PEGASUS Trial Investigators Bet on Combination Approach AMX0035 for Alzheimer Disease


The PEGASUS principal investigator and Translational Neurology Head of the Interdisciplinary Brain Center at Massachusetts General Hospital and Harvard Medical School spoke about the Amylyx Pharmaceuticals product’s potential in Alzheimer.

Dr Steven Arnold

Steven E. Arnold, MD, Translational Neurology Head of the Interdisciplinary Brain Center at Massachusetts General Hospital and Harvard Medical School

Steven E. Arnold, MD

Amylyx Pharmaceuticals recently announced the dosing of the first of 20 enrolled patients in the recently expanded PEGASUS trial of AMX0035, an investigational combination approach to Alzheimer disease.

The double-blind, multicenter, placebo-controlled trial is expected to read out results in 2020. Principal Investigator Steven E. Arnold, MD, Translational Neurology Head of the Interdisciplinary Brain Center at Massachusetts General Hospital and Harvard Medical School, and colleagues plan to enroll 100 patients with late-stage mild cognitive impairment or dementia due to Alzheimer in a 3:2 randomized fashion for a 24-week treatment period.

To find out more about AMX0035 and its novel approach to treating the neurodegenerative disease that has seen a number of recent therapeutic failures, NeurologyLive® spoke with Arnold.

NeurologyLive ®: What makes AMX0035 a novel approach to Alzheimer?

Steven E. Arnold, MD: Historically, in the field, there’s been a fairly exclusive focus on amyloid pathology, which I think has been very reasonable based on people’s historic understanding of the disease and the primacy of amyloid being a problem in Alzheimer disease. But I think many of us, for many years now, have realized that Alzheimer is a much more complicated disease than just one focused in amyloid and tau.

There’s been suspicion, long-standing suspicion, that amyloid just does not relate that well to the degree of cognitive impairment that people have and that you can clear all that amyloid out of the brain and people will still have cognitive impairment. I think that we know more now and as difficult as the news was about the aducanumab trial a couple of weeks ago (which was a very well-designed trial), the trial was thoroughly negative in terms of its clinical benefit.

Many of us really have thought that Alzheimer is a complicated disease. There are more fundamental problems in the biology of neurons in the brain and that we should—that we need to—really attack. One biological mechanism that is abnormal in Alzheimer disease is ER stress, endoplasmic reticulum stress, also called the unfolded protein response. Then another is mitochondrial dysfunction. That’s important for the energetics of cells and oxidative damage which can damage proteins and lipids in the cells and also plays a central role in apoptotic cell death.

What was the rationale for the 2-drug combination approach?

What we know is that this is a complicated disease—there are many ways in which the cell that neurons, other brain cells, are breaking down in the disease. The idea of using combination therapy to attack multiple pathophysiological mechanisms has been very appealing but people haven’t really figured out what the best way to start is.

What Amylyx did was to take 2 very important mechanisms, endoplasmic reticulum stress and the unfolded protein response, as well as mitochondrial dysfunction—and there’s a lot of interaction there. These are important for protecting cells from cell death, these are important mechanisms in terms of handling the metabolism of cells and neuroplasticity, and they took 2 drugs that are already in use for other conditions but have never really been studied that much in neurology and combined them to see if you can handle, see if you can address and improve the functioning of several different pathophysiological mechanisms.

Which drugs comprise the combination that is AMX0035?

One of the drugs is sodium phenylbutyrate, this one is used in urea cycle abnormalities, but it also does get into the brain and it is a histone deacetylase inhibitor. It has wide-ranging functions and one of its important functions is to suppress the unfolded protein response which is overactive in Alzheimer disease. The other drug is tauroursodeoxycholic acid (TUDCA), and that’s used in Europe, I believe, exclusively now for liver disease, gallstones, and biliary disease What TUDCA does is actually stabilize mitochondrial membranes, and in that way, it improves the bioenergetics of cells. It reduces, or makes cells more resistant to, oxidative stress, and also works as a neuroprotectant by preventing apoptosis.

The interesting thing is it showed some real benefits in pre-clinical studies in cell culture and animal models of Alzheimer disease and other neurodegenerative diseases and putting it together it appears that they have a synergetic benefit for protecting cells. That’s the rationale for using the AMX0035 in the PEGASUS trial.

We recognize that there are a lot of mechanisms that are driving neurodegeneration in Alzheimer, and if you just hit one thing and others are left unaddressed, you may have some very modest benefit, but you may have no benefit because everything else is working against the cell. By combining drugs to ameliorate the damaging effects of these different mechanisms that are active, overactive, or abnormally active in Alzheimer, we have a better chance of rescuing sick and dying cells.


Amylyx Pharmaceuticals Announces First Patients Dosed in PEGASUS Phase 2 Trial of AMX0035 in Alzheimer’s Disease and Expansion of the Trial [press release]: Cambridge, MA: Amylyx Pharmaceuticals; Published April 9, 2019. Accessed April 10, 2019.

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