vTv Therapeutics said it will end current clinical trials of its lead candidate, the Alzheimer’s disease treatment azeliragon, after it failed a Phase III study. The disclosure marked yet another clinical setback for treatments aimed at the neurodegenerative disorder, and one that sent the company’s shares plunging more than 70% in market trading this morning.

Azeliragon missed both co-primary efficacy endpoints in the Phase III STEADFAST study, which assessed the treatment candidate in patients with mild Alzheimer’s disease. Patients taking azeliragon compared with placebo did not improve in either cognitive or functional outcomes as measured by the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) subscale and the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb), vTv acknowledged.

As a result, vTv said, it will end current clinical studies involving azeliragon, including the open-label extension study (NCT02916056) and Part B of the STEADFAST study (NCT02080364).

STEADFAST consists of two independent and identical, randomized, double-blind, placebo-controlled Phase III trials—Part A and Part B—with 400 patients studied over 18 months in each trial. The first trial enrolled patients in the U.S. and Canada who had a clinical diagnosis of mild Alzheimer's disease and an MRI consistent with this diagnosis. The second trial enrolled patients in the U.K., Ireland, Australia, New Zealand, and South Africa.

The azeliragon treated group in Part A had a 4.4 point decline from baseline in ADAS-cog and a 1.6 point decline from baseline in CDR-sb compared to placebo declines of 3.3 and 1.6, respectively. While the azeliragon group declined more in ADAS-cog than placebo-treated patients, the differences were not statistically significant.

vTv added that it expects a substantial portion of the patients in Part B of STEADFAST will have completed 12 months of treatment under the study protocol, given the progress to date of STEADFAST Part B.

“We will continue to analyze the datasets and trends within subgroups from both Part A and Part B to determine if there are potential benefits or future uses and applications for azeliragon,” vTv CEO Steve Holcombe said yesterday in a statement.

Azeliragon was generally well-tolerated, with a 25% withdrawal rate over 18 months that was similar in both the placebo and treatment arms, vTv added.

71% Stock Plunge

vTv disclosed the failure of azeliragon in the STEADFAST trials yesterday after the close of the NASDAQ markets, where its shares are traded. Investors responded to the failure with a stock selloff that sent vTv shares plummeting 71% from yesterday’s closing price of $3.26, down to 95 cents a share as of 10:07 a.m.

Azeliragon, also known as TTP488, is an orally active small molecule discovered and developed by vTv using its proprietary TTP Translational Technology® drug discovery platform. Azeliragon is designed to inhibits the receptor for advanced glycation endproducts (RAGE). RAGE is an immunoglobulin supergene family member expressed on multiple cell types in the brain and the periphery—and is found on the cells of the neurovascular compartment. Endothelial cells and microglia prominently express RAGE whose expression is upregulated in Alzheimer’s.

According to vTv, previous studies have suggested that RAGE contributes to Alzheimer’s by promoting vascular leakage, promoting influx of peripheral amyloid beta into brain, mediating amyloid beta induced oxidative stress, mediating AGE induced hyperphosphorylation of tau and amyloid beta–mediated neuronal death.

vTv is the latest drug developer to stumble in the long struggle to create successful new drugs for Alzheimer’s. Only a handful of drug successes have ever reached the market, and even they have merely slowed progression of symptoms by 6 to 12 months.

A 2014 Cleveland Clinic study found a 99.6% failure rate of clinical trials for Alzheimer's drug candidates between 2002 and 2012. That study found high attrition rates for Alzheimer’s treatments, with 72% of agents failing in Phase I, 92% failing in Phase II, and 98% failing in Phase III.

“The high rate of attrition of compounds requires a constant supply of new approaches (new chemical entities, immunotherapies, repurposed drugs, devices) that can be assessed for efficacy in Alzheimer's disease,” Jeffrey L. Cummings, M.D., Sc.D., of the Cleveland Clinic, and colleagues, concluded in that study.

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