Interview – VTV aims to make novel Alzheimer’s target all the Rage

With the amyloid hypothesis of Alzheimer’s disease in tatters, pharma might need to face up to the fact that it needs to explore new avenues of research. Handily a novel candidate, VTV Therapeutics’ Rage inhibitor azeliragon, will soon be put to the test, with its first phase III data due in April.

Hopes are not high for the project – analysts and investors alike are wary after countless failures in Alzheimer’s, and azeliragon has already been ditched by Pfizer. But if VTV does manage to pull off an improbable victory it will attract attention, and the company is confident of its chances with azeliragon, which not only targets amyloid but also Tau and inflammation.

Company VTV Therapeutics
Project Azeliragon
Market cap $243m
Event type Phase III trial results
Date April 2018

Amyloid still has a role in Alzheimer’s therapy, the company’s chief medical officer, Larry Altstiel, contends: “If you don’t believe amyloid has anything to do with the disease you’re barking at the moon,” he says.

However, hitting just amyloid might not be enough. “We’re addressing all three pillars of what’s deemed to be involved in Alzheimer’s. My guess is that addressing one of these components in the absence of the others is not the way to go,” he tells EP Vantage.

Rage against the machine

Rage, which stands for receptor for advanced glycation end-products, is thought to be upstream of these other targets. As well as being involved in inflammation, “Rage increases the production of enzymes that help make the amyloid-beta peptide, and helps transport the amyloid-beta peptide from the peripheral vascular system into the brain. And it seems to promote the abnormal phosphorylation of the Tau protein,” Mr Altstiel says.

He puts the fact that few other companies are currently looking at Rage down to the very broad patent portfolio granted to Columbia University, which originally identified the target.

“If we publish positive results I’d be astonished if people [interested in working on Rage] didn’t come out of the woodwork,” says VTV’s chief executive officer, Stephen Holcombe. “We do know about some earlier projects in the lead optimisation phase. But I’d bet there’s a bunch of others.”

Still, the scarcity of Rage developers might also be explained by the fact that Pfizer pulled out of a partnership with VTV midway through phase II, after efficacy issues with the 20mg dose of azeliragon  (vTv paddles out to catch summer Alzheimer’s wave, July 21, 2015).

In its phase III trial VTV has focused on a 5mg dose and has only enrolled mild patients, who showed a greater benefit than the overall mild-to-moderate population in phase II

Data from part A of the Steadfast phase III study are due in April, and results from the identical part B are expected by the end of the year. Each section of the trial has enrolled 400 mild Alzheimer’s patients, randomised to receive placebo or 5mg azeliragon once-daily for 18 months, on top of acetylcholinesterase inhibitors and/or memantine. The co-primary endpoints are change from baseline in the ADAS-cog and CDR sum of boxes scores.

Long shot

Stifel, one of the few sellside groups to cover VTV, gives azeliragon a 50% chance of success and forecasts probability-adjusted sales of nearly $420m by 2022.

The difficulty of developing Alzheimer’s therapies means that, in reality, VTV’s chances are probably lower. But an emphatic success would be a huge coup for a small company based in North Carolina.

Strong results could tempt a bigger player, which would have no problem digesting VTV’s current market cap of just $250m. True, companies have been dropping out of the Alzheimer’s space, either via late-stage failures or by choice, with Pfizer reportedly scrapping R&D in the disease earlier this month. But Biogen, for one, is still committed to Alzheimer’s, and there would be no shortage of interest in a truly disease-modifying drug. 

On the other hand, would a phase III failure mean the end for azeliragon or could the project stumble on, perhaps in even earlier-stage disease? 

“You’d have to commit to running a study in another population,” says Mr Altstiel. “Would we do it ourselves? Unlikely. We’re not Biogen or Merck. But if the data are compelling, if there’s enough interest in the target, I think it’s worth exploring.”

As the failures have mounted up, research into anti-amyloid MAbs has moved into even earlier-stage disease, such as prodromal Alzheimer’s or mild cognitive impairment, based on the theory that these drugs need to be given early in the disease process in order to be effective. Could this also be the case for Rage?

“The definitions in the field tend to evolve, so you’re always going to be a little bit behind people who are doing trials now, because you’re committed to the trial that you designed three to four years ago,” replies Mr Altstiel.

Still, he believes that even just putting the brakes on mild Alzheimer’s would be enough. “People with mild disease are still functional – they have a lot to offer.”

With the next big Alzheimer’s hope, Biogen’s anti-amyloid MAb aducanumab, not due to yield phase III data until 2019, VTV finds itself in pole position. “We used to tell people we’re next in line – we’re at the front of the line now,” says Mr Holcombe.

VTV will have to hope that, against the odds, the upcoming data will be enough to keep it there. 

Study Trial ID Data due
Steadfast, part A NCT02080364 April
Steadfast, part B NCT02080364 End 2018

To contact the writer of this story email Madeleine Armstrong in London at madeleinea@epvantage.com or follow @ByMadeleineA on Twitter

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