Garetosmab

Garetosmab is contraindicated for use during pregnancy. Based on its mechanism of action and data from animal reproduction studies, garetosmab can cause fetal harm when administered to a pregnant woman. There are no available data on garetosmab 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 garetosmab exposure during pregnancy, monoclonal antibodies can be actively transported across the placenta. Inhibition of activin A signaling by garetosmab during pregnancy may adversely affect embryogenesis and fetal organogenesis, including development of the reproductive system.

In an enhanced pre- and post-natal developmental (ePPND) toxicity study, intravenous administration of garetosmab 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 garetosmab 10 mg/kg or 3 mg/kg every 4 weeks, respectively. If pregnancy occurs during treatment with garetosmab, 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.

There are no data on the presence of garetosmab 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 garetosmab are unknown. Because of the potential for serious adverse reactions of garetosmab 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 garetosmab and for 6 months after the last dose.

Carcinogenicity studies have not been conducted with garetosmab. The mutagenic potential of garetosmab has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.

Dedicated fertility studies have not been conducted with garetosmab. Reproductive organs and fertility-related parameters were assessed in sexually mature cynomolgus monkeys in a 26-week study in which garetosmab was administered intravenously once weekly at doses up to 50 mg/kg (approximately 14 times or 49 times the recommended human doses of garetosmab 10 mg/kg or 3 mg/kg every 4 weeks, respectively, based on AUC). Minimal to moderate seminiferous tubule degeneration was observed in male monkeys, which was reversible after a treatment-free recovery period. Changes in sperm concentration, sperm motility, or testosterone levels were not observed.

In 5-week toxicology studies in male rats, intravenous administration of garetosmab resulted in adverse effects including inflammation, granulomas, and epithelial degeneration in the male reproductive tract (testes, epididymis, and efferent ducts) associated with decreases in sperm motility at exposures less than the recommended human doses of garetosmab 10 mg/kg or 3 mg/kg every 4 weeks.

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 garetosmab 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 garetosmab 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.

Table 1 summarizes the adverse reactions occurring in ≥10% of patients treated with garetosmab (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 Garetosmab 10 mg/kg or 3 mg/kg and more Frequently than Placebo Through Week 56:

^* Abscess includes abscess, abscess limb, subcutaneous abscess, and tooth abscess.
^†Increased hair growth includes hirsutism, hypertrichosis, hair growth abnormal, and hair disorder.
^‡ Oral ulcers includes aphthous ulcer, lip ulceration, mouth ulceration, oral mucosal blistering, and stomatitis.

Clinically Significant Adverse Reactions Occurring in <10% of Adults with FOP

Cellulitis was reported in 1 (4%) patient receiving garetosmab 10 mg/kg every 4 weeks and in none of the patients receiving garetosmab 3 mg/kg every 4 weeks or placebo.