The Reality: Clinical Trial Readiness Determines Tractability and Pharma/Biotech Interest

Ensuring clinical trial readiness is critical for any rare disease. If the patients to participate in clinical trials can’t be identified (function of registries), disease progression is not well understood (function of natural history studies), measures of target engagement and modulation aren’t available (function of pharmacodynamic biomarkers), and clinically meaningful measures are not available and validated (function of validated clinical outcome measures), then it is difficult to convince drug developers that a disease is tractable. The myotonic dystrophy field and MDF have been working toward checking these boxes to de-risk the disease for development of drugs and biologics. Yet, the majority of the efforts and accomplishments in achieving clinical trial readiness have been for DM1. There is a clear need to further invest in trial readiness for DM2.

What is the Status of Clinical Outcome Measures for DM2?

A systemic review has just been published, assessing one aspect of clinical trial readiness for DM2—the status of functional tests and patient-reported outcome measures that have been used in clinical studies and trials of DM2 patients. Drs. Emanuele Rastelli and Benedikt Schoser, and their colleagues at University of Rome Tor Vergata and Ludwig-Maximilians University, report their assessment and the critical need to invest further effort and resources into identification and validation of clinical outcome measures for DM2.

In their meta-analysis, the research team identified outcome measures used in studies of genetically confirmed DM2 subjects that were published before April 2018 (identified via key word searches of PubMed, EMBASE, Cochrane Reviews, and Cochrane trials databases). A similar search was conducted for the broader neuromuscular disease literature in order to identify and evaluate other outcome measures that could potentially be used for DM2.

The systematic process of identifying, screening, and determining eligibility resulted in inclusion of 10 studies of DM2 and 48 studies of outcome measures used in other neuromuscular diseases.

The most significant conclusion from this study is that none of the measures considered (either clinical function or patient-reported) have yet been validated in DM2. Utilization and pros/cons of each of the outcome measures in the studies evaluated here are reported in tabular form in the  paper.

INQoL, SF-36, MPQ, and BPI were the most frequently used patient-reported measures. It appeared that none of these were particularly effective in assessing the mild myotonia that characterizes DM2. MPQ showed value in differentiating characteristics of a prominent DM2 symptom, pain, while BPIsf exhibited difficulty in distinguishing pain in DM1 vs. DM2. Data on assessment of pain with a pressure algometer showed its potential as an outcome measure. The research team also identified liabilities in the broader patient-reported indices, INQoL and SF-36.

For evaluation of muscle strength, the team noted the frequent use of both MMT and QMT in assessment of DM2 subjects. While QMT was regarded as having higher potential to evaluate changes in strength over time (e.g., in longitudinal natural history studies or clinical trials), they suggest that inter-rater reliability has not yet been established in DM2. No publications came through the selection and screening process for clinical evaluation of myotonia in DM2; the authors noted the low reported disease burden of myotonia in DM2, thus quantitative testing may have little value for clinical trials in this patient group. Finally, the research team list in tabular fashion a total of 21 other outcome measures gleaned from the literature on other neuromuscular diseases that they deem as “suitable” for use in DM2. Assessment and validation of these measures would have to be performed in a DM2 cohort.

Path Forward

Taken together, the take-away from this systemic review is that availability of reliable and validated outcome measures represents an important gap in trial readiness for DM2. That is not to say that some measures already identified in studies of DM2 and other neuromuscular diseases might ultimately prove to be very adequate for use in natural history studies and interventional clinical trials.

Reference:

Towards clinical outcome measures in myotonic dystrophy type 2: a systematic review.
Rastelli E, Montagnese F, Massa R, Schoser B.
Curr Opin Neurol. 2018 Oct;31(5):599-609. doi: 10.1097/WCO.0000000000000591.