Elamipretide Hydrochloride

FORZINITY is indicated to improve muscle strength in adult and pediatric patients with Barth syndrome weighing at least 30 kg. This indication is approved under accelerated approval based on an improvement in knee extensor muscle strength, an intermediate clinical endpoint [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. FORZINITY™ is a mitochondrial cardiolipin binder indicated to improve muscle strength in adult and pediatric patients with Barth syndrome weighing at least 30 kg. ( 1 ) This indication is approved under accelerated approval based on an improvement in knee extensor muscle strength, an intermediate clinical endpoint. ( 14 ) Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Injection: 280 mg/3.5 mL (80 mg/mL), sterile, clear, colorless to yellow aqueous solution for injection supplied as single-patient-use vials. Injection: 280 mg/3.5 mL (80 mg/mL) solution for injection in single-patient-use vials. ( 3 )

Serious hypersensitivity to elamipretide or any of the excipients in FORZINITY [see Warnings and Precautions (5.2) ]. Serious hypersensitivity to any of the ingredients ( 4 , 5.2 )

Benzyl alcohol toxicity : Do not use in neonates. ( 5.1 )

5.1 Risk of Benzyl Alcohol Toxicity in Neonates FORZINITY is not approved for use in neonates. Serious adverse reactions, including fatal reactions, of new onset or worsening metabolic acidosis that progressed to neurotoxicity, and in some cases gasping syndrome, have been reported in low-birth weight neonates (less than 2,500 grams) and preterm neonates (gestational age less than 34 weeks) who received benzyl alcohol (BA)-containing drugs intravenously. FORZINITY is not approved for intravenous use [see Dosage and Administration (2.1) ] . Gasping syndrome is a life-threatening condition in neonates caused by BA toxicity and is primarily characterized by multiorgan dysfunction secondary to metabolic acidosis, which leads to gasping respirations and death. The minimum amount of BA at which these serious adverse reactions, including fatal reactions, may occur is not known (FORZINITY contains 20 mg of BA per mL). [See Use in Specific Populations (8.4) .]

5.2 Hypersensitivity Hypersensitivity reactions, including serious allergic reactions requiring emergency medical intervention, have been reported in patients receiving FORZINITY. These reactions have included skin manifestations such as rash, papular lesions, and eczematous dermatitis, as well as respiratory symptoms including cough [see Adverse Reactions (6.1) ] . Reactions may occur within minutes to months after treatment initiation. Monitor patients for signs and symptoms of hypersensitivity reactions during treatment. If a serious hypersensitivity reaction occurs, do not administer further doses of FORZINITY and institute appropriate emergency treatment, including epinephrine, antihistamines, and corticosteroids as clinically indicated. Patients who have experienced a serious hypersensitivity reaction should not be rechallenged with FORZINITY [see Contraindications (4) ] . For mild to moderate skin reactions, consider treatment with topical corticosteroids and oral antihistamines. Consider discontinuation of FORZINITY if persistent or severe skin reactions develop.

Most common adverse reactions are injection site reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Stealth BioTherapeutics Inc. at 1-844-444-6486 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the FORZINITY clinical development program, 12 male patients aged 12 to 35 years with genetically-confirmed Barth syndrome received treatment with daily subcutaneous injections of 40 mg FORZINITY. Eleven of these 12 patients were Caucasian. Patients first participated in a double-blind, placebo-controlled crossover trial where they were randomized to one of two sequences: 12 weeks of FORZINITY in Period 1 then a 4-week washout followed by 12 weeks of placebo in Period 2 or 12 weeks of placebo in Period 1 then a 4-week washout followed by 12 weeks of FORZINITY in Period 2 Ten patients completed the randomized trial and entered the open-label extension period where they received FORZINITY once daily. Eight of these patients received FORZINITY for 168 weeks, three of whom received FORZINITY for a total of 192 weeks. Adverse reactions occurring more commonly on FORZINITY than on placebo include injection site reactions such as injection site erythema, pain, induration, pruritus, bruising, and urticaria (Table 2). Table 2: Summary of Adverse Drug Reactions in the Placebo-Controlled Crossover Study, Barth Safety Population Combined (Periods 1 and 2) Elamipretide Placebo N=12 N=12 n (%) n (%) Any local administration reaction 12 (100) 8 (67) Injection site erythema 12 (100) 3 (25) Injection site induration 8 (67) 2 (17) Injection site pruritus 8 (67) 2 (17) Injection site pain 9 (75) 5 (42) Injection site bruising 3 (25) 0 Injection site urticaria 3 (25) 0 Injection site hemorrhage 0 1 (8) Eosinophilia Increases in absolute eosinophil counts were noted frequently in studies where duration of administration of FORZINITY was 30 days or greater. Eosinophil counts generally peaked around 90 days after initial exposure (mean increase from baseline ~0.5 to 0.6 × 10 3 /uL) and returned to baseline levels after 6 to 12 months of continuous exposure or after discontinuation of FORZINITY. The elevation in eosinophils was not associated with clinical manifestations or changes in other laboratory parameters.

8.1 Pregnancy Risk Summary Barth Syndrome is a rare, X-linked, recessive, genetic disorder and is not likely to affect females. Therefore, there are no data with FORZINITY use in pregnant women to evaluate for a drug-related risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental outcomes occurred at any dose tested (see Data ). FORZINITY contains benzyl alcohol as a preservative. Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In pregnant rats, once-daily intravenous infusion of elamipretide during the period of organogenesis [gestation day (GD) 7 to GD 17] did not result in embryo-fetal developmental toxicity at doses tested up to 10 mg/kg/day, approximately 4 times the clinical exposure at the maximum recommended human dose (MRHD) of 40 mg/day, based on area under the concentration-time curve (AUC). In pregnant rabbits, intravenous infusion with elamipretide once daily during the period of organogenesis (GD 7 to GD 19) did not result in embryo-fetal developmental toxicity at doses tested up to 50 mg/kg/day, approximately 10 times the clinical exposure at the MRHD, based on AUC. In a pre- and postnatal study in rats, elamipretide was subcutaneously administered at doses of 0, 5, 10 or 15 mg/kg/day throughout pregnancy and lactation (GD 6 to Lactation Day 20). No adverse developmental effects were observed at doses up to 15 mg/kg/day, approximately 6-times the clinical exposure at the MRHD, based on AUC.

8.2 Lactation Risk Summary Barth Syndrome is a rare, X-linked, recessive, genetic disorder and is not likely to affect females. Therefore, there is no data to evaluate the presence of FORZINITY in human milk, the effect on the breastfed infant, or the effects on milk production. FORZINITY contains benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a lactating female, benzyl alcohol exposure in the breastfed infant is unlikely. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for FORZINITY and any potential adverse effects on the breastfed infant from FORZINITY or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of FORZINITY to improve muscle strength have been established in pediatric patients with Barth syndrome weighing at least 30 kg. Use of FORZINITY for this indication is supported by improvement in knee extensor muscle strength, an intermediate clinical endpoint, observed in an open-label extension study of FORZINITY that included seven pediatric patients aged 12 years and older. [see Dosage and Administration (2.1) , and Clinical Studies (14) ] . The safety and effectiveness of FORZINITY have not been established in pediatric patients weighing less than 30 kg. FORZINITY is not approved for use in neonates. Serious adverse reactions, including fatal reactions, of new onset or worsening metabolic acidosis that progressed to neurotoxicity, and in some cases gasping syndrome, have been reported in low-birth weight neonates and preterm neonates who received BA containing drugs intravenously (FORZINITY is not approved for intravenous use) [see Dosage and Administration (2.1) ] . Gasping syndrome is a life-threatening condition in neonates caused by BA toxicity that is characterized by new onset or worsening metabolic acidosis with gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and gasping respirations followed by death. In reported cases, BA in amounts of 99 to 234 mg/kg/day produced blood BA levels of 6.6 to 14.9 mg/dL, but the minimum amount of BA at which gasping syndrome may occur in neonates is not known (FORZINITY contains 20 mg of BA per mL) [see Warnings and Precautions (5.1) ] .

8.5 Geriatric Use Clinical studies of FORZINITY did not enroll subjects with Barth syndrome aged 65 years and older.

8.6 Renal Impairment No dosage adjustment is required for patients with mild (eGFR 60 to 89 mL/min) or moderate (eGFR 30 to 59 mL/min) renal impairment. The FORZINITY dose should be reduced by one half administered subcutaneously once daily in adults with severe renal impairment (eGFR less than 30 mL/min) who are not on dialysis [see Dosage and Administration (2.2) ] . FORZINITY has not been studied in patients with renal failure on dialysis [see Clinical Pharmacology (12.3) ] .

FORZINITY is a mitochondrial cardiolipin binder that localizes to the inner mitochondrial membrane and improves mitochondrial morphology and function.