Products – Mimrylo (rusfertide)

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.

*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.

• Adjust the dose of MIMRYLO based on efficacy or safety [see Dosage and Administration (2.2)].

2.2Dose 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%

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

2.3Missed 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.

2.4Preparation 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.

5.1New 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 10⁹/L, and 6% had platelet counts that exceeded 1,000 x 10⁹/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.

5.2Injection-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)].

5.3Embryo-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)] .

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)

^a Includes anemia and hemoglobin decreased.
^b Includes thrombocytosis and platelet count increased.
^c Includes dyspnea and dyspnea exertional.

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.

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

In healthy participants receiving single subcutaneous doses of 9.5 mg, 19 mg, 28 mg, 41 mg, and 54 mg MIMRYLO, the maximum reduction in serum iron was noted approximately 24 to 48 hours post dose. The higher doses (41 mg and 54 mg) of MIMRYLO resulted in a more sustained reduction in serum iron up to 96 hours.

In the Phase 3 VERIFY study, mean ferritin concentrations increased from 21 mcg/L at baseline to 124 mcg/L at Week 32 and 174 mcg/L at Week 52 for patients who were randomized to receive MIMRYLO. The exposure-response relationships of MIMRYLO have not been fully characterized.

Cardiac Electrophysiology
At 1.3 times the geometric mean rusfertide maximum plasma concentration (C_max) achieved with the maximum recommended weekly dose of 108 mg MIMRYLO, clinically significant QTc interval prolongation was not observed.

12.3 Pharmacokinetics

Rusfertide pharmacokinetics were characterized after a single-dose of 9.5 mg to 54 mg in healthy participants. After subcutaneous administration, rusfertide C_max and AUC increased less than dose proportionally over the dose range of 9.5 mg to 54 mg (0.5 to 2.8 times the recommended starting dosage).

Rusfertide pharmacokinetics were predicted in patients with PV using population PK analysis. At the weekly recommended starting dose of 19 mg MIMRYLO, the predicted mean (±SD) rusfertide steady state C_max and AUC were 220 (±76.1) ng/mL and 17,800 (±6140) h·ng/mL, respectively. At the weekly dose of 82 mg MIMRYLO, the predicted mean (±SD) rusfertide steady state C_max and AUC were 751 (±254) ng/mL and 66200 (±23,300) h·ng/mL, respectively. At the maximum recommended weekly dose of 108 mg MIMRYLO, the predicted mean (±SD) rusfertide steady state C_max and AUC were 867 (±297) ng/mL and 105,000 (±36,900) h·ng/mL, respectively.

In healthy participants, steady state concentrations of rusfertide were achieved after approximately 3 once weekly doses. Mean accumulation ratios of rusfertide following once weekly subcutaneous administration of 54 mg were 1.6 and 1.3 for AUC and C_max, respectively.

Absorption
Following subcutaneous administration of 19 mg MIMRYLO in healthy participants, the median (min, max) rusfertide time to peak concentration (T_max) was 24 hours (4, 48 hours). The absolute bioavailability of rusfertide following subcutaneous administration of 19 mg MIMRYLO is approximately 51%.

At steady state, rusfertide exposures were similar following subcutaneous administration of MIMRYLO in the abdomen, thigh, or upper arm.

Distribution
Rusfertide is highly bound to plasma proteins (>99%). The blood-to-plasma ratio is 2.7. Following subcutaneous administration of 19 mg MIMRYLO in healthy participants, the mean (±SD) rusfertide apparent volume of distribution (Vz/F) was 38.4 (±19.1) L.

Elimination
Following subcutaneous administration of 19 mg MIMRYLO in healthy participants, the mean (±SD) rusfertide apparent clearance (CL/F) was 0.930 (±0.233) L/h, and the mean (±SD) rusfertide plasma elimination half-life was 28.6 (±11.3) hours.

Metabolism
Rusfertide is catabolized into smaller peptides via 2 independent pathways. One pathway involves proteolysis by trypsin-like proteases to form metabolite M1, which undergoes further proteolysis to form metabolite M4. Rusfertide also undergoes hydroxylation to form metabolite M9. M1 is a minor metabolite (<1% of total drug-related exposure). M4 and M9 are pharmacologically active but have potencies that are approximately 65% and 14% of the potency of rusfertide, respectively. Following multiple-dose subcutaneous administration of 54 mg MIMRYLO in healthy participants, M4 and M9 account for approximately 15% and 31% of total drug-related exposure, respectively, at steady state.

Excretion
Following subcutaneous administration of MIMRYLO, rusfertide concentrations in the urine were below the detection limit.

Specific Populations
No clinically meaningful differences in the pharmacokinetics of rusfertide were observed based on age (20 to 86 years), race (White, Asian, Other), sex, body weight (44.5 to 151 kg), or mild-to-moderate renal impairment (eGFR 30 to 89 mL/min).

Patients with Renal Impairment
Following subcutaneous administration of 19 mg MIMRYLO, no clinically meaningful difference was observed in rusfertide systemic exposures (AUC) between participants with severe renal impairment (eGFR <30 mL/min) and participants with normal renal function (eGFR ≥90 mL/min).

Patients with Hepatic Impairment
Following subcutaneous administration of 19 mg MIMRYLO, no clinically meaningful difference was observed in rusfertide systemic exposures (AUC) between participants with moderate hepatic impairment (Child-Pugh B) and participants with normal hepatic function. MIMRYLO has not been studied in participants with severe (Child-Pugh C) hepatic impairment.

Drug Interaction Studies
In vitro Studies
Cytochrome P450 (CYP) Enzymes: Rusfertide does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A at clinically relevant concentrations. Rusfertide does not induce CYP1A2, CYP2B6, or CYP3A.

Transporter Systems: Rusfertide is not a substrate of and does not inhibit BCRP, BSEP, MATE1, MATE2K, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, or P-gp.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the study described below with the incidence of anti-drug antibodies in other studies, including those of MIMRYLO.

The incidence of anti-rusfertide antibodies to MIMRYLO using a drug-tolerant enzyme-linked immunosorbent assay (ELISA) method for patients in the VERIFY study, with a median duration of exposure of 61 weeks and ADA samples evaluated up to 108 weeks, was 34% (97 out of 282). Of these 97 patients, 35 (36%) developed neutralizing antibodies (NAb) and 12 (12%) developed antibodies that showed cross-reactivity to human hepcidin. The incidence of NAb may be underreported due to the lack of adequate assay sensitivity. However, all ADA responses were of low magnitude (maximum titer value of 1:1000) with titers progressively decreasing or returning to baseline.

Overall, there was no apparent correlation of anti-rusfertide antibody development on the pharmacokinetics, effectiveness, and safety of MIMRYLO in the VERIFY study.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.