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Alzheimer's disease continues to RAGE as Vtv falls victim in phase III effort

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By Marie Powers
News Editor

The global scourge that is Alzheimer's disease (AD) claimed another biopharma victim as azeliragon (formerly TTP-488), the orally active small-molecule antagonist of receptor for advanced glycation end products, or RAGE, from Vtv Therapeutics Inc., crashed and burned in part A of the phase III STEADFAST study. The High Point, N.C.-based company was expected to enroll some 800 individuals with mild AD – 400 in each of two identical parts in the randomized, double-blind, placebo-controlled effort. Part A missed on both co-primary efficacy endpoints, as individuals who took azeliragon failed to improve in cognitive or functional outcomes as measured by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and by the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb), compared to those who received placebo.

The first 18-month trial enrolled patients in the U.S. and Canada who had a clinical diagnosis of mild AD and an MRI consistent with the diagnosis, while enrollment of the second trial included sites in the U.K., Ireland, Australia, New Zealand and South Africa.

Individuals in the azeliragon arm of part A showed a 4.4-point decline from baseline in ADAS-Cog – a steeper loss than the 3.3-point decline among those who received placebo. Individuals in both the treatment and placebo arms showed a decline of 1.6 points from baseline in CDR-sb. The differences were not considered statistically significant, according to the company.

Vtv said azeliragon was generally well-tolerated. STEADFAST had a 25 percent withdrawal rate over 18 months, similar across both the placebo and treatment arms.

In a statement, CEO Steve Holcombe said the company "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." Nevertheless, Vtv said it was halting studies of azeliragon, including the open-label extension and part B of STEADFAST. The company estimated that "a substantial portion" of participants in part B likely completed 12 months of treatment under the study protocol.

Vtv officials were not available to discuss the timing of its analysis or next steps, according to a spokeswoman.

The news, disclosed following Monday's market close, sent Vtv's shares (NASDAQ:VTVT) plummeting Tuesday to a historic low of 69 cents before closing at 71 cents for a loss of $2.55, or 78.1 percent.

Vtv used its drug discovery engine, TTP Translational Technology, to discover and develop azeliragon and target RAGE, an immunoglobulin supergene family member expressed on multiple cell types in the brain and periphery, including those on the cells of the neurovascular compartment. RAGE ligands include A-beta, S100b, HMGB1 and advanced glycation endproducts, or AGEs.

RAGE-ligand interactions lead to sustained inflammatory states that play a role in chronic diseases such as diabetes, inflammation and AD, and some researchers have suggested that RAGE may contribute to AD pathology by such mechanisms as promoting vascular leakage, promoting influx of peripheral A-beta into brain, mediating A-beta-induced oxidative stress or mediating AGE-induced hyperphosphorylation of tau. The proposed role of RAGE in AD pathology, however, was largely described using rodent models.

Until Vtv. The company completed phase I studies in healthy volunteers and 10-week and 18-month phase II studies in patients with mild to moderate AD to support the phase III registration trial. The randomized, double-blind, placebo-controlled phase IIb trial, TTP488-203, assessed azeliragon in 399 patients with mild to moderate AD. Participants were randomized to an oral dose of 20 mg per day (following a loading dose of 60 mg/day x six days) of azeliragon, 5 mg per day (following a loading dose of 15 mg/day x six days) of azeliragon or placebo – in all cases, added to stable doses of acetylcholinesterase inhibitors and/or memantine.

The 20-mg/day dose was stopped by the study's data monitoring committee due to acute, reversible, concentration-dependent cognitive worsening and the study was halted prematurely for apparent futility. Nevertheless, Vtv reported that the study achieved its pre-specified objective, demonstrating a statistically significant 3.1-point difference (p = 0.008) in the change in ADAS-cog at 18 months that favored azeliragon 5 mg/day over placebo. STEADFAST subsequently began enrolling in May 2015 under an FDA special protocol assessment.

Late last month, Roth Capital Partners analyst Robert LeBoyer maintained that "we're on the edge of our seats waiting for STEADFAST data," downplaying volatility in the company's stock in the run-up to the findings. Although LeBoyer deemed success in meeting the co-primary endpoints a "best case" scenario, he suggested that a "good" case would be for the trial to meet its efficacy endpoints in a less convincing manner.

On Tuesday, LeBoyer lowered Vtv's rating to "neutral," from "buy," and slashed the price target on shares to $1, from $17, acknowledging that "although the company has two other products for diabetes in early clinical development, our investment thesis was based on azeliragon in Alzheimer's disease."

Going forward, Vtv's survival may depend on success in those diabetes programs, Piper Jaffray analyst Charles Duncan suggested. Although the azeliragon phase III failure was "not a big surprise to investors," he wrote, "given the provocative phase II results, unmet need and outside-the-box thinking on the mechanistic rationale for the target and this RAGE antagonist, we are disappointed that some clinical activity wasn't seen."

The STEADFAST data now put any value from azeliragon "deep in the 'show-me' category," Duncan added, removing the asset from projections, and "now relying solely on ongoing phase II [trials with] two diabetes candidates and residual platform value."

Duncan lowered the price target on shares to $4 from $24 and downgraded the stock to "neutral" from "overweight."

Vtv was formed in 2015 by combining Transtech Pharma LLC and its affiliate High Point Pharmaceuticals LLC and then completing an IPO to raise $117.2 million. (See BioWorld Today, June 17, 2015.)

At last year's annual meeting of the American Diabetes Association in San Diego, the company rolled out data with its orally bioavailable, non-peptide agonist of GLP-1R, TTP-273, that confirmed the candidate's positive effect on blood glucose as well as lack of nausea and vomiting side effects sometimes associated with injectable GLP-1 receptor agonists. Vtv had previously reported phase II data showing that TTP-273 might help type 2 diabetics on stable doses of metformin achieve mean placebo-subtracted HbA1c differences of up to -0.86 percent. (See BioWorld Today, Dec. 16, 2016, and July 17, 2017.)