Funding Priorities start with Clinical Trials

FRAXA Research Funding PrioritiesWhile FRAXA Research Foundation’s research goals remain largely unchanged, the landscape in which we operate has changed significantly in the past few years.  Negative results from the major clinical trials of investigational agents have resulted in cessation of development of mGluR5 antagonists for fragile X syndrome.  There is still much evidence that this drug class could be successful as a fragile X therapeutic, but we do not see the need for more “proof of principle”-type preclinical research on mGluR5 antagonists.

Studies of possible mechanisms of tolerance in fragile X would be appealing as a topic going forward, as would studies of circuit function in fragile X, since available evidence suggests some form of circuit-based (rather than synaptic) tolerance in fragile X mice and humans.

Other potential areas of interest would include exploration of combination treatment strategies, both in animal models and in clinical trials.  An integrative approach seems essential at this point, one which recognizes the wide array of different disease-modifying therapeutics which have already demonstrated rescue in preclinical models of fragile X and attempts to prioritize them in some way.  In short, many compounds seems capable of rescuing fragile X in mice, but even the best of them don’t yet work in humans -- we need to know why.

Funding, per the “new normal”, will be limited again this year.  Depending on the success of year-end fundraising, we anticipate funding 6-8 postdoctoral fellowships ($45,000 per year for 2 years).  Funding for FRAXA Program Grants (which have more flexible budgets) will depend entirely on the specifics of proposals received, but we will be more stringent than ever in our requirement that Program Grant applications demonstrate the highest level of clinical relevance.  Only applications which have obvious near-term therapeutic potential will be considered.  Program Grants were originally conceived as a mechanism for funding of clinical trials, but most of the actual funding in recent years has gone to relatively basic work.  We reiterate our desire to fund clinical trials of rational therapeutics for fragile X.  It is essential that any proposed clinical work be based on our latest understanding of disease mechanisms in fragile X.

Given these requirements, randomized controlled trials (RCT) of available drugs, like lithium, are our highest priority and we are actively seeking proposals for such trials.  In consideration of FRAXA’s modest resources, cost-effectiveness is essential; we anticipate that relatively large numbers of subjects will need to be treated for a relatively long time to demonstrate clear evidence of efficacy, and this must be affordable.  Other available drugs have also been shown to be potentially disease-modifying in fragile X (minocycline, baclofen, and lovastatin, etc.) and we encourage proposals to study any of these in combination, whether in RCTs or smaller pilot studies.  We are willing to make many exceptions for clinical trials; for example, clinical researchers may submit an outline of a clinical trial proposal for our consideration, and we would be willing to negotiate details and forgo any deadlines.  Clinical research is much more difficult to plan and conduct than animal studies, and we can be accommodating.

We recognize the need for improved outcome measures in fragile X and other autism spectrum disorders clinical trials.  However, most of the applications we have received to date propose only minor refinements of available rating scales.  We are looking for more objective measures, such as biomarkers, biophysical or neuromotor assessments, etc.  As always, proposed outcome measures require validation, and they require testing in trials to demonstrate that they can measure actual treatment response.  This is an obvious Catch-22:  in order to show that an outcome measure “moves” with treatment, we need a proven, effective treatment; but, in order to get proven, effective treatments, we need better outcome measures.  Any insight into resolution of this paradox would be greatly appreciated.

Most importantly, we are looking for new ideas.  The best idea is always one that we haven’t thought of yet.  Please feel free to innovate, and always feel free to contact us in advance to see if we’re interested.

 

Best of luck!

Michael Tranfaglia, MD
Medical Director, FRAXA Research Foundation
mtranfaglia@fraxa.org

 

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