Pain Therapeutics’ Protein-targeting Alzheimer’s Therapy Is Safe, Phase 1 Trial Indicates

Pain Therapeutics’ Alzheimer’s therapy PTI-125 was safe, and patients tolerated it well, a Phase 1 clinical trial shows.

The therapy is aimed at countering a faulty version of the filamin A protein. Scientists believe this abnormal version contributes to Alzheimer’s by facilitating the buildup of toxic nerve cell plaque and promoting nerve cell inflammation.

Researchers said the trial also demonstrated that PTI-125 has a favorable pharmacokinetic profile — that is, it moves through the body in a way that could make it effective.

The results prompted Pain Therapeutics to plan additional trials.

“The clinical data are encouraging,” Remi Barbier, president and chief executive officer of Pain Therapeutics, said in a press release. “Given the absence of dose-limiting effects in healthy adults, an excellent non-clinical safety database, a strong scientific rationale, and multiple peer-reviewed publications and research grant awards, we are eager to move this drug program to the next level of development.”

The reference to an “absence of dose-limiting effects” indicated there was no evidence that increases in the treatment’s dose causes problems. The “non-clinical safety” reference was to the therapy’s safety profile before human studies began.

Pain Therapeutics presented the trial results at the 10^th Annual International Conference on Clinical Trials on Alzheimer’s Disease in Boston, Nov. 1-4. The presentation was titled “Single ascending dose phase I clinical trial of PTI-125 in healthy volunteers.”

The study covered three oral doses of PTI-125 — 50, 100 or 200 mg — in 24 healthy volunteers aged 18 to 45. They were divided into three groups of eight each. Six of the eight in each group received PTI-125 and two a placebo.

No patient experienced an adverse effect to PTI-125, and all tolerated it well. In addition, patients’ bodies absorbed the therapy rapidly — one measure of its potential effectiveness.

Pain Therapeutics received a $1.7 million National Institutes of Health grant to test PTI-125 in the Phase 1 trial. The U.S. Food and Drug Administration set the stage for the study by accepting an Investigational New Drug application for PTI-125.

PTI-125 is a small molecule that binds to a faulty version of the filamin A (FLNA) protein. Scientists believe defects in two other proteins — amyloid beta and tau — are what cause Alzheimer’s.

Misfolding of amyloid beta and tau leads to toxic accumulations of each. In the case of amyloid beta, the clumps are called plaque, and in the case of tau they are called tangles.

A study in the journal Neuroimmunology and Neuroinflammation showed that faulty FLNA contributes to Alzheimer’s.

It does this by interacting with two receptors in a way that allows amyloid beta protein to send abnormal signals, the researchers said. The title of their study is “Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer’s disease.”

By disrupting one of the receptors, a7nAChR, FLNA facilitates the formation of amyloid beta plaque. FLNA also activates the TLR4 receptor, which is responsible for releasing inflammation-triggering molecules. This leads to nerve cell inflammation.

“In both cases, altered FLNA associates with these receptors to allow their aberrant signaling by Aβ [amyloid-beta],” they wrote.

PTI-125 works by disrupting FLNA’s interaction with the two receptors, helping them maintain their normal function.

“The novel AD [Alzheimer’s disease] therapeutic candidate PTI-125 binds and reverses the altered FLNA conformation to prevent Aβ’s [amyloid-beta] signaling via α7nAChR and aberrant activation of TLR4, thus reducing multiple AD-related neuropathologies,” the researchers wrote.

Earlier this year, the National Institutes of Health awarded awarded Pain Therapeutics $1.8 million to develop a blood test to diagnose Alzheimer’s.