Advancements in Clinical Trial Design in ALS


A panel of experts provides insights into recent improvements in clinical trial design in amyotrophic lateral sclerosis (ALS) and discusses implications of recent clinical trial results.

Richard S. Bedlack, MD, PhD, MS: I am smiling as I look at this next question on our agenda because I know we could easily spend hours on this. All of you are thought leaders and are passionate about clinical trials. I am going to ask you each to tell me 1 thing that excites you about the way we are doing ALS [amyotrophic lateral sclerosis] clinical trials now compared with 10 years ago. Ammar, I will start with you.

Ammar Al-Chalabi, MB, ChB, PhD: The most exciting thing is that we are working collaboratively with a specific aim that was not there many years ago, which is that we learn from every single trial. Regardless of whether the drug shows efficacy, we have learned something about ALS from that trial. Whether it is that biomarkers change and what the biomarker might be, or whether it is that gene variants affect prognosis, there is no trial that is giving us that information. 

That is important because patients and their families are giving huge amounts of time and effort into going into a trial. If the trial does not show a benefit at the end, then that is not respecting the time that they have given. If we are learning something, regardless of whether the drug itself works, even if it is a disappointing result, and we do not have a drug that works, then it at least means that we have learned something that we can take back to improve and do the next trial better because we have that extra information.

Richard S. Bedlack, MD, PhD, MS: How about you, Jeremy?

Jeremy M. Shefner, MD, PhD: I will be quick and say 2 things. One is that our expanding knowledge of the pathophysiology of ALS has led to a whole host of new targets that we can now assess whether we are influencing. As Ammar said, given that we can assess that, we can make a determination of whether that specific intervention has promise in ALS. I would then say that, not necessarily for phase 3 trials but for middle phase trials, the development of both fluid and other kinds of biomarkers gives us the potential to see drug- and disease-related activity based on your drug in a much shorter period of time with a smaller number of patients. We have the potential to speed up clinical development based on those 2 aspects. 

Richard S. Bedlack, MD, PhD, MS: Jinsy?

Jinsy A. Andrews, MD, MSc: I do not have much more add except for the fact that what both Ammar and Jeremy pointed out lend lends itself to being innovative in the trial design itself. Using biomarkers to enrich the population that you would evaluate for a particular therapy because it is pertinent of the target might make us more successful in clinical trials by using clinical trial design to evaluate multiple drugs quickly. That is the basis behind what we call platform trials, which is an infrastructure that is set up both in Europe and also in the United States to evaluate drugs efficiently and quickly while being respectful of a participant’s time and altruism for their participation in the clinical trial.

Thinking innovatively about adaptive trial designs as well, we are at a time with ALS where all these components interplay with one another: collaborating, studying outcomes, studying biomarkers, and implementing them in trial design makes sure that we get to an answer more quickly. 

Richard S. Bedlack, MD, PhD, MS: I cannot help but answer this question myself as well. For me, it is patient engagement. In the past decade, we have seen patients transform from just subjects in our studies to partners. We now have a massive group of patients and families who are trained to understand research, and we are networking with them on a regular basis to get them more involved. 

They are helping us raise money. They are helping us change laws to get more studies. They are helping us ask more relevant questions. They are helping us with trial designs that are more attractive, where people are not going to drop out in such high numbers. They are helping us spread the word. They are helping sponsors craft a message about the results that the community understands. They are working with regulators like the FDA so they have a better understanding of what benefit-risk ratios look like from a patient’s perspective. That is my answer to that one. 

Let’s now shift our attention and talk a bit about some drugs in development. Jinsy, what can you tell us about AMX0035?

Jinsy A. Andrews, MD, MSc: AMX0035 is an investigational product being evaluated in ALS. It recently completed a clinical trial. It is a combination of 2 compounds: sodium phenylbutyrate and tauroursodeoxycholic acid, also called tarso. Its mechanism of action targets a couple of different things, but it primarily targets ER [endoplasmic reticulum] stress and mitochondrial dysfunction. It hits on a couple of other things as well. There was a 6-month or 24-week study that was placebo controlled that evaluated the rate of decline of the ALS Functional Rating Scale, which is the main functional scale that we use to assess patients. People will typically lose about 1 point on this 48-point scale per month. 

In this trial, there was a slowing of the rate of decline in the treated population compared with the placebo arm. That difference was 0.24 point per month. It was statistically significant with a P value of .03. Essentially, all those numbers mean that, for a person living with ALS, time is a commodity. Essentially, there is an inherent progression of loss of function over time. This study, over the 6-month period, showed that AMX0035 was effectively able to slow down disease progression as measured by this Functional Rating Scale.

There was an open-label extension. How that was structured is this: After the placebo-controlled portion was completed, everybody was converted to the active treatment, which was AMX0035. When you looked at survival, it was published in the second publication; the initial results were in the New England Journal of Medicine, and the second publication of the survival data was in Muscle & Nerve. In that evaluation, they looked at patients who were initially started on AMX0035 and continued in the open-label extension compared with those who were on placebo initially and then converted later. 

There was a survival advantage of about 44%, which means that it is effective in line with some other approved medications like edaravone and riluzole.

Transcripts Edited for Clarity

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