Interventions with Potential to Mitigate Injection Site Reactions
Following Subcutaneous Elamipretide Administration: A Phase 1, Crossover
Study
Abstract
Aim: Elamipretide is a mitochondrial-targeting agent being developed for
the treatment of mitochondrial dysfunction-associated diseases. While
prior studies have shown that subcutaneous elamipretide is generally
safe/well tolerated, injection site reactions (ISRs) were reported in
most subjects. 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 60 mg 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 SQ-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.