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 restoring the physical and biochemical properties of the IMM by
irreversibly associating with cardiolipin (CL), a
mitochondrial-membrane-unique phospholipid (Szeto 2008; Birk 2013;
Grazioli/Pugin 2018; Mitchell 2020). This association improves membrane
stability, enhances ATP synthesis in several organs including the heart,
kidney, neurons, and skeletal muscle, and reduces reactive oxygen
species (ROS) production (Zhao 2005; Manczak 2010; Szeto/Schiller 2011;
Dai 2013; Siegel 2013; Birk 2014; Brown 2014; Eirin 2014; Nickel 2014;
Szeto/Birk 2014; Alam 2015; Roshanravan 2021). Elamipretide has been
extensively examined in multiple preclinical and clinical studies for
diseases involving mitochondrial dysfunction, consistently demonstrating
amelioration of pathologic symptoms, including improvement in skeletal
muscle strength, cardiac stroke volume, and kidney function (Manczak
2010; Birk 2013; Dai 2013; Siegel 2013; Eirin 2014; Stauffer 2016;
Daubert 2017; Saad 2017; Karaa 2018; Sabbah 2019; Allen 2020; Reid
Thompson 2021).
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
requiring long-term elamipretide administration (Karaa 2018; Sabbah
2019; Karaa 2020; Reid Thompson 2021). Clinical development of
elamipretide has focused on subcutaneous (SC) administration. Prior
studies showed that SC elamipretide up to 80mg once daily is generally
safe and well tolerated, although most longer-term studies have used SC
elamipretide 40mg or 60mg once daily [DOF, 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 typically mild in nature,
resolving within 4hours of elamipretide administration, they can lead to
subject withdrawal or discontinuation during chronic daily
administration [DOF, Stealth BioTherapeutics Inc.].
The Mas-related G-protein coupled receptor member X2 (MRGPRX2),
expressed almost exclusively by mast cells that populate connective
tissues, including the skin (Tatemoto 2006; Motakis 2014), has
relatively recently been linked to ISRs (McNeil 2021a). Skin
mast-cell-activation causes immediate inflammation, and many therapeutic
drugs associated with high frequencies of ISRs have been shown to
activate MRGPRX2 directly, thereby triggering inflammation via mast
cells. MRGPRX2 is preferentially activated by drugs with cationic and
aromatic properties (Grimes 2019), such as elamipretide, making it an
MRGPRX2 agonist. While the current management of ISRs consists of
alternating daily injection sites around abdominal quadrants,
interventions that target mast cell activation or the effects of
mast-cell-derived mediators warrant investigation. 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 60mg SC elamipretide administration. The study agents
(mometasone, tacrolimus, doxepin, diphenhydramine) have dosing regimens
supported by the product label and their ability to reduce inflammatory
responses by targeting mast cell activation.