"Bummed" was what this author felt after the recent announcement of the failed trial of creatine for Huntington's disease (HD). We can put some positive spins on recent trial failures; we have learned how to run large clinical trials, we can learn from negative outcomes, and best of all hundreds of HD individuals are freed up to participate in other (potentially better) trials. But the reality is that this is one more disappointing failure in an increasingly long string of negative trials. The community is bummed. Saying it straight is better, helps us to get over it, get up and go on to what comes next.

A story comes to mind . .

The Stockdale Analogy: James Stockdale was an Navy Admiral captured during the Viet Nam War. After being released after 8 years of torture and imprisonment at the end of the war, he described characteristics he observed in soldiers who survived and those who did not. Those who were overly optimistic about rescue in the short term didn't survive for the long term. Those who survived were "brutally honest" about their low chance of any quick rescue and consistently worked hard to maintain health by staying as physically and emotionally fit as possible.

The present challenge for the HD community as we wait for rescue is just that: Being realistic about HD clinical trials AND working towards being as physically and emotionally strong as we can. A newly published study called MEND shows us what we might do to maintain brain health.

The MEND Report: In September, Dr. Dale Bredesen from the Buck Institute in California published results of a small study of nine individuals with early Alzheimer's disease [Bredesen DE 2014] reporting reversal of cognitive decline in a study that included use of several combined therapies. People actually improved. Many of the therapies are components of a healthy life style, others are agents that have some scientific rationale, but not proof of human benefit.

Scientific Rationale for the MEND study: Alzheimer's (AD), like HD has many cell networks that are known to push cells toward injury and death. At the same time there are known processes (like exercise) that push cells toward better health. Believing that no one drug can shift the balance by itself (as many failed single drug trials suggest) from pro death to pro life, the MEND program combines treatments. His study suggests that multiple components of the MEND program might shift the balance enough to make a substantial difference, at least for a while. A very recent publication by Dr. Richard Morimoto of Northwestern University describes one of these network cell systems that degrade toxic proteins and the shift that occurs from pro-health to pro-death in aging, HD, AD, and Parkinson's disease in an open-source article in Cell Reports (not yet referenced on Pub Med).

While we wait for the "knock-out" punch that successful gene therapy will bring, this "holistic" approach that has some real scientific rationale may be helpful to HD. Therapies that were individualized for each person included:

  • Regular exercise: 30-60 minutes/day 4-6 times/week
  • Healthy diet defined as low carbohydrate,
  • 12 hour fast overnight
  • No food within 3 hours of sleep
  • Active stress reduction (Yoga, meditation)
  • Cognitive stimulation
  • Minimize inflammation (dental hygiene, gluten inflammation.
  • Optimize sleep
  • Optimize antioxidants (blueberries)
  • Vitamin B12/thiamine/folate/supplementation
  • Selenium
  • Resveratrol/Curcumin
  • DHA/EPA
  • Treat sources of inflammation: dental hygeine
  • NAC (N-acetyl cysteine) probably particularly important in HD
  • others (the entire list can be downloaded from the Bredesen open-access article)

The rationale and the results from the MEND program are both interesting, and is a good program to follow for maintaining best health. But it is next to impossible to test in the real world of clinical trials for drug approval.

Moving on to new clinical trials: Let's hope (realistically) that one or all three trials newly initiated in Europe and North America sponsored by TEVA and Pfizer will show safety and clinically relevant results. TEVA pridopidine (which has shown a positive signal in earlier trials) and Pfizer trials are recruiting now in Europe and North America at some sites, while the TEVA laquinimod trial will soon be open for enrollment. Check at your site, and when/if these trials become available we encourage you to sign up.

Author's comments: Being "bummed" aside, clearly some good comes out of failed clinical trials. For instance, using data from CoQ-10 and creatine trials, we should be able measure and describe placebo effect in HD, by comparing participant measures to those from Registry and COHORT observational trials. Failures also dictate that our HD experts and organizations work towards collaborative "best practice" criteria for what drug goes into clinical trial and innovative clinical trial designs. I hope our community will soon hear more about this work in progress.

References

Bredesen DE. Reversal of cognitive decline: a novel therapeutic program. Aging (Albany NY). 2014 Sep;6(9):707-17. PubMed abstract