Alzheimer Therapy Development: 3 Experts Sketch Out the Road Ahead

How recent failures may bring disease-modifying success a bit closer

After a long string of failed trials of investigational pharmaceuticals for Alzheimer disease (AD), confidence within the market is increasing, thanks in part to the advent of treatments with potential to modify the disease rather than simply treat symptoms.

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That’s a key message that emerged from a panel discussion — “Renewed Hope for Treating Alzheimer’s with Drugs and Biologics” — at Cleveland Clinic’s neuroscience-focused 13th Annual Medical Innovation Summit held late last year.

The session explored the state of AD drug development by drawing on the insights of three pharmaceutical industry scientists with a collective 100 years of neurocognitive drug development experience:

  • Richard Mohs, PhD, at the time VP of Neuroscience Early Clinical Development, Eli Lilly, and currently VP of Clinical Development, AgeneBio (also the developer of the Alzheimer’s Disease Assessment Scale cognitive subscale [ADAS-Cog])
  • Lawrence Friedhoff, MD, PhD, Chief Development Officer, Axovant Sciences (also led the approval process for Aricept [donepezil] in the 1990s)
  • David Michelson, MD, VP, Clinical Neuroscience Research, Merck & Co.

The discussion was a Q&A moderated by AD clinical trialist Jeffrey L. Cummings, MD, ScD, Director of Cleveland Clinic’s Lou Ruvo Center for Brain Health. Themes included lessons from failed trials of the recent past and emerging factors that might finally make disease-modifying AD treatments a reality. Here’s a sampling of the exchange.

Overcoming traditional obstacles to success

Dr. Cummings: What factors have inhibited successful development of drugs and biologics to treat AD, and how can they be addressed?

Dr. Mohs: The single biggest factor holding back investment is the recent record of failures. In other therapeutic areas, once breakthroughs happened, investments followed. We won’t see a quantum leap in AD drug development expenditures until we see some successes.

Dr. Friedhoff: One of the big deficiencies is the lack of predictive animal models for AD. We recognize that we don’t have good animal models, so we fall back on other approaches for developing drugs for AD. One of them is to use validated targets.

We need to have a broader attitude about where to look for drug candidates, and we should concentrate on more than just targets. We need to look for other kinds of evidence — for example, epidemiologic studies and big data trends identifying drugs that may be “anti-correlated” with, and thus potentially protective against, AD. We’ve been focused too much on targets and not enough on a broad approach.

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Pros and cons of pharma’s changing role

Dr. Cummings: Who has responsibility for target validation: NIH, academic medical centers or pharma/biotech? Is pharma moving away from discovery and more into development?

Dr. Michelson: A lot of the evidence around targets is generated from science on the academic side. Pharma is particularly good at taking that science and figuring out how to turn it into a “druggable” target. Once there’s a hypothesis about a disorder’s etiology, pathogenesis and pathophysiology, pharma essentially translates that into a drug mechanism that can work.

Dr. Mohs: Industry is good at building pharmacology around some bit of biology. In the past, a lot of target validation was based on similar pharmacologic agents working in a given space — for example, SSRIs. Recently, as a result of advances in genetics and biochemistry, many newer targets aren’t yet pharmacologically validated. Instead, they come from genetic or biochemical evidence that a given pathway has something to do with the disease. It wouldn’t be easy to make a business case in a pharma company for doing the basic genetic work to gather that information, because it’s so distant from any product.

Dr. Friedhoff: It would be a shame if pharma got completely out of trying to understand fundamental biology, but it’s getting harder to justify. Where we can contribute better is in looking at quicker ways of judging clinical efficacy. We now have a lot more technology — MRIs, CTs, functional MRI, PET scanning — which can serve, to some degree, as a surrogate end point.

A terrible problem in AD is the cost of failure. If you spend $1 billion on a trial that fails, that’s at least 10 drugs that could have gotten approved for $100 million apiece. Where we can contribute is making sure we have rigorous development programs so we don’t jump ahead to expensive studies before laying the proper infrastructure in earlier studies.

Supportive technologies and the impact of early diagnosis

Dr. Cummings: What about supportive technologies that could help in drug development?

Dr. Friedhoff: One thing we’re doing at our company is using modern internet technology to enhance patient recruitment at all our trial sites. We’re hopeful, based on initial results, that this approach will help get the right patients into our studies promptly.

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Dr. Cummings: Sometimes there seems to be a gap between academic discoveries and the validated targets pharma companies want. How can that gap be closed?

Dr. Mohs: The best thing we could do is to pair up biologists in academic labs with drug development experts at pharma companies so they understand what’s involved in taking a piece of biology and building some pharmacology around it so you can actually test pharmacologic hypotheses about that target. Unless you get those interactions, you won’t have a system that effectively translates basic biology into clinical development.

Dr. Cummings: How important is early diagnosis, and how will that play out against pharmacologic mechanisms?

Dr. Friedhoff: From a regulatory point of view, if we begin treating people very early in the disease process, we have to have a very, very clean safety profile. There’s no AD drug yet that’s been approved for that indication, so there’s no scale in place that we’re aware of.

Dr. Michelson: From a target discovery standpoint, we need to better understand what’s going on with pre-pathophysiology and tease that out from potential targets.

Dr. Mohs: Early diagnosis is important because it gives an indication of a first biologic abnormality. But we must remember that delaying onset of the disease is not the same as prevention.

A video of the panel discussion and other 2015 Medical Innovation Summit sessions is available here (select “Videos” tab and Video 33).