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spk03: Hello, ladies and gentlemen. Thank you for standing by and welcome to the Alnylam Pharmaceuticals Q3 2021 earnings call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you need to press star 1 on your telephone. If you require any further assistance, please press star 0. I would now like to turn the call over to the company who may begin.
spk12: 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 Maragonori, Chief Executive Officer of Tolga Tangular, Chief Commercial Officer, 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, investors.alnylam.com slash events. During today's call, as outlined in slide two, John will provide some introductory remarks, provide some general context, and discuss the planned leadership transition. Yvonne will provide some remarks on the leadership transition plans. Togo will provide an update on our global commercial progress. Akshay will review recent clinical and preclinical updates, including the new positive top-line results of the 18-month endpoints of the Helios-A study of Butresaran. Jeff will review our financials and then provide a brief summary of upcoming milestones before opening the call to your questions. I would like to remind you that this call contains remarks concerning ILM'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 recently quarterly report on file with the SEC. In addition, any forward-looking statements represent our views only as to 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 will turn the call over to John.
spk08: Thanks, Christine, and thank you, everyone, for joining the call today. In the third quarter and recent period, we made continued progress bringing our commercial RNAi therapeutics to patients around the world, We advanced our clinical pipeline of over a dozen potential transformative medicine programs, and we delivered on the promise of sustainable innovation with R&AI, with our industry-leading platform and our preclinical efforts. Of course, a highlight for the period was the positive top-line 18-month results from the Heli-OSA phase 3 study of Butrisaran that we announced just yesterday. And Akshay will review those results very shortly. As we announced this morning, after much thoughtful consideration and planning, I've decided that this is the right time to begin a smooth transition of leadership at El Nilo. I've decided that this is the time for me to begin a new chapter in my career of yet again pushing the bounds of biomedical innovation by helping entrepreneurs and companies advance new modalities to improve the lives of patients. I couldn't be more pleased that Yvonne Green Street has agreed to help lead El Nile in a planned transition that will occur at the end of this year. Of course, I am so honored to have had the opportunity to build El Nile over the last 19 years, bringing RNA therapeutics to patients around the world. I am so proud of what we've accomplished, and I'm so thankful for the opportunity to have worked with our past and present Alnylam team to build this incredibly special company. I have no doubt that Alnylam will continue to soar in the years to come, helping patients with its transformative science and medicines. So with that, let me turn it over to Yvonne to make some remarks as well. Yvonne?
spk04: Thank you, John, and good morning, everyone. We've been so fortunate as Alnylam to have had your tremendous leadership, John, over these last 19 years, and I know I speak for the entire Alnylam team in thanking you for your commitment, passion, and excellence. You have been the architect and the inspiration behind our success to this stage, and I'm so grateful that you've given me the opportunity to advance Alnylam in its next exciting chapter. And I couldn't be more excited about our Nilem's prospects going forward with our Nilem pizza fifth times 25. This is our clear roadmap for delivering RNAi therapeutics to help patients around the world and deliver value to our shareholders. And in the coming year, we expect to bring our fifth RNAi therapeutic to market and potentially expand our TTR franchise opportunity significantly. We expect steady and continued growth of our three directly marketed products with excellence in our commercial performance while also advancing sustainable innovation from our organic product engine, including our first extrahepatic program. These are very bright days for Alnylam, and I really encourage you to join us at our upcoming R&D day on November the 19th to hear some of the exciting new progress. With that, Let me now turn the call over to Tolga for a view of our commercial performance. Tolga?
spk16: Thank you, Ivan, and good morning, everyone. We're pleased with our third quarter performance, particularly with Ompatro, but also with our two ultra-rare medicines, Givlari and Oxlumo, where we're still in launch phases and seeing some continued impact from the pandemic, particularly for Givlari. For Ompatro, We achieved $120 million in global net product revenues, representing approximately 6% quarter-on-quarter growth compared with the second quarter. We ended the quarter with over 1,875 patients on commercial treatment. In the U.S., we continue to see strength on many fronts, including 12% growth in demand and notable growth in new prescribers. We have also continued to see encouraging signs of the healthcare system reopening. As an example, we've also seen an uptick in face-to-face interactions between our field team and HCPs in the third quarter, resulting in the second highest number of start forms for OnPatro in the U.S. in any quarter since launch. Further, patient diagnosis is evolving well, with continued growth in the use of PYP scans which is often the start of the patient journey towards HATTR polyneuropathy diagnosis. Treatment compliance has returned to pre-COVID levels and remains stable at over 90%, a remarkable result for an infused medicine. We also have confirmed access to over 98% of covered US lives with no payer headwinds. Now, with regard to the rest of the world, market access has been achieved in over 30 countries worldwide. A notable highlight in Q3 was the achievement of pricing and reimbursement in Ireland, which is a country with endemic disease due to the T68 mutation. We're also observing a good balance of first-line use and switches from other products, including stabilizers, in rest of world markets. Moving to GiveLari. We continue to execute on this product's launch, having achieved $32 million in global net product revenues in the third quarter. representing approximately 4% quarter-on-quarter growth compared with Q2. As of September 30th, we attained over 300 patients worldwide on commercial therapy. We observed a steady quarter-on-quarter patient growth rate of over 10%, driven primarily by geographic expansion. And we're optimistic GIVLAR will continue to perform well over time. In the U.S., we continue to make strong progress toward establishing value-based agreements with over 10 finalized to date with commercial payers. We also have confirmed access for over 94% of covered U.S. lives with no pushback or headwinds. We continue to make great progress with market access efforts outside of the U.S. with recent launches in Japan and Spain and achievement of pricing and reimbursement in the U.K. and France. Moving now to Oxlumo, which is also still in a launch phase. We achieved $15 million in global net product revenues in the third quarter, which represented a decrease of approximately 9% from Q2 revenues. This decrease reflects the transition of the initial bolus of commercial patients from their monthly loading doses to their quarterly maintenance dosing. as we previously highlighted as a dynamic expected the following launch. As of September 30th, we attained over 120 patients on commercial Oxlumo treatment globally, representing over approximately 25 patient growth versus Q2. We believe this demonstrates that not withstanding the degrees in revenues during the quarter, Oxlumo's fundamental growth remaining strong. Our market access efforts are also progressing well, now with over 10 VBAs finalized to date with commercial payers and confirmed access for over 85% of covered U.S. lives with no payer headwinds. Geographic expansion of Oxlumo is moving along steadily with two important launches underway in Germany and France, supported by timely execution of the transitions to commercial drugs for patients previously treated through early access programs. In the SEMeA region, we continue to be pleased by the broad utilization of HoxLumo across age groups and EGFR categories at this early stage of the launch. In conclusion, we are very pleased with our third quarter commercial results with strong Lompatro performance and continued launch execution on Givlari and HoxLumo. With that, I will now turn it over to Akshay to review our recent R&D and pipeline progress. Akshay?
spk02: Thanks, Tolga, and good morning, everyone. I'll start with our efforts in ATTR amyloidosis, where we're advancing two clinical stage product candidates, Petitran and Vutrisran. While Sanpatria is currently approved in multiple markets around the world to treat the associated ATTR 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 III study, which is fully enrolled with over 300 patients and where we expect to report top-line results in mid-2022. We're also advancing butriceran, which is delivered by a quarterly subcutaneous injection and is also in development for ATT amyloidosis. Here, we're conducting two Phase III studies. The first is Helios A, evaluating butriceran in HAT-tramyloidosis patients with polyneuropathy. Earlier this year, we presented positive nine-month results from the study, which showed that the study met its primary and secondary endpoints at nine months. These data formed the basis for our regulatory submissions to both the FDA and EMA. The FDA has accepted the submission and assigned a PDUFA date to Vutriceran of April 14, 2022, and the EMA has validated our MAA submission. Patients dosing in Helios A continued past the nine-month mark, and yesterday we were happy to report positive top-line results from the 18-month time point of the Helios A study, which I will now review. Please note that we plan to present the full 18-month results from the study at a medical congress in early 2022, and as such, we'll need to limit our discussion to the top-line results only. These results mark an important step in bringing vitreous RAN, a low-dose once-quarterly and potentially biannual subcutaneously administered therapy, to patients living with HAT pheromonoidosis with polyneuropathy, as well as progressing our efforts to build an industry-leading franchise of medicines for the treatment of these patients. As a reminder, Helios-A is a randomized open-label study in patients with hereditary AT cannabinoid doses with polyneuropathy. The study enrolled 164 patients who were randomized three to one to receive butriceran at a dose of 25 milligrams administered subcutaneously once every three months, or paticeran administered intravenously once every three weeks at a dose of 0.3 mg per kick. The primary endpoint was measured at nine months and was the change from baseline in the MNIST plus seven neuropathy impairment score as compared to the external placebo group from the Apollo phase three study. We're delighted to report today that the Helios A met all secondary endpoints measured at 18 months, including statistically significant improvements in progression of neuropathy as measured by the MNIST plus seven score, quality of life, gait speed, nutritional status, and overall disability relative to the placebo data from the Apollo Phase III study of Patisran. The final secondary endpoint reduction in serum TTR levels with Vutrisran demonstrated non-inferiority relative to the within-study Patisran arm as expected. These results build on the positive nine-month Vutrisran data we shared earlier this year and demonstrated that the reduction of neurological improvement and improvement in quality of life in patients with HAT2 amyloidosis seen at nine months is maintained at 18 months. Furthermore, at 18 months, butrysoran-treated patients showed quantitative improvement across a variety of exploratory endpoints evaluated in both the intent-to-treat population as well as a pre-specified cardiac cell population. Improvements were seen in a number of exploratory endpoints, including the biomarker NT-proBNP, a measure of cardiac stress, and certain echocardiographic parameters relative to the external placebo group. Other echocardiographic endpoints showed trends towards improvement but did not reach significance due to the small sample size. Finally, in a cohort of 48 patients, treatment with Vutrisran was associated with an improvement in technetium uptake, that is reduced tracer uptake, in the heart relative to baseline in a majority of patients. This is the largest study conducted to date using imaging to characterize the impact of a TTR silencer on cardiac amyloid. Whilst it's important to recognize that these are exploratory data, that these patients have predominantly polyneuropathy, we believe these results are very encouraging with respect to providing potential evidence for reduced cardiac amyloid burden with vitreous saran treatment. Vutriceran's potential impact on cardiac manifestations of the disease is currently being studied in the Helios B trial. Let's now review the safety results during the 18-month treatment period. Vutriceran demonstrated an encouraging safety and tolerability profile. Study discontinuations occurred in three patients, or 2.5%, and were due to adverse events in the Vutriceran arm by month 18. The single new discontinuation since month nine was an event of cardiac failure considered unrelated to study drug by the investigator. By month 18, there were two deaths, neither of which were considered related to study drug. There were two serious adverse events deemed related to Vutrisran by the study investigator consisting of dyslipidemia and a urinary tract infection. These deaths and related SAEs all occurred by month nine and have been previously reported. Treatment-emergent adverse events occurring 10% or more of patients included fall, diarrhea, pain in extremity, peripheral edema, arthralgia, dizziness, urinary tract infections. With the exception of pain in extremity and arthralgia, each of these events occurred at a similar or lower rate as compared with the external placebo. Injection site reactions were reported in five patients, or 4.1%, and were all mild and transient. There were no hepatic safety concerns. In summary, Vutriceran has demonstrated an encouraging efficacy and safety profile in Helios A through 18 months. Moreover, within the realm of reproducing clinical trial data, we're delighted to see the extent to which Helios A results with Vutriceran recapitulate the Apollo data with Perticeran. As previously noted, the other Phase III Vutrisran study is Helios B, which is our ongoing Phase III cardiac outcome study with Vutrisran in hereditary and wild-type ATTR amyloidosis patients with cardiomyopathy. We were excited in the third quarter to complete enrollment in the study with over 600 patients, well ahead of schedule due to strong enrollment demand. Beyond Patisran and Vutrisran, the newest addition to our ATTR amyloidosis franchise is the preclinical program ALN-TTRS-C04. Using our iCarrier platform, we've generated a new TTR-targeting siRNA, ALN-TTR-CO4, that we believe could support an annual dosing regimen with greater than 90% TTR knockdown. ALN-TTR-CO4 is planned to enter clinical development with an IND filing at or around year end 2022. Let's now move on to LumassRAM. Our RNAi therapeutic approved late last year in the EU and U.S. as the first treatment for primary hyperoxaluria type 1, or PH1. In the third quarter, we were pleased to announce positive top-line results from the Illuminate-C phase 3 study of Lumasran, and we announced today that we plan to present full results from the study at the American Society of Nephrology meeting being held next week. We also now intend to submit supplemental regulatory filings with the FDA and EMA in late 2021 with the goal of further strengthening the labeling supporting oxalumab. We're also excited about the potential for Lumaceran for patients with recurrent renal stones, and later this year, we plan to start a Phase II trial to evaluate that potential. Now, in addition to our late-stage programs, we believe we're also making great progress with our early and mid-stage programs. Whilst I can't cover all these programs due to limited time today, one of the exciting parts of our story is the expansion of RNAi therapeutics beyond rare diseases into prevalent disease opportunities. Our program for hypertension is a great example. Zalbiceran, formerly known as LNAgt, is our investigational RNAi therapeutic targeting the genetically validated target angiotensinogen in development for the treatment of hypertension. We look forward to presenting additional clinical results from the Phase 1 study at the American Heart Association meeting later this month, including in patients on a low-salt diet and in patients receiving co-administration of the conventional RAS inhibitor, erbisartan. We also recently initiated our Cardio Phase 2 program with Zolbisaran. The first of the two studies, Cardio 1, is designed to evaluate the efficacy and safety of Zolbisaran as a monotherapy in patients with mild to moderate hypertension. This study is currently enrolling patients. In late 2021, we plan on initiating Cardia 2, which is designed to evaluate the efficacy and safety of Zalbiceran as add-on therapy in patients with hypertension despite treatment with standard of care. We also continue to harness our organic product engine with the goal of achieving sustainable innovation with two to four INDs per year. To this end, we're on track to file a CTA for LNXDH in development for the treatment of gout in late 2021. We're also on track to file a CTA for LNAPP in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy in late 2021. We're very excited about our APP program, as it's the first investigational RNAi therapeutic for our CNS platform, which was also a feature at the OTS meeting this past month. We believe that our initial human data for LNAPP expected next year, if positive, could open the frontiers of RNAi therapeutics for many CNS diseases and also herald the potential growth of our broader extrahepatic efforts. Now, in closing and on a personal note, John, thank you for your remarkable leadership over the last 19 years as Alnylam built a whole new class of medicines, RNAi therapeutics. It has been my great privilege to work with you. You will leave us in a remarkably strong position as we build towards P to the 525 and beyond, my friend. With that, I'll turn it over to Jeff.
spk03: Jeff?
spk06: Thanks, Akshay, and good morning, everyone. I'm pleased to be presenting our online Q3 2021 financial results, which reflect another quarter of progress on our journey toward building a self-sustainable financial profile aligned with our P to the 5th by 25 goals. Turning to our results first for Enpatro, we generated $120.3 million in net revenue for the quarter, representing 6% growth from the second quarter of 2021 and 46% growth compared with Q3 2020. U.S. on PATRO sales decreased 2% versus Q2 2021 and were impacted by the following. Demand growth was 12%, consistent with Q2, primarily driven by an increase in patients on therapy and greater than 90% patient treatment compliance. Demand growth was offset by inventory destocking in Q3 compared with stocking in Q2, representing an approximate 10% headwind to reported Q3 growth and higher gross to net deductions, which negatively impacted reported Q3 growth by approximately 3%. And our international markets on PATRO performance remain strong, with growth of 12% versus Q2 2021, primarily driven by increased patient demand broadly across markets in Europe, Canada, and Japan. Turning to our results for Giblari, we generated $31.8 million in net revenue in Q3, representing 4% growth compared to the second quarter of 2021 and 91% growth versus Q3 2020. U.S. Giblari sales were flat versus Q2 2021 and were impacted by the following. Demand growth was 9%, primarily due to an increase in patients on therapy and greater than 90% patient treatment compliance. Demand growth was offset by inventory destocking in Q3 compared with stocking in Q2, negatively impacting Q3 reported growth by approximately 8%. With Oxlumo, we generated $14.9 million in net revenue in the quarter, representing a 9% decrease compared with Q2. As Tolga previously mentioned, despite patient growth of approximately 25% in the quarter, Sales decreased due to the transition of the initial bolus of commercial patients from monthly loading dose to quarterly maintenance dose regimens. Turning now to a summary of our full P&L results for the quarter with the following highlights. Total combined product sales in the second quarter were $167 million, representing 68% growth versus Q3 2020. Net revenue from collaborations for the quarter was $20.1 million, a decrease from Q3 last year, primarily due to less revenue recognized from our collaboration with Beer. Our combined non-GAAP R&D and SG&A expenses for the quarter increased 12% versus Q3 2020. Key drivers of the increase continue to be additional R&D investment in advancing our early, mid, and late-stage pipeline programs and increased SG&A investment to support our three commercial brands, including the launch of Oxlumo. Non-GAAP operating loss for the quarter decreased by approximately $20 million versus the same period in 2020, driven by strong top-line growth and more moderate growth in operating expenses, continuing our progress towards achieving profitability. Cash, cash equivalents, and marketable securities were $2.3 billion as of September 30, 2021, compared to $1.9 billion as of December 30, 2020. Notably, the third quarter included the second $500 million payment from Blackstone for the monetization of 50% of increased RAN royalties. Lastly, turning to our full year 2021 financial guidance, we are reiterating our guidance. For combined product sales, $640 to $665 million. For net revenue from collaborations and royalties, $150 to $200 million. And for non-GAAP combined R&D and SG&A expenses, $1,175,000,000 to $1,275,000,000. Let me now turn to a review of upcoming milestones. We are very excited about the positive 18-month data from Heliose for HATTR amyloidosis. Patients with polyneuropathy and plan to present the full results at a medical conference in early 2022. With salbiceran, as Akshay mentioned, we plan to present additional data from the Phase I study at the AHA meeting later this month and plan to initiate the CARDIA-2 Phase II combination study later this year as well. From lamacerin, we plan to initiate a Phase II study for renal stone events in late 2021. This Phase II study will be important for lifecycle management of oxalumo with the potential to enable a Phase III trial to significantly expand the overall opportunity. We also intend to submit supplemental regulatory filings with the FDA and the EMA in late 2021 based on the results from the Illuminate-C study with the goal of strengthening the labeling supporting Oxalumo. Turning to Simdesiran for complement-mediated diseases, our partner Regeneron plans to initiate a Phase III study of Simdesiran and Pozelumab combination and Myasthenia gravis. With ALN-HSD, as Akshay mentioned, we expect to report initial safety results in healthy volunteers from the phase one study at our upcoming R&D day. We're very excited to file our first CNS CTA for ALN-APP in late 2021, setting us up for potential initial clinical proof of concept data in late 2022. And as another step toward expanding our prevalent disease opportunities, we plan to advance ALN, XDH, and development for the treatment of gout toward a CTA filing in late 2021. Let me now turn it back to Christine to coordinate our Q&A session. Christine?
spk12: Thank you, Jeff. Operator, we will now open the call for your questions. To those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have additional questions.
spk03: Good morning, everyone, and congrats on the updates and congrats on the CEO transition to both John and Yvonne. I look forward to next steps.
spk18: For my question for the Helios A data, just wondering if you can contextualize what you have relative to Apollo A And are there any new observations that could inform how the Apollo B and Helios B studies could read out? And I'm just wondering, just checking based on the data, do you plan to make any supplemental filings for vitricerin?
spk08: So, Maury, let me start by just thanking you and your congratulatory comments, but the question here really goes right to Akshay. Akshay, take it away.
spk02: Yeah, Maury, obviously the current data now with butryceran only further strengthen our belief in the drug. The data look outstanding in HAT-tramyloid doses with polyneuropathy. These new exploratory data with the cardiac endpoints are extremely encouraging. We're very excited about the technetium scan observations that show reduced uptake of the technetium, and in addition to the previously reported finding at nine months, which we see again at 18 months improvement in proBNP, improvement in aspects of the echocardiogram, and these new technician data. I think this all bodes well for the performance of butrycerin in Helios B and strengthens our hypothesis that TTR lowering is an important way to address TTR-related cardiac disorders. And so our confidence in Apollo B, of course, also goes up significantly because of these observations. So I'll stop there and have to take any other questions.
spk08: Does that answer your question, Marty?
spk18: Yes, and just wondering if you do plan on supplementing the return filing.
spk08: Yeah, just real quickly on that. Obviously, for the European filing, we will be including these 18-month data in the European filing. That was agreed to by the FDA. But with the FDA, there's no needed update in that filing.
spk18: Got it. Okay, thank you for taking my questions.
spk03: Thanks, Maureen. Our next question comes from Gina Wang with Barclays.
spk15: Thank you for taking my questions. Yvonne, congrats on the new position. And John, we will surely miss you. My best wishes to your next journey, and I hope our roads will cross again in the near future. So I have a two-part question on the ATTR franchise. So the first one is regarding the Helios A. Just wondering regarding the 30% cardio subpopulation, you know, based on your definition, on the cardio subpopulation, which NYHA class these patients will belong to? And then another short question regarding Apollo B. I understand that patients will be allowed to take a tefadimus at some point in the study. So is there any set time restriction before allowing these patients to take a tefadimus? And this is referring to the 70% patient population that will not be on tefadimus on the baseline.
spk08: Yeah, thank you. Thank you, Gina. Akshay, do you want to handle both questions?
spk02: Yeah, so with respect to Helios A, you know, we'll present the full data, Gina, at an upcoming medical meeting, but suffice it to say, you know, the vast majority of patients would have New York Heart Association 1 or 2 level disease. With respect to Apollo B and to Famidis, Pushkar Garg is with us. Pushkar, do you want to comment on that?
spk07: Sure. Thanks, Akshay. Gina, your question about TAP drop-ins, You know, ethically, patients can drop in or position to do that, but they're discouraged from doing that in the first 12 months. And our statistical analysis plan also accounts for the potential for drop-ins. So we feel very good about the design of the study and accommodating that.
spk15: Thank you.
spk03: Our next question comes from Tazina Med with Bank of America.
spk11: Good morning, guys. Thank you for taking my questions. John, you've been a terrific CEO. We will certainly miss you. We wish you the best in your future endeavors and look forward to working with Yvonne. Just a clarification question. Are you just going to be joining the Scientific Advisory Board, or are you going to be staying on with the full Board of Directors? And then a quick question. How is enrollment progressing in the CAR-DA1 trial? Thank you.
spk08: Yeah, thank you. Tazine, thanks for your very warm comments. And you're going to love working with Yvonne. She's nothing short of terrific. I'm going to be staying on the Scientific Advisory Board because I cannot do anything other than love the science of L. nilum and can't wait to continue to be involved with the great science and progress that we're making here in the company. As you can imagine, being on boards for a former CEO is, is always a complicated thing. And I just think it's a lot better for Yvonne if I'm not on the board and I just focus on the science, which I'll do, and I'll torture Akshay instead. Leave Yvonne in good place. But, no, it's a decision that I made because I think it's very difficult for former CEOs to stay on boards. And, obviously, I will participate in the company on the scientific advisory board. But, Akshay, do you want to comment on Cardio? Yeah.
spk02: Cardio 1 enrollment is going well. You know, generally speaking, Tasneem, we let the trial progress, and we have a clear line of sight on the last patient in before we give further guidance. But it's going very well. I mean, this is hypertension as over 1.2 billion patients around the world. So it's an eminently enrollable study, and it is going well.
spk04: I mean, John, if I could just add that I'm looking forward to actually what is going to be quite a sort of reasonable transition period here. I'm not actually taking on the role as CEO until January the 1st next year, and John will be staying on as an advisor for the, you know, three or so months following that period. So we're going to be seeing quite a lot of each other still, I think, John, in the next period of time.
spk08: I think so. Thanks, Dazeen. Does that answer your question? Questions?
spk11: Yep. Thank you, guys.
spk03: Thank you. Our next question comes from Ted Tenthoff with Piper Sandler.
spk09: Great, thanks. And, John, my sincere congratulations to you. I wish you nothing but personal and professional success. It's such a pleasure. It's been a long time. And a lot of congrats. It's a really exciting transition point for the company. So I wanted to ask a little bit more on pipelines in terms of AAP. Maybe, again, not to steal too much thunder from the upcoming R&D day, but can you give us a little bit more insight into how you anticipate developing that asset with Regeneron? Thanks.
spk08: So, Ted, you were coming in and out. Which asset with Regeneron specifically?
spk09: ALNAPP.
spk08: APP, oh, fantastic. Okay. Yeah, no, I mean, let me just start by saying one of the really exciting next frontiers for El Milam is the broader extrahepatic delivery opportunities, and you'll hear a lot about that at our upcoming R&D day, and I think you're going to be really pleased to with what you hear. And, of course, the program that's pushing that frontier is ALNAPP, which targets amyloid precursor protein. And we are really excited that the IND should be filed, or CTA in this case, will be filed by the end of the year. And we do expect to have human data next year from that program, which will be really important because if we can reproduce the, you know, 70%, 80% lowering of APP and beta fragments that we have observed so durably in the primate, that would be a major milestone for the entire field and, frankly, for the treatment of neurodegenerative diseases in the future. So we really look forward to that. Now, specifically on the development plans, maybe I can point it over to Pushkol to maybe make some high-level comments. Pushkol?
spk07: Sure. Thanks, John. So with regard to ALN APP, as Akshay mentioned in his comments, we're going to be filing a the IND later this year to take that molecule forward. We think it has broad applicability across, you know, if it meets its proof of concept, as John highlighted, in Alzheimer's disease, as well as another very, very disabling and fatal condition, cerebral amyloid angiopathy, both of which APP has been strongly implicated in. The initial study that we're planning to do will be opening the IND and CTA in early onset Alzheimer's disease, which is a well-characterized population of patients with severe unmet need. And then based on the results there, where we will be looking initially for safety, tolerability, as well as pharmacologic activity, we'll be able to branch into, you know, a broader Phase II and III program in those two diseases. So that's our plan. Does that answer your question, Ted? Sure does.
spk09: Thanks, everybody.
spk03: Thank you. Our next question comes from Salvin Richter with Goldman Sachs.
spk01: Good morning. Thanks for taking my questions. And John, it has been a pleasure working with you. You'll be missed here. And Yvonne, congratulations on the new role. In terms of Apollo B and this tefamidus drop in here, how do you account for this in the statistical plan, just given that patients still do have the option to pursue it, notwithstanding discouragement? And then secondly, on the CNS platform, maybe help us understand just where you stand in the ability to deliver to that tissue.
spk08: Yeah. Well, let me have Pushkal answer the Apollo B question, and then Akshay can answer the APP question. But let me just start, Sylvain, first of all, by thanking you for your comments at the beginning, of course, but also just reminding you that, you know, obviously in the design of both the Helios B and Apollo B study, we come at this with enormous experience in doing clinical studies in ATTR amyloidosis. And we come at this, of course, with a very solid track record, as you know, from our overall clinical development team in designing very robust, typically highly overpowered studies, I might say, as you can note from our traditional p-values. So with that as background, Pushkar, do you want to answer Selvin's specific question?
spk07: Sure. Hi, Selvin. Look, I think, you know, I understand why you're asking your question. Again, as John highlighted, as we designed the study, we were obviously very cognizant of the availability of tefamidus and the potential for drop-in. There was an allowance for a certain amount of baseline tefamidus use on entry into the study, as we talked about, and we modeled out a variety of parameters. The studies do allow for patients to drop in on TAF, particularly guiding after the first year. And as you'll recall, in Apollo B, the primary endpoint is a 12-month endpoint of six-minute lock test. The other thing to remember is that as we think about the geographic deployment of this study, we also are aware of where TAF is available to patients. And so through the way we operationally manage the study, we can also have some control about the availability of TAF and the potential risks around drop-ins. And then also statistically, we assumed some very conservative assumptions. As John highlighted, we were very thoughtful about how we designed these studies, and so we considered very conservative assumptions in terms of drop-in and made sure that our powering considerations were robust. to even the worst-case scenarios. So we feel very, very comfortable with that. And then finally, our analysis plan also takes into account the potential for drop-ins, and there are analytic methods where we can, for example, sensor drop-ins and look at analyses with and without drop-ins, et cetera. And I'll just highlight that we monitor this very closely, as does our DMC, and we feel very, very confident and good that the numbers continue to be low, and we're monitoring that, and we feel very comfortable with the overall conduct of the study.
spk08: Great. Thank you, Pushkal. Akshay, the question on APP.
spk02: Yeah, so we're very excited about the CNS delivery approaches we have in hand. You know, we shared at OTS that we've got a novel conjugate that's a lipid-based system, C16, and we've shown, you know, Reproducibly both in small animals rodents and in non-human primates that we get Widespread delivery in the central nervous system with potent knockdown 80% or greater durable knockdown of up to a year And against multiple targets and these targets, you know, we've looked at cell specific markers So we know we get knocked down in all the major cell types in the nervous system the neuron the astrocytes microglial cells and And, you know, anatomically, the biodistribution looks very encouraging indeed with knockdown in deep brain structures, which I know has been a challenge for other modalities, cortical structures, cerebellar structures in the spinal cord. So, you know, with that kind of preclinical pharmacology package, one has to be excited. And with, you know, therefore the LNAPP program, which we discussed just a few minutes ago, really is in the vanguard of what's to come, and we look forward to exciting data from that program in 2022 with biomarker knockdown, hopefully.
spk10: Thank you.
spk03: Our next question comes from Paul Matias with Stiefel.
spk17: Great. Thanks so much. And I'll echo what everyone else said, John, about working with you. And, Yvonne, congratulations. I wanted to ask a few more questions just about the transition and why now. And I guess, you know, one thing that I noticed going back to the last quarter press release was that Mike Bonney was named executive chair really recently, and it had to do with legal and compliance functions. And I guess I wanted to just kind of understand, is there anything beyond what was disclosed here as it just relates to kind of, John, your vision strategically, the board's vision strategically? I guess really just flat out, was there any kind of disagreement at all on where Al Milam is going, or is this purely just voluntary and you feel like it's the right time? And I guess if you do feel like it's really just the right time, why not wait until after Apollo B, given how big of a value-creating event that could be for Al Milam? Thanks so much.
spk08: You know, Paul, thanks for the question and your kind words at the beginning. And let me try to be really clear. This was my decision. I want to begin a new chapter. I've been running this company for 19 years. Came here when there were Six employees as the founding CEO, $17.5 million post-money valuation, and took it to $25 billion. And obviously, 1,600 employees in 20 countries around the world and four approved medicines. So after a 19-year tenure like that, it's not unreasonable to say, okay, things are really good. Things are going great. I might want to not be a running CEO for the next 19 years. And, you know, in terms of timing, yeah, I could have waited until next year. I could have waited until two years. I could have waited until 30 years, but I'd probably be dead. So at some point, you've just got to make the call about when to make a transition. And I couldn't be... more excited about where the company is right now, and I couldn't be more excited about the fact that Yvonne is here as my successor. I mean, if I waited for a year and Yvonne got lured to go someplace else, I'd have no successor. So I'd have to keep kicking the can down the road. So the bottom line is, this is the right time. There's never a great time, of course, but I think this is the right time. And in terms of value creation, I'm still a major shareholder of the company. and I'm going to stay a major shareholder of the company, and I'm obviously going to benefit from the very, in my view, very likely outcome of Apollo B, which I think will be a very defining event for the company. Does that answer your question? I don't know, Yvonne, if you want to say something.
spk04: Well, I just want to add that, you know, John and I created the P to the 5 times 25 goals together, and as you all know, this lays out the very bold vision that we have for the company, delivering transformative medicines to patients around the world with both rare and more prevalent diseases from our amazing product engine, as well as delivering excellent financial performance. And we put this strategy together, and going forward, I'm fully committed to progressing the strategy. I think it serves as well as a roadmap to guide us through the next chapter. And I kind of am planning to execute fully against this plan without any loss of momentum.
spk05: Thank you.
spk17: Yeah, it does. If I can just ask one follow-up. You know, given that Barry left a year ago, and John, now you're deciding it's time. Yvonne, again, congrats. Do you expect the rest of the management team to remain in place?
spk08: I mean, absolutely, Paul. I mean, we have a very committed team of leaders here in the company. And I have no reason to believe that any changes are going to happen. But we also have a really strong bench. You know, we have a strong group of people that are right underneath these leaders that we have right now. And so we are in very, very strong position to as a result of all that, and I have every confidence that this company will continue to perform unbelievably well for the future. No doubt about it in my mind.
spk17: Great. Thank you again.
spk08: Thanks, Paul.
spk03: Our next question comes from Ritu Bharu with Callen.
spk10: Thanks for taking the question, everyone. Yvonne, congrats. Really looking forward to working with you. And, John, we'll miss you, but that Lyric Opera offer still stands on my part. All right, I'm in.
spk00: Sounds good. I'm in.
spk10: I wanted to ask, you know, without getting you in trouble with maybe ACC, I wanted to ask about the potential technetium data that we're going to be seeing out of Helios A next year and especially how that could be important for differentiation and marketing potentially going forward. I guess, one, can you walk us through, like, the units of that scan and, and what's a meaningful burden reduction, and are we gonna get that same data out of Apollo B and Helios B?
spk08: Okay, great. So let me have Akshay answer. You asked a question about differentiation as well, so I'm going to have Tolga weigh out of that part of it. Let me start, though, with Akshay commenting without getting into trouble with ACC, if that's where we present it. So, Akshay, go ahead.
spk02: Yeah, we do. You know, we will have to wait for the full data to share in more detail. But at a high level, what I would say is this is a, there's the metric evaluation tool where you look at the extent of tracer uptake into the heart. And what we've done in a significant number of actually the largest number of patients in a study of this kind ever looked at pre and post treatment. And we're very encouraged by the fact that the majority show reduction in trace or update with technetium. Now, you know, that's not a clinically approvable endpoint today. What we know scientifically is that we're encouraged by this because the data would suggest that this could be potential evidence or reduction in cardiac amyloid, and that, of course, would be very exciting. So we'll share the full data set with you in due course, but, you know, the data can only be supportive and encouraging of what's to come in Apollo B and Helios B, and our overall belief that reduction of TTR levels without drugs, Patisran and Butrocin, hopefully will convert to significant clinical benefit for patients with ATTR cardiomyopathy. And, Toby, do you want to comment a little bit?
spk10: Oh, sorry, go ahead, Ritu. Akshay, will those two trials also generate technetium cohort data?
spk02: Yeah, technetium is an optional assessment in that not all patients will have it. And of course, you know, the availability will vary at sites around the world. But yes, there'll be some technetium data. More importantly, I think, in those studies, Rita, will be the clinical endpoints, of course, right, which six-minute walk distance for Apollo B and mortality and hospitalization for Helios B.
spk08: And, Tolga, do you want to comment a little bit on Rich's question around the potential differentiation of these data as it relates to the competitive landscape and so forth?
spk16: Sure. I mean, first of all, obviously we're very pleased with the on-patriot performance and how we've been able to expand our prescriber base and increase our start forms. Now, there will be patients and physicians who are waiting in the C category, And I believe with combination of efficacy safety and once quarterly in the future and possibly semi-annual subcutaneous treatment regimen, along with coupled with the strong commercial capabilities that we already built, I believe this product will enable us to further expand the franchise that we already established. Especially in markets where increased convenience, for instance in Japan we have limited home infusion availability, the switch dynamic will certainly increase, as well as in the EU, where increased convenience could accelerate the switch dynamic from a stabilizer to increase our category share of first-line versus other treatment options.
spk04: I'd just like to add one point, and that's just to emphasize that our commercial organization has done a fantastic job, but, you know, we have something like 1875 patients that are currently on commercial treatment. We have an opportunity that's much, much larger than that. If you look at the patients that would be appropriate for On Patro and hopefully shortly for TreeSaran, you're looking at over 30,000 patients. So we really are at the beginning of this journey that I think are going to just continue to pick up steam as time goes on.
spk10: Great. Thanks, Yvonne.
spk03: All right. Thank you. Our next question comes from Anupam Rama with JP Morgan.
spk05: Hey, guys. Thank you so much for taking the question. John, sad to see you go, but it's been really cool to see everything you've built, man, and wishing you the best. Yvonne, congrats, and look forward to seeing you at the conference in January. On Patis Fran and Apollo B, more of a market research question. What does your market research say about a knockdown agent within every three-week IV regimen at a six-minute walk distance and point? How does that kind of fit in versus a tefamidus, particularly in wild-type cardiomyopathy, where we know they have hospitalizations and mortality type of data?
spk08: Thanks so much.
spk05: Yes.
spk08: Yeah, thanks, Anupam, and I will miss you in January, but I'll perhaps be in the audience watching Yvonne. But getting back to your question on differentiation and specifically the question on how does it all play out, I'll let Tolga answer in just a minute. But let me just start by saying that obviously, you know, if we generate positive results out of Apollo B and if the drug is approved for the wild-type and hereditary ATTR cardiomyopathy segment, those are, of course, important ifs. We think that the profile of a TTR silencer and the mechanism of action of a TTR silencer will be a valued part of the treatment options that are available for patients and with this disease. And we certainly believe, based on market research we've done that Tolga can comment on, that that type of availability, you know, certainly for patients that may be progressing in their ongoing treatment with a stabilizer drug, if they're on a stabilizer drug, that that type of treatment option may be important for the patients, again, assuming positive Apollo B data and positive approval. So that's at least the foundational aspect of it. Tolga, do you want to add anything more to that as well?
spk16: No, John. I mean, essentially what we shared earlier as well, based on some of the market research studies we've done, we've certainly seen the early indicators of cardiomyopathy or cardiac disease data, secondary endpoints, tend to be seen very favorably by the cardiologist if the product is obviously approved. And obviously, given the profile of the product, there being a quarterly subcutaneous injection clearly addresses the adherence issue, which, again, would be another important indicator.
spk07: Yeah. Yeah. Bushmo, do you want to comment? Sure. I think it's an important question. I think maybe just a couple of points to reiterate around on PATRO and the profile of tefamidus. You know, I think it's important to recognize that patients on tefamidus, even coming out of the ATTRACT study, continue to decline in terms of their six-minute walk test. And so we think there's an opportunity, again, based on the data we've seen more broadly with silencing, to potentially have a very differentiated clinical profile. The other, you know, point around this, and we're starting to see some evidence of that, while there haven't been head-to-head studies, it was interesting, for example, that there was a recent abstract presented at the EU TTR meeting that looked at technetium scans in patients given to silencer and patients given to famitis. And, you know, Akshay mentioned early on that we've seen evidence of improvements or reduced uptake on technetium scanning with with a silencer. In this case, with butreceran and heliose, in that study, they looked at patients on PATRO and saw similar results. And interestingly, in that study with tefamidus patients and stabilizer patients, they did not see those kinds of improvements. So again, a small study, academic study, but I think as we start to look at the totality of data that's emerging on our class of silencers versus stabilizers, we are starting to see differentiation in And we'll see then when we get the results from Apollo B how those materialize, clinical trial data.
spk16: By the way, just to keep the record straight, I was referring to Helios B, not Apollo B, so sorry about the subcutaneous one. No, thanks.
spk08: Does that answer your question, Adam?
spk05: Yep.
spk03: Thanks so much for taking the question.
spk13: Thank you.
spk03: Thank you. Our next question comes from Alethea Young with Cantor.
spk13: Hey, guys. Thanks for taking my questions. Yvonne, you've been killing it over there. Keep on killing it. Congrats. And John, you guys always have a special place in my heart, and it's been great working with you and one of the first companies I've ever covered. So all the best, man. Thank you. So I guess I want to talk a little bit about big picture. You guys have a lot of things going on. I'm obviously now starting to branch out into many different indications. So when you look across the next three to five years, as some of these start to come potentially to fruition, Are you looking to kind of build deeper commercial organizations that do more and diversify, or are you kind of thinking about different other strategic ways and things to do things? Thanks.
spk08: Well, it's a terrific question, Olivia, and you've always been such a great covering analyst, so it's wonderful to have been one of the first companies you've covered. But I think your question is a really terrific one for Yvonne, so I'm going to just pass it right over to her.
spk04: Yeah, no, that's great. I think we're in a really strong position with what we've put in place to continue to execute. If we look at the opportunities that are ahead of us, They're going to be focused around the cardiac market for the next few years. Obviously, hopefully we get great data out of Apollo B and Helios B, and then we look forward to Zalbisran for hypertension, which we believe is going to completely reimagine the treatment of hypertension. I think we're going to be able to build on this footprint. from a commercial perspective within the company. But clearly, you know, as we go forward with all the opportunity we have, what that gives us is tremendous optionality for thinking about how we want to build the business. We're just incredibly fortunate to be standing on the foundation that John has built over the last 19 years. And, you know, I couldn't be more excited about what we have in front of us.
spk08: Does that answer your question? I'll let you go.
spk13: It does, and congrats, guys.
spk03: Thank you. Our next question comes from David Leibowitz with Morgan Stanley.
spk14: Thank you very much for taking my question. Yvonne, congratulations on the new role, and John, it's been great working with you over the years. Thank you. Quick question on the data from the Vutrisran trial. Would you be able to compare the safety profiles of Ampatro, Butresaran, and Revuceran, the discontinued therapy, as far as similarities and differences across the platforms?
spk08: Well, let me give some context, and then maybe, Akshay, you can comment on it. I mean, you know, Rebusaran, of course, is a completely different animal. Early generation, STC, galnet conjugate, poorly stable, not very stable, required extremely high doses, and turned out to be not well tolerated in a frail patient population. And obviously that program was discontinued. You know, I think the big difference between the sub-Q-delivered butreceran versus the IV-infused Onpatro really comes down to the type of administration that's involved. If you look at sub-Q injection, we see a low incidence of mild to moderate, generally always reversible type of injection site reactions with sub-Q-delivered butreceran. With intravenously administered on PATRO, we see a low incidence, you know, roughly 15 or so percent of infusion-related reactions, which are not uncommon with IV-infused drugs as well. And so I think that's really the biggest difference between them. Of course, vitreceran also does not require premedication, which is a nice feature around vitreceran as well. And so, in general, I think those are the main differences. Akshay, do you want to comment any further?
spk02: No, I think you covered it well, John. I would just add that, you know, the safety profile of Butrisran looks extremely encouraging on its face and comparing to the placebo data from Apollo. And, you know, just as one marker of that, I would say, you know, three study discontinuations in a study of this length with over 120, 30 patients on butyricine is pretty remarkable. These are very frail, sick patients. And with the encouraging efficacy data we've discussed today, I think that all adds to a very encouraging benefit-risk profile. Of course, we'll submit these data to regulators and they have the final judgment, but we're certainly very encouraged by the overall profile of this drug.
spk08: Yeah, and I would just add, to wrap it up, that obviously both Butresaran and Ampatro, well, in the case of Ampatro, we also have post-marketing data, and we are encouraged by the very consistent post-marketing data as it relates to the study results that we saw in Apollo. But then in terms of ongoing clinical studies for both Butresaran and Butresaran in the cardiomyopathy study, the Apollo B and Helios B studies, We have data safety monitoring boards that review the unblinded safety data quarterly, and so far so good in terms of any certainly support for continuing to move forward. So, you know, that's the landscape, David. You know, we've learned a lot over the years in terms of how to make these molecules better and better, and I think knock on wood, so far so good in terms of how that's played out.
spk14: Thank you very much for that. If we jump over to Oxlumo, I know that you were talking about the bolus patients at the beginning who had the loading dose led to the, I guess, the downtick from last quarter. How should we view that factor going forward from this point as far as mapping out run rates going forward for the drug?
spk08: And maybe Tolga and Jeff can take that on. Tolga, do you want to start?
spk16: I mean, look, at the end of the day, we were able to grow our patient bases of 5% and now we're at 120 patients. Majority of the patients that we've been able to build over time has been coming from either naive patients, where you do see this starting dose impact, and as well as early access program patients that already were getting there, starting those prior to the program, that before they were commercial. The way I would really think about this is, as we are expanding geographically, we would still see some level of this impact to a degree based on the markets that we're expanding, as well as our continuous performance in the U.S., where we didn't really have a lot of early access program patients. So this dynamic will continue, but maybe not to the magnitude that we currently see at this stage. Jeff, do you have anything else?
spk06: The only thing I'd add just on top of that is I think as the scale of the opportunity grows, some of the noise that you see from these dynamics will dissipate. Exactly. Excellent. Thank you very much for taking my questions.
spk08: Thank you.
spk03: I will now turn the call back to the company for closing comments.
spk08: All right, well, thank you, everyone, for joining on this call. This is my last one at El Milam. I want to thank all of you for the support over the last 19 years. We built a remarkable company that's absolutely here to last, and our next chapter has so much promise for patients and our broader stakeholders. Thank you. Have a great day.
spk03: Ladies and gentlemen, this concludes today's presentation. You may now disconnect and have a wonderful day.
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