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spk22: 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 Merriganori, Chief Executive Officer, Andy Orth, Senior Vice President and Head of the U.S. Business, Akshay Vaishnav, 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. During today's call, as outlined in slide two, John will provide some introductory remarks and provide some 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 would like to remind you that this call will contain certain remarks concerning O'Neill'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 and quarterly reports and APAs on file with the SEC. In addition, any forward-looking statement represent our views only as 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.
spk11: Thanks, Christine, and thank you, everyone, for joining the call today. We believe the third quarter and recent period highlight the tremendous progress El Nilem has made as a global commercial organization with a highly productive R&D platform. Starting with our commercial execution, we saw strong Onpatro and Giblari 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 Onpatro revenue guidance range for 2020 and another beat for Giblari 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 Lumaceran, and Lecvio, or Inclisiran, which set us up with the potential to achieve four RNAi therapeutic approvals and launches in less than three years, a truly remarkable achievement. You'll also hear from Jeff on our financial performance and our progress toward achieving a self-sustainable financial profile. We believe we're on our way. Indeed, at Almilum, we're focused on continued global commercial execution on 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 multi-product, 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 very bold goals, which we're on track to actually exceed, and we couldn't be more excited for the next phase of Alnylam's evolution, We will lay out our multi-year 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 the mornings of December 15th and 16th, 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?
spk03: Thanks, John, and good morning, everyone. I'll begin by reviewing our commercial performance in this third quarter, as well as our medical affairs progress. For OnPatro, we achieved $82.5 million in global net product revenue, delivering 24% growth versus Q2, primarily driven by increased patient demand. As of September 30th, over 1,150 patients were on commercial on-patro 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 Onpatro with TTR stabilizers and expect this trend to continue to grow. Turning to the rest of the world, we made very encouraging progress with Onpatro 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 also pleased with the continued growth in Japan, a country of strength for Onpatro. An important dynamic observed in XUS is patients switching to Onpatro from stabilizers for the potential to halt or reverse disease progression in HATTR patients with polyneuropathy. This dynamic represents greater than 50% of new Onpatro 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 a pathogenic TTR mutation. We are encouraged by the recovery in L-Nylomac 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 amyloid. As you know, HATTR amyloidosis is a multisystemic 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. Untatro continues to be recognized as a breakthrough for patients with HATTR amyloidosis with polyneuropathy, and we're honored to have received the highly prestigious Pre-Galien USA Award just last week. Moving on to Givlari, we achieved $16.7 million in global net product revenues in the quarter, with over 150 patients now on commercial drugs. 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 Giblari to date, and we're pleased to see the majority of plans adopt medical policies without restrictions to the number of baseline attacks. The Samia region saw great progress as well. with a successful ongoing GIVLARI launch in Germany and name patient sales in other countries, including France. We're off to a very strong start for market access in Samia. In France, GIVLARI received an improvement of medical benefit, or ASMR, score of two, concluding it offers significant additional therapeutic value. Additionally, GIVLARI 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 HCA 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 Domaceran. With a positive CHMP opinion in hand in the EU, and an FDA PDUFA date just weeks away on December 3rd, we look forward to soon bringing our third RNAi therapeutic to patients around the world. We are well-prepared with our Oxlugal 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 the 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 OnPatro, the continued launch of GiveLawry, and the preparation for the launch of Oxlumo. And we'll be watching with excitement as Novartis prepares to launch Lecvio or Inclisiran, which will mark the entry of RNAi therapeutics into a highly prevalent chronic disease indication. With that, I will now turn it over to Akshay to review our recent R&D and pipeline progress.
spk26: Akshay? Thanks, Andy, and good morning, everyone. I'll start with our efforts in AT-Tamilidosis, where we're advancing our two product candidates, Patisiran and Vutrisiran. Basal and Patra is currently approved in multiple markets around the world to treat the polyneuropathy associated with hereditary ATT amyloidosis. We're committed to expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild-type ATT amyloidosis patients. To this end, we're conducting the Apollo B Phase 3 study. We continue to enroll patients in Apollo B and continue to 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 butrysran for the treatment of ATTR. Butrysran is delivered by a quarterly subcutaneous injection. Here, we're conducting two phase three studies. The first phase three study is Helios A, which is evaluating butrysran 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 vitreous RAN is Helios B, which has been conducted in hereditary and wild-type ATK amyloidosis patients with cardiomyopathy, and this study is actively enrolling. On our TTR RNAi roundtable in September, we shared modeling data suggesting the potential for a biannual dosing regimen for vitreous RAN. which could further differentiate Vutrisran from other products currently approved or in development. We're 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 GIVLARI, which is approved in the US, EU, Brazil, and Canada to treat acute hepatic porphyria. We're pleased with continued data supporting a positive risk-benefit profile. For example, during the third quarter, we presented new interim data from the Phase I to OLE study of GIVLARI, 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 Lumasran, an investigational RNAi therapeutic that we're developing for the treatment of primary hypoxylurea type 1 or PH1. We're also thrilled to receive last month a positive CHMP opinion recommending approval of Limaciran for the treatment of PH1 in all age groups. Recently, we presented full results from the Illuminate B study of Limaciran in pediatric patients less than six years old. In the study, treatment with Limaciran led to a 71% mean reduction in spot urinary oxalate to creatinine ratio from baseline to month six. This was the primary endpoint of the study. Lumastran 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 70% of patients. The overall efficacy and safety profile of Lumastran was consistent with that observed in adults and children six years or older in the Illuminate A study. In both the Illuminate A and B studies, we continue to see encouraging evidence towards certain clinical events such as nephrocalcinosis and renal stone events, or RSEs. In Illuminate A, we previously reported on encouraging results with improvements in nephrocalcinosis and exploratory endpoint. At ASN, we showed some initial results from Illuminate A on improved RSEs with continued dosing. Based on the preliminary analysis of exploratory endpoints in Illuminate B, Treatment with Lumastran 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 Lumastran 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 Lumaciran for the treatment of advanced PH1 patients of all ages with data expected in 2021. As you know, we have two additional late-stage programs that are in development with partners. This includes Inclisiran in development for hypercholesterolemia, partnered with Novartis, which is in registration in the United States and the EU. We're delighted that Inclisran 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 Lekvio. Our late-stage programs also include Fetuceran in development for hemophilia A or B with or without inhibitors partnered with Sanofi. Fetuceran is under evaluation in the Phase III ATLAS program. Now, in addition to our late-stage clinical programs, we believe we've also been making great progress with our early and mid-stage programs. Our partner, VIA, has initiated dosing of LNHBVO2 or VO221A 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 control of 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, co-commercialization option on this program, with Alnylam retaining the lead. LnCoV, or LnCoV, is our investigational RNAi therapeutic targeting the genome of SARS-CoV-2, the virus that causes COVID-19. It's 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 and upcoming R&D Day virtual event planned for December 15 and 16 later this year. With that, let me now turn it over to Jeff to review our financial results. Jeff?
spk04: Thanks, Akshay, and good morning, everyone. I'm pleased to be presenting Outline Loans' third quarter 2020 financial results. As Andy has already highlighted, it was a very strong quarter with outstanding results for both Onpatro and Giblari. Turning to our results first for OnPatro, we generated $82.5 million in global net OnPatro 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 on PATRO 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 pre-pandemic levels, as well as the addition of new patients during the quarter. Modest inventory stocking during the quarter compared with destocking during Q2 2020. offset by a slight increase in gross-to-net sales reductions, favorably impacted Q3 growth by 7%. We ended the quarter with less than two 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. And our international markets on PATRO performance remain strong, with growth of 27% versus Q2 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. 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 Gibraltar, 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 VEER 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 OnPatro full-cost inventory, while last year benefited from zero-cost OnPatro inventory. as well as having a higher proportion of sales in the third quarter of 2020 coming from lower margin international markets and a write-off of on-patro 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 Onpatro and Gablari and the launch of preparation activities for Oxaluma. 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 will 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 and Klee Saran 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 OnPatro results, we are increasing our full year 2020 revenue guidance for OnPatro from 280 to 300 million to 295 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 are expecting 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 Oxaluma. 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 a 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. And with that, I'll now turn the call over to Yvonne to review our goals for the remainder of the year. Yvonne?
spk24: 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 Onpatro and Givlaris. We're also expecting two additional regulatory approvals by the end of the year for Lumasterin 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 Piticeran and Helios B with Vitritiran. 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 the 13th. And our partner Regeneron plans to initiate a phase one study of semgiseran in combination with pizellamab 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 is a global multi-product 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?
spk22: Thank you, Yvonne. Operator, we will now open the call for questions. To those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have additional questions.
spk12: Thank you. If you would like to ask a question, please press star 1 on your telephone keypad. If you're using a speakerphone, just make sure that your mute function is turned off to allow your signal to reach our equipment. Again, that is star one to ask a question. We'll pause for just a brief moment to allow everyone an opportunity to signal for questions.
spk18: Once again, that is star one to ask a question.
spk19: We'll take our first question from Jenna Wang from Barclays. Please go ahead. Your line is open.
spk13: Thank you. Thank you for taking my questions, and congrats on a very strong quarter. So one question regarding the commercial. First, you know, for the Ampatro, do you expect, you know, for the 4Q, any thoughts on the inventory and where the major driver will be for the remaining of the years? And also for Lumacerin, could you share with us the number of patients in early access programs right now?
spk11: Yeah. So, thank you, Gina. Let's, let's, I'll go to, I'll go to Andy and Jeff on the Ampatro question specifically. Regarding the Lumacerin EAP, you know, we're not giving out specifics on patients that are in the program. But I will say at a high level that obviously we do have patients in our expanded access program. And obviously, as the master end gets approved, we will be transitioning those patients onto commercial product on a country-by-country basis based on P&R being achieved. So that's where we'll leave that question. Andy, do you want to start? And then maybe, Jeff, you can comment on the impact of inventory. But I think, Andy, you can give a bigger picture on Q4 expectations for on Patreon.
spk03: 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.
spk04: Yeah, hi, everybody. In terms of where we are in inventory, Gina, at the end of the third quarter for OnPatro, we're less than two weeks. And based on the distribution agreements we have, that range is typically in the one to three weeks range. So, again, we're right maybe right in the middle of that at this point.
spk13: Okay, great. Thank you very much.
spk18: Thanks, Gina.
spk19: We'll now take our next question. from Hazeen Ahmed from Bank of America. Please go ahead. Your line is open.
spk17: Good morning. Thank you so much for taking my questions. 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 and the Helios B study? Thanks.
spk11: Yeah, that's a great question to Zine. And I'll let Akshay handle it. Let me just start by saying we're very excited about Butrisaran because it is obviously going to enable a once-quarterly subcutaneous dose administration, and potentially, with additional work, we believe that we can introduce a biannual dosing regimen for patients with HATTR. Initially, it'll be for the polyneuropathy setting with the Helios A study, and then, obviously, the focus will be in Helios B on cardiomyopathy, both hereditary and wild-type. So, Akshay, do you want to comment specifically on Tazeem's questions around what will be available at the top line and what potential read-through there will be on cardiomyopathy from Helios A. Yeah, thanks, John.
spk26: So vis-a-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 give the primary endpoint and relevant secondaries and Also, of course, the safety information on the study at a high level that's relevant to the report. We will then report more fully on all the details at an upcoming scientific meeting after that. So those dates should be very informative as to how the study is done, I think. And vis-a-vis the read-through into cardiomyopathy and heliospeed, If we harken back to Apollo, the original Apollo study with Onpatro, I think we learned a lot there about the impact on biomarkers, the impact on echo finding in about 50% of the patients that had some evidence of cardiomyopathy within that study population for Onpatro. Now, it remains to be determined exactly what proportion of patients have cardiac involvement here in Heliocene. but it'll be exciting to see, you know, what the impacts have been on not just biomarkers, but other aspects of the disease in terms of further read-through.
spk20: That very much depends on the input population. Thanks, Akshay.
spk11: Does that answer your question?
spk17: Yes, and when you say early next year, is it possible that the data would be in January, or are you not providing that level of granularity?
spk11: Yeah, we're not going to provide that level of granularity, Kazim. Our early period, as you know, is Q1 or Q2. But I think it's going to be early.
spk18: Okay. Thank you. We'll now take our next question from Paul Matias from Seifel.
spk19: Please go ahead. Your line is open.
spk08: Great. Thanks so much, and congrats on the quarter. Two questions. One, on Dutrisiran, Do you think you could bridge to the six-month dose with just TTR lowering data and safety? And if so, what's the status of that clinical work? And then second, on Lumacerin, on the Wall Street side, expectations for this drug are materially lower than that of Gavoceran. But I think some of the prevalence data for PH1 and 2, 3 that you've outlined are not that dissimilar to AHP. So do you think Gavoceran is a realistic analog for this? And if so or if not, can you give any context? Thanks.
spk11: Yeah, thanks, Paul, and great questions. You know, I think for starters on the VUTRI Q6 monthly, you know, at a high level, it is certainly our belief that TTR lowering combined with safety should support that approach, and we've been encouraged by engagement that we've had with regulators on that point. So I think that is certainly a path forward. And that would be consistent with other types of medicines where dose regimens with a strong biomarker have been supported in future labeling. But obviously, that'll require those data to be generated and then obviously 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 on that further. But I think in general, When we look at the prevalence out there, we do believe that there are 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 comment any further on the PH1 population and how we should think about the mass rent relative to Giblari?
spk03: Sure, John, thanks. And as you said here, we're at this point expecting that number somewhere between 1,000 and 1,700 that would be addressable and on-label. And overall market opportunity, we do see Luma becoming a $500 million brand as it launches globally. And furthermore, we're excited to get out there and continue to shape this market, which is largely to this point pretty underserved, so we'll be learning a lot as we go.
spk18: Terrific. Does that answer your question, Paul? Yep. Thank you, Paul. Thank you.
spk19: We'll now take our next question from Anita Gupta from Coing. Please go ahead. Your line is open.
spk14: Hi, guys. This is Anvita for Ritu today. Congrats on the quarter. So two questions from our side. Do you expect the four-quarter year EU 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 us a group cardiac analysis, what would be the primary function outcome of such an analysis? Thank you.
spk11: Great. Well, I'm going to have Akshay answer the second part, the second question. But regarding the first question, let me just give a high level, then Andy, you can comment. You know, look, 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 globally from a global perspective. And for the most part, we have seen a return to medical procedures, and diagnostic tests being done globally. And therefore, we believe that even with shutdown of countries that will occur, could occur as we go into Q4 to deal with the second wave or third wave, depending on where you are, we do expect the medical system to stay relatively open relative to what it was like in Q2. Andy, do you want to add any more color to that?
spk03: Yeah, you've got it right, John. And furthermore, Yes, the healthcare systems learned how to navigate and are showing that now with increased patient flows coming through, maintenance of therapy for all levels of all patients continuing. But we have learned as well how to navigate this, both on a promotional basis and continuity of care. So we're in a much better position here to weather what may come.
spk11: Fantastic. And Akshay, do you want to answer the Helios A question?
spk26: Yeah, thanks, Anvisa. You know, we've got to remember that the primary goal of the study is to study the neuropathic aspects of the disease. So most of the endpoints are focused on that, certainly the primary endpoint and so forth. Now, as I said before to a previous question, we'll see how many cardiomyopathy patients or patients with true cardiomyopathy we have and report out all the data that we've collected, including biomarkers, echo, In terms of the primary functional outcome, as you put it, I guess the most important would be hospitalizations and deaths. But, you know, again, this study is not orientated towards cardiomyopathy, so I don't know exactly how many of those events would have occurred, but we'll certainly be sharing them in due course.
spk18: Great. Does that answer your question? Yes, thank you. Fantastic.
spk19: Moving on to our next question. This is from Alicia Young from Cantor Fritz Charlotte. Please go ahead. Your line is open.
spk15: Great, thanks. This is Emily. I'm for Alicia. Thanks for taking my question. 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 this medicine for RNAi. And do you think that combinations of systemic and RNA therapies are kind of the long-range goal here? Thanks.
spk11: So I'm not... I'm not sure I heard you clearly on the first part. Emily, could you repeat what area are you commenting on specifically?
spk15: For AAT.
spk11: Oh, alpha-1 and 2-trypsin.
spk15: Yeah.
spk11: Okay, got it. Absolutely. Yeah, look, I mean, we are excited about the potential for RNA therapeutics to treat the liver disease associated with alpha-1 and 2-trypsin deficiency, and and obviously have advanced a molecule, ALN-AAT-02, into development. Now, earlier this year, we decided to partner that program together with Dicerna, who had their own independent effort as well. And so the combined effort between Almylam and Dicerna now really is positioned to advance quite nicely and is currently going to be in a Phase I-II study, will be going into a Phase II-III in due course. So we're definitely excited about the opportunity. The way the partnership with Dicerna works is they will advance the program 100% on their cost. We retain an opt-in right at the end of phase three. So after all the risk is taken out, it's a free opt-in that we have to commercialize outside the U.S. market. So they'll keep the U.S. and we'll have the rest of the world. So we are encouraging our colleagues at Dicerna to move swiftly with the program, and we do think that it becomes a very competitive opportunity to deal with the liver manifestations of the disease. Yvonne, anything else from your perspective to add as it relates to the Dicerna relationship?
spk24: No, John, I think you've covered it really well.
spk18: Great. Emily, does that answer your question? Yes, thank you.
spk19: We'll now take our next question from Ted Henthoff from Piper Sandler. Please, Ted.
spk25: Hey, thank you very much. And just to congratulate you on continued excellent execution on the commercial side, especially during a difficult time. Really incredible to see just how, over the years, the visions come together and how you're treating patients so effectively now. My question had to do with the T-SWAN. 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 a little bit over the last year? And where do you think that fits for Sanofi and for you guys going forward? Thanks.
spk11: Yeah, thanks, Ted. Thanks, first of all, for the comments, the congratulatory comments at the beginning. But on Fetuceran specifically, As you know, this is partnered, and as you mentioned, this is partnered with Sanofi. It's an RNA therapeutic that targets antithrombin with the goal of increasing thrombogeneration to improve hemostasis in patients with hemophilia A, hemophilia B, with and without inhibitors. So it really is an attractive target product profile that we've constructed for the molecule. The program is in phase three. It's being led by Sanofi. And, you know, we really rely on their continued execution of the program. So we hope to learn more in, you know, the next period. And so that's where it is. But, you know, I think for the most part, Sanofi really has been the driver of the program. And it's ultimately their call in terms of how they advance it. I don't know, Akshay or Yvonne, anything else to add to that from your perspectives?
spk26: I think the only thing I'd add is that the hemophilia landscape, you know, 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. And so we're excited about Fertuzoran. Hopefully there's a great home for it both in hemophilia A and B with and without inhibitors. But as John said, you know, Sanofi would guide you on further progress with the program.
spk25: Great. Can you just remind us your commercial interest there? Thanks, guys.
spk11: Yeah, so we have a very important point. So we have reciprocal – we have royalties on Tattoo Saran that range from 15% to 30%. It's here to sales. So we do have a significant and attractive financial interest in the product success, no question about it.
spk18: Great. Thanks so much. Thanks, Ted. Thanks, Ted.
spk19: Our next question comes from Anupam Rama from JP Morgan. Please go ahead.
spk01: Hi, guys. Good morning. This is Tessa on the call for Anupam. Thanks for taking our question. So, for with the Apollo B trial enrolling in ATTR-CM, I think you noted that enrollment is expected to complete in 2021. Sort of when considering a potential for an interim analysis here, what are the factors that you're considering? And then a second quick one, on the ILM-AGT update next week at AIHA, can you just give us a quick sense of the size and scope of the data we'll be seeing at the conference there next week? Thanks so much.
spk11: Yeah, terrific. Great questions. Let me just first clarify with Apollo B, which is the Petit-Saran study in both hereditary and wild-type ATTR cardiomyopathy, that's a 12-month study. There is no interim analysis. You certainly are right regarding an interim analysis on Helios B. So I just want to clarify, what trial?
spk01: Yeah, I'm sorry, John. I met Helios B when I spoke. Yeah.
spk11: Okay, that's why I wanted to clarify it. Okay. So, Akshay, do you want to comment on Helios B a little bit and interim analysis?
spk18: Akshay, are you on mute?
spk26: The Helios B interim analysis obviously, you know, is going to be very interesting to execute on. We've picked up enrollment very well this year, you know, after that slow Q2 with COVID. And as we further enroll in that study, and also, importantly, completion of the Apollo B study, which will give important information on how our TTR-reducing approaches impact cardiomyopathy, that information will be of strategic importance, I think, in design of the interim analysis, which we're busy working on. And we'll share further details with you as the enrollment picks up and we get more from Apollo B, ultimately, as the result reads out. With respect to your other question, Tesla, on L and AGT at American Heart next week, yep, that's the first time we'll be sharing, you know, all the data that we have. There'll be obviously safety first and foremost. It's the first in human study. We'll also be sharing all the pharmacodynamic data on target knockdown and how that relates to change in blood pressure. We've reported that there are significant changes in blood pressure, but you'll see all the data in full, including dose dependence and the extent of change in systolic and diastolic, et cetera. And I think people will come away with a good insight into the frequency of dosing, and we obviously continue to believe that this will be an infrequently administered therapeutic for hypertension as we further develop it, which will be of great advantage to this patient population, where compliance is a huge, huge issue in about half the patients. So that's kind of a thumbnail on what's coming up next week.
spk01: Great. Thanks so much, both, for taking the questions.
spk20: Thanks, Catherine.
spk19: We'll take our next question from Joel Beate from CITI. Please go ahead. Your line is open.
spk23: Great. Thanks for taking the question. For L-Nylon ASD in NASH in that recently initiated study, could you discuss the potential to evaluate any efficacy or biomarker endpoints?
spk11: Absolutely. Akshay, do you want to talk about the HSD phase one?
spk26: Yeah, so that study is ongoing. We'll progress from healthy volunteers in a dose-sending fashion into a subset of patients with NASH itself. You know, the target HSD, it doesn't circulate in the blood. So like a lot of our programs, we won't have direct biomarker data on the target itself, but there are a number of other downstream factors that we're looking at in terms of biomarkers and we believe will be highly informative. We'll share more on that as the program progresses and the study progresses next year. And ultimately, I think what goes on in the liver in the NASH patients will be of great importance, both biochemically as well as radiologically, and we'll share that as the study matures.
spk11: Yeah, and I'll just add to that that, you know, we also have our upcoming R&D day in December, and that'll be an opportunity for us to do more of a deep dive on the HSD opportunity and the clinical plans for that program. But it is an exciting program because it is a genetically validated target for NASH, and we think it obviously holds great promise in that important indication.
spk18: Thanks, Jim.
spk19: We'll now take our next question from Maury Raycroft from Jefferies. Please go ahead. Your line is open.
spk06: Hi, everyone. Good morning. Congrats on the progress, and thanks for taking my question. First one is also on the ALNAGP program. For the data next week, I'm just wondering if you're going to have some data from the additional exploratory cohorts, including the obese patients, the self-control cohort, and the ARB combo cohort as well. And if not, I guess what's the latest status with those cohorts? How meaningful are they? And then what are next steps with the program?
spk11: Okay, great questions. I mean, the simple answer is you won't see those cohorts next week because they haven't been dosed yet. But Akshay, do you want to comment a little bit on the next steps for those cohorts and just the completion of the phase one?
spk26: Yeah. So, Mario, you know, obviously the study did get delayed in part through Q2 with COVID and so forth, which hit that study like so many others. We've picked up steam. We haven't commenced those things as John said yet, but we're in place now to start those things, those cohorts, and that will be ongoing through the rest of the year. And in due course, we'll report where we'll give a further update on the phase one study early next year in terms of scientific meeting where we can bring that information to everybody. But most importantly next year, I think beyond the clear antihypertensive effect, which we believe we've established and everyone will share in next week at AHA, the most important thing is to take that observation into the phase two setting. And we're very busy, you know, aligning on the design of the phase two effort and getting going with that next year. So that's the crucial next goal.
spk11: Yeah. And I would just add, Maury, that again, our upcoming R&D day, we will do a deep dive on the hypertension opportunity because we think it is obviously an exciting prospect for new innovation coming from the L9 pipeline.
spk18: Got it. Thank you very much for taking my questions. Thank you.
spk19: Moving on to our next question. It comes from Salveen Richter from Goldman Sachs. Please go ahead. Your line is open.
spk16: Hi, this is Sonia on for Salveen. So just really a quick question on the progress of your ex-liver portfolio, particularly with ALN APT. When can we expect first data there?
spk11: Yeah, thanks, Sonia. Well, I'm glad to get a question like this, and I'm sure Akshay is as well. You know, let me just say at the start and remind everybody that one of the exciting breakthroughs that we achieved over the last couple of years is the delivery, the efficient and highly durable delivery of RNA therapeutics to the CNS and other tissues as well, including the eye and more recently the lung. So we are obviously quite excited about that because it opens up new prospects for our pipeline growth outside of the liver. And in the setting of the CNS itself, of course, it is really an opportunity to go after the many, many neurodegenerative diseases that are caused by gain-of-function mutations or gain-of-function expression of proteins in the CNS. With a dose regimen that we think intrathecally can be given once every six months, if not as frequently. So it is a great opportunity for the company, and we've partnered with Regeneron on a 50-50 basis in that regard. Akshay, do you want to specifically talk about APP and the next steps?
spk26: Yeah. So speaking of Regeneron and APP, it was great that they've partnered with us. We'll be taking the program with them into phase one next year. We continue to guide that. We'll enter phase one in the middle of next year or so. And, you know, further guidance on when we'll actually see data will be given once we've gotten going with that phase one study. And the other thing is, of course, there's a very interesting time with the aducanumab review ongoing, and there's a lot of excitement around what those data are showing. So it'll be interesting to see the outcome of that on Friday. But we continue to believe in APP as a very important target for Alzheimer's disease and beyond. And not only can we tackle the A-beta deposits, we believe, in the extracellular space, but tackling the target at source and turning off the tap, so to speak, and all the intra-neuronal effects of A-beta will also be impacted. So we think this could have a really significant contribution to play. So excited to get into phase one next year, and we'll update on data expectations after that.
spk11: And Yvonne, do you want to comment a little bit on how this works within our Regeneron relationship vis-a-vis our lead, et cetera, that might be useful context?
spk24: Yeah, no, that's great. I mean, we were delighted that Regeneron have opted in. We're actually going to be leading the program and we're very excited about that. And obviously, you know, share the economics with Regeneron, but we're very excited to be leading the first CNS program.
spk18: out of our platform. Good.
spk19: Our next question comes from Alan Carr from Needham and Company. Please go ahead.
spk21: Hi, thanks for taking my questions. Can you give a little more detail around your COVID candidate? What exactly, or I think, Stan, what can you do around that? I'm kind of curious about where things stand, because I believe you were looking at other candidates, too, and other targets around COVID-19. Can you give us a more comprehensive update around that program?
spk11: Yeah. Yeah, happy to, Alan. And let me start, and then, Akshay, you can comment as well. Yeah, we continue to be committed to advancing our COVID program. Obviously, there's the opportunity of targeting the SARS-CoV-2 genome, which is an RNA genome, directly with an RNA therapeutic is certainly an appropriate thing to do from a technology perspective. And our recent advances in lung delivery obviously have come just in time to help us help us advance this program. We've done some work in the Syrian hamster model, which is an established model for SARS-CoV-2 infection, and we have seen antiviral activity in the model specifically, and we're encouraged by that, but we want to do more model work before we commit to specific IND timing and specific clinical development plans so that we can understand the best place to position this molecule in the context of emerging therapies for the treatment of COVID-19. And, you know, we're going to play the long game on this program as it relates to how it could play into, you know, the management of COVID-19 in the future, which we think there will be an opportunity longer term for therapies, just like there is for diseases like flu. But that's how we're thinking about it, and those are the specific results. And we look forward to presenting those at some point in the future. Akshay, anything to add to that?
spk26: No, I think you covered it, John. That's exactly right.
spk21: Great. All right. Thanks for taking my questions, and congratulations on your progress.
spk20: Thanks, Alan.
spk19: We'll now take our next question from Patrick Trucchio from HC Wainwright. Please go ahead. Your line is open.
spk09: Thanks. Hi, good morning. You know, with the understanding that the closure in the U.S. election may take some time, I'm wondering if you can comment 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.
spk11: Okay, great. So, yeah, obviously, you know, we are hoping that there is a completion and clarity on the election here in the coming days or coming weeks. And I think it's great to see our democracy going through the process of counting all the votes, which is the way democracies need to work. And so it's great to see that happening. And we certainly stand by to sort of see how it emerges overall. But I think that regardless of the outcome, whether Trump or Biden get elected. You know, we believe that there's going to be a dialogue and continue to be a dialogue around, you know, drug pricing, you know, politically. But I think that Al-Nilem is very well positioned in that dialogue because of the type of innovation that we consistently deliver from our platform. And I think, you know, the type of medicines that we bring forward, the type of ways that we've engaged with payers around, you know, sharing of risk and obviously delivery of value ultimately, these are the type of approaches that we think will bode well for continued success and continued ability to get the value of our innovation recognized by governments and payers around the world. So we do think that we're in a good position to, regardless of the outcome, regardless of the policies that emerge, to be able to continue to do what's right for patients, first and foremost, and obviously deliver on the value of that from our platform. So we think we're in a good place, Patrick, on that overall. But we certainly have been active in helping different stakeholders in this discussion, and we will remain active as a company. in this discussion. But we are generally optimistic, and maybe there will be some changes that occur, but we think we're very well equipped to do well through all of that.
spk18: That's helpful. Thank you very much. Thanks, Patrick.
spk19: We'll now take our next question from Leland Gershel from Oppenheimer. Please go ahead.
spk02: Hey, good morning. Thanks for taking my questions, and I echo others' comments on the solid execution. Just a question on the reimbursement in progress with Absolumo. Having been through the DBA discussions with others on Givlory recently, just wanted to ask if you have any comments on any differences you're seeing in that progress, and if we would expect you to basically be on pace with where you were for Givlory as you execute on Absolumo. Thank you.
spk11: Yeah, that's a great question, Leland. Let me just start by saying how proud I am of our access teams around the world with the great job they've done with OnPatro, the great job they're doing right now with GiveLari. And, you know, right now we have over 30, just about, actually just about 30 value-based agreements that we've signed with commercial payers in the U.S., and we continue to work in global markets very effectively with the payer stakeholders. And we've demonstrated and brought a lot of innovation forward on these VBAs, both the general structure of them and how we share risk around performance of the product, but also on some of the new features that we've introduced, like the prevalence-based adjustment model that we've introduced on Givlari. So with that as context, Andy, do you want to get more specific on Oxlumo? And obviously, we can't share all the details that we'll share when we launch the product, but maybe you can give some context on how our discussions are going.
spk03: Sure, sure. So similar to on Patro and GiveLari, we will and are pursuing an aggressive value-based agenda with all payers globally. And feedback from early days on that front has been exceptionally positive. So we expect similar results in terms of open access for Oxalimo as we had with Givlari and Ampatro, which are really, really strong. So we'll continue our industry leadership here. Yeah.
spk20: Thanks, Andy. Perfect.
spk19: Thank you. Moving on to our next question comes from Manny Foroja from Sprevink. Please go ahead. Your line is open.
spk20: Thanks for taking the questions, guys.
spk05: A quick one, I guess, starting off for Jeff. Talk a little about increasing compliance as a driver of on-patch performance. I presume some of that is from patient hesitance to come in for their IV during the height of the pandemic. Has that compliance trend reversed entirely, or there's still a little bit of juice for next quarter and beyond? And then for Akshay, there's a lot of talk about what Helios A tells us about Helios B. I'm inclined to agree that maybe Apollo B is the more useful lead forward. Can you give us a little detail on how you think about taking the optional Helios B interim? Is the most appropriate approach to wait until you have Apollo B data to inform that? Or do you think that just data that you gather on a blinded basis from Helios B itself as the study proceeds we'll provide you the information you need to decide if and when to take that interim.
spk11: Okay, those are great. Those are two great questions. Manny, why don't we start with Jeff, and then we'll have Akshay talk about the CAR-DB, as we call them collectively, strategery, and how that relates to the interim. So, Jeff, you want to start first on the compliance question?
spk04: Yeah, sure. So just a reminder on the results that Andy commented on earlier, and I did as well. We grew 21% in Q3 in the U.S. for Onpacho versus Q2. 14% of that was demand-related, and that was a mix of new patients coming on to therapy and the increased compliance that we saw in Q3. And that returned in the U.S. to pre-pandemic levels, Monty, so I don't see know sort of a big impact of that on growth going forward. And just a reminder, outside the U.S., we didn't see the same impact on compliance in Q2 that we saw in the U.S. So outside the U.S., the healthcare system seemed to do a better job of maintaining patients on therapy and compliance wasn't impacted. So again, I don't see a big impact of increased compliance going forward on our growth rates.
spk11: And just before I hand it over to Akshay, I would just add that the site of care adjustments that we made in Q2 have, I think, bolstered any potential downside of pandemic resurgence, the third wave that might happen in the U.S., et cetera. So I think that we're better sheltered in Q4 and beyond to not, if things get much worse, to not have any significant impact from what we saw like in Q2. Akshay, do you want to now handle the more complicated but interesting question that Manny has asked?
spk20: Would love to, John.
spk26: The question, Manny, you know, focused on Apollo B and the read-through to Helios B, and I agree that that's a very important aspect of the work we're doing, and the insights we'll glean there will be very important for us. I would also say that, you know, continuing work with patients from Apollo itself in the open-label extension study gives us important insights into long-term outcomes on neuropathy and cardiomyopathy. We've had a number of studies ongoing out in the field, and Dr. Gilmore from the UK group just published a paper in Jack Imaging on reversal of amyloid depositions. in TTR cardiomyopathy patients of the inherited type. And I think that's just something important. And we continue to work with groups like that to understand what they're seeing and the outcomes that they're seeing both clinically and radiologically. As we discussed earlier, to your point, it's not as rich a data set for cardiomyopathy, but there could be some important information there. And then Apollo B itself. And I think Ultimately, we'll just have to see on the timings of all these data points and how they factor in. And as we get greater insight into the Apollo B readout, I think we can guide on what the exact Helios B interim will be and use all these points of information to guide that. But I think we're fortunate because there's so much to teach us about what to expect ultimately from Helios B, and that should lead to a very informed structure around the interim.
spk11: Yeah, absolutely agree. Does that answer your question, Manny?
spk05: Yeah, that's great. Thanks, guys. Also, Cardi, you would have been a great trial man, too. Agree.
spk20: Thanks, guys.
spk19: We'll now take it.
spk20: Thank you.
spk19: We'll now take our next question from Navin Jacob from UBS. Please go ahead.
spk27: Hi, everyone. This is John on for Naveen. Thank you for taking our question. So with respect, you've alluded to the COVID recovery across geographies, and we're curious if COVID has caused any shifts in payer mix for your assets, GiveLawry and OnPatro. We're also curious as to which analog might be better as we prepare for the OxLumo launch. Would it be more like GiveLawry with a bit more Medicaid or perhaps more like OnPatro? Any color would be appreciated.
spk11: Those are great questions. I'm going to hand them right over to Andy to answer.
spk20: Thanks.
spk03: So let's start with the first one. So changes in payer mix. Specifically in the United States, we're seeing little to no changes in payer mix. Remember that on Patro is the vast majority Medicare. And at this point in time, Giblari is pretty early days here, but largely commercial. And we're not seeing any material changes to those due to COVID. And then the second question with Oxlumo, in terms of payer mix analog, actually, neither are perfect. But of the two, it's certainly going to be less of a Medicare population, right? We think Oxlumo is more of a commercial and or Medicaid insurance one. So that's, I guess, a little bit more similar to Giblari, if that helps.
spk18: Certainly. Thank you. Thank you.
spk19: And moving on to our next question comes from Vincent Chen from Bernstein. Please go ahead. Your line is open.
spk10: All right. Thanks for taking the question. Well, probably a little far out, but going over to the CNS side of things for a moment, I was wondering if I could ask you for your latest thoughts on ALN-HTT in Huntington's and how that might offer advantages over competitive programs in this space, most notably Rosh Iones' Toma Nerson program. Are there reasons to expect that ALN, HTT, and the siRNA platform in the CNS will outperform the Roche-Innes program from the perspective of sort of the degree of knockdown achieved, the breadth, or ultimately the efficacy?
spk11: So let me hand it over to Akshay. Thanks for the question, Vincent. I'll just start by saying that obviously what we've seen with our platform in the CNS has been pretty consistent with what we've seen in the platform with liver. And when you compare an RNAi therapeutic approach in the liver compared to an antisense oligo-based approach, what you see is you see deeper, better knockdown and much greater durability in the liver. We've seen that all the way through marketed products. And we see similar profiles in non-human primates between antisense oligos and RNAi therapeutics. So by all accounts, we expect a deeper knockdown potential with our platform and a much more durable approach that would allow for less frequent intrathecal administration, which, of course, is a burden in the administration of oligos in the CNS. But there's some more to that. There's more to the HTT opportunity that I'll leave to Akshay to comment on, specifically on Exxon 1. Akshay?
spk26: Yeah, and before I go to Exxon 1, the other thing I'll add to what you said in terms of pharmacologic attributes shown, potency, durability, of course, but also just much better biodistribution based on our preclinical findings. We think that the RNAi approach gives much better knockdown in deeper brain structures like the... basal ganglia, which is where you need to get to for hunting those predominantly. Those pharmacologic attributes and then the actual target strategy itself. There's an abundance of literature now or significant literature suggesting that exon 1 itself has a very important role to play in the pathology of the disease. There are truncated transcripts that come off exon 1 that appear in and of themselves to be neurotoxic. And then there are protein aggregates made from the truncated exon 1 transcript that aggregates and causes pathology. So, you know, going for an exon 1 agnostic approach may not be the strongest. And we've focused on an exon 1 approach so we can have the best approach to target that the literature currently would support and the KOL supports. And that, along with the pharmacologic attributes we've discussed, I think really sets us up for a very attractive product profile.
spk20: I look forward to getting to the clinic. Thank you. Does that answer your question, Vincent?
spk18: Yes. Thank you very much.
spk20: Thank you. Thank you.
spk19: We'll now take our next question. It comes from Luca Issa from RBC. Please go ahead.
spk07: Oh, terrific. Thank you for taking my question, and congrats on the commercial execution here. Maybe going back to Cardi B for a second, but maybe with a little bit more of a commercial angle here. Do you think that actually Apollo B will be sufficient for Doc to change their prescribing habits from Vindical to Ompatro? Or do you think that most Doc will actually need to wait for Helios B, given that, again, Apollo B is just power for a six-minute walk and you're still dealing with an IV drug? Any thoughts there would be helpful. Maybe the second question, we've seen a few of your competitors actually going after ENAC for cystic fibrosis. Wondering if, one, you have any thoughts on that approach, and, two, what's your appetite to potentially enter that race? Thank you.
spk11: Okay. Well, great questions. I think, obviously, the first one, Andy, I'd like you to answer. I'll just start by reminding everybody that, obviously, you know, the Apollo B study is a study of Petit Ceram, which is a non-branded name for Onpatro. which is an investigational agent right now, and it's being studied in patients with both wild-type and hereditary ATTR amyloidosis with cardiomyopathy. And that study uses the six-minute walk distance as the primary endpoint at 12 months. And then the Helios B study with Butresaran uses CV hospitalization and mortality as the primary endpoint at 30 months of treatment. And so that's an important distinction. But in general, and then Andy, you should comment, we do feel very encouraged that if Apollo B is positive and if we're able to get an approval with the FDA based on the study and other regulators, that this will be a very attractive alternative for the cardiology community to treat their patients with both hereditary and wild-type ATTR. And while the ultimate presentation of a TTR silencer with a, you know, quarterly or six-monthly sub-Q approach will be, you know, certainly much more exciting in the future, in the meantime, PATRO with this broader label will be an important treatment option for patients. Andy, do you want to comment a little bit on our perspective on that in more detail?
spk03: Sure, John, happy to. We're very excited about the Apollo B potential here and the launch into hereditary and wild-type cardiomyopathy. To note, in the United States today, cardiologists are currently having very strong experience with Onpatro in treating the polyneuropathy. And upon approval, we do expect a meaningful amount of physicians to choose a TTR silencer versus a stabilizer. And furthermore, there also will be physicians who don't decide to choose, and frankly, they use both. And so reimbursement will be something we'll be proactively looking to solve on that front as well.
spk11: Terrific. And then, Akshay, do you, or maybe Yvonne, do you want to comment a little bit on, from a portfolio standpoint, how we think about programs and ENAC, for example, and Is that, and whether or not that's an area that we would consider?
spk24: Yeah, no, sure, John. Look, I think what's been incredible about our platform is actually the kind of productivity that we've had. And, you know, we're increasingly demonstrating our ability to access tissues in addition to the liver, CNS, and ocular. And many of you may be aware that, you know, Ireland's had a history of with lung delivery as well, with an RSV program many years ago. So we have a tremendous amount of opportunity in front of us. And clearly we need to think how we prioritize the best opportunities for us. We have a lot on our plate to move forward from an execution perspective. But we remain open about continuing to explore the broad utility of our platform going forward. But nothing to share specifically on cystic fibrosis at this time. John, do you want to add anything?
spk11: No, I don't know. Akshay, anything you want to add to that?
spk26: No, I mean, part of the airline COVID efforts, obviously lung delivery has come front and center. We had that preliminary data set about a year ago now showing we've achieved lung delivery, which is very exciting. And just as we've done with many other settings and organs, the idea of genetically validated targets comes into the mix. And we have knowledge of, you know, a number of very interesting genetically validated targets beyond ENAC itself and cystic fibrosis. So it's really the new vista that's forming before us, and it will be exciting to take it on beyond the COVID effort itself.
spk18: Great. Terrific. Thanks, guys. Thanks, sir. Thanks, Luca.
spk19: We will now take our next question from Shishang Xu. Please go ahead. Your line is open.
spk28: Thank you very much. Thank you very much. Good morning. Congrats on the strong quarter here. Quick question. Quick question on, I guess, on Apollo B. Have you guys looked at any, I guess, clinical or translational data in terms of the correlation between baseline disease severity and the potential response to the drug, you know, six minutes walk or hospitalization? I recall the stabilizer actually has a different trend when it comes to different patient population. And then second question quickly on AGT program, given the drug will be potentially target a large population, patient population. Have you guys started to think about partnership opportunity there? Thank you.
spk11: Right. Well, let me start with, let me just, Akshay, you should take the Apollo, the very interesting Apollo B question. But let me just on the AGT comment real quickly. Our intent with the AGT program is to advance it to the market. We certainly are a company that as we bring a medicine like AGT forward, we're going to have an opportunity to, at that stage of our growth and company, to commercialize a medicine like that. If we, at that point in the future, choose to bring on a promotional partner, we may do that. But our key goal is to retain the program and develop it ourselves, and that's how we're focused on it. And so that's what we're doing there. But actually, do you want to answer the Apollo B question that was asked? Sure.
spk24: Actually, John, maybe if I can just come in really quickly on the point you made. I think the other thing to remember is with our sort of TTR suite of opportunities, we are actually building up a very robust commercial footprint in the cardiovascular arena. So that's something else that we can consider as we plan for AGT.
spk11: Yeah, absolutely. Agree completely. Thanks for jumping in on that, Yvonne. Akshay, do you want to then deal with Apollo-B?
spk26: Yeah, so, Yucheng, good question about Apollo-B. Now, of course, there's an ongoing blinded study, so we don't, you know, sort of look at all the data currently, and that's what it should be to maintain study integrity, so I can't comment on, you know, relationships between various parameters. I can tell you that there are very good associations between New York Heart Association stage and six-minute walk distance. We know that from prior work, ours and other people's work, and we know how that relates to biomarkers such as BMP and other imaging biomarkers. In terms of the other aspect of your question was outcomes with and without prior tofamilis, There we can look at older information from Apollo itself, the original study from the phase three study. And what was very clear there actually is whether patients had previously been on a stabilizer, whether it was tofamilis or diphalinizol or had never been on a stabilizer, their outcome was equivalent. And that is on average their MNIS plus seven, their neuropathy endpoint improved, their quality of life improved. So that's very encouraging for us that Our mechanism of action seems to be potent. And whilst it wasn't a head-to-head study, everything pointed to, you know, Onpaptra really having a profound impact and resulting in improvement of disease in the context of the Apollo study. And we believe that's one of the very attractive features of the drug. And, you know, we know from Tafamidis, from the Phase III ATTRACT study, that whilst clearly there was benefit in terms of hospitalization and mortality, All the curves went down. It's just the curve for tofamilis didn't go down as much as it did for placebo, which is a good thing for patients. But sadly, disease progress is quite clear, whichever endpoint you looked at, including six-minute walk distance. And, you know, walk distance declined over time in the active group as was placebo. So if we can stabilize six-minute walk distance, I think that's great. If we can actually improve six-minute walk distance, even better. The recently published study by Professor Gilmore and others from the UK group in JAK imaging, where they took a cohort of cardiomyopathy patients and they were given T-SRAM one year, comparing to historic control, they saw stabilization of 6-minute walk distance there and regression of amyloid, something that neither of those things have been seen with tofamilis up to now. So we think the fundamental mechanism of action to remove the pathogenic protein to a great extent Outcomes in neuropathy that we know well, and also some of the preliminary evidence emerging around cardiomyopathy and use of on-pattern in investigational setting all suggest that we look forward to stabilizing disease and hopefully improving outcomes.
spk18: Thank you very much. Mr. Chang, does that add to your question? Yes. Thanks very much. Thank you. Thank you.
spk19: At this time of moment, I would like to turn the conference back to the company for any additional or closing remarks.
spk11: Okay, thank you. And thanks, everyone, for joining us on this call. Look, Alnylam is at a very exciting stage of its continued growth and development as a leading biotech. We're really pleased with our Q3 results and our execution from our commercial and R&D teams. We look forward to updating you on our continued progress at our R&D day in December. Until then, I hope you all stay safe and healthy and have a great day. Bye-bye now.
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