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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.