Hi, good afternoon, everyone, and thanks for joining us for this next session of Baird's Biotech er Health, Healthcare Conference. I'm Joel Beatty, one of Baird's biotech analysts, and I'm pleased to have with us today Amylyx. And with us, we have Justin Klee, co-CEO, and as well as Camille Bedrosian, the Chief Medical Officer. Thank you so much for joining us.
Yeah, our pleasure. Thanks so much for having us here.
Okay, so to begin, could you just give us an overview of Amylyx?
Yeah, very, very happy to. So, we're very excited that the position we're in and our pipeline, and so maybe to go through our assets in brief. So our lead asset is avexitide. It's a first-in-class GLP-1 antagonist with Breakthrough Therapy Designation for the indication of post-bariatric hypoglycemia. So post-bariatric hypoglycemia is a condition that happens in a rare subset of people in the years following bariatric surgery. They develop this very progressive, persistent, severe form of hypoglycemia. There are about 160,000 people, we estimate in the United States, who currently have post-bariatric hypoglycemia, and there are no treatments available. So the asset of avexitide, there have been five clinical studies, including two phase II studies supporting its use in PBH.
Very clinically and statistically significant on the outcomes, including reduction in level two and level three hypoglycemic events, which is what led to the breakthrough therapy designation. So next steps there is to get our phase III up and running. That will happen in the first quarter of the coming year, with data readout the following year. Our next program, AMX0035, for the treatment of Wolfram syndrome. We announced interim data earlier this year, showing an increase in C-peptide, which is a direct measure of insulin production or secretion by the beta cells. That was surprising in a very good way. We were hoping to perhaps slow disease progression, but to see an increase in a marker that typically decreases over time, it's very exciting.
In October, the principal investigator, Dr. Fumihiko Urano, will be presenting data on all 12 participants from the study. That's in October at the International Society of Pediatric and Adolescent Diabetes, and as well as longer term data for the participants who are out now to week 36 or week 48. In our PSP program, again, AMX0035 for the treatment of PSP, we will have interim analysis data mid-next year, and that will be a full look at efficacy. The rationale for PSP was following a study in Alzheimer's disease, where AMX0035 showed very significant reductions in both total tau and phospho tau 181.
PSP is a tau-driven neurodegenerative disease, so this will be a very exciting look at both the ability to lower tau in people with PSP, as well as the potential impact on clinical outcomes, namely the PSP Rating Scale. And then finally, our AMX0114 antisense oligonucleotide targeting calpain-2, we are working to get that into clinic by the end of this year. That is for the treatment of ALS. Calpain-2 is one of the key effectors in axon degeneration, and this is an antisense oligonucleotide that knocks down calpain-2 production, and thereby helps with axon degeneration, including preclinically, we've seen effects on neurofilament light chain.
We'll be excited to get that into clinic, and then, next year we'll start to have our cohort level data in CSF biomarkers, as well as, of course, safety. We're very excited about our pipeline. We have many milestones coming up and in the near future, and excited to get to dig into those.
Awesome. Yeah, so a lot to dig into there, and let's begin by going back to avexitide for PBH. Could you help frame how large the potential market opportunity is there?
Yeah, I'm happy to, and then maybe I can pass to Camille as well. So post-bariatric hypoglycemia, we estimate occurs in about 8% of people following bariatric surgery. Now, on average, it takes one to three years, sometimes even longer, for this to present. Now, post-bariatric hypoglycemia is not just hypoglycemia following bariatric surgery. That occurs in probably one in three people. This is a particular condition where people have a very persistent, often progressive form of hypoglycemia, where people may experience hypoglycemic events multiple times in a week. To give a sense, what that means is neuroglycopenia. So our brains are probably the largest glucose utilizers in the body, so when we don't have enough glucose, our brains stop functioning the way that they're supposed to.
So first, it presents as perhaps autonomic symptoms, sweating or tingling sensations, but then, lack of focus, inability to remember things, even loss of consciousness and seizures, occur. And for people with PBH, this can occur multiple times in a week. We've heard some people may have multiple episodes in a day. And the challenge is essentially their set point is wrong. Their glycemic index is too low. Based on the fact that there have been well over 2 million bariatric procedures that have happened, that have been performed over the past decade, we estimate that about 160,000 people who have post-bariatric hypoglycemia today. It's a persistent condition, so that number will only grow over time. So it's an orphan disease, but it's a large orphan condition, and there are no treatments available.
The data of avexitide in the phase II trials of PBH suggest that this may be a game-changing treatment for people with PBH, which we're, you know, very excited about and hopeful that we can provide a real difference to people who really need it.
Got it, and trying to think through that market opportunity a little bit more, is there a like spectrum of PBH in these patients post-bariatric surgery? And if so, you know, kind of what's the definition of a patient that you believe, you know, could benefit from avexitide?
It's a great question, and I would say, when we define PBH, what we really are meaning is people who have this persistent hypoglycemia. So when we talk about the addressable market, we really mean the 160,000 people. If you were to look at people who had hypoglycemia following bariatric surgery, you'd be looking in the, you know, many hundreds of thousands of people. Now, I think further in development, we may test to see is it worth testing earlier or testing in a larger population. But for the moment, the Breakthrough Therapy Designation is in that 160,000, which, as you might imagine, is a very high unmet need.
When talking with endocrinologists, many have even set up multidisciplinary care teams to help people with PBH because it's quite complicated, and unfortunately, we really don't have therapies that can address the underlying disease yet.
To give you a sense of the hypoglycemia that these individuals experience, and we spoke about Level 2 and Level 3 hypoglycemia, which are the endpoints that the event rates that were studied in phase II, and the endpoint that we plan to study as well in phase III. Level 2 events are defined by glucose levels below 54 mg/dL. We would be woozy, not really thinking sharply or clearly if that was our glucose level. Level 3, and in the studies, it was measured by continuous glucose monitoring, followed by a finger stick when the alarm of the monitor went off, when the glucose went below a certain level.
And then Level 3 is less about an absolute glucose level and more about the fact that these individuals are unable to help themselves and recover from a hypoglycemic event, and they need another person there physically to help them get them out of harm's way and also give them something to raise their glucose levels.
Got it. So maybe on that point, in the previous studies of avexitide, how much of a benefit was shown in those endpoints?
Sure, sure. In the phase II-B, where the dose that we plan to study in phase III was studied, 90 mg once a day or 45 mg twice a day. Then in the 90 mg dose cohort, the decrease in Level 3 events went down by 66% and Level 2 events by 53%, which is, you know, and highly statistically significant, several zeros before a p-value. So p-value 0.0004 or 0.0003 or 0.003. And that was in a relatively small study, and yet they're highly statistically significant. During the run-in period, where patients were deemed eligible or not, they had to have a certain number of events during that time, and they averaged about three events per week, and I think that's what you mentioned also.
During the study, the event rate overall went down to one per week, and some had no events at all.
And so, to you know underscore that, so the phase III acceptable endpoint, it's in the FDA guidance for hypoglycemia, is a composite of Level 2 and Level 3 hypoglycemic events. So we're going into phase III, having run two prior phase II studies that hit exactly the Level 2 and Level 3 events with high degrees of significance and clinical significance, as Camille was saying.
Terrific. So maybe let's move on from here to Wolfram syndrome. Could you review the data to date in that setting?
Sure, I'm happy to do so. Thanks. Yes, so, earlier this year, we presented interim analysis of eight of the 12 participants in the Wolfram study. And, just to remind, Wolfram is a monogenetic disorder, rare, to be sure, that is a neurodegenerative disorder. It actually manifests, the neurons degenerate, and also, in this condition, based on the gene, the beta cell also degenerates, and, the beta cells are lost over time. So individuals actually have insulin-requiring diabetes as early as six years of age. Between six and nine, they manifest their, that first symptom, and then during the course of childhood, they develop a progressive visual loss due to retinal ganglion cell loss, not retina, but the ganglion, optic nerve atrophy. And other manifestations of the disease include, brainstem cell loss, which manifests as ataxia, difficulty swallowing, breathing, et cetera.
So in our study, we focus on two of the main manifestations of the disease that occurs in most people, and that is the insulin-requiring diabetes and visual acuity, and what we showed in the eight individuals earlier this year was, well, first, let me say that the hypothesis going into the study was that we would slow progression of the disease, so slow the progressive loss of beta cell function, or the ability of the beta cell to secrete insulin. And what we saw was, very much to our surprise, happy surprise, that we actually saw improvements in beta cell function and improvements in insulin release in the setting of a mixed meal tolerance test challenge.
That insulin secretion was measured by C-peptide, which is separate from exogenous insulin and is a measure of beta cell function. We saw that and also other measures of glycemic control. Hemoglobin A1c was improved in six out of the eight participants, and then the visual acuity also in individuals, in this case, who are adults with many, many years of this condition, with substantial visual acuity loss already. We saw five of the eight individuals have actual improvement in their visual acuity. It was modest improvement, to be sure, but we were expecting maybe to slow down the deterioration and slow down the loss of visual acuity. We were very excited about that, those data.
Yeah, so nice update that we had recently, and then another fuller update coming in about a month.
Correct. Yes. So, in October.
What can we expect?
So in October, yes, absolutely, Joel. So in October, there'll be an oral presentation, as Justin mentioned at the ISPAD Congress, International Society of Pediatric and Adult Diabetes, where we'll share all the results of all 12 participants through 24 weeks. And the subset of individuals who we, about whom we shared earlier this year, will have reached their 36 or 48 week milestone, and we'll share data from those, at those time points as well. Similar sets of data at that time, including, of course, safety, as we did before.
Great, and then thinking ahead to the phase III, what could be the potential, I mean, trial design or primary endpoints that you'd be focused on?
Right. So, we're in the midst of working through that, those exact points, Joel, through discussions with many stakeholders, including experts in the field, as well as the FDA. So when we have reached our decision about that and concurrence on that, we'll share that plan as well.
Sounds good. And you may not be able to share more, but I'll ask you: Do you have a sense on if that would be able to be a single arm study or a randomized control study?
Yeah, so we're working through that. First, there will be another study, and we do believe that potentially a single study will serve, assuming positive, of course.
Got it. All right, so let me... let's move on to the next setting of PSP. You've got a large study underway there. What prompted such a large study for PSP?
Yeah.
I think what drove it was first the preclinical data that we have on AMX0035 and protecting against neuron loss. Then also the mechanism, I think, ER stress and mitochondrial dysfunction are very clearly associated with degeneration in PSP, and then I think what was really exciting was we ran 100 participant Alzheimer's study. We just published that data last month, and the drug showed very significant lowering of total tau and phospho tau in CSF, so we went to experts in various fields of neurodegeneration, and the feedback we got was PSP is considered really the sort of purest tauopathy. It seems to be a very tau-driven neurodegenerative disease. In fact, the genetic association of mutations in tau with PSP is, like, 10 to the negative hundred, so it's very, very clearly a tau-driven neurodegenerative disease.
There's also a very clear pattern of brain degeneration in PSP, and the rating scale is quite reliable, as sadly, is the progression rate in PSP, so all of that combined, there is very strong rationale to test AMX0035 for the treatment of PSP, and very sadly, there's no treatments available, despite it being a very significant population who really, really need treatments. So when we were designing the study, I think the questions were twofold. First, how can we have an efficient path to a potential approval, given the high unmet need and the rationale here, but also, how can we get a sense that the treatment is doing what we hope it should in PSP, so I think we've achieved both.
So we're running an operationally seamless phase II-B/III trial. We are doing an interim analysis, where we will look at efficacy, including biomarkers, including the rating scale, at a you know midpoint in the trial, so we'll have that mid-next year. And so that will give us, I think, a good go, no-go signal to then expand the population or not. But I think what's really exciting is, in many ways, this is the first small molecule or agent that can cross the blood-brain barrier and be intracellular and lower tau and to be tested in PSP, being a tau-driven neurodegenerative disease. So the PSP experts are very excited about this study. I think it's a very important study to see if, first, we can lower tau.
Like we showed in our Alzheimer's study, and then second, if we lower tau, do you have the effects on the clinical outcomes as well?
Got it. And roughly, when do you expect the interim analysis to occur?
In the middle of next year, so you know, trial's actively recruiting, you know, people are actively participating in the study, so on track for readout, interim readout mid-next year.
Got it. And, as you, and I believe it's 100, about 100 patients .
In that interim analysis. Once you hit an enrollment of a hundred, would you continue to enroll, or does enrollment kind of pause once you hit a hundred until we learn the results of the interim?
Yes, that's sort of the definition, if you will, of an operationally seamless study. We will pause enrollment, although the study will still be active. The 100 participants will continue being treated in the study, and we'll do a fulsome analysis, as Justin indicated, unblinded, so that we can understand the results in a total way. And then, you know, hopefully there'll be a go decision. Then we'll resume enrollment with a new cohort of patients for the phase III portion of the study.
Got it. So what could positive data look like this? Kind of what specifically are you looking for when you consider making the go, no-go- decision and, you know, what are the potential outcomes? So can you kind of just should we think about two kind of binary outcomes, go or no-go?
It really will depend on the totality of the data. You know, what was the effect of the biomarkers, tau, p-tau in particular? There are a few other biomarkers too, but those are the main ones, given the role of tau in progressive supranuclear palsy. We have some imaging to see if we are slowing down the loss of brain matter in the disease. We'll look at the PSP rating scale, which, as Justin indicated, is very reliable, relatively speaking, for a neurodegenerative and a rating scale type measure, because three other studies have been conducted in PSP.
Unfortunately, they were not positive, but in each instance, the placebo group showed the same rate of decline in PSPRS over a year as across the three studies. So we have a good sense of how, unfortunately, people with PSP progress over time. So we'll be able to not only compare between placebo and AMX0035, but also judge that based on how the disease generally progresses.
So seamless phase II, phase III, any sense of how large the phase III trial would be, or do you kind of fill that out from the interim analysis?
Yeah, the interim analysis will inform us quite a bit, including the ultimate power for the phase III.
Great. So moving to ALS and the calpain-2 agent, could you tell us more about what makes calpain-2 a promising target for ALS?
Yeah, very happy to. So calpain-2 has been studied for decades, and it's one of the key effectors of axon degeneration. In ALS, one of the hallmark pathophysiological signals is that the neuromuscular junction sort of breaks off from the muscle, and the axon retracts. So the question is, you know, how does that occur? And we think, at least based on preclinical studies, we have a pretty good sense of how that process goes. And one of the main drivers of that is calpain-2, which is a calpain-driven protease.
Calpain-2, being a protease, it cleaves many things, including the actual filaments, which we believe is perhaps one of the reasons that we see such elevations in neurofilament and particularly neurofilament light chain in ALS, is that there's very high calpain activity, which is cleaving the axon, and then you get these filament fragments that show up in the CSF and actually plasma as well. So the question then is: Well, if this is such a great target, why has it not been targeted before?
And I think the challenge is a fewfold. First, there are multiple calpains, and we believe that you want to very particularly target calpain-2, t hat's where having antisense oligonucleotide is a really nice approach because you can be very confident that you are knocking down calpain-2 and not calpain-1, calpain-3, calpain-5, et cetera. There's also the ever-present conundrum in neurology of: How do you get sufficient exposure in the CNS? Well, I think there have been many examples now that ASOs and RNAi and other drugs can be administered intrathecally at regular intervals, and I think particularly in areas of high unmet need, like ALS, it's a reasonable dosing regimen. So that's why we developed in-house a 5-10-5 gapmer antisense oligonucleotide targeting calpain-2. It's very potent.
As you can see from some of our presentations, it very potently knocks down calpain-2 mRNA, and the mRNA stays knocked down, which is nice as well, so that we can have a not burdensome dosing frequency. So in the upcoming study, we will be dosing participants intrathecally. These will be people with ALS, and we'll be looking, of course, primarily at safety as we increase dose, but also at biomarkers, including neurofilament light chain. Given in our preclinical studies, the calpain-2 ASO AMX0114 showed very strong reductions in neurofilament light chain. So, we're really looking forward to getting that study up and running, and we hope to have the first cohort-level data on safety and on biomarkers next year.
Great. And what type of dosing regimen are you planning on using in that first-in-human study?
Right. So, we'll plan initially at once-a-month dosing intrathecally, and of course, we'll be gaining pharmacokinetic data to dovetail with the pharmacodynamic data, and that will also inform us over time what the ultimate ideal regimen might be based on those parameters.
Great. So maybe to begin closing things out, could you tell us about the cash runway for Amylyx, and kind of what's included from all these programs in that cash runway?
Yeah, critical question. So we ended last quarter with about $310 million in cash, no debt. Now, that did not include our acquisition of the avexitide, which we did just in this current quarter, and we acquired it for $35.1 million. But so we're in a strong financial position. We believe that will get us into 2026, and to the key milestones I mentioned. So certainly our Wolfram data in October, as well as funding for a further Wolfram study, our PSP interim analysis mid-next year, our cohort-level data from our AMX0114 ASO, and critically the readout from our PBH study with avexitide, which we expect in 2026.
So, we're very excited about the number of catalysts we have, and of course, having both the finances and team to make sure that we execute on those.
Terrific. I think with that, we're reaching our time, so, thank you so much for the overview and for joining us today.
Excellent. Thank you so much.
Thank you. Thanks for your questions.