FORZINITY Solution for injection Ref.[116071] Active ingredients: Elamipretide

Effects on QTc Interval

Cardiac electrophysiology:

Clinically significant QTc interval prolongation was not observed at 3 times the peak concentration of the maximum recommended FORZINITY dose.

Elamipretide exposure increases proportionally over a dose range of 2 to 80 mg following daily subcutaneous injections with minimal accumulation.

Absorption

Maximum elamipretide concentrations were reached between 0.5 to 1 hour after subcutaneous administration. The absolute bioavailability following subcutaneous administration is approximately 92%. FORZINITY exposure is comparable after subcutaneous injection to the thigh or to the abdomen.

Distribution

Elamipretide is distributed throughout total body water with an approximate volume of distribution of 0.5 L/kg. There is low binding to plasma proteins (approximately 39%).

Elimination

Metabolism

Elamipretide is metabolized via sequential C-terminal degradation to the M1 tripeptide and M2 dipeptide metabolites, which do not have pharmacological activity.

Excretion

Elamipretide and its metabolites M1 and M2 are excreted in the urine. At 48 hours post-dose, approximately 100% of the FORZINITY dose was recovered in the urine as either elamipretide, M1, or M2 in patients with normal renal function.

Specific Populations

Patients with Renal Impairment

Elamipretide exposure (AUC) increased by 39% in subjects with creatinine clearance 60 to 89 mL/min, 75% in subjects with creatinine clearance 30 to 59 mL/min, and 125% in subjects with creatinine clearance less than 30 mL/min not on dialysis. Renal impairment was categorized based on 24-hour measured urinary creatinine clearance. There was minimal accumulation of elamipretide with daily dosing, regardless of the severity of renal impairment. There was a significant increase in exposure of the M1 and M2 metabolites, up to 280% and 640%, respectively, in subjects with severe renal impairment not on dialysis (creatinine clearance less than 30 mL/min).

While the effect of renal impairment on elamipretide pharmacokinetics was characterized using 24-hour measured urinary creatinine clearance, analyses conducted with estimated glomerular filtration (CKD-EPI equation) support the recommendations for use in this specific population [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

No hepatic metabolism was observed for elamipretide in vitro. Hepatic impairment is not expected to alter the pharmacokinetics (PK) of elamipretide.

Drug Interaction Studies

In Vitro Studies

CYP enzymes: Elamipretide does not inhibit CYP1A, CYP2D6, CYP2E1, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A. Elamipretide does not induce metabolism by CYP1A2, CYP2B6, or CYP3A4.

Drug transporters: Elamipretide does not inhibit the activity of OCT2, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, P-gp, or MATE2-K. Elamipretide is an inhibitor of MATE1 (IC₅₀ 3.53 μM).

In Vivo Clinical Studies

Aspirin: administration of elamipretide (0.1 mg/kg/hour for 4 hours via intravenous infusion) starting 4 hours after a single dose of 650 mg aspirin did not affect the PK of aspirin and its metabolite, salicylic acid. There was no impact on the antiplatelet activity of aspirin when co-administered with elamipretide.

Clopidogrel: administration of elamipretide (0.1 mg/kg/hour for 4 hours via intravenous infusion) starting 4 hours after a single dose of 300 mg clopidogrel did not significantly affect the PK of clopidogrel. There was no impact on the anti-thrombotic activity of clopidogrel when co-administered with elamipretide.

Unfractionated heparin: administration of elamipretide (0.25 mg/kg/hour for 4 hours via intravenous infusion) had no significant impact on activated partial thromboplastin time (aPTT) and anti-factor Xa activity of unfractionated heparin, when co-administered 7 hours after starting the unfractionated heparin infusion.

Carcinogenicity studies have not been conducted with elamipretide.

Elamipretide was negative in an in vitro bacterial reverse mutation assay, a chromosomal aberration assay in Chinese hamster ovary cells, and an in vivo rat bone marrow micronucleus assay.

Subcutaneous doses of elamipretide in rats of up to 20 mg/kg/day, approximately 5-times the clinical exposure at the MRHD of 40 mg, did not adversely affect fertility or reproductive performance.

FORZINITY was evaluated in a randomized, double-blind, placebo-controlled, crossover trial and its 192-week, open-label, single-arm extension period.

The randomized trial evaluated the efficacy and safety of once daily FORZINITY 40 mg injected subcutaneously for 12 weeks in 12 subjects ≥12-years-old and >30 kg with genetically confirmed Barth syndrome. The primary endpoints for the randomized trial were distance walked during 6-minute walk test and Total Fatigue Score on the Barth syndrome Symptom Assessment. FORZINITY was not superior to placebo on these primary endpoints. Ten subjects completed the randomized trial and entered the extension period designed to evaluate long-term safety and tolerability of FORZINITY. Eight of these 10 subjects participated through Week 168 of the extension period.

Knee extensor muscle strength measured by handheld dynamometry was evaluated as one of the secondary endpoints in the randomized trial and in the extension period. Increases in knee extensor muscle strength were not observed during the randomized trial but were observed during the extension period. At the pre-dose baseline visit at the start of the randomized trial, median (min, max) muscle strength was 124 (92, 176) newtons. Table 3 shows descriptive changes from pre-dose baseline for knee extensor muscle strength during the randomized controlled trial and extension period.

Table 3. Descriptive Statistics, Changes from Baseline ?footnote?in Muscle Strength (newtons):