Mechanism Matters

Posted on February 27, 2015

Why Mechanism Matters – The Case of Dimebon
If a drug helps HD patients, why does it matter how it does so? In a sense it doesn’t; there are a number of drugs commonly prescribed for various illnesses whose methods of action aren’t fully understood. If a drug works and is safe and well tolerated, there is no reason not to approve it and figure out the mechanism later.

However, Huntington’s disease is a complex, multi-hit disease which causes many pathogenic processes. Knowing how a treatment works allows physicians to prescribe a rational combination of drugs which address different targets. Further, there may be another existing drug which acts on the same target or targets and if so, a comparison of effectiveness and side effects may be warranted. It might also be possible to further develop a new or existing drug to address its target more precisely. Mechanistic studies can also point to potential side effects that would rule out a trial without further development of the drug.

Another important consideration is that knowing the target might predict whether a drug which has been tested for its ability to improve symptoms might also be neuroprotective rather than just a symptomatic treatment. Trials to determine neuroprotection take much longer and are more costly.

Perhaps of most importance is the limitation of resources. We do not have all the resources – money, time, and trial participants — to test every promising drug in the HD Pipeline. For the HDSA Pipeline Chart, we have selected a couple dozen promising drugs which appear to be moving through the pipeline as a result of ongoing research, but there have been many more which have been proposed over the years. This is encouraging but it means that prioritization is necessary. Selecting a drug which is both promising in preclinical studies and for which the mechanism is known and which makes sense based on what we have learned about the disease should increase the likelihood of success in clinical trials.

Dimebon is an example of a drug which went to clinical trials before extensive preclinical research had been done. Dimebon was chosen by Medivation to take to Phase III (final) clinical trials in both Alzeheimers and Huntington’s diseases based on promising research in Russia. Phase II study results for AD in Russia were outstanding and a Phase II study for HD in North America also looked good. Unfortunately, Phase III AD and HD clinical trials were not successful.

Dimebon is an example of a drug which went to clinical trials before extensive preclinical research had been done. Dimebon was chosen by Medivation to take to Phase III (final) clinical trials in both Alzeheimers and Huntington’s diseases based on promising research in Russia. Phase II study results for AD in Russia were outstanding and a Phase II study for HD in North America also looked good. Unfortunately, Phase III AD and HD clinical trials were not successful.

The mechanism by which Dimebon might have worked was never clear. Medivation has presented some data from the independent lab or Dr. Maria Ankarcrona that suggests that Dimebon may act to strengthen the mitochondria in cultured neurons under conditions of stress although not as well as Brain Derived Neurotrophic Factor (Zhang).

The study has been critiiczed based on the method of inducing the stress (the use of ionomycin, a nonphysiological method), the lack of a strong dose dependent effect, and because the mechanism was never identified (Bezprozvanny). However, if we assume that the data is meaningful, it raises the question of how stronger mitochondria could lead to improved cognition. Since we know that energy metabolism is impaired in HD, shouldn’t a follow-up study be done in an HD mouse model to see if Dimebon is neuroprotective? If so, disease progression might be a more appropriate clinical trial endpoint.

Back in 2003, Bachurin found that in cultured liver cells Dimebon prevents the irreversible opening of the mitochondrial permeability transition pores caused by neurotoxins including excessive calcium. MPT pores routinely transfer ions and peptides in and out of the mitochdria and play an important role in maintaining calcium homeostasis. This possible mechanism could be important for HD treatment since there is evidence that excessive calcium influx activates the mitochondrial permeability pore in HD causing the release of chemicals such as cytochrome C which trigger apoptotic cell death.

However, the mitochondria of brain cells are known to respond differently

than liver cells to this kind of challenge. Recently, Naga and Geddes looked at mitochondria transition permeability in brain cells when challenged by calcium influx both with and without Dimebon treatment and found that Dimebon failed to prevent mitochondrial permeability transition. Although mitochondrial swelling was reduced, the mitochondia’s ability to retain calcium was not improved and cytochrome c was released.

Dimebon was never studied in the HD mice. There were some studies which reported minor cognitive improvement in normal or AD model rodents. Wang and colleagues found minor improvement in spatial memory in both normal and AD mouse models and Schaffhauser and colleagues found an acute improvement in short term social recognition memory in normal rats.

Dimebon has an affinity for a number of receptors – achetylcholinesterase, N-methyl-d-aspartate (NMDA), the 5-HT(6) receptor, and histamine — which may be involved in cognition (Wu). Could Dimebon’s effect on one of these receptors account for the effects on animals?

Studies have shown that Dimebon is a weak antagonist of achetylcholinerase (AChE) receptors. In a rat study, Dimebon improved cognition in a novel object recognition task but did not reduce the levels or activity of AChE or block NMDA-induced calcium influx (Giorgetti). Dimebon is also a very weak NMDA antagonist, 200 fold weaker than memantine, so it seems unlikely that this could ever have been an effective mechanism.

Two studies which looked at excitotoxicity have found that the concentrations necessary to act on the NMDA receptors and inhibit voltage gated calcium channels in cell models are very much higher than those used in animal and human studies (Bachurin, Wu).

As critic Eric Sharps points out, these two possible methods of action, AChE and NMDA antagonism, which have since been rejected as possibilities by both Medivation and other researchers, were the original impetus for trying Dimebon as an Alzheimer’s treatment to begin with. The mitochondrial strengthening hypothesis came later.

Dimebon’s effect on histamine and 5-HT(6) receptors have been suggested as potential mechanisms explaining the animal improvement in cognition (Wu for the former, Bezprozvanny 2010 for both, Schaffhauser for the latter). Modulation of histamine receptors is currently being studied for the effect on cognition and a variety of neurological and psychiatric disorders.

Dimebon is a strong antagonist of the 5-HT(6) receptor. A study using rats found that Dimebon occupies the 5-HT(6) receptor in vivo and enhanced cognition (Schaffhausser). Blocking this receptor partially reduces the antidepressant effect of fluoxetine (Prozac) in rats so this might have been a potential issue for some HD patients.

A serious concern for Alzheimer’s patients was raised by a study which found that Dimebon actually increased levels of the extracellular amyloid beta protein aggregates that are characteristic of AD in both AD cell and mouse models (Steele).

In hindsight, perhaps more preclinical work was warranted before Dimebon was taken into trials for neurogenerative disease. The mitochondria strengethening hypothesis needs more extensive data to back it up. The minor cognitive improvements in rodents were not associated with an effect on cognitive deficits caused by neurodegeneration and did not translate into improvement in HD or AD patients. Negative results might have been predicted and costly trials avoided. In the absence of more preclinical work, had Dimebon actually been found to be successful in clinical trials, important questions would have remained unanswered for doctors and patients about Dimebon’s role in treatment.

Although all of us in the HD community are disappointed with the failure of this trial, it is important to remember that this drug did not emerge from basic and preclinical HD research. It was taken to clinical trials in HD, understandably, because of encouraging results in Alzheimer’s Disease which shares some pathological mechanisms with HD. Unfortunately, those Phase II results were not replicated in the Phase III studies, and the preclinical research that has continued while the trials were going on suggests that research into possible mechanisms should have been done before the AD trials. This reinforces the idea that mechanistic data should be given weight along with preclinical effectiveness data in selecting drugs for trials in HD.

The disappointing results do not, however, predict a lack of success for current HD drugs which are in development. Dimebon was not discovered in a high throughput assay designed to screen for potential HD treatments and it was not studied in any of the HD mouse models.

Dr. Samuel Gandy, who has studied Dimebon in AD models, has commented that “This was a drug with no plausible mechanism that emerged from an incomprehensible series of screens that then had a ‘better than anything ever’ effect in a Russian trial and then gave absolutely zero effect in a US replicate trial” (Jeffrey).

The exciting Phase II AD results in Russia undoubtedly pushed the trials forward for AD while the Phase II HD results were promising enough for Medivation to want to go forward with the Phase III HD trial. Hopes were initially high but the final results for the trials for both diseases show why it is important to have large scale, double-blind placebo controlled trials.

Sergey O. Bachurin, Elena P. Shevtsova, Elena G. Kireeva, Gregory F. Oxendkrug, and Sergey O. Sablin. “Mitochondria as a Target for Neurotoxins and Neuroprotective Agents.” Annals of the New York Academy of Science 2003 May (993):334-349.

Ilya Bezprozvanny. “The Rise and Fall of Dimebon.” Drug News & Perspectives 2010, 23(8): 518-523.

Marco Giorgetti, Jacqueline A. Gibbons, Sebastiean Bernales, Ivan e. Alfaro, Christophe Drieu La Rochelle, Thomas Cremers, C. Anthony Altar, Robert Wronski, Birgit Hutter-Paier, and Andrew A. Protter. “Cognition-Enhancing Properties of Dimebon in a Rat Novel Object Recognition Task Are Unlikely to Be Associated with Acetylcholinesterase Inhibition or N-Methyl-d-aspartate Receptor Antagonism.” The Journal of Pharmacology and Experimental Therapeutics 2010 Jun;333(3):748-57.

Susan Jeffrey. “Dimebon disappoints: is there hope for novel Alzheimer’s agent?” Medscape Medical News. March 26, 2010.

Roy W. Jones. “Dimebon disappointment.” Alzheimer’s Research and Therapy. 2010 Sep 13;2(5):25.

Kranthi Kumari Naga and James W. Geddes. “Dimebon Inhibits Calcium-Induced Swelling of Rat Brain Mitochondria But Does Not Alter Calcium Retention or Cytochrome C Release.” Neuromolecular Medicine 2011 Mar;13(1):31-6

Hervé Schaffhauser, Joanne R. Mathiasen, Amy DiCamillo, Mark J. Huffman, Lily D. Lu, Beth A. McKenna, Jie Qian and Michael J. Marino. “Dimebolin is a 5-HT6 antagonist with acute cognition enhancing activities.” Biochemical Pharmacology Volume 8, Issue 8 15 October 2009, Pages 1035-1042.
Eric S. Sharps. Medivation and Dimebon. Foursquare Partners report, February 16, 2009.

John W Steele, Soong H Kim, John R Cirrito, Deborah K Verges, Jessica L Restivo, David Westaway, Paul Fraser, Peter St George Hyslop, Mary Sano, Ilya Bezprozvanny, Michelle E Ehrlich, David M Holtzman, and Sam Gandy. “Acute dosing of latrepirdine (DimebonTM), a possible Alzheimer therapeutic, elevates extracellular amyloid-β levels in vitro and in vivo.” Molecular Neurodegeneration 2009 Dec 17;4:51.

Per Svenningsson, Eleni T. Tzavara, Hongshi Qi, Robert Carruthers, Jeffrey M. Witkin, George G. Nomikos, and Paul Greengard. “Biochemical and Behavioral Evidence for Antidepressant-Like Effects of 5-HT6 Receptor Stimulation.” The Journal of Neuroscience, April 11, 2007 27(15):4201- 4209.

Jun Wang, Mario G. Ferruzzi, Merina Varghese, Xianjuan Qian, Alice Cheng, Mathew Xie, Wei Zhao, Lap Ho, and Giulio M Pasinett. “Preclinical study of dimebon on β-amyloid-mediated neuropathology in Alzheimer’s disease.” Molecular Neurodegeneration 2011 Jan 19;6(1):7.

J Wu, Q Li, Ilya Bezprozvanny. “Evaluation of Dimebon in cellular model of Huntington’s disease.” Mol Neurodegener 2008, 3(1): 15.

Shouting Zhang, Louise Hedskog, Camilla A. Hansson Petersen, Bengt Winblad, Maria Ankarcrona. “Dimebon (Latrepirdine) Enhances Mitochondrial Function and Protects Neuronal Cells from Death.” Journal of Alzheimer’s Disease.2010;21(2):389-402.

– Marsha L. Miller, Ph.D., April 14, 2011

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