Amylyx Pharmaceuticals’ neurodegeneration drug, AMX0035, has been studied in volunteers with mild cognitive impairment (MCI) or Alzheimer’s in a Phase 2 clinical trial. Topline results from the trial are set to be released in the coming weeks.
In 2013, Amylyx Pharmaceuticals co-founders Justin Klee and Josh Cohen, undergraduate students at Brown University at the time, hypothesized that targeting two dysfunctional pathways instead of one, could slow neurodegeneration. According to Dr. Rudy Tanzi, professor of neurology at Harvard Medical School and founding chair of the Amylyx Scientific Advisory Board, Klee and Cohen’s goal was to develop a “bulletproof vest for neurons.” Eight years later, Amylyx’s AMX0035, a dual compound drug that has been shown to block pathways of cell death and inflammation, is the product of that quest.
In November 2020, the company announced that the last remaining participant completed their final study visit in the PEGASUS Phase 2 clinical trial, a 24-week placebo-controlled study, which tested AMX0035 to determine its safety and efficacy in treating Alzheimer’s. One hundred participants with MCI or early-to-moderate dementia were enrolled in PEGASUS. In the coming weeks, the company is set to release news of the study results.
During the Alzheimer’s Disease Expert Panel and Q&A held on March 17th to discuss the PEGASUS clinical trial, Dr. Tanzi further explained that in their first meeting together, Klee and Cohen made the point that most trials attempting to prevent neuronal cell death only focus on protecting the function of a single organelle – mainly the mitochondria or the endoplasmic reticulum. However, the two argued that if you only deliver one form of protection, half of you is exposed, and that in order to have a full “bulletproof vest,” you must have both forms of protection.
Klee and Cohen’s initial experiments in 2013 showed that the combination of two existing compounds – one that reduces stress in the endoplasmic reticulum, and another that reduces mitochondrial permeability – resulted in over 90 percent survival of neurons. Four years later in 2017, the CENTAUR clinical trial was initiated to test AMX0035 in Amyotrophic Lateral Sclerosis (ALS). In the following year, the PEGASUS clinical trial was initiated to test the same drug in Alzheimer’s.
“If we do see a signal, if this does look like a therapy
that is really worth pursuing in later stage trials in MCI
and Alzheimer’s, we’re not going to wait. We’re not going to
move slowly. We’re going to move as quickly as we can.”
To thoroughly assess whether AMX0035 prevents neurodegeneration in people with Alzheimer’s, the PEGASUS trial was designed to incorporate broad inclusion criteria and a robust panel of outcome measures. To enroll in the trial, participants were required to be between the ages of 55 and 89 with a diagnosis of probable Alzheimer’s or MCI through biomarker detection. Montreal Cognitive Assessment (MoCA) scores between 8 and 30 were accepted, and participants could continue to remain on stable doses of cholinesterase inhibitor and/or memantine throughout the study if desired. Participants received AMX0035 or a placebo for 24 weeks.
Following the intervention period, Amylyx began detailed evaluation of neuroimaging, biofluid, and clinical-based biomarkers. The team is analyzing structural and functional changes in the brain with MRI, and quantifying measures of hallmark Alzheimer’s proteins, oxidative damage, endoplasmic reticulum stress, synaptic and axonal damage, and inflammation in the cerebrospinal fluid and plasma of participants. Cognition will also be measured with five different clinical assessments.
Initial news regarding the results of the Phase 2 trial is on the horizon. Amylyx Chief Scientific Officer Kent Leslie told Being Patient that individuals who were unable to participate in the PEGASUS trial should know: “If we do see a signal, if this does look like a therapy that is really worth pursuing in later stage trials in MCI and Alzheimer’s, we’re not going to wait. We’re not going to move slowly. We’re going to move as quickly as we can.”
When asked if future work will be done to see if AMX0035 could be used in a preventative manner earlier in life, Leslie said, “Assuming that we see this sort of biological activity that we hope to see, and that the preclinical data would suggest, I think it’s certainly going to open doors into moving into earlier stage patients, pre-symptomatic patients, but we’re going to have to wait and see on that.”
Further, Dr. Tanzi told Being Patient, “If you have a combination drug like AMX0035 that protects neurons, you might want to think about using it to protect against neuroinflammation, to protect against the normal cell death due to oxidative stress at both the level of mitochondria and the endoplasmic reticulum.” He added, “The idea of curbing neuroinflammation early and often throughout life, knowing when to do so by early detection, whether that’s with blood based biomarkers or otherwise, that’s going to be an important way that we manage brain health and we become proactive, preventing disease, rather than reactive, in future generations.”
The initial hypothesis of Amylyx co-founders Klee and Cohen — that targeting two dysfunctional pathways is better than one — highlights an important need for the future of Alzheimer’s treatment. Alzheimer’s Drug Discovery Foundation Founding Executive Director and Chief Scientific Officer Dr. Howard Fillit emphasized on the panel that attacking only one pathway of neurodegeneration will not be enough. Since there are numerous processes implicated in Alzheimer’s, combination therapies are needed.
When asked if he envisions combination therapies that could potentially include Amylyx’s experimental drug to be delivered through a precision medicine approach, Fillit told Being Patient, “This is the beginning of precision medicine for Alzheimer’s disease. If you think about cancer, it started with one drug … and now the average cancer patient is on four or five drugs tailored to their biomarkers. That’s the vision of the future of Alzheimer’s disease.”
“This is the beginning of precision medicine for
Alzheimer’s disease. If you think about cancer, it started
with one drug … and now the average cancer patient is
on four or five drugs tailored to their biomarkers. That’s
the vision of the future of Alzheimer’s disease.”
“We’re going to have precision medicine, the same way that diabetics are on three or four drugs and cancer patients are on four or five drugs,” Fillit said, adding, “We envision people with Alzheimer’s disease, based on their biomarker status, to be able to measure whether they have inflammation …whether they have beta-amyloid, whether they have tau tangles and to what degree, and then tailor their therapy accordingly. I think by doing that we will have combinations of therapy that will be highly effective in combination, much more than any single drug.”
While we’re still awaiting news on the efficacy of AMX0035 in treating Alzheimer’s, promising results were recently shared from the ALS CENTAUR clinical trial testing the same drug. On March 18th, Amylyx presented results at the Muscular Dystrophy Association (MDA) Virtual Clinical & Scientific Conference, demonstrating significantly lower long-term risk of death or permanent assisted ventilation (PAV) and risk of first hospitalization. These results represent the first time an investigational ALS therapy has demonstrated a benefit in both functional outcomes and survival.