Alnylam Pharmaceuticals, Inc. (ALNY) Earnings Call Transcript & Summary

Hi, everyone. My name is Maurice Raycroft and I'm one of the biotech analysts at Jefferies. I would like to introduce Yvonne Greenstreet, the CEO of Alnylam. Great to see you, Yvonne, and thanks so much for joining us today.

Thanks, Maurice. And a pleasure to be here and to be in person again across the live audience. It's a lot more fun doing it with you today. So I'm just going to make a few introductory remarks if that's the case but I just want to remind people that Alnylam is the leading RNAi company. We're incredibly proud of our progress. We now have 4 marketed medicines, 3 that we are commercializing ourselves ONPATTRO, GIVLAARI and OXLUMO and Leqvio which has been commercialized by Novartis. We have a very rich clinical pipeline, which continues to deliver exciting progress. And you may have seen today that we are sharing the results from a Phase II study with Cemdisiran in patients with IgA nephropathy. Just to remind you, there are about 350,000 to 450,000 patients with IgA nephropathy. It's one of the commonest inflammatory glomerular diseases, and we're delighted to be able to demonstrate a clinically significant reduction in urine protein to creatinine ratio, 37%, which we're delighted by and so we're looking forward to moving this program forward. And I think, again, another example, the productivity of our clinical pipeline. We're also being able to progress programs in not just rare diseases but prevalent diseases like that's an important growth opportunity for the company as well as not just liver targeted diseases, but now CNS diseases as well. So we're excited about that. And all this is based on the foundation of what is an incredibly innovative and sustainable innovation engine where we're hoping to see planning for 2 to 4 INDs a year. So incredibly proud of what we've achieved as we look out in the near term committing the planning for an approval of vutrisiran subcutaneous -- [indiscernible] subcutaneous formulation for patients with hereditary ATTR amyloidosis with polyneuropathy. PDUFA date is July 14. So we're eagerly anticipating that. All eyes are on the APOLLO-B study with ONPATTRO to expand the label to patients with cardiomyopathy. I think there's been a lot of controversy about this particular study. We have said probably all we're going to say as a company on the topic, we've been very forthcoming with all of our perspectives. And just to add that given the intense focus on the study, we will be entering into a quiet period, sometime beginning this July, that's APOLLO-B. And then as we look out, for the rest of the year, continued catalyst will be continuing to develop vutrisiran into a 6-monthly regimen, which we're very excited about. And then I think importantly, at the end of the year expecting to see clinical data from our ALN-APP program for patients with early onset Alzheimer's disease. I think it's an incredibly important proof point for the company in terms of our ability to address the needs of patients with CNS diseases. And many of you may have read recent publication in Nature where we shared some data on our C16 ligand, which has demonstrated the potential to affect broad distribution in the brain as well as multiple cell types of the brain. So we're eagerly waiting for those data at or around the year end. So I'll stop there, and I'll turn it over to you for some questions.

Yes. I think that was a great intro. And you mentioned the APOLLO-B study, which I've got a couple of questions on that, you're not in the quiet period yet. So maybe starting off, I guess, what's your confidence in the trial meeting the 6-minute walk test at 12 months? And maybe remind us what gives you confidence in that.

Yes. So just as a reminder, the APOLLO-B study with ONPATTRO is addressing the 6-minute walk test at 12 months as the primary endpoint. We also have a number of secondary endpoints, not including outcome measures. Now the study is not powered to demonstrate the difference in those outcome measures. But we are actually kind of very excited about turning the card on the study because we feel very confident in the way that we designed the study and the way that we have executed the study, driven by I think a really impressive track record of the last 10 years of successfully delivering studies in the TTR space. In terms of how we thought about the diagnostic enrollment criteria for the study, patients either had to have a positive biopsy or Grade 2 to 3 Perugini score on Technetium scanning. We've over-enrolled the study. We plan to do a number of patients. We ended up with 360 [indiscernible]. It's a one-one randomization. Importantly, I think this plays on the experience that we have delivering TTR studies. We have focused really quite robustly on the oversights of the study, particularly with respect to the 6-minute walk test, which needs to be conducted very carefully in terms of the consistency of the measure across sites and across time. We feel very good about that. We've enrolled a broad patient population, including patients with hereditary form of the disease. We managed the number of patients that also received tafamidis. We're having a tafamidis cap of 30% in the study. And I think probably the most important thing to sit back is we strongly believe that [ TTRSC02 ] mechanism is a very potent mechanism when we generate a substantial amount of supportive data indicating the potential benefit of ONPATTRO in patients with cardiomyopathy and our APOLLO studies, HELIOS-A study and also independent investigators who has looked at various endpoint echoes, NT-proBNP as well as I think, importantly, amyloid uptake in the heart with Technetium scanning where we've been able to demonstrate the reduction in amyloid uptake in the heart, which I think is actually very supportive for the likely benefit of ONPATTRO and later vutrisiran in patients with the cardiomyopathy manifestation of disease. I just want to take a step back and explain this why we conducted the APOLLO study with ONPATTRO. Now ONPATTRO was a drug that was approved, whereas vutrisiran the subcutaneous formulation was still in development. And remember that whilst tafamidis is available for patients with TTR amyloidosis with cardiomyopathy, patients continue to progress. And we wanted a near-term opportunity to try to address the needs of these patients, whilst we continue to progress vutrisiran in an outcome study in patients with hereditary and wild-type TTR amyloidosis with cardiomyopathy. So it's really a near-term opportunity to bring forward ONPATTRO to these patients. And as I said, we're eagerly anticipating the data, which we've guided will be in mid-2022.

Got it. And I think that all supports your confidence behind this readout. Maybe a question on the patients. It's been a discussion point for investors. Based on BridgeBio's patient profile, their skepticism that APOLLO-B patients are sticking up because today, ATTR cardiomyopathy patients are diagnosed at earlier stages due to increased awareness and more use of imaging techniques to diagnose. What are your thoughts on this issue? And is this something you saw when you enroll patients in your study?

So look, I think it's an interesting hypothesis. If we sit back and think about what happened in the BridgeBio acoramidis study, where 6-minute walk test failed at 12 months, and there was a little placebo decline in the placebo patients. When you look at the other endpoints, KCCQ and NT-proBNP, they behaved exactly as you would expect them to in terms of progression on placebo and improvements with acoramidis. If you also compare what we know about the baseline demographics in the BridgeBio acoramidis study, it's what I think is the largest data set in TTR patients with cardiomyopathy. At this point in time, the Pfizer ATTRibute study -- ATTR-ACT study, sorry, the BridgeBio's study is the ATTRibute study, very similar baseline demographics in terms of 6-minute walk test and NT-ProBNP. So when you look at all of this, Maurice, I think we step back and I think BridgeBio would probably agree that something happened with a 6-minute walk test. And nobody is quite sure exactly what. There have been other number of factors that have been mentioned. Maybe it's around the conduct of the 6-minute walk test, the number of screening tests that patients had in the BridgeBio study before they enter the study. So I think we're left believing that it really is something to do with the 6-minute walk test. So that's why we're really pleased about how we've designed the APOLLO-B study, and we remain confident in the outcome of that study, results of which we will have in mid-2022.

Got it. So it seems like you primarily think it was something with how they were acquiring the 6-minute walk test data for BridgeBio. For the -- I had a question about the variant proportion, you seem to start talking more about that around the JPMorgan meeting earlier this year. Can you clarify if that was respectively defined to be in line with Pfizer's Phase III ATTR-ACT study? Or was the study designed to adapt by enrolling more variant patients?

So in the protocol, we specified a target for enrolling variant patients of 20% heredity patients and the remaining 80% wild-type patients. That was just a target. And as we design the study, what we wanted to do was include a patient population that reflected the real-world TTR dynamics. That was the rationale behind that decision. But I just want to emphasize it's a target. It's not a cap, and we'll be able to see exactly how we met that target when we turned over the targeted study.

Got it. Okay. So you're not saying if you're at that 20% yet or...

It's a target. It's a target. It's a target of the protocol.

Makes sense. And can you give us a sense of whether these variant patients were enrolled early on, potentially due to site investigators familiarity in those settings?

No, I'm afraid I can't. We're not commenting on sort of how variant patients came into study other than, as I said, the 20% target that I've just described.

Got it. Okay. And then APOLLO-B allows some tafamidis drop-ins if the investigator deems it to be necessary during the first 12 months. What was the rationale for including this option in the design? And what type of patients would require mNIS intervention on top of vutrisiran?

So to take a step back in terms of the design of the study, we elected here -- we elected to institute a cap on the number of tafamidis patients enrolled in the and that cap is 30%. And to get into the study on tafamidis, investigators have to assess if the patients were continuing to progress with their disease despite receiving tafamidis. So that put a cap on the numbers of patients with tafamidis coming in to the study and the physician had to believe that the patient wouldn't be starting tafamidis during the study within the year. Having said that, we did not believe that it was ethical to prevent patients from receiving tafamidis if they continue to progress in the study, given the severity of this disease, it's morbidity, it's mortality. It was absolutely the right thing to do to allow patients to receive tafamidis if their disease state was progressing. Having said that, we've had very few drop-ins, and we've talked about low single digits in terms of drop-ins of tafamidis. So again, I think it's a study that we've managed very carefully. We talked about geographical distribution of the study, et cetera. So we think that we're in a really good spot there.

Got it. And for the primary endpoint of 6-minute walk test, based on your discussion with regulators, it's showing a static difference sufficient for approval? And can you talk about some of the precedents in the space?

So clearly, we had conversations with the regulators before commencing the study. And we aligned on the appropriateness of the 6-minute walk test at 12 months as an approvable endpoint. So yes, what we need to deliver in the study is significance around that endpoint, the 6-minute walk test compared to placebo. Now clearly, as all of you know, when you file for a drug, the agency is going to look holistically at all the data you have, including safety. But in terms of securing regulatory approval, it's around delivering significance with respect to that with that primary endpoint so well accepted endpoint by the regulators.

Got it. Okay. And for -- I guess, just another question about the study, not sure if you're going to be able to say. But for diagnosing patients, can you say what proportion of your patients are biopsy confirmed?

So I can't speak for specifics of this. But just to remind everybody that to get into the study you either had to have a positive cardiac biopsy or you had to have a Perugini Grade 2 or 3 score on Technetium scanning in order to be enrolled in the study. So that allowed us to feel confident that we are aiding patients that indeed had TTR amyloidosis and not some other causes of heart failure.

Got it. Okay. And you've shown improvements in cardiac cell populations, which you referred to from APOLLO and HELIOS-A but those patients had medium baseline NT-proBNP levels of approximately 800-nanogram per liter. You have the individual patient data with higher baseline levels that are more in line with Pfizer and BridgeBio of approximately 3,000 nanogram per liter level. And can you talk about what you saw in those patients?

So clearly, we're not going to be talking about individual patient data. And that clearly wouldn't be appropriate. But what I can say is that in terms of our inclusion criteria, we were enrolling patients that had between 300 -- between 800 and 3,500 nanogram per liter NT-proBNP, that's how the study is [ enrolled ].

Okay. Okay. So not much you can say about what you're seeing in the higher proBNP levels. Okay. And then I know it's difficult to speculate on what another company is doing. But based on your experience with your own study, why do you think Ionis, AstraZeneca recently amended and upsized their CARDIO-TTR -- CARDIO-TTRansform Phase III? Do you think they are not seeing enough events that could imply healthier patients enrolled? Or are they seeing lower decline driven by concomitant tafamidis?

So Maurice, of course, I'm not going to want to be the spokesperson for Ionis and AstraZeneca in this regard. But I think if you think about the likely causes for wanting to upsize their study, they upsized the study from 750 to 1,000 patients. They increased the duration of study from 120 to 140 weeks. And I think the reasons for that may well be due to what they saw with the [indiscernible] blinded event rates. But also, as I understand it, I'm not sure that they have a tafamidis cap in that study. So they extended the duration from 120 to 140 weeks. And that actually puts them very much in line with where we are with HELIOS-B. To recall, the HELIOS-B is an outcome study with vutrisiran. And being an outcome study, that endpoint is between 30 and 36 months. So we feel that we've sized the study appropriate. Again, HELIOS-B is a study overenrolled, conservatively powered. So I think we feel very good about where HELIOS-B is, clearly, when we see the APOLLO-B data will give us an opportunity to reflect on where we are with HELIOS-B and make any refinements at that point in time. Now one of the approaches that we've discussed in the past has been the option to conduct an interim analysis. And that remains an option for us. When we see the APOLLO-B data, we'll decide whether we want to do an interim analysis or not. We'll decide if we do want to do an interim analysis, the specifics of what that interim analysis should look like in terms of patient numbers, time lines, endpoints, et cetera. So that's something that we will obviously have to wait for the APOLLO-B data before we make a brand decision in this direction. Of course, depending on the decision we make, if we decide we want to go forward with, we're going to have to engage with regulators. And so when we think about that scenario against where we are with respect to time lines of the HELIOS-B study, we actually managed to enroll the study much more quickly than we expected. And therefore, there's not a huge amount of time to be gained from doing an interim analysis, given you need to wait for APOLLO-B, you need to wait to discuss with the regulators. And so we'll think very carefully about the appropriateness of doing an interim analysis when we see the APOLLO-B data.

Got it. Makes sense. And recently, you showed the 18-month data for vutri but did not report the same measures for the smaller patisiran arm for mNIS and Norfolk Quality of Life. APOLLO-A data shows patisiran-treated patients improve further on mNIS from 9 months to 18 months, whereas vutri-treated patients show to rebound some from 9 months to 18 months. You mentioned the difference is due to variability, but just wondering if the variability is innates the drug? Or is it due to patient's baseline or another explanation?

It's absolutely not due to any innate feature of the drug and if you look at serum TTR curve, they're more or less superimposable. Actually, we were incredibly pleased with how well HELIOS-A recapitulate what we saw in the quality. If you imagine, 1 drug is ONPATTRO, the other was vutrisiran. We're doing the studies across different time periods and yet the results are more or less superimposable. And I think that, again, is a testament to how thoughtfully we both designed and conducted studies in this space. So we're very pleased with what we're be able to deliver with vutrisiran in the HELIOS-A study.

Got it. And you mentioned vutri PDUFA is coming up on July 14. Just wondering, in your discussion with FDA, what were some of the arguments that FDA used to push back on using the placebo arm from APOLLO-A as a comparator arm in the HELIOS-A study? And are there precedents for using the separate studies, placebo arm?

I wasn't aware that we've ever discussed the FDA pushing back on the study. It's a study that we're fully aligned on with the FDA in terms of the primary analysis being comparing vutrisiran for the external placebo arm. And I think we feel very pleased with the arrangement that we have with the agency. And we're looking forward for potential approval by July 14, PDUFA.

Got it. Makes sense. And I also wanted to ask you if there's a threshold or a requirement for efficacy comparability between vutrisiran and...

I mean we're not going to be discussing details -- in-depth details of dialogue that we've had with the FDA. Just to reiterate for the point analysis was on that what we're going to be moving forward with. And as I said, we're hoping to secure the approval by the PDUFA date.

Got it. Okay. And assuming vutri gets approved, what will be your key commercialization strategy in the U.S. and ex U.S. markets?

This is the one major advantage of having a second product in the same disease. We really have a TTR franchise now that we're building. And clearly, we're very confident about the commercial capability that we built for ONPATTRO with in terms of sales and marketing efforts, our medical affairs efforts. And then some of the approaches that have been very, very successful with ONPATTRO in terms of genetic testing with unanimous -- patient support with unanimous shifts, I think, are groundbreaking approaches with respect to securing [ payer ] access. And we're going to bring all of these things to [indiscernible] the launch of vutrisiran. And just to highlight that as of the end of the first quarter this year, we had 2,200 patients treated with ONPATTRO out of the addressable population of around about 20,000 to 30,000 patients. So there's a lot more patients out there with polyneuropathy that would benefit from [indiscernible] like vutrisiran. Anecdotally, we're actually hearing that the patients that are waiting for vutrisiran to be approved. And we are also waiting. So we're looking forward to that.

Got it. And maybe just a quick question on the Cemdisiran update today. Congrats on that. Wondering if you're seeing a proportion of patients that had complete remission. And when could we learn more about next steps for that base?

So there are a number of secondary endpoints that I don't have time to go into that we're all pointing in the right direction. So we're very pleased with the study results, and we're planning for next steps in terms of regulatory interactions and moving forward to Phase III in partnership with [indiscernible].

Got it. Well, we're pretty much out of time. Maybe just to close out, if there are some key things to add that investors should be focused on that you're most excited about in the second half of the year?

Well, I think just the number of catalysts that we have as a company, which I think just reflects the breadth and potential of Alnylam as a company, just two to touch on [indiscernible] a really important program as we start to point this technology to much more prevalent diseases and imagining a few times a year, subcutaneous injection for chronic prevalent disease like hypertension, I think is absolutely amazing. And we should have completed enrollment in one of our Phase II studies, Cardio-2, by the end of this year. So I'm really looking forward to that. And I'm very excited about ALN-APP program for early onset Alzheimer's disease. If we can crack the code around CNS, it's going to be a lot more to come yet, but looking forward to that.

Great. Well, Yvonne, thanks so much for joining us.

My pleasure.