Modifying muscle metabolic dysregulation in inclusion body myositis with pioglitazone: a single-arm trial.

This single-arm, open-label phase 1 trial evaluated the PPARγ agonist pioglitazone in patients with inclusion body myositis (IBM). After a 16-week observation (lead-in) period, participants received pioglitazone 45 mg daily for 32 weeks. The primary outcome was the change in PPARGC1A expression and related metabolic pathways in muscle after 16 weeks of treatment compared with the lead-in period. Of the 16 enrolled participants, 13 initiated pioglitazone and completed at least one on-treatment assessment; the trial was terminated early due to the COVID-19 pandemic. At baseline, muscle metabolomics revealed broad metabolic abnormalities compared with controls. Pioglitazone reversed elements of this signature, increasing PPARGC1A expression (p = 0.099) and modulating downstream pathways in muscle, including enhanced oxidative phosphorylation. Clinical outcomes were unchanged overall, but a subset with favorable metabolic responses showed slower decline in the IBM-Functional Rating Score (IBM-FRS) and Modified Timed Up and Go (m-TUG). Reported adverse effects included myalgia and heart failure exacerbation. As a phase 1 trial with a limited cohort, these findings provide preliminary evidence that pioglitazone modulates muscle metabolism and warrants further investigation in IBM. This study was supported by the Ira T. Discovery Fund and the Peter and Carmen Lucia Buck Foundation Myositis Discovery Fund. Clinical Trials Registration: NCT03440034.