Another Phase 3 trial of Dimebon has fallen flat. In the multicenter CONCERT trial, patients with mild to moderate Alzheimer’s disease who took 5 or 20 mg of Dimebon three times per day for 12 months, on top of the cholinesterase inhibitor donepezil, fared no better than those taking donepezil and a placebo. This is according to a statement released yesterday by Pfizer and Medivation, company sponsors of the drug. Primary outcome measures were cognition and activities of daily living. The companies will halt their collaboration to develop and market Dimebon, according to the press release. In 2008, Pfizer, the maker of donepezil, agreed to pay Medivation at least $725 million for worldwide rights to Dimebon, based on certain regulatory milestones. Pfizer assumed 60 percent of Dimebon development costs and paid Medivation $225 million up front.

“The results were not unexpected, but there was a tiny part of me that was still hoping it would pan out, mostly for the sake of all the families who volunteered for the study,” wrote Murali Doraiswamy, Duke University Medical Center, in an e-mail to Alzforum. Doraiswamy was one of the CONCERT investigators. “The big question is to see if we can learn anything postmortem about why the drug looked so good in the first trial,” added Doraiswamy. Investigators had initially reported that Dimebon improved cognition in a Phase 2 trial conducted in Russia (see ARF related news story). In the U.S., the drug failed in prior Phase 3 trials for AD (see ARF related news story) and, most recently, Huntington’s disease patients (see ARF related news story).

“My biggest worry is that this is going to make investors even more gun shy about this field,” wrote Doraiswamy. That concern has dogged the field ever since a flood of negative trial results began pouring in. Promising anti-inflammatory drugs, Aβ immunotherapies, γ-secretase inhibitors, DHEA, and a Rage inhibitor, to name a few, have all come up short so far.—Tom Fagan.

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  1. This is another unfortunate setback to the Alzheimer's community of researchers, clinicians, and patients. A possible way to turn this into something positive is to perform failure analysis, an approach used in many other industries (think aerospace) to learn as much as possible about the conditions that led to this failure. This would help avoid similar (costly) mistakes in the future. Failure analysis is one of the top priorities proposed to make drug discovery and development more efficient in a recent NIH White Paper on Quantitative Systems Pharmacology.

    Although the primary target of Dimebon was supposed to be mitochondrial stability (Zhang et al., 2010), its off-target pharmacology is relatively complicated, interacting with a number of neuromodulatory receptors and enzymes (Schaffhauser et al., 2009; Okun et al., 2010). Of course, such an analysis has to explain also the positive results in the first Phase 2 study (Doody et al., 2008) and the acute effects on memory in primates (Webster et al., 2011).

    Quantitative Systems Pharmacology is a translational, computer-based tool that attempts to combine preclinical physiology in a mechanistic, disease-based model with clinical data on pathology and cognitive outcomes. As such, sensitivity analysis of virtual clinical trials can identify the drivers of positive or negative outcomes.

    It is to be hoped, for the benefit of the AD research community, that data from the clinical trials will be published, because that will help such a study tremendously.

    References:

    . Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study. Lancet. 2008 Jul 19;372(9634):207-15. PubMed.

    . From anti-allergic to anti-Alzheimer's: Molecular pharmacology of Dimebon. Curr Alzheimer Res. 2010 Mar;7(2):97-112. PubMed.

    . Dimebolin is a 5-HT6 antagonist with acute cognition enhancing activities. Biochem Pharmacol. 2009 Oct 15;78(8):1035-42. PubMed.

    . The acute effects of dimebolin, a potential Alzheimer's disease treatment, on working memory in rhesus monkeys. Br J Pharmacol. 2011 Oct;164(3):970-8. PubMed.

    . Dimebon (latrepirdine) enhances mitochondrial function and protects neuronal cells from death. J Alzheimers Dis. 2010;21(2):389-402. PubMed.

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References

News Citations

  1. AD Clinical Pipeline: Immunotherapy Woes, Dimebon Boons
  2. Dimebon Disappoints in Phase 3 Trial
  3. No Effect Seen in Huntington’s Disease Trial of Dimebon

External Citations

  1. CONCERT
  2. statement

Further Reading

News

  1. AD Clinical Pipeline: Immunotherapy Woes, Dimebon Boons
  2. Dimebon Disappoints in Phase 3 Trial
  3. No Effect Seen in Huntington’s Disease Trial of Dimebon