Introduction
Elamipretide is an aromatic-cationic tetrapeptide that readily
penetrates the cell membrane and transiently localizes to the inner
mitochondrial membrane (IMM) where energy (adenosine triphosphate
[ATP]) production occurs, thereby improving mitochondrial function
by restoration of the physical and biochemical properties of the IMM
through its reversible association with cardiolipin (CL), a phospholipid
that is unique to mitochondrial membranes (Szeto, 2008; Birk et al.,
2013; Grazioli & Pugin, 2018; Mitchell et al., 2020). Specifically,
this association improves membrane stability, enhances ATP synthesis in
several organs including the heart, kidney, neurons, and skeletal
muscle, and reduces reactive oxygen species production (Zhao et al.,
2005; Manczak et al., 2010; Szeto & Schiller, 2011; Dai et al., 2013;
Siegel et al., 2013; Birk et al., 2014; Brown et al., 2014; Eirin et
al., 2014; Nickel et al., 2014; Szeto & Birk, 2014; Alam et al., 2015;
Roshanravan et al., 2021). Elamipretide has been extensively examined in
multiple preclinical studies and clinical trials for diseases involving
mitochondrial dysfunction, consistently demonstrating amelioration of
pathologic symptoms, including improvement in skeletal muscle strength,
cardiac stroke volume, and kidney function (Manczak et al., 2010; Birk
et al., 2013; Dai et al., 2013; Siegel et al., 2013; Eirin et al., 2014;
Stauffer et al., 2016; Daubert et al., 2017; Saad et al., 2017; Karaa et
al., 2018; Sabbah et al., 2019; Allen et al., 2020; Reid Thompson et
al., 2021).
The investigational agent, elamipretide, is being developed for the
treatment of patients with a variety of diseases, such as Barth syndrome
(BTHS) and Primary Mitochondrial Myopathy (PMM), among others, in which
genetic abnormalities affecting the mitochondria lead to life-long
symptoms that require long-term administration of elamipretide (Karaa et
al., 2018; Sabbah et al., 2019; Karaa et al., 2020; Reid Thompson et
al., 2021). Clinical development of elamipretide has focused on
subcutaneous (SC) administration. Prior studies have shown that SC
elamipretide up to 80 mg once daily is generally safe and well
tolerated, although most longer-term studies have used SC elamipretide
40 or 60 mg once daily [data on file, Stealth BioTherapeutics Inc.].
However, injection site reactions (ISRs) were reported in the majority
of subjects receiving treatment. In multiple-dose clinical trials
lasting >8 days, ISRs were relatively common in subjects:
injection site erythema (47%), pruritus (45%), pain (22%), induration
(19%), swelling (14%), urticaria (13%), bruising (12%), hemorrhage
(6%), and mass (6%). Although these ISRs are typically mild in nature
and resolved within 4 hours of elamipretide administration, they can
lead to subject withdrawal or discontinuation during chronic daily
administration [data on file, Stealth BioTherapeutics Inc.].
The Mas-related G-protein coupled receptor member X2 (MRGPRX2), which is
expressed almost exclusively by mast cells that populate connective
tissues, including the skin (Tatemoto et al., 2006; Motakis et al.,
2014), has received increasing attention in recent years for its link to
ISRs (McNeil 2021a). Mast cell activation in the skin causes immediate
inflammation, and many therapeutic drugs associated with high
frequencies of ISRs have been shown to activate MRGPRX2 directly, and
thus trigger inflammation via mast cells. Notably, MRGPRX2 is
preferentially activated by drugs with cationic and aromatic properties
(Grimes et al., 2019), and since elamipretide has these properties, it
is highly plausible that elamipretide is an MRGPRX2 agonist. While the
current management of ISRs consists of alternation of daily injection
sites around abdominal quadrants, interventions that target mast cell
activation or the effects of mast-cell-derived mediators warrant
investigation. To improve patient comfort, the aim of the present study
was to evaluate the efficacy of potential interventions used to mitigate
elamipretide-induced ISRs, identify any role of the MRGPRX2 receptor in
elamipretide ISRs, and further understand the PK and safety of 60 mg SC
elamipretide administration. The agents chosen for study (mometasone,
tacrolimus, doxepin, diphenhydramine) have dosing regimens supported by
the label for the product and are supported by their ability to reduce
inflammatory responses by targeting mast cell activation.