The Road to Success in ALS: Details of the AMX0035 CENTAUR Trial

Sabrina Paganoni, MD, PhD

Amylyx Pharmaceuticals recently announced positive top-line results from its phase 2 CENTAUR trial (NCT03127514) in amyotrophic lateral sclerosis (ALS), showing that treatment with its novel drug, AMX0035, resulted in a statisically significant slowing of disease progression as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). Just a week after the ALS community suffered another significant loss in patient advocate and ALS Ice Bucket Challenge promoter Peter Frates, the findings have invigorated a global community that is longing for signfiicant treatment advancement.

In an interview with NeurologyLive, CENTAUR principal investigator Sabrina Paganoni, MD, PhD, discussed some of the unique elements of the carefully designed trial that she called "a great example of ALS community collaboration."

NeurologyLive: What makes AMX0035 different from current treatments available for ALS?

Sabrina Paganoni, MD, PhD: The drug is actually a combination of two drugs: sodium phenylbutyrate (PB) and tauroursodeoxycholic acid (TUDCA), and was designed to simultaneously target 2 pathways that are thought to be important in ALS pathophysiology. Specifically, the 2 drugs target endoplasmic reticulum stress and mitochondrial dysfunction, which are thought to be cellular pathways that are broadly involved in ALS. The current FDA-approved medications for ALS, riluzole and endaravone, target different pathways. We're still learning more about these drugs and their exact mechanism of action but broadly speaking, riluzole targets glutamatergic pathways and endaravone targets oxidative stress although again, we're still learning about the exact mechanism of action. While AMX0035 targets other important pathways, it's really good that we have drugs targeting different pathways because we know that ALS pathophysiology is complex and there are probably multiple mechanisms that lead to motor neuron death.

Were there any unique elements to the design and implementation of the trial that sets CENTAUR apart?

The CENTAUR trial has been a great example of ALS community collaboration with partnerships between Amylyx Pharmaceuticals and academia, and specifically the NEALS Consortium, The Neurological Clinical Research Institute at MGH, and the Barrow Neurological Institute.

In terms of study design, we designed inclusion/exclusion criteria to target a relatively homogenous, fast-progressing patient population. That was possible because the study design was modeled after PRO-ACT, which is the largest publicly available clinical trial database that includes data from over 10,000 ALS patients who participated in previous clinical trials. So by looking at the rate of progression of patients in this trial and also in the ceftriaxone trials for ALS, we were able to design inclusion/exclusion criteria to enroll a population of fast progressors because we knew that would increase our statistical power to see a treatment effect. These patients are not biologically different from other people with ALS; this was basically a statistical strategy to increase our power to see a treatment effect with a relatively smaller trial.

READ MORE: ALS Treatment AMX0035 Slows Disease Progression

Are the results perhaps more meaningful since they were observed in a cohort of patients with faster progressing disease?

I think it's good news that we were able to see the treatment effect in people who have a fast progressing form of the disease and the hope, again, is that it will translate to everyone, and that this can be a new therapeutic for everyone. We're not yet sure what is going to happen in terms of development, but the trial was positive and we're very excited about that.

What were some of the details of the trial? What primary and secondary endpoints did you explore?

We recruited 135 participants, and they were treated for 24 weeks with either AMX0035 or placebo in a 2:1 randomization, so more people were given active drug than placebo. All people who completed the placebo controlled trial were eligible to move on to the open-label extension trial, and the majority of people did, as they wanted to continue to get access to the drug. So we still have people taking the drug as part of this open-label extension. The primary endpoints were a combination of classic, well-established endpoints for ALS, as well as novel endpoints and new biomarkers. So the primary endpoint was the ALS Functional Rating Scale-Revised (ALSFRS-R), which is the gold-standard ALS functional endpoint; its essentially a questionnaire that evaluates function, where the highest scores indicate people who are more independent and lower scores indicate less independency on things like ability to talk, swallow, write, cut food, walk, climb stairs, and read. It's a clinically meaningful scale because it evaluates the ability of people to function in these important domains. We also had other biomarkers, more exploratory biomarkers, to contribute to our knowledge about treatment effect.

Detailed analysis of the results is still ongoing, but at this point, top-line results show that the trial met its primary outcome, meaning that it showed a statistically significant slowing in the ALSFRS-R. Additional outcomes and analysis will be presented soon in a publication and conference.

What's next in terms of development and steps to bring this therapy to the public?

As you know, most ALS trials do not have positive results in the primary outcome, so we're particularly excited to have hit the primary outcome. And now we will continue to analyze data and present all of these in 2020 in detail and we'll see where we land with that. It's very exciting news for the patients. I know that there is a commitment to advancing the process further so that hopefully we can give access to patients in the near future. I can tell you on the scientific side, it's exciting and I hope to see next steps soon.

This is a time of great hope for ALS and so we need to continue to raise awareness and fund research. I think we will see new treatments on the horizon because of the interest from the scientific community and the investments and the fundraising efforts. All of this contributes to providing people with hope, and hopefully with results as well.

Transcript edited for clarity.