Commentary: Search for Alzheimer’s Drugs Marked by Boundless Optimism and Failed Trials

Some researchers question venerable amyloid hypothesis

The current state of Alzheimer’s disease (AD) research is nothing to crow about, according to BioSpace reporter Mark Terry. One of the problems with developing drugs for the disease is that it isn’t very well understood, he says. The predominant theory is the so-called “amyloid hypothesis,” which posits that amyloid-beta proteins build up in the brains of patients with AD. These proteins form plaques that are believed to block cell-to-cell communication. Therefore, most drug makers have focused on finding medications that clear amyloid-beta.

Unfortunately, amyloid-beta–lowering treatments have failed to improve the disease itself, leading some experts to question the vaunted amyloid hypothesis. In 2016, researchers at Harvard Medical School and Massachusetts General Hospital reported that amyloid-beta was actually linked to an immune reaction to bacteria or other pathogens in the brain.

Tau proteins are another suspected cause of AD, Terry notes. These proteins occur later in the disease and cause tangles of protein fibers, which appear to damage the transport system that moves nutrients through cells in the brain.

A third theory of the cause of AD centers on acetylcholine, which is believed to be important for memory. The three approved drugs for patients with mild-to-moderate AD—galantamine (Razadyne, Janssen); rivastigmine (Exelon, Novartis); and donepezil (Aricept, Pfizer)—all work by boosting acetylecholine levels.

A fourth medication, memantine (Namenda, Forest Pharmaceuticals), is used to treat patients with moderate-to-severe AD and seems to delay the progression of certain symptoms, Terry writes. Researchers aren’t sure how the drug works, but they believe it regulates glutamate, which may lead to cell death when produced at high levels in the brain.

According to Terry, statistics indicate that the failure rate for investigational AD drugs is 99.6%. More than 125 drug candidates for AD have failed in late-stage clinical trials, he says.

For example, in September 2016, idalopirdine (Lundbeck), a serotonin 6 receptor antagonist designed to improve acetylcholine levels, failed a pivotal phase 3 study. Two months later, Eli Lilly walked away from solanezumab, an antibody that targets amyloid-beta, after a phase 3 trial showed no significant improvements compared with placebo. In February 2017, Merck pulled the plug on a phase 2/3 study of verubecestat, a beta-secretase inhibitor, after an external data-monitoring committee determined that there was “virtually no chance of finding a positive clinical effect.” Also in February 2017, the investigational drug AC-1204 (Acera), which targets glucose in the brain, failed to improve AD in a phase 3 study.

Hopeful pharma companies continue to soldier on, however. Axovant is developing interperdine, which it acquired from GlaxoSmithKline, even though the drug had flopped in four mid-stage trials in AD patients. In December 2016, Biogen released promising early (phase 1b) data on an amyloid-beta antibody, aducamumab. Biogen’s drug, however, is similar to Lilly’s unsuccessful solenazumab. In February 2017, Neurotrope concluded patient monitoring in a phase 2 trial of the AD drug bryostatin-1. Results are expected in April. Bryostatin-1 takes a new approach to AD by trying to reverse the course of the disease. Its mechanism of action involves the activation of protein kinase C epsilon, which is believed to restore synaptogenesis.

Other pharma companies in the AD sweepstakes include Pfizer, Genentech, and Allergan.

Source: BioSpace; April 28, 2017.