DefinedHealth

Ginger S. Johnson, PhD

Alzheimer’s disease poses a grave and growing challenge to our Nation.

Many experts already recognize that Alzheimer’s will severely affect the lives of millions of Americans who either suffer from this disease or care for someone who does. Less appreciated are the grave economic consequences that Alzheimer’s disease, with its cumulative costs, will impose on the country. Unless we take decisive action now,the Alzheimer’s crisis could very easily surpass even the current economic crisis in the damage it inflicts on individuals and our economy.

A National Alzheimer’s Strategic Plan: The Report of the Alzheimer’s Study Group, March 2009.

Virtually every big pharma company has an Alzheimer’s (AD) program targeting disease modification and is dedicating significant resources toward what promises to be an enormous market. Big pharma has biotech to thank for much of the innovation.

The reward of this still elusive market comes with considerable risk, evidenced by late-stage failures in the clinic (e.g., Flurizan, Myriad Pharmaceuticals and Alzhemed, Bellus, f.k.a Neurochem).  In fact, the risk may be too big for even the biggest of the big pharma to face alone.  As the result of a July 2009 deal, the risk associated with one of the most advaced and most controversial disease modifying AD therapies, bapineuzumab, will be shared by Elan, Wyeth, Pfizer and J&J.   J&J purchased 18.4% of Elan’s Alzheimer’s Immunotherapy Program (AIP) with Wyeth (and now Pfizer) and will roll out the program into a new J&J company that will be 49.9% owned by Elan.  J&J has also committed to investing another $500 million toward the AD clinical program.  The bapineuzumab program has now advanced to large and expensive Phase III studies following a Phase II trial that did not reach statistical significance on the primary endpoints for the overall study population; however, a post-hoc analysis did show statistical significance in patients not carrying the apolipoprotein E (ApoE) genotype. Bapineuzumab is joined by two other Phase III disease modifying therapies, both Eli Lilly programs - LY206430 a passive amyloid vaccine and LY450139, a gamma secretase inhibitor.

As the believers in the beta amyloid theory of AD (so called ‘BAptists’) begin to doubt their faith, companies are spreading the risk to other mechanisms, and thanks to the slow but steady advancement of Alzheimer’s basic biology in the public sector, targets are plentiful.  The next wave of big pharma deals is likely to be focused on approaches targeting the other side of the historical AD divide, tau, and its role in the formation of neurofibrially tangles (the doctrine of the ‘TAUists’). Tau made a big splash in mid-2008 with TauRx’s Rember (meythlene blue) which is thought to protect against tau aggregation.  In a 321 patient Phase II trial, Rember showed that cognitive decline was remarkably slowed for 84 weeks (which is muddled by the fact that the trial was placebo controlled for only 24 of the 84 weeks and the highest dose did not show significant efficacy).  Other tau-based therapies in development include Allon Therapeutics’ small peptide neuroprotectant, AL-108/davunetide (Phase II) and Noscira’s NP-12, which also inhibits β-amyloid aggregation. Both of these programs are yet to be partnered.  The big issue for the future of AD disease modification is that our ability to write and perform clinical studies in the correct patient populations lags behind our improving knowledge of the basic underlying science of AD.  Significant questions and controversy remain around trial design and the optimal point of intervention in the progression of the disease.  A major concern is that treatment is being introduced too late in the course of the disease at a point when the damage (to the brain) has been done. However, identifying patients at the very earliest stages of the disease requires biochemical markers or imaging techniques that correlate with clinical response.  To date there is no clinically accepted surrogate marker of efficacy for AD.

This webinar will discuss the current state of Alzheimer’s R&D as well as what’s next in terms of novel targets, trial design and the use of biomarkers