Interventions with Potential to Mitigate Injection Site Reactions Following Subcutaneous Elamipretide Administration: A Phase 1, Crossover Study

Author(s): Alana Sullivan, Sandrin C. Bergheanu, Laura E. Kropp, Li Zhang, Lisa A. Beck, Benjamin McNeil, Anthony Abbruscato

Aim: Elamipretide is a mitochondria-targeting agent in development for treating mitochondrial dysfunction-associated diseases. While prior studies showed that subcutaneous elamipretide is generally safe/well tolerated, most subjects reported injection site reactions (ISRs). We evaluated the efficacy of interventions to mitigate ISRs, identify underlying ISR mechanisms, and evaluate the pharmacokinetic and safety profile of subcutaneous elamipretide.

Methods: Subcutaneous elamipretide 60mg was administered to healthy subjects (N=10) on six separate occasions with/without potential ISR interventions (mometasone furoate, ice application, tacrolimus ointment, doxepin cream, and oral diphenhydramine). ISR clinical/self-assessments, blood samples, and safety data were collected at predetermined intervals. Preclinical studies investigated mast cell-specific receptor MRGPRX2 mediation of ISRs.

Results: Mometasone significantly reduced the incidence of induration/swelling and pruritus. Diphenhydramine significantly decreased the incidence of induration; 50% reported somnolence. Ice application significantly reduced the incidence of pain, although it reduced elamipretide’s maximum plasma concentration and area-under-the-curve from time 0-6hrs versus elamipretide alone. Preclinical data suggest that subcutaneous-elamipretide induced ISRs by activating MRGPRX2 in humans and its ortholog, Mrgprb2, in mice.

Conclusion: Elamipretide activated MRGPRX2 and Mrgprb2 receptors, resulting in activation of mast cells and inflammation in mouse models, suggesting that targeting mast-cell activation may ameliorate elamipretide ISRs. Topical mometasone prior to subcutaneous elamipretide demonstrated significant reductions in ISR signs and symptoms and did not cause significant changes in elamipretide plasma exposure or additional adverse events. Therefore, mometasone prior to subcutaneous injection of elamipretide warrants further investigation in clinical studies for alleviating ISRs.