Rusfertide

There are no available data on rusfertide use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Based on findings from animal studies, rusfertide may cause fetal harm when administered to a pregnant woman. In animal reproductive studies, subcutaneous administration of rusfertide to pregnant rats and rabbits during organogenesis at exposures lower than the human exposure (based on AUC) at the maximum recommended human dose (MRHD) resulted in malformations and embryo fetal lethality, respectively.

The estimated 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 defect and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

There are no data on the presence of rusfertide in either human or animal milk, the effects on the breastfed child, or the effects on milk production.

Because of the potential for serious adverse reactions in the breastfed child, including impaired iron absorption, advise patients not to breastfeed during treatment with rusfertide and for 30 days after the final treatment.

Rusfertide was not carcinogenic in a 6-month transgenic mouse study at subcutaneous doses up to 25 mg/kg/week or in a 2-year rat carcinogenicity study at doses up to 3 mg/kg/ week. In rats, systemic exposure at the highest dose tested was comparable to clinical exposure at the maximum recommended human dose (MRHD), based on AUC.

Rusfertide was not mutagenic in a bacterial reverse mutation assay (Ames), in vitro chromosomal aberration test (cultured human peripheral blood lymphocytes) or in a rat in vivo lymphocyte chromosome aberration study.

In separate fertility and early embryonic development studies in female and male rats, rusfertide was administered subcutaneously once weekly in females at doses of 0.3, 1, or 3 mg/kg/dose beginning 15 days prior to cohabitation and then once every three days during the cohabitation and gestation periods until gestation day 7, and once weekly males at doses of 1, 3, or 10 mg/kg/dose for 4 weeks prior to cohabitation, and during cohabitation and post cohabitation mating periods, for a total of ≥7 weeks. Rusfertide had no effect on mating, estrous cycle, fertility, sperm parameters, or any ovarian and uterine parameters at any dose at exposures approximately 1-fold in females and 2.6-fold in males the clinical exposure at the MRHD based on AUC.

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.

Polycythemia Vera

VERIFY

The safety of rusfertide was evaluated in VERIFY, a Phase 3, randomized double-blind, placebo-controlled study in patients with PV. During the randomized controlled period (Week 0 to Week 32), 145 patients received rusfertide and 146 patients received placebo. Following the randomized controlled period, patients in the placebo arm crossed over to rusfertide, resulting in a total of 285 patients exposed to rusfertide during the study. The median duration of exposure to rusfertide was 61 weeks (range; 2 weeks to 133 weeks) with 65% of patients exposed to ≥52 weeks.

During the randomized controlled period (Week 0 to Week 32), the most common (>15%) adverse reactions in the rusfertide arm were injection site reactions (56%) and anemia (16%).

One (0.4%) patient experienced a serious adverse reaction of anemia. Dosage reductions of rusfertide due to an adverse reaction occurred in 30 (11%) patients. Adverse reactions which required dosage reduction included anemia in 28 (10%) patients, dyspnea in 2 (0.7%) patients and thrombocytosis in 1 (0.4%) patient. Adverse reactions which resulted in permanent discontinuation of rusfertide included injection site reactions in 2 (0.7%) patients, thrombocytosis in 2 (0.7%) patients and anemia in 1 (0.4%) patient.

The table below summarizes the adverse reactions occurring in ≥5% of the patients with a difference of ≥5 percentage points between the rusfertide arm and the placebo arm in the randomized part (Week 0 to Week 32) of the VERIFY study.

Adverse Reactions Occurring in ≥5% Patients with a Difference of ≥5 Percentage Points Between the Rusfertide Arm and the Placebo Arm in VERIFY (Week 0 to Week 32):

^* Includes anemia and hemoglobin decreased.
^† Includes thrombocytosis and platelet count increased.
^‡ Includes dyspnea and dyspnea exertional.