Interview – Alzheon’s bid to prove the beta amyloid doubters wrong

At a time when every anti-beta amyloid project has failed late-stage trials in Alzheimer’s disease it should come as a surprise that Alzheon, a private US start-up, has staked its entire business model on the beta amyloid hypothesis.

Not only that, but its work derives from tramiprosate, a project that flunked phase III eight years ago and was ditched by its originator, Bellus Health. That said, Alzheon's chief executive, Martin Tolar, sees a clear logic in working on a prodrug of tramiprosate that, being a small molecule, can overcome one major shortcoming of antibodies like Lilly’s solanezumab.

In Alzheon’s lead project, ALZ-801, “we have a drug that penetrates the blood-brain barrier”, he tells EP Vantage. By contrast, he says the amount of antibody able to cross is “miniscule”; indeed, it is likely that whatever action large molecules exert could be limited to circulating amyloid beta.

Of course even if ALZ-801 is able to target amyloid beta efficiently the jury is still out over the documented relationship between increased levels of this protein and Alzheimer’s disease. As every statistician knows, correlation does not imply causation.

But Mr Tolar, who has been studying Alzheimer's for many years, is under no doubt that targeting amyloid beta is the right way to treat it. “And we have a much better position to address amyloid pathologies in the brain.”

Clinical backing

To support this he cites two studies Alzheon presented last week at the International Conference on Alzheimer's and Parkinson's Diseases in Nice, France, where the company was somewhat overshadowed by Biogen’s phase I trial of BIIB037 (Biogen clears one Alzheimer’s hurdle; now comes the tricky bit, March 20, 2015).

The first is a reanalysis of tramiprosate’s failed US phase III trial, this time excluding patients who did not have the ApoE4 genotype responsible for the most aggressive disease. Looking only at ApoE4-positive patients, tramiprosate showed statistically significant effects on cognition and function, as measured by the Adas-Cog and CDR-SB tests, Mr Tolar states.

This addresses directly what he sees as one of the key problems of Alzheimer’s: incorrect diagnosis. “By focusing on ApoE4 patients you take away the misdiagnosis noise,” he states.

The second presented study – a previously unpublished phase I trial – squares the circle, showing ALZ-801 to have a half-life of almost 15 hours, versus five hours for tramiprosate. ALZ-801 is a valine prodrug of tramiprosate, resulting in “increased exposure – you have more drug available in plasma and in the brain; and longer half-life allows us potentially to do once-a-day dosing.”

From Bellus, which was refocusing on orphan diseases, Alzheon acquired ALZ-801, backup compounds, and “all of the data” relating to tramiprosate (Bellus is owed a single-digit royalty).

The logic is clear: to develop the prodrug cheaply, backing it with tramiprosate’s safety database comprising some 2,000 patient exposures. The IP situation also helps, and Mr Tolar cites “full composition-of-matter coverage worldwide” for ALZ-801.

On to pivotal trials

Assuming talks with regulators go well he reckons ALZ-801 could go straight into pivotal studies, by virtue of the tramiprosate database, at the end of this year.

He plans to start a phase II/III trial mimicking the tramiprosate programme and endpoints, but testing the subgroup effect prospectively. Thus only ApoE4-positive patients are to be enrolled, and a 400mg daily ALZ-801 dose is to be given; this is equivalent to the 100-150mg of tramiprosate in phase III – an important consideration in referencing the latter’s safety.

The advantage? “We don’t need to raise hundreds of millions of dollars; we need to raise tens of millions,” says the chief executive. However, he is cagey when asked about specifics, and will not say how much Alzheon has raised since inception, though he reveals that a current fund-raising has been oversubscribed.

“There has been a lot of renewed interest in Alzheimer’s,” he adds. “The whole field is coming to life again.” On Friday Biogen’s market cap put on $10bn after the phase I readout, so he can probably say that again.

To contact the writer of this story email Jacob Plieth in London at or follow @JacobPlieth on Twitter

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