recent R&D progress shortly, but the highlight in the recent period is the positive CHMP opinions recommending approval of OXLUMO or lumasiran and LEQVIO or inclisiran, which set us up for the potential to achieve 4 RNAi therapeutic approvals and launches in less than 3 years, a truly remarkable achievement. You'll also hear from Jeff about our financial performance and our progress toward achieving a self-sustainable financial profile. We believe we're on our way. Indeed, at Alnylam, we're focused on continued global commercial execution of potentially transformational medicines, excellence in productivity from our organic R&D efforts, while maintaining a clear line of sight toward financial self-sustainability. In fact, this is what we envisioned when we established our Alnylam 2020 goals back in 2015, that we'd be a multiproduct, global company with a deep clinical pipeline for future growth and an organic product engine for sustainable innovation. That moment is now upon us and we couldn't be prouder of our achievements toward those variable goals, which we're on track to not only meet but actually exceed. We couldn't be more excited for the next phase of Alnylam's evolution. We will lay out our multiyear vision soon, and we look forward to delivering on our potential as a top-tier biopharmaceutical company focused on advancing medicines with transformative potential to patients around the world. Now before I hand it over to Andy, I'd like to mention that we plan to host a virtual R&D Day event on December 15 and 16, where we'll be reviewing progress across our pipeline of investigational RNAi therapeutics. We hope you'll be able to join us online. So with that, let's now turn to a review of our commercial and medical affairs progress. Andy?
Andreas Orth, Senior Vice President and Head of the U.S. business
Thanks, John, and good morning, everyone. I'll begin by reviewing our commercial performance in the third quarter as well as our medical affairs progress. For ONPATTRO, we achieved $82.5 million in global net product revenue, delivering 24% growth versus Q2, primarily driven by increased patient demand. As of September 30, over 1,150 patients were on commercial ONPATTRO treatment worldwide. Turning to the U.S., we saw notable increases in demand and new patients starting therapy. Also, with many patients now having successfully transitioned to alternate sites of care, including home care, we benefited from strong patient compliance, which also contributed to the rebound in revenues. We continue to see progress with new prescribers in the U.S., with cardiologists making up more than half of new prescribing physicians. In the United States, we also continue to see a steady rate of concomitant use of ONPATTRO with TTR stabilizers and expect this trend to continue to grow. Turning to the rest of the world, we made very encouraging progress with ONPATTRO in the third quarter with $43.5 million in revenues from ex-U.S. markets. As noted last quarter, we have secured access in all priority markets in Western Europe, including Portugal, following our Q3 launch. We are pleased with the continued growth in Japan, which is a country of strength for ONPATTRO. An important dynamic observed in ex-U.S. is patients switching to ONPATTRO from stabilizers for the potential to halt or reverse disease progression in hATTR patients with polyneuropathy. This dynamic represents greater than 50% of new ONPATTRO patients outside the U.S. Our medical affairs team also remains committed to addressing the challenge of raising disease awareness and improving diagnosis rates of hATTR amyloidosis, including with Alnylam Act, our third-party genetic screening initiative in the U.S., Canada, and Brazil. As of October, greater than 30,000 samples have been submitted, out of which approximately 1,800 have tested positive for pathogenic TTR mutations. We are encouraged by the recovery in Alnylam Act genetic testing volumes we've seen in recent months, and we believe these volumes will continue into the fourth quarter. We've also seen continued recovery in the number of PYP scans conducted for detection of cardiac amyloidosis. As you know, hATTR amyloidosis is a multi-systemic disease, and in the U.S., detection of cardiac amyloid is often the first step in an overall diagnosis of the disease as many of these patients also have polyneuropathy. ONPATTRO continues to be recognized as a breakthrough for patients with hATTR amyloidosis with polyneuropathy, and we're honored to have received the highly prestigious Prix Galien USA award just last week. Moving on to GIVLAARI, we achieved $16.7 million in global net product revenues in the quarter, with over 150 patients now on the commercial drug. Our progress with patient access in the U.S. has been strong, having now finalized 10 value-based agreements, or VBAs, with U.S. payers. We currently have confirmed access for over 90% of covered U.S. lives. We've not experienced any payer headwinds with GIVLAARI to date, and we're pleased to see the majority of plans adopt medical policies without restrictions to the number of baseline attacks. The CEMEA region saw great progress as well, with a successful ongoing GIVLAARI launch in Germany and named patient sales in other countries, including France. We're off to a very strong start for market access in CEMEA. In France, GIVLAARI received an improvement of medical benefit, or ASMR score of II, concluding it offers significant additional therapeutic value. Additionally, GIVLAARI obtained a Considerable Added Benefit rating in Germany with only 15% of all orphan drugs achieving such a high rating, and we secured a strong HTA rating in Italy. We're also excited to soon get our launch underway in Canada, following the recent approval, and look forward to the completion of the ongoing review of our NDA in Japan, which was submitted in September. Finally, our commercial affairs teams are prepared for the upcoming launch of OXLUMO, the brand name for lumasiran. With a positive CHMP opinion in hand in the EU and an FDA PDUFA date just weeks away on December 3, we look forward to soon bringing our third RNAi therapeutic to patients around the world. We are well prepared with our OXLUMO supply chain and are ready to deploy our trained U.S. field team upon approval to help get this important medicine to the underserved primary hyperoxaluria type 1 or PH1 community. As with our other launches and guided by our patient access philosophy, we are hard at work making sure that patients who need OXLUMO are able to access it. Constructive conversations are ongoing with payers regarding VBA arrangements, and we look forward to updating you further upon launch. In conclusion, the third quarter highlighted the broad capabilities of our commercial and medical affairs operations, including the continued growth of ONPATTRO, the continued launch of GIVLAARI, and the preparation for the launch of OXLUMO. We'll be watching with excitement as Novartis prepares to launch LEQVIO or inclisiran, which will mark the entry of RNAi therapeutics into a highly prevalent chronic disease indication.
Akshay Vaishnaw, President of R&D
Thanks, Andy, and good morning, everyone. I'll start with our efforts in ATTR amyloidosis, where we're advancing our 2 product candidates, patisiran and vutrisiran. Whilst ONPATTRO is currently approved in multiple markets around the world to treat polyneuropathy associated with hereditary ATTR amyloidosis, we 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 expect completion of enrollment in 2021 due to impacts from the COVID-19 pandemic. During Q3, we saw a pickup in the pace of enrollment and are still aiming to make up for lost time that we experienced during Q2 due to the pandemic. We're also advancing vutrisiran for the treatment of ATTR. Vutrisiran is delivered by a quarterly subcutaneous injection. Here, we're conducting 2 Phase III studies. The first Phase III study is HELIOS-A, which is evaluating patisiran in hATTR patients with polyneuropathy. Enrollment is complete in HELIOS-A, and we remain on track to report top-line results early next year. The second Phase III study of vutrisiran is HELIOS-B, which has been conducted in hereditary and wild-type ATTR amyloidosis patients with cardiomyopathy, and this study is actively enrolling. On our ATTR roundtable in September, we shared modeling data suggesting the potential for a biannual dosing regimen for vutrisiran, which can further differentiate vutrisiran from other products currently approved or in development. We are actively advancing our efforts to bring a q6 monthly dose of the regimen to the market in parallel with our ongoing development of the q3 monthly regimen. Moving now to GIVLAARI, which is approved in the U.S., EU, Brazil, and Canada to treat acute hepatic porphyria, we're pleased with continued base supporting a positive risk-benefit profile. For example, during the third quarter, we presented new interim data from the Phase I/II OLE study of GIVLAARI, showing maintenance clinical activity with continuous monthly dosing with a further numeric reduction in the annualized attack rate. The safety profile remains consistent with no new safety findings. I'll now turn to recent progress with lumasiran, an investigational RNAi therapeutic we're developing for the treatment of primary hyperoxaluria type 1 or PH1. We're also thrilled to receive last month a positive CHMP opinion recommending approval of lumasiran for the treatment of PH1 in all age groups. Recently, we presented full results from the ILLUMINATE-B study of lumasiran pediatric patients less than 6 years old. In the study, treatment with lumasiran led to a 71% mean reduction in the spot urinary oxalate:creatinine ratio from baseline to month 6, which was the primary endpoint of the study. Lumasiran also demonstrated positive results across secondary endpoints, including 50% of patients that achieved urinary oxalate levels at or below 1.5 times the upper limit of normal. The most common drug-related adverse events were mild and transient injection site reactions reported in 17% of patients. The overall efficacy and safety profile of lumasiran was consistent with that observed in adults and children 6 years or older in the ILLUMINATE-A study. In both ILLUMINATE-A and B studies, we continued to see encouraging evidence towards certain clinical events such as nephrocalcinosis and renal stone events or RSE. In ILLUMINATE-A, we previously reported encouraging results with improvements in nephrocalcinosis and exploratory endpoints. At ASM, we showed some initial results from ILLUMINATE-A on improved RSEs with continued dosing. Based on the preliminary analysis for exploratory endpoints in ILLUMINATE-B, treatment with lumasiran led to bilateral or unilateral improvements in nephrocalcinosis in 44% of patients, with no patients worsening and eGFRs remaining stable. These results were similar to effects on nephrocalcinosis seen in the ILLUMINATE-A study. We now await regulatory decisions and continue to believe that lumasiran will be approved by the FDA by the PDUFA action date of December 3 and by the EMA later this year as well. In the meantime, we continue to enroll patients in the ILLUMINATE-C Phase III study of lumasiran for the treatment of advanced PH1 patients of all ages, with data expected in 2021. As you know, we have 2 additional late-stage programs that are in development with partners. This includes inclisiran in development for hypocholesterolemia, partnering with Novartis, which is in registration in the United States and the EU. We're delighted that inclisiran has also received a positive CHMP opinion recommending approval of the drug in the EU for the treatment of adults with hypercholesterolemia or mixed dyslipidemia. If approved, it will be marketed under the brand name LEQVIO. Our late-stage programs also include fitusiran, in development for hemophilia A or B with or without inhibitors, partnered with Sanofi. Fitusiran is under evaluation in the Phase III Atlas program. Now in addition to our late-stage clinical programs, we believe we have also been making great progress with our early and mid-phase programs. Our partner Vir has initiated dosing of ALN-HBV02 or VIR-2218 with interferon in a Phase II study in patients with chronic hepatitis B infection. We're very excited about the clinical data already presented for this molecule. As a reminder, Alnylam has retained the right to opt into a 50-50 share of the program prior to the start of Phase III. In our ALN-AGT program, we believe we have an opportunity to reimagine the treatment of hypertension with tonic-controlled blood pressure. We look forward to presenting results from the Phase I study of ALN-AGT at the American Heart Association meeting next week. Also, in the recent period, we made progress with ALN-HSD, an investigational RNAi therapeutic for the treatment of NASH that is being advanced in collaboration with Regeneron. We were pleased to report today that we've initiated dosing in the Phase I study of ALN-HSD. We also continue to make strong 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, and we're pleased that Regeneron has elected to exercise its co-development and co-commercialization option on this program with Alnylam retaining the lead. ALN-COV is our investigational RNAi therapeutic targeting the genome of SARS-CoV-2, the virus that causes COVID-19 and is partnered with Vir. Based on recent preclinical studies in a hamster model of COVID-19 infection, we've decided to generate additional animal model data prior to further program advancement. Accordingly, our IND filing timeline will be delayed. As John previously mentioned, we look forward to highlighting all of this progress in an upcoming R&D day virtual event planned for December 15 and 16 later this year.
Jeffrey Poulton, CFO
Thanks, Akshay, and good morning, everyone. I'm pleased to be presenting Alnylam's third quarter 2020 financial results. As Andy has already highlighted, it was a very strong quarter with outstanding results for both ONPATTRO and GIVLAARI. Turning to our results for ONPATTRO, we generated $82.5 million in global net ONPATTRO revenue for the quarter, which represents a return to growth driven by strong commercial execution and improving market conditions following Q2, which was negatively impacted by the pandemic. Global sales increased 24% versus the second quarter of 2020 and 79% compared with Q3 2019. U.S. sales of ONPATTRO increased 21% versus Q2 2020, with primary sources of growth from the following: Patient demand increased 14%, driven by an improvement in patient compliance, which returned to prepandemic levels, as well as the addition of new patients during the quarter. Modest inventory stocking during the quarter compared with destocking during Q2, offset by a slight increase in gross to net sales reductions, favorably impacted Q3 growth by 7%. We ended the quarter with less than 2 weeks of inventory in the channel. We are really pleased with the strength of the results in the U.S. in the quarter, with Q3 sales representing the highest level since launch. In our international markets, ONPATTRO performance remained strong with growth of 27% versus Q2 of 2020, with primary sources of growth from the following: An increase in patient demand contributed 19% growth and was primarily from major markets in Europe, where we achieved recent PNR outcomes, including from Portugal. We also saw continued excellence from Japan. The source of new patients in our international markets remains balanced between patient switches from a TTR stabilizer and new patients naive to treatment. Additionally, there were one-time benefits associated with finalizing our price in France and with completing our initial access agreement in Canada, which contributed an additional 8% growth in the quarter. Turning to our results for GIVLAARI, we had a strong third quarter generating $16.7 million in global net revenue, representing 52% growth compared to the second quarter of 2020. This positive performance continues to be driven by ongoing launches in both the U.S. and Europe, and we now have more than 150 patients on commercial therapy globally. Turning now to a summary of our full P&L results for the quarter. Net revenue from collaborations for the third quarter was $26.6 million, primarily due to revenue recognized from our Vir and Regeneron collaborations. Gross margin as a percentage of total revenue was 83% for the quarter, down from 93% in Q3 2019, primarily due to the current utilization of ONPATTRO fully costed inventory, while last year benefited from $0 cost ONPATTRO inventory as well as having a higher proportion of sales in the third quarter of 2020, coming from lower margins in international markets and a write-off of ONPATTRO inventory at our contract manufacturer. Our R&D expenses increased on a non-GAAP basis in the third quarter of 2020 compared to the same period in 2019, primarily due to the continued investment in advancing our late-stage pipeline programs. SG&A expenses increased on a non-GAAP basis in the third quarter of 2020 compared to the same period in 2019, primarily due to increased investment in commercial and medical affairs activities to support the ongoing launches of ONPATTRO and GIVLAARI and the launch preparation activities for OXLUMO. Our non-GAAP operating loss for the quarter decreased by approximately $12 million compared with the same period in 2019, driven by strong top-line growth and moderate growth in operating expenses. We remain confident that 2019 represents our peak non-GAAP operating loss year, as we expect the trend of strong top-line growth and moderate growth in operating expenses to continue for the remainder of the year. We ended the quarter with cash, cash equivalents and marketable securities of $1.8 billion, which includes $600 million in proceeds received in the second quarter of 2020 from the partial sale of future inclisiran royalties and issuance of common stock to Blackstone. Finally, turning to our financial guidance. We believe our results for the third quarter continue to demonstrate successful commercial execution in challenging circumstances. As a result of the strength of our Q3 ONPATTRO results, we are increasing our full-year 2020 revenue guidance for ONPATTRO from $280 million to $295 million to $310 million, representing a 4% increase from the midpoint of the prior range to the midpoint of the new range. Our guidance for net revenue from collaborations and our guidance range for combined non-GAAP R&D and SG&A expenses remain unchanged. However, we expect our combined non-GAAP R&D and SG&A expenses to end the year towards the upper end of our guidance range driven by an expected increase in Q4 in both R&D expense as we continue to make good progress in advancing key clinical stage programs and SG&A expense primarily driven by increased spend in support of our planned launch of OXLUMO. Please note we have revised the midpoint of our GAAP combined R&D and SG&A operating expense guidance range upward by $30 million, primarily reflecting an increase associated with the contingent liability related to our arbitration with Ionis. Regarding cash, as mentioned in our second-quarter call, we continue to believe our strategic financing collaboration with Blackstone adding up to $2 billion secures Alnylam's bridge towards a self-sustainable financial profile without the need for future equity financings.
Yvonne Greenstreet, President and COO
Thanks, Jeff, and hello, everyone. As we look to close out 2020, we have a number of very important and exciting milestones lined up. For starters, we plan to continue our global commercialization of both ONPATTRO and GIVLAARI. We're also expecting 2 additional regulatory approvals by the end of the year for lumasiran and inclisiran in both the U.S. and Europe. We expect to launch OXLUMO in the U.S. by year-end. We plan to continue enrollment in our ATTR cardiomyopathy studies, specifically APOLLO-B with patisiran and HELIOS-B with vutrisiran. We look forward to presenting additional clinical results from the ongoing Phase I trial of ALN-AGT in hypertension at the AHA meeting on November 13. Our partner, Regeneron, plans to initiate a Phase I study for cemdisiran in combination with pozelimab as a potential therapeutic option for the treatment of complement-mediated diseases. We also look forward to updating you on overall pipeline progress and strategy at our virtual R&D day event in December. As John noted earlier, these are very exciting times for Alnylam, as we expect to exceed our original Alnylam 2020 guidance, exiting this year as a global multiproduct commercial company with a robust clinical pipeline for continued growth and an organic product engine delivering sustainable innovation. Let me now turn it back to Christine to coordinate our Q&A session.
Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications
Thank you, Yvonne. Operator, we will now open the call for questions.
Operator, Operator
We'll take our first question from Gena Wang from Barclays.
Huidong Wang, Analyst
And congrats on a very strong quarter. So one question regarding the commercial. First, for the ONPATTRO, do you expect for the 4Q, any thoughts on the inventory and where the major driver would be for the remaining of the year? And also for lumasiran, could you share with us the number of patients in the early access program right now?
John Maraganore, CEO
Thank you, Gena. I'll turn to Andy and Jeff about the ONPATTRO question specifically. We aren’t disclosing specifics on the patients in the lumasiran expanded access program. However, I can confirm that we do have patients in it. As lumasiran receives approval, we will transition those patients to the commercial product in each country as regulatory approvals are obtained. Andy, would you like to start? Perhaps Jeff can then address the inventory impact. Andy, you can provide an overview of the Q4 expectations for ONPATTRO.
Andreas Orth, Senior Vice President and Head of the U.S. business
Sure. Happy to. So as we noted, Q3, the growth was a mixture of both net new patient demand as well as a return to an increased compliance rate, specifically in the United States post that Q2 COVID impact. In Q4, we expect the growth to come primarily from that net new patient demand. And I'll turn it over to Jeff here on the inventory side.
Jeffrey Poulton, CFO
Yes. In terms of where we are in inventory, Gena, at the end of the third quarter for ONPATTRO, we're less than 2 weeks. Based on the distribution agreements we have, that range is typically in the 1 to 3 weeks range. So again, we're right in the middle of that at this point.
Operator, Operator
We'll now take our next question from Tazeen Ahmad from Bank of America.
Tazeen Ahmad, Analyst
So I wanted to get a sense of what information we should expect to see when the top line reads out from the HELIOS-A study early next year. And whatever that data does show, should we have any reason to think that there would be read-through into the population that you guys are studying in cardiomyopathy in the HELIOS-B study?
John Maraganore, CEO
Yes, that's a great question, Tazeen, and I'll let Akshay handle it. Let me just start by saying we're very excited about vutrisiran because it is obviously going to enable a once-quarterly subcutaneous dose administration and potentially with additional work, we believe we can introduce a biannual dosing regimen for patients with hATTR. Initially, it will be for the polyneuropathy setting with the HELIOS-A study. The focus will then shift to HELIOS-B and cardiomyopathy, both hereditary and wild-type. So Akshay, do you want to comment specifically on Tazeen's questions around what will be available at the top line and what potential read-through there will be on cardiomyopathy from HELIOS-A?
Akshay Vaishnaw, President of R&D
Yes. Thanks, John. So vis-à-vis HELIOS-A top line, we continue to believe that we'll have the data early next year. So that's very exciting. Our general habit when we present top line is to provide the primary endpoint and relevant secondary endpoints, and of course, the safety information on the study at a high level that's pertinent to the report. We then report more fully on all the details at an upcoming scientific meeting after that. Those should be informative as to how the study is done. As for the read-through into cardiomyopathy in HELIOS-B, if we recall the original APOLLO study with ONPATTRO, we learned a lot about the impact on biomarkers and the impact on echo findings in the heart in about 50% of the patients that had some evidence of cardiomyopathy in that study population for ONPATTRO. Now it remains to be determined exactly what proportion of patients have cardiac involvement here in HELIOS-A, but it will be exciting to see what the impacts have been on not just biomarkers, but other aspects of the disease, but it is very much dependent on the patient population.
John Maraganore, CEO
Thanks, Akshay. Tazeen, does that answer your question?
Tazeen Ahmad, Analyst
Yes. When you mention early next year, can you confirm if the data could be available in January, or are you unable to provide that level of detail?
John Maraganore, CEO
Yes. We're not going to provide that level of granularity, Tazeen. Our early period, as you know, is Q1 or Q2. But I think it's going to be early.
Operator, Operator
We'll now take our next question from Paul Matteis from Stifel.
Paul Matteis, Analyst
Congrats on the quarter. Two questions. One, on vutrisiran, do you think you could bridge to the 6-month dose with just TTR lowering data and safety? And if so, what's the status of that clinical work? And then second, on lumasiran, on the Wall Street side, expectations of this drug are materially lower than that of givosiran, but I think some of the prevalence data for PH1 and 2, 3 that you've outlined are not that dissimilar to AHP's. So do you think givosiran is a realistic analogue for this? If so or if not, can you give any context?
John Maraganore, CEO
Yes. Thanks, Paul, and great questions. For starters, on the vutrisiran q6 monthly, at a high level, it is certainly our belief that TTR lowering combined with safety should support that approach. We've had engagement with regulators on that point. So I think that is certainly a path forward. That would be consistent with other types of therapies where dose regimens with a strong biomarker have been supported in future labeling. Obviously, that will require those data to be generated and submitted as part of an SNDA, and that would be the overall plan. Regarding OXLUMO and the market size, I'll let Andy comment a little bit further on that, but I believe we see somewhere between 1,000 and 1,700 patients that are diagnosed and would be on label, if you will, patients that have mild to moderate PH1, which would be the initial label prior to then expanding it to include severe PH1. Andy, do you want to add any further details on the PH1 population and how we should think about lumasiran relative to GIVLAARI?
Andreas Orth, Senior Vice President and Head of the U.S. business
Sure, John. Thanks. At this point, we’re expecting that number to be between 1,000 and 1,700 patients that would be addressable and on label. We see lumasiran becoming a $500 million brand as it launches globally. Furthermore, we're excited to be active in this market, which has been largely underserved so far. We’ll be learning a lot as we move forward.
John Maraganore, CEO
Perfect. Does that answer your question, Paul?
Paul Matteis, Analyst
Yes, definitely.
Operator, Operator
We'll now take our next question from Anvita Gupta from Cowen.
Anvita Gupta, Analyst
This is Anvita on for Ritu today. Congrats on the quarter. So two questions from my side. Do you expect the fourth quarter new lockdown impact to be better or worse than the second quarter lockdown impact? And then, secondly, understood that it's unclear how many cardiomyopathy patients would be in HELIOS-A study, but if you do plan to provide a subgroup cardiac analysis, what would be the primary function outcome of such an analysis?
John Maraganore, CEO
Great. I'm going to have Akshay answer the second question, but regarding the first question, let me just give a high level and then Andy, you can comment. At a high level, it’s our belief that the medical system is more adapted at this point than it was in Q2. I'm saying this from a global perspective. For the most part, we have seen a return to medical procedures and diagnostic testing globally. Therefore, we believe that even with shutdowns occurring as we go into Q4 to deal with the second or third wave, we expect the medical system to stay relatively open compared to what we saw in Q2. Andy, do you want to add any more color to that?
Andreas Orth, Senior Vice President and Head of the U.S. business
You've got it right, John. Furthermore, the healthcare systems have learned how to navigate this and are showing that with increased patient flows coming through and continuity of care. We're in a much better position here to weather what may come.
John Maraganore, CEO
Fantastic. Akshay, do you want to answer the HELIOS-A question?
Akshay Vaishnaw, President of R&D
Yes. Thanks, Anvita. We must remember that the primary goal of the HELIOS-A study is to study the neuropathic aspects of the disease. Most of the endpoints focus on that. As I said before, we will see how many patients with true cardiomyopathy we have and report all data we’ve collected, including biomarkers and echo findings. The primary functional outcome would, I believe, be hospitalizations and deaths. But again, the study is not oriented towards cardiomyopathy.
John Maraganore, CEO
Great. Does that answer your question?
Anvita Gupta, Analyst
Yes.
Operator, Operator
Moving on to our next question, it's from Alethia Young from Cantor Fitzgerald.
Emily Bodnar, Analyst
This is Emily on for Alethia. In light of some of the recent progress and challenges in AAT, we're curious to see how you're thinking about plans going forward with ALN-AAT. And do you think that combination therapies are some of the long-range goals here?
John Maraganore, CEO
I'm not sure I heard you clearly on the first part, Emily; could you repeat what area you're commenting on specifically?
Emily Bodnar, Analyst
For AAT.
John Maraganore, CEO
Okay. I got it. Absolutely, we are excited about the potential for RNAi therapeutics to treat the liver disease associated with alpha-1 antitrypsin deficiency and obviously have advanced a molecule ALN-AAT02 into development. Earlier this year, we decided to partner that program with Dicerna, who had their independent effort as well. The combined effort between Alnylam and Dicerna now is well positioned to advance this and is currently in a Phase I/II study. We are very excited about this opportunity, and we think it becomes a very competitive opportunity to deal with the liver manifestations of the disease.
Yvonne Greenstreet, President and COO
No, John, I think you've covered it very well.
Operator, Operator
We'll now take our next question from Ted Tenthoff from Piper Sandler.
Edward Tenthoff, Analyst
Just to congratulate you on continued excellent execution on the commercial side, especially going through difficult times. Really incredible to see just how, over the years, the vision to come together on how you're treating patients so effectively now. My question is related to fitusiran. A lot of the others were answered. But kind of what's the latest there? And we haven't really talked about that one as much recently just because there's been such a focus on the success with the other programs. But kind of how have you seen that market change over the last year? Where do you think that fits for Sanofi and for you guys going forward?
John Maraganore, CEO
Yes. Thanks, Ted. First of all, for your comments, the congratulatory remarks at the beginning. On fitusiran specifically, as you know, this is partnered, and as you mentioned, it targets antithrombin with the goal of increasing thrombin generation to improve hemostasis in patients with hemophilia A and B, with and without inhibitors. It's a highly attractive target product profile that we've constructed for the molecule. The program is in Phase III, being led by Sanofi, and we rely on their continued execution of the program. We hope to learn more in the next period. That's where it is. Sanofi has been the driver of the program, and it’s ultimately their call as to how they advance it. I don’t know if Akshay or Yvonne have anything else to add from your perspective?
Akshay Vaishnaw, President of R&D
The only thing I'd add is that the hemophilia landscape continues to need innovation. The adoption of Hemlibra shows that people are keen to find therapies other than multiple times a week intravenous factor replacement. I'm excited about fitusiran. There's a great home for it both in hemophilia A and B with and without inhibitors. However, as John said, Sanofi would guide you on further progress with the program.
John Maraganore, CEO
Yes. Great. Can you just remind us your commercial interest there? Yes. So we have royalties on fitusiran that range from 15% to 30% tiered to sales. We do have a significant and attractive financial interest in the product's success.
Operator, Operator
Our next question comes from Anupam Rama from JPMorgan.
Tessa Romero, Analyst
This is Tessa on the call, John. Regarding the APOLLO-B trial enrolling in ATTR-CM, I believe you mentioned that enrollment is expected to finish in 2021. When thinking about an internal analysis, what factors are you taking into account? Also, can you give us a brief overview of the size and scope of the data we can expect at the AHA conference next week regarding the ALN-AGT update?
John Maraganore, CEO
Yes. Terrific. Great questions. Let me first clarify with APOLLO-B, which is the patisiran study in both hereditary and wild-type ATTR cardiomyopathy. That's a 12-month study. There is no interim analysis. You certainly are right about an interim analysis on HELIOS-B. So I just want to clarify the trial. Tessa, you meant HELIOS-B.
Tessa Romero, Analyst
Yes. I'm sorry, John; I meant HELIOS-B. I misspoke.
John Maraganore, CEO
Okay. That's what I wanted to clarify. Akshay, do you want to comment on HELIOS-B a little bit in terms of interim analysis?
Akshay Vaishnaw, President of R&D
The HELIOS-B interim analysis will be very interesting to execute on. We've picked up enrollment well this year after that slow Q2 with COVID. As we further enroll in that study, and importantly, as we approach the completion of APOLLO-B, this will give important information on how our TTR reducing approaches impact cardiomyopathy. That information will be of strategic importance regarding the design of the interim analysis, and we will share further details with you as recruitment increases and we get more from APOLLO-B ultimately as the results read out.
Tessa Romero, Analyst
Okay, thanks.
Akshay Vaishnaw, President of R&D
Yes. Regarding your other question about ALN-AGT at American Heart next week, yes, that's the first time we'll be sharing all the data that we have. There will be safety information, especially since it's the first-in-human study. We'll also be sharing all the pharmacodynamic data on target knockdown and how that relates to changes in blood pressure. We've reported that there are significant changes in blood pressure, and you’ll see all the data in full, including dose dependence and the extent of change in systolic, diastolic, etc. I think attendees will gain valuable insight into the frequency of dosing. We believe this will be an infrequently administered therapeutic for hypertension as we further develop it, thus addressing compliance issues for patients.
John Maraganore, CEO
Does that answer your question?
Operator, Operator
We'll take our next question from Joel Beatty from Citi.
Joel Beatty, Analyst
Great. For Alnylam HSD in NASH and that recently initiated study, could you discuss the potential to evaluate any efficacy or biomarker endpoints?
John Maraganore, CEO
Absolutely. Akshay, do you want to talk about the HSD Phase I?
Akshay Vaishnaw, President of R&D
Yes. That study is ongoing. It will progress from healthy volunteers, dosing in ascending dosage fashion into a subset of NASH patients. The target HSD doesn't circulate in the blood. Like many of our programs, we won't have direct biomarker data on the target itself, but there are other downstream factors we are looking at in terms of biomarkers and we believe will be very informative. We’ll share more on that as the study progresses next year. Ultimately, what goes on in the liver of NASH patients will be very important, both biochemically and radiographically, and we'll share our progress as the study matures.
John Maraganore, CEO
I’ll also add that our upcoming R&D Day in December will be an opportunity for us to do more of a deep dive on the HSD opportunity and the clinical plans for that program. It is an exciting area as it's a genetically validated target for NASH, and we think it holds great promise in that important indication.
Operator, Operator
We'll now take our next question from Maury Raycroft from Jefferies.
Maurice Raycroft, Analyst
Congrats on the progress. First one is also on the ALN-AGT program. For the data next week, I'm just wondering if you're going to have some data from the additional exploratory cohorts, including obese patients, a soft control cohort, and our combo cohort as well. If not, what's the latest status with those cohorts? How meaningful are they? And what are the next steps with the program?
John Maraganore, CEO
Great questions. The simple answer is you won't see those cohorts next week because they haven't been dosed. Akshay, do you want to comment on the next steps for those cohorts and the completion of Phase I?
Akshay Vaishnaw, President of R&D
Yes. The study did get delayed in part due to Q2 COVID, which impacted many others. We've picked up steam and haven't commenced dosing as John said yet, but we're now in place to start dosing those cohorts, which will continue through the rest of the year. In due course, we’ll report a further update on the Phase I study early next year at a scientific meeting where we can bring that information to everybody. However, most importantly, next year, beyond the clear antipertensity effect we believe we've established and everyone will get to see next week at AHA, the most important thing is to transition that observation into the Phase II setting. We are aligning on the Phase II effort and are eager to get that going next year.
John Maraganore, CEO
Again, our upcoming R&D Day will feature a deep dive into the hypertension opportunity because it is obviously an exciting prospect for high innovation in Alnylam's pipeline.
Operator, Operator
Moving on to our next question, it comes from Salveen Richter from Goldman Sachs.
Sonya Bhatia, Analyst
This is Sonya on for Salveen. Just a quick question on the progress of your extrahepatic portfolio, particularly there with the ALN-APP. When can we expect first data there?
John Maraganore, CEO
Thanks, Sonya. At the outset, we’re excited about our ability to access non-liver tissues. We have a lot of opportunity in front of us with partnerships that enable us to do more. Regarding the APP program, we'll be taking that into Phase I next year, with guidance to enter Phase I around mid-next year. Further guidance on when we'll actually see data will arrive once we’ve commenced the Phase I study.
Akshay Vaishnaw, President of R&D
It’s a very interesting time with the ongoing aducanumab review, and there is a lot of excitement around what those data will show. It'll be interesting to observe the outcome of that.
John Maraganore, CEO
Yes. We continue to believe that APP is vital for the Alzheimer's disease treatment framework and that we can influence both a-beta deposits and intra-neuronal aspects of the disease to make a significant contribution that impacts in that area.
Operator, Operator
We'll now take our next question from Alan Carr from Needham & Company.
Alan Carr, Analyst
Can you provide more detail about your COVID candidate? Where do things stand and what work is still needed? I’m interested in your views on potential candidates and other targets related to COVID-19. Can you give a more detailed update?
John Maraganore, CEO
Yes. Happy to, Alan. We're committed to advancing our COVID program, targeting the SARS-CoV-2 genome directly with our RNAi technology. We’ve done some work, particularly in the hamster model, which validates our investigation of SARS-CoV-2 infections. We’re encouraged by our results in that model but will conduct further testing before finalizing our clinical development plans and IND timing, allowing us to understand the most promising position of this molecule in treating COVID-19. We're playing the long game with this program, addressing ongoing health challenges relatable to COVID-19, similar to ongoing management approaches for diseases like flu.
Akshay Vaishnaw, President of R&D
No, I think you've covered it, John. That's exactly right.
Operator, Operator
We'll now take our next question from Patrick Trucchio from H.C. Wainwright.
Patrick Trucchio, Analyst
With the understanding that the closure in the U.S. election may take some time, I'm wondering if you can comment on how a potential change in the administration could impact healthcare policy and what impact, if any, this could have on Alnylam's R&D or commercial execution in the U.S. in 2021 and beyond.
John Maraganore, CEO
Okay, great. Yes, we hope to see clarity on the election soon. It’s heartening to see our democracy at work, counting all the votes. Regardless of the outcome, we believe that the dialogue on drug pricing will continue. Alnylam is well positioned because of the type of innovative medicines we consistently deliver from our platform. The ways we've engaged with payers around risk-sharing and value delivery will bode well for continued success. We are optimistic and expect to navigate changes with governmental and payer discussions effectively.
Operator, Operator
We'll now take our next question from Leland Gershell from Oppenheimer.
Leland Gershell, Analyst
I echo others' comments on the solid execution. Just a question on the reimbursement and progress with OXLUMO having gone through the VBA discussions with others. On GIVLAARI, I wanted to ask if you have any comments on the differences you're seeing in that progress, and if you would expect it to be on pace with where you were with GIVLAARI as you execute on OXLUMO.
John Maraganore, CEO
That’s a great question, Leland. Let me say how proud I am of our access teams around the world for their excellent work with ONPATTRO, GIVLAARI, and now with OXLUMO. We're very optimistic about OXLUMO's potential as we signed approximately 30 VBAs with commercial payers in the U.S. Too, early feedback on OXLUMO discussions has been exceptionally positive, indicative of access goals similar to those we established with GIVLAARI and ONPATTRO. Andy, do you want to elaborate on OXLUMO specifics?
Andreas Orth, Senior Vice President and Head of the U.S. business
Certainly. Similar to our previous products, we are pursuing an aggressive value-based agenda with all payers globally. Feedback during early stages has been exceptional. We expect similar results regarding open access with OXLUMO as we did with GIVLAARI and ONPATTRO, which is, really, really strong. We will continue to lead in this industry.
Operator, Operator
Moving on to our next question, it comes from Mani Foroohar from SVB Leerink.
Mani Foroohar, Analyst
A quick one, I guess, starting with Jeff. Talk a little bit about the increasing compliance as a driver of ONPATTRO performance. I presume some of that is from patient wariness about coming in for their IV during the height of the pandemic. Has that compliance trend reversed entirely? Is there still a little room for growth into next quarter and beyond? And for Akshay, there's been much discussion about what HELIOS-A tells us about HELIOS-B. I'm inclined to agree that maybe APOLLO-B is the more useful leap forward. Can you give us detail on how you are considering an option on HELIOS-B interim? Is the best approach to wait until you have APOLLO-B data to inform that? Or do you think that the data you gather on a blinded basis from HELIOS-B itself will provide you with the information needed on if and when to take that interim?
John Maraganore, CEO
Sure. Those are great questions, Mani. Let’s start with Jeff and then Akshay can address the second question. Jeff?
Jeffrey Poulton, CFO
Certainly. Just to remind you, growth in Q3 was a mix of net new patient demand, as well as an increase in compliance rates specifically in the U.S. after Q2 COVID impacts. In Q4, we expect the growth to primarily stem from that net new patient demand. Now regarding inventory, Gena, we ended Q3 for ONPATTRO at less than 2 weeks. The distribution agreements allow for that 1 to 3 weeks, so we are right in the middle of that at this point.
John Maraganore, CEO
Fantastic. Akshay, do you want to tackle the more elaborate question regarding HELIOS-B?
Akshay Vaishnaw, President of R&D
The HELIOS-B interim analysis looks to be very interesting as we ramp up enrollment. We have resumed after slow pace due to COVID in Q2, and as recruitment progresses, importantly, we will gain insight from APOLLO-B to inform the interim analysis, thus leveraging findings from both studies toward our end goals.
John Maraganore, CEO
Yes, does that answer your question, Mani?
Mani Foroohar, Analyst
Yes. That's great.
Operator, Operator
We'll now take our next question from Navin Jacob from UBS.
Jonathan Lim, Analyst
This is Jon on for Navin. Regarding your comments on COVID recovery across geographies, we're curious if there have been any shifts in the payer mix for your assets on GIVLAARI and ONPATTRO. Could you comment on which analogue might be better for us to prepare for the OXLUMO launch?
John Maraganore, CEO
Those are great questions. I’m handing this over to Andy to address these queries as best as possible.
Andreas Orth, Senior Vice President and Head of the U.S. business
Thanks. Let's start with changes in payer mix. In the United States, we’re seeing little to no changes in payer mix. ONPATTRO is predominantly Medicare, while GIVLAARI is primarily commercial, and we haven’t seen material shifts due to COVID. For OXLUMO, in terms of payer mix analogue, neither product suits perfectly, but OXLUMO will likely lean more towards commercial and/or Medicaid insurance, making it closer to GIVLAARI.
Operator, Operator
Moving on to our next question, it comes from Vincent Chen from Bernstein.
Vincent Chen, Analyst
A little far off, but looking at the CNS side of things regarding ALN-HTT in Huntington's, I'd like to gauge your thoughts on how this might offer advantages over competitive programs in this space, particularly Roche and Ionis' tominersen. Are there reasons to expect ALN-HTT to outperform in terms of knockdown achieved, breadth, or ultimately, efficacy?
John Maraganore, CEO
I will hand that over to Akshay. Thanks for the question, Vincent. It's noteworthy that our RNAi approach, with proven efficacy in the liver, points to potential advantages in CNS applications as well. We anticipate deeper knockdown with our platform compared to anti-sense oligos as illustrated with marketed products. We believe ALN-HTT will demonstrate similar benefits, especially in targeted CNS structures.
Akshay Vaishnaw, President of R&D
Yes. I completely agree. Along with our platform's pharmacologic attributes, the target strategy is also critical. The literature suggests exon 1 plays an essential role in disease pathology with neurotoxic properties, making our exon 1-centric approach unique and relevant to clinical expectations. We look forward to beginning the clinical stages for ALN-HTT.
Operator, Operator
We'll take our next question from Luca Issi from RBC.
Luca Issi, Analyst
Congrats on the commercial execution. Maybe returning to the cardiomyopathy discussion but with a more commercial angle here. Do you think APOLLO-B will be sufficient for clinicians to shift prescribing habits from Vyndaqel to ONPATTRO? Or will most physicians need to wait for HELIOS-B, considering that APOLLO-B primarily focuses on the 6-minute walking distance?
John Maraganore, CEO
Great questions. Andy, would you care to expand on that for us? Keeping in mind that APOLLO-B is currently not branded ONPATTRO, but the investigational study which assesses hereditary and wild-type ATTR amyloidosis.
Andreas Orth, Senior Vice President and Head of the U.S. business
Of course, John. We're excited about the potential of APOLLO-B with approval expectations for hereditary and wild-type cardiomyopathy later. Audiologists working with ONPATTRO have strong existing experience treating polyneuropathy, which we believe will shift physician preferences in favor of TTR silencers like ours versus stabilizers. We anticipate reimbursement conditions will also be favorable.
John Maraganore, CEO
Awesome, does that answer your question, Luca?
Luca Issi, Analyst
Yes.
Operator, Operator
I'll turn the conference back to the company for closing remarks.
John Maraganore, CEO
Thank you, everyone, for joining us. We're in an exciting growth phase as a leader in biotech. We're proud of our Q3 results and our efforts from our commercial and R&D teams. We’ll continue to keep you updated on our progress at our upcoming R&D Day in December. Until then, stay safe and healthy. Have a great day. Bye-bye.
Operator, Operator
And that concludes today's call. Thank you for your participation. You may now disconnect.