We're on the clock.
Okay. Good morning, everyone. My name is Gena Wang. I'm senior care biotech analyst at Barclays. Welcome to Barclays Global Healthcare Conference. Today is the last day, I hope everyone had a very productive meetings or 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 Programs. Thank you for coming to our conference.
Thank you to Barclays for having us. It's always nice to be in Miami at this time of year.
Yes, certainly better than Boston.
Much better.
Maybe I will just dive into the questions.
Sure.
I know we've got tons of questions on the APOLLO-B outcome. Maybe, you know, give us a little bit color why, you know, you think the FDA wanted an outcome, especially when we saw so many different programs the FDA announced initially outcome, we actually don't need outcome? You have lots of NDA submission that did not have outcome. Maybe give a little bit more color why you, I know you may not know exactly, but what could be the possible reasons?
Yeah. Thanks for the, for the question. Let me sort of go back and sort of, you know, recapitulate what we've said already. We heard from the FDA a couple of weeks ago. We put out in mid-February that the file, the sNDA for patisiran had been accepted. No review issues noted to date. Standard review, they also noted that.
Mm-hmm.
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 that they want to focus on associated 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 per the, you know, the likely process, we would likely hear a couple of months in advance of the meeting of the advisory committee itself, what the specific focus areas will be. We don't know today. It's possible, you know, 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 without outcomes data based on functional and health status endpoints. six minute walk and KCCQ in this case as it relates to APOLLO-B. It's possible that they're looking for some input. Let me pause for a second and go back. If you think this is the first therapy brought forward with, again, the functional and health status endpoints as a potential pathway to approval. It's possible that the FDA, given that it's the first one, would like to get some input on the application. Again, we'll know more as the process progresses, but that's possible.
Very helpful. Has the outcome date already been communicated?
The date's not been set yet at this point.
Mm-hmm.
For, per FDA goals and a standard review, the expectation is that it will be in early August or prior to that, right? At this point, the specific date has not been set. We'll learn about that in due course.
Okay. Very helpful. For 120- days safety data, maybe, you know, if you can give any color there. Has this already been submitted? Then what was included in the package?
The day 120 safety update is a standard process. FDA always wants to have a refreshed look at the safety a little bit later in the study. As the name implies, that's due to the FDA about four months after the initial submission. Our early December's kind of play forward. Those will be due around early April and those have not yet gone in, but obviously imminently.
Okay. Very helpful. Also I think there's another very important data point is the 18- months APOLLO-B data. When should we expect to see that data?
Yep. Recall in APOLLO-B, patients were in the double-blind randomized portion for 12- months. They had the option to switch over to patisiran open label for a continuation of dosing. We are currently gathering even bringing those data in and evaluating them. We'll be looking to present those data sometime shortly at a medical conference.
I will seek revenue question later. I will continue with HELIOS-B since.
Yeah.
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 design so far?
So-.
Like events you've seen so far.
We're in a fairly fortunate position. We have the two different products, both lowering TTR for the treatment of this cardiomyopathy of both hereditary and wild type. APOLLO-B obviously smaller study, about 360 patients, only a 12-month endpoint. The primary endpoint was six minute walk. We hit on that with a statistical and we think clinically meaningfulness. We also hit on a quality of life as a first secondary endpoint, we did have further secondary endpoints looking at outcomes data. Mortality, hospitalization, urgent heart failure visit. 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 powering that we had for HELIOS-B.
We've 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 ATTRACT and what we think the patient population would be. Most importantly for the design itself, for HELIOS-B is, you know, three times as long. There's a variable follow-up and double blind portion of 30-36 months. Most patients will go out to the full three years, and it's twice as big as APOLLO-B. We have, you know, 650, 660 patients enrolled in HELIOS-B. We think we've learned a lot from APOLLO-B. It obviously doesn't fully de-risk HELIOS-B, but we're continuing to feel confident about HELIOS-B.
maybe, Eric, I will go through specific details why you're thinking, you know, APOLLO-B make you feel more confident on HELIOS-B. maybe just starting with the patient baseline characteristics.
Mm-hmm.
we saw APOLLO-B patient baseline, right? Regarding HELIOS-B, you know, are these patient population very similar to APOLLO-B? We are, you know, the question will be regarding patient on tafamidis, regarding percentage of patient with hereditary ATTR and also NYHA class, you know, one, two, three.
Mm-hmm.
Like, and actually baseline six minute walk test and the NT-proBNP. If we look all these individual and I know you cannot, you know, describe, you know, like in very specific way...
Yeah.
If you can give a more.
Yeah.
Overall the, you know, what is the range? Are they within the similar or are they have some kind of diverge because 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. Guess this mic doesn't work. When we eventually do present the top line results and ultimately the more detailed results from HELIOS-B, that's typically when we share the detailed demographics. 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. A couple specific differences on the top 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. 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. Roughly, we think the populations were fairly similar, given the broader macro changes in the treatment of the disease. I think, we could expect generally in similar populations.
Okay. Which means the hereditary percentage also could be very similar, NYHA class one to three, also very similar.
Likely.
Okay.
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. Importantly, you know, the biomarker NT-proBNP, is that also within similar range?
That I think is we have maximums and minimums of where.
Yeah.
To have biomarkers as well as six minute walk distance so that we have, you know, we're not getting the worst of the worst or too mild of patients. Again, those requirements are the same for both studies. Roughly they should be similar.
They should be similar. 'Cause when we look across different study, like also including BridgeBio, actually NT-proBNP, your study, APOLLO-B actually is the lowest compared to BridgeBio. I think they are 3,000 something. You guys were 2,000.
Which are both very elevated, obviously compared to normal.
Yeah.
It's maybe a little bit of a variance of degree, but.
Mm-hmm.
They're still very sick patients.
You think that overall, if we look through all these category, largely similar? Tafamidis, if you have now you have a 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? It is obviously a confounding factor.
Mm.
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.
Mm-hmm. Another housekeeping question. The endpoint, the outcome measurement for APOLLO-B and the HELIOS-B, are these very similar?
Similar, yeah. Again, APOLLO-B is one of the secondary endpoints.
Yeah.
By looking at the composite of mortality, urgent heart failure visits, which includes hospitalization, are the similar or the same components.
Mm-hmm.
It's just kind of the how and where we put it in the hierarchy of events.
Mm-hmm.
With HELIOS-B, that composite is the primary endpoint.
Yeah.
Which is different.
The order of the hierarchy within that composite, are these also the same?
Yeah, I believe it's the same statistical method we'll use.
Okay.
Which then compares when you take all these components of this composite endpoint, how they're actually compared across all the different patients. I believe those methods are the same across both.
Okay, very good. You do allow tafamidis dropping. I remember, I think end of last year when maybe beginning of this year asked was still low single digit for HELIOS-B dropping. Is that still the case?
That is still the case. Obviously part of it's where we've operationalized the study, we've enrolled patients globally. In a lot of countries, tafamidis simply isn't available either through access or it's not yet approved. A lot of patients don't have options to drop into tafamidis, but even in those places where they do, we have not seen significant drop-ins yet.
Okay. I have two questions on this dropping. One is that when we follow APOLLO-B is that it seems from a very wide range, what is definition of, progressor on tafamidis?
Mm.
Oh, sorry. Just the disease progression. With the HELIOS-B, do you have some standardized protocol to define progression?
No. Again, recall in APOLLO-B, as you mentioned, that it was a 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 it's frankly at the physician's discretion if it's necessary to add on or drop in with tafamidis use. We don't have any formal definitions.
Okay. you know, low drop-in, you know, on one way we're thinking, oh, that's good because tafamidis may be, you know, in like increasing placebo arm, benefit. On the other hand, does that means if you don't have a drop-in, means patient did not progress enough? Like, you know, that will hurting you. Like, try to think through what is the.
Yeah. Yeah. I mean, you could argue it almost any given way, right?
Mm-hmm.
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.
Okay.
Again, whether or not the drug's even available for those patients, whether physicians think it's normal progression of the disease.
Mm.
Patients are still blinded, physicians are still blinded, so they can't truly know if they're on placebo.
Okay, good. For the APOLLO-B events, 12- months data, and then you have 18- months, of course, patient crossover.
Mm-hmm.
When you look at those outcome, if we're only focusing on the outcome, events, like would that align with your, say, HELIOS-B, you know, trial design in mind? So far, I'm pretty sure you saw on the blinder base or the events. Like, do you see this is aligned with HELIOS-B?
The comparison of the events as a secondary endpoint of APOLLO-B is meaningful versus placebo only through the first 12- months. Now we're just kinda capturing overall events in the patisiran arm at this point.
Yeah.
I don't think we've had any comments about specific event rates, but it's nothing that weren't expecting, I believe. Jeff, anything else that you've heard?
No, I think that's it.
Basically, APOLLO-B events so far you're seeing 12- months, nothing surprise when comparing to the thought process you had when you designed HELIOS-B.
As we've said we've looked very closely, obviously at HELIOS-B, the power in the study design. We've said numerous times we don't expect any changes to that study.
Mm-hmm.
We enrolled the completed enrollment, you know, a year ago, a year and a half ago now at this point.
Mm-hmm.
We feel quite confident in the design and our powering assumptions.
Okay.
HELIOS is-.
Maybe I'll throw a hard question to you. Some investors say, "Oh, the reason you did not increase the trial size because you missed the opportunity, before BridgeBio announced the data, you already closed the study.
Mm-hmm.
How would you counter-argue with that?
In, in clinical development, we always wanna enroll the studies as fast as possible so we can get to the data and get to patients ultimately. It's kinda funny to think that we somehow had a bad outcome by enrolling faster than we had expected. It is what 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.
Okay.
I think we have APOLLO-B. We're waiting now.
Okay, good.
Anxiously.
Jeff, anything to add?
No, I mean, I think Eric really characterized it well up front, 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 getting questions about this, we've continued to restate no plan to change that.
Mm-hmm. Okay. Then we know that BridgeBio attributed data they will report in July. You know, any thoughts how that will help you understand, you know, the events or like, you know, understand the read-through to the HELIOS-B?
Yeah. Obviously, we'll be really interested in understanding the patient demographics, who they actually enrolled in the study. For us, most important, most interesting probably would be the placebo arm. Did they progress as they would expect given the, you know, the severity of the patients that they enrolled? Of course, as a potential competitor, we'll be interested to see how the drug itself did and how that compares to placebo. For us in the short term, it'll be really looking at those event rates, we think, in the placebo arm.
Mm-hmm. Okay.
As far as I think I've heard from them, it's like the first week of July, so it may make for a challenging Fourth of July weekend for us.
Yeah. Good. We're looking forward to the more color, evolving field. Going back to Jeff, now asking about revenue.
Yeah.
If, say, APOLLO-B of the ONPATTRO got approval for cardiomyopathy, where do you see the initial patient population that could be coming from and then meaningful revenue contribution?
Let me just talk a little bit about ONPATTRO CM. When we put the guidance out, one thing I just wanna highlight is obviously the PDUFA date being October 8th. The expectations in terms of contribution to revenue this year are pretty modest as a result of the approval in Q4. The revenue impact expectation would be greater in 2024. In terms of where we see opportunities for ONPATTRO, upon, you know, if we get the FDA approval, I think two 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, I think based on being a Part B medicine that will have some advantages there that may allow easier access for patients. The second area is for those patients that don't respond adequately to the current therapy in the market. Remember, this is.
Progressive fatal disease. For patients that are not doing well on the current therapy, you know, frankly, there's a desire and in some cases a desperation to have access to another therapy. 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. How do you see AMVUTTRA and ONPATTRO revenue dynamic in, say, 2023 going forward?
Yeah. 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. We got approval about mid-year 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. 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 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., 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 150-200 patients a quarter. 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 two quarters, right, we've had ONPATTRO on the market since 2018, and with two quarters of launch under our belt with AMVUTTRA, we've expanded the prescribers, first-time prescribers, by about 30% in the U.S. over those two quarters. We're really encouraged with that. In terms of the dynamics between ONPATTRO and AMVUTTRA, you know, my expectation is as we switch more and more patients off of ONPATTRO, you're gonna see less of that just because there's fewer patients remaining on ONPATTRO.
Mm-hmm.
The driver for growth here is certainly gonna be, you know, new starts on AMVUTTRA going forward.
Okay. Very helpful. We have a few minutes. I do want to touch on pipelines. You have actually very rich pipeline.
Mm-hmm.
Starting with APP program. You will have a data set early 2023.
Yep.
Can you give a little bit more color? First quarter is almost done, like, is it fair to say we will see 2Q?
Yeah. At this point, we expect it to be more in Q2. Our nomenclature early is Q1 or Q2, but we're almost done with March and Q4.
Okay. You know, the expectation on the data and also what is, you know, what is the impact to the CNS indication?
ALN-APP, just to step back, is our first siRNA program to target the CNS. 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. For phase I, we're in a single ascending dose portion of the study. Primary endpoint will 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. We'll really be looking for approximately 50% knockdown. We've, you know, kinda we don't really know what's gonna be appropriate or necessary clinically in this disease.
Nobody's actually tried to target the upstream APP protein itself. Given the genetics we see in those diseases where APP production is increased or the proteolysis is increased, where the peptide fragments are actually increased, you see earlier onset of disease. Conversely, there's some pro-protective mutations, in particular Iceland, where you have less APP production and you actually see a protective benefit. Human genetics give us a little bit of insight, and that's why we're aiming for this around 50% knockdown.
Mm-hmm. Regarding the dosing frequency, you know, what will be your goal?
Goal? Well, because this is an intrathecal infusion, obviously the less frequent, the better. We have really interesting non-human primate data that showed significant knockdown of the protein out to six months. We don't know the translatability from NHP to humans in CNS products. We obviously have a great database in liver, we often see an extension of durability once it translates to humans. 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. Ideally, I think we'd be looking for at least every six months dosing, if not even annually, given the IT infusions.
Very good. Maybe I will save the Alzheimer question to a different time. You know, mechanistically, what does that mean, you know, to the actual, like, the turnover of amyloid? If you can have a quick comment. Yeah.
Briefly, we don't know, right? No, no, to our knowledge, no mechanism has 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.
Mm-hmm.
than the active removal from the monoclonal antibodies.
Mm-hmm.
We think that may have some upsides too, where you may not see some of the safety
Concerns, I guess you could say, with the 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. Another important part of this will be your first indication in CNS.
Yes.
You know, then what will be Like, if you were able to achieve biannual minimum and, you know, 50% the target engagement, then with that data, where do you think you can, you know, the translatability to other indications, what will be the next top candidate you will be thinking about?
Yeah. Excellent point, right?
Mm-hmm.
there's success in the data that will help with this APP program.
Mm-hmm.
Also what does it mean for the broader platform?
Mm.
ALN-SOD1 is one program we've already talked about.
Mm-hmm.
with the public for SOD1 driven ALS. That's being led by our partners, Regeneron, but we're participating in that.
Mm-hmm.
We've also talked in the past about Huntington's as another potential area. 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.
Okay.
It could be very exciting to open up a whole another tissue type for us in our platform.
I think Huntington's is the indication I think a lot of companies show the interest. Like, was the steering committee, you together with Regeneron, determining this to move to the next step?
Where arrangement, once a target is named into the relationship, in this case, Huntington's, we on our element, our research groups works on developing a product that actually hits that that target.
Mm-hmm.
There's a joint steering committee that ultimately reviews the data and says, "Yes, we'll name this a development candidate." You figure out who's taking it forward and moving it into the clinic.
Okay, good. I know we are running out of time.
I know.
Maybe-.
Much to talk about.
I know. Maybe quickly on the hypertension program.
Mm-hmm.
You know, the what could be approvable endpoint, you know, data expectation, and also the magnitude of benefit that will be considered clinical meaningful.
..zilebesiran is our program targeting angiotensinogen, which is at the top of the RAS cascade, a known mechanism for lowering blood pressure. In phase II, it's currently a KARDIA-1 study and monotherapy, really a dose exploration study for different doses and dose regimens. KARDIA-2 is a combination study on top of one of three 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 six months after the single dose. we're hoping and expecting to see, you know, something greater than 5 millimeters of systolic blood pressure reduction would be considered clinically meaningful. based on our phase I data, especially in a monotherapy setting, we would expect to see something more than that. those data are expected in KARDIA-1.
The monotherapy study is expected in mid this year. For KARDIA-2, the combination studies, we're expecting those data at or around year-end 2023.
Okay. Very good. Well, thank you very much, and I will look forward to a tons of update later this year.
Thank you.
Thank you, everyone.