With the Simpliciti-T1 phase II trial testing new-mechanism TTP-399 as adjunct therapy in type 1 diabetes (T1D), High Point, N.C.-based Vtv Therapeutics Inc. nailed the HbA1c endpoint with none of the safety concerns foiling developers of type 2 diabetes (T2D) drugs who sought to broaden their labels.

CEO Stephen Holcombe noted that “there really isn’t anything out there” for T1D except insulin and related technology such as pumps and monitors. He told BioWorld that a registration trial testing the liver-selective glucokinase activator likely will start before the end of this year.

Shares of Vtv (NASDAQ:VTVT) closed at $3.20, up $1.10, or 52%, after trading as high as $4.23, as Wall Street learned of positive results from the 12-week trial, conducted with support from Juvenile Diabetes Research Foundation International. Simpliciti-T1 explored the efficacy and safety of 800 mg of TTP-399 compared with placebo in 85 people with T1D on optimized insulin therapy.

The experiment achieved its primary objective analyzed using two statistical approaches to evaluating the effect of the drug. For the primary statistical analysis, researchers evaluated the effect on HbA1c regardless of treatment adherence or notable changes in insulin administration. That measure turned up statistically significant improvements in HbA1c with TTP-399 vs. placebo (p=0.03).

But the endpoint by itself is “tricky, because if you take more insulin during the day, you will lower your HbA1c,” Holcombe said. To eliminate the possibility that the HbA1c drop was driven by the administration of excess insulin, a second estimand analysis was performed. People treated with TTP-399 gained a statistically significant placebo-subtracted reduction in HbA1c of 0.32% (p=0.001). Those taking TTP-399 experienced a 0.21% knockdown, while placebo patients turned up a 0.11% increase, from a mean study baseline HbA1c of 7.6% following a multiweek insulin optimization period before treatment. “In our view, the next steps are registration trials,” he said. The company will engage the FDA and “lay out what we believe should be a possible course.”

TTP-399 has already been tried in T2D for six months. It worked, but Vtv turned to T1D because T2D represents “a very crowded space with a lot of therapies available, a lot of pricing pressure, etcetera,” Holcombe said. “We don’t need to test it in a lot of patients to see the efficacy” in T1D, he said. “It’s not like these thousand-plus patient trials that you see in T2D. The only question is, what are [regulators] looking for in a safety database.” Five hundred patients have been exposed to the drug in experiments that involved healthy and T2D patients, and now more than 100 in T1D. “The only endpoint, at least as the FDA sits here today that they’re looking for is an improvement in HbA1c, and even those levels are fairly modest,” he said.

Also in the works, Vtv has azeliragon undergoing a phase II proof-of-concept study as a potential treatment of mild Alzheimer’s disease (AD) with T2D. Azeliragon inhibits the receptor for advanced glycation end products (RAGE), a target licensed early in Vtv’s history from Columbia University. RAGE is associated with diabetic complications, including retinopathy, nephropathy and some cardiovascular issues. The company unveiled disappointing 18-month phase III results in April 2018 from an all-comers study in mild AD. But about 10% of the study participants had T2D. “What we found – it was all post hoc – was that, in those folks who were diabetic and took the drug, their AD didn’t advance at all after 18 months,” Holcombe said. The six-month phase II effort is testing the candidate in 100 patients. “If it’s positive, it would repeat what we saw on the post-hoc basis, and we could move that program very quickly into a confirmatory phase III trial,” he said. “We’ll have that data in the first half of next year.” The AD space is seeing new approaches involving targeted populations, he pointed out. “This fits right in there.” Millions of diabetics suffer from dementia.

Thanks to the earlier phase III study, “we’ve done all the work that’s necessary for this drug to get through the FDA,” including toxicity work, drug-drug interactions and chemistry, manufacturing and controls, Holcombe said. “We just need the efficacy, which is no small feat. It may only be a few hundred more [patients] that we would test.” The FDA typically wants two endpoints investigated, one involving cognition and one in function, though “it sounds as if they are starting to maybe consider loosening up those criteria because they want to see some drugs get to the market,” he said.

H.C. Wainwright analyst Vernon Bernardino reiterated his buy rating on Vtv shares and bumped the price target from $5 to $6. “We believe the results strongly position Vtv for partnership discussions with a diabetes-focused major pharmaceutical company that could result in lucrative up-front, milestone and TPP-399 sales-associated royalty patients,” he wrote in a report. Last summer, in a separate report, he took up the prospects for azeliragon, citing data rolled out by Vtv at the Alzheimer’s Association International Conference in Los Angeles. “Activation of RAGE at the blood-brain barrier (BBB) leads to BBB leakage and monocyte infiltration and further RAGE expression, which results in a pro-inflammatory feedback loop that ends in neurodegeneration and synaptic loss,” he said. “Thus, the hypothesis behind azeliragon is antagonism of RAGE reduces inflammation and improves cell survival. We look for positive results” from the phase II POC study “to be a significant catalyst in late 2020.”

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