NIH steps in on Alzheimer’s where industry fears to tread

The $45m set aside by the US National Institutes of Health for research into Alzheimer’s disease agents would not be sufficient to put a single candidate through a complete clinical programme. However, as a means of priming the R&D pump, it could be a good start – and it is a clear sign that the lack of progress in treating the degenerative disease is getting attention at the highest levels of government.

There is no doubt that Alzheimer’s is a space crying out for innovation: just three truly novel projects are in late-stage study, one of which has shown only the slightest glimmers of efficacy in its first phase III trial, and a spate of modestly effective marketed compounds have been around long enough to be losing patent protection. The pull of a patient population forecast to reach more than 100 million worldwide has not been enough to overcome the reputation for failure in Alzheimer’s; government has decided to provide a gentle push.

Quiet space

For a disease expected to affect so many people as populations age around the world, Alzheimer’s is a fairly inactive space: EvaluatePharma identifies 90 commercial clinical-stage trials, although many of these are testing imaging products or extending the lifecycles of the established cholinesterase inhibitors like Aricept. As a comparison, another CNS indication, schizophrenia, has 123 trials under way.

Eliminating imaging products, nutriceuticals and more speculative products, only three agents are in late-stage trials – one, solanezumab, has already cost its sponsor, Lilly, an enormous amount in phase III with little to show for it, although this has not discouraged the Indiana group (Once more, with feeling: Lilly sings sola again, July 15, 2013).

So it probably will not hurt to get a boost from government sources. As a sign of the importance being placed on Alzheimer’s research, much of the funding will come from the NIH director’s budget rather than the subsidiary National Institute on Aging. The NIH as a whole has suffered a 5.5% reduction in funding as a result of the federal budget sequester beginning in March, so it is notable that Alzheimer's has been given the special funding.

Three of the six trials funded under the NIH initiative identify specific drugs or classes, with the remaining three focused on identifying biological targets and potential molecules to hit them. Some very late-stage projects will be included.

The Washington University in St Louis Dian-Tu trial, backed with up to $6m in federal funding, will test the anti-amyloid beta antibodies solanezumab, gantenerumab from Roche, and a third compound yet to be named – Elan’s bapinezumab would be a likely candidate – in an inherited form of early-onset Alzheimer’s (see table).

Allopregnanalone, a modulator of the GABA A receptor, will be the subject of a 12-week phase I dose-finding trial supported with $2.4m from the NIH. Investigators at the University of Southern California will be hoping to repeat preclinical findings that the natural brain steroid can cause brain-cell regeneration, inhibit amyloid production and restore cognitive function.

The NIH awarded the biggest amount to the Banner Alzheimer’s Institute in Arizona, for a prevention trial of an as-yet unnamed anti-amyloid agent in non-symptomatic patients with two copies of the apolipoprotein E4 allele, the best-known genetic risk factor for late-onset disease. This study will receive $33.2m, and investigators expect additional private funding.

Trends in Alzheimer's

Two trends are clear from the funding awards: scientists are not giving up on the hypothesis that inhibiting beta amyloid, which is believed to be linked to the distinctive brain lesions found in Alzheimer’s patients, can slow disease progression even if the candidates that have targeted it have not been successful; and earlier treatment might address some of the weaknesses of those products.

The former trend continues to be the case even in commercial trials, where non-antibody products like Merck & Co’s MK-8931 still attack amyloid-beta (Merck & Co puts its faith in amyloid beta hypothesis, December 4, 2012); the latter was seen both in Lilly’s new trial for solanezumab, which is enrolling mildly affected patients, as well as Roche's gantenerumab, whose phase III trial is treating patients with the mild form of the disease called “prodromal” Alzheimer’s.

Pharma has little to show for the millions of dollars spent on Alzheimer’s research in recent years, and this does nothing to encourage development of novel treatments. Government probably cannot step in where the private sector has faltered, but it can provide incentive for the industry to persevere.

Late-stage trials of Alzheimer's disease candidates
Brief title Status Enrolment Trial ID Acronym Conditions Commercial project Sponsors Primary Completion Date
Phase III A Study of Gantenerumab in Patients With Prodromal Alzheimer's Disease Recruiting 770 NCT01224106 - Alzheimer disease Gantenerumab Roche 01/04/2018
Safety and Efficacy Study Evaluating TRx0237 in Subjects With Mild Alzheimer's Disease Recruiting 500 NCT01689233 - Alzheimer's disease LMTX TauRx Pharmaceuticals 01/06/2015
Safety and Efficacy Study Evaluating TRx0237 in Subjects With Mild to Moderate Alzheimer's Disease Recruiting 833 NCT01689246 - Alzheimer's disease LMTX TauRx Pharmaceuticals 01/02/2015
Progress of Mild Alzheimer's Disease in Participants on Solanezumab Versus Placebo Recruiting 2,100 NCT01900665 EXPEDITION 3 Alzheimer's disease Solanezumab;
Amyvid;
AV-45
Eli Lilly 01/12/2016
Continued Safety Monitoring of Solanezumab in Alzheimer's Disease Active, not recruiting 1,275 NCT01127633 EXPEDITION EXT Alzheimer's disease Solanezumab Eli Lilly 01/07/2014
Phase II/III An Efficacy and Safety Trial of MK-8931 in Mild to Moderate Alzheimer's Disease (P07738 AM3) Recruiting 1,960 NCT01739348 EPOCH Alzheimer's disease MK-8931 (Merck & Co) Merck & Co 01/04/2017
Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation. Recruiting 210 NCT01760005 DIAN TU Alzheimer's disease
dementia;
familial Alzheimers disease
LY2062430 (Eli Lilly);
gantenerumab (Roche)
Washington University School of Medicine; Eli Lilly Roche
Alzheimer's Association
01/07/2014

To contact the writer of this story email Jonathan Gardner in London at jonathang@epvantage.com or follow @JonEPVantage on Twitter

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