FDA Approves SARCLISA (isatuximab-irfc) for the Treatment of Adult Patients with Multiple Myeloma

On March 2, 2020 the U.S. Food and Drug Administration (FDA) approved SARCLISA (isatuximab-irfc) for the treatment of adult patients with multiple myeloma (MM) in combination with pomalidomide and dexamethasone, who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. The approved recommended dosage of SARCLISA is 10 mg/kg actual body weight as an intravenous infusion every week for 4 weeks followed by every 2 weeks in combination with pomalidomide and dexamethasone until disease progression or unacceptable toxicity. Patients should receive premedications prior to SARCLISA infusion to reduce the risk and severity of infusion-related reactions. No dose reduction of SARCLISA is recommended. Dose delay may be required to allow recovery of blood counts in the event of hematological toxicity.

SARCLISA is contraindicated in patients with severe hypersensitivity to isatuximab-irfc or to any of its excipients. Additional information regarding dosage and administration, including recommended premedications and infusion rates for SARCLISA administration, as well as important warnings and precautions related to infusion-related reactions, neutropenia, second primary malignancies, laboratory test interference, and embryo-fetal toxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)

• MOA: Isatuximab-irfc is a CD38-directed cytolytic antibody.

   

• General PK: Following the administration of isatuximab-irfc at the recommended dose and schedule, the steady state isatuximab-irfc mean (CV%) predicted maximum plasma concentration (C_max) was 351 µg/mL (36.0%) and area under the plasma concentration-time curve (AUC) was 72,600 µg∙h/mL (51.7%). The median time to reach steady state of isatuximab-irfc was 8 weeks with a 3.1-fold accumulation.

   

• Dose-Proportionality: Isatuximab-irfc AUC increases in a greater than dose proportional manner over a dosage range from 1 mg/kg to 20 mg/kg (0.1 to 2 times the approved recommended dosage) every 2 weeks. Isatuximab-irfc AUC increases proportionally over a dosage range from 5 mg/kg to 20 mg/kg (0.5 to 2 times the approved recommended dosage) every week for 4 weeks followed by every 2 weeks.

   

• Distribution: The mean (CV%) predicted total volume of distribution of isatuximab-irfc is of 8.13 L (26.2%).

   

• Elimination: Isatuximab-irfc total clearance decreased with increasing dose and with multiple doses. At steady state, ≥99% elimination of isatuximab-irfc from plasma after the last dose is predicted to occur in approximately 2 months. The elimination of isatuximab-irfc was similar when given as a single agent or as combination therapy.

   

• Metabolism: Isatuximab-irfc is expected to be metabolized into small peptides by catabolic pathways.

   

• PD: In MM patients treated with SARCLISA combined with pomalidomide and dexamethasone, a decrease in absolute counts of total NK cells (including inflammatory CD16^+ low CD56^{+ bright} and cytotoxic CD16^{+ bright} CD56^{+ dim} NK cells) and CD19⁺ B cells was observed in peripheral blood. Additionally, a relationship between isatuximab-irfc exposure and overall response rate and progression-free survival was observed.

   

• Immunogenicity: In a randomized, open-label clinical trial in patients with previously treated MM, no patients tested positive for antidrug antibodies (ADA). Therefore, the neutralizing ADA status was not determined. Overall, across 6 clinical studies in MM with SARCLISA single agent and combination therapies (N=564), the incidence of treatment emergent ADAs was 2.3%. No clinically significant differences in the pharmacokinetics, safety, or efficacy of isatuximab-irfc were observed in patients with ADAs.

Drug Interactions

• Interference with Serological Testing: Before the first SARCLISA infusion, conduct blood type and screen tests on SARCLISA-treated patients. Consider phenotyping prior to starting SARCLISA treatment. SARCLISA may interfere with blood bank serologic tests with false positive reactions in indirect antiglobulin tests (indirect Coombs tests), antibody detection (screening) tests, antibody identification panels, and antihuman globulin crossmatches in patients treated with SARCLISA. Additional information on the serological test interference can be found under Warnings and Precautions in the full prescribing information linked below.
• Interference with Serum Protein Electrophoresis and Immunofixation Tests: SARCLISA may be incidentally detected by serum protein electrophoresis and immunofixation assays used for the monitoring of M-protein and may interfere with accurate response classification based on International Myeloma Working Group (IMWG) criteria.

Use in Specific Populations

Isatuximab-irfc exposure (AUC) at steady state decreases with increasing body weight. The following factors have no clinically meaningful effect on the exposure of isatuximab-irfc: age (36 to 85 years, 70 patients were >75 years old), sex, race (Caucasian, Black, Asian), renal impairment (eGFR<90 mL/min/1.73 m²), and mild hepatic impairment (total bilirubin 1 to 1.5 times upper limit of normal [ULN] or aspartate amino transferase [AST] > ULN). The effect of moderate (total bilirubin >1.5 times to 3 times ULN and any AST) and severe (total bilirubin >3 times ULN and any AST) hepatic impairment on isatuximab-irfc pharmacokinetics is unknown.

No dose adjustments are recommended in these specific patient populations.

Efficacy and Safety

Efficacy and safety of SARCLISA in combination with pomalidomide and low-dose dexamethasone was demonstrated in a multicenter, multinational, randomized, open-label, 2-arm, phase 3 study in patients with relapsed and refractory MM. Patients had received at least two prior therapies including lenalidomide and a proteasome inhibitor. The efficacy of SARCLISA was based upon progression-free survival. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions (in ≥20% of patients) were neutropenia, infusion-related reactions, pneumonia, upper respiratory tract infection, and diarrhea. The most common hematology laboratory abnormalities (in ≥80% of patients) were anemia, neutropenia, lymphopenia, and thrombocytopenia.

Full prescribing information is available at https://go.usa.gov/xdfYv.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.