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spk02: Hello, thank you for standing by and welcome to the Alnylam Pharmaceutical Second Quarter 2022 Earnings Conference Call. At this time, all participants are in a listen-only mode. After the speaker presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star 1-1 on your telephone. Please be advised that today's conference may be recorded. I would now like to hand the conference over to the company. Please go ahead.
spk12: Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are Yvonne Greenstreet, Chief Executive Officer, Tolga Tangular, Chief Commercial Officer, Akshay Vaidyanand, 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 of our website, investors.alnylam.com. During today's call, as outlined in slide two, Avon will offer introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress. Akshay will review recent clinical and preclinical updates, and Jeff will review our financials and guidance, followed by a summary of upcoming milestones before we open the call for your questions. Please note we are in a quiet period with regard to the upcoming Apollo B results and therefore will not be addressing any questions on that matter. I would like to remind you that this call will contain remarks concerning Allen Island's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent quarterly report on file with the SEC. In addition, any forward-looking statements represent our views only as to the date of this recording and should not be relied upon as representing our views 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?
spk09: Thanks, Christine, and thank you, everyone, for joining the call today. We're very pleased with our second quarter results and the progress we've made towards our near and long-term goals. we achieved 14% product sales growth compared with the first quarter as we continue to drive a steady increase in patients on therapy across our portfolio of marketed products, including Onpatro, Iblari, and Oxlumen. And we're excited to have expanded that portfolio with a recent U.S. approval and positive HMP opinion for Ambutra for HATTR amyloidosis patients with polyneuropathy. and we're looking forward to executing on Ambuta's launch and the potential for further global expansion. Five RNAi Therapeutics from our organic platform approved in under four years is truly remarkable. In addition to our growing commercial portfolio, we continue to make great strides with our RNAi Therapeutic pipeline programs. This includes our progress in establishing our TTR franchise, where we are tracking towards plan and are on the cusp of seeing results from the Apollo B phase three study of the TTRAN in patients with ATTR amyloidosis with cardiomyopathy. We've announced today that we expect to share top line data within the next three weeks with full data to be released thereafter at the medical congress. In addition to these highly anticipated results, We also continue to make exciting progress across numerous other progress within our pipeline. We have and continue to innovate upon what we believe to be one of the most productive, organic and self-sustainable platforms in biotech, which has the potential to deliver meaningful value creating therapies for rare and prevalent diseases in the years to come. To that end, There are many recent and upcoming milestones that underscore the breadth and scope of our pipeline. For Semdesiran, we reported positive top-line Phase II results in patients with IgA nephropathy, a kidney disease with significant unmet medical needs. We're now working with Regeneron to finalize Phase III plans and potentially initiate a program by the end of this year. We were also excited to see positive data presented by Sanfi from the Phase III ATLAS PPX study of Fetuceran in patients with hemophilia, which met its primary endpoint and demonstrated that Fetuceran prophylaxis significantly reduced bleeding episodes compared to prior factor or bypassing agent prophylaxis. Looking through to the end of this year, we expect to have updates across our pipeline, including the potential for top-line results from early studies of ALN HSD in NASH, ALN XCH in gout, and ALN APP in early-onset Alzheimer's disease, our first CNS endeavor. Taken together, this all highlights our focus on these three key drivers for our Nylund growth over the next several years. First is the potential near-term expansion of our TTR franchise opportunity, where we aim to become a global leader in delivering impactful and highly differentiated medicine to patients. The second key growth driver is our expansion beyond rare diseases into prevalent diseases. And the third 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 those positions as well to deliver on our NILAM piece of fifth by 25 goals, making our NILA 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 all 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. Q2 was a strong quarter for our commercial portfolio with 14% quarter-over-quarter growth, as Ivan highlighted. We're also excited about the SGA approval and launch of Ambutra in June, and we're encouraged by early promising size of Ambutra uptake. I'll have more details to share on that shortly. As anticipated, we are also experiencing improved market conditions following COVID-impacting Q1, as we saw increased promotional activities, improved patient flows, healthy demand, and improved patient compliance across our portfolio. I'll now provide details on the performance of each of our products. We continue to see growth for El Patro, achieving $153 million in global net product revenues in the second quarter, representing a 12% increase compared with the first quarter and 35% growth compared with Q2-21. At the end of Q2, over 2,400 patients were on commercial on-patriot treatment worldwide, up from over 2,200 patients at the end of the first quarter, representing a steady 9% quarterly patient growth. In the U.S., sales of on-patriot increased 14%. versus the first quarter, and were primarily impacted by an increase in patients on therapy and improved patient compliance following Q1, which was negatively impacted by COVID. In our international markets, Ompatro Q2 product sales increased 10% versus Q1-22, primarily due to an increase in patients on therapy and the timing of orders in distributors and partner markets. Important to note, our global results continue to be challenged by foreign exchange headwinds, with Onpatra year-over-year reported growth of 35%, being held back seven percentage points by the strengthening U.S. dollar. As you are aware, we received U.S. approval for Amutra at the end of the second quarter, and we're very pleased with the initial launch so far, as our teams continue to execute in line with our plans. We received 133 start forms from launch through July 22nd, keeping demand generation on track with approximately one-third of start forms generated from patients new to Allen Island and two-thirds from switches from OnPatro. Over 20% of those start forms came from new prescribers, which we believe is an encouraging early sign of potential market growth. We hit the ground running, reaching over 61,000 key stakeholders within 48 hours of launch, serving as a catalyst for field engagement. We have also been engaging with health systems and the formulary processes has been started in over 60% of the priority delivery networks. Further from an access standpoint, our teams have been engaged and feedback has been positive to date. In fact, there is one national policy published with a large national payer covering 24 million lives. The first amputee patient has also been treated, and we're looking forward to continuing this rollout and updating you further on our Q3 call. Moving to our ultra-rare disease franchise, first with Dilari, we achieved $45 million in global net product revenues in the second quarter. representing a 28% increase compared with Q1-22 and 47% growth versus Q2-21. At the end of Q2, over 420 patients were on commercial Giblari treatment worldwide, up from over 400 at the end of the first quarter, representing a 5% quarterly patient growth. In the U.S., Sales of Givlar increased 25% versus the first quarter and were primarily a result of the following. A healthy demand growth of 12% driven by an increase in patients on therapy and improved patient compliance following a soft Q1 primarily impacted by COVID. Inventory starting dynamics, which favorably impacted reported growth by 8%. and a decrease in gross net deductions in the quarter, which favorably impacted reported growth by approximately 5%. In our international markets, Jiblari delivered 34% growth compared with the first quarter, with the growth primarily driven by new patient ads, including a strong launch in the UK, and favorability in gross net deductions. Finally, global Givari year-over-year reported growth of 47% was also held back by 6 percentage points due to unfavorable foreign exchange rates. Moving now to our second ultra-rare disease product, Oxlumo. We achieved $15 million in global net product revenues in the second quarter, representing a 2% increase compared with the first quarter. At the end of Q2, over 200 patients were on commercial Opsluma treatment worldwide, up from over 160 at the end of the first quarter, representing 25% quarterly patient growth. In the U.S., sales of Opsluma increased 32% versus the first quarter, and were primarily impacted by an increase in patient demand, as well as inventory stock dynamics, and a decrease in gross-to-net deductions during the quarter. In our international business, despite an increase in patients on therapy during the quarter, Q2 Oksuma sales decreased by 15% compared with Q1, primarily due to an increase in gross-to-net deductions during the quarter and the timing of orders in our distributor and partner markets. On a year-over-year basis, global Opsuma sales decreased 9%, despite an approximately doubling of patients on therapy. The decrease was primarily due to a higher proportion of patients on the monthly loading dose portion of their treatments, as well as lower net pricing in our international markets in Q2-22. Additionally, as with Onpetra and Givlari, Changes in foreign exchange rates also negatively impacted Oxlumo Q2-22 results, with reported year-over-year growth of minus 9% held back by 5 percentage points due to the strengthening U.S. dollar. In conclusion, we are pleased with the growth in revenues and patient demand achieved in Q2 and look forward to our Q3 results, which will include the first full quarter of Amutra's launch. With that, I will now turn it over to Akshay to review our recent IMD and pipeline progress.
spk08: Akshay? Thanks, Tolga, and good morning, everyone. I'll start with our efforts in ATTR amyloidosis, where we're advancing two clinical stage product candidates, Patisaran and Vutrisaran. While Patisaran or Onpatro 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 label for the treatment of cardiomyopathy in both hereditary and wild-type AT-tramyloidosis patients. Excuse me. To this end, we're conducting the Apollo B Phase III study, and as announced this morning, we expect to report top-line results within the next three weeks. We're also advancing butrycerin, which is delivered by a quarterly subcutaneous injection and was recently approved in the U.S. under the brand name Ambutra to treat the polyneuropathy of H. atetanoidosis in addition to receiving a positive CHMP opinion in the EU. Here, too, we're committed to expanding the label to the treatment of cardiomyopathy in hereditary and wild-like patients. Butrycerin is also in development for Stargardt disease. Helios A, evaluating Vutriceran in HAP tramloidosis patients with polyneuropathy, formed the basis for our regulatory submissions and recent U.S. approval of AntVutra. 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. We continued to report results from the study and recently presented new 18-month results from exploratory cardiac endpoints at the ESC-HF meeting. These findings show that in a variety of predefined cardiac subpopulation of HATT amyloidosis patients with polyneuropathy, treatment with Vutrasran was associated with improvements in exploratory cardiac endpoints relative to external placebo, including levels of NT-PROBNP and a trend towards improvement in exocardiographic parameters. These findings in the cardiac subpopulation were consistent with the previously reported results in the MITT population. Additionally, in a planned cohort of patients from the MITT population, Lutris-Rand treatment reduced cardiac uptake of technetium on scintigraphy imaging relative to baseline in a majority of accessible patients, including those with perigene greater than or equal to 2 at baseline, suggesting that patients with the highest degrees of cardiac amyloid burden may recognize benefit from RNAi therapeutics. Butryceran also continued to demonstrate an encouraging safety and tolerability profile. As mentioned, this is just the start for Butryceran, as it is also being evaluated in the Helios B Phase III study for the treatment of patients with AT channel amyloidosis with cardiomyopathy, including both oratory and wild-type AT channel amyloidosis. Helios B, which is fully enrolled, has a 30-month endpoint of all-cause mortality and CV events, with many patients followed up to 36 months, and we expect the full results in early 2024. The study design includes the potential for an interim analysis, and we will consider this following results from POLI-B and engagement 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. Notable highlight in the second quarter was our announcement of positive top-line results from our Phase II study of semdisaran, an investigational RNA therapeutic targeting the C5 component of the complement pathway and is in development in collaboration with Regeneron for the treatment of IgA nephropathy, or IGAN. In this study, at week 32, treatment with semdisaran resulted in a 37% mean reduction from baseline in the 24-hour urine protein to creatinine ratio relative to placebo. This was the primary endpoint of the study and an important prognostic marker of disease progression. The results of secondary endpoints were also consistent with the therapeutic benefit of semidisarand in IGAM. There were no significant drug-related safety signals, and we believe these collective efficacy and safety data support continued clinical development of semidisarand molotherapy in patients with IGAM. We now look forward to gaining alignment with Regeneron to finalize plans for Phase 3 and hope to initiate a program by the end of this year pending regulatory agency feedback. Moving on, a key growth driver for Alnylam in the years to come will be our organic product engine driving sustainable innovation. The second quarter featured a new highlight in this regard. In Nature Biotechnology, we published data from preclinical research on the delivery of lipophilic sRNA conjugates to extrahepatic tissues, including the CNS. These data provide early evidence of a potential role for two-prime O-hexadecimal C16 conjugated sRNAs in treating diseases of the CNS, eye, and lung. We're further exploring the potential for lipid conjugates to help achieve delivery to other organs. In another publication in Nature Communications this time, we published research findings identifying mutations in the inhibin E gene associated with protection against abdominal obesity and metabolic syndrome, a condition impacting more than 20% of adults worldwide. Findings support the potential of inhibin E, which was previously referred to as gene X, to be evaluated as a novel therapeutic treatment for the treatment of cardiometabolic disease since inhibit E loss of function improves waist-to-hip ratio and is associated with an improved lipid profile. We plan to pursue a development candidate for inhibit E and its gene product active in E, leveraging our ICARIA platform. As you can appreciate, we have an incredibly broad and innovative platform that continues to advance, and these are just a few recent highlights. We look forward to updating you on a number of these programs in the coming months. With that, let me now send the call over to Jeff to review our financials and upcoming milestones. Jeff.
spk01: Thanks, Akshay, and good morning, everyone. I'm pleased to be presenting a summary of Al-Nilem's Q2 2022 financial results and an update to our full year guidance. Starting with a summary of our P&L results for Q2 2022. Total product revenues for the quarter were $214 million, or 33% growth, versus Q2 2021. It's also worth noting that year-over-year growth in combined product revenues was held back by approximately 7% due to the foreign exchange impact of a strengthening U.S. dollar, which reached a 20-year high recently, and given that approximately 50% of our product revenues are generated via sales in international markets. Net revenue from collaborations for the second quarter was approximately $9 million, representing an 85% decrease compared with Q2 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. We do expect an increase in collaboration revenue and royalties in the second half of the year, primarily driven by increased activity across our Regeneron programs, as well as from an increase associated with LECVIO royalties and sales milestones as Novartis' U.S. launch progresses. Our non-GAAP R&D expenses increased 15% in the second quarter compared to the same period in 2021, primarily due to increased spend on early development activities and increased headcount to support the growth of our pipeline. Our non-GAAP SG&A expenses increased 19% in the second quarter compared to the same period in 2021, primarily due to increased headcount and other expenses to support the growth of our commercial portfolio. Our non-GAAP operating loss for Q2 2022 was $161 million, representing a $47 million higher loss compared with Q2 2021, which was primarily impacted by the reduction in collaboration revenue during the quarter. Finally, we ended the quarter with cash, cash equivalents, and marketable securities of $2.1 billion compared to $2.4 billion at the end of 2021. We 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. Following the strength of our operating results in Q2, we are reiterating the financial guidance we provided on our Q1 results call in April. Starting with net product revenues, we anticipate combined net product revenues for our four commercialized products will be between 870 and 930 million. However, given the continued strengthening of the U.S. dollar since we issued our guidance in April and the fact that approximately 50% of our global product sales are generated in international markets, we are currently trending towards the lower half of our 870 to 930 million dollar guidance range. Our guidance for net revenue from collaborations and royalties is a range between $175 and $225 million. And our guidance for combined non-GAAP R&D and SG&A expenses 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, Givlari, and Oxlumo. as well as the launch of MBUTRA. Next, our TTR franchise will have important updates. With butycerin, top-line results from the Apollo Phase III study are expected within the next three weeks. With butycerin, we plan to report results on a biannual dose regimen and initiate a Phase III study in Stargardt disease, both in late 2022. Lastly, we plan to file an IND and initiate a Phase I study for ALN, TTRS, CO4, and healthy volunteers by the end of the year. In our mid-stage portfolio, we are looking forward to milestones that include completion of enrollment in the Phase II study of Lumacerin in patients with recurrent renal stones by year-end, completion of enrollment in our Phase II Cardia II study of Zolbizarin at or around year-end, and results from the phase two study of ALN-HBVO2 in combination to monoclonal antibody VIR3434, which our partners at VIR expect to report later this year. Wrapping up, we have a few early stage readouts coming as well. These include top line results from part B of the phase one study of ALN-HSD in patients with NASH, expected mid-2022. Preliminary top line results from the phase one study of ALN, ATP in patients with early onset Alzheimer's disease expected in late 2022. And preliminary top line results from the phase one study of ALN, XBH in patients with gout also expected for late 2022. Let me now turn it back to Christine to coordinate our Q&A session. Christine?
spk12: Thank you, Jeff. Operator, we will now open the call for questions. For those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have any additional questions. Also, as a reminder, we are in a quiet period with regard to our Apollo B study and will not be responding to questions on that topic.
spk03: Thank you.
spk02: As a reminder, to ask a question, you'll need to press star 11 on your telephone.
spk03: Our first question. Comes from Paul Matisse with Stiefel. You may proceed.
spk04: Hey, good morning. Thanks so much for taking my question. Just on butrycerin, just a two-part question, the commercial dynamics. I guess, one, can you talk about the initial prescribing for patients new to a silencer and how much of that is coming from cardiologists? And then just curious on the economics of in-office dosing for butrycerin and How does that compare for a physician versus on pastoral as an infusion? Thank you.
spk09: Thanks, Paul, you know, for that question. You know, I'd just like to start off by saying that we really are delighted to have our fifth hour of therapeutic infusion in less than four years with Amfutra, and it's great to have a additional option for patients here. And as Tolga said on the call, the initial signs for launch are very, very encouraging. But Tolga, I'd like to hand over this question to you. So it's around the commercial dynamics with respect to the initial launch, how much from cardiology, and then any commentary on the economics with respect to, or Patrick, compared to the physician. Thanks, Toto.
spk07: Absolutely. Hi, Paul. This is a really exciting time. We launched the product and reporting the information that's available to us within the five weeks. In that five weeks, we were able to receive over 130 start forms. And of those, one-third of those were actually naive patients. They are new to Alnylam. And that's actually a very good, robust number. It's early for us. And these are only start forms. Patients need to go through the system and make sure that they actually get the product in. But as an early sign, one-third as new naive patient dynamic is very encouraging. In terms of the economics, Essentially, the product is Part B. Therefore, it is still a buy-in bill, and those patients that are going to be looking at a very similar dynamics as we see in Onpatro. What we're also excited about is, frankly, 20 prescribers in this very short period are new prescribers of TTR, new prescribers of So that's also a very exciting dynamic that I like on the line. Thanks, Logan.
spk06: Thanks, Paul. Next question, please.
spk02: Thank you. One moment for questions. Our next question comes from David Leibowitz with Citi. You may proceed.
spk11: Thank you very much for taking my question. First, on the tree saran, this is not with respect to any details on the data. I just want to, as far as presentation, I know historically in the past for top line releases, you put out P values. I just want to confirm that we would likely see P values certainly on the primary endpoint, but also the secondary endpoints as well. And one little add-on here, as far as pricing goes, Could you at least give us perspective on what type of shift we might see once cardiomyopathy gets added to the label?
spk09: Great. David, thanks for that question. I think the first one actually is for you.
spk08: Yeah. Just clarifying, Dave, that you said but I suspect you meant with respect to the Apollo B results. Am I correct?
spk11: Indeed. Of course.
spk08: Yeah. And, you know, you're right, we'll present top-line results in the form of a PR with P values as we test the primary and secondaries in a hierarchical order. So that's as much as I can say on that at the present time.
spk09: Thanks, Ash. And maybe, Tolga, you could take the second question with respect to pricing and any shifts as we go.
spk07: We're excited about the possibility of serving cardiomyopathy patients, but as you can appreciate, it's a little too soon for us to share any information because it's a little too soon. But we will obviously update appropriately when we make those decisions.
spk06: All right. Thanks, David. Next question, please.
spk03: Thank you.
spk02: Our next question comes from Salveen Richter with Goldman Sachs. You may proceed.
spk13: Good morning. Thanks for taking my question. Could you just speak to the dynamics with regard to switching and combination that's playing out between your TTR franchise and Pfizer's Tefanidis? Thank you.
spk07: I think, Talbot, that question is straight over to you. Yeah, I mean, switching-wise, obviously, In the U.S., we're indicated for pulmonaropathy and paphamidus is indicated for cardiomyopathy. Therefore, we do not see any switching dynamics. In terms of concomitant use, we see similar rates that we've seen in the past. It's about anywhere between 15% to 20%. What we see, what we're excited about switching dynamics is in ex-U.S., particularly in Europe and Japan. where both of those products are available in public property, we've seen a significant source of our business is really built by the switches. Obviously, we continue to add new naive patients both in Europe and Japan, but early on, we've seen a good, strong dynamic, which alludes to us that The physicians believe that there is actually probably more opportunity to use Ompatro as a silencer in the earlier part of the disease to get adequate treatment.
spk06: Thanks, Olga. Next question.
spk03: Thank you.
spk02: Our next question comes from Ritu Baral with Cowen. You may proceed.
spk16: Good morning, guys. Thanks for taking the question. I was hoping for, just to follow up to Paul and Salveen's, just a little more detail on the new patients. Tolga, you mentioned the prescribers, but are you seeing less severe patients? Are you seeing more mixed phenotype patients? And does this sort of bolus imply that there's sort of warehoused patients to work through as we look at the new patient question for Imbutra.
spk07: It's a great question. Thank you. As I indicated before, it's a little too soon for us to really give a lot of specific dynamics. It's an area where we're obviously closely monitoring. What we're encouraged about is the early signs indicate that we do see some, you know, a little younger patients. But, again, it's difficult to generalize at this point. We're only five weeks into the launch. What we're, again, excited about is the fact that we are seeing a broad range of patients quickly getting either switched or naively being treated. Part of it, I'm sure, is going to be a little bit of the warehousing, but it's important to highlight that in Q1, we had a great, strong robust olfactory growth. What we originally thought was probably the physicians would be waiting and warehousing some of those patients for Ambutra. That didn't exactly happen, but I'm certain that part of the uptake that we see in the first five weeks might be contributed to that warehousing dynamic.
spk09: Yeah, I know. Thanks, Pog. It really does look at the introduction of Ambutra as helping us, will help us grow the overall TTR franchise going forward, which I think is very encouraging. Thanks, Richie. Next question.
spk02: Thank you. Our next question comes from Kazin Ahmad with Bank of America. You may proceed.
spk15: Hi, good morning. Thank you for taking my question. Mine's on Helios B. So you've reiterated your confidence that the early 2024 target for data readout is something that you feel confident about. I'm just wondering, is there at all a scenario in which you would opt to extend the observation period, though, to allow for a higher chance of seeing a significant improvement in mortality benefit?
spk09: Maybe I'll start by reiterating our confidence in an early 2024 data readout from HEDIS-B. And, Akshay, any perspectives on you know, how we might think about that study going forward.
spk08: Yeah, you know, we've revisited the study designs and thoroughly assessed how robust is the study, is it structured and powered in a way to help us meet the primary endpoint and the secondary endpoints, and we're comfortable with the study design, and so the study designs are altered. The only thing we'll consider is the interim analysis, of course, in due course. And the other thing I would say, by the way, is that, You know, as patients come in over a long period in the study, in a large study like that, so many of them will have gone to 36 months, and that provides additional coverage in terms of the robustness of the study. So we're comfortable, and we'd reiterate data early 24, and looking forward to positive results.
spk06: Thanks, Akshay. Next question, please.
spk03: Thank you.
spk02: Our next question comes from Joseph Stringer with Needham. You may proceed.
spk18: Hi. Thank you for taking our question. Our question was for Ambutra. I know it's early days, but how do you anticipate the time from start form to getting patient on drug? How do you think this compares relative to your experience with Onpatro? Thank you.
spk09: Yeah, that's a great question, Joanne. And clearly, with Ambutra being our second product in the TTR franchise, we're really building on what's a very robust commercial operation that we have under Tolga's leadership. But Tolga, perhaps you could talk a little bit about So, yeah, I mean, how that looks.
spk07: Thanks. Obviously, we're very well positioned to be able to maximize the opportunity for Amutra, given our experiences with Amutra, and Amutra's really attractive profile, being subcutaneous injectable every three months. In regards to how the timing is going to work is, Look, I mean, at the end of the day, we do have the right capabilities, right patient services, benefit verification, and so forth already in place within this category. And what we've so far done is working very closely with not only with major national and regional payers, but also with integrated delivery networks and other health providers to make sure that formularies are in place. Given the fact that we actually also set the price, despite its very attractive profile, it's parity with OnPatro, we have not so far seen any significant headwinds. Nevertheless, like any new product, it does take time for the healthcare system to absorb and make sure the P&T committees and so forth are in place to get the product approved. We're very pleased with the early signs of what we've so far done and how the healthcare systems are reacting, but I'm sure we're going to see some delays early on and eventually get to a place where I think it's going to be and even maybe a little faster approval dynamic. But it's a little too soon for us to share where we are right now with that.
spk09: Thanks, Olga. I think good progress thus far. We're very pleased. So next question, please.
spk02: Thank you. Our next question comes from Maury Raycroft with Jefferies. You may proceed. Hi.
spk05: Good morning, and thanks for taking my questions. I was going to ask a question on Zolbicerin for hypertension. I'm just wondering if you can elaborate on steps you've taken to streamline the protocol to speed up enrollment and what the status is on that.
spk09: Yeah, just straight away. Reminder, we unfortunately experienced some delays with Arcadia, one study with . Primarily due to the fact that we selected sites in the Ukraine and obviously with the ongoing war, you know, those sites were unable to move forward. We've expanded our site footprint and are very pleased with progress thus far. We also took the opportunity to you know, just refine the protocol to make it an easier study to execute for physicians. I don't know, actually, do you want to add any?
spk08: No, I think you covered it, Yvonne. The only other thing more specifically on the streamlining is, you know, inevitably, more in these protocols, one tries to capture as much scientific information as one can. But given the needs of the program, we were able to remove some of the assessments that assessments that don't take anything away from the core issue of antihypertensive effects and safety and so and yet maintain two large robust circles which will be easier to accrue one in monotherapy and one in combination therapy so between the site expansion and these changes in the protocols we're optimistic about readouts next year great and just to add that we're expecting to complete enrollment in CARTIGA 2 at the end of this year that's right
spk09: Looking forward to that. Thank you.
spk06: Next question, please.
spk02: Thank you. Our next question comes from Luca Issi with RBC Capital. You may proceed.
spk22: Oh, great. Thanks so much for taking my question. Congrats on the quarter. Maybe one on TTR polar neuropathy. How are you thinking about a competitive landscape here? of the IONISs have reported successful phase three and they seem very confident they can compete commercially given the AstraZeneca global footprint. I know we don't have the full data at this point, but how are you thinking about implications of that launch for your franchise? Thanks so much.
spk09: Thank you. I think that was the primary question about how we believe that we're going to compete in the TTRPN space, particularly with potential new competitors coming on stream. with AstraZeneca.
spk07: Yeah, thank you, Yvonne. Look, first of all, we are always excited to bring new modes of medication, different alternative treatments to patients, because there's a lot of wood to chop when it comes to TTRPN prevalence and what the patients that are currently being treated. We anticipate the prevalence numbers around 25,000 to 30,000 patients worldwide, and we are a very small fraction of that that we've been able to deliver. So what we've seen in similar categories, a good expansion of diagnosis and treatment rates going on. In regards to where we are, look, at the end of the day, we have been able to actually establish ourselves in the last four years as the major driver, including in Europe and Japan, against Tepamidus that is also being promoted by an important company. One of the important, I think, drivers of our growth is going to be, obviously, making Ambutra available worldwide. And we are well positioned to do that. We have Europe and Japan, a geographic footprint, and available in over 50 markets through other partners and distributors. Given the fact that we're going to be a year ahead already of that competition, and plus, again, a very attractive profile that Ambutra offers for the patients with the subcutaneous injectable over three months and soon with six months if those trials work. We really like our chances in terms of how we're well positioned to be able to make this product available and continue to be a leader as a portfolio leader. But again, I just want to reiterate, having said that, there are going to be products available, and that's good for patients, and we're excited about that.
spk09: Thanks, Olga. Actually, do you want to say anything about the effective profile?
spk08: Yeah, no, I'll just add to what Tolga said, which makes a lot of sense. But in terms of the data themselves, I think we've got a very comprehensive data associated with vitreous renal rambutra in HATTRP. And, of course, the primary showing improvement in neuropathy, which is exciting. And in terms of the other endpoints for the secondaries, but not just those, the exploratory cardiac endpoints, the impact on the heart, but still notable, particularly with the new observation of reducing technetium scan uptake. And that's very exciting for patients and physicians. And so, you know, along with the convenience Q3 and then hopefully soon Q6 monthly dosing, this is a very differentiated product. In the market, as Tolga explained, we've been leaders in. And ultimately, I will add that Whilst patients need good options in this space, we'll want to see the full data package associated with epinephrine testing, recalling that the first time around with inner testing, there were some safety issues of note, including renal effects, ejection site reactions, platelet effects. And, you know, I'm sure they and everybody is keen to know that the safety is good. So let's see. But I think we're off to a great start with Dr. Butcher.
spk09: So very helpful. Thank you. Next question, please.
spk02: Thank you. Our next question comes from Gary Nachman with BMO. You may proceed. Okay, great.
spk17: So back to Ambutra and the start forms and the two-thirds switches from Empatro. What's the profile of initial patients that are switching from Empatro? Are you getting a sense if it's more patient or physician-driven or Do they stay on Ampatra up until they get Ambutra, if that takes some time? And how do you expect that split between new and switches to shift over the next couple of quarters? Thank you.
spk09: Well, I think that one. I see lots of interest in the Ambutra early dynamics.
spk07: Again, I mean, look, at the end of the day, what we're really excited about is our Moot Trust profile is giving us the ability and physicians the ability to be able to actually treat, diagnose and treat more patients. And what we've so far seen early signs is, in terms of initiations, it's both. when it comes to switches, as well as in IU patients. We have a good robust patient services, and our patients have been informed about the availability, and some of those patients proactively reached out to their physicians. What we've also seen is, as I indicated earlier, good new prescribers coming into the treatment of this condition and excited to be actually providing this medicine to those patients that probably were on the fence, given that, you know, it was an infusion with Onpantra early in profile. And Amutra tends to offer a very convenient option with great safety and efficacy data. Therefore, what we've so far seen in the 133 start forms is a good, broad range of both patient prescriber base as well as patient demographics that ranges across younger as well as more traditional demographics.
spk09: Thanks, Tolga.
spk06: Let's take the next question.
spk02: Thank you. Our next question goes from Manu Palmarama with J.P. Morgan. You may proceed.
spk10: Hey, guys. Thanks so much for taking the question. Maybe following on the last question on Ambutra on switching dynamics, what does your market research suggest on the timeframe in which you would expect switching to kind of peak or where most patients that are going to switch have made the switch? I think that's what we're trying to understand, many of us. Thanks so much.
spk09: That's a great question, and thank you for putting it forward very precisely. So I think, Tolga, there's a specific question here around what our market research is telling us about the time for sort of peak switching.
spk07: What we're really interested at this point is really to make sure that the overall category is growing. So our focus is actually right now is really to make sure that we are bringing as many as new patients as possible, given this new option. The switch is what we believe is going to play out a little more organically. And we'll obviously update the street for about a year about the switch and that naive patients. what we expect that to occasionally to organically happen is most patients will end up with with with um with regularness profile however we also know that you know in rare diseases there are patients who are pleased with their existing treatment some of these patients never had any new treatment before Ompatra was available. So we do expect some patients to remain on therapy. But in similar dynamics that we've seen in other categories, patients tend to gravitate towards a better option, which we believe Ompatra is. But I also wanted to take the opportunity to remind everyone that We're going to be updating on the start form dynamics for two to three quarters.
spk01: Just one other comment. From a modeling perspective, it doesn't matter if you're on OnPatro or on Lutra, they're the same price, same value per patient per year. So just a reminder on that point. Great point.
spk09: Good. Okay. Let's take the next question.
spk02: Thank you. Our next question comes from Tong Lu with Barclays. You may proceed.
spk21: Hello? Actually, can you hear me? This is Gina.
spk06: Yes, we can hear you. Okay, good.
spk21: This is Gina Nguyen from Barclays. Yeah, so I have a question, but maybe follow up the start form, 133 start form. You said 34 new to Alnalen. Just if you can give a little bit more clarity, what percentage of these are the switcher from Texanti versus truly naive patients? And then quickly on Helios B, I just wanted to it's a maintenance check. You know, last time we discussed the Thesatomus dropping rate maintained at a low single digit. Any change in the dropping rate?
spk09: Okay, let's start with Tolga, the Ambutra question, and then to Akshay for the Helios B question.
spk07: We really appreciate the excitement around the strong launch of Ambutra, yet it's only five weeks of data. So we wanted to make sure that We all recognize that the granularity of the data we're providing is as good as we possibly can at this point. Those 34 new patients are naive to us. And in terms of your own modeling, one should also remember that, you know, the TX-80 remains a very small portion of the overall category. So we wouldn't necessarily index our naive patients just only on switches from an alternative to this one.
spk09: Yeah. Good opportunity to grow, you know, new patients coming into Amputra. So, actually, tedious fee, TAF drop-in rate.
spk08: Yeah, thanks, Gina. You know, I can reiterate that the drop-in rates remain well within expectations, and I think as discussed before, we obviously had put in a buffer in the sample size to account for TAF drop-ins. We're well within those estimates. So, we're comfortable with the design, Gina. Thank you.
spk09: Thanks, Akshay. That's great. Next question.
spk03: Thank you.
spk02: Our next question comes from Ellie Merle with UBS. You may proceed.
spk14: Hey, guys. Thanks for taking the question. I guess not an ATTR question, but on the pipeline for Lumaceran and recurrent renal stones, I guess maybe just with the Phase II finishing and rolling later this year and thinking about Phase II data next year, I mean, how should we think about what you're looking to see here? It's obviously a much broader population. I guess what could we learn in terms of the relationship between oxalate reduction and reduction in stone formation in this broader population and, you know, your confidence in the biology there and then I guess thinking about sort of the regulatory pathway from there, like what a potential phase three could look like and, you know, any types of like patient segmentation in terms of accessing this much larger population.
spk09: Actually, I'm not sure if you caught all of that. I think, you know, it's around the recurrent bone study, what we're looking to see from phase two data, how we're thinking about, you know, oxalate reduction, and then I think, you know, plans for moving forward that study.
spk08: Yeah, so thanks for the question. So the lumen recurrence stone formation study is ongoing. There's obviously a very large population globally, numbering in the millions probably. And what we want to see is a reduction in uranyxolate. Now, in the PH1 population, of course, we saw very substantial reductions in uranyxolate. They have an enzymatic defect in the liver. And the targeting of GO1 leads to 70 plus percent reduction in urinary oxalates. This is a hypothesis we're testing. One of the interesting things is we may not need to achieve levels like that to see a reduction in stone events. And so let's look at the data as it comes out next year and see. And I say that because the important thing is once oxalate becomes at saturating levels, in the urine. That's when stone formation occurs. So you may not need to take it all the way back down to normal. You might just need to get it out of that supersaturation range by some relatively modest margin to prevent stone formation. And so lots more work to do here, and we'll update you as we get data. But this is a very exciting opportunity with an approved drug that looks very safe so far in the PH1 population. And that just reminds me, of course, safety will also be important to see in the RSF populations, but we're optimistic with what we've seen so far with luma in PH1.
spk09: Thanks, actually. And, you know, another, you know, program in our pipeline, which is orientated around, you know, patients with much more common diseases, I think an exciting potential development for Alnylam.
spk06: Next question, please.
spk03: Thank you.
spk02: Our next question comes from Miles Minter with William Blair. You may proceed.
spk19: Thanks for taking the question. Just on some disaran and the RGA nephropathy data, can you just sort of discuss where you see, like, the complement inhibitor methodology sitting in the lines of therapy and, I guess, how it relates to the data that we've seen from the endothelin receptor 1 antagonist? And I guess, is that a key concern? in how they would potentially design a pivotal study and the types of patients that you would enroll in that pivotal study. Thanks.
spk09: So quite a few questions there. I mean, really just to, yeah, I think start off by, you know, reiterating that we were really pleased with the Phase II results in diabetes-drowned patients with IgG and hepatopathy, very common condition, 37% reduction in proteinuria. I think this is great. And if it's another potential phase three program for our model, so we're very pleased to be working with our partners, Regeneron, moving forward the next steps. Actually, I think there were a number of questions in there that I think are much more specific around how we're thinking about that.
spk08: Yeah, we're very excited about the phase two result with a 37% reduction in urinary proteinuria. You know, busy working with Regeneron right now. We take the lead in this program in the ICANN study design. And we're sort of very busily looking forward to engaging regulatory authorities and hopefully kicking off the study by the year-end. The specifics of where complement or anti-complement approaches fit, you know, the interesting thing is the fundamental underlying pathology here are IgA immune complexes that deposit in the glomerulus and activate complement. That activated complement then damages the glomerular basement membrane and pertineal results. An additional aspect of the disease, I don't think anyone really understands how this occurs, is hyperfiltration in the kidney, and so blood flow dynamics change through the glomerulus. So we have the opportunity here, orthogonally, to impact two key pathogenic factors. With anti-complement approaches, we can get at the fundamental underlying immunopathology, and we've seen the preliminary results we've shared. So this will have a foundational role, I believe, in the future in what will end up being a polypharmacy situation where there'll be anti-inflammatory approaches like anti-complement. Femdisram would be a great fit for that. It could be a once a month, once every three months type injection. And then in addition to that, things that alter blood flow, so endothelium antagonists, ACE inhibitors, ARBs, et cetera. And so you'll see drugs from both classes, the antihypertensive type drugs and anti-complement drugs being combined. And we'll see if steroids will also become part of the picture, but there's more work to do there, although they're rather general, non-specific agents and can have a lot of side effects.
spk09: And just to add, of course, these favorable results open up the potential for Benaducerans of patients with other emeritus diseases. So we're enthusiastically moving forward here. Thank you for the question. One more question. I think we have one more question before we close. Last question please.
spk02: Thank you. Our last question comes from Olivia Bear with Cantor. You may proceed.
spk20: Hey, good morning, guys. Thanks for the question. I know you're in a quiet period with respect to Apollo B, but I wanted to ask if there are any monitoring requirements after patients reach that 12-month mark, you know, that are built into the study. And then I've got a follow-up on sequencing for mixed phenotype patients. Is there anything you can do to improve access for patients that could move on to Ampatro or Amlucha after tifamidus? Thank you.
spk09: So I just want to say, you pointed out we are in a quiet period, so we're not going to be taking any questions on Apollo B, but I didn't actually quite catch your second question. I think it was something to do with Ambutro, but I didn't hear it properly. Could you repeat the question, the second part of the question?
spk20: Yeah, sure. It's just about mixed phenotype patients, right, and whether there's anything you guys can do to improve payer access there for patients that could sequence onto Ampatro or Ambutro after tifamidase.
spk07: You mean pulse neuropathy mixed phenotype patients?
spk06: Yeah.
spk07: Yeah, I mean, look, we certainly have the right capabilities to support those patients. The fact that we've been able to position this at parented pricing will certainly, we believe, help increase access. So far, we haven't really heard any headwinds around the access piece. But we are indicated for polymyopathy, and in the U.S., tefamidase is indicated for cardiomyopathy. So in terms of providing any brief strategy for access would not be something we would consider. Like any of our new patients, we have great support of benefit verification and patient access support, which those patients would certainly be eligible if they go through our patient services program.
spk09: Thanks, Olga. Okay, so thank you, everyone, for joining us on this call. We're very happy with the progress that we've made in the second quarter and first half of 2022. We've delivered strong commercial results. We've advanced our diverse pipeline programs and development, and we've got a number of exciting catalysts on deck in the coming months. So we look forward to updating you along the way while we continue to deliver on our near and long-term goals. Thanks, everyone, and have a great day.
spk06: Goodbye.
spk03: Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.
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