PTI-125 Reduces Neurodegeneration After 28 Days of Treatment, Data Show

PTI-125, Cassava Sciences’ lead therapeutic candidate for the treatment of Alzheimer’s disease, significantly reduced the levels of disease biomarkers, brain inflammation, and neurodegeneration after 28 days of treatment, top-line data from a Phase 2 trial show.

“Based on these encouraging biomarker results, this new treatment could be an important part of the research dialogue in Alzheimer’s disease,” Jeffrey Cummings, research professor of the Department of Brain Health at the University of Nevada, Las Vegas and director of the Center for Neurodegeneration and Translational Neuroscience of the Cleveland Clinic Lou Ruvo Center for Brain Health, said in a press release.

“This drug candidate appears to target some of the more toxic components of the illness. Results will need to be replicated in larger studies to prove it’s a definitive advance in the field,” Cummings said.

PTI-125 is an investigational therapy that has been designed to bind to an abnormal form of a protein called Filamin A (FLNA) to restore its normal structure and function. FLNA is misfolded in patients with Alzheimer’s disease and is thought to contribute to the buildup of toxic plaques inside nerve cells.

Its effects in patients with mild to moderate Alzheimer’s disease have been evaluated in this open-label, Phase 2a trial (NCT03748706) sponsored by the National Institutes of Health (NIH). The study enrolled 13 patients who received 100 mg of PTI-125 orally twice a day for 28 days.

The main goal of the trial was to evaluate the effects of PTI-125 on the levels of several disease biomarkers in patients’ cerebrospinal fluid (CSF, the liquid that circulates in the brain and spinal cord) before and after treatment. Top-line data from the trial has shown that:

• All patients responded positively to treatment with PTI-125;
• The total levels of tau protein decreased by 20% and the levels of phosphorylated tau protein by 34%;
• The levels of neurofilament light chain (NfL), a biomarker of neurodegeneration, dropped by 22%;
• The levels of neurogranin, a biomarker of cognitive decline, dropped by 32%;
• The levels of YKL-40, a marker of brain inflammation triggered by the over-activation of glial cells (cells that support and protect neurons), decreased by 9%;
• The levels of inflammatory molecules, including interleukin 6 (IL-6), interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNFα) decreased by 14%, 11%, and 5%, respectively;
• The ratio of phosphorylated tau and beta-amyloid protein (P-tau/Aβ₄₂), a biochemical indicator of Alzheimer’s, improved in all patients.

“We conclude from this study that PTI-125 was able to reduce biomarkers of neurodegeneration and neuroinflammation in Alzheimer’s patients at a dose that appears safe and well-tolerated,” said Nadav Friedmann, PhD, MD, chief medical officer of Cassava Sciences. “To our knowledge, no other drug has shown such promising results on objective, validated biomarkers of disease.”

Cassava is now preparing to launch a randomized, double-blind, placebo-controlled, Phase 2b trial (NCT04079803), also sponsored by the NIH, which builds on the promising findings generated by this Phase 2a trial. One of the main goals of the new study will be to confirm the effects of PTI-125 on the levels of disease biomarkers in a larger group of patients.

The company expects to enroll approximately 60 patients with mild to moderate Alzheimer’s, who will be randomly assigned to receive one of two doses of PTI-125 (50 mg or 100 mg) or a placebo twice a day for 28 days. Cassava expects patient enrollment — which has already begun — to be completed within a year.

“We are excited to lead the way in the effort to bring a new treatment paradigm to Alzheimer’s, a disease that has seen few scientific advancements to date despite massive research efforts,” said Remi Barbier, president and chief executive officer of Cassava Sciences.

“The relationship between biomarkers and Alzheimer’s disease is crucial, well-known and widely published. As a result, we’re cautiously optimistic that PTI-125 moves us closer toward the goal of a disease-modifying treatment. And as always, we are grateful for the support of our collaborators, advisers, and NIH, whose peer-review system of evaluation has enabled us to advance PTI-125 step-wise from basic research to clinical testing within 10 years,” Barbier said.