Brepocitinib

Based on findings in animal studies, brepocitinib may cause fetal harm when administered to a pregnant woman. Available data from brepocitinib use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

In animal reproduction studies, fetal skeletal malformations, and post-implantation loss were observed when brepocitinib was administered to pregnant rats and rabbits during the period of organogenesis at 1.6- and 3-times the exposure at the MRHD, respectively. In a pre- and postnatal study in rats, brepocitinib did not cause adverse effects in maternal animals or offspring at exposures up to 5.5 times the MRHD.

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

Disease-Associated Maternal and/or Embryo/Fetal Risk

Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with dermatomyositis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

There are no data on the presence of brepocitinib in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed infant, including infections, GI perforation, and malignancy, advise patients that breastfeeding is not recommended during treatment with brepocitinib and for 3 days (approximately 5 half-lives) after the last dose.

Carcinogenesis

The carcinogenic potential of brepocitinib was evaluated in Wistar Han rats and Tg.rasH2 mice. No evidence of tumorigenicity was observed in mice administered brepocitinib orally up to 150 mg/kg/day. In male rats that received brepocitinib for 104 weeks at oral doses of 30 mg/kg/day (approximately 33 times the MRHD), brepocitinib caused benign Leydig cell tumors. The relevance of this finding to humans is not known. No evidence of tumorigenicity was observed in male or female rats that received brepocitinib for 104 weeks at oral doses up to 10 mg/kg/day or 30 mg/kg/day, respectively (approximately 10 or 33 times the MRHD).

Mutagenesis

Brepocitinib was negative for mutagenesis in the in vitro microbial reverse mutation assay (Ames assay). Brepocitinib was negative for mutagenesis in the in vivo micronucleus assay within rat peripheral blood cells.

Impairment of Fertility

In male rats, brepocitinib had no effect on fertility at oral doses up to 55 mg/kg/day (approximately 54 times the MRHD).

In female rats, brepocitinib reduced fertility at an oral dose of 10 mg/kg/day (approximately 10 times the MRHD) based upon higher early resorptions, higher post-implantation loss and a lower number of live embryos compared to control females. Additionally, maintenance of pregnancy was adversely affected at 55 mg/kg/day (approximately 50 times the MRHD) based upon findings of significantly lower corpora lutea and implantation sites and all pregnant females having total litter loss due to higher pre- and post-implantation loss. Brepocitinib had no effect on female fertility at 3 mg/kg/day (approximately 2 times the MRHD).

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 brepocitinib in adult patients with dermatomyositis was evaluated in a 52-week Phase 3, double-blind, placebo-controlled trial (Trial DM). In this trial, 241 adult patients were randomized to receive brepocitinib 30 mg once daily (81 patients), brepocitinib 15 mg once daily (unapproved dosage) (81 patients), or placebo (79 patients) once daily for 52 weeks.

Table 1 summarizes the adverse reactions that occurred in ≥5% of brepocitinib-treated patients and ≥2% greater than placebo-treated patients in the 52-week placebo-controlled period. A total of 81 adult patients with dermatomyositis were exposed to brepocitinib during this period.

Table 1. Adverse Reactions Reported in ≥5% of Adult Patients with Dermatomyositis Who Received Brepocitinib and ≥2% Greater Than Patients Who Received Placebo (Trial DM):

Specific Adverse Reactions

Thrombosis

Thromboses were observed in clinical trials of brepocitinib. During the open-label extension period of Trial DM, a case of peripheral arterial thrombosis was reported in a brepocitinib-treated patient.

Overall Infections

During the 52-week treatment period of Trial DM, infections were reported in 45 (57%) placebo-treated patients and 56 (69%) brepocitinib-treated patients. The most commonly reported infections with brepocitinib were upper respiratory tract infections, urinary tract infections, bronchitis, and COVID-19.

• Serious Infections: During the 52-week treatment period of Trial DM, serious infections were reported in one (1%) placebo-treated patient and 8 (10%) brepocitinib-treated patients. The most common serious infections in brepocitinib-treated patients were pneumonia (two patients) and sepsis (two patients).
• Viral Reactivation: During the 52-week treatment period of Trial DM, viral reactivations were reported in 4 (5%) brepocitinib-treated patients. All viral reactivations with brepocitinib were herpes zoster.

Laboratory Abnormalities

• Hepatic Transaminase Elevations: During the 52-week treatment period of Trial DM,
  • Alanine transaminase (ALT) ≥3 x upper limit of normal (ULN) were observed in 7 (9%) placebo-treated patients and 8 (9.9%) brepocitinib-treated patients.
  • Aspartate transaminase (AST) elevations ≥3 x upper limit of normal (ULN) were observed in 3 (3.8%) placebo-treated patients and 4 (4.9%) brepocitinib-treated patients.
  • One case of probable drug-induced liver injury (mixed pattern with marked GGT elevation, normal bilirubin, and low concurrent creatine kinase [CK]) was reported in a patient who received brepocitinib 15 mg. The event resolved following discontinuation of brepocitinib.
• Lipid Elevations: During the 52-week treatment period of Trial DM, brepocitinib treatment was associated with increases in total cholesterol, HDL cholesterol, and LDL cholesterol. Elevation in LDL and HDL cholesterol peaked by Week 8 and remained stable thereafter. In the 52-week treatment period of Trial DM, changes from baseline in lipid parameters in brepocitinib-treated patients are summarized below:
  • Mean LDL cholesterol increased by 3.8 mg/dL.
  • Mean HDL cholesterol increased by 4.5 mg/dL.
  • Mean LDL/HDL ratio remained stable.