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spk08: Good day, and thank you for standing by. Welcome to the Alnylam Pharmaceuticals first quarter 2022 earnings conference call. At this time, all participants are in listen-only mode. After the presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star, then 1 on your telephone keypad. Please be advised, today's conference may be recorded. If you require operator assistance during the call, please press star, then 0. I'd now like to hand the conference over to your host today, Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications.
spk00: Christine Lindenboom Good morning.
spk09: I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are Yvonne Greenstreet, Chief Executive Officer, Tolga Tangular, Chief Commercial Officer, Sushil Varg, Chief Medical Officer, and Jeff Fulton, Chief Financial Officer. Akshay Vaishnav, President, is unable to join the call today due to a personal conflict. 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.lnylum.com slash events. During today's call, as outlined in slide two, Yvonne will provide some introductory remarks in general context. Tolga will provide an update on our global commercial progress. which will review recent clinical and preclinical updates, and Jeff will review our financials, followed by a summary of upcoming milestones before we open the call for your questions. I would like to remind you that this call will contain remarks concerning LLM's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor provision under 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 of the SEC. In addition, any forward-looking statements represent our views only as the date of this recording. It 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'll now turn the call over to Yvonne. Yvonne?
spk06: Thanks, Christine, and thank you, everyone, for joining the call today. The first quarter of 2022 with another quarter of continued progress at Alnylam across our commercial and pipeline portfolios. First, despite an expected quarter-on-quarter decrease in combined product revenues from our commercial portfolio of Ompatro, Givalari, and Oxalumo, we observed a steady increase in patients on therapy. Alongside that commercial progress, our RNAi therapeutic pipeline programs continue to advance With the TTR franchise, we presented positive 18-month results from the Helios A Phase 3 study of butryceram. The NDA for butryceram is under review, with a new PDUFA date of July the 14th, 2022, following the three-month delay we announced earlier in April to allow for the review of newly added information related to a new secondary packaging and labeling facility. We also brought new programs into the clinic with the initiation of two phase one studies. And today, we announced that the phase one study of ALNXCH in patients with gout has been initiated. Additionally, the first down myelin RNAi therapeutic targeting a CNS disorder, ALNAPP, has entered phase one, a very exciting milestone for our platform. And initial top line results from both of these programs are expected in late 2022. Looking further out, we believe our Nilem is poised for significant growth based on three key drivers. First is the potential near-term expansion of our TTR franchise, where we aim to become the global leader in delivering impactful and highly differentiated medicines to patients. Second, is our expansion beyond rare diseases into prevalent diseases. And the third key growth driver for the company comes from our sustainable innovation engine comprised of new platform enhancements, opportunities with extra-hepatic 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 as well to deliver on our Alnylam P5 by 25 goals, making Alnylam a top biotech company, developing and commercializing transformative medicines for rare and common 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?
spk07: Thanks, Ivan, and good morning, everyone. The first quarter reflected steady progress as we increased the number of commercial patients on therapy across our three products by 9%. In spite of this increase, Q1 reported revenues decreased by 6% compared with Q4 2021, as Q4 benefited from a variety of non-recurring stocking and gross net benefits. Additionally, we did experience some headwinds from COVID in the early part of Q1, particularly in the U.S., where we saw a decrease in patient compliance across our portfolio in January and February when Omicron cases were at their peak. We are encouraged by improved market conditions that developed in March that have extended further into April. And we're cautiously optimistic that COVID will have minimal impact on our commercial operations for the balance of the year, recognizing that the course of the pandemic remains uncertain. I will now provide details on the performance of each of our products. For Ompatro, we achieved $137 million in global net product revenues in the first quarter. representing a 1% decrease compared with the fourth quarter and 34% growth compared with Q1 2021. At the end of Q1, over 2,200 patients were on commercial on-patriot treatment worldwide, up from over 2,050 patients at year-end 2021, representing steady 7% quarterly patient growth. In the US, sales of Onpatro increased 4% versus Q4 2021 and were primarily impacted by the following. A 7% increase in demand driven by an increase in patients on therapy, which was negatively impacted by a decrease in patient compliance, primarily in January and February when Omicron cases were at their peak. Inventory stocking dynamics, which contributed to a 6% decrease in reported growth, and a modest decrease in gross-to-net deductions in the quarter, contributing to a 3% increase in reported growth. In our international markets, Onpatro Q1 product sales declined 5% versus Q4, despite an increase in patients on therapy due to an increase in gross-to-net deductions following Q4, which included several non-recurring benefits, along with an unfavorable foreign exchange impact due to strengthening US dollar in Q1, which impacted results across all three commercial products. Moving to Vivlari, we achieved $35 million in global net product revenues in the first quarter, representing a 13% decrease compared with Q4 2021 and 43% growth versus Q1 2021. At the end of Q1, over 400 patients were on commercial Givlari treatment worldwide, up from over 350 at year end, 21, representing robust 14% quarterly patient growth. In the US, sales of Givlari decreased 22% versus Q4, 21, and were primarily impacted by the following. Flat patient demand, despite a 5% increase in patients on therapy, due to reduced patient compliance, which was negatively impacted by COVID in January and February, inventory stocking dynamics, which negatively impacted reported growth by 15%, and an increase in gross net deductions in the quarter, which negatively impacted reported growth by 7% following the fourth quarter, which included several non-recurring gross net benefits. In our international markets, Givlari delivered 11% growth in Q1 compared with Q421, with the growth primarily driven by new patient ads across key markets and geographic expansion, including an initial contribution from the UK following Q1 commercial launch. Moving now to Oxlumo, we achieved $50 million in global net product revenues in the first quarter, representing a 24% decrease compared with Q4 2021 and 59% growth versus Q1 2021. At the end of Q1, over 160 patients were on commercial Oxluma treatment worldwide, up from over 140 at year end 2021, representing 14% quarterly patient growth. In the US, sales of Oxluma decreased by 5% versus Q4 2021, and were primarily impacted by the following. A 6% increase in patient demand, driven by an increase in patients on therapy, and an increase in gross to net deductions in the quarter, which more than offset the demand growth and negatively impacted reported growth by 11%. Oksuma sales decreased in our international markets by 32% during the first quarter compared with Q4. despite an increase in patients on therapy during the quarter, primarily due to an increase in gross to net deductions following Q4, which included several non-recurring benefits, as well as the timing of order in partner and emerging markets. In conclusion, as expected, despite the reduction in reported revenue growth during the quarter and challenges from COVID in the early part of the quarter, we remain encouraged by the steady growth in patients, we achieved across three products, particularly our performance with Onpatro during the quarter. Additionally, even though we were disappointed by the three-month PDUFA delay for Vutris Ren in the US, we are poised to launch the product upon potential FDA approval by the new July 14 PDUFA date, and we remain confident that this will continue to represent an attractive option for TTR polyneuropathy patients and an incremental growth opportunity for our TTR franchise. With that, I will now turn it over to Pushkal to review our recent R&D and pipeline progress. Pushkal?
spk02: Thanks, Tolga, and good morning, everyone. Let me begin by updating you on our efforts in ATTR amyloidosis, where we are advancing two product candidates, Butisran and Butrisran, across a number of clinical indications. While Patisran or Onpatro is currently approved in multiple markets around the world to treat the polyneuropathy associated with hereditary ATTR amyloidosis, we are committed to expanding the product's label to the treatment of cardiomyopathy in both hereditary and wild-type ATTR amyloidosis patients. To this end, we're conducting the Apollo B Phase III study, and we remain on track to report top-line results in the middle of this year. We're also advancing Vutriceran, which is delivered by a quarterly subcutaneous injection and is also in development for ATTR amyloidosis, as well as Stargardt disease. In ATTR amyloidosis, we're conducting two Phase III studies. The first is Heliose, which is evaluating Vutriceran in hereditary ATTR amyloidosis patients with polyneuropathy. In April 2021, we presented positive results from the study at the AAN meeting, which showed the study met its primary and secondary endpoints at nine months. Those data form the basis for our regulatory submissions to both the FDA and EMA, which are currently under review. As we announced a few weeks ago, the FDA has extended the review timeline of the NDA to allow for the review of newly added information related to a new secondary packaging and labeling facility. Specifically, we submitted an amendment to our NDA upon learning that the original third-party secondary packaging and labeling facility we planned to use for the Butresaran launch was recently inspected as part of a routine CGMP inspection. This inspection was unrelated to the Butresaran application, but as its outcome was unknown, it nevertheless could have resulted in Butresaran receiving a complete response letter with uncertainty regarding the timeframe for resolution. While our amendment resulted in a three-month extension, we believe that this approach offers the fastest path to a potential approval. The updated PDUFA goal date to allow for this review is July 14, 2022. I'd like to reiterate that the inspection issues raised at the original facility were not specifically related to Patrisaran. There have been no questions with regard to the safety or efficacy of the product, and there have been no additional clinical data or trials requested. In addition to these nine-month results, we also presented positive data from the 18-month analysis of the study in January of this year at the SFNP meeting in France. We're delighted that Heliose met all secondary endpoints measured at 18 months, including statistically significant improvements in neuropathy, as measured by the modified neuropathy impairment score, or MNIST plus 7, quality of life, gait speed, nutritional status, and overall disability relative to external placebo data from the Apollo Phase III study. Further, at 18 months, Butristrand also demonstrated improvement compared to external placebo in the exploratory cardiac endpoint NT-PROBNP and trends towards improvement in echocardiographic parameters as well as improvement compared to baseline in cardiac uptake of technetium on scintigraphy imaging. We believe that, taken together, these data, along with the exploratory cardiac data from the original Apollo study, provide evidence to suggest that TTR silencing by butycerin and butycerin treatment may potentially improve the cardiac manifestations of this disease. Butycerin also demonstrated an encouraging safety and tolerability profile, as shown by the data on this slide. We're very pleased with the totality of the results and the profile of Rutriceran that continues to evolve. We believe that based on these data, Rutriceran, if approved, will present an exciting commercial opportunity, providing an attractive treatment option for patients with HATTR amyloidosis with polyneuropathy. In addition, I'll also remind you that we are seeking to further reduce the burden of treatment for patients by evaluating an every six-month regimen of butreceran in the extension period of Heliose with data expected later this year. Of course, this is just the start for butreceran as we are also conducting another Phase III study, Helios B, which is our ongoing Phase III cardiac outcome study, with butreceran in hereditary and wild-type amyloidosis patients with cardiomyopathy. Ilios B, which is fully enrolled, has a 30-month endpoint of all-cause mortality in CV events, and we expect the full results in early 2024. The study design includes the potential for an interim analysis, and we'll consider this after reviewing the results from Apollo B and engaging with regulatory authorities. In addition to our late-stage clinical programs, we believe we've also been making great progress with our early and mid-stage programs. As we've highlighted for some time, a key growth driver for Alnylam is our expansion beyond rare diseases into prevalent conditions. A great example is our program in hypertension. Zalbiceran is our investigational RNAi therapeutic targeting angiotensinogen, or AGT, which is in development for the treatment of hypertension. Zalbiceran is being evaluated in the Phase II CARDIA program. The first of these two studies, CARDIA-1, is designed to evaluate the efficacy and safety of Zalbiceran as a monotherapy in patients with mild to moderate hypertension. The second of these studies, CARDIA-2, was initiated late last year and is designed to evaluate the efficacy and safety of Zalbiceran as an add-on therapy in patients with hypertension despite treatment with standard of care agents. We've announced this morning that we are experiencing enrollment delays in CARDIA-1 in part due to impacts of the situation in Ukraine, as well as the ongoing pandemic. We're expanding the geographic footprint of the study and are also streamlining certain aspects of the protocol to facilitate enrollment. As a result, we now expect to complete enrollment in CARDIA-1 in early 2023, with top line results expected in mid 2023. We are implementing similar measures in CARDIA-2 as well so as to complete enrollment at or around year end. Another key growth driver for Alnylam in the years to come will be our organic product engine driving sustainable innovation with the goal of bringing two to four new molecules into the clinic each year. Here, we achieved some notable progress in the first quarter. We announced this morning that the Phase I study of ALN XTH in patients with gout has been initiated. This is an exciting program based on our work with the UK Biobank, where we found that heterozygous loss of function of XTH was associated with significantly reduced serum urate and a lower risk of gout. We expect top-line results in late 2022. We also achieved a major milestone with the initiation of our Phase I study of ALN APP, our first RNAi therapeutic targeting a CNS disorder. ALN-APP is an innovative program with the potential to address both Alzheimer's disease and cerebral amyloid angiopathy. Initiating this program is a key step towards expanding our pipeline into extrahepatic tissues, and we look forward to top-line results in late 2022 here as well. These are just a few highlights among the many exciting programs we're advancing to address important unmet needs for patients. and we look forward to updating you on our progress throughout the year. With that, let me now turn it over to Jeff to review our financial results and upcoming milestones.
spk14: Jeff? Thanks, Pushkol, and good morning, everyone. I'm pleased to be presenting Alnylam's Q1 2022 financial results, and I will also provide an update on our 2022 financial guidance. Turning now to a summary of our full P&L results for Q1 2022. Total product revenues for the quarter were $187 million, or 38% growth, versus Q1 2021, with all three marketed products contributing more than 30% year-over-year growth. It is also worth highlighting that year-over-year growth in combined product revenue was held back by approximately 5% due to the foreign exchange impact of a strengthening U.S. dollar and given that approximately 50% of our product revenues are generated via sales in international markets. Net revenue from collaborations for the first quarter was approximately $26 million, representing a 38% decrease compared with Q1 2021, primarily due to a reduction in revenue from our Regeneron collaboration, which is subject to quarter-to-quarter variability dependent on a variety of factors, including the level of work completed during the quarter, which is reimbursed by Regeneron. Our non-GAAP R&D expenses decreased 2% in the first quarter of 2022 compared to the same period in 2021, primarily due to modestly reduced clinical trial expenses across the portfolio. However, we do expect an increase in year-over-year R&D expenses for the balance of the year, primarily driven by an increase in spend associated with our plans to increase enrollment in our Zolvisa RAND Cardio 1 and Cardio 2 Phase 2 studies. Our non-GAAP SG&A expenses increased 18% in the first quarter of 2022 compared to the same period in 2021, primarily due to increased legal expenses, charitable contributions, and other expenses to support our strategic growth. Our combined non-GAAP R&D and SG&A expenses were approximately $295 million in Q1 2022, representing 6% growth versus Q1 2021, as we continue to advance our pipeline and deliver strong top-line growth while maintaining discipline and how we invest in our operations. Our non-GAAP operating loss for Q1 2022 was $117 million, representing a $13 million improvement compared with Q1 2021 as we continue to progress on our journey towards building a self-sustainable financial profile aligned with our P to the fifth by 25 goals. Finally, we ended the quarter with cash, cash equivalents, and marketable securities of $2.2 billion compared to $2.4 billion at the end of 2021. Now turning to our financial guidance. Despite steady progress in adding patients across our three commercial brands in Q1, we have decided to reduce our combined product revenue guidance for two primary reasons. First, as we announced earlier this month, our FDA PDUHA date for butreceran has been delayed by three months. And secondly, a strengthening U.S. dollar has created a foreign exchange headwind for our international operations, which today comprise approximately 50% of our global sales. As a result, we have reduced our full-year combined product revenue guidance from an original range of $900 million to $1 billion to a revised range of $870 million to $930 million, representing a 5% reduction at the midpoint of the ranges. This updated guidance assumes approval of butrycerin in the US by the revised PDUFA date of July 14th, as well as foreign exchange rates as of April 18th that are footnoted at the bottom of our guidance slide. Additionally, we have also reduced our non-GAAP combined R&D and SG&A expense guidance from an original range of 1.4 billion to 1.5 billion to a revised range of 1,390,000,000 to 1,450,000,000 as we seek to partially offset the reduction in our top-line guidance. Let me now turn from financials and discuss some key goals and upcoming milestones on deck through mid-2022. To start, we will continue executing on our global commercialization of OnPatro, GiveLawry, and OxLumo. On the R&D side, we have an exciting clinical readout coming up with SymD-Saran, where we plan to report Phase II monotherapy results in IgA nephropathy in early 2022. We plan to continue advancing our TTR franchise. With Petit Saran, we look forward to top-line results from the Apollo B Phase III study in mid-2022. With Petit Saran, we look forward to the potential approval and U.S. launch of our fifth RNAi therapeutic, with a new PDUPA date of July 14th. Approval in the EU is anticipated mid-year, with subsequent launches in key markets to follow, pending finalization of pricing and reimbursement. With ALN-HSD, we expect to report top-line results from Part B of the Phase 1 study in patients with NASH in mid-2022. 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. To those dialed in, we would like to ask you to limit yourself to one question each and then get back from the queue if you have any additional questions.
spk08: If you'd like to ask a question at this time, please press the star, then the number one key on your touch-tone telephone. To withdraw your question, press the pound key. Our first question comes from David Leibovitz with Citi.
spk04: Thank you very much for taking my question. When you look at the On Patro performance in the quarter, did you happen to notice any different dynamics in the prescriber, a cardiologist versus a neurologist, to start?
spk06: So thanks for that question, Dave. Look, we're pleased with the growth that we're seeing with respect to patient demand with Onpatro, but I'll turn it over to Tolga to answer your specific question.
spk07: Yes, hi, good morning. Look, at the end of the day, this is a multisystem disease, and we do know that both neurologists and cardiologists play a very important role in the treatment. We have not really seen any changes in the way the product is prescribed across the globe. We certainly had seen some, as we indicated on the call, some softness in January and February, particularly in the adherence compliance rates. But we are very encouraged by what we've seen in March. And the Omicron impact obviously is dissipating, as we also seen in April.
spk04: Got it. And when looking at the shift in guidance, as you cited, reduction relative to the vitreous saranpiduphidase being put up delayed. How are we supposed to look at it as a component of that change, the vitreous saran delay for the overall guidance change? And I guess I'm trying to level in on how should we view expectations for the drug for this year.
spk14: Yeah, hi, this is Jeff. We updated our guidance, as I said, on the call for two primary reasons. One is the FX strengthening U.S. dollar, given the percentage of revenue that we generate from ex-U.S. markets. And secondly, because of the delay in the PDUFA date for butresaran. And the thinking there is that, you know, we've talked about butresaran being a growth driver overall for the TTR franchise for, I would say, for three primary reasons. One is that we think it will be very attractively positioned for those mixed phenotype patients. We think for potential switches from competitive products. And then lastly, for patients that have been diagnosed but not yet on treatment. We think Patrice Rann will grow our overall franchise as a result of its profile. So the guidance just reflects the fact that we'll have, you know, assuming approval by July 14th, that we'll have the product on the market for one less quarter than we originally anticipated when we got it in February.
spk06: Tolga, anything you'd like to add?
spk07: Yeah, I mean, look, we're really excited about Woodtree. It clearly provides another growth opportunity for the TTR franchise. We built what we like to think a good, strong growth engine within the TTR franchise across our key markets. And we'll be a great addition to that. What we've also seen is, although anecdotally, patients are excited about this. There is a group of patients that actually are going to be making an important decision. They're early in their disease progression, so they may not be willing to get them to start with the infusion. And it's going to be a really great treatment option for those patients who would then be able to take advantage of our subcutaneous quarterly injection.
spk04: Thank you very much. And I guess just one more question on the delay and the PANUFA date itself. Could you just reiterate what information the FDA has asked for and versus what information you have elected to send them thus far? And you also spoke that there was no other areas of discussion. I expect that that won't change going forward.
spk02: Yeah, so I think, look, in terms of, I'll probably have to reiterate a little bit of what I said on the call already. This is really all a result of a third-party secondary packaging and labeling facility that had a routine CGMP or current good manufacturing practice inspection, just a routine inspection. It was not related to Voutree Saran, but this was a facility that we were going to, we had proposed to help with the launch of Voutree Saran. But as a result of that, there were some inspection findings, and the FDA has a timeline by which they have to sort of classify that and determine what action is necessary. That timeline was beyond the PDUFA date, the April 14 PDUFA date for butrycerin. And so, as a result, if it wasn't classified, we ran a risk of getting a complete response letter. And, you know, the timeline for resolution of that, as you know, can be somewhat uncertain. So based on that, we had discussions with the FDA, and we elected to file an amendment to bring on board a secondary, a different facility. And we were able to do that quickly and file an amendment to the existing NDA. That resulted in this three-month clock extension and the PDUFA date. But just to reiterate, there was no request for additional clinical data of any sort. There's no more safety or efficacy data that were asked for. There's no new clinical trials, et cetera. This really just came about because of this inspection finding at this facility unrelated to butrycerin and our decision to really find the most expedited path to get butrycerin approved into patients. And we think this was the best path to do that. So that's what this was all about.
spk06: Thanks, Pascal. And we're absolutely ready to launch, you know, assuming. FDA approval by the July 3rd date. Thank you, Dave. Next question. Thank you so much.
spk08: Our next question comes from Maury Raycroft with Jefferies.
spk05: Hi, good morning. Thanks for taking my question. I had a question about Apollo B. So one difference between Apollo B versus BridgeBio's attribute phase 3 is inclusion of up to 30% stabilizer progressors. Can you elaborate on the criteria to classify patients as stabilizer progressors for the trial? Maybe talk about what gives you confidence the RNAI mechanism is gonna work in these patients.
spk02: Yeah, absolutely. Thanks, Maury, for your question. Look, I think We've talked about this at some length over the last several months since the BridgeBio results. We remain quite confident about the design and the execution of the ApolloB study for a variety of reasons, both the criteria we're using to include patients with the disease, the clinical criteria that we require to show that they have disease that's likely to progress during the course of the study and likely to benefit from therapy, the sizing and powering of the study, the methods that we put in place in terms of the oversight and execution of the six-minute walk test. To your specific question, Maury, about we do allow in Apollo B up to 30% of patients to have been previously on tefamidus, assuming that they have been determined to progress based on the investigator's assessment. There's no formal criteria for that. That's really based on the investigator's assessment of the patient. And I think, you know, we powered very conservatively our study to allow for that. It's a global study, and so we knew there was going to be some background to faminus use in the population. We certainly want to establish what the effect size of the drug is, both as a monotherapy and in combination, because we know that's some of the reality of what's going to be happening in the marketplace. But we took very conservative powering assumptions. And I'll remind you, we actually over-enrolled by 20% in the study as well. So I think we're very well positioned for that. With regard to what gives us confidence, you know, I think ultimately what gives us confidence is really the fact that we're targeting an upstream mechanism. And in every data set that we've generated, both Apollo as well as with Helios A, as well as external data sets that have been generated through investigator studies, You know, there's an accumulating amount of data that suggests that silencing may have an important effect on the cardiac aspects of this disease, whether it's measured by biomarkers, whether it's measured by echocardiographic parameters, or even outcomes. So we look forward to the results in the middle of this year.
spk06: Great. That's a pretty good summary.
spk05: Yeah, thank you for taking my question. Yes, yeah, very helpful. Thank you.
spk08: Our next question comes from Salveen Richter with Goldman Sachs.
spk01: Good morning. Thanks for taking my questions. Can you help us understand what the impact of COVID in the Ukraine are on the CARDIR-1 study on the ladder? What proportion of the study is based in the Ukraine? And then just curious also on the lowered revenue guidance, are you comfortable with the FX assumptions for the forward here?
spk06: Two great questions. You know, clearly the CARDIA studies are incredibly important to us, and we're focused on enrolling these as expeditiously as we can. Obviously, the Ukraine situation is devastating from a geopolitical and human perspective, but has had an impact on enrollment in CARDIA-1. But perhaps, Pushkar, you can address that and also some of the approaches that we're taking to try and assure enrollment into the study.
spk02: Sure. Thanks, Yvonne.
spk06: And then we'll go to Jeff for that. Rep, you got a question?
spk02: Yeah, and thanks, Salveed, for your question. So, look, with, you know, we've got these two studies that we've kicked off, as we said, for Salveed's strand, which is a very exciting program for us that we think can actually transform the landscape for hypertension. Cardio 1 is a monotherapy study. It started in the middle of last year. And then Cardio 2 is a study looking at combination therapy that started towards the end of last year. As is pretty common in diseases like in hypertension, other common diseases, we did envision a geographic footprint for this study that was heavily reliant on Eastern European countries, and for CAR-D1, specifically Ukraine. That was the first country that was up and running, and we were expecting there was a lot of investigator interest in this study in the Ukraine. Unfortunately, because of global conditions, the global events that's been severely impacted. So while we were enrolling, we've actually had to stop, curtail all our activities in the Ukraine, including interacting with investigators, being able to continue hosting patients, et cetera, and have had to put those activities on hold. There was also a headwind with COVID with regard to this sort of a prevalent condition. that we were also facing. So what we've done is we've actually expanded the geographic footprint to this study. We're bringing additional countries online, additional sites online as an important mitigation measure. And then the second thing is that we've had the opportunity to go back and look at our protocol and look for areas where we can actually just facilitate enrollment by streamlining certain activities, reducing any burdens that may have been included in the protocol as originally conceived and streamline that. And we think that's going to help as well. So that's what's led to that change. Cardia 2 was not formally in the Ukraine, but it has been. There are sites in Eastern European countries that may have some impact as well or feel some impact. And so we're also really employing similar measures there, broadening the footprint and have amended the protocol to sort of streamline some of the procedures in the study as well. So that's the story there.
spk06: Yeah, and just to remind everybody that we expect to complete enrollment of Cardia 1 in early 2023 with the top line data expected mid-2023, and for Cardia 2, complete enrollment at around year end 2022. So the data will be forthcoming in due course, which we'll be looking forward to. So, Jeff, I think a question for you in terms of how we thought about FX. Yeah.
spk14: Let me give you a little bit more detail, Selvyn. So we, in our guidance slide, updated guidance slide, we did footnote at the bottom what the FX rates are that we've included in the updated guidance, which were as of April 18th. And we also provided what we included in in our original guidance on January 31st. So you can see the strengthening of the dollar there. Just to make sure it's clear, the exposure that we've got to ex-US revenue, based on our Q1 revenues, 49% of our revenues were in the U.S. dollar in Q1. 38% were in Europe, so primarily in the euro. And 13% were in ROW markets, primarily Japan. So those are, you know, the yen and the euro are our two biggest exposures. You know, if you use the revised rates, that we have compared to what we used in the original guidance that's about a 20 million dollar headwind relative to the original guidance that we gave and the dollar is actually further strengthened since april 18th now in terms of the sensitivity to that um just as a rough estimate sort of you know from this point going forward each you know one percent strengthening of the dollar against you know x us currencies is about a three million dollar headwind for us So the guidance range that we gave hopefully would accommodate additional movements in FX, but obviously we're not in the business of predicting which way the FX rates are going to move.
spk08: Our next question comes from Palmatis with Stiefel.
spk13: Great. Thanks so much for taking my question. On the retreats, I just wanted to clarify two things. One, I don't know how much detail you go into, but, you know, given the proximity of this amendment to the PDUFA, you know, how deep were you in labeling discussions? And I guess how confident are you that all other aspects of the review were kind of largely resolved and more in the check-the-box phase? And then just second on you, Teresa, and can you just clarify, is this going to be a 100% in-office dose product? And are you comfortable that from a market opportunity perspective, there isn't some meaningful subpopulation of patients that really might prefer the independence of home dosing. Thanks so much.
spk06: Okay, so I think the first question, Prashkan, I think is for you. You know, how confident are we in achieving approval by the need-to-do-for date, given the proximity to putting in the amendments?
spk02: Yeah, thanks for your question, Paul. I think, look, I think what I will say is, again, this amendment was solely prompted by this inspection issue at the secondary packaging and labeling facility. You know, we feel all other activities with regard to the review that the agency was conducting were on track, and we felt good about it. I can't comment specifically about the label, but, you know, I think we feel everything else was really going well and on track. And this is really solely about this one issue that needed to be, as I've discussed.
spk06: Thanks, Pushkar. And, Tolga, perhaps you could take the second question with respect to whether there's a market opportunity for population with respect to home dosing.
spk07: Yeah. Hi, Paul. So this study was obviously designed with physician-administered routing. Therefore, we are eligible for Part B. in the U.S. Through the Omicron and COVID, we actually were able to build a pretty substantial site of care and home injection capabilities. Therefore, we believe these capabilities will be nicely applied to quarterly dosing and subsequently six-monthly dosing. And given the severity of these patients, We still believe these patients are being monitored by the physician, and quarterly or biannual checkups of these patients are actually very much a peril to the regiment that the doctors would like to see. So in either way, we have the right capabilities that would be able to accommodate what the patient needs are.
spk13: Okay. So the home dosing, just to clarify, would be via a healthcare provider visiting the patient. Is that right?
spk07: That's exactly right. And right now at the moment, we actually serve about 20% of our patients through home infusion. Makes sense. Thank you.
spk08: Our next question comes from Matthew Harrison with Morgan Stanley.
spk03: Great. Good morning. Thanks very much. I guess just one quick follow-up. Can you there seems to be where I've gotten a lot of questions on the filing here. And just to make sure, was this a voluntary action by you or was it suggested by the FDA? If you could just clarify that, I think that would help a lot of people. And then my sort of key question is just, can you talk a little bit about what you're doing in CNF more in depth and in particular sort of where you're starting in terms of dosing, how long you think it might take before we see some clear knockdown and what you see are some maybe of the key safety risks to watch out for. Thanks.
spk06: Yes, so maybe it was the first question with respect to the filing. Yes, it was a voluntary action that we decided in close consultation with the FDA, so I think that's another factor that gives us confidence. in actually achieving an approval by the producer date. Maybe, Pushkar, you could take the question on the CNS opportunity, where we are with ALN-APP.
spk02: Absolutely. So as we announced today, we're very excited that we've kicked off this program. We filed the CTA at the end of last year with ALN-APP, which is our first CNS-directed RNAi therapeutic. and we've kicked off the initial study in patients with early-onset Alzheimer's disease. We're going directly into patients with this therapeutic, first with some single doses and ultimately with some multiple doses in the context of the study. And it is a very interesting upstream target that we think has applications for broadly Alzheimer's disease as well as for another indication, cerebral amyloid angiopathy, which is a devastating disease that results in cerebral hemorrhage. So both of those are part of the development plan. The initial study, as I said, goes into EOAD patients as a population that we think has a tremendous unmet need, lacks a lot of other confounding comorbidities, et cetera, so it should allow for a clean background for us to assess the safety and tolerability and knockdown of this first CNS therapeutic. So we'll be looking closely in the single ascending dose cohorts for safety and tolerability, and then important biomarkers that we'll be looking at, particularly soluble APP alpha and beta in the CSF, and that's going to help us understand knockdown. You know, there are also imaging modalities that are incorporated into the study, other biomarkers that we'll be looking at in the context of the study to follow patients. and look for pharmacologic activity. But the main thing we'll be looking at will be soluble ADP-alpha and beta in the CSF. In terms of the exact timeframe, we're actively conducting the study at multiple sites. And as we've said, assuming enrollment goes as predicted, we expect to be able to report out some proof-of-concept data at the end of the year.
spk06: And just to add, you know, one of the reasons why we're so excited about this program is obviously there's a huge on-net medical need in patients with, you know, Alzheimer's as well as cerebral amyloid angiopathy. But if we're successful with these indications, it really does unlock the opportunity to be able to bring the power of our RNAi platform to many, many other CNS diseases where, as you know, they're you know, huge medical needs. So we're very focused on ensuring progress with this program and hopefully delivering support data at around the end of the year.
spk08: Our next question comes from Ritu Baral with Cowan. Good morning.
spk11: Thanks for taking the question. Just a quick follow-up to Paul's question. Can you comment on whether you guys had started labeling discussions before the retreats ran to do for delay? And also, has there been any indication that the new fill and finish plant requires an inspection at this point after, I guess, the FDA has had a chance to? review the additional CMC package submitted.
spk06: I think there's two questions for you, Pushkal, with respect to label discussions and any indications around the potential for an inspection.
spk02: Yeah, so Ritu, it's Pushkal. I think, yes, I mean, what I can say is that, you know, we've had a late cycle meeting. We, you know, label discussions, et cetera, is an ongoing process that happens in parallel with the regulatory review of the application. So all those activities were underway. And as I said, you know, this was really all about this unrelated inspection that happened at this packaging and labeling facility. And, you know, I actually think we should What I would say is that it's a compliment to our teams and the discussions that we were actually able to, you know, with agility, put in an amendment quickly for this second facility and actually mitigate this risk quite substantially. So I think that's you know, a testament to your second question, which is somewhat related to that. The facility that we've amended to is one that we actually have experience with. It's a facility that we already use on PATRO. We use it for GiveLawry. We were actually planning to be using it for OxLumo, and it's been, in fact, inspected by FDA and EMA in 2020 and 2021. So we have a lot of reasons to have confidence in sort of regulatory standing of that particular facility. It's always up to the FDA with an amendment to make their own determination as to whether an inspection is necessary, and obviously we defer to their judgment. But what we do feel is quite confident in the facility that we've supplemented or amended to in our application and the quality of what's done in that facility. So hopefully that answers your question.
spk11: Got it. And if I can squeak in one very quick follow-up, Jeff and Tolga, you mentioned January, February compliance had headwinds, COVID headwinds. It's not something that you guys have previously talked about despite, you know, sort of definitely worse points in the pandemic. Was there something unique to the January, February Omicron wave that hit on PATRO versus the prior years?
spk06: I think, Tolga, that's a question for you. I mean, some more color on the COVID impacts. Absolutely. Particularly with respect to OnPatro.
spk07: I mean, look, each variant humbles us. We always learn new things about how the health system impacts. We have actually anticipated and I think shared some of our insights early on, particularly with the AHP patient when it comes to Givlari. With OnPatro, yes. Given the elderly patient population and given the health care system, how the health care system reacted across the world, we certainly had seen that, some skip dosing. But it has nicely recovered in March. So we're rather comfortable where the direction is going.
spk06: Yeah, that's great, Tolga. I mean, we're optimistic with you going forward. But as Tolga said, I think this virus has shown the potential to surprise us on multiple occasions. Thank you. Next question.
spk08: Our next question comes from Tazeen Ahmad with Bank of America.
spk12: Hi, good morning. Thanks for taking my question. Just another point of clarification on your revised guidance. So it does include VUTRI, assuming that it gets approved, but how are you thinking about the early days of the launch for VUTRI and PN and Specifically, its interaction with OnPatro. Do you expect cannibalization to be part of the early launch metrics there? Or are you assuming a different patient population will start on butry versus who's already on OnPatro? And if you could give some color on that, that's great. And then secondly, IONIS does have some data due soon as well for ATTR. And I'm just wondering how you think that could potentially change the competitive dynamic in the marketplace with another entrance. Thank you.
spk06: I think you can answer both. The first question around the interplay with respect to route three. And on PATRO, how are we thinking about the early days of the launch?
spk07: Right. So, Tazin, I think if you, we should kind of maybe take a quick step back and look at the numbers that we're discussing here. I think from both from VUTRI opportunity as well as any new competitive entrance dynamic, we're still looking at, you know, 20,000 to 30,000 patients, PN and mixed genotype patients. And being the market leader, We're now, as we announced this quarter, we moved from 1,525 in Q1-21 to 2,200 patients this past quarter. So we're adding a steady increase of patients for, you know, the treatment of this devastating condition. And Woodtree will certainly help us. I believe, to bring in some net naive patients, especially those patients that are diagnosed early in their treatment. We start seeing that dynamic already with Onpatro. We also certainly anticipate an acceleration of switches from the existing therapies that they may have been progressing or may not have found, you know, the best treatment regimen. WooTreat certainly provides that opportunity. And we do anticipate a number of home pathway patients that might be interested in this new treatment regimen. They may prefer it. We're not guiding right now about the net and switch numbers, but we do overall anticipate growth to accelerate.
spk06: Yeah, no, that's a great answer, Tolga. And maybe just to add that we really are still in the early stages of, you know, building the TTR franchise. You know, we're currently addressing the needs of 2,200 patients. with Onpatro, but there are another, you know, 30 or 40,000 patients there who, you know, are addressable by Onpatro. So, there's still lots of growth to come here. The second question, Torb, I think is also for you. How are you thinking about, you know, new entrants into the market, particularly from Iona?
spk07: Yeah, I mean, specifically with the PN category, we see an accelerated growth and also in diagnosis. And I think more share of voice, increased share of voice, I think is going to certainly help that pattern. If you think of Voutry's profile of subcutaneous injection every quarter, it certainly, we believe, will remain an attractive and will continue to help us be the market leader. But I think, again, we shouldn't think of this category as a zero-sum game. I believe more entrants like in the MS category will probably help further expansion of the category given what Yvonne indicated that there are still a lot of undiagnosed and untreated patients.
spk00: Thanks.
spk08: Our next question comes from Dina Wang with Barclays.
spk10: Thank you for taking my questions. I have two clarification questions and one hypothetical question. So for Apollo B, do you see data on the blinded base? And then for overlapping sites, do you use the same CRO versus Bridge-Bowles attribute study? And for hypothetical questions, you know, just say in an unfortunate event, Apollo B missed a six-minute walk test endpoint. what kind of a secondary endpoint data that will convince you Helios B outcome data will be positive?
spk06: So, Priskel, I think, you know, three questions for you there. Yeah, absolutely.
spk02: Hi, Gina. So, look, on a couple of these blinded data, so as every sponsor does running a blinded clinical trial, we have folks, and our clinical team, data management, et cetera, who are responsible for looking at blinded data over the course of the study. That's really to ensure that the study is being conducted properly, to make sure the proper patients are being enrolled and they meet enrollment criteria, to look at outlying data points. You know, if someone has a two-meter walk in six minutes or 2,000 meters to query the site and see if there was a data entry error, for instance, to see if there's patterns where sites are not conducting following procedures properly. So that's all part of what's happening. So there are people who are looking at blinded data over the course of the study. It is all blinded. And so that's just part of the norms of how a study is done and conducted to ensure that when we finally lock the database that we have a clean data set that allows for interpretable data. And so those activities are underway as is done in every clinical trial that's done by every sponsor. In terms of overlapping sites, You know, we don't actually have the exact count, but we probably estimate that 20 to 25 percent of sites may be overlapping. I'd remind you that doesn't, A, reflect necessarily the number of patients that are overlapping between the two different studies. And three, you know, where we do our study, it's all under the context of our protocol with the CROs that we work with. and our protocol has clear trial procedures, training procedures, oversight, et cetera, that is all specific to Apollo B. I can't comment on the CROs that Bridge Bio used. I actually don't know. And then I think your third question was what you called hypothetical. What I'll say is we'll be looking at the totality of data coming out of this study. As you know, the primary endpoint is around six-minute walk tests, but we'll be looking at KCCQ, which is an important secondary endpoint. We'll be looking at BNP. We'll be looking at echocardiographic parameters. And importantly, we'll be looking, although it's a short study, 12 months, we will be looking at event rates with regard to mortality and, importantly, hospitalization and be looking at the totality of those data to understand what we're seeing in terms of the impact of silencing in this patient population. And that will help us, A, interpret the data within Apollo B, but also help us think about the impact in this disease overall as it relates to Heliospeed. So hopefully that answers your questions.
spk06: Thanks, Dr. Gold. Do you want to answer that one, too, question?
spk10: Yes, like, you know, regarding the secondary and more like TCCQ, BNP event rates, any particular separation you will be looking for that you think will be confident that Helios B will be positive?
spk02: It's really, it's impossible to answer that question. I think we'll be looking at the totality of the data, you know, to really make that assessment. at. There's no single number that I'll be looking at. Yeah, thanks.
spk08: I think we've got time for one more question. Our last question comes from Anupam Rama with J.P. Morgan.
spk15: Hey, guys. Thanks so much for taking the question. Maybe I had a follow-up on Gina's question, but I just wanted to confirm that you'll have some of that mortality CB hospitalizations in the top-line results versus waiting for, you know, a full presentation at a medical conference or something like that and Specifically, what your expectations on those two metrics would be at a 12-month look. Thanks so much.
spk02: Yeah, so on a public – we – Those are pre-specified secondary endpoints. It's been our practice to, when we report top line results, to speak to p-values with regard to primary and secondary endpoints. So you can expect that to be provided in the top line, but additional color and detail, of course, will come at a medical conference subsequently. And I'm sorry, I think I missed the second part of your question.
spk15: what would be your expectations at a 12-month look on CV hospitalizations and mortality?
spk04: Oh, yeah.
spk02: So, you know, what I would say is The study was not powered for those endpoints at all, so they are being captured, but they're not powered endpoints. As you can imagine, 12 months is a relatively short time to necessarily see effects on those. I'll remind you that tefamidus, it took nine months to start to see a hospitalization separation and roughly 12 to 18 months to see a mortality separation. That said, our post-hoc data from Apollo showed potentially a much earlier separation on those events, some of the data that had been published in circulation a few years ago. So, you know, there's some potential, and, you know, we've seen on other parameters effects of silencing potentially on echocardiographic parameters, technetium, et cetera, at earlier time points. So I think we're looking forward to seeing the results and seeing what that looks like. So there's – and that's why we've captured these as important secondary endpoints to look at.
spk06: We are indeed. So, look, thank you, everyone, for joining us on this call. 2022 is also a steady start as we continue to advance our financial system. We think with all the exciting pipeline programs that we have in development, They're all of exciting and important upcoming milestones over the course of the year, and we look forward to updating you on these. So thank you to everybody for joining our call today, and have a great day.
spk08: This concludes today's conference call. Thank you for participating. You may now disconnect.
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