Expert Insight on Pivotal Phase 2 Data of AMX0035 in Wolfram Syndrome

Fumihiko Urano, MD, PhD

Wolfram syndrome is a rare, monogenic neurodegenerative disease characterized by childhood-onset diabetes, optic nerve atrophy, and neurodegeneration. Because of the lack of approved therapies, treatment for the disease has consisted of managing the symptoms and complications as they arise. The use of anticonvulsants for seizures and physical therapy to manage the movement disorders aspect of the disease have been well-documented.

One agent, AMX0035 (Amylyx), which is a combination of sodium phenylbutyrate and taurursodiol, has shown promise as a potential therapeutic option for patients with Wolfram syndrome. Recently, Amylyx announced positive topline data from a phase 2 open-label study, dubbed HELIOS (NCT05676034), a 12-participant, single-site, single-arm, proof of biology trial. All told, treatment with the agent resulted in significant improvements in the primary end point of pancreatic function, as measured by C-peptide response, after 24 weeks, in contrast to the expected decrease seen with typical disease progression.

The analysis performed included week 24 data for all 12 participants and data for all participants who completed their week 36 (n=10) and week 48 (n=6) assessments as of the data cutoff. Based on these positive data, Amylyx plans to meet with the FDA and other stakeholders to inform a phase 3 program and expects to provide an update in 2025.

Following the data update, principal investigator Fumihiko Urano, MD, PhD, provided comment on the significance of the findings and what clinicians should key in on. Urano, the Samuel E. Schechter Professor of Medicine at Washington University School of Medicine in St. Louis, gave insight on the reasons behind C-peptide as the primary end point, the safety profile of AMX0035, and the current unmet needs in Wolfram syndrome. In addition, he provided a brief comment on the potential plans of the drug, and how this study will help shape future decisions.

NeurologyLive: Among the topline findings, what stands out from a clinical perspective?

Fumihiko Urano, MD, PhD: The HELIOS topline data are encouraging for several reasons. In HELIOS, we observed that participants experienced improvements in the C-peptide response, Hemoglobin A1C levels, as well as other measures of glycemic control. These data suggest that treatment with AMX0035 improved beta cell function potentially by reducing beta-cell endoplasmic reticulum (ER) stress. Furthermore, the longer-term data indicated sustained improvement in these measures.These results are particularly encouraging given that natural history studies show that C-peptide levels progressively decline in patients with Wolfram syndrome, which is a progressive disease with both progressive loss of beta cell function as well as progressive neurodegeneration.

What is particularly interesting about these findings related to C-peptide or diabetes-related outcome measures is that AMX0035 is not a diabetes drug, yet our current data show improvements in beta-cell functions and also diabetes-related outcome measures. These findings strongly suggest that AMX0035 targets the root cause of the pathophysiology of the disease, which is ER stress and resulting mitochondrial dysfunction. Thus, AMX0035 may also reduce ER stress in different organ systems or tissues such as retinal ganglion cells in the eyes (associated with vision loss) and brain cells.

Why the choice to use change in C-peptide as the primary end point?

C-peptide is a well-established, objective measure that is used as a surrogate marker of pancreatic beta cell function and glycemic control. It has been used as a primary outcome in several major diabetes trials for type 1 and type 2 diabetes. Wolfram syndrome is a progressive disease, and the natural history is for C-peptide levels to deteriorate or decline over time. In HELIOS, change from baseline in C-peptide was assessed using a Mixed Meal Tolerance Test (MMTT).

And to our knowledge, this is the first time there's been an increase in C-peptide across any diabetic trial.

Besides being well-tolerated, what did the safety profile look like for AMX0035?

Safety findings for HELIOS were consistent with previous AMX0035 clinical trial data, namely AMX0035 was generally well-tolerated and no new safety signals were identified. Diarrhea was the most common treatment-emergent adverse event, and all cases were of mild intensity. It is important to note that while nearly all participants reported at least one treatment-emergent adverse event, none led to discontinuation.

While there are no approved therapies for Wolfram, what are the best ways we can try to impact the disease and change patients’ trajectory course?

The Wolfram syndrome community is the driving force of innovation, and it was their advocacy that encouraged me to dedicate my career to uncovering solutions for this devastating disease. Time and time again, parents and patients are told that there are no options, yet they refuse to give up hope - and neither can we.

We have made incredible progress in understanding the pathophysiology of Wolfram syndrome over the last two decades as we work toward a cure. I believe before I retire, we will find a cure or a way to stabilize the disease so patients can have a good quality of life - that is a goal that myself, my lab, and our research and industry collaborators share, and it drives us forward each day.

Any early thoughts on what a phase 3 design would look like? Obviously nothing set in stone, but if there were some key things you’d know you’d incorporate, I’m curious.

While I can’t speak to Amylyx’ discussions with regulators and other stakeholders regarding a Phase 3 trial, from a clinical perspective, I am encouraged by the Phase 2 data of all 12 participants through 24 weeks and look forward to continuing this research. I’d be interested in continuing to look at important outcomes for patients, like C-peptide, Hemoglobin A1c, visual acuity, neurogenic bladder symptom score, assessment and rating of balance, etc., to build on what we have observed in HELIOS.