Pharma

After 18 years, will vTv Therapeutics’ Alzheimer’s drug sink or swim?

vTv Therapeutics has spent nearly two decades advancing its Alzheimer’s drug, and results from two Phase 3 trials are expected in 2018.

There’s no denying that vTv Therapeutics has a lot riding on 2018. After 18 years of R&D, its lead drug, azeliragon, will either sink or swim based on two Phase 3 trials in Alzheimer’s disease (AD). The first is expected to be presented in the first quarter and the second by the end of the year.

“With positive results from both, we’d be in a position to go to the FDA in 2019 for new drug approval,” said vTv CEO Stephen Holcombe in an interview earlier in January. He added that azeliragon has fast track designation to expedite the agency’s evaluation.

It would be the first new therapy the field has seen in 15 years, sweeping into a market projected to be worth $11.3 billion by 2021. But there’s no guarantee that the drug won’t stumble at the line. It’s high risk, high reward to say the least.

Holcombe and Chief Medical Officer Larry Altstiel have high hopes for azeliragon. The landscape is not promising with recent Phase 3 failures, including Axovant’s intepirdine and Merck’s verubecestat.

Targeting RAGE
It’s a billion-dollar question: How can vTv succeed where so many others have failed?

The biggest differentiator is the drug target. Azeliragon stands alone as an oral antagonist of the receptor for advanced glycation endproducts (RAGE), which interacts with many proteins associated with cellular degeneration.

The receptors are found on a variety of cell types, including nerve cells, glial cells, and on the inside lining of blood vessels. That seems to sync with the clinical symptoms of Alzheimer’s, which include chronic inflammation and vascular dysfunction. RAGE activity also contributes to the build-up of amyloid-beta and tau proteins in the brain, the clinical hallmarks of the disease.

As a result, High Point, North Carolina-based vTv considers itself agnostic to the two dominant schools of thought, which assign blame to either amyloid-beta or tau. Both are part of the RAGE paradigm, but they’re downstream, which might explain why drugs that clear those proteins from the brain haven’t proven to be sufficient in large trials.

“I think the science is very robust,” Altstiel said of vTv’s agent. “And it doesn’t address one component of the illness to the exclusion of anything else.”

Azeliragon would ideally be a preventive therapy, he noted. It can’t reverse any damage that is done, but it could theoretically slow progression of the disease.

In Phase 2b trials, vTv tested the drug in both mild and mild-to-moderate Alzheimer’s patients over 18 months. Both groups demonstrated statistically significant benefits taking the drug, as measured using the ADAS-Cog11 assessment scores. However, the patients with mild Alzheimer’s fared slightly better on average, registering a 4.0 point improvement versus the 3.1 point improvement observed in the mild-to-moderate cohort.

“With the mechanism that we have, it at least makes sense that the earlier you get to the patient the better off they’re going to be,” Altstiel explained.

In terms of safety and tolerability, it’s a mixed bag. At the 5 mg dose, Altstiel said there has been “some mild, self-limiting G.I. effects that haven’t resulted in any issues as far as people dropping out of studies.”

Both Phase 3 trials are using the 5 mg dose. An earlier trial of the drug at 20 mg was prematurely stopped, however, due to signs that patients were worsening on the drug. That ill-fated study ended vTv’s licensing deal with Pfizer, first signed in 2006, and cast some gray clouds over the compound.

Somewhere between 5 mg and 20 mg, the drug seems to turn toxic. Clearly, there is no room for error, as azeliragon would theoretically be taken long-term as a preventive therapy by a wide range of patients.

Both Phase 3 randomized, controlled trials will run for 18 months, to be followed by an open-label extension study. This should give FDA reviewers a decent look at safety and efficacy over time.

What could patients expect?
If azeliragon were approved, it would likely be used in combination with the standard-of-care. That’s how it is being tested and it would be a relatively easy addition, given it’s an oral pill. In terms of its positive effects on quality of life, Altstiel is cautious:

“I don’t want to overstate,” Altstiel said with a pause. “I think that what it means is that people will have more quality time; they’ll be able to spend more time with their families, more time with their friends, and be able to do the things that they care about with the people that they love for a longer period of time.”

It won’t change the course of the disease, but it could slow its progression. And as a former neurologist, Altstiel is conscious that Alzheimer’s affects more than just the individuals.

“I think by improving the quality of lives of the patients we, therefore, improve the quality of life for their caregivers and families,” he said.  

On an economic level, patients may be able to stay at home for longer and their level of care may be reduced. More than anything, an approval would be a symbolic first step towards curbing the burden of the disease after a 15-year hiatus.

“There’s really not one silver bullet out there,” Holcombe said, echoing the sentiment of many in the field. “It’s probably going to be ultimately a combination of different drugs going after different mechanisms.”

Planning for the unknown

Looking ahead, if the drug was successful and well-tolerated, the immediate market could be enormous. More than five million Americans have Alzheimer’s disease and vTv is not discriminating based on genetic subtypes or other markers.

The team has done some preliminary work to understand what’s required for the company to commercialize the drug on its own, however, out-licensing the drug or even being acquired by a Big Pharma company may make more sense due to the size of the market.

“There’s no lack of interest from large pharma,” Holcombe said. “They know this trial is reading out. They see that this is a drug that can be added on to the standard therapy. It can be used down the road, potentially, in combination with what they’re working on.”

Some 85 different Alzheimer’s drugs were in development in 2017, according to a report by industry advocacy group PhRMA. Keep in mind, however, that between 1998 and 2014, 123 investigationalAlzheimer’s drugs were pulled from clinical trials, with just four gaining FDA approval. No new therapies have been approved for Alzheimer’s since 2003.

Data from three important Phase 3 programs are expected to be presented in 2019 or the year after. That includes Biogen’s antibody-based therapy aducanumab, which targets amyloid-beta clusters in the brain. The two other drugs, Eli Lilly and AstraZeneca’s lanabecestat and Merck’s verubecestat, inhibit an enzyme called BACE, which should theoretically prevent the build-up of amyloid-beta.

For now, it’s up to vTv to break the therapeutic losing streak in the fieldAD. To get this point, Holcombe estimates the company has raised around $750 million through private investors, venture capital, partnerships, and an IPO in 2015 — though not all of that has gone to the Alzheimer’sD program. vTv has other clinical assets, most notably in type 2 diabetes.

But for 18 years, azeliragon has been the company’s lead program. And everything nows rests on the data.

“When I heard it was going to take 15-20 years to run all the studies you had to do, that your odds, once you go into the clinic, were probably one in 10 and probably one in 5,000 in discovery; that it was going to take anywhere from $500 million to $2 billion. I thought well the business model doesn’t really make a lot of sense,” Holcombe laughed. “But 18 years later, we’ve done all the work… I think we have followed that roadmap, which is not an easy one.”

Photo: Aleutie, Getty Images

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