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

Good morning, everyone. My name is Gena Wang. I'm SMID-cap biotech analyst at Barclays. Welcome to Barclays Global Healthcare Conference. Today is the last day, and I hope everyone had a very productive meetings -- all having additional productive meetings. It is my great pleasure to introduce today's first presenting company, Alnylam. With us today, we have Jeff Poulton, Chief Financial Officer; also Eric Green, SVP, Head of Development Profiles. Thank you for coming to our conference.

Thank you. Thanks to Barclays for having us. It's always nice to be in Miami in this time of year.

Yes, certainly better than Boston.

Much better.

So maybe I will just dive into the questions. I know we've got tons of questions on the APOLLO-B and AdComm. And so maybe give us a little bit color why you think the FDA want an AdComm, especially when we saw many different programs that FDA announced initially. AdComm -- so we actually don't need AdComm, and then you have a lots of NDA submission that did not have AdComm. So maybe give a little bit more color why you I know you may not know exactly, but what could be the possible reason.

Yes. Thanks for the question. Sort of go back and sort of recapitulate what we've said already, so we heard from the FDA a couple of weeks ago, and we put out in mid-February that the file for the sNDA for patisiran had been accepted. No review issues noted to date, standard review, but they also noted that they will hold an advisory committee as part of the review process. At this point, they haven't communicated the specifics associated with what the topics are, what they want to focus on. So same with the advisory committee, which again is not that unusual given where we are in the process. We do expect to learn more about what those specific areas are. I think for the likely process, we would likely hear a couple of months in advance of the meeting of the Advisory Committee in itself, what the specific focus areas will be. So we don't know today it's possible one of the areas of focus will be on interpretation of the efficacy data. Recall that in 2019, the FDA put out new heart failure guidance which created a pathway forward for an approval of outcomes data based on functional and health status endpoints. So it's a [ standard walk from cases in queue ], as in this case as it relates to APOLLO-B. So it's possible that they're looking for some, pause for a second and go back. You think this is the first therapy brought forward with the functional and health status end point, as a potential pathway to improve it. So it's possible that the FDA, given this is the first one would like to get some input on the application. So again, we'll know more as the process progresses, but that's possible.

Very helpful. Has the AdComm date already been communicated?

The date has not been set yet at this point, but for per PDUFA goals kind of standard review. The expectation is that it will be in early August or prior to that, right? But at this point, the specific date has not been set, but we'll learn about that in due course.

Okay. Very helpful. And then for 120-day safety data. So maybe if you can give any color there has already been submitted? And then what was included in the package?

So the day 120 safety update, the standard process, FDA always wants to have a refreshed look at the safety a little bit later in the study. So as the name implies, that's due to the FDA about 4 months after the initial submission. So our early December kind of fight forward those we do around early April, and those have not yet gone in, but obviously imminently.

Okay. Very helpful. And also, I think there is another very important data point is the 18 months APOLLO-B data? And when should we expect to see that data?

Yes. So recall in APOLLO-B patients were in the double-blind randomized portion for 12 months, and then they had the option to switch over to patisiran open-label for a continuation of dosing. So we are currently gathering even bringing those data in and evaluating them, and we'll be looking to present those data sometime shortly at a medical conference.

I will ask the revenue question later, I will continue with HELIOS-B since you mentioned like how much do you think you can learn from APOLLO-B data, especially the outcome events and help you understand the HELIOS-B trial designs so far, like events you've seen so far?

Yes. So we're in a fairly fortunate position. We have the 2 different products, both lowering TTR for the treatment of this cardiomyopathy of both predatory and wild type. APOLLO-B, obviously, a smaller study, about 360 patients, only a 12-month endpoint, primarily looking, the primary endpoint was 6-minute walk. We hit on that with statistical and we think clinically meaningfulness. We also hit on the quality of life as the first secondary endpoint, but we did have further secondary endpoints looking at outcomes data, so mortality, hospitalization, urgent heart failure visits. So that has given us some data, especially in this first 12 months in the double-blind portion that will help us feel more confident in our power that we had for HELIOS-B. And we said this repeatedly, we think what we've learned from APOLLO-B only increases our confidence in what we have for HELIOS-B. We feel we've conservatively powered HELIOS-B based on what we knew at the time from ATTR-ACT and what we think the patient population would be. And most importantly, for the design itself for HELIOS-B is 3x as long, there's a variable follow-up in the double-blind portion of 30 to 36 months. Most patients will go on to the full 3 years. and it's twice as big as APOLLO-B. So we have 650, 660 patients enroll in HELIOS-B. So we think we've learned a lot from APOLLO-B. It obviously doesn't fully derisk HELIOS-B, but we continue to feel confident about HELIOS-B.

So maybe, Eric, I will go through specific details why you're thinking APOLLO-B make you feel more confident on HELIOS-B. So maybe just starting with the patient baseline characteristics. So we saw APOLLO-B patient baseline, right? And then regarding HELIOS-B, these patient population very similar to APOLLO-B and we are -- the question will be regarding patient on tafamidis, regarding percentage of patients with hereditary ATTR and also NYHA Class I, II, III. So like actually, baseline 6-minutes walk test and the proBNP, so if we look all these individual -- I know you cannot describe like very specifically, but if you can give a more overall what is the range? Are they within the similar? Or are they some kind of diverge because of different time of enrollment?

Excellent question. And you're correct. We have not yet shared the detailed demographics from HELIOS-B we'll obviously do that. I guess this mic doesn't work -- when we eventually do present the top line results and they're going to be more detailed results from HELIOS-B, that's typically when we share the detailed demographics. However, we have stated that the inclusion/exclusion criteria for both APOLLO-B and HELIOS-B were very similar. So it's very likely to expect we would have found similar patient populations. So a couple specific differences in the protocols, in APOLLO-B, we actually had a protocol specified maximum of 30% of patients could come in on baseline tafamidis. If they'd already been on tafamidis for 6 months and in the opinion of the investigator had progressed. In HELIOS-B, we didn't have a protocol defined limit. We had an operational limit of about 50%. And we've said before, we've actually came in under that target. So that could be a slight difference in the patient population. Both studies were actively enrolling at roughly the same time, APOLLO-B being smaller, actually finished enrollment earlier, but HELIOS-B finished enrolling only a few months later. So roughly, we think the populations were fairly similar, given the broader macro changes in the treatment of the disease. So I think we could expect generally in the similar populations.

Okay. So which means the hereditary percentage also could be very similar NYHA Class I, II, III, all very similar.

Likely, we don't control for those as much. We do obviously stratify to make sure they're well balanced across the placebo and the active arms in both studies. But we would expect something relatively similar.

Okay. And then important the biomarker or proBNP, is that also within similar range?

That, I think, is we have maximums and minimums of where we expect to have biomarkers as well as 6-minute walk distance so that we have -- we're not getting the worst of the worst of the 2-mile patients. So begin those requirements are the same for both studies. So roughly, they should be similar.

They should be similar. Because when we look across different studies, like also including BridgeBio, actually proBNP, your study, APOLLO-B, actually is the lowest compared to BridgeBio. I think they are 2000 -- some of you guys with 2000.

Which are both very elevated, obviously, as compared to normal. So it's maybe a little bit of a variance of degree, but -- they're still very sick patients.

Okay. So you think that overall, if we look through all these categories, largely similar. And then tafamidis, if you have -- now you have more tafamidis compared to APOLLO-B. And do you think that, that will help you with the stats part, the -- in terms of the outcome?

Hard to know, right? But it is obviously a confounding factor. So our statisticians have taken that into account. We assumed how many patients may come in on baseline tafamidis and what possible contribution that would have to any of the outcomes measures and we've tried to account for that.

So another housekeeping question. The endpoint, the outcome measurement for APOLLO-B and HELIOS-B, are these very similar?

Similar, yes. So APOLLO-B is one of the secondary endpoints, but looking at the composite of mortality urgent heart failure visits, which includes hospitalization, are the similar or the same components. It's just kind of the how and where we put it in the hierarchy of events. Obviously, with HELIOS-B, that composite is the primary end point which is different.

And then the order of hierarchy within that composite are these also the same?

Yes, I believe it's the same statistical method we'll use, which then compares when you take all these components of this composite endpoint and how they're actually compared across all the different patients. I believe those methods are the same across both.

Okay. Very good. And then you do allow tafamidis dropping. And I remember -- I think end of last year, when I -- or at the beginning of this year ask was still low single digit for HELIOS-B dropping. Is that still the case?

That is still the case. And obviously, part of it is where we've operationalized the study. We've enrolled patients globally. And in a lot of countries, tafamidis simply isn't available either through access or it's not yet approved. So a lot of patients don't have options to drop tafamidis amines. But even in those places where they do, we have not seen significant dropping yet.

Okay. So I have 2 questions on this dropping. One is I think when we follow APOLLO-B is that it seems like a very wide range, what is the definition of a progressor tafamidis -- sorry, just the disease progression. So with the HELIOS-B, do you have some standardized protocol to define progression?

No. So again, recalling APOLLO-B, as you mentioned, it was -- progression was needed to be attested to by the PI, basically. But we didn't have requirements or definitions for what that progression looks like. In HELIOS-B, there is no requirement for progression to enable patients to come in on tafamidis and is frankly at the physician's discretion, if it's necessary to add on or drop in with tafamidis use. But we don't have any formal definitions.

Okay. And then low dropping on one way we're thinking that's good because tafamidis may be like increasing placebo arm benefit. On the other hand, does that means if you don't have a dropping these patients did not progress enough like that were hurting you or try to think through what is the...

Yes. Yes. I mean you could argue it almost any given way, right? So you could be worried on the placebo arm if they're not getting any benefit, obviously, from placebo. They may be more likely to progress more likely to drop in it's just so hard to tell. Again, whether or not the drug is even available for those patients where the physicians think this normal progression of the disease, patients are still blinded, physicians are still blinded, so they can't truly know if they're on placebo.

Okay. Good. And then for the APOLLO-B events, 12 months data and then you have 18 months, of course, patient crossover. When you look at those outcomes, if we're only focusing on the outcome events, like would that align with your HELIOS-B trial design in mind? And so far will you see -- I'm pretty sure you saw on the blinded base or the events. Like do you see this is aligned with HELIOS-B?

So the comparison of the events as a secondary endpoint of APOLLO-B is meaningful versus placebo only through the first 12 months. So then now we're just kind of capturing overall events in the patisiran arm at this point. I don't think we've had any comments about specific event rates, but it's nothing that we weren't expecting. I believe, Jeff, anything else that you've heard.

No, I think that's it.

Okay. So basically, APOLLO-B event so far, you're seeing 12 months. Nothing surprised when comparing to the thought process you have when you designed HELIOS-B?

As we've said, we've looked very closely, obviously, HELIOS-B, the power in the study design, we said numerous times, we don't -- at this point, don't expect any changes to that study. We enrolled the -- completed enrollment 1 year, 1.5 year ago now at this point. So we feel quite confident in the design and our powering assumptions.

So maybe I'll throw a hard question to you. Some investments or the reason you did not increase the transit because you missed the opportunity. When the BridgeBio -- before BridgeBio announced the data, you already closed the study. So how would you counterargue that?

In clinical development, we always want to enroll the studies as fast as possible, so you can get to the data and get to patients ultimately. So it's kind of funny to think that we somehow had a bad outcome by enrolling faster than we had expected. So it is where it is. We enroll our patients. We design the study. We work with regulatory agencies to align on that design, those endpoints. And we enroll the patients per our inclusion, exclusion criteria. So I think we have APOLLO-B, we're waiting now.

Jeff, anything to add there?

No, I mean I think Eric really characterized it well upfront is we were pleased with the outcome of APOLLO-B for a variety of reasons that increased our confidence in Helios B. HELIOS-B was -- is a much larger and a much longer study, but we remain confident in that design. We've sort of throughout the process of been getting questions about this, we've continued to restate, no plan to change that.

Okay. And then we know that BridgeBio attributable data they will report in July. Any thoughts how that will help you understand the events or like understand the readthrough to the HELIOS-B?

Yes. Obviously, we'll be really interested in to understand the patient demographics, so they actually enroll in the study. And then for us, most important most interesting probably would be the placebo arm. Did they progress as they would expect, given the severity of the patients that they enrolled. Of course, as a potential competitor, it will be interested to see how the drug itself did and how that compares to placebo. But for us in the short term, we'll be really looking at those event rates, we think, in the placebo arm. And as -- I think I've heard from them, it's like the first week of July. So it may be a challenging Fourth of July weekend for us, yes.

Good. So we are looking forward to more color evolving field. Now going back to Jeff now, asking you about revenue. If, say, APOLLO-B or ONPATTRO got approval for cardiomyopathy, where do you see the initial patient population [ has ] to be coming from and the meaningful revenue contribution?

Yes. So let me just talk a little bit about ONPATTRO CM. So when we put the guidance out, one thing I just want to highlight is obviously the PDUFA date being October 8, the expectations in terms of contribution to revenue this year are pretty modest as a result of the approval in Q4. So the revenue impact would be -- expectation would be greater in 2024. In terms of where we see opportunities for ONPATTRO upon -- if we get the FDA approval, I think 2 potential areas of opportunity based on the market research we've done. I think the first area is not everybody can access the current therapy in the market. There are some challenges with that. And I think based on being a Part B medicine that will have some advantages there that may allow easier access for patients. And the second area is for those patients that don't respond adequately to the current therapy in the market. Remember, this is a progressive fatal disease. So for patients that are not doing well on the current therapy, frankly, there's a desire and in some cases, a desperation to have access to another therapy. And this would be the second therapy in the market in the U.S. if we get approval by the end of the year.

Very good. And how do you see AMVUTTRA and ONPATTRO revenue dynamic in, say, 2023 and then going forward?

Yes. Maybe just talk a little bit about how things have gone since the launch in the U.S. And this is, again, in the hereditary polyneuropathy population. So we got approval about midyear in the U.S. and the launch has gone very well. We also added a couple of markets outside the U.S. late in Q4, which contributed some revenue in the fourth quarter as well. But for the year, we did just over $90 million in revenue for AMVUTTRA again, focused on the U.S., I think, some really encouraging signs there in terms of demonstrating an expansion of the opportunity in a hereditary PN. We've received about 760 start forms in the U.S. year-to-date. More than half of those represent new patients, and that's ultimately what drives growth. The other less than half are switches from ONPATTRO. I think the really encouraging thing is what we've seen is in terms of the number of new patients on a monthly basis in terms of start forms that we've been receiving since the launch of AMVUTTRA. It's doubled from what we were getting prior to the launch of AMVUTTRA in the U.S. And you saw that in Q4, frankly, in terms of the number of patients that initiated therapy globally. We added about 400 patients globally in the fourth quarter in our TTR franchise. And prior to that, we've been adding about 150 to 200 patients a quarter. So again, really, I think, encouraging signs, particularly in the U.S. in terms of expanding the opportunity. Another nice metric, I think, that speaks to that was the increase that we've seen in prescribers in the U.S. In just 2 quarters, right? We've had ONPATTRO on the market since 2018. And with 2 quarters of launch under our belt with AMVUTTRA, we've expanded the prescribers, full-time prescribers by about 30% in the U.S. over those 2 quarters. So we're really encouraged with that. In terms of the dynamics between ONPATTRO and AMVUTTRA, my expectation is as we switch more and more patients off of ONPATTRO, you're going to see less of that just because there's fewer patients remaining on ONPATTRO. And so the driver for growth here is certainly going to be new starts on AMVUTTRA going forward.

Okay. Very helpful. We have a few minutes. I do want to touch on pipeline in the U.S., actually very rich pipeline. Starting with APP program. So you will have data early 2023? Can you give a little bit more color. We are almost -- first quarter is almost down. Like is it fair to assume we'll see 2Q?

Yes. At this point, we expect it to be more in Q2. And I know it's quite early as Q1 or Q2, but we're almost done with March.

Okay. And then the expectation on the data? And also, what is the impact to the CNS indication?

So ALN-APP, just to step back, is our first siRNA program to target the CNS. And this is really exciting for us now to go beyond the liver, our first extrahepatic program. It's currently in a Phase I study. We initiated that early last year in early onset Alzheimer's patients. So for Phase I, we're in a single ascending dose portion of the study. Primary endpoint was safety and tolerability. This is the first time an SI has ever been dosed to the CNS. We'll be looking very carefully at how it is tolerated in these patients. Secondarily, we're obviously looking for target engagement. And we'll do that via CSF biomarkers, soluble APP alpha and beta. And we'll really be looking for approximately 50% knockdown. We've kind of -- we don't really know what's going to be appropriate or necessary clinically in this disease. Nobody has actually tried to target the upstream APP protein itself. But given the genetics we see in those diseases where APP production is increased or the proteolysis has increased where the peptide fragments are actually increased. You see earlier onset of disease. Conversely, there's some protective mutations, in particular, Iceland, where you have less APP production and you actually see a protective benefit. So human genetics give us a little bit of insight, and that's why we're aiming for this around 50% knockdown.

And then regarding the dosing frequency, what would be your goal?

Goal? Well, because this is an IT infusion, obviously, the less frequent, the better. We have really interesting nonhuman primate data that showed significant knockdown of the protein out to 6 months. We don't know the translatability from NHPD humans and CNS products. We obviously have a great database in the liver, and we often see an extension of durability once it translates to humans. So we'll learn from this Phase I as we follow up these patients after their single dose, what the knockdown is and eventually any recovery. But ideally, I think we'd be looking for at least every 6 months dosing, if not even annually, given the IT infusions.

Very good. And single way. So if you -- so what will be -- maybe I will save the Alzheimer question to a different time. Mechanistically, what does that mean to the actual, like the turnover of amyloid? If you can have a quick comment.

Briefly, we don't know, right? So there's no mechanism that's ever tried to shut down the production of APP and therefore, you're basically stopping, if you will, turning off the faucet of new APP and all the fragments from it. What's the endogenous clearance mechanism and the timing to do that is unclear. It's likely much slower than the active removal from the monoclonal antibodies, but we think that may have some upsides to where you may not see some of the safety concerns, I guess, you could say with monoclonal antibodies with the rapid removal of plaques and amyloid, but it's to be determined. We will not know that for a while.

Okay. Good. And then another important product, this will be your first indication in CNS. And then what will be additional, like if you were able to achieve by annual minimum and 50% of target engagement. And then with that data, where do you think you can -- the translatability to other indications? What will be the next top candidate you will be thinking of?

Yes. Excellent point, right? So there's success in the data that will help with this APP program, but also what does it mean to the broader platform? ALN SOD1 is one program we've already talked about in public for SOD1-driven ALS. That's being led by our partners, Regeneron, but we're participating in that. And then we've also talked in the past about Huntington's as another potential area. So all of these CNS programs are involved with our Regeneron partnership, and we actually have a number of other targets we're working on. We just have not yet made them public. But it could be very exciting to open up a whole another tissue type for us in our platform.

Huntington is the indication, I think a lot of the companies showed interest. And do you have -- like with the steering committee you together with Regeneron determined this to move to the next step?

So we're in arrangement once a target is named into the relationship. In this case, Huntington's, we [ ALN ], and our research group works on developing a product that actually hits that target. And then there's a joint steering committee that ultimately reviews the data and say, yes, we'll name this a development candidate, then you figure out who's taking it forward and moving it into the clinic.

Okay. Good. And I know we are running out of time. Maybe quickly on the hypertension program, what could be the approvable endpoint, data expectation and also the magnitude of the benefit that will be considered clinically meaningful.

So zilebesiran is our program targeting angiotensinogen, which is the top of the RAS cascade, a known mechanism for lowering blood pressure. In Phase II, currently, CARDIO-1 study in monotherapy, really a dose exploration study for different doses and dose regimens. CARDIO-2 is a combination study on top of 1 of 3 standard classes of antihypertensive medicines. From our Phase I data, we saw a great and durable knockdown of AGT angiotensinogen, which translated into significant blood pressure reductions that persisted for up to 6 months after the single dose. So we're hoping and expecting to see something greater than 5 millimeters of systolic blood pressure reduction would be considered clinically meaningful. But based on our Phase I data, especially in a monotherapy setting, we would expect to see something more than that. And those data are expected in CARDIO-1. The monotherapy study is expected in mid this year. And for CARDIO-2, the combination studies we're expecting those data at or around year-end '23.

Okay. Very good. Well, thank you very much. And I will look forward to tons of update later this year. .

Thank you.

Thank you.

Thank you, everyone.