Alzheimer's Matters Blog

Stepping Forward in Alzheimer’s Disease Research: A Combination Therapy Approach

December 10, 2019

Category: Developing Drugs



The past three decades of Alzheimer’s disease research has focused on addressing the accumulation of amyloid beta plaques, among other therapeutic targets, and clinical trials are ongoing to confirm early promises.  Despite these efforts no treatment to impact the neurodegenerative process of Alzheimer’s disease has been approved for use.

Patients, their caregivers and families have not given up hope, however, and neither have researchers or committed groups such as the Alzheimer’s Drug Discovery Foundation (ADDF). The ADDF’s support of the PEGASUS trial since 2017 encourages us and is contributing to cutting a new and much-needed path to get critical therapies to patients faster. We’ve taken a closer look at how far we’ve come with an exciting trial underway, all of which is possible thanks to those fighting relentlessly alongside us: our study participants, their families and support from the ADDF, the Alzheimer’s Association and Cure Alzheimer’s Fund. 

Alzheimer’s disease is characterized by progressive dementia in patients due to the loss of neurons in critical cognitive centers within the brain. There is not one theory for why these neurons die but rather many different theories and risk factors ranging from lifestyle and cholesterol to specific biochemical pathways.

A promising and multi-faceted approach to the treatment of Alzheimer’s disease is use of a combination of drugs to target underlying cellular pathologies, with the goal of preventing neuronal death and degeneration by targeting multiple mechanisms involved in disease pathogenesis. A combination therapy targeting the concomitant patho-physiologies present broadens the therapeutic attack compared to single target approaches, which is the basis for evaluation of AMX0035 in the PEGASUS trial Alzheimer’s trial supported by Amylyx Pharmaceuticals.

Part of how neurons die in Alzheimer’s may involve activation of pathways originating in the mitochondria and endoplasmic reticulum—small structures within the neuron cell which are important to control energy production and protein folding. These processes are in close communication with each other and when they go awry, a neuron goes into a death spiral.

AMX0035 is a combination product comprised of sodium phenylbutyrate (PB) and taurursodiol (TURSO) designed to target two independent pathways involved in neurodegenerative pathology.  PB is an FDA-approved drug for the treatment of hyperammonemia in patients with urea cycle disorders (UCDs), while TURSO is used for the treatment of cholesterol gallstones in Europe. Experiments by Amylyx suggest a combination of these drugs makes for more resilient neurons which can survive and maybe even thrive through harsh cellular conditions like those in Alzheimer’s and other neurological diseases.

Importantly, we have designed the PEGASUS trial with broad eligibility criteria to involve patients at different stages of Alzheimer’s disease, from early mild cognitive impairment (MCI) to moderate Alzheimer’s disease. Alzheimer’s disease is driven by multiple interacting pathological processes. Enrollment of patients at various stages of disease will allow us to assess the biological effects of AMX0035 across the spectrum of the disease and determine if there are particular patients who might see greater benefit from therapy.

The trial uses a series of biomarkers which PEGASUS Principal Investigator Dr. Steven Arnold’s laboratory at the Massachusetts General Hospital has helped to validate, and a statistical scale developed by Dr. Susanne Hendrix to measure whether AMX0035 is having a treatment effect. The trial was expanded this year to 100 patients, which should improve our ability to confirm preliminary effects of treatment.

Hopefully, AMX0035 is able to make neurons more resilient and slow the progression of symptoms of Alzheimer’s Disease. We have embraced the research that has led us to this trial and its learnings to date, as well as hope from the contributions of this strong community that shares our goals of one day soon delivering the answers people need.

Patrick Yeramian, M.D., MBA, chief medical officer at Amylyx Pharmaceuticals, has supervised the clinical development of new drugs, biopharmaceuticals, vaccines and cellular therapy agents over more than 30 years in the industry. The PEGASUS trial is a 3:2 randomized, double-blind, multi-center, placebo-controlled study evaluating the safety, tolerability and neurobiological activity of AMX0035 in patients with late mild cognitive impairment or early dementia due to Alzheimer’s disease over 24 weeks. The biomarker-focused trial design will assist in understanding the effects of AMX0035 and its potential in treating Alzheimer’s disease. Study results are expected in 2020.