Combination Therapy: The Right Approach for Alzheimer’s

The Alzheimer’s Drug Discovery Foundation (ADDF) believes that combination therapy will be the most effective treatment for Alzheimer’s disease. As the name implies, combination therapy involves giving patients two or more treatments for a single disease. And it’s already the standard of care for many diseases, including rheumatoid arthritis and HIV/AIDS.

Alzheimer’s has many underlying causes, which can change as it progresses. These include inflammation, epigenetic (i.e., gene expression) changes, oxidative stress, vascular issues, mitochondrial dysfunction, and the accumulation of misfolded proteins into toxic plaques and tangles. Its complexity makes it difficult to treat with any one drug.

To build a roadmap for combination therapies in Alzheimer’s, we convened a think tank in 2015 at the Cleveland Clinic Lou Ruvo Center for Brain Health. The two-day meeting included experts from academia and the pharmaceutical industry as well regulatory experts from the FDA. Based on the think tank’s recommendations, we decided to co- fund a combination therapy clinical trial with the Alzheimer’s Association.

Best Practices for Alzheimer’s Combination Therapies

The think tank members agreed that conducting successful combination therapy clinical trials in Alzheimer’s would be difficult, but that we could increase the odds of success in a few ways.

1. We should begin by testing repurposed drugs. These are drugs that have been approved by the FDA for another disease, and have shown promise for Alzheimer’s in preliminary research. Regulatory guidelines require that all drugs undergo safety testing individually before being tested as a combination, and there are additional concerns about additive toxicity from drugs being given together. Repurposed drugs, which have known safety profiles, can address some of these issues and allow us to proceed to clinical trials faster.

2. Each drug in a combination therapy must target distinct causes of Alzheimer’s, rather than the same one. For example, one drug could target inflammation and the other vascular issues. Our goal is to increase the odds of slowing the progression of Alzheimer’s disease by tackling it on multiple fronts. 

3. Combination trials should include target engagement biomarkers. These are diagnostic tools that ensure a drug’s proposed target (e.g., an inflammation pathway) is actually being reached. It can be difficult to determine a single drug’s effect when it’s given in combination with another, so information provided by biomarkers is vital.

The Trial

The clinical trial we are now funding through the 2015 agreement with the Alzheimer’s Association addresses all the best practices. It is a phase 2 study of AMX0035, a promising drug combination developed by the biotechnology company Amylyx Pharmaceuticals.

1. AMX0035 combines sodium phenylbutyrate (PB) and tauroursodeoxycholic acid (TUDCA). PB is a repurposed drug approved by the FDA for urea cycle disorders and TUDCA is a bile acid available as an over-the-counter supplement.

2. PB targets “epigenetics,” which are processes that regulate how much our genes are expressed. Specifically, it affects the expression of a number of genes that can help protect brain cells from death. TUDCA works very differently than PB. TUDCA affects the mitochondria, which are energy powerhouses within our cells. As we age, our mitochondria can become less efficient at using energy and TUDCA can improve that efficiency and keep our brain cells from dying. Amylyx hypothesized that the two drugs would work synergistically, increasing each other’s benefits.  In preliminary studies, this seems to be the case.

3. To determine target engagement, Amylyx plans to use a novel PET scan that can detect epigenetic changes in the brain. It was developed by Dr. Jacob Hooker with support from the ADDF. Amylyx also plans to use multiple spinal fluid assessments to get a fuller picture of target engagement and any synergistic effects of the combination therapy. As this is the first combination therapy clinical trial for Alzheimer’s to follow the best practices, the researchers want to learn as much as possible about how the therapy is working.  

While the primary goal of this trial is to evaluate the combination therapy’s safety, Amylyx is hoping to find that its drug reverses or at least stabilizes the biomarkers it’s measuring. This would provide an indication that the therapy is effective and be a strong rationale for advancing to a much larger clinical trial. Amylyx plans to begin recruiting 50 patients for the phase 2 trial in the first half of 2018.