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spk19: Thank you for standing by, and welcome to the Nile and Pharmaceuticals Third Quarter 2022 Financial Results Conference Call. At this time, all participants are on a listen-only mode. After the speaker's presentations, there will be a question-and-answer session. To ask a question at that time, please press star-one-one on your touch-tone telephone. As a reminder, today's conference call is being recorded. I would now like to turn the conference over to the company. Please go ahead.
spk10: Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam.
spk09: With me today on the phone are Yvonne Greenstreet, Chief Executive Officer, Phil Wittangular, Chief Commercial Officer, Akshay Vishnow, President, and Jeff Poulton, Chief Financial 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 for our website, investors.alnylam.com slash events. During today's call, as outlined in slide two, Yvonne will offer introductory remarks and provide some general context. Olga will provide an update on our global commercial progress. Akshay will review early pipeline updates and clinical progress. And Jeff will review our financials and guidance, followed by a summary of upcoming milestones before we open the call to your questions. I'd like to remind you that this call will contain remarks concerning L9LM'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 as only at the date of this reporting 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 Yvonne. Yvonne?
spk08: Thanks, Christine, and thank you, everyone, for joining the call today. We're very pleased with the results delivered in the third quarter, both commercially and with our pipeline. This is the first full quarter of our Ambutra launch since U.S. approval back in June, which drove 30% growth in the U.S. for the TTR franchise compared to quarter two. Clinically, the TTR franchise is a highlight as well. We presented positive results for the Apollo B phase three study of the TCRAM in patients with ATTR amyloidosis with cardiomyopathy, validating the therapeutic hypothesis that RNAi-mediated silencing of TTR has the potential to result in a disease-modifying impact on the cardiac manifestations of ATTR amyloidosis. We're delighted with the totality of these results, and we look forward to submitting a supplemental NDA from PATRO by year-end. This also gives us increased confidence in the Helios B Phase III outcome study of vitreous RAN in ATTR amyloidosis with cardiomyopathy. which is on track for top-line results in early 2024. Our earlier stage programs advanced as well, with positive results presented from the Phase II study of Semdesram in patients with IgA nephropathy, as well as preliminary data in patients from the ongoing Phase I study of ALN-HSD in development for the treatment of NASH. In the coming courses, we expect to have more exciting updates from our pipeline, including results for potential biannual dose regimen for vitreceram, preliminary phase one results in healthy volunteers for ARN-XDH, an investigational RNAI therapeutic for the treatment of gout, completion of enrollment in the cardiac two phase two study of zarbiceram, and initiation of a phase one healthy volunteer study of ALN-TTI-SCO4, for which we filed a CTA earlier this month. This execution is in line with our focus on these key drivers for our NINEMS growth over the next several years. Firstly, the potential near-term expansion of our TTR franchise opportunity, where we aim to become a global leader in delivering impactful and highly differentiated medicines to patients. Second, our expansion beyond rare diseases into prevalent diseases. And a third growth driver for the company comes from our sustainable innovation engine, comprised of new platform enhancements, opportunities with extrahepatic delivery, and our ability to find new genetically validated targets, which can drive further pipeline expansion to 2025 and beyond. We believe all of this positions us well to deliver on our Alnylam P525 goals, making Alnylam a top biotech company, developing and commercializing transformative medicines for rare and prevalent diseases for patients around the world, driven by a high-yielding pipeline of first and or best-in-class product candidates from our organic product engine, all while delivering exceptional financial results. With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga?
spk06: Thanks, Ivan, and good morning, everyone. Q3 was a strong quarter for our commercial portfolio, with 9% quarter-over-quarter growth driven by a strong launch of Ambutra in the U.S., as Ivan highlighted. While still early, we are encouraged by several signs indicating that Ambutra is expanding the size of the opportunity for our HATTRPN franchise. I'll have more details to share on this shortly. The strengthening of the U.S. dollar continues to impact product revenues from our international operations, as Onpatro, Givlari, and Oxlumo Q3 product sales each experienced FX headwinds compared with the prior quarter and prior year periods. With initial sales of Ambutra now reflected in our quarterly financial results, moving forward, we will highlight our results for Onpatro and Ambutra on a combined franchise basis, We saw robust growth in our TTR franchise in Q3, achieving $170 million in global net product revenues for Onpatro and Ambutra, representing an 11% increase compared with the second quarter and a solid 41% growth compared with Q3 2021. At the end of Q3, over 2,580 patients were on commercial Onpatro or Ambutra treatment worldwide, up from over 2,400 patients at the end of the second quarter, representing steady 8% quarterly patient growth. In the U.S., combined sales of Ampatra and Ambutra increased a robust 30% versus the second quarter and were primarily impacted by the following. A 19% increase in demand growth, which was driven by the strength of the initial Ambutra patient uptake, more than offsetting the decrease in patients on Ampatra that switched to Ambutra, In total for the quarter, 180 patients initiated ombutra treatment with over 40% representing new patients to on-lilum and the balance representing patients switching from Onpatra. Initial ombutra launch inventory stocking in the distribution channel increased growth an additional 11% in the quarter. In our international market, Onpatra Q3 product sales decreased 5% versus Q2-22, despite an increase in patients on therapy as the timing of orders in partner markets and FX headwinds offset the increase. Our global results continue to be challenged by foreign exchange headwinds, with Ompatra year-over-year reported growth of 41%, held back 11 percentage points due to the foreign exchange impact of the strengthening US dollar. Now, I'd like to provide you with some additional color on our Ambutra US launch. In the first four months of launch, new patient start forms have doubled to an average of 60 start forms per month, excluding switches, in comparison to 30 start forms per month for Onpatro in the first half of this year, which we believe highlights the strength of the Ambutra launch today. Our demand generation has been healthy and balance between community accounts and centers of excellence, while about 17% of start forms have been generated from new prescribers. We're seeing our patient base broaden to include a variety of newly and previously diagnosed patients starting on Ambutra, with significant enthusiasm being expressed for Ambutra's product profile, including quarterly subcutaneous dosing. Meanwhile, on the access front, Given our parity pricing to date, we have not faced with any significant access headwinds and have made significant progress with formulary approvals, providing smooth access to patients that are put on Ambutra therapy. Additionally, we are pleased with the average time from receipt of start forms to initiation of therapy for Ambutra patients, which is already in line with our OnPatro benchmark. To wrap up with Ambutra, we're also excited about the recent regulatory approvals in the EU and Japan for HAI, CTR, Emily-Diosis patients with polyneuropathy, and are looking forward to launches in Germany and Japan in the fourth quarter. Moving to our ultra-rare disease franchise, first, Givlari, we achieved $46 million in global net product revenues in the second quarter, representing a 1% increase compared with Q2-22, and 43% growth versus Q3 21. At the end of Q3, over 460 patients were on commercial Givlari treatment worldwide, up from over 420 at the end of second quarter, representing 10% quarterly patient growth. In the US, sales of Givlari increased 5% versus the second quarter, primarily due to demand growth of 7% by an increase in patients on therapy, which was modestly offset by changes in inventory, stocking, and gross to net sales deductions. In our international markets, Givlari sales decreased 6% compared with the second quarter, with growth in patients on therapy more than offset by lower net pricing and FX headwinds. Finally, the reported 43% increase in year-over-year global net product revenue growth of Givlari was held back seven percentage points due to unfavorable movements in foreign exchange rates. Moving now to our second ultra rare disease product, Oxluma, we achieved $16 million in global med product revenues in the third quarter, representing a 10% increase compared with the second quarter. At the end of Q3, over 230 patients were on commercial Oxluma treatment worldwide, up from over 200, at the end of the second quarter, representing 15% quarterly patient growth. In the US, sales of Oxluva decreased 10% versus the second quarter, as growth in patients on therapy was more than offset by decreased average patient utilization during the quarter, driven by fewer patients on the monthly loading dose portion of their initial treatment. In our international business, Sales of Oxlumo increased 29% compared with the second quarter due to an increase in patients on therapy and higher net realized price during the quarter, partially offset by FX headwinds. Additionally, as with Onpatra and Givlari, changes in foreign exchange rates also negatively impacted Oxlumo to 322 results, with reported year-over-year growth of 10% held back by 10 percentage points due to the strengthening U.S. dollar. In conclusion, we're pleased with the growth in revenues and patient demand achieved in Q3, and particularly with early signs of strong performance associated with the Amvutra launch, which we believe represents an important therapy option for HATTR amlidiosis patients with polyneuropathy and an accelerated growth opportunity for our TTR franchise. With that, I will now turn it over to Akshay to review our recent R&D pipeline progress. Akshay?
spk07: Thanks, Tolga, and good morning, everyone. I'll start with our efforts in ATTR amyloidosis, where we're advancing two clinical stage product candidates, Patisran and Butrisran. Barton-Patro is currently approved in multiple markets around the world to treat the polyneuropathy associated with hereditary ATTR amyloidosis. We're committed to expanding the product's label to the treatment of cardiomyopathy in both hereditary and wild-type AT triamyloidosis patients. At this end, we're excited to have recently presented positive results from the Apollo B Phase III study, where Patisran achieved a statistically significant and clinically meaningful improvement relative to placebo in the six-minute walk test at 12 months, the primary endpoint of the study. It also achieved a statistically significant and clinically meaningful improvement relative to placebo at 12 months on the Kansas City cardiomyopathy questionnaire, the study's first secondary endpoint, and a key measure of patient self-reported health status and quality of life. Furthermore, the T-SRAM demonstrated an acceptable tolerability profile, and we're very encouraged by the overall safety profile of the T-SRAM. Collectively, we believe these efficacy results validate the therapeutic hypothesis that RNAi-mediated silencing of TTR has the potential to result in a disease-modifying impact on cardiac manifestations of ATTR amyloidosis. With these results in hand, we remain on track to submit a supplemental NDA finding for review by the FDA by the end of this year, with the goal of obtaining regulatory approval in the U.S. and making this medicine available to patients with ATTR amyloidosis and cardiomyopathy as rapidly as possible. Also, advancing butriceran, which is delivered by a quarterly subcutaneous injection, now marked as Ambutra, to treat the polyneuropathy of HATTR amyloidosis. and VUTRA was approved based on results from the Helios A Phase III study. That study includes an ongoing randomized treatment extension where we're evaluating a biannual dose regimen, and we're on track to share results in late 2022. As with Onpatro, here, too, we're committed to expanding the label to include the treatment of cardiomyopathy in hereditary and wild type A T-tramloidosis patients. This is being accomplished by the Helios B Phase III study of investigational vitreous RAM. Helios B, which is fully enrolled, has an endpoint of all-cause mortality and CV events assessed after at least 30 and up to 36 months. And we're on track to share top-line results in early 2024. As was announced this morning, after careful consideration, we've made the decision not to conduct the optional interim analysis for Helios B. Several factors drove us to this decision, including, one, the early completion of enrollment of Helios B, which meant that any potential acceleration in the approval based on an interim analysis was minimal relative to waiting until the readout from the fully completed study in early 2024. Two, our desire to conclude Helios B with the strongest possible data set, including outcomes data. And three, further enhancement in confidence in Helios B with the recently positive Apollo B readout. As such, we look forward to the Helios B readout as scheduled early in 2024. We also announced this morning that while we remain very excited about the opportunity for TTR lowering to address Stargardt's disease, we do not plan to initiate a Phase 3 study-off, which was ran this year as previously planned, as we evaluate the impact of the Inflation Reduction Act on therapies being developed for more than one orphan disease. We're continuing to consider options for the best path forward in Stuttgart disease, as we recognize the significant unmet medical need in this patient population. Lastly, with regard to our TTR franchise, we're excited to announce that a clinical trial application has been filed for ALNT-TRS-CF4, the first clinical program from our iCarrier platform, which aims to achieve an annual dosing regimen with highly potent and reversible effects. We expect to initiate a phase one study in healthy volunteers by year end. In addition to our late-stage clinical programs, we believe we have also been making great progress with our early and mid-stage programs. A notable highlight this quarter was our announcement of positive results from our phase two study of Semdisram, an investigational RNA therapeutic targeting C5 component of the complement pathway, which is in development in collaboration with Regeneron for the treatment of IgA nephroscopy, or IGAM. In the study at week 32, treatment with semidisaran resulted in a 37% mean reduction baseline in the 24-hour urinary protein to creatinine ratio relative to placebo. The primary readouts of the study are an important prognostic marker of disease progression. The results of secondary endpoints were also consistent with the therapeutic benefit of semidisaran in IGAM. There were no significant drug-related safety signals, and we believe these collective efficacy and safety data support continued clinical development of Sambiceram monotherapy in patients with IGAM. We look forward to gaining alignment with Regeneron to finalize plans for Phase III and sharing those updates with you in due course. Another exciting highlight recently was the announcement of the preliminary Phase 1 data supporting the clinical advancement of ALN-HSD and investigational RNA therapeutic targeting HSD17B13 in development for the treatment of non-alcoholic steatohepatitis, or NASH. After single-dose evaluation in healthy adult volunteers, Part A, multiple doses of ALN-HSD are being studied in adult patients with NASH, Part B. Patients in the first two Part B cohorts, mainly 200 and 400 milligrams quarterly, have completed at least six months on the study. The remaining cohorts are exploring a lower dose or a later biopsy time point. In the first two Part B cohorts, ALN-HSD was associated with robust target knockdown and numerically lower liver enzymes and biopsy-derived non-alcoholic fatty liver disease activity score over six months in patients receiving ALN-HSD relative to placebo. The study was not powered to achieve statistical significance on these endpoints, and the primary outcome measure is frequency of adverse events. LNHSD has exhibited an encouraging safety and tolerability profile to date. Based on these results, we plan to initiate a phase two study in adult patients with NASH in late 2022 in collaboration with Regeneron. Now turning to our LNAPP program, which is in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy. LNAPP is our first investigational conjugate RNA therapeutic targeting a gene expression in the central nervous system. We continue to make progress in enrolling patients with early onset Alzheimer's disease and are progressing through this single ascending dose portion of the phase one study. As we announced in our press release this morning, we now expect initial clinical data from this study in early 2023, a slight change from our previous guidance of late 22. This change reflects the continued progression through dose escalation codes at a measured pace and the rigor with which we are screening for appropriate patients for this study that meet all necessary inclusion-exclusion criteria. We believe these initial clinical data with LNAPP, if positive, will be an important milestone for our CNS platform to show that RNAi can achieve clinically relevant degrees of target knockdown in the CNS with a safety and dosing profile that supports further development. And we look forward to reporting top line results from the study in early 2023. These are just a few highlights from our broad and innovative pipeline driven by our underlying organic product engine that will drive sustainable innovation and represents a key growth driver for Island Island in the years to come. Representative of the productivity of our engine, we look forward to two further CTA or IND filings for the first in human studies before year end. namely ALN-KHK for the treatment of metabolic liver disease, including diabetes, which is an Alnylam-Holion program, and ALN-PNP for NASH in collaboration with Regeneron. We'll be discussing all this in greater detail at our upcoming R&D day, being held virtually on December 15, and I encourage you to tune in. With that, let me now turn it over to Jeff to review our financial results and upcoming milestones.
spk18: Jeff? Thanks, Akshay, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's Q3 2022 financial results and an update on our full year guidance. Starting with a summary of our P&L results for Q3 2022. Total product revenues for the quarter were $232 million or 39% growth versus Q3 2021. It is also worth noting that year-over-year growth in combined product revenues was held back by approximately 10% through the foreign exchange impact of a strengthening U.S. dollar, and given that approximately 45% of our product revenues are generated via sales and international markets. That revenue from collaborations for the third quarter was approximately $29 million, representing a 45% increase compared with Q3 2021. primarily due to an increase in revenue recognized in connection with our collaboration agreement with Regeneron, attributed to an increase in reimbursable activities under our research services arrangement, in addition to an increase in revenue recognized associated with partnership clinical trial activities. Our non-GAAP R&D expenses increased 6% in the third quarter 2022 compared to the same period in 2021, primarily due to increased compensation and related expenses as a result of increased employee headcount and an increase in development expenses, primarily associated with a ramp-up in enrollment in the CARDIA-1 and CARDIA-2 Zolbisaran Phase 2 studies, offset by decreased clinical batches manufactured during the quarter. Our non-GAAP SG&A expenses increased 33% in the third quarter of 2022 compared to the same period in 2021, primarily due to increased headcount and other strategic investments in support of our Ambutra launch and other corporate purposes. Our non-GAAP operating loss for Q2 2022 was $130 million, representing an $18 million improvement compared with Q2 2021, driven by strong top-line growth offset by more moderate growth in operating expenses. Finally, we ended the quarter with cash, cash equivalents, and marketable securities of 2.3 billion compared to 2.4 billion at the end of 2021 with a decrease primarily due to our year-to-date operating loss in 2022. This decrease was largely offset by approximately 200 million received from employee option award exercises and approximately 135 million received from the issuance of convertible debt net of repayment of our blackstone credit facility inclusive of prepayment premiums purchase of cap call transactions and offering expenses continue to believe our current cash balance is sufficient to bridge us to a self-sustainable financial profile now i'd like to turn to our full year 2022 financial guidance Starting with net product revenues, we continue to anticipate combined net product revenues for our four commercialized products will be between $870 and $930 million. Additionally, given the continued strengthening of the U.S. dollar since we issued our current guidance in April, we are currently trending towards the lower half of our $870 to $930 million guidance range. We are reducing our guidance for net revenue from collaborations and royalties from a range of between $175 and $225 million to a range between $100 and $150 million, primarily due to the timing of reimbursable activities in our collaboration with Regeneron and lower-than-anticipated LECBO royalties and sales milestones. And our guidance for combined non-GAAP R&D and SG&A expenses remain unchanged and is a range between $1,390,000,000 and $1,450,000,000. Let me now turn from financials and discuss some key goals and upcoming milestones on deck through the end of 2022. We will continue executing on our global commercialization of Onpatro, Ambutra, Givlari, and Oxlumo. Next, our TTR franchise will have important updates. With Petisiran, we plan to submit an SNDA for review by the FDA for the treatment of patients with ATTR amyloidosis with cardiomyopathy. With Lutrisiran, we plan to report results on a biannual dose regimen from Heliose and HATTR amyloidosis patients with polyneuropathy. Lastly, for ALN TTRSCO4, we are on track to initiate a phase one study in healthy volunteers. In our mid- and early-stage portfolio, we are looking forward to milestones that include completion of enrollment in the Cardio 2 Phase 2 study of Zabisaran at or around year-end, preliminary results expected from healthy volunteers in the Phase 1 study of ALN-XDH in development for patients with gout, and submission of CTA filings for ALN-KHK for the treatment of metabolic liver disease, including diabetes, and ALN-PNP for NASH. Let me now turn it back to Christine to coordinate our Q&A session. Christine?
spk09: Thank you, Jeff. Operator, we will now open the call for your questions.
spk10: To those dialed in, we would like to ask you to limit yourself to one question each and then get back on the queue if you have any additional questions.
spk19: Thank you. Again, ladies and gentlemen, if you'd like to ask a question, please press star 1-1 on your touchtone telephone. Again, to ask a question, please press star 1-1. Our first question comes from Mari Raycroft. Your line is open.
spk02: Hi, good morning, and thanks for taking my question. I was wondering if you can talk about whether you've gotten any feedback from FDA on Apollo B data and what the NDA package would contain, and also if you can talk about confidence around your primary M.P. value and whether FDA has provided any specific comments on this.
spk08: Thanks for that question. Mary, I mean, clearly we're delighted with the results from our Apollo B study where we deliver clinically meaningful and significant benefits across, you know, the six-minute walk test and KCCQ, which are important measures, actually, for patients in terms of how they function and feel. And we got good safety and numerical reduction in deaths. So we're very confident with the package of data that we have supporting this indication holistically, particularly given the small size and short duration of the study. Actually, perhaps you could comment on regulatory progress.
spk07: Yeah, so thanks, Mari, and thanks, Yvonne. I mean, I think you addressed at a high level the key positives that came out of the study that reinforced the hypothesis that RNAi therapeutics can have a significant impact, we believe, in AT channel A doses, including in the cardiomyopathy. We're proceeding to file the supplemental NDA by the end of the year, as we've said. We're confident in this package per the points Yvonne outlined. As the file goes under review, You know, the FDA always gets a safety update, 180-day safety update during reviews, so we'll be providing that, of course, and we'll be very responsive to any questions they have. And so that's about as much as I can say at this point in time, but we've shared the data across two meetings at ISA and HFSA, had extremely strong and positive responses from investigators, KOLs, and others, and so we're excited about this SMDA.
spk08: That's great. So moving forward expeditiously.
spk03: Thank you, Mary.
spk08: Next question.
spk04: Thank you. Our next question comes from . Your line is open.
spk13: Did the outcomes analysis of Apollo B impact your thinking on treated or placebo separation here, and how much time do you save? Thank you.
spk08: Actually, I think that's one for you. Could you repeat the full question? I think something about the outcomes analysis, but the line's not brilliant, so we didn't quite catch the second half of your question. Could you repeat it for us?
spk13: Sure. Could you explain the factors you considered when deciding not to conduct the Helios B interim? I'm just wondering whether the outcomes analysis of Apollo B impact your thinking on treated placebo separation and how much time you save here.
spk08: the questions around our thinking behind not progressing the interim analysis.
spk07: Yeah, I mean, Sylvie, as you as you intimate the positive data out of the follow these significantly increase our confidence and belief that the design and conduct of Helios-B is the right test of the hypothesis that Zutrisan can help patients with ATTR cardiomyopathy. So we feel quite involved most of which we've shared already at these international meetings, but there are others. And so that was one major factor. The second was we obviously want to have the best data associated with trisoran to make it the best in-class product, hopefully for patients with ATTR cardiomyopathy. The best way to do that is to preserve alpha and not mess around with the statistics, which obviously if you do an interim, then that has a significant downstream consequence. on how, on those statistics for the final readout in early 24. And thirdly is just the speed at which everything has moved, which we're delighted by. So, you know, the fact that Helios B actually over-enrolled at the speed that it did means it's such a narrow timeframe between any putative interim and any potential approval thereof versus the full readout in early 24 and hopefully getting a great label and serving patients with ATTF cutting marks.
spk03: That's great, actually. Thank you very much. Next question.
spk19: Thank you. One moment, please. Our next question comes from Kazeen Ahmad of Bank of America. Your line is open.
spk11: Hi. Good morning, guys. Thanks so much for taking my question. Maybe, Yvonne, can you just clarify whether your team has already met with FDA for your pre-SNDA meeting regarding the Apollo B results yet, or is that still to come? And then secondly, do you have any expectations about whether or not an adcom would be needed to review this filing? It is the second indication proposed for an already approved drug, but just wanted to get your latest thoughts on that. Thanks.
spk08: Yeah, thanks, Christine. I mean, as you know, we don't comment on regulatory interactions. I think, you know, I actually covered this in an earlier question. We're very confident with the package that we have supporting this indication when moving forward. as planned with a submission later this year. That's about all I can say on the topic, but thanks for the question.
spk19: Thank you. Our next question comes from Eliana Merle of UBS. Your line is open.
spk01: Hey, thanks so much for taking the question. Just another one in terms of thinking about Helios B as well as the potential uptake in cardiomyopathy. Could you help us understand how you interpret the data in tofamidus combination and what this could potentially mean in terms of uptake in, say, tofamidus progressors or combination use in the real world commercially? And, you know, any initial feedback, say, you're hearing initially? I know it's early, but just curious your thoughts.
spk08: Right. So, I think there may be kind of two parts to the question. I think one actually may be starting off with you, you know, perspectives around you know, data in combination with TAS, and then, you know, maybe talk again from perspectives on how you see things in the commercial. Thank you.
spk07: You know, vis-a-vis your question, Ileana, on the family subgroup concomitant treatment, just to set a fact, this was a large, robust study that considered the real-world population out there. The majority of them don't have any drug right now. About 75% of the study was on placebo and no background therapy. and about 25% of patients had background to thiaminib. You know, I refer you to our HFSA output and Dr. Maurer's very eloquent discussion of why, you know, it's a little bit of a fool's errand just to use a phrase, to cut into small subgroups and, you know, analyses that really are not powered, and the study was not designed to test, so we fooled ourselves. And again, Dr. Mara explained and discussed all this very well, I thought, at HFSA. The overall readout of the study, I think, was robust and excellent, impacting patients' functionality via the 6-minute walk distance and the quality of life. There's lots of internal consistency in the data. So this is a strong package. And we're delighted with it. I appreciate the interest of subgroups, but that's really not what the study was about, to read out.
spk08: Yeah, I thought that just generally all the factors around how to do the commercial. Yeah.
spk05: Just to build on Akshay's point, it'd be premature for us to comment anything specific without the label. But what we can tell you is, if you just look at the numbers since the launch of tefamidus, the diagnosis rate went up by 10 times. And we certainly anticipate that to continue. This is a highly devastating disease. Across the US and ex-US, there's about 250,000 to 300,000 patients suffer from this devastating disease. And what we know is those patients, there are a lot of untreated patients and those patients who continue to progress on TAF. So we believe, you know, our upcoming therapies, if they're approved, will be a very attractive option, both for physicians and obviously for patients.
spk08: Thank you, Tolga. Absolutely. Lots of medical needs still there for these patients, unfortunately. Next question, please.
spk19: Thank you. Our next question comes from . Your line is open.
spk12: Good morning, guys. Thanks for taking the question. Ivana, Akshay, should we be expecting priority review on the SNDA, just given what you and your regulatory consultants see as the unmet need in TTR cardiomyopathy? And can you just also remind us when the last interaction you had with FDA was in the past, obviously not forward-looking, and if there's been any significant turnover in the review team or senior members in the review division since then.
spk08: Thanks, Ritu. So, you know, another question about, you know, the regulatory outlook here, actually, in terms of expectations with respect to R2 review, and another really just asking us to comment on our progress with regulatory interactions. So I think you've sort of answered the question, but maybe you can reiterate the point.
spk07: Yeah, I mean, I think, Ritu, thanks for the question. As you know, we don't discuss the back and forth with the regulators. I will reiterate what I said earlier, that we're confident in this data package. We're on track to file the supplemental NDA by the end of the year, and the priority review, well, that's the FDA's decision, and they have to evaluate, you know, the pros and cons of this therapy in the data package we've submitted, and we'll eagerly await their decision, but there's not much more I can say.
spk08: And Rich can't really comment on review team turnover. You know, I think that's what the FDA managed, and we're not really in a position to speak to that.
spk03: Thank you. Next question.
spk19: Thank you. Our next question comes from Jessica of JP Morgan. Your line is open.
spk13: Hey, guys. Good morning. Thanks for taking my question. Did you have a pre-NDA meeting yet for the On Patro cardiomyopathy filing, or if not, do you expect to?
spk07: Yeah, thanks for the question. I mean, again, I think there's lots of interest around this. The most important thing is that, you know, we obviously have lots of back and forth with regulators across all our programs. And let me just reiterate that we will file the supplemental NDA by the end of the year for this program based on everything we've discussed so far on this call and in many other settings. So, thanks for the question.
spk19: Thanks, actually. Next question, please. Thank you. Our next question comes from David Lebowitz of Citi, your line is open.
spk14: Thank you very much for taking my question. When you look at the Ambutra new patient start forms, I noticed that the number of new patients percentage upticked from what was announced in the first quarter of launch, I think from about a third to nearly 50%. Could you comment on what the expectations for new patients be coming to market is and and how that might impact growth of the overall franchise relative to what Ampatra would have done without the presence of Ambutra?
spk08: Yeah, no, that's a great question. I mean, we're particularly pleased with the performance of our GTR franchise, especially the progress of the Ambutra launch in the U.S., and we're seeing a kind of great dynamic with approximately half of new patients and half switches. And I think you make the point about a TTR franchise, which I'd like to underscore. I think we now really have a TTR franchise, and we expect to be able to grow the PN market, encourage earlier treatment, given the very attractive regimen of Ambutra. But, you know, Tolga, if you want to add some more color, maybe for how you're seeing the outlook for the TTR franchise?
spk05: No, no, absolutely, Ivan. Look, early signs of U.S. Ambutra launch is a good testament to the overall TTR franchise future. Our TTR franchise grew by 30% versus last quarter, driven mainly by Ambutra. Two-thirds of this growth was really demand. In our view, early signs of performance really confirm three key beliefs. One is, despite available treatments, there's a significant unmet need. and the role of Ambutra in its attractive product profile will continue to increase growth. That's going to be important. And also, we do have the strong foundational capabilities that we build over time. across customer-facing capabilities that will allow us to continue to expand this growth. So we're really excited about this. We're still scratching the surface in terms of diagnosis and treatment. There are 10,000 to 15,000 patients in the U.S. that suffer from this condition. We believe Amutra's product profile will be a very nice fit to that treatment regimen.
spk03: Thanks, Tolga. Next question, please.
spk19: Our next question comes from the line of Gina Wang of Barclays. Your line is open.
spk17: Thank you for taking my questions. Sorry, I will ask Apollo B question again. I think because there are quite some questions were raised on its approvability since it's only one study and then there is no outcome data. So maybe, you know, if you could refresh our memory, the history of Apollo B study, So basically how study was designed and was it aligned with the FDA?
spk07: Yeah, thanks, Gina. I think we've discussed much of this on other calls, but let me just reiterate, Gina, that I think this is... I'm losing track a little bit, six or seven phase three study or seven phase three studies we've negotiated with the FDA and other regulators around the world. All our work is in collaboration with guidance from regulators. We have four Allen Island products approved based on that excellent set of dialogues and relationships we have and understanding how regulators are trying to guide us. this product and this trial was no different from that and so if any credibility or confidence is derived from our prior performance i would like you to apply it here now in the specifics here when apollo was done and we all remember the conversations those of you that were involved then um the cardiac data the cardiac subgroup data from apollo were very promising And the FDA said, yes, that is the case. And we've discussed that before. And based on that, they guided us that we should do a separate study in a cardiomyopathy population. And with that conversation and collaboration, the design that you see in Apollo B resulted. And so this study was done in close collaboration with regulators and we're grateful for the guidance and we're very happy with the outcome, where clearly we've shown an impact on patient functionality and quality of life, which are two cornerstones of FDA base of approval of drugs and safety looks very encouraging to us too and then finally on the mortality front you you'll recall that four patients died on placebo rather on T-strand and 10 on placebo so that's encouraging although it's a small number so this package we believe is rather strong for a trial that was designing in collaboration with regulators and so we're looking forward to filing the FMDA thank you
spk19: Thank you. Our next question comes from the line of Paul Matisse of Stiefel. Your line is open.
spk22: Hey, thanks so much. I was really interested in your comments in the press release and in the prepared remarks on drug positioning related to the Inflation Reduction Act and kind of broader drug pricing risk. And to that point, you just filed a CTA for a once annual TTR knockdown drug. How do you think about positioning that and kind of balancing Stargardt's versus this potentially just being a next-gen and TTR cardiomyopathy and also enabling you to maintain premium pricing beyond a decade in that space. Thanks so much.
spk08: Thank you for the question here. I think, you know, Look, the Inflation Reduction Act is a significant shift in Medicare and how the federal government regulates our industry. We are supportive of the new Part D patient out-of-pocket caps, but we have considerable concerns about a couple of other aspects of the legislation. Clearly, the first is around, you know, concerns that small molecules medicines face negotiated Medicare and reimbursement rates only nine years after approval compared to 13 years for monoclonal antibodies. I think very pertinent to us in the near term is that while there are exemptions in the Inflation Reduction Act from Medicare price negotiation for a drug that has a single orphan drug indication, there are now disincentives to pursuing the approval of drugs in additional indications. You know, look, we're still digesting the legislation, but, you know, as you point out, in the meantime, we decide to pause both the T-SER and Phase III study in Stargardt's disease as we consider options for the best path forward. I'd like to just kind of note three points, really. One is that, you know, we remain excited, actually, by the opportunity for an RNAi-mediated CTR-lowering method as a potential therapy in patients with Stargardt's disease. We think it's an important unmet medical need. And the second, I think you touched on it when you talked about TTR-SCO4. I mean, as a platform company, we really have the opportunity to, you know, continuously innovate and bring optionality to how we think about developing, you know, our medicines. And I think, you know, TTR-SCO4 is, you know, another TTR lowering program that we're moving forward, which we're very excited about. I think the other point that I'd like to make, which I think is quite important, is just to remind everybody that retreat SRAM actually has often disease designation for TTR amyloidosis, be it polyneuropathy or cardiomyopathy. So, you know, as with many other companies, we're reflecting on the implications of this relatively new legislation on how we think about our portfolio. But as a company, we actually think we're very well positioned, given our platform and our ability to continuously innovate around our medicines.
spk03: Maybe next question.
spk19: Our next question comes in the line of Gary Notchman of BMO. Your line is open.
spk16: Hi, good morning. If you end up getting the Ompatro Apollo B approval, let's say end of next year, but then you'll be bumping up against the Vutriceran Helios B data in early 24, how much of an impact do you think that might have on your launch of Ompatro in CM when physicians will be anticipating this other important data set I know it's a bit early thinking about the launches, but given the timing of these, I was curious to get some of your early thoughts on that. Thanks.
spk08: I'll just start off by saying that the reason why we progressed on PATRO in the cardiomyopathy indication was really just the level of unmet medical need that there is there for patients who continue to progress despite available therapies. And really, you know, we took the opportunity with on PATRO to try to bring a near-term solution for these patients, whilst we continue to develop butreceran in our Helios B study. And as you pointed out, we'll have those results shortly at the beginning of 2024. So we think that we're able to meet the needs of patients in the near term, hopefully, with the approval of Ompatro and CM. And then as we progress Helios B, bring forward an even more attractive regimen. for these patients shortly afterwards. But maybe, Tolga, you can comment on how we're thinking about, you know, the launch of OnPatro with the opportunity, hopefully, of bringing PatriceRan to these patients in the medium term.
spk05: Yeah, no, I think you summarized perfectly, Ivana. All I would add is, There is a big unmet need. There are patients who are currently on available treatments that are continuing to progress. And to your point, we want to make an alternative treatment available as quickly as possible so we can actually meet those needs and also continue to build our capabilities for the larger indication. We're obviously very pleased with the capabilities that we've built. based on what we're actually able to demonstrate with Ambutra PN launch. And as we continue to expand the indication, we believe our experience with the CM is going to help us to have even a stronger launch with Ambutra CM if it's approved.
spk08: Thanks, Sabah. That's great. So again, the sort of TTR franchise approach, which we think will be important for patients and our commercial performance going forward. Next question.
spk19: Thank you. Our next question comes from Luca Issy of RBC Capital.
spk20: Oh, great. Thanks so much for taking my question. Maybe one on the pipeline, if I may. So maybe on APP, kind of any additional color on why the readout has been pushed out and maybe bigger picture, can you level set expectations into data next year? What reduction in CSS, APP, alpha and beta would you consider meaningful? And maybe what's the earliest we could possibly see functional data for that data set? Thanks so much.
spk08: Great. Thanks, Luca, for a question on ALN-ATP. Look, we're clearly excited about the potential for RNAi therapeutics in addressing CNS diseases. And this is the first one out of the gate. And, you know, we're progressing kind of very well, but thoughtfully, as actually described in his introductory remark. But actually, maybe you can speak to the data that we're expecting out of the after the ongoing study?
spk07: Yeah, the crucial data, I think, first and foremost is safety. This is our first candidate in the central nervous system, so that's of keen interest. The study is progressing well, so we are very comfortable so far. You know, beyond that, obviously, there's lots of interest in the biomarker outlook, and so we'll be looking for APP knockdown and the fragments, the various fragments, proteolytic fragments from APP, changes in those in the CSF. um and um you know in in in addition to that there's going to be important pk because again it's the first time we've injected the jug intrathecally so those are the key data points in the short term that we'll be looking at and looking forward to reporting in early 23. absolutely and you know as we move forward in al and app we're able to demonstrate impacts on patients with
spk08: early onset Alzheimer's disease, of course, it opens up the opportunity for a whole host of other devastating CNS disorders. So, a very important program for us as we're progressing well. Thank you for the question. Next question, please.
spk19: Thank you. Our next question comes from Joseph Stringer of Niedermann Company. Your line is open.
spk15: Hi. Good morning. Thanks for taking our question. A question on mVutra start forms and the percentage source from new prescribers. I think this quarter you have around 17%. That was similar to 20% from your last update. Do you sort of see this continuing in a fairly stable net 15% to 20% range going forward, or how do you see that going forward? Thank you.
spk08: Robert, that's clearly a question for you. How do you see the percentage of new prescribers going forward?
spk05: Yeah, look, I mean, I'm glad you highlighted that. We're really excited about sort of how we're displaying those strong foundational capabilities that we've been able to build from diagnosis all the way to access support. One of those excitements is we see a healthy balance of physicians, both from academic centers and community specialists, start prescribing this medication. And as you pointed out, another important metric is the new prescribers. We see a steady increase of these new specialists. around 20% month after month being added to the prescriber base. And as a result of that, we also see patients are treated a bit younger, a sign that patients are getting diagnosed, and obviously they're getting the Ambutra treatment. Another important metric that we also see, and we're obviously going to pay a lot of attention to this, is our start forms to treatment rates. Despite having a temporary J-code, it's been similar to Onpatro. And again, thanks to our good access support, VBAs, and our price parity strategy. So because of those elements, we believe we're going to continue to see a good expansion of new prescribers and net new patients for Onbutra that's going to drive the TTR franchise to the next level.
spk08: Well, that's super.
spk05: Thank you very much.
spk08: I think we've got time for one more question. Thank you.
spk19: Our next question comes from Miles Minter of William Blair. Your line is open.
spk21: Hey, thanks for squeezing me in. Just on Oxlumo, actually, just with the recent FDA label expansion, are you expecting a significant amount of warehouse advanced PH1 patients? And I guess, how are you thinking about growing that franchise moving forward, considering it's looked somewhat flat over the past quarter? Thanks.
spk03: Okay, do you want to make a... Yeah.
spk05: Look, KH1 is a devastating disease, and we're very pleased to be able to actually provide important treatment for these ultra-rare disease patients. Eliminate C has been a great addition. We do see a good addition to our data, suite of data that we have. We see a good... group of patients both from pediatric and as adult level as well as various progressive stage of their diseases and eliminate C is simply another important element that will allow the prescribers to be able to prescribe this medicine to a broad range of patients that suffer from this ultra rare disease so thanks Olga look you know we've had a great quarter we really are very pleased with our commercial performance and we're seeing strong growth and
spk08: patients on therapy across all of our commercials. So I'm certainly very pleased with our performance. So thank you, everyone, for joining us on this call. Great program for the third quarter of 2022. Talks about our strong commercial results, but also we're pleased with how we're advancing our diverse pipeline programs that are in development. There's a lot of excitement ahead. Catch us on deck in the coming months. And we, of course, look forward to updating you along the way as we continue to deliver on our near and long-term goals. So thank you, everybody, and have a great day.
spk19: Thank you. Ladies and gentlemen, this does conclude today's conference. Thank you all for participating. You may now disconnect. Have a great day.
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