Rusfertide

MIMRYLO is indicated for the treatment of erythrocytosis in adults with polycythemia vera (PV). MIMRYLO is a hepcidin mimetic indicated for the treatment of erythrocytosis in adults with polycythemia vera (PV). ( 1 )

For injection: a sterile, white to off-white lyophilized powder for reconstitution in single-dose vials containing 9.5 mg, 19 mg, 28 mg, 41 mg, and 54 mg rusfertide (provided as rusfertide acetate) per vial, co-packaged with a clear diluent solution. For injection: 9.5 mg, 19 mg, 28 mg, 41 mg, and 54 mg of rusfertide as a lyophilized powder in single-dose vials for reconstitution. ( 3 )

None. None. ( 4 )

New or Worsening Thrombocytosis: MIMRYLO may increase platelet counts in patients with PV. After initiating MIMRYLO and during dose modifications, monitor complete blood count (CBC) every 2 to 4 weeks, or as clinically indicated. ( 5.1 ) Injection-Site Reactions: Injection site reactions have been reported in patients treated with MIMRYLO. Use ice, topical corticosteroid creams, antihistamines or analgesics, as needed, to treat injection site pain and swelling. ( 5.2 ) Embryo-Fetal Toxicity: Based on animal data, MIMRYLO can cause fetal harm. Advise females of the potential risk to the fetus and to use effective contraception. ( 5.3 )

5.1 New or Worsening Thrombocytosis MIMRYLO may increase platelet counts in patients with PV. Within 4 weeks of treatment initiation, platelet counts increased by an average of 31% from baseline. Thirty-six percent of patients had platelet counts that exceeded 600 x 10 9 /L, and 6% had platelet counts that exceeded 1,000 x 10 9 /L. Platelet counts generally plateaued on treatment by Week 8. MIMRYLO was discontinued due to increased platelet counts in 1% of patients. After initiating MIMRYLO and during dose modifications, monitor CBC every 2 to 4 weeks or as clinically indicated. Platelet elevations associated with MIMRYLO may require cytoreductive therapy initiation, modification, or MIMRYLO dose modifications or discontinuation.

5.2 Injection-Site Reactions Injection site reactions occurred in 135 (47%) patients treated with MIMRYLO in VERIFY. The most common (>5%) injection site reactions reported were erythema (27%), pruritus (17%), pain (15%), and swelling (8%). Two patients experienced Grade 3 injection site reactions, and all other patients experienced Grade 1 or Grade 2 injection site reactions; most did not require medication for treatment. Two patients (0.7%) experienced injection site reactions that led to treatment discontinuation. Use ice, topical corticosteroid creams, antihistamines or analgesics, as needed, to treat injection site pain and swelling [see Dosage and Administration (2.4) ] .

5.3 Embryo-Fetal Toxicity Based on findings from animal reproduction studies, MIMRYLO may cause fetal harm when administered to a pregnant woman. Administration of MIMRYLO to pregnant rats and rabbits during organogenesis resulted in structural anomalies and embryo-fetal lethality, respectively, at exposures lower than the maximum recommended human dose. Pregnancy testing is recommended for females of reproductive potential prior to treatment with MIMRYLO. Advise females of reproductive potential to use an effective method of contraception during treatment with MIMRYLO and for at least 30 days after the final dose. Advise patients to stop taking MIMRYLO if they become pregnant [see Use in Specific Populations (8.1 , 8.3) ] .

The following clinically significant adverse reactions are described elsewhere in the labeling: New or Worsening Thrombocytosis [see Warnings and Precautions (5.1) ] Injection-Site Reactions [see Warnings and Precautions (5.2) ] Most common adverse reactions (incidence >15%) were injection site reactions (56%), and anemia (16%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America, Inc. at 1-877-TAKEDA-7 (1-877-825-3327) 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. Polycythemia Vera VERIFY The safety of MIMRYLO was evaluated in VERIFY [see Clinical Studies (14) ] , 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 MIMRYLO and 146 patients received placebo. Following the randomized controlled period, patients in the placebo arm crossed over to MIMRYLO, resulting in a total of 285 patients exposed to MIMRYLO during the study. The median duration of exposure to MIMRYLO 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 MIMRYLO arm were injection site reactions (56%) and anemia (16%). One (0.4%) patient experienced a serious adverse reaction of anemia. Dosage reductions of MIMRYLO 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 MIMRYLO included injection site reactions in 2 (0.7%) patients, thrombocytosis in 2 (0.7%) patients and anemia in 1 (0.4%) patient. Table 4 summarizes the adverse reactions occurring in ≥5% of the patients with a difference of ≥5 percentage points between the MIMRYLO arm and the placebo arm in the randomized part (Week 0 to Week 32) of the VERIFY study. Table 4: Adverse Reactions Occurring in ≥5% Patients with a Difference of ≥5 Percentage Points Between the MIMRYLO Arm and the Placebo Arm in VERIFY (Week 0 to Week 32) Adverse Reaction MIMRYLO (n = 145) PLACEBO (n = 146) All Grades (%) Grade 3 (%) All Grades (%) Grade 3 (%) Injection site reactions 56 0.7 33 0 Anemia Includes anemia and hemoglobin decreased. 16 0 4.1 0 Thrombocytosis Includes thrombocytosis and platelet count increased. 8 0 0.7 0 Dyspnea Includes dyspnea and dyspnea exertional. 8 0 1.4 0

Lactation: Breastfeeding not recommended. ( 8.2 )

8.1 Pregnancy Risk Summary There are no available data on MIMRYLO 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, MIMRYLO may cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.3) ] . 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 [see Data ] . 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. Data Animal Data In an embryo-fetal development study in pregnant rats, rusfertide administered subcutaneously at 0.3, 1, and 3 mg/kg/dose administered every three days from gestation day (GD) 6 to 15 caused dose-dependent increases in the incidence of craniofacial and CNS malformations (narrowed nasopharynx, dilated cerebral ventricles, enlarged olfactory lobes, eye defects and fused ribs) at doses 1 mg/kg/dose and higher at exposures less than the clinical exposures at the MRHD based on AUC. In an embryo-fetal development study in pregnant rabbits, rusfertide administered subcutaneously at 0.03, 0.1, 0.3, and 1 mg/kg/dose from GD 7 to 16 caused embryo-fetal lethality at a dose of 1 mg/kg at exposures less than the clinical exposures at the MRHD based on AUC.

8.2 Lactation Risk Summary 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 MIMRYLO and for 30 days after the final treatment.

8.3 Females and Males of Reproductive Potential Based on animal data, MIMRYLO may cause fetal malformations at doses with exposures less than the clinical exposure at the MRHD [see Use in Specific Populations (8.1) ] . Pregnancy testing Pregnancy testing is recommended for females of reproductive potential. Contraception Females MIMRYLO may cause fetal harm when administered to pregnant women. Advise female patients of reproductive potential to use effective contraception during treatment with MIMRYLO and for at least 30 days after the final dose of MIMRYLO [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1) ].

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use There were 71 (25%) patients 65 years of age and older that received MIMRYLO in the VERIFY study [see Clinical Studies (14) ] , while 22 (8%) were 75 years of age and older. No overall differences in safety or effectiveness of MIMRYLO have been observed between patients 65 years of age and older and younger adult patients.

Rusfertide is a mimetic of the endogenous hormone hepcidin that blocks the iron transporter ferroportin. Inhibition of ferroportin by rusfertide reduces availability of iron for production of red blood cells resulting in lower hematocrit levels.