Dimebon for HD—A Hint of Cognitive Benefit?

This story was updated on 15 February 2010.

12 February 2010. The results of the first U.S. Phase 2 trial for Dimebon in Huntington disease are finally out in print. The February Archives of Neurology carries the report from the Huntington Study Group DIMOND Investigators, a multicenter coalition in the U.S. as well as the U.K. The drug, which is also under investigation for Alzheimer disease (see ARF related news story on Doody et al., 2008) was safe and well tolerated by the 46 people who received it. And over the 90-day treatment period, people taking Dimebon gained approximately one point on the Mini-Mental State Examination (MMSE). The study was sponsored by Medivation, Inc., San Francisco, which is developing the drug for treatment of both Alzheimer and Huntington disease.

Karl Kieburtz of the University of Rochester Medical Center in New York led the study. The researchers recruited 91 subjects for the double-blinded, randomized trial. Half received 20 milligrams of Dimebon thrice daily, and the other half received placebo. Tolerability was the primary outcome, and dropouts and adverse effects were reported equally between the two groups. The researchers also used three different scales to rate cognitive performance: the Unified Huntington’s Disease Rating Scale (UHDRS), the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog), and the MMSE. They rated participants at days 0, 60, and 90.

Kieburtz noted that not all participants had cognitive impairment to begin with, so a cognitive effect might not stand out in a small study. Neither the UHDRS nor the ADAS-cog showed any difference between the Dimebon and placebo groups. But with the MMSE, people on the drug improved by about one point between the start and end of the study—a “hint of benefit,” Kieburtz said. Because the study was small, and the researchers were mainly focused on tolerability, it is hard to say exactly what specific cognitive function was responsible for the improvement. Kieburtz noted that some participants improved on tasks such as counting backwards from 100 by sevens. “Those kinds of tasks are actually very tricky for people with HD,” he said. MMSE scores for placebo recipients remained flat over the study time period.

None of the three tools is really ideal for evaluating Huntington disease, said Rachelle Doody of the Baylor College of Medicine in Houston, Texas, who was not involved with the study. “The whole notion of doing anything about cognition in Huntington disease is fairly new,” she said. Although the UHDRS includes cognitive measures, it is weighted toward the movement side of the disorder, Doody noted. The ADAS-cog is designed for Alzheimer disease, not the subcortical dementia characteristic of HD. And the MMSE, Doody said, is more of a “blunt instrument” lacking sensitivity. “The fact that there was a signal on the MMSE raises the possibility that there is a cognitive effect; it does not by any means pin it down and prove it,” she said. Doody is a scientific and clinical advisor to Medivation and holds, or has held, stock in the company.

Dimebon’s mechanism remains unclear (see ARF related news story). It appears to protect neurons and mitochondria by affecting calcium and NMDA receptors (Bachurin et al., 2001). The drug also inhibits serotonin receptors (Wu et al., 2008); this kind of inhibition is known to enhance cognition (Schaffhauser et al., 2009). It is this activity that is likely responsible for the MMSE results, said Ilya Bezprozvanny of the University of Texas Southwestern Medical Center in Dallas, who was not part of the study. “It is like drinking a cup of coffee,” he said, and probably does not actually slow disease. If serotonin receptor inhibition is responsible for the cognitive boost, Bezprozvanny suggested, then other molecules more specific for the right receptor might make a better drug. An alternate theory was suggested by Sam Gandy of the Mount Sinai School of Medicine in New York City, who was not an author on the study. He noted that Dimebon may reduce protein inclusions in an animal model of synucleinopathy (see Bachurin et al., 2009). With the drug linked to multiple protein aggregation diseases, “this is looking to be a common theme,” Gandy wrote in an e-mail to ARF.

Currently, Kieburtz is leading the Phase 3 HORIZON trial for Dimebon in HD. This multisite study—including centers in North America, Europe, and Australia—will use the same dosage of Dimebon with the MMSE as the primary outcome. HORIZON is planned to include 350 subjects, four times that of the DIMOND study. In addition, only people with cognitive impairment can enroll, making the study more likely to find a cognitive effect if there is one.—Amber Dance

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References

News Citations

  1. AD Clinical Pipeline: Immunotherapy Woes, Dimebon Boons
  2. Dimebon: Bright Star or Black Hole?

Paper Citations

  1. Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D, . 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.
  2. Bachurin S, Bukatina E, Lermontova N, Tkachenko S, Afanasiev A, Grigoriev V, Grigorieva I, Ivanov Y, Sablin S, Zefirov N. Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. Ann N Y Acad Sci. 2001 Jun;939:425-35. PubMed.
  3. Wu J, Li Q, Bezprozvanny I. Evaluation of Dimebon in cellular model of Huntington's disease. Mol Neurodegener. 2008 Oct 21;3:15. PubMed.
  4. Schaffhauser H, Mathiasen JR, Dicamillo A, Huffman MJ, Lu LD, McKenna BA, Qian J, Marino MJ. Dimebolin is a 5-HT6 antagonist with acute cognition enhancing activities. Biochem Pharmacol. 2009 Oct 15;78(8):1035-42. PubMed.

External Citations

  1. Medivation, Inc.
  2. Bachurin et al., 2009

Further Reading

Papers

  1. Doody RS. Dimebon as a potential therapy for Alzheimer's disease. CNS Spectr. 2009 Aug;14(8 Suppl 7):14-6; discussion 16-8. PubMed.
  2. Okun I, Tkachenko SE, Khvat A, Mitkin O, Kazey V, Ivachtchenko AV. From anti-allergic to anti-Alzheimer's: Molecular pharmacology of Dimebon. Curr Alzheimer Res. 2010 Mar;7(2):97-112. PubMed.
  3. Gauthier S. Dimebon improves cognitive function in people with mild to moderate Alzheimer's disease. Evid Based Ment Health. 2009 Feb;12(1):21. PubMed.
  4. Burns A, Jacoby R. Dimebon in Alzheimer's disease: old drug for new indication. Lancet. 2008 Jul 19;372(9634):179-80. PubMed.
  5. Grigorev VV, Dranyi OA, Bachurin SO. Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons. Bull Exp Biol Med. 2003 Nov;136(5):474-7. PubMed.
  6. Sabbagh MN, Shill HA. Latrepirdine, a potential novel treatment for Alzheimer's disease and Huntington's chorea. Curr Opin Investig Drugs. 2010 Jan;11(1):80-91. PubMed.
  7. Yamashita M, Nonaka T, Arai T, Kametani F, Buchman VL, Ninkina N, Bachurin SO, Akiyama H, Goedert M, Hasegawa M. Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models. FEBS Lett. 2009 Jul 21;583(14):2419-24. PubMed.

Primary Papers

  1. Kieburtz K, McDermott MP, Voss TS, Corey-Bloom J, Deuel LM, Dorsey ER, Factor S, Geschwind MD, Hodgeman K, Kayson E, Noonberg S, Pourfar M, Rabinowitz K, Ravina B, Sanchez-Ramos J, Seely L, Walker F, Feigin A, . A randomized, placebo-controlled trial of latrepirdine in huntington disease. Arch Neurol. 2010 Feb;67(2):154-60. PubMed.

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