Abstract << 237/250
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Aim: Elamipretide is a mitochondrial-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 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.