Produces insulin and raises the Blood sugar nadir, which is particularly important in diseases of hypoglycemia. It has FDA breakthrough therapy designation in both Post-bariatric hypoglycemia and congenital hyperinsulinism. Our focus right now is on Post-bariatric hypoglycemia, where there have been five prior trials, all of which showed significant effects on glucose and insulin. We are now conducting the phase III trial. We have started recruitment. We expect to have recruitment complete by the end of the year, with data in the first half of 2026. That is our lead program, and we can talk a lot more about that as we go through, including kind of the unmet need that these patients face, which is quite significant. Very briefly, on the rest of the pipeline, we have AMX 0035, which targets endoplasmic reticulum stress and mitochondrial dysfunction.
We just reported data in Wolfram syndrome, phase II data that showed benefit across all the measures that we were measuring in Wolfram syndrome, which is an ultra-rare kind of endocrine and neurodegenerative disease. We also have data coming in the third quarter in progressive supranuclear palsy, which we've been excited about based on tau lowering that we've seen with AMX 0035. In our view, AMX 0035 is the only drug that both crosses the blood-brain barrier and gets intracellular and reduces tau. PSP is a Tauopathy, so that's where that kind of makes a lot of sense. Finally, we've started recruiting with AMX 0114, our antisense oligonucleotide targeting calpain-2 in ALS. We expect to have some early cohort data by the end of the year. With that drug, we've seen effects in the preclinic, including on biomarkers like neurofilament. We'll be interested to see if those translate into the clinical data as we get later into the year. But back over to you.
Great introduction, Josh. I actually want to take a step back. Just yesterday, you guys presented the long-term data from the Helios trial in Wolfram syndrome. Can you just get the room up to speed on what Wolfram syndrome is and what has the data told you?
Yeah, very happy to. Thank you. Wolfram syndrome is a monogenic disease caused by mutations in WFS1. Those mutations, WFS1 encodes for the Wolframin protein. Wolframin is a trans-membrane protein. When it's dysfunctional, it directly causes endoplasmic reticulum stress and mitochondrial dysfunction. That genetic cause causes degeneration and dysfunction, first in the beta cells of the pancreas and then in different neuron types. As you might imagine, from how I'm describing it, the disease presents as early onset diabetes, kids 6, 7, 8. What sort of cues physicians on that maybe this isn't just early onset diabetes is that kids get progressive vision loss and progressive hearing loss and early mortality. It's really a tough disease. We estimate there are about 3,000 people with Wolfram syndrome in the United States. It's very much a global disease as well.
We've been working in Wolfram syndrome now for almost eight years. As you might imagine, with the mechanism of Sodium phenylbutyrate and taurursodiol targeting stress and mitochondrial dysfunction, it's very much a match of the mechanism of the drug to the mechanism of disease. We've been evaluating AMX 0035 in a 12-person open-label clinical study in adults with Wolfram syndrome. When we went into the trial, our hope in a progressive disease, especially in adults who have had the disease for some time, was to slow progression. We've actually seen stabilization or even improvement over time. What we just presented yesterday was the full cohort out to week 48, so about a year of dosing now. What we've seen is actually the sustained improvement over time, particularly in C-peptide. C-peptide is a direct measure of insulin production. It's how much the body is producing, secreting insulin, which means the beta cells are functioning better. To our knowledge, this is the first time in any diabetic condition that C-peptide is increased because, again, it means that the beta cells are functioning better. We're very excited about the data, what it might mean for people with Wolfram syndrome. Now we're working on the design of a phase III study, and we'll update on that this year.
One of the really exciting things about this most recent data update is it's supposed to inform your discussions with the FDA. What can you tell us about what they're looking for, trial design, anything you can share?
Yeah, I'd say probably at the highest level, stay tuned. We're still having those discussions. Certainly, when we have the final design of a phase III, we will share that. I'd say, though, we are quite excited about the data as just well. We show improvement numerically on the C-peptide. All the other measures move in lockstep with that. You see on the Hemoglobin A1c , on the time and target range by CGM, all those are moving in lockstep together with the C-peptide, which is what you hope to see. It kind of gives you added confidence in what you're seeing. Additionally, we saw stabilization or some improvement on Visual Acuity . These are patients who generally go blind over time. To see the vision pretty flat or even possibly improving was quite exciting. Patients were also asked, and the clinician was asked, is the patient stable, improving, worsening? Every patient was described as at least stable or improving by both the clinician and by the patient. It was a strong initial result, but it's also the first, we're the first company to be developing an Interventional therapy in Wolfram syndrome. I think that's, and it's a multi-system disease. There are a lot of things you could measure. I think those are kind of what drive the discussions with the FDA of what is the best measure, hopefully, to bring this ultimately to patients.
Maybe just in the interest of time, let's turn to Avexitide, which is the company's lead asset. Again, can you just set the stage for the audience? What have you seen in the phase II data? And how do you expect the data to show up in phase III?
Yeah, certainly, I wish I knew the answer to that now, but I'd say our hope is really if we can even replicate what we saw in phase II, I think that would be a really meaningful advance for people with post-bariatric hypoglycemia. The phase II trials showed very significant reductions in Level 2 and Level 3 hypoglycemic events. Level 2 is defined by blood glucose. Level 3 means that the person is so incapacitated that they need independent help. That can be severe confusion. It can be loss of consciousness. It can be seizures. These are really dangerous episodes. In both phase II trials, Avexitide showed very significant reductions in both of these types of events. Furthermore, it showed dose dependency as well. In the phase III trial, we're testing the highest daily dose tested, 90 mg once daily. These are what supported FDA Breakthrough Therapy Designation . The fact that PBH is a really significant unmet need. We estimate about 160,000 people in the United States currently have PBH. Unfortunately, it doesn't go away. The population will only grow. There are no treatments currently approved for PBH. As Josh was saying, we go into this trial with a lot of excitement at the potential of what this could mean for people with PBH. We'll look forward to having those results in the first half of next year.
Maybe just to highlight as well, probably one of the key results from the past trials, five past trials, so maybe this is still one of the key results. In the phase II- B, the 90 mg dose, which is the dose we're taking forward in phase III, showed a 53% reduction in Level 2 hypoglycemic events with a P-value of 0.004 and a 66% reduction in Level 3 events with a P-value of 0.0003. In the phase III trial, we're measuring Level 2 and Level 3 hypoglycemic events. Our primary outcome is the composite of Level 2 and Level 3 hypoglycemic events. We'll share the data on the composite as well at ENDO upcoming in July. As Justin said, strong evidence coming from the past trials and the hope to again see that benefit on the Level 2 and Level 3, which is the agreed-upon primary outcome with FDA. Again, this program is breakthrough therapy status. There has been a lot of FDA interaction. That is the agreed-upon endpoint we believe to support a potential approval.
Just to make it really clear, in your discussions with the FDA and physicians, what's considered a clinically meaningful number of PBH event reductions?
Yeah, it's a really important point and question. I'd start with, currently, as I said, there's no approved treatments for PBH. Unfortunately, the bar is low, especially given what a severe condition this is. In terms of the FDA, as Josh was saying, I think the composite endpoint that we're looking at as a primary outcome is particularly meaningful. The Level 2 and Level 3 hypoglycemic events have been defined now for several decades by the American Diabetes Association and other endocrinology fields, as well as in FDA guidance. When we talk with physicians, what we really hear from them is that they want to keep their patients safe.
If you think any one of these Level 3 events can be life-altering, we've heard many stories about someone driving a car, their blood glucose crashes, they pass out, they crash their car, they end up in the hospital. As we've started to do market research, the number of times people end up in the hospital because of post-bariatric hypoglycemia is just astonishing. You understand from the physician's perspective, really being able to reduce any number of these events is really meaningful. For people with PBH, what we hear consistently is, "Gosh, I just wish I had something." I mean, I think it's so frustrating for them that they finally get the diagnosis and then only to find out that, well, try to stick to this very draconian diet, avoid all carbs, eat small meals very, very frequently. Besides that, there are no approved therapies for PBH. I think it just highlights what an unmet need there is. And again, our hope that we can change that.
One thing to touch on very, very quick too. In the past studies, patients were also interviewed in kind of a structured interview that was conducted with the patients. They were asked, "Now that you've completed this trial, been on this therapy, how would you rate it on a scale of 1 to 10?" Every patient but one that was interviewed rated it a 10. The one other patient rated it a nine. Their reasoning was, yes, the reduction in hypoglycemic events, but they also described just being able to feel a difference in terms of energy, fatigue, things like that. Because if you imagine constantly having hypoglycemia, sometimes severe enough to cause loss of consciousness or otherwise, but even when you have hypoglycemia that's just severe enough to make you lethargic, low energy, et cetera, to suddenly be out of that fog is a dramatic thing for patients. We are certainly, as it relates to the events, as Justin said, even one Level 3 event, which could be losing consciousness or otherwise, is a big deal. Preventing even one of those. What we hope is kind of a more holistic ability for patients to kind of return to their normal life and their normal activities.
Okay, maybe just to wrap up on Avexitide, we know that you guys will have top-line pivotal data in the first half of 2026. But just coming back to something you mentioned, you'll be presenting some data at ENDO very soon. Can you just highlight what the main takeaways investors should have from this data?
Sure. Two abstracts that we'll be presenting. One on pharmacokinetics, basically showing that Avexitide's pharmacokinetics last through 24 hours. We stay above the level where we believe there's therapeutic benefit through 24 hours. We have one abstract kind of on PK/PD modeling. An additional one is running kind of the phase III model on the phase II data so that you can kind of see how that performs. I'll say neither of these do we expect to be particularly surprising, but nice kind of confirmatory and further evidence as we continue going along. I'd say we also noticed at the conference, there is an abstract on the prevalence of PBH. It's a question we get frequently about, since it's a new market, exactly how many patients have this, how severe are they, et cetera. It was quite an interesting abstract, arrived at pretty similar numbers to our 160,000, but arrived from a very different angle and different methods. It is an interesting abstract to look at as well.
With that, I think we're coming to the end of our presentation time. We have another company presenting. I just wanted to add that, as you mentioned earlier, you will have data in PSP in Q3 2025. Look for Josh and Justin to maybe follow up on that. With that, let's stop there.
Excellent. Thank you.
Thank you so much.