A Game-Changing Trial Offers New Hope for ALS

This transcript has been edited for clarity.

Andrew N. Wilner, MD: Welcome to Medscape. I'm Dr Andrew Wilner, reporting from the 2021 American Academy of Neurology (AAN) annual meeting. With me today is Dr Sabrina Paganoni, assistant professor of physical medicine and rehabilitation at Harvard Medical School and co-director of the Neurological Clinical Research Institute at Massachusetts General Hospital. Welcome, Dr Paganoni.

Sabrina Paganoni, MD, PhD: Thank you for having me.

The CENTAUR Trial

Paganoni: We were honored to be featured at AAN and to present additional results from the CENTAUR trial, which looked at a new drug for amyotrophic lateral sclerosis (ALS) called AMX0035. The reason we're very excited about it is because the drug in this trial provided both functional benefits and a survival advantage in people living with ALS. As you know, ALS is a fatal disease with limited options, so being able to conduct a trial with a positive result was really fantastic.

Wilner: There's an available medication for treating ALS patients called riluzole. What I remember about it was that it was very expensive and it didn't help too much. Does AMX0035 do any better? Did you do a comparative study with riluzole?

Paganoni: There's been some good progress in the field of ALS in recent years. Riluzole is now available at a more reasonable price than in the past; there's another approved drug known as edaravone; and a third, dextromethorphan HBr and quinidine sulfate, that really helps with some symptoms and to some extent with other functions.

Nevertheless, these drugs don't completely resolve the problem and don't really slow down the disease in a significant way, which makes it very important to add new therapeutics.

AMX0035 is the first therapeutic to provide both a functional impact and a survival advantage in the same trial in people with ALS. It's definitely exciting news.

We didn't really do a head-to-head comparison because we allowed trial participants to remain on standard-of-care medication. In fact, the majority of the participants were already taking riluzole, edaravone, or both when they entered the trial.

Results from our sensitivity analysis were independent of baseline medication use. That most likely means that we have to treat ALS with a combination of medications, all the medications can be safely combined, and AMX0035 provided added value on top of standard of care, which is obviously good news because we really want to keep adding and continuing to provide added value for our patients.

Wilner: I'd like to ask you to put these results in perspective of the typical survivorship following an ALS diagnosis. If you read the results of, for example, oncology studies that conclude that they've doubled survival, everybody gets very excited. But then you notice that it just went from something like 3 months to 6 months, which isn't really that impressive. Is it true that the average lifespan of someone with ALS is just a few years?

Paganoni: Yes. There is a lot of variability among the population, I should say. But if you just look at the average numbers, we are talking about a rapidly progressing disease with a survival of 3-4 years after the first symptoms.

AMX0035's Effects May Be Underestimated

Wilner: How do you think that will change taking this new drug?

Paganoni: In our trial, we saw a survival advantage of 6.5 months over a 3-year follow-up period in people who were started on AMX0035 compared with placebo.

Now, I want to mention that the trial design was very patient centered. The placebo-controlled portion of the trial lasted 6 months, after which we gave participants the opportunity to take the active drug long-term. By allowing people who originally started with placebo to access AMX0035 after 6 months of the randomized trial, in addition to other treatment, we hypothesize that these results represent a very conservative estimate.

Based on some predictive modeling that we did, we estimate that the true survival advantage may be as long as 1 year. The drug is not stopping or reversing the disease. Nevertheless, I would say that considering the circumstances, it is actually a very significant change and significant impact.

Wilner: This may be an impossible question to answer, because I don't know how well established the pathophysiology of ALS is beyond the fact that it's a neurodegenerative disease, but how does this new drug work?

Paganoni: That's a great question. AMX0035 is a co-formulation of two compounds, sodium phenylbutyrate and taurursodiol. These two components were known to mitigate separate pathways that are implicated in ALS: endoplasmic reticulum stress and mitochondrial dysfunction, respectively.

We already knew from previous studies that each individual compound had neuroprotective activity in clinical models of neurodegenerative diseases, including ALS. When the two components were combined, they were noted to have an even greater neuroprotective effect. The CENTAUR trial was the first time that we studied this particular combination in people living with ALS.

What's Next?

Wilner: Would you consider this a phase 3 trial?

Paganoni: This was designed as a phase 2 trial. Most typically, a phase 3 trial follows a phase 2 trial to confirm the results and provide additional data.

After we completed the phase 2 CENTAUR trial, the company behind AMX0035 announced that there will very soon be a phase 3 trial to provide more data in a larger population with longer follow-up. It will be a global trial conducted in the United States and Europe as well. I think that will allow us to provide definitive answers and ultimately support new drug applications worldwide. The company is already filing some in some categories.

It's a complex landscape, but I think it's getting exciting results so far, and we certainly look forward to working on the phase 3 trial starting very soon.

Wilner: That's what I was getting at. If it's phase 3 trial, then you can present to the US Food and Drug Administration. The current study may not have had enough patients. I wonder if this is something they can look at in the phase 3 trial.

Could you tell whether it mattered how advanced the disease was in terms of the benefit that the patient received? In other words, if you just been diagnosed with ALS, did it really slow the progression a lot, or if you had it for 3 years and were a couple steps away from the ventilator, did it stop that progression or not really work as well?

Paganoni: In this particular trial, we enrolled people who were early in the disease course. By definition, they had to have been within 18 months from symptom onset.

We assume in neurodegenerative diseases that if you intervene early, you have a better effect. Having said that, it's important to test the drug in broader populations to see if it might have an effect in different stages. The phase 3 trial will have broader inclusion criteria to try to answer that question of whether it works in more advanced stages of the disease.

Wilner: Dr Paganoni, I want to thank you for sharing your research. It really is exciting.

We're going to have to put you on the schedule for a year from now so we can look at the phase 3 results and hopefully see how close we are to making this available to patients, who are waiting for something that's really going to help them.

Paganoni: Absolutely. I would be happy to come back anytime.

Wilner: Thank you very much for joining me on Medscape. I'm Dr Andrew Wilner, reporting from AAN's virtual annual meeting.

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