Garetosmab

PASATRU is indicated to reduce formation of new heterotopic ossification (HO) lesions and clinician-assessed flare-ups in adults with fibrodysplasia ossificans progressiva (FOP). PASATRU is an activin signaling inhibitor indicated to reduce formation of new heterotopic ossification (HO) lesions and clinician-assessed flare-ups in adults with fibrodysplasia ossificans progressiva (FOP). ( 1 )

Injection: 300 mg/5 mL (60 mg/mL) clear to slightly opalescent, colorless to pale yellow solution in a single-dose vial. Injection: 300 mg/5 mL (60 mg/mL) solution in a single-dose vial. ( 3 )

PASATRU is contraindicated during pregnancy. PASATRU can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1 , 8.3) ] . Pregnancy. ( 4 , 5.1 , 8.1 , 8.3 )

Embryo-Fetal Toxicity: PASATRU can cause fetal harm. Verify females of reproductive potential are not pregnant prior to initiating PASATRU and advise of the potential risk to a fetus and to use effective contraception. Advise the patient to discontinue PASATRU immediately if pregnancy occurs during treatment and to contact their healthcare provider. ( 2.1 , 4 , 5.1 , 8.1 , 8.3 ) Skin and Soft Tissue Infections: Have occurred in patients treated with PASATRU. Advise patients to report signs or symptoms of infection to their healthcare provider. ( 5.2 ) Epistaxis: Spontaneous epistaxis, including serious cases requiring medical intervention, has been reported in patients receiving PASATRU. Advise patients to seek medical attention if they experience epistaxis that is severe, prolonged and does not resolve with standard first-aid measures. ( 5.3 )

5.1 Embryo-Fetal Toxicity PASATRU is contraindicated during pregnancy. Based on its mechanism of action and findings from animal reproduction studies, PASATRU can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1) ] . Intravenous administration of garetosmab-grts to pregnant cynomolgus monkeys resulted in embryo-fetal toxicity, infant mortality, and post-natal malformations at exposures equivalent to or higher than those in patients at the recommended human doses of PASATRU 10 mg/kg or 3 mg/kg every 4 weeks, respectively. For females of reproductive potential, verify that the patient is not pregnant prior to initiating treatment. Advise females of reproductive potential to use effective contraception during treatment with PASATRU and for 6 months after the last dose. Advise the patient to discontinue PASATRU immediately if pregnancy occurs during treatment and to contact their healthcare provider [see Use in Specific Populations (8.1 , 8.3) ] .

5.2 Skin and Soft Tissue Infections Skin and soft tissue infections requiring treatment and/or hospitalization, including abscesses and cellulitis [see Adverse Reactions (6.1) ] , have occurred in patients receiving PASATRU in clinical trials. Advise patients to report signs or symptoms of skin infection, including erythema, pain, swelling, or fever, and to seek medical attention if these occur.

5.3 Epistaxis Spontaneous epistaxis, including serious cases requiring medical intervention, has been reported in patients receiving PASATRU. In clinical trials in the FOP population, one serious case of spontaneous epistaxis occurred that required hospitalization for nasal packing and application of a clotting agent. Advise patients to seek medical attention if they experience epistaxis that is severe, prolonged (e.g., lasting more than 20 minutes) and does not resolve with standard first-aid measures.

The following clinically significant adverse reactions are described elsewhere in the labeling: Skin and Soft Tissue Infections [see Warnings and Precautions (5.2) ] Epistaxis [see Warnings and Precautions (5.3) ] The most common adverse reactions (incidence ≥10%) are abscess, acne, increased hair growth, madarosis, oral ulcers, and epistaxis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at 1-877-372-7287 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. The safety of PASATRU was evaluated in a randomized, double-blind, parallel-group, multicenter, placebo-controlled trial that enrolled a total of 63 adults with FOP. Patients received placebo or PASATRU 10 mg/kg or 3 mg/kg every 4 weeks in the 56-week double-blind treatment period then continued their originally assigned treatment in a double-blind extension phase [see Clinical Studies (14) ] . Table 1 summarizes the adverse reactions occurring in ≥10% of patients treated with PASATRU (10 mg/kg or 3 mg/kg) every 4 weeks and more frequently than placebo through Week 56. Table 1: Adverse Reactions Occurring in ≥10% of Adults with FOP Treated with PASATRU 10 mg/kg or 3 mg/kg and more Frequently than Placebo Through Week 56 Adverse Reaction Placebo PASATRU 10 mg/kg every 4 weeks PASATRU 3 mg/kg every 4 weeks N=21 n (%) N=23 n (%) N=19 n (%) Abscess Abscess includes abscess, abscess limb, subcutaneous abscess, and tooth abscess. 2 (10%) 8 (35%) 2 (11%) Acne 2 (10%) 7 (30%) 3 (16%) Increased hair growth Increased hair growth includes hirsutism, hypertrichosis, hair growth abnormal, and hair disorder. 0 6 (26%) 8 (42%) Madarosis 4 (19%) 6 (26%) 3 (16%) Oral ulcers Oral ulcers includes aphthous ulcer, lip ulceration, mouth ulceration, oral mucosal blistering, and stomatitis. 1 (5%) 6 (26%) 1 (5%) Epistaxis 5 (24%) 4 (17%) 10 (53%) Folliculitis 2 (10%) 2 (9%) 3 (16%) Paronychia 0 1 (4%) 2 (11%) Rash 0 1 (4%) 5 (26%) Clinically Significant Adverse Reactions Occurring in <10% of Adults with FOP Cellulitis was reported in 1 (4%) patient receiving PASATRU 10 mg/kg every 4 weeks and in none of the patients receiving PASATRU 3 mg/kg every 4 weeks or placebo.

Lactation: Breastfeeding is not recommended. ( 8.2 )

8.1 Pregnancy Risk Summary PASATRU is contraindicated for use during pregnancy. Based on its mechanism of action and data from animal reproduction studies, PASATRU can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on PASATRU during pregnancy to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Although there are no data on PASATRU exposure during pregnancy, monoclonal antibodies can be actively transported across the placenta. Inhibition of activin A signaling by PASATRU during pregnancy may adversely affect embryogenesis and fetal organogenesis, including development of the reproductive system (see Clinical Considerations ) . In an enhanced pre- and post-natal developmental (ePPND) toxicity study, intravenous administration of garetosmab-grts to pregnant cynomolgus monkeys resulted in developmental toxicity, including post-natal malformations, neurobehavioral deficits, and infant mortality at exposures equivalent to or higher than those in patients at the recommended human doses of PASATRU 10 mg/kg or 3 mg/kg every 4 weeks, respectively ( see Data ). If pregnancy occurs during treatment with PASATRU, discontinue treatment immediately, and advise the patient to contact their healthcare provider. 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. Clinical Considerations Fetal/Neonatal Adverse Reactions Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses, and peaks during the third trimester. Therefore, it is expected that PASATRU may be present in infants exposed in utero. The potential clinical impact of PASATRU exposure in infants exposed in utero should be considered. Data Animal Data In an ePPND toxicity study, pregnant cynomolgus monkeys were administered intravenous doses of garetosmab-grts 5 mg/kg or 50 mg/kg once weekly beginning from gestation day 20 through delivery, with no evidence of maternal toxicity at either dose level. An increased incidence of post-natal malformations, including neurological deficiencies and testes malformations, were observed in offspring at 5 mg/kg/week (approximately equivalent to or 4 times the recommended human doses of PASATRU 10 mg/kg or 3 mg/kg every 4 weeks, respectively, based on area under the concentration curve [AUC]). Increased incidences of stillbirth, premature delivery, post-natal malformations including generalized alopecia, and infant mortality were observed in offspring of pregnant monkeys receiving treatment with garetosmab-grts at 50 mg/kg/week (approximately 9 times or 31 times the recommended human doses of PASATRU 10 mg/kg or 3 mg/kg every 4 weeks, respectively, based on AUC).

8.2 Lactation Risk Summary There are no data on the presence of PASATRU in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to PASATRU are unknown. Because of the potential for serious adverse reactions of PASATRU absorption in the breastfed infant, including skin and soft tissue infections, and the potential for effects on male reproductive organ development based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with PASATRU and for 6 months after the last dose.

8.3 Females and Males of Reproductive Potential Based on animal data and mechanism of action, PASATRU can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1) ] . Pregnancy Testing Verify that the patient is not pregnant prior to initiating PASATRU [see Dosage and Administration (2.1) ] . Contraception Females Advise females of reproductive potential to use effective contraception during treatment with PASATRU and for 6 months after the last dose of PASATRU. Infertility Males Based on findings from animal studies, PASATRU may impair male fertility [see Nonclinical Toxicology (13.1) ] .

8.4 Pediatric Use The safety and effectiveness of PASATRU have not been established in pediatric patients.

8.5 Geriatric Use Clinical studies of PASATRU did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

FOP is caused by gain-of-function mutations in the intracellular domain of activin receptor type 1 (ACVR1, also known as ALK2), a bone morphogenetic protein (BMP) type I receptor that is expressed in many tissues, including skeletal muscle and cartilage. In patients with FOP, mutant ACVR1 is activated by activin A resulting in heterotopic ossification. Garetosmab-grts is a human IgG4 monoclonal antibody that specifically binds to and inhibits signaling by activin A to block the activation of FOP-mutant ACVR1 and reduce the formation and progression of new heterotopic bone lesions.