AMO Pharma Ltd, UK
Title: The utility of concordant trend analyses in a Phase 2 study in Congenital and Childhood Onset Myotonic Dystrophy Type 1: a case example
Dr Mike Snape received his BA with Honors at Oxford University, England and his PhD from London University after study at the Maudsley and Bethlem Hospital. Mike presently holds an adjunct Professorship at CASE Western university. He has 30 years of experience in pharmaceutical research and development and has managed relevant projects from pre-clinical through clinical stages of development. He is named as an inventor on 5 pharmaceutical patents including 3 new chemical entities and has published numerous abstracts in international scientific and medical journals. He previously worked in CNS R&D at AstraZeneca and also has extensive experience of research and development projects in the field of CNS disorders in a small life science company environment having been Principal Scientist at Cerebrus Ltd and Associate Director at Vernalis, and was a founder of Neuropharm. Mike initiated one of the first industry sponsored clinical projects in autism in 1997, lead the first industry sponsored multi-center studies of a core symptom of autism, and some of the first industry sponsored studies in Fragile X Syndrome. More recently Mike was one of the founders of AMO Pharma Ltd. The company is working to identify and advance promising therapies for the treatment of serious and debilitating diseases in patient populations with significant areas of unmet need, including rare, debilitating childhood onset neurogenetic disorders with limited or no treatment options. AMO Pharma submitted the first successful application for Fast Track Status for congenital myotonic dystrophy program to be granted by the FDA.
Statement of the Problem: Proof-of-concept clinical trials in rare diseases such as congenital and childhood onset myotonic dystrophy Type 1 are often hampered by a lack of knowledge concerning optimal outcome measures to detect efficacy. The concordant trends analysis offers a solution in which efficacy is assessed by evaluating the trends on several within-study assessments, provided the assessments are quasi- or wholly-independent. Positive findings using this analytical technique are unlikely to arise due to chance alone. Methodology & Theoretical Orientation: AMO-02/tideglusib is a novel, orally administered GSK-3β enzyme inhibitor. Overactivity of GSK3β has been identified as a key pathophysiological feature of congenital and childhood onset myotonic dystrophy. Accordingly, this Phase 2a clinical trial explored the utility of AMO-02 in 16 adolescents and adult subjects with this form of myotonic dystrophy across a 12-week treatment period. Outcome measures included disease-specific rating scales, functional/performance-based assessments, and biomarkers. Findings: AMO-02 rendered clinical benefit to the majority of subjects after 12 weeks of treatment. The concordant trend analysis revealed a clear dose-response relationship that favored the 1000 mg over 400 mg dose. Four of the 10 efficacy variables (i.e. grip strength, Clinician VAS rating scale, Caregiver Top 3 Concerns rating scale, and OSU CGI-I rating scale) differed in favor of 1000 mg over 400 mg dose and there was no worsening in the remaining six variables. Conclusion & Significance: The concordant trend analysis provides reiterative confidence about the study findings. This is important since this novel therapeutic area lacks gold standard outcome measures and this study was the first clinical trial conducted in this specific population. Accordingly, AMO-02 merits further progression in clinical development in this population of individuals affected by early-onset myotonic dystrophy, and the 1000 mg dose may have the best prospect of establishing a consistent efficacy signal.