Despite Failing to Meet Primary End Point, AMO-02 Shows Additional Benefits in Myotonic Dystrophy

Joe Horrigan

Newly announced data from the ongoing REACH-CDM clinical study (NCT05004129) showed that AMO-02 (AMO Pharma), an investigational agent in development for congenital myotonic dystrophy, failed to meet its primary end point; however, achieved clinically and statistically significant benefit in various functional and objective assessments.¹

The phase 2/3 study featured 56 patients across sites in the US, Canada, Australia, and New Zealand who received 1000 mg of AMO-02 once daily for 52 weeks, with an optional further 32-week extended access period. After a year’s worth of treatment, the agent was unsuccessful in distinguishing itself from placebo on the primary end point of Clinician-Completed Congenital DM1 Rating Scale (CDM1-RS), an 11-item rating scale assessing symptom severity of domains relevant to congenital myotonic dystrophy.

Despite this, treatment with the agent was associated with clinically significant improvements in cognitive performance, as assessed through Peabody Picture Vocabulary Test (P <.05), an improvement in the 10-meter walk/run test (P = .054). Treated patients also saw significant reductions in creatine phosphokinase, a widely used biomarker of skeletal and cardiac muscle integrity (P <.05). Notably, 98% of patients opted to continue treatment in the open-label extension (OLE), and 85% of patients opted to continue treatment at the conclusion of the 1-year OLE study.

"We are very encouraged by the consistent benefit shown across multiple clinically confirmed measures of efficacy," Joe Horrigan, chief medical officer, AMO Pharma, said in a statement.¹ "These data reflect a broad profile of benefit in cognitive, motor, muscle, real world adaptive behavior and biochemical measures associated with treatment with no reported treatment-related serious adverse events."

In the study, a composite statistical analysis of outcomes assessing motor skills, muscle strength, cognitive ability, daily living skills, and biomarker data revealed statistically significant benefits through treatment with AMO-02 vs placebo (P <.05). Of note, the benefits and clinical improvement seen in treated patients were related to pharmacokinetic parameters that showed increasing plasma levels of AMO-02. Overall, more participants showed a positive response following AMO-02 treatment than placebo on 10 of the 12 quantifiable measures.

AMO-02, otherwise known as tideglusib, is also in development for other conditions such as adult-onset myotonic dystrophy and other central nervous system, neuromuscular indications. In cellular and animal models of congenital myotonic dystrophy as well as in muscle biopsies from patients, activity of glycogen synthase kinase 3 beta (GSKß) has been shown to increase. AMO-02 is an inhibitor that has demonstrated an ability to normalize levels of GSK3ß in transgenic models and in ex vivo tissue samples in patients with congenital myotonic dystrophy.

READ MORE: NeuroVoices: Sandeep Rana, MD, on Progress in Adult-Onset Spinal Muscular Atrophy

"We are immensely grateful to all the families who took part in this study, patient advocates in the myotonic dystrophy community, investigators who worked with us to face the challenges presented by the COVID pandemic, and our investors for supporting this work," Ibs Mahmood, chief executive officer, AMO Pharma, said in a statement.¹ "These results provide strong further validation of the potential benefits of treatment with AMO-02 in multiple key areas that represent the most severe symptoms and disabilities associated with DM1. We are now working to discuss next steps with regulators in order to advance this program."

In 2020, a phase 2 study (NCT02858908) of AMO-02 in congenital and childhood-onset myotonic dystrophy type 1 was published in Pediatric Neurology. The trial featured 16 participants aged 13 to 34 years who received 12 weeks of single-blind fixed-dose oral treatment with either 400 mg (n = 8) or 1000 mg (n = 8) of AMO-02. At the conclusion of the analysis, findings showed that AMO-02 plasma concentrations conformed to a 2-comparment model with first-order absorption and elimination, along with dose-dependent increases in exposure were observed.²

The therapy showed a safe and tolerable profile, with no discontinuations because of adverse events or dose adjustments. After 12 weeks of treatment, a majority of treated patients showed improvement in their central nervous system and neuromuscular symptoms relative to placebo baseline, with a larger response noted in the 1000 mg/day group. AMO-02 exposure was significantly correlated with change from baseline on several key efficacy assessments.

REFERENCES
1. AMO Pharma announces affirming data from REACH-CDM clinical trial for AMO-02 in treatment of myotonic dystrophy. News release. AMO Pharma. September 6, 2023. Accessed September 6, 2023. https://www.prnewswire.com/news-releases/amo-pharma-announces-affirming-data-from-reach-cdm-clinical-trial-for-amo-02-in-treatment-of-myotonic-dystrophy
2. Horrigan J, Gomes TB, Snape M, et al. A phase 2 study of AMO-02 (Tideglusib) in congenital and childhood-onset myotonic dystrophy type 1 (DM1). Pediatr Neurol. 2020;112:84-93. doi:10.1016/j.pediatr.neurol.2020.08.001.