Particularly during this past year, living with Huntington's disease (HD) has been full of its ups and downs. First there was the hope in ongoing clinical trials of both coenzyme Q-10 and creatine. Then there was sadness and fear that came with their failures. And now hope is springing again for new drugs coming to clinical trials now that will take a few years to complete. No doubt this Yin-Yang cycle will continue for HD, just as it does for other diseases.

However, there may be reason to believe in the chance of greater success this next time around.

Why Better Chances of Success with New HD Trials? The rationale to bring coenzyme Q-10 and creatine to clinical trial was based on research that is now more than a decade old, and that in large part relied on information obtained from genetic mouse model studies. Further, these trials also utilized functional capacity as an endpoint, which even in a best case scenario would take several years to evaluate for change.

There are a number of factors to suggest that new trials and trial designs may be more likely to succeed. For instance:

  • Exponential growth in basic knowledge of disease mechanisms in HD that informs and guides drug development.
  • Development of larger genetic animal models including primates that give information more relevant to human HD drug development.
  • Direct study in humans -- not just genetic models of HD -- to guide decisions for drugs going forward to trial.
  • Development of technologies that can show that an experimental drug either gets into brain, or that the drug effect can be documented in brain.
  • Usage of motor "endpoints" that are more likely to document a drug effect over a shorter time period than functional measures.
  • Development of more accurate measures of motor function.
  • Greater involvement by large pharmaceutical companies that have the financial resources to move drugs efficiently through all phases of clinical trials.
  • Development of greater international collaboration for more rapid recruitment
  • Standardization of international trials so they can be directly compared.

Importantly, a lot "science" is known, and a lot more work has been done prior to moving drugs into these present clinical trials for HD. And though none of these trials are directly testing for neuroprotective effects, there is some suggestion of such effects for each of the following 3 drugs entering clinical trial.

Specific factors associated with new trials beginning recruitment:

TEVA Pridopidine (PRIDE HD): This drug has already been shown in two separate trials to improve motor scores in HD, with more improvement at the higher dose while having no more side effects than placebo. The amount of improvement was relatively small at the dosages of pridopidine used in the earlier trials though there is expert argument of clinical significance at the level of improvement demonstrated [Reilmann R 2013]. The new trial will be testing 4 different dosages, with the lowest dose (45 mg twice daily) in this new PRIDE trial corresponding to the highest dose in the earlier trials. It is hoped that testing higher dosages in this new trial will show larger improvements in motor scores without causing unacceptable side effects. Each participant has a 80% chance of receiving drug in this placebo controlled trial. Total motor score is the endpoint for this 6 month trial that is recruiting participants from Australia, North America and Europe.

The positive signals in early trials makes this one a good bet for (at least) motor symptom benefit.

Pfizer PDE-10 inhibitor (Amaryllis): This drug has already been in human clinical trial (which was probably terminated due to lack of benefit) for schizophrenia. In HD, extensive human study sponsored by CHDI has shown that this drug gets into brain and is working at the intended PDE-10 site in striatum. Work has also been presented at conferences showing that this drug improves nerve connections between the striatum and the cortex or surface of the brain in nerve cells (at least in genetic models of HD). Total motor score is the endpoint in this six month trial in process of recruiting participants from Australia, Europe and North America.

TEVA Laquinimod (LEGATO): This drug has been and remains in human clinical trial for multiple sclerosis (MS). This is a drug has a"damping" effect on the immune inflammatory responses that occur in both HD and MS. This drug has the advantage of previous study in humans with MS, where it has shown promising results. Using experience gained in MS, 3 doses used in Legato will be similar to those used in the MS study. The endpoint is Total Motor Score in this 1 year trial of early stage individuals with HD. Cognitive and MRI studies will also be part of this trial. This trial is also recruiting internationally.

And More (planned) trials coming Soon: First safety trial of gene lowering therapy, mesenchymal stem cell therapy, and least 3 other drug trials in different stages of pre-trial planning.

Author's comments: A lot is happening in clinical research for HD therapies. And, it is fair to say that present trials should have a better chance of success through Phase 3 than earlier ones. But there is still a lot of uncertainty, and probably the yen-yang of clinical trials in HD will continue for a while. For sure we'll be disappointed with failures. But it is vital to design the best trials possible, and that we keep trying.

It will take a few years to know, but I'm betting we'll see some "ups" this time around.


Reilmann R. The pridopidine paradox in Huntington's disease. Mov Disord. 2013 Sep;28(10):1321-4. doi: 10.1002/mds.25559. Epub 2013 Jul 11. PubMed abstract