Characterizing platelet count reductions below 75×10⁹/L in patients with DMD treated with givinostat from the phase 3 EPIDYS trial and LTSE study

Topic:

Clinical Trials

Poster Number: 67 S

Author(s):

Michela Guglieri, MD, Newcastle University, Newcastle upon Tyne, England, UK , Mariacristina Scoto, PhD, Dubowitz Neuromuscular Centre and MRC Centre for NMD, London, UK, Mary Jane Salinas, PharmD, ITF Therapeutics, Concord, Massachusetts, USA, Andrea Parodi, MSc, Italfarmaco SpA, Milan, Italy, PAOLO UMBERTO BETTICA, MD, PhD, Italfarmaco SpA, Erika Finanger, MD, Oregon Health & Science University

Background: Givinostat is an oral histone deacetylase (HDAC) inhibitor investigated for Duchenne muscular dystrophy (DMD) in ambulant boys aged ≥6 years. Thrombocytopenia is a known pharmacological effect of HDAC inhibitors.

Objectives: To evaluate platelet reductions in the phase 3 EPIDYS trial and the ongoing open-label, long-term safety, tolerability, and efficacy (LTSE) study in boys with DMD aged ≥6 years.

Methods: In EPIDYS, patients received a flexible, weight-based dose of oral givinostat (N=118) or placebo (N=61) over 18 months, along with systemic corticosteroids. The LTSE included patients from EPIDYS and a prior phase 2 study (N=177) plus those screened but not randomized in EPIDYS (N=30). For protocol-defined dose modifications based on platelet counts, ≥2 consecutive counts ≤150×10⁹/L (Common Terminology Criteria for Adverse Events grade 1) triggered dose reduction unless stopping criteria were met. Treatment was interrupted for counts <75×10⁹/L but >50×10⁹/L (grade 2), resuming at a reduced dose once normalized (>150×10⁹/L). Treatment was permanently discontinued for counts ≤50×10⁹/L (grade 3).

Results: Three patients experienced platelet counts <75×10⁹/L. One patient had grade 1 platelet reduction on day 50, prompting dose reduction; levels dropped <75×10⁹/L on day 168 but returned to normal 13 days later without further adjustment. In another patient, levels dropped <75×10⁹/L 389 days after givinostat initiation following 2 prior grade 1-related dose reductions. Levels normalized within 15 days of dose interruption, and the patient resumed givinostat at a reduced dose. The third patient had a platelet count <75×10⁹/L 45 days after givinostat initiation, with recovery by day 6 following a 10-day dose interruption and resumed the initial dose. None were symptomatic and all continued givinostat. Conclusions: In clinical trials, givinostat-associated platelet reductions <75×10⁹/L were rare. Platelet levels recovered quickly to normal following dose reduction or temporary interruption but did not require permanent discontinuation.