Mike Snape, PhD, chief scientific officer at AMO Pharma explains the Congenital DM1 Rating Scale to assess outcome measures in patients with congenital myotonic dystrophy type 1.
Transcription:
The Congenital DM1 rating scale is a variant of a scale created between Rochester University and Utah, which is a composite assessment that attempts to capture the whole of the presentation of the disorder. Rather than measure, for example, the strength of the grip in your hand, it enables a clinician to say, “I’m going to assess your hand function, your ability to walk, your cognitive skills, and get the entire picture.” We worked with the developers of this suite of rating scales, of which this is one, and the FDA, to produce a rating scale as a novel attempt to have a one-stop shop to capture the whole of the presentation of any given individual on any given day. It’s a novel rating scale. Of course, no one’s ever done a trial in congenital myotomic dystrophy before.
It’s not like if we were doing a trial to develop a new anti-hypertensive agent to treat high blood pressure. There would be an accepted approach going forward if we were developing a drug to treat multiple sclerosis. Precedents have been set. FDA has said this is what you’ve got to do to get approved. No one’s ever done a trial in these children before. No one’s ever defined what outcome measure is provable before. Discussing with the regulators as to how to go forward with this is really important.
The reason why we’ve picked a composite rating scale is these children don’t just have one thing wrong with them. A high proportion have cognitive disabilities. A high proportion of them have features similar to classical autism. A high proportion of them, sorry, a slightly less high proportion of them have difficulty walking, they will have difficulty controlling their hands, they will have difficulty with speech, they will have difficulty with their GI tract. They likely, at some point in time, will be prone to cardiac issues. My point is, there is the potential that almost any organ system of the body can show a problem in this condition. Not every child has every potential issue. Again, it becomes really hard to find a single outcome measure that will capture everything.
Conversely, if you just measure one thing, you’re not really getting to the heart of whether your molecule is treating the whole of the condition. That’s just something we need to bear in mind going forward. What we did, and the other issue that we’re dealing with is this is an ultra-orphan condition. There’s a very small number of individuals in the world, so your statistical power in analyzing your data is limited. You’re never going to get two groups of 5,000 patients for these diseases and have the ability to do really easy statistics.
What we measured, we can put the outcome measures that we used into “buckets”or rating scale instruments, where a clinician assigns a rating. In this case, a score between zero and four for the severity of symptoms. We had another rating instrument used by the caregivers. Those rating instruments fit into one bucket. Then we had neurophysiologists at the site doing computer-based assessments of cognitive skills, and we had the physiologists and physiotherapists at the site doing assessments of how well the children could walk, how strong their hands were. Then we looked at biomarkers things that are present in the blood or body tissues that you can measure. There are four buckets of outcome measures and what we did for the reasons I’ve described, we were hoping that the CDM1Rs rating instrument would be a single one-stop to enable us to capture effects across the entire body, the entire presentation or possible presentation of symptoms.
The study is complete and we’ve done the lion’s share of the analyzes. We now have to report the data we obtained from those efficacy outcome measures I described and the safety perspectives of the study to the regulators and have a negotiation or discussion ask their advice on how to advance. What we showed in the study was the rating scale instrument but showed benefit for all the patients. There was a rating of positivity in the placebo group as well as the treated individuals. Any treatment benefit that would have been registered would have been masked by this placebo effect separately.
The other measures that were done in the study where we had a physiotherapist or a neuropsychologist or a blood-based test of a biomarker. Those assessments were much less prone to a placebo effect, so they gave interpretable data. The short version of it is, it was difficult to interpret the rating scale information, but all of the other measures pointed towards better responses on the drug than on placebo. Our view is that there is a strong argument that the drug conferred benefit in this study.
To learn more about this and other musculoskeletal disorders, go to https://checkrare.com/diseases/musculoskeletal-diseases/
Reference
Veerappandiyan A et al. Development of the Clinician-Completed Congenital Myotonic Dystrophy Type 1 Rating Scale (CDM1-RS) for Use in Phase 2/3 Pivotal Clinical Trials. Poster presented at the MDA Clinical & Scientific Conference 2023, Dallas TX. March 19-22, 2023. Abstract available at https://www.mdaconference.org/abstract-library/development-of-the-clinician-completed-congenital-myotonic-dystrophy-type-1-rating-scale-cdm1-rs-for-use-in-phase-2-3-pivotal-clinical-trials/ Accessed Sept 28, 2023.