A litany of promising therapies for Alzheimer’s disease have crashed and burned in late-stage testing. So it was an ominous sign when the FDA recently placed a clinical hold on a big Phase 3 trial for an experimental drug from Waltham, MA-based Forum Pharmaceuticals.
What’s more, the side effects that have triggered the pause—or at least the few details Forum has shared so far—are puzzling, according to Alzheimer’s experts.
Forum, which has been backed with hundreds of millions of dollars mainly by the financial behemoth Fidelity, announced on September 14 that two of its studies were on hold due to gastrointestinal safety problems. The studies were a Phase 3 trial in Alzheimer’s for the drug encenicline, as well as a long term extension study of encenicline in schizophrenia patients.
The FDA didn’t stop Forum’s two other trials—fully enrolled Phase 3 tests also in schizophrenia patients—although investigators will now conduct “additional vigilance around GI safety monitoring of patients,” the company said. Forum expects data from those two tests in the middle of next year.
When Xconomy reached CEO Deborah Dunsire for comment, she said that the clinical hold was prompted by “a very small number of GI-related safety events that were somewhat varied in presentation.”
She didn’t specify what those were, but she said Forum is working to understand what caused them.
“We are in active discussions with the FDA to define a potential path forward to lift the clinical hold,” she said.
It’s too early to say what kind of delay Forum faces, and what it means for the future of encenicline.
The most common side effect seen in Alzheimer’s patients was mild constipation; in schizophrenia patients, headaches, and Dunsire said that encenicline hasn’t been tied to any serious GI problems before. She also pointed out that even though the FDA placed a hold on an Alzheimer’s and a schizophrenia trial, the problems had cropped up only in the Alzheimer’s patients.
Perhaps that’s not surprising. A 2011 study published in the Journal of the American Geriatrics Society, for instance, concluded that Alzheimer’s patients 65 and older are more likely to suffer serious upper- and lower GI problems—like ulcers and bleeding—even among patients that don’t have a history of GI problems. The patients in Forum’s Alzheimer’s study are an average of about 75 years old; those in its schizophrenia study are much younger, around 40, Dunsire said.
“Most Alzheimer’s patients are elderly” and have other problems besides the Alzheimer’s itself that require medications, said Dunsire, noting that many of those drugs “themselves are associated with a GI risk for this patient population.”
Xconomy reached out to several outside Alzheimer’s experts for their thoughts. The bottom line: There was no consensus about the nature or the gravity of the encenicline problems, and there was even some conflicting information.
Shauna Yuan, an assistant professor of neurology at UC San Diego Health System who specializes in dementia, says that in the 2011 study, other cognitive boosters weren’t deemed to have contributed to the GI bleeds. “Depending on what the serious side effects are from this experimental drug, it’s hard to speculate what the mechanisms might be and if this is a special problem for the Alzheimer’s patients,” she said.
Banner Alzheimer’s Institute director Pierre Tariot said that prior to these Phase 3 trials, encenicline showed a “GI signal”—a hint that it might cause some sort of GI problems. He says this “would not be a surprise at all” given “virtually all” drugs that impact the neurotransmitter acetylcholine—as encenicline does—tend to have “GI liability.”
But Joseph Rogers, the executive director of SRI Biosciences’ brain sciences program, suggested the opposite, that the class of drugs that encenicline belongs to, which target what’s known as the alpha 7 nicotinic receptor, might actually protect the gut from GI-related side effects, according to a number of published studies.
“Why encenicline should increase gastrointestinal side effects is unclear,” he said. “One might have predicted just the opposite.”
Why, indeed. One scientist requesting anonymity who has done due diligence on encenicline in the past, but isn’t associated with Forum, said he didn’t remember GI problems being an issue. But that was before Phase 3. The drug is now being tested in a much larger population—1,600 people instead of the roughly 400 in Phase 2—where a previous unseen side effect may be showing up, or where encenicline could be exacerbating the GI problems associated with the two approved drugs for Alzheimer’s, donepezil (Aricept) and memantine (Namenda). (It wouldn’t be practical for Forum to test encencline in people without exposure to those drugs.)
Alzheimer’s disease affects millions around the world and has bedeviled scientists for years; there’s still no effective treatment. That significant need is why Biogen (NASDAQ: BIIB) gained and lost billions of dollars in market value after releasing just a snippet of data from a Phase 1 trial earlier this year.
And some of biotech’s most dramatic moments of the past decade have been the high wire Phase 3 tests, and ensuing failures, of recent Alzheimer’s hopefuls like solanezumab and bapineuzumab.
The FDA delay comes at a particularly inopportune time for Forum, which is very unusual as biotechs go. It started more than a decade ago, as EnVivo Pharmaceuticals, mainly bankrolled by Fidelity thanks to former Fidelity CEO Ned Johnson’s passion and support for Alzheimer’s research.
It existed apart from the Fidelity Biosciences portfolio, more of a “mission oriented business,” as former Fidelity partner Jason Rhodes told me in March.
With its separate status, Forum didn’t have to do deals or woo outside investors to survive. Indeed, Fidelity wanted it to stay private and commercialize its own drugs despite the prohibitive cost.
Under Dunsire, however, there’s a new mandate: find outside investors to lay the foundation for a future IPO. But the star of the portfolio remains encenicline. Should it persevere in either Alzheimer’s or schizophrenia—which doesn’t have any drug approved for cognition—Forum will likely have a blockbuster drug on its hands. And the hypothesis that the drug could impact other diseases like ADHD, depression, and traumatic brain injury could gain traction, as well.
If it fails? All that value disappears, and Forum must focus on its earlier-stage compounds for orphan-type neurological disorders like frontotemporal dementia.
Encenicline is a lot like the cognitive boosters that have won FDA approval for Alzheimer’s. Each is meant to help people think more clearly for longer, and each target different proteins in the brain. Forum believes it has a better solution—longer-lasting cognition boosts, in more patients, without the side effects—based on differences in the target and chemistry between encenicline and those drugs.
Whether the GI problems that have put the drug on hold argue against that belief remains to be seen. It’s unclear, for instance, how long it’ll take for Forum to resolve the issue. Some clinical holds are lifted quickly, such as the one the FDA placed on a cancer immunotherapy trial run by Memorial Sloan-Kettering Cancer Center in 2014. Others can take years, like the 2012 hold on pain drug prospect tanezumab that was lifted just a few months ago.
But Dunsire says the company has the cash to wait out the hold and complete the encenicline trials without raising another round. Safe to say that Alzheimer’s experts will be paying attention to the findings.
“Exactly what was seen here I don’t know and, while it is unfortunate that at least some participants had problems, it is very important information to have,” Tariot says.