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Failed Alzheimer’s Drug To Get Another Shot, If Investors Pony Up

Xconomy Boston — 

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: 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: 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 mild or no outward symptoms of the disease. Roche’s Genentech group made a similar call last year with a drug called crenezumab, moving it into Phase 3 for asymptomatic or mild Alzheimer’s despite disappointing 2014 results from a Phase 2 trial in mild-to-moderate patients.

There’s a notable difference between those efforts and the one Alzheon has planned. With solanezumab and crenezumab, industry and academic researchers are responding to clinical signals that clearing the amyloid from the brains of Alzheimer’s patients seems to work better before symptoms have really taken hold. Past a certain point, these amyloid-clearing drugs have had little effect—the pharmaceutical equivalent of putting a band-aid on someone who has nearly bled to death.

Biogen (NASDAQ: BIIB) is also putting the early-disease theory to the test, jumping its amyloid-clearing antibody drug aducanumab from Phase 1 to dual Phase 3 trials now underway that could cost $2.5 billion to reach a conclusion.

But Alzheon is pressing ahead in the mild-to-moderate population. Tramiprosate also acts upon amyloid, but it does so “upstream”—that is, it blocks the protein fragments from clumping together into sticky plaques.

The different mechanism—blocking the fragments instead of busting up the plaques— could have important implications for safety. One positive sign from the Neurochem study was that tramiprosate did not cause the edema, or brain swelling, that in years since has hampered trials of other experimental Alzheimer’s drugs. One theory is that clearing amyloid plaques also damages blood vessels and causes the edema. It’s a safety question Biogen and others have to address by testing huge numbers of patients. (Biogen’s Phase 3 tests are aiming for 2,700 people.)

Tolar, who is making his case Friday at an Alzheimer’s meeting in Athens, Greece, says Alzheon can keep the numbers smaller and, therefore, the costs down.

The company has run a small trial to show that the new tramiprosate is “bioequivalent” to the old one, which means they can lean on the old safety data. Tolar says for good measure he hired outsiders to examine MRIs of the Neurochem trial patients; about 25 percent had their brains imaged. None of the people taking tramiprosate had signs of swelling.

Alzheon might also save on trial costs because it won’t have to scan people’s brain for signs of amyloid. The diagnosis of ApoE4 on both chromosomes is assurance enough of having elevated levels of amyloid in the brain—about 90 percent likelihood, says Snyder.

Overall, Alzheon is shooting to test 450 people, all with the ApoE4 mutation in both chromosomes. Half will get tramiprosate, half a placebo.

One challenge the company faces moving forward with tramiprosate: Fair or not, the drug carries the taint of its previous owners’ suspect marketing practices. After the trial failure in 2007, Neurochem changed its name to Bellus Health and sold tramiprosate in Canada and on the Internet as a supplement called Vivimind. A 2008 press release trumpeted it as “Canada’s scientifically proven natural health product to protect memory function.”

That led to swift rebukes from Neurochem’s former allies. In an Alzforum article, Paul Aisen, then of Georgetown University and the lead investigator in the old tramiprosate trials, was quoted saying, “I do not think that compounds should be marketed for ‘protection of memory function’ unless they have been demonstrated to be effective and safe. The trials of tramiprosate did not demonstrate efficacy.”

(Aisen is now director of the University of Southern California’s new Alzheimer’s institute, a position at the center of a legal fight. Aisen did not respond to requests for comment.)

Alzheon has raised $20 million so far, half in what Tolar describes as a “friends and family” Series A round, and half as debt that could convert into equity during the next fundraising. To fuel the next step, Tolar is eager for an IPO—unprompted, he mentioned a news article that suggested the window could re-open—but he’ll have to convince investors, whether they are public or private, that tramiprosate is worth the bet.