When NASA, the National Aeronautics and Space Administration launches a rocket into space they call it "lighting the candle". This is the awesome moment after years of careful planning, testing and retesting -- they decide to push the ignition button. Launching a drug into clinical trial for Huntington's is a similar situation. It takes years of science, planning, testing and retesting before decisions are made to start a clinical trial.

How are decisions made to launch a drug candidate into clinical trial? Have you wondered why CHDI has not yet decided to "light a candle" with one of their drug candidates? As a recent observer at a CHDI working group, I had a chance to look at part of what goes into this decision-making process. What does it take to light a candle? It depends . . .

CHDI graciously invited me to observe an expert working group that included academic scientists from within and outside the Huntington community, CHDI Foundation scientists, and representatives from both the pharmaceutical industry and National Institute for Neurologic Disease and Stroke (NINDS). This lively discussion centered on energy-based therapeutics for Huntington's. Importantly, because much discussion centered on CoQ-10, it gave me the opportunity to observe decision-making processes used by CHDI as they plan for clinical trials, and to compare them to HSG and drug companies.

How are drugs chosen for clinical trials? As the following "real life" Huntington examples show -- it varies greatly with each sponsoring organization.

The Amarin Miraxion-EPA example: Amarin decided to take Miraxion EPA into clinical trial based on positive results in mouse models that had used a combination of EPA and DHA. They presumed (probably incorrectly [Arterburn LM 2006]) that EPA would be converted into DHA in people. This drug was taken to a large Phase 3 clinical trial without any significant indication (proof of concept study) that suggested that the drug was active in the brains of people, or a phase 2 study suggesting benefit in selected motor endpoint. Phase 3 failed, as did the concurrent pure EPA mouse study [Van Raamsdonk JM 2005]. In retrospect, Amarin had very little pre-trial data that suggested their drug would be successful in clinical trial.

The HSG CoQ-10 example: The Huntington Study Group high-dose CoQ-10 Phase 3 (2CARE) trial is in process. The decision to bring this drug to clinical trial is based on its presumed mechanism of direct action on energy dysfunction in Huntington mitochondria, positive results in some -- but not all -- mouse model study, and most importantly on the trend toward benefit observed in the earlier lower-dose CoQ-10 human clinical trial [Huntington Study Group 2001]. Note that there has been no "proof of concept" testing in people using the higher dose CoQ-10, though arguments can be made that the earlier lower-dose trial rates as "proof of concept".

The CHDI CoQ-10 analogue example: CoQ-10 analogues made by Edison Pharmaceuticals can achieve higher levels of the drug in the brain than conventional preparations (such as the CoQ-10 agent used in HSG trials). However, moving the Edison drug forward into clinical trial has been slowed by recent basic research that questions the previously accepted (electron transport) explanation for Huntington's mitochondrial energy defects [Lee JM 2007]. So instead of taking this drug to clinical trial now, CHDI is first testing exercise-induced energy dysfunction (in muscle) in Huntington's patients -- with the hope that results from this study will provide a method for confirming drug effect in people (proof of concept study) for Edison drugs, or others that work in energy dysfunction pathways. This of course presumes that the findings from muscle will translate to brain, and that CoQ-10 works only in energy dysfunction pathways.

An advantage of the CHDI method (if the muscle trial is successful) is that they will have potentially defined a more rapid approach to determining best dosage of any drug that effects energy dysfunction pathways. And, indeed if the CoQ-10 analogue goes to clinical trial using improved tracking tools identified in the ongoing TRACK-HD trial, it likely would be completed before, or along-side of HSG's 2CARE.

Which CoQ-10 approach is better? The short answer is that nobody knows. No one knows which decision is better -- whether to take it to trial now or wait for more analysis. How much analysis is enough clearly depends on the organization.

HDAC drugs: Another CHDI example: Based on animal model studies, CHDI began collaborative work on HDAC inhibitor drugs (that decrease function of HDAC enzymes) several years ago. The first HDAC collaborating companies provided "non-selective" drug candidates, or those that decreased function of many different kinds of HDAC enzymes. This non-selective type of drug showed some benefit in animal models of HD, but had unwanted toxic side effects.

So instead of taking this type of non-selective HDAC drug to clinical trial at that time, CHDI worked with collaborators to narrow down the type of HDAC enzymes most involved in HD, and to identify those that were not. In information presented in recent months at the Hereditary Disease Foundation (HDF) and European Huntington Disease Network (EHDN) meetings, Dr. Bates and colleagues from London (in press) reported identification of HDAC 4 as an important class, and has eliminated several other types of HDAC that have no effect on HD. Based on this information from research partially sponsored by CHDI, Repligen Corporation has announced positive results in a mouse model for their HDAC 4 drug candidate in a press announcement [Thomas EA 2008].

Why did CHDI decide not to take the first (non-selective HDAC) drug to clinical trial? Were years lost be worth the wait for the more selective HDAC 4 candidate drug that appears more effective and less toxic -- at least in the mouse?

Importantly they have also identified tests (gene profiling) that correlate with HDAC 4 drug activity. This is important because similar test results could be used in people to test both for drug response (proof of concept) and to determine best dosing. These types of studies could be done in a few weeks, not months or years -- which has been the past reality for HD studies.

Was it the "right" decision to wait on taking the first HDAC drugs to clinical trial? In this case "waiting" probably lost us no time because the dosing studies will be much shorter.

Medivation and NeuroSearch examples: Dimebon and ACR-16, both initially brought forward by small biotechnolgy pharmaceutical companies have entered into human clinical trial with scientific rationale, but without the extensive preclinical validations and model testing used by CHDI. In addition "best" dosing was not determined in Phase 2 trials by either of these sponsors. If either of these drugs succeed in Phase 3, it will be due mostly to the combination of some scientific rationale, clinical intuition and good luck.

How much testing for a drug candidate is enough? Is more better? Or does more testing just take more time? Though experts in the pharmaceutical industry believe that CHDI type of trials may be better, and rationally it might make more sense -- the answer is still unknown.

But stay tuned, we'll know more after they decide to light a candle . . .


Arterburn LM, Hall EB, Oken H. Distribution, interconversion, and dose response of n-3 fatty acids in humans. Am J Clin Nutr. 2006 Jun;83(6 Suppl):1467S-1476S. PubMed abstract

Van Raamsdonk JM, Pearson J, Rogers DA, Lu G, Barakauskas VE, Barr AM, Honer WG, Hayden MR, Leavitt BR. Ethyl-EPA treatment improves motor dysfunction, but not neurodegeneration in the YAC128 mouse model of Huntington disease. Exp Neurol. 2005 Dec;196(2):266-72. Epub 2005 Aug 29. PubMed abstract

Huntington Study Group. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease. Neurology. 2001 Aug 14;57(3):397-404. PubMed abstract

Lee JM, Ivanova EV, Seong IS, Cashorali T, Kohane I, Gusella JF, MacDonald ME. Unbiased gene expression analysis implicates the huntingtin polyglutamine tract in extra-mitochondrial energy metabolism. PLoS Genet. 2007 Aug;3(8):e135. Epub 2007 Jun 27. PubMed abstract

Thomas EA, Coppola G, Desplats PA, Tang B, Soragni E, Burnett R, Gao F, Fitzgerald KM, Borok JF, Herman D, Geschwind DH, Gottesfeld JM. The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15564-9. doi: 10.1073/pnas.0804249105. Epub 2008 Sep 30. PubMed abstract