Alzheimer’s disease has been a pharmaceutical minefield the past decade, with several experimental drugs backed by pharmaceutical giants such as Pfizer, Roche, Eli Lilly, and Johnson & Johnson blowing up after being tested in thousands of patients.
The first of those failures, nearly a decade ago, was a drug called tramiprosate. But now, after a dubious detour into the world of nutritional supplements, it’s back.
Boston-area biotech Alzheon has revived tramiprosate and is on the hunt for investors to help pay for two trials, run in parallel, with an estimated price tag of $100 million—actually a bargain compared to many other Phase 3 Alzheimer’s trials.
If the trials go well—a big if—approval could follow within a few years, although drug development is a capricious process, no more so than in Alzheimer’s. Only two drugs have ever been approved to treat the disease, and they only slow down patients’ cognitive decline for a few months, at best.
The FDA once shot down tramiprosate, which aims to improve patients’ mental and physical state by blocking formation of the telltale clumps, or plaques, of the protein beta-amyloid that accumulate in the brains of Alzheimer’s patients. But in a meeting last month, the agency gave Alzheon a green light to proceed with its Phase 3 plans based on data the company has pulled together in recent months, according to Alzheon CEO Martin Tolar.
Once owned by Montreal-based Neurochem and branded as Alzhemed, tramiprosate never made it to market. Data unveiled in 2007 showed that overall it had little to no effect slowing the mental and physical decline of Alzheimer’s patients. And the people running the trial couldn’t explain why the effects varied wildly among the dozens of testing sites.
Tolar is a veteran of Alzheimer’s drug programs, first at Pfizer (NYSE: [[ticker:PFE]]), then Comentis, which struck an ultimately ill-fated deal with Astellas. He detoured into genomics, running a company called Knome for a short time, before founding Alzheon in 2013.
Tolar says Alzheon has made two fixes to tramiprosate. One is chemical, adding a structure that acts as a chaperone when the once-a-day pill is swallowed. The active drug itself, derived from an amino acid found in seaweed, hasn’t changed, but it’s now supposed to get to its target more precisely and cause fewer gastrointestinal side effects. The chemical tweak should also smooth out the wildly variable effect that plagued the Neurochem trials, says Tolar.
The second fix is bigger; in fact, it’s the key to the revival. Alzheon analyzed the data from Neurochem’s failed U.S. trial, as well as one in Europe that was shelved—which together included about 2,000 patients—and found that tramiprosate seemed to help a subset of people who carry a specific mutation of a gene called apolipoprotein E, or ApoE. The mutation is ApoE4. People who have it on one chromosome have a higher risk not just of developing Alzheimer’s but suffering from early onset. For those who have it on both chromosomes the risks are higher still.
These double carriers will be the sole subjects of Alzheon’s trials, which means, if approved, tramiprosate will be available for roughly one third of people diagnosed with Alzheimer’s.
People with ApoE4 are almost guaranteed to have extra beta amyloid in their brains. Those without ApoE4 might not, and if a lot of people without that extra load were in Neurochem’s trial, tramiprosate wasn’t going to work for them. Those tests were designed nearly 15 years ago. But Alzheon has benefited from a large body of work in recent years—including failed clinical trials, and others ongoing—that has solidified the link between ApoE4 status and amyloid levels.
“Carriers of [ApoE4] are at substantially higher risk of having amyloid burden, particularly if they are already expressing clinical symptoms,” says Peter Snyder, an Alzheimer’s specialist who teaches at Brown University and is chief research officer at Lifespan Hospital Systems in Providence, RI. Using “E4” status to select patients leads to a trial with more people who have higher amyloid levels than the general population—“the exact type of patients that Alzheon believes will benefit from this therapeutic,” he says. (Snyder is on Alzheon’s scientific advisory board.)
Neurochem didn’t select patients based on ApoE4 status, but it did record everyone’s status. A look back at the data showed what Tolar calls a “gene-dose effect”: the people with one copy of ApoE4 responded better to the drug than those without the mutation; those with two copies responded better yet. “We consistently see that the more amyloid you have, the more efficacy you see,” Tolar says.
Looking for the silver lining in a failed trial often smacks of desperation in drug development. But in Alzheimer’s, Alzheon isn’t alone in the practice. Eli Lilly’s solanezumab failed a big Phase 3 trial in mild to moderate Alzheimer’s patients in 2012. Lilly ((NYSE: [[ticker:LLY]]) pressed ahead with a new Phase 3 trial in people with mild symptoms, and independent investigators are also using solanezumab in a trial with people who have
