After Merck Stops Study, What Remains Of The Alzheimer's Drug Pipeline?

Merck & Co, Inc. MRK Tuesday reported it was halting its Phase 3 study of Alzheimer's treatment verubecestat in people with mild to moderate Alzheimer's disease (AD) after it was determined it had "virtually no chance of finding a positive clinical effect."

In light of this news — the latest in a string of disappointing Alzheimer's drug announcements — below is a list of Alzheimer's treatments still making their way optimistically through clinical trials.

Merck

While Merck abandoned its Phase 2/3 study of verubecestat, Merck Research Lab President Dr. Roger Perlmutter pointed out in the company's press release that Merck will continue to study verubecestat in folks with "less advanced disease." Merck expects clinical data from those studies in February 2019. A Merck spokesperson told Benzinga, "It is hoped that by evaluating verubecestat in people at the earlier prodromal stage, who have lower levels of damage to the brain, we will be better able to slow disease progression."

Eli Lilly And AstraZeneca

One of the most resounding AD drug failures of 2016 was that of Eli Lilly and Co LLY and its solanezumab, which failed to slow down cognitive decline in AD patients. In collaboration with AstraZeneca plc (ADR) AZN, Eli Lilly is still exploring the use of a beta secretase enzyme (BACE) inhibitor to clear amyloid plaque deposits in the brain (which most believe is the cause of AD). The treatment — AZD3293 — is currently undergoing one Phase 2/3 study and enrolling participants for another. Concerning, however, is that the BACE inhibitor approach is what just failed for Merck. When asked how Merck's trial suspension may read-through for Lilly, the company told Benzinga, "Lilly can't comment on how or if these results will impact our program, but we look forward to Merck making these data available as soon as they can."

Biogen

Considered by some to be the most promising drug in its class is Biogen Inc BIIB and its drug aducanumab, which targets amyloid plaque build-up through the use of an antibody rather than a BACE inhibitor. The company isn't expected to have final data on the treatment until 2019, however.

AC Immune

Together with Roche Holding Ltd. (ADR) RHHBY subsidiary Genentech, AC Immune Ltd ACIU is developing a drug called crenezumab for patients with mild AD. Crenezumab is also based on an antibody that works against amyloid proteins. The company is currently enrolling patients for its CREAD phase 3 trial of the drug.

There are only four FDA-approved AD drugs, and they're all for the treatment of its symptoms, not the disease itself. A drug being developed by Allergan plc Ordinary Shares AGN is likewise designed for symptomatic relief. Phase 2b data analysis recently suggested Axovant Sciences Ltd AXON's intepirdine helped AD patients spend more time in the less dependent stages of the disease. Intepirdine is currently in trials with mild-to-moderate AD patients with data expected this year, but its odds of success have come into question after a similar drug being developed by Danish pharmaceutical company Lundbeck failed its pivotal phase 3 study.

The Wild Cards: Neurotrope And Accera

Hope for AD patients may spring from a couple of companies that are not household names, but whose innovative approaches are breathing new life into an arena of research that has gone stale.

Neurotrope Inc NTRP, soon to be listed on the Nasdaq stock exchange, awaits Phase 2 results from its groundbreaking drug bryostatin, which actually seeks to reverse — rather than treat — the disease in late-stage patients by regenerating degraded synapses. Top-line data is expected in April.

Accera, a private company backed by Nestle, expects to announce data from its first Phase 3 trial of compound AC-1204 in March. Accera's drug approaches AD as a metabolic condition that can be combated by stimulating a mild form of ketosis by generating ketones for use in neurons, improving neuronal metabolism and cognition and function in patients with mild to moderate AD.

Drug Failures And The Elephant In The Room

If you haven't noticed, one thing all but Neurotrope and Accera's prospective treatments have in common is their reliance on what is referred to as the 'amyloid hypothesis,' the idea that removing or preventing the build-up of amyloid plaque deposits and tau tangles is the most promising path to treating AD. But this approach has increasingly come under fire for "inconsistencies and controversies."

Benzinga spoke with Neurotrope Chief Scientific Officer and President Dr. Daniel Alkon following Merck's trial suspension. Alkon was unequivocal in his response.

"Here's the punchline," Alkon said, "It's the same target - getting rid of amyloid. That target has been shown over and over again for 20 years not to be correlated with the causing of deficits. The only thing that's well correlated, clearly established, is the loss of the synaptic connections."

A study by professor Clive Holmes published in the Lancet supports the criticism of the amyloid hypothesis. Holmes found, during autopsies of dementia patients who'd undergone treatment for the removal of amyloid plaque, that while some had virtually complete plaque removal, seven of the eight still died with severe end-stage dementia. "In the whole cohort," Holmes wrote, "there was no evidence of improved survival or of an improvement in the time to severe dementia" versus the placebo group.

Accera has also criticized the amyloid hypothesis. In a press release titled, "Beyond the Failed Beta Amyloid Hypothesis" Accera's senior medical advisor Michael Gold said, "Now more than ever we need to focus on alternative mechanisms to address Alzheimer's disease." Accera seeks to address what it believes to be the fundamental metabolic defect in Alzheimer's patients.

Citing Lilly's failed trial and Merck's suspended trial, Alkon said, "There is a long line of trials, all going after amyloid in different ways, that never have worked. What we're trying to say is, look at the elephant in the room. The elephant in the room is look at the loss of wiring in the brain."

Is The Bar Set Too Low?

Something else you may have noticed: Virtually all clinical work in AD at present is performed on patients with only mild cognitive impairment and promodal AD. When asked what its recent trial news meant for the prevailing industry theory of AD treatment, Merck told Benzinga, "It is too early to speculate on what the EPOCH trial results mean for the validity of the amyloid hypothesis. It is hoped that by evaluating verubecestat in people at the earlier prodromal stage, who have lower levels of damage to the brain, we will be better able to slow disease progression."

In fact, Leerink analyst Geoffrey Porges in a research note suggested that the Merck suspension presented no added risk to the amyloid hypothesis but instead validated "the strategy of moving away from testing anti-amyloid drugs in moderate patients."

Alkon would disagree. "These trials are not working, and moving it up earlier and earlier is not going to change it," Alkon said. "Look at Biogen's trial. What people don't realize is that Biogen moved their trial so far up that there wasn't one Alzheimer's patient in the trial. They only looked at people who were mild cognitively impaired or confused. Only half of which go on to get Alzheimer's."

Neurotrope's bryostatin was developed through a focus on PKC epsilon - an enzyme which has been shown to be at a deficit in brains of AD patients. "It's not just restoring the synaptic networks, it's actually preventing the cascade of biochemical events whereby the neurons actually die. And PKC epsilon stimulated by bryostatin actually inhibits that, it prevents neuronal death and then in addition it stimulates synaptic growth. Those two things are unique."

So, why won't another, much larger company simply change focus from antibodies and BACE inhibitors to working with PKC epsilon? Well, in time one may do that, but to go to market with it is another story.

Neurotrope holds around 70 patents on its bryostatin and even more importantly, the rights to use PKC epsilon for treatment of AD. Alkon put it this way, "Suppose somebody else, let's say Lilly, came up with a new PKC epsilon activator, and let's say that it had good efficacy. The drug they came up with would be theirs, but to use it to treat Alzheimer's they'd have to work with us." And of the prospect of teaming up with pharma partners? "We'd be happy to work with them."