Abstract << 250/250
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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.
Keywords: Elamipretide, Injection Site Reaction, mitigation,
mometasone, safety, tolerability, MRGPRX2