MIMRYLO Solution for injection Ref.[116914] Active ingredients: Rusfertide

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.

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.

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.

VERIFY

The efficacy of MIMRYLO was evaluated in a multicenter, randomized, double-blind, placebo-controlled Phase 3 study in 293 adult patients with PV [NCT05210790]. Eligible patients required at least 3 phlebotomies in the 28 weeks or 5 phlebotomies in 1 year prior to randomization due to inadequate hematocrit control while receiving ongoing standard of care therapy which included phlebotomy alone or phlebotomy plus one or more cytoreductive agents. The mean age at baseline was 57 years (range 27-86 years); 27% of patients were female and73% were male; 262 patients (89.4%) were White, 9 patients (3.1%) were Asian, 2 patients (0.7%) were Black or African American, 2 patients (0.7%) were American Indian or Alaska Native, and 18 patients (6.1%) were of other, not reported, or unknown race; 14 patients (4.8%) were of Hispanic or Latino ethnicity.

At randomization, patients were receiving phlebotomy only (44.7%), phlebotomy + hydroxyurea (38.9%), phlebotomy + ruxolitinib (2.4%), phlebotomy + interferon (13.3%), and phlebotomy + combination of cytoreductive therapies (0.6%). Of all enrolled patients, 53.2% of patients were considered low risk defined as age less than 60 years and no history of previous thrombotic event(s). 46.8% of patients were considered high risk defined as age greater than or equal to 60 years and/or a history of previous thrombotic event(s). At baseline, the mean ± SD hematocrit was 42.4 ± 1.97 for the placebo arm and 42.2 ± 2.21 for the MIMRYLO arm.

Patients were randomized 1:1 to MIMRYLO or placebo from Week 0 to Week 32. The patients that completed 32 weeks of treatment were eligible to receive open-label treatment with MIMRYLO until Week 52 followed by long-term extension treatment with MIMRYLO until week 156. The starting dosage of MIMRYLO was 19 mg subcutaneously once a week. The dose was then titrated to control and maintain hematocrit <45%. During the 32-week randomized controlled period, the median duration of MIMRYLO treatment exposure was 32 weeks, and 91.2% of patients completed through Week 32.

The efficacy of MIMRYLO was based on the proportion of patients achieving a response (defined as absence of phlebotomy eligibility) between Week 20 to Week 32. Phlebotomy eligibility was defined as a confirmed hematocrit greater than or equal to 45% that is at least 3 percentage (absolute) points higher than the hematocrit obtained at baseline or a hematocrit greater than or equal to 48%. Fatigue was measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 8a standardized score, where higher scores indicate greater fatigue.

Efficacy results are presented in Table 5.

Table 5. Efficacy Results of VERIFY Study:

ANCOVA=Analysis of Covariance; CI=confidence interval; HCT=hematocrit; LSM=least-squares means; SE=standard error
^* Responders are defined as patients with absence of phlebotomy eligibility. Phlebotomy eligibility was defined as either (1) A confirmed HCT ≥45% that was at least 3% (absolute) higher than the baseline HCT, where confirmation was defined as 2 consecutive HCT assessments that were ≥45% and at least 3% higher than the baseline HCT, or (2) HCT ≥48%.
^† P-value is obtained from the Cochran-Mantel-Haenszel test stratifying by ongoing standard of care therapy.
^‡ LS Means, 95% CI, and p-value are obtained from ANCOVA model adjusted for pre-treatment number of phlebotomies, treatment, and stratification variable (ongoing standard of care therapy).
^§ A single HCT ≥45% was permitted.
^¶ For the PROMIS T score, week 32 change from baseline is available for 120 patients in the MIMRYLO arm and 115 patients in the placebo arm.
^# LS Means, 95% CI, and p-value are obtained from MMRM model adjusted for baseline, treatment, visit, treatment by visit interaction, baseline by visit interaction, and stratification variable (ongoing standard of care therapy).

The mean change from baseline in hematocrit levels (Week 0 to Week 32) increased in the placebo arm but remained approximately 0 or lower in the MIMRYLO arm. During Week 32 to Week 52, when the patients in the placebo arm were switched to MIMRYLO, the mean change in hematocrit decreased rapidly.