Science News: Safety and Tolerability of Phenylbutyrate in Inclusion Body Myositis

Submitted by: Sarah Breevoort, MD
Edited by: Nandita Keole, MD

Citation: Jabari, D., Heim, A., Ciersdorff, A., Wilkins, H., Agbas, A., Kosa, E., Hunt, S., Pasnoor, M., Dimachkie, M., & Barohn, R. (2024). Safety and tolerability of phenylbutyrate in inclusion body myositis. RRNMF Neuromuscular Journal, 5(1).

Summary: This is a pilot study that demonstrates the safety and tolerability of phenylbutyrate (PBA) for the treatment of inclusion body myositis (IBM). IBM is the most common acquired muscle disorder in individuals over the age of 50. IBM was classically defined as an inflammatory myopathy based on inflammatory infiltrates found on muscle biopsy. The lack of response to treatment, however, raised concerns that IBM is a degenerative disorder with secondary inflammation. The abnormal accumulation of amyloid-beta protein precursor and its proteolytic fragment amyloid-beta is thought to be the key pathogenic event. Amyloid-beta oligomers, which are highly cytotoxic, have been demonstrated in IBM muscle tissues. Many neurodegenerative disorders are characterized by the accumulation of intracellular and extracellular protein aggregates that act to catalyze downstream processes that result in additional aggregation of proteins. A highly conserved class of proteins called molecular chaperones have evolved to prevent inappropriate interactions between polypeptides, enhance efficiency of protein folding and promote refolding repair of proteins. PBA, an orally active chemical chaperone approved by the FDA for the treatment of urea cycle disorders, mimics the function of intracellular molecular chaperones. Recent studies reported a novel function for PBA in cultured human muscle fibers that resulted in improved lysosomal activity and ameliorated impaired autophagy, providing a rationale for considering PBA for the treatment of IBM. This is a single-site phase I pilot study. Ten patients with sporadic IBM were enrolled, and following a 3-month run in period, treated with PBA for 3 months. All 10 subjects completed the study, and PBA was well tolerated with no serious adverse events. The most common adverse events were gastrointestinal-related and did not require stopping treatment. One of the biomarkers (MitoTracker^TM) showed a statistically significant drop over the treatment period. There was no statistically significant change in other secondary outcome measures (multiple strength and functional measures), but the study was limited by small sample size and short treatment period.

Comments: While limited by small sample size and short treatment period, the group met their primary endpoint of demonstrating safety and tolerability of PBA. This chemical chaperone already is FDA approved for the treatment of urea cycle disorders and has demonstrated in pre-clinical models the ability to restore the cellular homeostasis that is disrupted in cultured human muscle fibers with experimentally inhibited autophagy and lysosomal activity. It is believed that the pathogenesis responsible for the degenerative process that results in IBM is due to these disrupted processes. As PBA is already FDA approved and in this study has demonstrated safety and tolerability in patients with IBM, it is a rationale potential therapeutic option and warrants further study. Additional studies looking at secondary functional measures following earlier initiation during disease course with longer follow up period will be insightful.