Safety and tolerability of phenylbutyrate in inclusion body myositis

Introduction Phenylbutyrate (PBA) showed positive effect on the muscle cell model of Inclusion Body Myositis (IBM) by improving lysosomal activity, ameliorating consequences of impaired autophagy, and decreasing vacuolization. This provides rationale to study this medication in patients with IBM. Objectives To evaluate the safety and tolerability of phenylbutyrate in IBM, and monitor for any early signal of effectiveness. Methods Open-label study of 10 subjects with IBM who received treatment with PBA for 3 months after a 3-month run-in period. The PBA dose was 3 gm twice daily. The primary outcome measure was adverse event reporting. Secondary outcome measures included manual muscle testing, timed up and go test, IBM functional rating scale, and grip strength, along with exploratory biomarkers evaluating the mitochondrial function, stress response, degenerative process, and apoptosis. Results Ten subjects completed the study. PBA was well tolerated with no serious adverse events related to it. The most common adverse events were gastrointestinal related and did not require stopping treatment. One of the biomarkers (MitoTracker) showed a statistically significant drop over the treatment period of the study (p-value of 0.02 for the mean change). There were no statistically significant changes in other secondary outcome measures, but the study was limited by a small sample size and short treatment period. Conclusions Phenylbutyrate was safe and well tolerated in patients with IBM in this pilot study. The change in the MitoTracker suggests target engagement, but a Phase II study is needed to confirm and study the efficacy of PBA in IBM