Signal to Noise
This is a measure used in science and engineering to compare the level of a desired signal (a measured outcome) to the background noise. In a way, this is the question of what information carries weight/is meaningful and what information clouds the issue.
While this sounds really complicated, we have witnessed the interaction of signal and noise first-hand in discussions around natural history of Duchenne and when looking at our own boys and comparing one to another. Each instance of Duchenne seems to be as unique as the person it affects. We struggle to explain why one boy continues to walk at age 14 and another loses ambulation at 8. We attempt to view this in light of a specific mutation, the impact of starting steroids early, specific steroid regimens, aggressive physical therapy, supplements, cardiac medications, growth hormone, and even a particular clinician. Parents try their very best to sort through all of the variables in an effort to understand why their son’s progression is different (better or worse) from another with the same mutation. It is heartbreaking, frustrating, and downright confusing.
For this reason, PPMD has been focused on identifying modifiers, is participating in consortia to identify clusters of individuals who progress in a specific/predictable way and understand the underlying causes (including cTAP), and now is launching a program with The Critical Path Institute called the Duchenne Regulatory Science Consortium (D-RSC).
Forming an All-Star Consortium
We are thrilled to announce the launch of the D-RSC. Dr. Brenda Wong and Cincinnati Children’s Hospital, PTC Therapeutics, Santhera Pharmaceuticals, and The Critical Path Institute are partners with us, and we are currently working together to reach a final agreement for Sarepta Therapeutics to join the D-RSC. Several additional consortium members will be added soon.
This consortium will integrate datasets with the objective of understanding and explaining the variability underlying Duchenne and use the resulting tool to develop more efficient clinical trials, shortening the time to new treatments. Like most problems of consequence, understanding the differences that we see among people with Duchenne will require accessing and standardizing data sets as well as interactive partnerships.
The Critical Path Institute has a stellar track record of working with companies, academic researchers, advocacy groups, and the FDA to develop a better understanding of the causes of phenotypic variability in disease and then putting that understanding to work as new drug development tools that help all drug discovery and development efforts.
At the recent PPMD Connect Conference, we held a panel discussion titled “Different Together: Explaining Phenotype Variability in Duchenne and its Implications in Clinical Trials.” The clinician-scientists on the panel described the variability that they see in their clinics and discussed on-going research to clarify the mechanisms behind these differences.
OK, all of us see the considerable variability in how people are affected by Duchenne. Likewise, we already understand some of the causes—that the differences from individual to individual can be caused by the nature and location of the dystrophin mutation, variants in other genes (genetic modifiers), and steroid regimens. At least one genetic modifier even explains differences in the response to steroids. But, the reality is that we’ve only scratched the surface with research to date and it’s likely that most of the underlying causes of the differences that we see in Duchenne are unknown.
Why is it important that we understand these differences and their underlying causes? In order to foster the development of drugs for Duchenne, one compelling answer is that any variability in the endpoints measured in a clinical trial makes it very difficult to show that the drug actually works. To compensate for this variability, clinical trials are “powered,” that is, they include appropriate numbers of young men, so that the “noise” in what is measured doesn’t drown out the “signal” of the drug working. A far better scenario would be to understand the causes of differences in progression of Duchenne and take these into account in designing clinical trials.
So, understanding not only the differences that we see in those living with Duchenne, but the underlying causes of those differences, can lead to quicker and better clinical trials. PPMD has entered into these partnerships with D-RSC and cTAP to help understand why people with Duchenne progress at different rates and then to use that understanding to improve current trials and to develop new tools to assess the efficacy and safety of candidate therapies for Duchenne.
We will come back to you periodically to keep you abreast of D-RSC’s efforts in applying a consensus science model to the ongoing fight to end Duchenne.
Duchenne is an incredibly complex disorder, but PPMD believes in the strength of these collaborations with great minds, great partners. This is just the beginning of an exciting new chapter in Duchenne research. More to come.