Rusfertide

MIMRYLO (rusfertide) for injection, for subcutaneous use, a hepcidin mimetic, is a synthetic cyclic peptide (disulfide) isolated as an acetate salt. The chemical name for rusfertide is S 6 , S 16 -cyclo[ N -isovaleryl-Asp-Thr-His-Phe-Pro-Cys-Ile- Nε -( N -palmitoyl-γ-Glu)-Lys-Phe-Glu-Pro-Arg-Ser-Lys-Gly-Cys-Lys-NH 2 ] acetate. Rusfertide acetate has the following chemical structure: Rusfertide acetate is an amorphous white to off-white powder, light sensitive and hygroscopic with low solubility in ethanol or acetonitrile. The aqueous solubility in pH range of 2.5 to 7.4 is ≥112 mg/mL. The average molecular weight for the free base is 2442.0 u. The molecular formula for the free base is C 114 H 181 N 27 O 28 S 2 . MIMRYLO for injection is supplied as a sterile, preservative-free, white to off-white lyophilized powder in a single-dose glass vial. The 9.5 mg dose strength delivers 9.5 mg of rusfertide (provided as rusfertide acetate), mannitol (25 mg), sodium acetate trihydrate (1.36 mg), and glacial acetic acid/sodium hydroxide for pH adjustment, for subcutaneous injection after reconstitution with the provided diluent. The 19 mg, 28 mg, 41 mg, and 54 mg dose strengths deliver 19 mg, 28 mg, 41 mg and 54 mg of rusfertide (provided as rusfertide acetate), mannitol (20 mg), sodium acetate trihydrate (1.36 mg), and glacial acetic acid/sodium hydroxide for pH adjustment, for subcutaneous injection after reconstitution with the provided diluent. The diluent for MIMRYLO is a sterile, preservative-free solution containing sodium acetate trihydrate (1.36 mg/mL), zinc acetate dihydrate (2.2 mg/mL), and glacial acetic acid for adjusting the pH to nominal pH of 5.4 in Water for Injection, USP. It is a clear, colorless solution, free from visible particles, and is provided in a glass prefilled syringe. After reconstitution, MIMRYLO is a clear and colorless solution free from visible particles. chemical structure

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 )

How Supplied MIMRYLO for injection is supplied in a carton for each individual dosage strength comprising a single-dose vial containing a sterile, preservative-free, white to off-white lyophilized powder and a single-dose prefilled syringe containing a clear, colorless solution (diluent) with a luer lock adapter and soft inner tip cap. Not made with natural rubber latex. Dosage Strength (mg/vial) Color Cap Indicator Vial NDC Number Carton NDC Number 9.5 Blue 63020-710-10 63020-715-10 19 Lime 63020-720-20 63020-725-20 28 Burgundy 63020-730-30 63020-735-30 41 Yellow 63020-740-40 63020-745-40 54 White 63020-760-60 63020-765-60 Prefilled Diluent Syringe NDC 63020-600-05 Storage and Handling Store at room temperature between 20°C to 25°C (68°F to 77°F). Do not freeze. Store in the original carton to protect from light. Do not use the vial or the diluent prefilled syringe after the expiration date on the carton. For detailed instructions on the preparation and administration of MIMRYLO, see the Instructions for Use provided in the product carton. After reconstitution, MIMRYLO may be stored at room temperature between 20°C to 25°C (68°F to 77°F) for up to 4 hours. After reconstitution, administer MIMRYLO within 4 hours. Discard reconstituted solution if not used within 4 hours.

Recommended starting dose: 19 mg by subcutaneous injection once a week. ( 2.1 ) Adjust dose based on efficacy or safety to a maximum of 108 mg weekly. ( 2.1 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.4 ) 2.1 Recommended Dosage MIMRYLO is for subcutaneous use only. The recommended weekly dosage range of MIMRYLO is 9.5 mg to 108 mg. The recommended starting dose of MIMRYLO is 19 mg once a week. Doses above 54 mg will require two injections. Doses greater than 82 mg should be administered on separate days. Administer MIMRYLO subcutaneously on a weekly dosing schedule. See Table 1 . Table 1: MIMRYLO Weekly Dosing Instructions MIMRYLO Weekly Dose Doses higher than 54 mg are administered as 2 injections. If the weekly dosage is greater than 82 mg, administer your first injection on day 1 and the second injection on day 4 or 5. Dosing Instructions Frequency During Each Week 9.5 mg Single injection Once weekly 19 mg 28 mg 41 mg 54 mg 69 mg 28 mg AND 41 mg Once weekly on the Same Day 82 mg 41 mg AND 41 mg Once weekly on the Same Day 95 mg Day 1: 54 mg Day 4 or 5: 41 mg Day 1 and Day 4 or 5 108 mg Day 1: 54 mg Day 4 or 5: 54 mg Adjust the dose of MIMRYLO based on efficacy or safety [see Dosage and Administration (2.2) ] . 2.2 Dose Modifications Monitor complete blood count (CBC) every 2 to 4 weeks or as clinically indicated during dose modifications. Dose increase: After a minimum of 2 weeks at the current weekly dose, dose increase may be considered according to Table 2 and based on medical judgement to reduce or to maintain hematocrit at the recommended level below 45%. Allow a minimum of 2 weeks between dose increases. Table 2: Recommended MIMRYLO Dose Increase to Reduce or to Maintain Hematocrit Below 45% Current Weekly Dose Increase Weekly Dose to 9.5 mg 19 mg 19 mg 28 mg 28 mg 41 mg 41 mg 54 mg 54 mg 69 mg 69 mg 82 mg 82 mg 95 mg 95 mg 108 mg Dose decrease: For Grade ≥2 anemia or for drug-related Grade ≥3 toxicities, reduce the dose of MIMRYLO according to Table 3 . Table 3: Recommended MIMRYLO Dose Decrease for Patients Experiencing Grade ≥2 Anemia or for Drug-Related Grade ≥3 Toxicities Current Weekly Dose Decrease Weekly Dose to 9.5 mg Discontinue treatment 19 mg 9.5 mg 28 mg 19 mg 41 mg 28 mg 54 mg 41 mg 69 mg 54 mg 82 mg 69 mg 95 mg 82 mg 108 mg 95 mg 2.3 Missed Dose For patients injecting once a week If the injection is missed by 1 to 4 days, take the missed injection immediately and then resume regular dosing schedule. If the injection is missed by more than 4 days, take the missed injection immediately. Take the next injection 3 days later and then resume the regular dosing schedule. For patients injecting two times a week If the injection is missed by 1 to 2 days, take the missed injection immediately and take the next injection 3 days later. Then resume the regular dosing schedule. If the injection is missed by more than 2 days, skip the missed injection and continue the regular dosing schedule. 2.4 Preparation and Administration Instructions Prior to treatment initiation, healthcare providers should show patient and/or caregivers how to prepare and inject MIMRYLO subcutaneously into the abdomen, thigh, or upper arm. Advise patients and/or caregivers to contact healthcare providers with questions. For detailed instructions on the preparation and administration of MIMRYLO, see the Instructions for Use provided in the product carton. Preparation : Determine the number of vial(s) of MIMRYLO needed for the full dose. MIMRYLO must be reconstituted using the provided diluent prefilled syringe. Attach the vial adapter to the vial(s). Attach the diluent syringe to the vial adapter. Inject all of the diluent from the attached syringe into the vial containing lyophilized powder. Do not remove the syringe from the vial adapter. Gently swirl the vial to reconstitute. This may take about 2 minutes. Do not shake. Set the vial on a clean flat surface and let it sit to allow the liquid to settle and any excess foam to disappear. This may take about 1 minute. Visually inspect that the reconstituted solution is clear with very little foam, colorless, and free from visible particles. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Withdraw all of the reconstituted solution from the vial into the syringe. After reconstitution, MIMRYLO may be stored at room temperature between 20°C to 25°C (68°F to 77°F) for up to 4 hours. After reconstitution, administer MIMRYLO as soon as possible, but no later than 4 hours. Discard reconstituted solution if not used within 4 hours . Administration : Attach the needle to the syringe. Administer subcutaneously into the abdomen at least 2 inches from the navel, outer area of upper arm, or front of the thigh. The outer area of the upper arms may be used only if the injection is being given by a caregiver. Do not select a site where the skin is tender, bruised, red, irritated, hard or broken. Do not inject into the same spot twice in a row. Change (rotate) sites between injections. Weekly doses exceeding 54 mg are administered as 2 injections. If the weekly dose is greater than 82 mg, administer your first injection on day 1 and the second injection on day 4 or 5.

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) ] .

Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ). Subcutaneous Dosing Technique Provide guidance to patients and caregivers on proper subcutaneous administration technique, and how to use MIMRYLO [see Instructions for Use ] . Missed Dose Instruct patients to call healthcare provider if they are unsure when to inject a missed dose [see Dosage and Administration (2.3) ] . New or Worsening Thrombocytosis Advise patients that MIMRYLO may increase platelet counts. Instruct patients to contact their healthcare provider if they experience signs or symptoms of bleeding or blood clots, such as unusual bruising or bleeding, chest pain, shortness of breath, leg pain or swelling, or sudden severe headache [see Warnings and Precautions (5.1) ] . Injection Site Reactions Advise patients that injection site reactions may occur with MIMRYLO. Instruct patients to contact their healthcare provider if they experience severe or persistent injection site reactions. Inform patients that ice, topical corticosteroid creams, antihistamines, or analgesics may be used to manage injection site pain and swelling [see Warnings and Precautions (5.2) and Dosage and Administration (2.4) ] . Embryo-Fetal Toxicity MIMRYLO may cause fetal harm. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1) ] . Advise female patients of reproductive potential to use effective contraception during treatment with MIMRYLO and for at least 30 days after the final dose [see Use in Specific Populations (8.3) ] . Lactation Advise females not to breastfeed during treatment with MIMRYLO and for 30 days after the final dose [see Use in Specific Populations (8.2) ] . Distributed by: Takeda Pharmaceuticals America, Inc. Cambridge, MA 02142 MIMRYLO is a trademark of Takeda Pharmaceuticals U.S.A., Inc. TAKEDA and are registered trademarks of Takeda Pharmaceutical Company Limited. ©2026 Takeda Pharmaceuticals U.S.A., Inc. All rights reserved. R1 logo

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.

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.

Safety and effectiveness in pediatric patients have not been established.

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.

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