May 13, 2009.

Project Cure SMA Group Publishes Open Label Valproic Acid Trial Results.  The paper entitled “Phase II Open Label Study of Valproic Acid (VPA) in Spinal Muscular Atrophy” was published today in the online Journal PLoS ONE.  This clinical trial was fully funded by Families of SMA.

The paper presents the data from an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future clinical trials.  The results indicated that VPA was well-tolerated and without evident hepatotoxicity.  Carnitine depletion was frequent, and temporarily associated with increased weakness in two subjects, indicating a need for co-administration of carnitine with VPA. Clear decline in motor function occurred in several subjects in association with weight gain.  Mean fat mass increased without a corresponding increase in lean mass, suggesting that weight gain is likely to be significant confounding factor in future VPA clinical trials.   A significant improvement in motor function, as measured by the Modified Hammersmith Functional Motor Scale (MHFMS), was observed in participants younger than 5 years of age.

The authors concluded that the study provides good evidence that VPA can be used safely in SMA subjects over 2 years of age in the setting of close monitoring of carnitine status.  However, they also indicated that further studies of VPA in infants and young children are needed to better assess safety in this more vulnerable cohort, since children under 2 were not included in the current study.

The results presented within the PLoS ONE publication suggest that while there may be a potential treatment benefit in a subset of younger non-ambulatory type II children, conversely, older subjects may be at risk due to excessive weight gain. Given the uncontrolled nature of the study, it is unclear whether the improvement in some younger subjects reflects a therapeutic drug effect, maturation, or increased cooperation leading to improved functional measurement scores.  These data underline the importance of randomized, controlled efficacy studies to assess the impact of therapies in SMA, and that the same drug could have differing results in select subsets of patients.

“These results are significant not only because they are a first step to determining the therapeutic benefit of VPA for SMA, but also because they inform us about proper clinical trial design.  These results demonstrate the need for randomized controlled trials in subsets of patients, since much weaker (Type I) and much stronger (Type III) patients may respond quite differently to the same intervention. In addition, the clinical outcome measures used to examine patients over such a wide range of strength and function will differ.  Using the correct measure for each population will be critical to prove efficacy”, says Dr. Kathryn Swoboda, lead author on this paper.

The data presented in the paper indicates that several additional clinical studies are warranted in order to assess the efficacy of VPA for SMA.  These studies, funded by Families of SMA, include:

1) A double-blind placebo controlled trial of VPA and carnitine in a non-ambulatory group of Type II children.

Click here to see preliminary results of a trial in this group called CARNIVAL.

2) An open label safety study in Type I infants, an extremely vulnerable group of patients.

Click here for details of an ongoing trial in this group called CARNIVAL TYPE I.

3) A double-blind placebo controlled crossover study in ambulatory adults with SMA.

Click here for details of an ongoing trial in this group called VALIANT.

“Families of SMA is pleased to have the first clinical trial results published from the work of the Project Cure SMA Clinical Trial Network.  Funding clinical trial initiatives  allows our community to achieve multiple goals.  It gives us the means to develop the required outcome measures to test drugs in all SMA populations, to conduct trials to test repurposed drugs for safety and efficacy in SMA patients, and to build the necessary infrastructure, including adequate regional clinical trial site representation across the US for future new drug trials”, says Kenneth Hobby, Executive Director of Families of SMA.

The Open Label Study of Valproic Acid in Spinal Muscular Atrophy was registered at: ClinicalTrials.gov NCT00374075. http://clinicaltrials.gov/ct2/show/NCT00374075?term=NCT00374075&rank=1

About Project Cure SMA:

In 2001, Families of Spinal Muscular Atrophy established and single-handedly funded a clinical trials network called Project Cure SMA.  This network has conducted natural history studies that increase our understanding of Spinal Muscular Atrophy disease progression, built models for designing SMA clinical trials, and now runs clinical trials with existing drugs.

Families of SMA’s investment of over $6 Million to date in five multi-center clinical trials is helping to test existing drugs that may lead to a treatment for Spinal Muscular Atrophy.  In addition, as novel drugs currently being designed for SMA become available, having a fully operational clinical network with a sufficient number of sites to conduct pivotal SMA drug trials will help attract and encourage biotech and pharmaceutical companies to invest in SMA drug development.