Interventions with Potential to Mitigate Injection Site Reactions
Following Subcutaneous Elamipretide Administration: A Phase 1, Crossover
Study
Abstract
Background and Purpose: 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. Experimental Approach: 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. Key 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 and
Implications: 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.