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spk08: pleased with the impact we're seeing from Amutra in expanding the opportunity for our TTR franchise as reflected by the robust 75% year-over-year quarterly growth that we achieved in Q1. Representing the third consecutive quarter of achieving TTR growth in excess of 70% on a year-over-year basis in the U.S., following Amutra's launch in the third quarter of 2022. Additionally, key operating metrics continue to trend favorably, including growth in new patient start forms, the switch rate from Ampetro, patient compliance rates, and the expansion of our prescriber base. In our international markets, Total TTR Q1 product sales increased 9% versus the fourth quarter, driven by strong demand in Japan following the fourth quarter launch of Amutra, offset by inventory destocking in Japan. The Amutra demand growth in Japan is particularly encouraging, with the new patient growth being driven by a mix of switches from tefamidus as well as patients naive to therapy. Additionally and importantly, Amutra continues to deliver steady growth in markets where Amutra is not yet launched, positioning these markets for the upcoming Amutra launch. Amutra also benefited from the timing of orders in our distributor markets. Our global results continue to be challenged by foreign exchange headwinds, with total TTR year-over-year reported growth of 49%, held back 5 percentage points due to changes in FX rates. Now, moving to our ultra-rare products. and the performance of Givlari and Oxlumo, which delivered $72 million in combined product sales during the first quarter, representing a 2% increase compared with the fourth quarter and a more robust 45% growth compared with the first quarter of 2022. We ended the quarter with more than 550 patients on Givlari commercial therapy and more than 300 patients on Okslova commercial therapy, representing 6% and 7% quarterly growth compared with the year-end 2022 for Givlari and Okslova, respectively. For Givlari, global growth of 2% in Q1 compared with the fourth quarter was impacted by the following. A decline in U.S. growth of 3% primarily due to reduced patient compliance associated with the seasonal impact from the annual pre-authorization required by payers during the first quarter that we expect will recover in subsequent quarters. Growth in our international markets increased 11% as demand increased in European markets and also benefited from the timing of orders in our distributor markets. For Oxlumo, global growth of 1% in Q1 compared with the fourth quarter was impacted by the following. U.S. reported growth increased 3%, driven by an increase in patient demand. Growth in international markets was flat, with a demand increase in European markets offset by the timing of orders in our distributor markets. Additionally, changes in year-over-year foreign exchange rates negatively impacted Q1, GIVLAR, and OXLUMA reported growth by 3 and 4 percentage points, respectively. In conclusion, we are pleased with the growth in revenues, particularly with the ongoing signs of strong performance associated with the Albuter launch, which we believe represents an important therapy option for HATTR amlidiosis patients with polyneuropathy and accelerated growth. opportunity for our TTR franchise. With that, I will now turn it over to Akshay to review our recent R&D and pipeline progress. Akshay? Thanks, Tolga, and good morning, everyone.
spk06: I'd like to start today with a recap of recent news that marks a very important milestone for Alnydum and the broader field of RNAi therapeutics, which is our progress with LNAPP, an investigational RNAi therapeutic in development for the treatment of Alzheimer's disease, and cerebral amyloid angiotopy. As announced last week, we reported the first-ever clinical results with an RNAi therapeutic directed to the CNS. Given the importance of the positive data and the intense interest in the study from all parties concerned, not least patients and physicians, I think it's worthwhile to further discuss the interim findings from our ALNAPP program. ALN-APP targets amyloid precursor protein, or APP, which we're investigating as a potential treatment for Alzheimer's disease and cerebral amyloid angiopathy, or CAA. Human genetics has shown that certain mutations or duplications in the APP gene can cause early onset Alzheimer's disease, where amyloid plaques form in brain tissue and are associated with neurodegeneration. Other mutations in the same gene can cause CAA, where A-beta fragments distinct from those that aggregate to form Alzheimer's plot deposit within the walls of blood vessels in the brain and result in bleeds. CAA is in fact the second leading cause of intracerebral hemorrhage. So this one-parent protein, APP, can be harmful in two distinct pathophysiological processes. In animal studies, we've shown that targeting APP with an sRNA showed great promise with broad CNS biodistribution after a single intrathecal injection, as shown on the left here, with knockdown in all major CNS cell types, such as the neuron, oligodendrocyte, microglia, and astrocytes. On the right, we can see that a single 60-milligram intrathecal dose in non-human primates resulted in significant and sustained target knockdown with durability out to six months, at which time the experiment was terminated, but APP suppression was still ongoing. These pharmacologic findings, which were reliable, reproducible, and appeared safe, increased our excitement around the therapeutic hypothesis. Specifically, that by lowering APP protein production in the CNS via an RNAi mechanism, we could reduce the downstream fragments that aggregate and deposit in tissues, and therefore hopefully alter the disease course. To support advancement to clinical testing, we conducted short-term IND-enabling GLP toxicology studies in the rat and nonhuman primate, where two low, medium, and high doses were given a month apart. i.e., where we greatly exaggerated dose and regimen relative to that expected in the clinic. These studies demonstrated a supportive safety profile and no significant CNS histopathology and thereby enabled the ALN-APP Phase I study. The Phase I trial is designed as a two-part study, a single ascending dose, Part A, followed by a multiple dose, Part B. Part A was enabled by the GLP toxicology studies I've just mentioned. Phase one is being conducted in patients with early onset Alzheimer's disease. The primary endpoint of this study is safety and tolerability of LNAPP. Secondary objectives are focused on characterizing the pharmacology of LNAPP. The study also includes a variety of exploratory biomarkers, which will allow us to assess whether LNAPP is showing any impact on other biomarkers of disease progression. Interim data shared are from the initial single ascending dose cohorts, and we continue enrolling in Part A as we explore further doses. Excuse me. At the time of this interim look, 20 patients with early onset Alzheimer's disease have been enrolled in three single-dose cohorts in Part A of the ongoing Phase I study. To date, L and APP has been well-tolerated with no study dropouts and all adverse events being mild or moderate in severity. available CSF data from white blood cells and protein appeared similar to placebo. Neurofilament light chain, or NSL, which is a mark of neuronal damage and which may be elevated in drug-induced neurotoxicity, was also monitored. Reassuringly, early data for NSL, which are currently available from two out of the three cohorts studied to date, also looked comparable to placebo. Now let's look at the pharmacodynamic results after single intrathecal doses. To date, we've studied three dose levels, 25, 50, and 75 milligrams. All available data to the three-month time point are shown. Excitingly, we observed that unlike placebo, LNAPP treatment resulted in rapid, dose-dependent, and sustained reductions of both SAPP-alpha and soluble APP-beta, both biomarkers of target engagement in the CSS. We saw rapid knockdown as early as day 15 and the maximum knockdown of up to 84, 90% respectively for APP alpha and APP beta. At the highest dose tested, 75 milligrams, the median knockdown was greater than 70% for both biomarkers and sustained for at least three months. Initially, per protocol, we intended to dose escalate from 75 to 225 milligrams. However, given that the knockdown observed at 75 milligrams substantially exceeded our initial target of 50% biomarker knockdown, we chose to deescalate to 50 milligrams. As you can see, at 50 milligrams, while we have a more limited data set, it appears equally promising and similar to the 75 milligram dose with substantial knockdown of both ABP alpha and beta. Now notably, the durability we see in humans reflects what we saw in non-human primate studies, where single doses gave similar profound durable knockdown extending to six months or beyond. Accordingly, we anticipate that the responses we see here in part A will continue. Indeed, for the data available beyond three months in this human study, we see continued target suppression. This durability of effect is important for ALN-APP as well as our overall CNS effort as it suggests the potential for infrequent dosing. We look forward to seeing with longer follow-up indeed how long this knockdown effect is sustained. We believe these data suggest that the drug will be able to be dosed quarterly at most and based on animal data and the translation of our platform in humans, we believe there's the potential to even dose every six months or less frequently. Enrollment in the single ascending dose portion of the Phase I study is ongoing in Canada, the Netherlands, the UK, and the United States. Additional enrollment in Part A will allow us to continue to explore single-dose PK and PD and characterize the durability and effect and long-term safety. Results from Part A will also inform the doses and regimens to be put forward into Part B, the multiple dose portion of the study, which will include patients from Part A. In parallel to Part A of the Phase I study, we conducted chronic GLP toxicology studies in animals to support the multi-dose Part B for Phase I. These chronic GLP tox studies were conducted without knowledge of the impressive knockdown in durability we see today at low doses of ALN and APT we see in this Phase I study. So, for standard practice, we exaggerated dosing and dosing frequency relative to any dose and regimen that would ultimately be used in clinical testing. Specifically, we administered low, medium, and high intrathecal doses monthly for six months in the rat and every other month for nine months in the non-human primate. The data from the chronic studies have been shared with regulatory authorities. We have already received regulatory approval to begin Part D in Canada, where in fact the majority of the Part A patients have been enrolled to date, and approval is pending in the UK and Netherlands. In the US, the FDA has currently placed partial clinical hold on the multi-dose Part B of the Phase I study due to findings observed in chronic toxicology studies. Of course, given the high exposures that we achieved with frequent administration of high doses, it's not unexpected that we would observe findings in these chronic toxicology studies. However, it's important to contextualize exposures by relative CSF volumes between toxicology species and humans. For example, Relative to a potential clinical dose and regimen of 75 milligrams given every six months, there's a more than tenfold greater annualized exposure at all doses tested in the rat and non-human primate. And at the top doses evaluated in those chronic tox studies, there's a 75 and 50-fold greater annualized exposure in rat and non-human primates, respectively, relative to the same potential human dose. And if we scale based on organ weight, then these annualized exposures would be even greater in the chronic tox studies. I want to nevertheless acknowledge that the FDA will be the ultimate arbiter of the data, and we look forward to getting further guidance from them. Accordingly, we plan to engage with them to discuss all preclinical information, as well as these new interim phase one clinical data, which provide important context to support potential initiation of Part B in the U.S. To close this part of the discussion, I'm absolutely thrilled about these incredible human data that provide the first-ever evidence that we may be able to use RNAi to silence disease-causing transcripts in the CNS. In animal studies, we've already demonstrated the reproducible and modular nature of our CNS platform with the knockdown against a diverse range of targets and hope that we can address disease-causing genes not just for Alzheimer's, CAA, ALS, and Huntington's, but also many other disorders. We look forward to presenting these interim dates from Part A of the Phase I ALN HIV study at an upcoming medical congress. With that, let me turn to our efforts in ATTR amyloidosis, where we're advancing three clinical stage product candidates, namely Patisran, Bifisran, and ALN TTRS-C04. As you know, Onpatra is currently approved in multiple markets around the world to treat hereditary AT2 amyloidosis with polyneuropathy, and we're committed to expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild-type AT2 amyloidosis patients. Announced in February, we're delighted that our supplemental new drug application for T-strand cardiomyopathy of AT2 amyloidosis has been accepted by the FDA with a standard review and a PDUFA date of October 8th. In their file acceptance letter, the FDA stated that they've not identified any review issues. The agency also noted that they're planning to hold an advisory committee meeting to discuss the application. Currently, we have no further details from the FDA regarding the timing of the outcome or the specific topics they wish to discuss. When we learn more, we will communicate that information in due course. If the FNDA is approved, this will allow us to extend the potential benefits of paticeram to many patients with wild-type and hereditary AT-tramyloidosis with cardiomyopathy. This filing is based on the pivotal Apollo B study, which demonstrated improved functional status and quality of life in patients with AT-tramyloidosis with cardiomyopathy given paticeram for 12 months without placebo. The clinical profile of Pertusseran is supported by an encouraging safety profile and exploratory data that favored Pertusseran treatment relative to placebo on various biomarkers of disease progression at month 12. We've announced this morning that 18-month data from the Apollo B study have been submitted to the FDA as part of the SNDA review, and we'll be presenting these results at the ESC heart failure meeting at the end of May. Now, similar to Ampatra, we're also committed to expanding the label for Ambutra to include the treatment of cardiomyopathy in both rotary and wild-type atrial amyloidosis. This is being done with the ILEOS-B Phase III study of investigational butrysram. ILEOS-B, which is fully enrolled, has an endpoint of all-cause mortality and CV events assessed after at least 30 and up to 36 months, and we remain on track to share top-line results in early 2024. Wrapping up with TTR-L and TTR-SCO4 is an investigational RNA therapeutic based on our iCarrier platform and offers the potential for more durable and potent TTR silencing with the possibility for annual dosing, a potentially transformative profile. TTR-SCO4 has entered the clinic and begun dosing in the phase one study, and we expect top-line results in late 2023. In addition to our late-stage clinical programs, we believe we've also been making great progress with our early and mid-stage programs. A notable highlight includes Zalbiceran, our investigational RNA therapeutic for hypertension, which we believe could transform the treatment of the disease and offer a highly differentiated profile from all existing antihypertensives, including oral RAS inhibitors. We look forward to the important upcoming milestones from the Phase II program and remain on track to deliver top-line results from CARDIA-1 in mid-2023 and top-line results from CARDIA-2 at or around year-end 23. These are just a few of the highlights from our broad and innovative pipeline, driven by our underlying organic product engine, and where we expect to deliver sustainable innovation, representing a key growth driver for Alnylam in the years to come. To wrap up these highlights, we're excited to have initiated dosing in the Phase 1 study of ALNKHK for the potential treatment of Type 2 diabetes, plus Regeneron has announced the initiation of a Phase 2 study of LNHSD in patients with NASH. Now, with that, let me now turn it over to Jeff to review our financials and upcoming models.
spk25: But it's Jeff. Thanks, Akshay, and good morning, everyone. I'm pleased to be presenting a summary of Allen Island's Q1 2023 financial results and discussing our full-year guidance. Starting with a summary of our P&L results for the first quarter. Total product revenues for the quarter were $276 million, a 48% growth versus Q1 2022. As Tolga previously indicated, the increase is primarily related to growth in TTR product revenues driven by the launch of Ambutra in the U.S. in the third quarter of 2022, as well as increased patients on Yabari and Oxaluma therapies. It's also worth noting that year-over-year growth in combined product revenues was held back by approximately four percentage points due to impact of changes in foreign exchange rates. That revenue from collaborations for the first quarter was approximately $36 million, representing a 41% increase compared with Q1 2022, primarily due to an increase in revenue from our collaboration arrangements with Regeneron attributed to an increase in reimbursable activities under our research services arrangement, in addition to an increase in revenue recognized associated with licensed programs within the collaboration. Royalty revenue during the quarter was $7 million, which was driven by Novartis' sales of Lectio, which launched in the U.S. in the first quarter of 2022. Gross margin on product sales was 85% in Q1, representing a 2% decrease compared with the first quarter of 2022. The decrease was primarily driven by increased royalties due to Sanofi on sales of Ambutra, which was partially offset by lower manufacturing costs for Ambutra compared with Ampatro. Our non-GAAP R&D expenses increased 35% in the first quarter compared to the same period in 2022, primarily due to increases in headcount to support our R&D pipeline, development expenses associated with the Apollo B, Helios B, and Cardio 1, Cardio 2 clinical studies, and manufacturing-related expenses with our preclinical activities. Q1 2022 non-GAAP R&D OpEx was disproportionately lower than all other quarters during 2022. Thus, we expect lower year-over-year quarterly growth rates for R&D in the remaining quarters of 2023. Our non-GAAP SG&A expenses increased 17% in the first quarter compared to the same period in 2022, primarily due to increased headcount and other investments supporting our strategic growth, including the global launch of Invitro. Our non-GAAP operating loss for Q1 2023 was $110 million, representing a $7 million improvement compared with Q1 2022, driven by strong top-line growth, offset by more moderate growth in operating expenses. Finally, we ended the quarter with cash, cash equivalents, and marketable securities of $2.1 billion, compared to $2.2 billion at the end of 2022, with a decrease primarily due to our operating loss in the quarter. 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 2023 financial guidance. We are reiterating the financial guidance we provided on our year-end results call in February. Starting with net product revenues, we continue to anticipate combined net product revenues for our four commercialized products will be between $1.2 and $1.285 billion. Our guidance for net revenue from collaborations and royalties remains a range between $100 and $175 million. And our guidance for combined non-GAAP R&D and SG&A expenses remains unchanged and is a range between $1.575 and $1.65 billion. Let me now turn from financials and discuss some key goals and upcoming milestones slated for early and mid-2023. We will, of course, be executing on global commercialization of our products on PATRO and VUTRA, GIVLARI, and XLUMO. From our TTR programs, we have a couple of upcoming data presentations. Eighteen-month results from Apollo B will be presented at the ESC heart failure meeting later this month, and the Heliose randomized treatment extension results looking at a biannual dose regimen for GUTRISERAN will be presented at ASNP also at the end of May. We expect to report top-line results from the CARDIA-1 Phase 2 study of Zalbiceran and also intend to complete enrollment in the CARDIA-2 Phase 2 study. With our partner programs, VEER expects additional results from Phase 2 combination trials of ALN-HVV02. Let me now turn it back to Christine to coordinate our Q&A session. Christine?
spk23: Thank you, Jeff. Operator, we will now open the call for questions. To those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have additional questions.
spk13: Thank you. At this time, we will conduct the question and answer session. To ask a question, you will need to press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster. And our first question comes from Richie Burrell from TD Collin. Your line is open.
spk10: Good morning, guys. Thanks for taking the question. I know I'm a lonely loud one, so I'm going to try and stick to it as much as I can. The 18-month data that's coming up from Apollo B, can you talk a little bit more about what will be presented, maybe how many patients are in continued follow-up at 18 months? Will we have key secondary endpoints like the Kansas City and additional safety follow-up as well? Thank you.
spk07: Yeah, so, you know, as a reminder, somebody on the call, Apollo B was a double-blind randomized study for 12 months. And after this point, patients who were on placebo were given the option to switch to Batista and Ferb continuation of dosing. These data corroborate really what we saw in the 12-month portion of the study, and as we noted on the call, we've submitted these data to the FDA, and we'll be presenting these data at the HCF in Prague in May. Pushkar, do you want to add any other comments about the data and engagement with the agency?
spk03: Yeah, absolutely. Thanks, Yvonne. Thanks, Ritu, for the question. You know, as Yvonne said, we're really excited about these data. You know, you asked Ritu about ongoing follow-up, right? All patients were randomized out to 12 months, and then all patients were offered the opportunity to be on active drug from 12 months and beyond. And this is a cut of data out to 18 months. And we've had very high retention on the study, which is important and corroborates the profile. And I think it's going to be an opportunity to look at sort of the continued profile of what we've seen on patients on active drug, which was, you know, we saw evidence of stabilization across key endpoints, particularly the six-minute walk test. sort of what was associated with, you know, around the age-related decline that's seen in that parameter, as well as stabilization in the key secondary endpoint of the Kansas City cardiomyopathy questionnaire. So that's important. It's an opportunity to look at the placebo patients as they cross over to active drug and look at ongoing safety. Net-net, as Akshay and Yvonne commented, Richie, we really feel quite confident and good about the data that we've seen, and that it corroborates the profile of paticerin and its potential role in this disease.
spk07: Yeah, and as a reminder, we've submitted the 120-day safety update as is routine in the submission process.
spk11: Thank you. Next question, please. Thank you very much.
spk13: Our next question comes from Tazine Ahmed from V of A. Your line is open.
spk15: Hi, Ed. Good morning. Thanks for taking my question. Maybe just one on embouchure sales.
spk14: It looks like you're off to a good start on the ramp. Just wondering what your internal data is saying about any kind of market share being taken from empatro. And whether or not, if that is the trend, you would expect that to be the case going forward as well. Thanks.
spk07: Okay. I think that's one that goes to you.
spk08: Thank you, Yvonne. Hi, Suzy. Look, first of all, we're incredibly excited at the fact that we have been able to build a category and essentially, you know, grow our business quarter over quarter by over 70% three subsequent quarters in the U.S. And what we see in terms of the dynamic with Onpatro is a very healthy switch rate while we're adding that naive patients in a very robust manner. So what our internal data really suggests is that there is lesser and lesser patients that are staying on Onpatro as we expect those patients' numbers to remain in small double digits or single digits over time.
spk07: Okay. Yeah, it's really just, I think, kind of emphasize how pleased we are with the launch metrics for Amvutra in terms of, you know, the balance of new patients as well as switches and really the expansion of the prescriber brace, which is, you know, very encouraging for continued growth in the trajectory of our TTR franchise. So thanks for that question, Suzanne. Next question, please.
spk11: Thank you.
spk13: Our next question comes from Ellie Merle from UBS. Your line is open.
spk18: Hi. Thanks so much for taking our question. This is Sarah on for Ellie. On your CAA program, I guess, can you talk about some of the timelines there and maybe the prioritization of that versus Alzheimer's and how we should think about the size of the CAA market opportunity? Thanks for that question.
spk07: I guess that question has been stimulated actually by the incredible results that we've shown, the quite remarkable results that we've shown in our phase one interim study. And clearly, that's the first step in, you know, the journey of bringing RNAi therapeutics to patients with CNS diseases in general. We're clearly starting off with early-onset Alzheimer's disease. But Tushkal, I think cerebral amyloid angiopathy is, again, another very, you know, important opportunity potentially for ALN-APP. given the genetics, but could you say a few words about how we're thinking about the opportunity in CAA?
spk03: Absolutely. Thanks, Yvonne. Thanks, Sarah. Look, as has been highlighted by both Akshay and Yvonne, CAA is really a devastating disease. It's the second leading cause of interest cerebral hemorrhage, only behind hypertension. and there's really no available therapies for these patients. And so, it's something where the genetics and the biology really strongly suggest that APP lowering may be a benefit to these patients. In some ways, you can think about it as very comparable to the hypothesis we've been pursuing with our TTR program, reducing amyloid can reduce downstream tissue damage in nerves and heart, in this case, in the parenchyma of the brain in Alzheimer's disease, and the vasculature of the brain in CAA. So these initial data that we've shared today really give us promise that we can advance ALN-APP towards both of these diseases, frankly, in parallel. We've not announced specifically what the timelines for that are. We're obviously working through and continuing the part A of the study to do further dose exploration and really establish, you know, what we're seeing in terms of the magnitude of knockdown, but also the durability so that we can identify multi-dose regimens, et cetera, characterize safety, and then we'll want to be pursuing phase two studies in both of these indications in due course, and we'll update.
spk11: Actually, anything to add? No. Oh, good. Good answer for school. Next question, please. Thank you for your question.
spk13: Our next question comes from Salveen Richter with Goldman Sachs. Your line is open.
spk17: Thank you for taking our question. This is Tommy on for Salveen, and congrats on the progress. So for Zalbiceran, can you frame what you're hoping to see in this upcoming phase two monotherapy and combo data, the path to registration here, given supportive data, and any updates on the reverse CR platform? Thank you.
spk07: Yeah, I think your question was referring to Zalbiceran. Is that correct? Just wanted to make sure. Yeah.
spk16: Yeah.
spk07: As you know, we're very excited about the opportunity for Zalbiceran in hypertension. It's a you know, condition that impacts, you know, 100 million or more people. And, you know, only 70% are able to, you know, achieve the goal in blood pressure reduction. So we think it's a really important area that we believe our platform has a real opportunity to completely transform how these patients are treated and hopefully lead to better outcomes with respect to morbidity and mortality. And we've got two phase two studies ongoing, Cardio 1 and Cardio 2. Clearly, we need to wait for those results before we speak more specifically about, you know, plans beyond that. But Prishkal, do you want to talk a little bit maybe around, you know, the current status of our studies and how we're thinking about future development?
spk03: Sure. Yeah. So, you know, look, salbicerin has the potential to be an incredibly transformative medicine. for high blood pressure. What we saw in the phase one study that we've already reported was, you know, opportunity to realize almost 20 millimeters of systolic blood pressure lowering with 24 hour ABPM lasting and durability lasting up to six months with a single injection. as Yvonne highlighted, that that can actually address a multitude of the issues that lead to hypertension being the number one addressable cause of cardiovascular morbidity and mortality around the world. We've got two studies. The CARDIAT-1 study is a monotherapy study. I think that was the first study you asked about. And that study completed enrollment at the end of last year, and so we're looking forward to data in the middle of this year. And that's really going to allow us to establish the dose and the regimen for ongoing pivotal studies. So we're looking at a range of doses from 150 to 600 milligrams in Q3 and Q6 month dosing. And so coming out of that study, we'll hopefully be able to establish what that pivotal dose and regimen is. The second study that we're doing is CARDIA-2. As you're probably familiar, in hypertension, combination therapy is sort of the standard of care. And so what we're doing in CARDIA-2 is looking at combining Zalvisarane with three common classes of medicines, diuretics, calcium channel blockers, and angiotensin receptor blockers. And what we'll want to be seeing there is the additive efficacy and safety, and that will help us design ongoing studies for our registrational program. I'm really excited that their enrollment has really been picking up in that study, and we are on track to complete enrollment, you know, early this year and report out data towards the at or around year end. So with those data together, we think we'll be able to provide more guidance on what the pivotal registration program will look like.
spk07: Yeah, perhaps important to add that actually from a regulator's perspective, to achieve an approval in a medicine for hypertension, to demonstrate a five millimeter of mercury lowering of systolic blood pressure. And of course, we've actually already demonstrated more than that in our phase one studies as is highlighted. So as we deliver the phase two days and hopefully move to larger numbers in the phase three and deliver, you know, similar efficacy and also robust safety, we feel that it's a fairly straightforward path to an approval here.
spk11: Thank you for the question. Thank you.
spk13: Our next question comes from Paul Matisse from Stifle. Your line is open.
spk21: Hey, thanks so much for taking the question. Congrats on the quarter and the recent CNS data. I wanted to ask just a commercial question. It looks like you saw this really nice jump in the sequential net patient ad rate when M. Butcher became available. It looks like that's kind of stepped back down to more of the normal rate we were observing throughout 2022. Is that kind of how you're thinking about the likely cadence going forward, that maybe there was this bolus of patients that were interested in a much more convenient product and now the growth rate from here is probably steadier?
spk08: Okay. Yeah. Thank you, Paul. I mean, look, first of all, I just want to reiterate the fact that we're incredibly pleased with how Avuto performance is taking shape in the U.S. and now in Japan and other European markets. What's really important to highlight is The product profile is very compelling that this category growth not only addressed the pent-up demand that we were anticipating, but it's also continuing to actually help us expand this franchise, mostly noted by the fact that we're seeing an expanding prescriber base. Our start form rates continue to go up. And what we see is also our ability to get naive patients, not just on petrol switches, are continuing to be at the stated rate. The result that you see in Q1, Paul, is mostly a bit diluted because given the insurance renewals, that we see in this Q1 tends to impact the net sales impact in the U.S. We're actually very encouraged with some of those internal metrics that I just shared with you, making us, you know, quite confident that in subsequent quarters we see the uptake continue to be at the similar rates that we see in the prior quarters.
spk07: Thank you so much, Tolga. Next question, please.
spk11: Thank you for your question.
spk13: Our next question, excuse me, comes from Jessica Five from JP Morgan. Jessica, your line is open.
spk19: Good morning. Thank you for taking our questions. This is JL for Jess. So we have a question on reimbursement around embouchure. So from a cost-benefit perspective for payers and recognizing, right, the Helios B data has yet to come out. How would you compare embouchure to defamitis for cardiomyopathy? And also curious, how are you thinking about this on petrol where you already have your positive pivotal data? And then moving to Medicare patients specifically, can you remind us what the out-of-pocket cost is like for embouchure per year for the Medicare patients? And how does it compare to the out-of-pocket cost for tefamidus, again, for the Medicare patients? And with the upcoming IRA changes to Medicare, how do you see this change potentially? How do you see the difference can change potentially? Thank you.
spk07: There's a lot of questions here. We'll try and remember them and pass them out. I mean, talk about maybe start with the last question first and talk a little bit about how we're being out of occupation costs, right? The sort of Medicare...
spk08: Context. So let's also kind of let the straight in the record. So we have about 70% of our patients on Medicare and Medicaid, and those are patients that are on Part B. And right now, if you look at our current cost burden on those patients, about 70% of our patients pay zero co-pay. in the Part B program, and it's consistent with both Onpatro as well as Avutra. As you all know, we have very innovative value-based agreements that actually really unburden the patients to be able to have access. And what we really see, that's probably the most important marker, is if you look at are these patients that are put on therapy with a start form do they actually end up stay getting the therapy and are they staying on therapy and what's really encouraging is both and we can say that now with our mutra uh three quarters in the market we see very similar exceptionally high compliance rates which also suggests that those patients that They have some copay burden or continue to be able to access thanks to our value-based agreements and other ways that we support those patients.
spk07: I think you've actually answered two out of the three questions. And the third question is how we're thinking about you know, pricing in cardiomyopathy, particularly with respect to . I mean, given that, you know, we're still, you know, awaiting a label for Onpatro and we're awaiting results for . I think it's probably too early to speak to that detail. So, thank you for your questions, and let's go on to the next question.
spk11: Thank you.
spk13: Our next question comes from Gina Wang with Barclays. Your line is open.
spk24: Thank you. Thank you for sharing your APP data. Indeed, a very impressive knockdown profile. I have one question on the data, but with three parts that hopefully can cover all three questions. So when we look at the nature biotechnology paper, 60 milligram from nonhuman primates data was only showing similar knockdown when we look at compared to the 75 milligram in human. So we'll let to almost nearly tenfold better translation to human. And my second question is that you show the median percentage knockdown. So what is the mean and the standard deviation look like if we only focusing on 75 milligram profile? And then lastly, do you need to run another non-human primates study in order to satisfy you know, FDA to remove the partial clinical hold.
spk07: Okay, so three questions there, and I think I could say, you know, I think they're kind of all for you. I think one was about the translation from the preclinical setting to clinical setting. Second was with respect to the percentage knockdown that we're seeing, and the third you know, our plans to address the clinical hold. I think the fool actually answers the questions on the clinical hold. I think it's really important to emphasize that Part A is ongoing, you know, in a number of countries, including the U.S. And in fact, we have approval to progress with, you know, Part B from Health Canada. In fact, it's actually said in its remarks, most of the patients actually in Part A come from Canada. So it's really important to note that we're able to progress with Part B, but clearly still a lot to learn from Part A in terms of, you know, PK, PD, durability, et cetera, before we define our plans for the next phase of the study. Actually, we maybe want to talk a little bit more about how we're thinking about addressing the clinical halls with the FDA and then the other two questions that relate to the data.
spk06: Yeah, thanks, Yvonne. Thanks, Gina. Let me just go in order. So I think your first question, Gina, if I got it right, was 60 milligrams in the monkey and expectations in man in terms of translation. I think, you know, even without doing a lot of calculations, if you think about the size of the monkey brain and the CSF volume and you have to administer 60 milligrams, to get something like the knockdown curves we're seeing at 50 milligrams here in humans and 75 milligrams. It just shows the gain in potency, and we believe we'll also see in durability in humans relative to non-clinical species. Now, you've watched this for a long time, and if you happen back to the liver data, that's exactly what we see in the liver setting. So these human phase one data are really rather exciting, and I think spell a product profile where We hope that low doses, rather than to the animals, we see, you know, very important, significantly significant knockdown for highly durable intervals that would allow, you know, infrequent dosing, hopefully every six months, maybe even annually. So that was question one. Your second question was we showed the medians. What about the mean and standard deviations at 75? Again, we haven't shown the patient-by-patient data. We'll, of course, share more data in an upcoming meeting. But I can reassure you that as you go from low to high dose, The kind of variability you see patient to patient at high dose, you now see, you know, track after track for each patient who's following the same curve. So the data will be very tight in terms of means and kind of deviations. In fact, we've looked at them, you know, at the 50 and 75 that we haven't shown today. So, again, that conforms exactly to what we see with RNAi in other tissues where at low doses, sub-pharmacologic doses, you see some variability between individuals, just as you see in placebo. But once you're at the operative pharmacologic doses, you get very tight knockdown and little intra-individual variability. Again, these are all small numbers, but very encouraging data. And finally, do we need a non-human primate study to get a hold? I mean, I think I shared today our impressions of the clinical data, the situation with the chronic tox studies, the exaggerations and exposures we had. We want to discuss all this with the FDA and get their guidance. Obviously, they have a very important voice in this. We want to benefit from their input. So let's go and do that. And from that, we'll learn whether we need to do more studies or not. But if we can administer at low doses and get up to a year of lockdown, who knows? We'll see. But certainly very exciting times.
spk07: Thanks, Gina. Thanks for your question. Next question, please.
spk11: Thank you.
spk13: Our next question comes from David Leibowitz with Citi. Your line is open.
spk09: Hi, this is Devanjana on for David. So, we wanted to ask, like, that the ATR space appears likely to have an additional TTR silencer entry. How does the competition shake out between your offerings and eventual competitors? And maybe one more if you have time, but assuming approval for ATTR-CM is going to be based on functional endpoint, how do you see the therapy getting utilized after that approval? Thanks.
spk07: Yeah. Actually, it would be really helpful if you could repeat your question and maybe just kind of hold yourself to kind of one question. So maybe you can just repeat the one key question you'd like us to address.
spk09: Sure. Okay. So, my first question was that the ATTR space appears to likely have an additional TTR silencer entry. How does the competition shake out between your offerings and eventual competitors? Thank you.
spk07: Okay. So, let's start off with Tolga, and then Pushkar will also add some remarks. Tolga?
spk08: Yeah. So, as you know, Avutra has really been a game changer. And it's been transforming the market and building the category growth. And frankly, the potential availability of more treatment options is really good for patients. This is a highly devastating disease. Patients are still either undiagnosed or undertreated. So similar to other competitive markets, it will increase disease awareness, support early diagnosis, enable early treatment initiations, which in turn supports a significant category growth that we already see as we expect to see. Now, in terms of the product profiles, obviously what we see is, and I'll have Pushkar comment a little bit on our clinical profile, but what we're really pleased to see is, first of all, the rapid onset is very important for patient outcomes. Disease reversal is important. And we're obviously very confident of our product profile, only four times a year administration. And also, given the fact that strong uptake is a clear signal of what this profile is, and our customer-facing profile, and how we're competing in the market. So with that, maybe I'll turn it over to Pushpal to comment on the product profile on the clinical level.
spk03: Yeah, I mean, I think, Tolga, I think you hit actually most of the key points. I mean, I think, you know, I think it's important to state that there's really no head-to-head studies between Eplentersen and We've just seen some, you know, early data here, and we look forward to learning more about it. But there's no head-to-head data between Eplenters and Guitrescu. And I think, you know, I think as we've been in the marketplace, as we've talked to clinicians, as we've talked to patients, what we've learned about, you know, what's important to them, obviously they're looking for strong efficacy and a good safety profile. And as you dive deeper into that, you know, speed of onset of action is quite important. We've been very pleased by the rapidity of knockdown, TTR knockdown that we see with our agents. And that seems to translate actually to patients feeling better. We've noticed that with the MVMI data and nutritional status, and we get reports of patients anecdotally feeling a lot better very early on therapy. And likewise, ultimately, people want to regain function as much as possible. They want to be able to live their lives basically as free of this disease as humanly possible. And what's, you know, this concept of disease reversal that Toga mentioned becomes very important. And we've been encouraged when you look across key parameters like the MNIST, when you look at the Norfolk quality of life, et cetera, in the PN space, that we have 50% or upwards of patients who are sort of reaching that reversal threshold. And so, again, we're really excited about the profile that we have with Ambutra, how it's been received, and the feedback that we've been hearing. And so I think, you know, we're very encouraged. And again, it's great that there'll be another agent out there, as Koga said, but we're very confident about the profile of Ambutra and what it offers.
spk07: No, that's great. And I think having sort of five years of experience marketing TTR medicines, I think, gives us, you know, the opportunity to really understand this market and, you know, extract insights that are helpful in terms of educating patients and physicians. So, thank you for that question. Next question, please.
spk13: Thank you. Our next question is from Mike Ulz from Morgan Stanley. Your line is open.
spk22: Good morning, and thanks for taking the question. For ALN TTR SC04, assuming you get some supportive data later this year, can you talk about the potential path forward there and if there's opportunity to maybe shorten that timeframe? And would you be looking to move forward in both polyneuropathy and cardiomyopathy? Thanks.
spk07: No, thanks for that question. We're really excited about progressing ALN and TTR SC04 for a number of reasons. You know, importantly, the potential for, you know, increased knock-down rates of 90% and frequency, perhaps, annual dosing. So, we think this is a real step forward for our platform in general. And, you know, Pritkal, maybe you can talk a little bit about, you know, how we're thinking about developing this program going forward.
spk03: Yeah, absolutely. Yeah, you know, SCO4, I think, really represents sort of the next generation of innovation in the TTR space where we want to bring the best possible offering to patients. And we believe that deeper knockdown and greater durability are the two things that will make a huge difference for patients. And obviously from a business perspective, it's also valuable to us because it doesn't, you know, it freezes some of the royalties, et cetera, that we have around Ambutris. So we're obviously motivated and excited to bring this forward to patients as quickly as we can. So to your point, we will be looking for ways to speed up the development program. And, you know, while it's early to speak to exactly what the details of that are, this first phase one study is going to allow us to look at both, you know, the magnitude of knockdown, the durability of knockdown, as well as safety. And with that, you know, maybe one way to think about this is to look back at what we did with the MBUTRA program, where we went directly from phase one studies into phase three pivotal trials. And moreover, you know, when we have, you know, patient-level data across a number of studies, it allows us to pursue some very innovative development approaches. For example, with Helios A, we did not have a placebo control group. We were able to use patient-level data and do a historical control against the Apollo placebo data. And so, you can imagine that we will be moving this forward and trying to use similar approaches to speed up development both in polyneuropathy and particularly in cardiomyopathy. But we'll have more to say about that as we advance our development plans.
spk07: Thanks, Pushkar. I think we've got time for one last question.
spk13: Yes. Our final question of the day comes from Kostas Belouris from BMO Capital Markets. Your line is open.
spk04: Hello, everyone. Congrats on the progress, and thanks for taking my question. One quick question on the on-path profiling. I'm wondering whether you have already submitted data to the FDA as part of the four-month safety update, and if so, whether you can elaborate on the type of additional safety data that you have submitted. Thank you.
spk03: Sure. Thanks for the question. So, you know, the review of the On Patro SNDA for cardiomyopathy is ongoing. And we have submitted both the day 120 safety update, which really just corroborates with additional safety across, you know, adverse events, laboratory data, et cetera. with some extended follow-up beyond what we've submitted in the initial NDA. And we also, as announced today, have submitted the month 18 efficacy update across primary and secondary endpoints to the agency as well, which we also think corroborates the efficacy that we saw, the clinical importance of those data, and a favorable benefit risk profile of the product in this disease population. So we look forward to the agency's ongoing review.
spk07: That's great. Thank you for the question, and thanks to everyone for joining this call. You know, we're really happy with the strong start that was made in 2023. We've got strong commercial execution, significant pipeline and platform development, which really underscore the power of RNAi therapeutics in addressing major unmet needs for patients. And we look forward to sharing more progress with you in the coming months and as we continue to deliver on both our near and long-term goals. Thank you, everybody.
spk13: Goodbye. Thank you for your participation in today's conference. This does conclude the program.
spk11: You may now disconnect. you Thank you. music music Thank you. We'll be right back. Thank you. Bye. Thank you. Thank you. Thank you.
spk00: Thank you. music music you
spk13: Thank you for standing by and welcome to the Anilin Pharmaceuticals first quarter 2023 financial results conference call. As a reminder, today's conference call is being recorded. I would now like to turn the conference over to the company. Please go ahead.
spk23: 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, Tilda Tanguilar, Chief Commercial Officer, Occupational President, and Jeff Poulton, Chief Financial Officer. Also in the room and available for Q&A is Pushpo Garg, our Chief Medical Officer. For those of you participating via conference call, the slides can be accessed by going to the events section of the investors page of our website, investors.almylam.com slash events. During today's call, as outlined in slide two, Yvonne will offer some introductory remarks and provide general context. Nova will provide an update on our global commercial progress. Akshay will review pipeline updates and clinical progress. And Jeff will review our financials and guidance, followed by a summary of upcoming milestones before we open the call for your questions. I'd like to remind you that this call will contain remarks concerning L-911's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision of 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 periodic report on file with the SEC. In addition, any forward-looking statements represent our views only as to the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I will turn the call over to Yvonne. Yvonne?
spk07: Thanks, Christine, and thank you, everyone, for joining the call today. 2023 is off to a great start. with Ambutra launch continuing its strong growth, with Q1 delivering 48% growth in total product sales compared to the first quarter of 2022. We've also made great strides with our pipeline, including the recent exciting announcement of positive interim results from the phase one study of ALM-APP, our investigational RNAi therapeutic in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy. These results mark a significant milestone for our nylons, as we believe they establish human proof of concept for RNAi therapeutics in the CNS and potentially unlock many additional opportunities where we may be able to address significant unmet medical needs. We also have a number of exciting upcoming milestones that highlight the depth and breadth of our pipeline, which includes the presentation of 18 month results from the Apollo B Phase III study of Batisran at ESDHF later this month, and top-line results from the CARDIA-1 Phase II study of Zalbusiran in patients with hypertension expected in mid-2023. This execution is in line with our focus on the following key drivers for our NILAMS 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 medicines for patients. Second is our expansion beyond rare diseases to also address more common disease areas. And the third growth driver for the company comes from our sustainable innovation engine, comprised of new platform enhancements, opportunities with extrahepatic delivery, and our ability to find new genetically validated targets which can drive further pipeline expansion to 2025 and beyond. We believe all of this puts us on track with our Niallem piece of fifth by 25 goals, making our Niallem a top tier biotech, developing and commercializing transformative medicines for rare diseases and beyond 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.
spk08: Tolga? Thanks, Ivan, and good morning, everyone. Q1 was a strong quarter for our commercial portfolio, driven by our TTR franchise and the strength of our ongoing launch of Bambutra, as we delivered 48% total product sales growth or 52% on a constant exchange rate basis compared with the first quarter of 2022. Let me now turn to a summary of our first quarter TTR performance. Our TTR franchise achieved $204 million in global net product revenues for Ompatro and Umbutra, representing a 7% increase compared with the fourth quarter and a solid 49% growth compared with the first quarter of 2022. with the U.S. market year-over-year growth standing out at a robust 75% driven by the ongoing launch of Ambutra. At the end of the first quarter, over 3,160 patients were on commercial on-patro or Ambutra treatment worldwide, up from over 2,975 patients at the end of the fourth quarter, representing 6% quarterly patient growth. In the U.S., combined sales of Ompatra and Ambutra increased 5% versus the fourth quarter and were primarily impacted by the following. A 7% increase in demand, which was driven by the strength of ongoing Ambutra patient uptake, more than offsetting the decrease in patients on Ompatra that switched to Ompatra. Inventory dynamics decreased reported growth by approximately 3%. as our inventory in the channel continues to decrease with ongoing patients switching to Ambutra. Overall in the U.S., we continue to be very pleased with the impact we're seeing from Ambutra in expanding the opportunity for our TTR franchise as reflected by the robust 75% year-over-year quarterly growth that we achieved in Q1. representing the third consecutive quarter of achieving TTR growth in excess of 70% on a year-over-year basis in the U.S. following Amutra's launch in the third quarter of 2022. Additionally, key operating metrics continue to trend favorably, including growth in new patient start forms, the switch rate from on-patro, patient compliance rates, and the expansion of our prescriber base. In our international markets, total TTR Q1 product sales increased 9% versus the fourth quarter, driven by strong demand in Japan following the fourth quarter launch of Amutra, offset by inventory destocking in Japan. The Amutra demand growth in Japan is particularly encouraging, with the new patient growth being driven by a mix of switches from tefamidus as well as patients naive to therapy. Additionally and importantly, Onpatra continues to deliver steady growth in markets where Amutra is not yet launched, positioning these markets for the upcoming Amutra launch. Onpatra also benefited from the timing of orders in our distributor markets. Our global results continue to be challenged by foreign exchange headwinds, with total TTR year-over-year reported growth of 49%, held back 5 percentage points due to changes in FX rates. Now, moving to our ultra-rare products. and the performance of Givlari and Oxlumo, which delivered $72 million in combined product sales during the first quarter, representing a 2% increase compared with the fourth quarter and a more robust 45% growth compared with the first quarter of 2022. We ended the quarter with more than 550 patients on Givlari commercial therapy and more than 300 patients on Okslova commercial therapy, representing 6% and 7% quarterly growth compared with the year-end 2022 for Givlari and Okslova respectively. For Givlari, global growth of 2% in Q1 compared with the fourth quarter was impacted by the following. A decline in U.S. growth of 3% primarily due to reduced patient compliance associated with the seasonal impact from the annual pre-authorization required by payers during the first quarter that we expect will recover in subsequent quarters. Growth in our international markets increased 11% as demand increased in European markets and also benefited from the timing of orders in our distributor markets. For Oxnumo, global growth of 1% in Q1 compared with the fourth quarter was impacted by the following. U.S. reported growth increased 3%, driven by an increase in patient demand. Growth in international markets was flat, with a demand increase in European markets offset by the timing of orders in our distributor markets. Additionally, changes in year-over-year foreign exchange rates negatively impacted Q1, GIVLAR, and OXLUMA reported growth by 3 and 4 percentage points, respectively. In conclusion, we are pleased with the growth in revenues, particularly with the ongoing signs of strong performance associated with the Ambuter launch, which we believe represents an important therapy option for HATTR amlidiosis patients with polyneuropathy and accelerated growth. opportunity for our TTR franchise. With that, I will now turn it over to Akshay to review our recent R&D and pipeline progress. Akshay? Thanks, Tolga, and good morning, everyone.
spk06: I'd like to start today with a recap of recent news that marks a very important milestone for Al-Nidam and the broader field of RNA-amid therapeutics. which is our progress with LNAPP, an investigational RNAi therapeutic in development for the treatment of Alzheimer's disease and cerebral amyloid angiotopy. As announced last week, we reported the first-ever clinical results with an RNAi therapeutic directed to the CNS. Given the importance of the positive data and the intense interest in the study from all parties concerned, not least patients and physicians, I think it's worthwhile to further discuss the interim findings from our LNAPP program. ALN-APP targets amyloid precursor protein, or APP, which we're investigating as a potential treatment for Alzheimer's disease and cerebral amyloid angiopathy, or CAA. Human genetics has shown that certain mutations or duplications in the APP gene can cause early onset Alzheimer's disease, where amyloid plaques form in brain tissue and are associated with neurodegeneration. Other mutations in the same gene can cause CAA, where A-beta fragments distinct from those that aggregate to form Alzheimer's plot deposit within the walls of blood vessels in the brain and result in bleeds. CAA is, in fact, the second leading cause of intracerebral hemorrhage. So this one-parent protein, APP, can be harmful in two distinct pathophysiological processes. In animal studies, we've shown that targeting APP with an sRNA showed great promise with broad CNS by distribution after a single intracetal injection, as shown on the left here, with knockdown in all major CNS cell types, such as the neuron, oligodendrocyte, microglia, and astrocytes. On the right, we can see that a single 60 milligram intrathecal dose in nonhuman primates resulted in significant and sustained target knockdown with durability out to six months, at which time the experiment was terminated, but APP suppression was still ongoing. These pharmacologic findings, which were reliable, reproducible, and appeared safe, increased our excitement around the therapeutic hypothesis. Specifically, that by lowering APP protein production in the CNS via an RNAi mechanism, we could reduce the downstream fragments that aggregate and deposit in tissues, and therefore hopefully alter the disease course. To support advancement to clinical testing, we conducted short-term IND-enabling GLP toxicology studies in the rat and nonhuman primate, where two low, medium, and high doses were given a month apart. i.e., where we greatly exaggerated dose and regimen relative to that expected in the clinic. These studies demonstrated a supportive safety profile and no significant CNS histopathology and thereby enabled the ALN-APP Phase I study. The Phase I trial is designed as a two-part study, a single ascending dose, Part A, followed by a multiple dose, Part B. Part A was enabled by the GLP toxicology studies I've just mentioned. Phase one is being conducted in patients with early onset Alzheimer's disease. The primary endpoint of this study is safety and tolerability of LNAPP. Secondary objectives are focused on characterizing the pharmacology of LNAPP. The study also includes a variety of exploratory biomarkers, which will allow us to assess whether LNAPP is showing any impact on other biomarkers of disease progression. Interim data shared are from the initial single ascending dose cohorts, and we continue enrolling in Part A as we explore further doses. Excuse me. At the time of this interim look, 20 patients with early onset Alzheimer's disease have been enrolled in three single-dose cohorts in Part A of the ongoing Phase I study. To date, L and APP has been well tolerated with no study dropouts and all adverse events being mild or moderate in severity. Available CSF data from white blood cells and protein appeared similar to . Neurofilament light chain, or NSL, which is a mark of neuronal damage and which may be elevated in drug-induced neurotoxicity, was also monitored. Reassuringly, early data for NSL, which are currently available from two out of the three cohorts to date, also looked comparable for fever. Now let's look at the pharmacodynamic results after single intratequel doses. To date, we've studied three dose levels, 25, 50, and 75 milligrams. All available data to the three-month time point are shown. Excitingly, we observed that unlike placebo, LNAPP treatment resulted in rapid dose-dependent and sustained reductions of both SAPP-alpha and soluble APP-beta, both biomarkers of target engagement in the CSS. We saw rapid knockdown as early as day 15 and the maximum knockdown of up to 84, 90% respectively for APP alpha and APP beta. At the highest dose tested, 75 milligrams, the median knockdown was greater than 70% for both biomarkers and sustained for at least three months. Initially, per protocol, we intended to dose escalate from 75 to 225 milligrams. However, given that the knockdown observed at 75 milligrams substantially exceeded our initial target of 50% biomarker knockdown, we chose to deescalate to 50 milligrams. As you can see, at 50 milligrams, while we have a more limited data set, it appears equally promising and similar to the 75 milligram dose with substantial knockdown for both APP alpha and beta. Now notably, the durability we see in humans reflects what we saw in non-human primate studies, where single doses gave similar profound durable knockdown extending to six months or beyond. Accordingly, we anticipate that the responses we see here in part A will continue. Indeed, for the data available beyond three months in this human study, we see continued target suppression. This durability of effect is important for LNAPP as well as our overall CNS effort as it suggests the potential for infrequent dosing. We look forward to seeing with longer follow-up indeed how long this knock-down effect is sustained. We believe these data suggest that the drug will be able to be dosed quarterly at most and based on animal data and the translation of our platform in humans, we believe there's the potential to even dose every six months or less frequently. Enrollment in the single ascending dose portion of the Phase I study is ongoing in Canada, the Netherlands, the UK, and the United States. Additional enrollment in Part A will allow us to continue to explore single-dose PK and PD and characterize the durability and effect and long-term safety. Results from Part A will also inform the doses and regimens to be put forward into Part B, the multiple dose portion of the study, which will include patients from Part A. In parallel to Part A of the Phase I study, we conducted chronic GLP toxicology studies in animals to support the multi-dose Part B for Phase I. These chronic GLP tox studies were conducted without knowledge of the impressive knockdown in durability we see today at low doses of ALN and APT we see in this Phase I study. So, for standard practice, we exaggerated dosing and dosing frequency relative to any dose and regimen that would ultimately be used in clinical testing. Specifically, we administered low, medium, and high intracepal doses monthly for six months in the RAD and every other month for nine months in the non-human primates. The data from the chronic studies have been shared with regulatory authorities. We have already received regulatory approval to begin Part D in Canada, where in fact the majority of the Part A patients have been enrolled to date, and approval is pending in the UK and Netherlands. In the US, the FDA has currently placed partial clinical hold on the multi-dose Part B of the Phase I study due to findings observed in chronic toxicology studies. Of course, given the high exposures that we achieved with frequent administration of high doses, it's not unexpected that we would observe findings in these chronic toxicology studies. However, it's important to contextualize exposures by relative CSF volumes between toxicology species and humans. For example, Relative to a potential clinical dose and regimen of 75 milligrams given every six months, there's a more than tenfold greater annualized exposure at all doses tested in the rat and non-human primate. And at the top doses evaluated in those chronic tox studies, there's a 75 and 50-fold greater annualized exposure in rat and non-human primates, respectively, relative to the same potential human dose. And if we scale based on organ weight, then these annualized exposures would be even greater in the chronic tox studies. I want to nevertheless acknowledge that the FDA will be the ultimate arbiter of the data, and we look forward to getting further guidance from them. Accordingly, we plan to engage with them to discuss all preclinical information, as well as these new interim phase 1 clinical data, which provide the important context to support potential initiation of Part B in the U.S. To close this part of the discussion, I'm absolutely thrilled about these incredible human data that provide the first-ever evidence that we may be able to use RNAi to silence disease-causing transcripts in the CNS. In animal studies, we've already demonstrated the reproducible and modular nature of our CNS platform with the knockdown against a diverse range of targets and hope that we can address disease-causing genes not just for Alzheimer's, CAA, ALS, and Huntington's, but also many other disorders. We look forward to presenting these interim dates from Part A of the Phase I ALN-HC study at an upcoming medical congress. With that, let me turn to our efforts in ATTR amyloidosis, where we're advancing three clinical stage product candidates, namely Patisran, Bifisran, and ALN-PTRS-C04. As you know, Onpatra is currently approved in multiple markets around the world to treat hereditary AT2 amyloidosis with polyneuropathy, and we're committed to expanding the product's label for the treatment of cardiomyopathy in both the hereditary and wild-type AT2 amyloidosis patients. Announced in February, we're delighted that our supplemental new drug application for T-strand cardiomyopathy of AT2 amyloidosis has been accepted by the FDA with a standard review and a PDUFA date of October 8th. In their file acceptance letter, the FDA stated that they've not identified any review issues. The agency also noted that they're planning to hold an advisory committee meeting to discuss the application. Currently, we have no further details from the FDA regarding the timing of the outcome or the specific topics they wish to discuss. When we learn more, we will communicate that information in due course. If the FNDA is approved, this will allow us to extend the potential benefits of paticeram to many patients with wild-type and hereditary AT-tramyloidosis with cardiomyopathy. This filing is based on the pivotal Apollo B study, which demonstrated improved functional status and quality of life in patients with AT-tramyloidosis with cardiomyopathy given paticeram for 12 months relative to placebo. The clinical profile of paticorin is supported by an encouraging safety profile and exploratory data that favored paticorin treatment relative to placebo on various biomarkers of disease progression at month 12. We've announced this morning that 18-month data from the Apollo B study have been submitted to the FDA as part of the SNDA review, and we'll be presenting these results at the ESC Heart Failure Meet at the end of May. Now, similar to Onpatro, we're also committed to expanding the label for Ambutra to include the treatment of cardiomyopathy in both rotatory and wild-type atrial amyloidosis. This is being done with the ILEOS-B phase three study of investigational . ILEOS-B, which is fully enrolled, has an endpoint of all-cause mortality and CV events assessed after at least 30 and up to 36 months, and we remain on track to share top-line results in early 2024. Wrapping up with TTR-L and TTR-SCO4 is an investigational RNA therapeutic based on our iCarrier platform and offers the potential for more durable and potent TTR silencing with the possibility for annual dosing, a potentially transformative profile. TTR-SCO4 has entered the clinic and begun dosing in the phase one study, and we expect top line results in late 2023. In addition to our late stage clinical programs, we believe we've also been making great progress with our early and mid-stage programs. A notable highlight includes our investigational RAI therapeutic for hypertension, which we believe could transform the treatment of the disease and offer a highly differentiated profile from all existing antihypertensives, including oral RAS inhibitors. We look forward to the important upcoming milestones from the Phase II program and remain on track to deliver top-line results from CARDIA-1 in mid-2023 and top-line results from CARDIA-2 at or around year-end 23. These are just a few of the highlights from our broad and innovative pipeline, driven by our underlying organic product engine, and where we expect to deliver sustainable innovation, representing a key growth driver for Allen Island in the years to come. To wrap up these highlights, we're excited to have initiated dosing in the Phase 1 study of ALN-KHK for the potential treatment of type 2 diabetes, plus Regeneron has announced the initiation of a Phase 2 study of LNHSD in patients with NASH. Now, with that, let me now turn it over to Jeff to review our financials and upcoming milestones.
spk25: Jeff? Thanks, Akshay, and good morning, everyone. I'm pleased to be presenting the summary of Alnylam's Q1 2023 financial results and discussing our full-year guidance. starting with a summary of our P&L results for the first quarter. Total product revenues for the quarter were $276 million, a 48% growth versus Q1 2022. As Tolga previously indicated, the increase is primarily related to growth in TTR product revenues driven by the launch of Ambutra in the U.S. in the third quarter of 2022, as well as increased patients on Givari and Oxlumo therapies. Also worth noting that year-over-year growth and combined product revenues was held back by approximately four percentage points due to impact of changes in foreign exchange rates. That revenue from collaborations for the first quarter was approximately $36 million, representing a 41% increase compared with Q1 2022. primarily due to an increase in revenue from our collaboration arrangements with Regeneron, attributed to an increase in reimbursable activities under our research services arrangement, in addition to an increase in revenue recognized associated with licensed programs within the collaboration. Royalty revenue during the quarter was $7 million, which was driven by Novartis' sales of Lectio, which launched in the U.S. in the first quarter of 2022. Gross margin on product sales was 85% in Q1, representing a 2% decrease compared with the first quarter of 2022. The decrease was primarily driven by increased royalties due to Sanofi on sales of Ambutra, which was partially offset by lower manufacturing costs for Ambutra compared with Unpatro. Our non-GAAP R&D expenses increased 35% in the first quarter compared to the same period in 2022, primarily due to increases in headcount to support our R&D pipeline, development expenses associated with the Apollo B, Helios B, and Cardio 1, Cardio 2 clinical studies, and manufacturing-related expenses with our preclinical activities. Q1 2022 non-GAAP R&D OpEx was disproportionately lower than all other quarters during 2022. Thus, we expect lower year-over-year quarterly growth rates for R&D in the remaining quarters of 2023. Our non-GAAP SG&A expenses increased 17% in the first quarter compared to the same period in 2022, primarily due to increased headcount and other investments supporting our strategic growth, including the global launch of Invitra. Our non-GAAP operating loss for Q1 2023 was $110 million, representing a $7 million improvement compared with Q1 2022, driven by strong top-line growth, offset by more moderate growth in operating expenses. Finally, we ended the quarter with cash, cash equivalents, and marketable securities of $2.1 billion, compared to $2.2 billion at the end of 2022, with a decrease primarily due to our operating loss in the quarter. 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 2023 financial guidance. We are reiterating the financial guidance we provided on our year-end results call in February. Starting with net product revenues, we continue to anticipate combined net product revenues for our four commercialized products will be between $1.2 and $1.285 billion. Our guidance for net revenue from collaborations and royalties remains a range between 100 and 175 million. And our guidance for combined non-GAAP R&D and SG&A expenses remains unchanged and is a range between 1.575 and 1.65 billion. Let me now turn from financials and discuss some key goals and upcoming milestones slated for early and mid-2023. We will, of course, be executing on global commercialization of our products on PATRO and VUTRA, GIVLARI, and XLUMO. From our TTR programs, we have a couple of upcoming data presentations. 18-month results from Apollo B will be presented at the ESC heart failure meeting later this month, and the Heliose randomized treatment extension results looking at a biannual dose regimen for GUTRISERAN will be presented at ASNP also at the end of May. We expect to report top-line results from the CARDIA-1 Phase 2 study of Zalvisiran and also intend to complete enrollment in the CARDIA-2 Phase 2 study. With our partner programs, VEER expects additional results from Phase 2 combination trials of ALN-HVV02. Let me now turn it back to Christine to coordinate our Q&A session. Christine?
spk23: Thank you, Jeff. Operator, we will now open the call for questions. To those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have additional questions.
spk13: Thank you. At this time, we will conduct the question and answer session. To ask a question, you will need to press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster. And our first question comes from Richie Burrell from TD Collin. Your line is open.
spk10: Good morning, guys. Thanks for taking the question. I know I'm a lonely loud one, so I'm going to try and stick to it as much as I can. data that's coming up from Apollo B. Can you talk a little bit more about what will be presented? Maybe how many patients are in continued follow-up at 18 months? Will we have key secondary endpoints like the Kansas City and additional safety follow-up as well? Thank you.
spk07: Yeah, so, you know, as a reminder to everybody on the call, Apollo B was a double-blind randomized study for 12 months. And after this point, patients who were on placebo were given the option to switch to batista and for a continuation of dosing. These data corroborate really what we saw in the 12-month portion of the study. And as we noticed on the call, we submitted these data to the FDA, and we'll be presenting these data at the HCF in Prague in May. Pushkal, do you want to add any other comments about the data and engagement with the agency?
spk03: Yeah, absolutely. Thanks, Yvonne. Thanks, Ritu, for the question. You know, as Yvonne said, we're really excited about these data. You know, you asked Ritu about ongoing follow-up, right? All patients were randomized out to 12 months and then all patients were offered the opportunity to be on active drug from 12 months and beyond. And this is a cut of data out to 18 months And we've had very high retention on the study, which is important and corroborates the profile. And I think it's going to be an opportunity to look at sort of the continued profile of what we've seen on patients on active drug, which was, you know, we saw evidence of stabilization across key endpoints, particularly the six-minute walk test. sort of what was associated with, you know, around the age-related decline that's seen in that parameter, as well as stabilization in the key secondary endpoint of the Kansas City cardiomyopathy questionnaire. So, that's important. It's an opportunity to look at the placebo patients as they cross over to active drug and look at ongoing safety. Net-net, as Akshay and Yvonne commented, Richie, we really feel quite confident and good about the data that we've seen, and that it corroborates the profile of paticerin and its potential role in this disease.
spk07: Yeah, and as a reminder, we've submitted 120-day safety updates as is routine in the submission process.
spk11: Thank you. Next question, please. Thank you very much.
spk13: Our next question comes from Tevina Med from V of A. Your line is open.
spk15: Hi, Ed. Good morning. Thanks for taking my question. Maybe just one on embouture sales.
spk14: It looks like you're off to a good start on the ramp. Just wondering what your internal data is saying about any kind of market share being taken from empatro. and whether or not if that is the trend, you would expect that to be the case going forward as well. Thanks.
spk07: Okay. I think that's one that goes to you.
spk08: Thank you, Yvonne. Hi, Tizine. Look, first of all, we're incredibly excited at the fact that we have been able to build a category and essentially, you know, grow our business quarter over quarter by over 70%, three subsequent quarters in the U.S., And what we see in terms of the dynamic with Onpatro is a very healthy switch rate while we're adding that naive patients in a very robust manner. So what our internal data really suggests is that there is lesser and lesser patients that are staying on Onpatro as we expect those patients numbers to remain in small double digits or single digits over time.
spk07: Yeah, to really just, I think, kind of emphasize how pleased we are with the launch metrics for Amvutra in terms of, you know, the balance of new patients as well as switches and really the expansion of the prescriber brace, which is, you know, very encouraging for continued growth in the trajectory of our TTR franchise. So thanks for that question, Suzanne. Next question, please.
spk11: Thank you. Thank you.
spk13: Our next question comes from Ellie Merle from UBS. Your line is open.
spk18: Hi. Thanks so much for taking our question. This is Sarah on for Ellie. On your CAA program, I guess, can you talk about some of the timelines there and maybe the prioritization of that versus Alzheimer's and how we should think about the size of the CAA market opportunity? Thanks for that question.
spk07: I guess that question has been stimulated actually by the incredible results that we've shown, the quite remarkable results that we've shown in our phase one interim study. And clearly, that's the first step in, you know, the journey of bringing RNAi therapeutics to patients with CNS diseases in general. We're clearly starting off with early onset Alzheimer's disease. But Tushkal, I think cerebral amyloid angiopathy is, again, another very, you know, important opportunity potentially for ALN-APP. given the genetics, but could you say a few words about how we're thinking about the opportunity in CAA?
spk03: Absolutely. Thanks, Yvonne. Thanks, Sarah. Look, as has been highlighted by both Akshay and Yvonne, CAA is really a devastating disease. It's the second leading cause of interest cerebral hemorrhage, only behind hypertension. And there's really no available therapies for these patients. And so, it's something where the genetics and the biology really strongly suggest that APP lowering may be a benefit to these patients. In some ways, you can think about it as very comparable to the hypothesis we've been pursuing with our TTR program. Reducing amyloid can reduce downstream tissue damage in nerves and heart, in this case, in the parenchyma of the brain in Alzheimer's disease, and the vasculature of the brain in CAA. So these initial data that we've shared today really give us promise that we can advance ALN-APP towards both of these diseases. frankly, in parallel. We've not announced specifically what the timelines for that are. We're obviously working through and continuing the Part A of the study to do further dose exploration and really establish, you know, what we're seeing in terms of the magnitude of knockdown, but also the durability so that we can identify multi-dose regimens, et cetera, characterize safety, and then we'll want to be pursuing phase two studies in both of these indications in due course, and we'll update.
spk11: Actually, anything to add? No. Oh, good. Good answer for school. Next question, please. Thank you for your question.
spk13: Our next question comes from Salveen Richter with Goldman Sachs. Your line is open.
spk17: Thank you for taking our question. This is Tommy on for Salveen, and congrats on the progress. So for Zalbiceran, can you frame what you're hoping to see in this upcoming phase two monotherapy and combo data, the path to registration here, given supportive data, and any updates on the RiverSeer platform? Thank you.
spk07: Yeah, I think your question was referring to Zalbiceran. Is that correct? Just wanted to make sure. Yeah.
spk16: Yeah, Zalbiceran.
spk07: As you know, we're very excited about the opportunity for Zalbiceran in hypertension. It's a you know, a condition that impacts, you know, 100 million or more people. And, you know, only 70% are able to, you know, achieve the goal in blood pressure reduction. So we think it's a really important area that we believe our platform has a real opportunity to completely transform how these patients are treated and hopefully lead to better outcomes with respect to morbidity and And we've got two phase two studies ongoing, Cardio 1 and Cardio 2. Clearly, we need to wait for those results before we speak more specifically about, you know, plans beyond that. But Prishkal, do you want to talk a little bit maybe around, you know, the current status of our studies and, you know, how we're thinking about future development?
spk03: Sure. Yeah. So, you know, look, salbicerin has the potential to be an incredibly transformative medicine. for high blood pressure. What we saw in the phase one study that we've already reported was opportunity to realize almost 20 millimeters of systolic blood pressure lowering with 24 hour ABPM lasting and durability lasting up to six months with a single injection. We think, as Yvonne highlighted, that that can actually address a multitude of the issues that lead to hypertension being the number one addressable cause of cardiovascular morbidity and mortality around the world. We've got two studies The CARDIA-1 study is a monotherapy study. I think that was the first study you asked about. And that study completed enrollment at the end of last year. And so we're looking forward to data in the middle of this year. And that's really going to allow us to establish the dose and the regimen for ongoing pivotal studies. So we're looking at a range of doses from 150 to 600 milligrams and Q3 and Q6 month dosing. And so coming out of that study, we'll hopefully be able to establish what that pivotal dose and regimen is. The second study that we're doing is CARDIA-2. As you're probably familiar, in hypertension, combination therapy is sort of the standard of care. And so what we're doing in CARDIA-2 is looking at combining Zalvisaran with three common classes of medicines, diuretics, calcium channel blockers, and angiotensin receptor blockers. And what we'll want to be seeing there is the additive efficacy and safety, and that will help us design ongoing studies for our registrational program. I'm really excited that their enrollment has really been picking up in that study, and we are on track to complete enrollment, you know, early this year and report out data towards the at or around year end. So, with those data together, we think we'll be able to provide more guidance on what the pivotal registration program will look like.
spk07: Yeah, perhaps important to add that actually from a regulator's perspective, to achieve an approval in a medicine for hypertension, to demonstrate a five millimeter of mercury lowering of systolic blood pressure. And of course, we've actually already demonstrated more than that in our phase one studies as is highlighted. So as we deliver the phase two days and hopefully move to larger numbers in the phase three and deliver, you know, similar efficacy and also robust safety, we feel that it's a fairly straightforward path to an approval here.
spk11: Thank you for the question. Thank you.
spk13: Our next question comes from Paul Matisse from Stifle. Your line is open.
spk21: Hey, thanks so much for taking the question. Congrats on the quarter and the recent CNS data. I wanted to ask just a commercial question. It looks like you saw this really nice jump in the sequential net patient ad rate when M. Butcher became available. It looks like that's kind of stepped back down to more of the normal rate we were observing throughout 2022. Is that kind of how you're thinking about the likely cadence going forward, that maybe there was this bolus of patients that were interested in a much more convenient product and now the growth rate from here is probably steadier?
spk08: Okay. Yeah. Thank you, Paul. I mean, look, first of all, I just want to reiterate the fact that we're incredibly pleased with how Amutra performance is taking shape in the U.S. and now in Japan and other European markets. What's really important to highlight is The product profile is very compelling that this category growth not only addressed the pent-up demand that we were anticipating, but it's also continuing to actually help us expand this franchise, mostly noted by the fact that we're seeing an expanding prescriber base. Our start form rates are continuing to go up. And what we see is also our ability to get naive patients, not just on petrol switches, are continuing to be at the stated rate. The result that you see in Q1, Paul, is mostly a bit diluted because given the insurance renewals, that we see in this Q1 tends to impact the net sales impact in the U.S. We're actually very encouraged with some of those internal metrics that I just shared with you, making us, you know, quite confident that in subsequent quarters we see the uptake continue to be at the similar rates that we see in the prior quarters.
spk07: Thank you so much, Tolga. Next question, please.
spk11: Thank you for your question.
spk13: Our next question, excuse me, comes from Jessica Five from J.P. Morgan. Jessica, your line is open.
spk19: Good morning. Thank you for taking our questions. This is JL for Jess. So we have a question on reimbursement around embouchure. So from a cost-benefit perspective for payers and recognizing, right, the Helios B data has yet to come out. How would you compare embouchure to defamitis for cardiomyopathy? And also curious, how are you thinking about this on petrol where you already have your positive pivotal data? And then moving to Medicare patients specifically, can you remind us what the out-of-pocket cost is like for embouchure per year for the Medicare patients? And how does it compare to the out-of-pocket cost for tefamidus, again, for the Medicare patients? And with the upcoming IRA changes to Medicare, how do you see this change potentially? How do you see the difference can change potentially? Thank you.
spk07: There's a lot of questions here. We'll try and remember them and pass them out. I mean, talk about maybe start with the last question first and talk a little bit about how we're being out of occupation costs, right? The sort of Medicare...
spk08: Contacts. So let's also kind of let the straight in the record. So we have about 70% of our patients on Medicare and Medicaid, and those are patients that are on Part B. And right now, if you look at our current cost burden on those patients, about 70% of our patients pay zero co-pay. in the Part B program, and it's consistent with both Onpatro as well as Avutra. As you all know, we have very innovative value-based agreements that actually really unburden the patients to be able to have access. And what we really see, that's probably the most important marker, is if you look at, are these patients that are put on therapy with a start form, do they actually end up getting the therapy, and are they staying on therapy? And what's really encouraging is both, and we can say that now with Amutra, three quarters in the market, we see very similar, exceptionally high compliance rates, which also suggests that those patients that may have some copay burden are continue to be able to access thanks to our value-based agreements and other ways that we support those patients along with the other questions i think i've actually answered two out of the three questions and the third question is how we're thinking about
spk07: you know, pricing in cardiomyopathy, particularly with respect to families. I mean, given that, you know, we're still, you know, awaiting a label for Onpatro and we're awaiting HDSP results for the two-span, I think it's probably too early to speak to that detail. So, thank you for your questions, and let's go on to the next question.
spk11: Thank you.
spk13: Our next question comes from Gina Wang with Barclays. Your line is open.
spk24: Thank you. Thank you for sharing your APP data. Indeed, a very impressive knockdown profile. I have one question on the data, but with three parts that hopefully can cover all three questions. So when we look at the nature biotechnology paper, 60 milligram from nonhuman primates data was only showing similar knockdown when we look at compared to the 75 milligram in human so we'll let to almost nearly tenfold better translation to human and my second question is that you show the median percentage knockdown so what is the mean and the standard deviation look like if we only focusing on 75 milligram profile and then lastly do you need to run another non-human primates study in order to satisfy you know, FDA to remove the partial clinical hole.
spk07: Okay, so three questions there, and I think, I'd say, you know, I think they're kind of all for you. I think one was about the translation from the preclinical setting to clinical setting. Second was with respect to the percentage knockdown that we're seeing, and the third you know, our plans to address the clinical hold. I think the poll actually answers the questions on the clinical hold. I think it's really important to emphasize that Part A is ongoing, you know, in a number of countries, including the U.S. And in fact, we have approval to progress with, you know, Part B from Health Canada. In fact, it's actually said in its remarks, most of the patients actually in Part A come from Canada. So it's really important to note that we're able to progress with Part B, but clearly still a lot to learn from Part A in terms of, you know, PK, PD, durability, et cetera, before we define our plans for the next phase of the study. Actually, we maybe want to talk a little bit more about how we're thinking about addressing the clinical halls with the FDA and then the other two questions that relate to the data.
spk06: Yeah, thanks, Yvonne. Thanks, Gina. Let me just go in order. So I think your first question, Gina, if I got it right, was 60 milligrams in the monkey and expectations in man in terms of translation. I think, you know, even without doing a lot of calculations, if you think about the size of the monkey brain and the CSF volume and you have to administer 60 milligrams, to get something like the knockdown curves we're seeing at 50 milligrams here in humans and 75 milligrams. It just shows the gain in potency, and we believe we'll also see in durability in humans relative to non-clinical species. Now, you've watched this for a long time, and if you harken back to the liver data, that's exactly what we see in the liver setting. So these human phase one data are really rather exciting, and I think spell a product profile where We hope that low doses relative to the animal, we see, you know, very important clinical significant knockdown for highly durable intervals that would allow, you know, frequent dosing, hopefully every six months, maybe even annually. So that was question one. Your second question was, we showed the medians. What about the mean and standard deviations at 75? Again, we haven't shown the patient-by-patient data. We'll, of course, share more data in an upcoming meeting. But I can reassure you that as you go from low to high dose, the kind of variability you see patient to patient at high dose, you now see, you know, track after track for each patient who's following the same curve. So the data will be very tight in terms of means and standard deviation. In fact, we've looked at them, you know, at the 50 and 75, but we haven't shown them today. So, again, that conforms exactly to what we see with RNAi in other tissues, where at low doses, sub-pharmacologic doses, you see some variability between individuals, just as you see in placebo. But once you're at the operative pharmacologic doses, you get very tight knockdown and little intra-individual variability. Again, these are all small numbers, but very encouraging data. And finally, do we need a non-human primate study to get off hold? I mean, I think I shared today our impressions of the clinical data, the situation with the chronic tox studies, the exaggerations and exposures we had. We want to discuss all this with the FDA and get their guidance. Obviously, they have a very important voice in this, and we want to benefit from their input. So let's go and do that, and from that, we'll learn whether we need to do more studies or not. But if we can administer at low doses and get up to a year of lockdown, who knows? We'll see. But certainly very exciting times.
spk07: Thanks, Gina. Thanks for your question. Next question, please. Thank you.
spk13: Our next question comes from David Leibowitz with Citi. Your line is open.
spk09: Hi, this is Devanjana on for David. So, we wanted to ask, like, that the ATR space appears likely to have an additional TTR silencer entry. How does the competition shake out between your offerings and eventual competitors? And maybe one more if you have time, but assuming unpatriotic approval for ATTR-CM is going to be based on functional endpoint, how do you see the therapy getting utilized after that approval? Thanks.
spk07: Yeah. Actually, it would be really helpful if you could repeat your question and maybe just kind of hold yourself to kind of one question. So maybe you can just repeat the one key question you'd like us to address.
spk09: Sure. Okay. So my first question was that the ADTR space appears to likely have an additional TTR silencer entry. How does the competition shake out between your offerings and eventual competitors? Thank you.
spk07: Okay. So let's start off with Tolga, and then Pushkar will also add some remarks. Tolga?
spk08: Yeah. So as you know, Avutra has really been a game changer. and it's been transforming the market and building the category growth. And frankly, the potential availability of more treatment options is really good for patients. This is a highly devastating disease. Patients are still either undiagnosed or undertreated. So similar to other competitive markets, it will increase disease awareness, support earlier diagnosis, enable earlier treatment initiations, which in turn supports a significant category growth that we already see as we expect to see. Now, in terms of the product profiles, obviously what we see is, and I'll have Pushkar comment a little bit on our clinical profile, but what we're really pleased to see is, first of all, the rapid onset is very important for patient outcomes. Disease reversal is important. And we're obviously very confident of our product profile, only four times a year administration. And also, given the fact that strong uptake is a clear signal of what this profile is, and our customer-facing profiles, and how we're competing in the market. So with that, maybe I'll turn it over to Pushpal to comment on the product profile on the clinical level.
spk03: Yeah, I mean, I think, Tolga, I think you hit actually most of the key points. I mean, I think, you know, I think it's important to state that there's really no head-to-head studies between Plinterson and We've just seen some, you know, early data here, and we look forward to learning more about it. But there's no head-to-head data between Eplinterst and Guitricerin. I think, you know, I think as we've been in the marketplace, as we've talked to clinicians, as we've talked to patients, what we've learned about, you know, what's important to them, obviously they're looking for strong efficacy and a good safety profile. And as you dive deeper into that, you know, speed of onset of action is quite important. We've been very pleased by the rapidity of knockdown, TTR knockdown, that we see with our agents. And that seems to translate actually to patients feeling better. We've noticed that with the MVMI data and nutritional status, and we get reports of patients anecdotally feeling a lot better very early on therapy. And likewise, ultimately, people want to regain function as much as possible. They want to be able to live their lives basically as free of this disease as humanly possible. And what's, you know, this concept of disease reversal that Tolga mentioned becomes very important. And we've been encouraged when you look across key parameters like the MNIST, when you look at the Norfolk quality of life, et cetera, in the PN space, that we have 50% or upwards of patients who are sort of reaching that reversal threshold. And so, again, we're really excited about the profile that we have with Ambutra, how it's been received, and the feedback that we've been hearing. And so I think, you know, we're very encouraged. And again, it's great that there'll be another agent out there, as Koga said, but we're very confident about the profile of Ambutra and what it offers.
spk07: Yeah, that's great. And I think having sort of five years of experience marketing TTR medicines, I think, gives us, you know, the opportunity to really understand this market and, you know, extract insights that are helpful in terms of educating patients and physicians. So, thank you for that question. Next question, please.
spk13: Thank you. Our next question is from Mike Ulz from Morgan Stanley. Your line is open.
spk22: Good morning, and thanks for taking the question. For ALN TTR SC04, assuming you get some supportive data later this year, can you talk about the potential path forward there and if there's opportunity to maybe shorten that timeframe? And would you be looking to move forward in both polyneuropathy and cardiomyopathy? Thanks.
spk07: No, thanks for that question. We're really excited about progressing ALN and TTR SC04 for a number of reasons. You know, importantly, the potential for, you know, increased knockdown rates of 90% and frequency, perhaps annual dosing. So we think this is a real step forward for our platform in general. And, you know, Pritkal, maybe you can talk a little bit about, you know, how we're thinking about developing this program going forward.
spk03: Yeah, absolutely. Yeah, you know, SCO4, I think, really represents sort of the next generation of innovation in the TTR space where we want to bring the best possible offering to patients. And we believe that deeper knockdown and greater durability are the two things that will make a huge difference for patients. And obviously, from a business perspective, it's also valuable to us because it doesn't, you know, it freezes some of the royalties, et cetera, that we have around Ambutris. So we're obviously motivated and excited to bring this forward to patients as quickly as we can. So to your point, we will be looking for ways to speed up the development program. And, you know, while it's early to speak to exactly what the details of that are, this first phase one study is going to allow us to look at both, you know, the magnitude of knockdown, the durability of knockdown, as well as safety. And with that, you know, maybe one way to think about this is to look back at what we did with the MBUTRA program, where we went directly from phase one studies into phase three pivotal trials. And moreover, you know, when we have, you know, patient-level data across a number of studies, it allows us to pursue some very innovative development approaches. For example, with Helios A, we did not have a placebo control group. We were able to use patient-level data and do a historical control against the Apollo placebo data. And so you can imagine that we will be moving this forward and trying to use similar approaches to speed up development, both in polyneuropathy and particularly in cardiomyopathy. But we'll have more to say about that as we advance our development plans.
spk07: Thanks, Pushkar. I think we've got time for one last question.
spk13: Yes. Our final question of the day comes from Costas Ballouris from BMO Capital Markets. Your line is open.
spk04: Hello, everyone. Congrats on the progress and thanks for taking my question. One quick question on the path of filing. I'm wondering whether you have already submitted data to the FDA as part of the four-month safety update, and if so, whether you can elaborate on the type of additional safety data that you have submitted. Thank you.
spk03: Sure. Thanks for the question. So, you know, the review of the On Patro SNDA for cardiomyopathy is ongoing. And we have submitted both the day 120 safety update, which really just corroborates with additional safety across, you know, adverse events, laboratory data, et cetera. with some extended follow-up beyond what we've submitted in the initial NDA. And we also, as announced today, have submitted the month 18 efficacy update across primary and secondary endpoints to the agency as well, which we also think corroborates the efficacy that we saw, the clinical importance of those data, and a favorable benefit risk profile of the product in this disease population. So, we look forward to the agency's ongoing review.
spk07: That's great. Thank you for the question, and thanks to everyone for joining this call. We're really happy with the strong start that we've made in 2023. We've got strong commercial execution, significant pipeline and platform development, which really underscore the power of RNAi therapeutics in addressing major unmet needs for patients. And we look forward to sharing more progress with you in the coming months and as we continue to deliver on both our near and long-term goals. Thank you everybody.
spk13: Goodbye. Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.
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