Sunday, March 4, 2012

Tekmira’s Drug Candidate for Alcohol Dependence Turns Intravenous Delivery into Strength

Tekmira’s SNALP delivery platform which makes up the majority of the active systemic RNAi Therapeutics pipeline symbolizes the potential efficiency of the RNAi Therapeutics platform: Once a delivery technology is found to be suitable for knocking down genes in a given tissue/cell type, only the sky, aka our understanding of disease genetics, is the limit. A frequently cited criticism of the SNALP platform, however, has been that the intravenous mode of delivery that most of its current applications call for would restrict the market potential of SNALP drugs. This particularly applies to chronic primary care applications in slowly, and often silently progressing diseases such as atherosclerosis. While I disagree that a once-a-month one-to-two-hour procedure will be a major hurdle towards market adoption for most applications that matter, Tekmira’s latest SNALP development candidate, TKM-ALDH2 for the treatment of alcohol dependence (AD), actually turns the intravenous mode of administration into a competitive advantage.

TKM-ALDH2 targets aldehyde dehydrogenase 2 in the liver and, as a result, causes very unpleasant hypersensitivity symptoms (e.g. flushing and nausea) after drinking alcohol which is the result of the inefficient removal of acetaldehyde during ethanol metabolism. The target is greatly validated by human genetics which has shown that individuals with a slow metabolizing isoform of ALDH2, particularly prevalent in Asia, are at much reduced risk of becoming dependent on alcohol. In fact, a mainstay of treating alcohol dependence in the US, disulfiram (Antabuse), works by inhibiting ALDH2 and thus deterring from drinking alcohol.

But disulfiram is not without its controversies. In fact, it is a drug that many like to hate. Perhaps not surprising to find that adults with an alcohol problem don’t have the same lobby as kids with a rare genetic disorder, although the costs of AD figures in the hundreds of billions a year in the US alone. Fuel for the detractors of disufiram and medicating alcoholics in general is the observation that a number of clinical studies have failed to show a benefit of disulfiram.

If one looks closer, however, it is pretty clear that the problem is not with the mechanism of disulfiram per se, but rather with patient compliance. Even in well supervised settings it may be difficult to make sure that the patient is actually swallowing the pill. Consequently, the pharmaceutical industry has become interested in developing disulfiram versions that are administered parenterally, e.g. via an implant or intravenously. TKM-ALDH2 thus would be related to intravenously administered disulfiram, but with the pharmacologic advantage of requiring less frequent administration. Based on population genetics a frequency of administration ensuring a ~60% trough knockdown should be a good target and should be achievable with current SNALP technology with once-a-month dosing.

I believe that TKM-ALDH2 is only the most obvious application to date where the intravenous route of administration is a beneficial feature of an RNAi Therapeutic. I also wonder how comfortable insurance companies are with relying on their patients diligently taking their $100,000+/year rare-disease medications in the comfort of their homes. Patient compliance is not just a huge issue when treating addiction, but with all types of medications.

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By Dirk Haussecker. All rights reserved.

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