SARCLISA

Isatuximab (formerly SAR650984) is a humanized, IgG1-derived monoclonal antibody (mAb) produced from a Chinese hamster ovary (CHO) cell line. 9, 2 Structurally, isatuximab is comprised of two identical immunoglobulin kappa light chains and two identical immunoglobulin gamma heavy chains.

It is a cytolytic antibody targeted against CD38, a glycoprotein found on the surface of some immune cells that is highly expressed by malignant plasma cells in multiple myeloma.

Along with daratumumab, another anti-CD38 mAb, isatuximab constitutes a novel treatment modality for patients with difficult-to-treat multiple myeloma.

Following three consecutive years on the yearly "Antibodies to watch" list published in "mAb", a peer-reviewed scientific journal dedicated to antibody research, 6, 7, 8 isatuximab was granted Orphan Drug designation and approved on March 2nd, 2020, for the treatment of multiple myeloma. 9, 10 It is.

Isatuximab is indicated for

In combination with pomalidomide and dexamethasone for the treatment of multiple myeloma in adults who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

In combination with carfilzomib and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1-3 prior lines of therapy.

In combination with bortezomib, lenalidomide and dexamethasone, for the treatment of adult patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant.

Isatuximab results in the apoptosis of malignant plasma cells via inhibition of a surface protein key to their survival and proliferation.

It has a relatively long residence time in the body, taking approximately 2 months to clear following the final dose, and may therefore be infused on a weekly or bimonthly schedule.

Isatuximab is given in combination with pomalidomide due to a synergy that exists between the two.

• isatuximab can induce a depletion in host NK lymphocytes, yet the ADCC effect of anti-CD38 mAbs has been shown to be superior in patient samples with a high ratio of NK to myleoma cells.

Pomalidomide, another antineoplastic agent, has the ability to induce and enhance NK lymphocyte activity 1, 5 and thus works synergistically to enhance isatuximab-mediated killing of myeloma cells.

Isatuximab is formulated as an intravenous infusion and its administration may result in infusion-related reactions characterized most commonly by dyspnea, cough, chills, and nausea.

All noted reactions started during the first infusion and 98% resolved on the same day. Reactions may be mitigated by pre-medication with acetaminophen, H2 antagonists, diphenyhdramine, and/or dexamethasone.

Patients with grade 1 or 2 reactions may restart the infusion at a slower rate following resolution of symptoms, but patients experiencing a grade 3 or higher reaction (e.g. hypertension, bronchospasm) should discontinue therapy indefinitely.

Isatuximab can generate false positive results for indirect antglobulin tests (indirect Coombs tests), immunofixation tests, and serum protein electrophoresis.

When administered at the recommended dose and schedule, the steady-state C max and AUC were found to be 351 µg/mL and 72,600 μg∙h/mL, respectively.

It takes approximately 8 weeks for isatuximab to reach steady-state.

Over a dosage range of 1 mg/kg to 20 mg/kg given every 2 weeks AUC increases in a greater than dose-proportional manner, whereas over a dosage range of 5 mg/kg to 20 mg/kg every 4 weeks (followed by every 2 weeks) AUC was found to increase proportionately with dose.

AUC is lower in patients with increased body weight, but not to the extent that dose adjustments are required.

T max ranges from approximately 2-5 hours, increasing with dose and with repeated dosing.

The predicted volume of distribution of isatuximab is 8.13 L.

Isatuximab metabolism is likely to involve catabolism to smaller proteins and peptides.

Total clearance decreases with increasing dose and with multiple dosing.

At steady-state, it takes approximately 2 months to eliminate ≥99% of isatuximab from plasma following the last dose.

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There is no known antidote for isatuximab, nor does there appear to be any clinical experience with overdose.

Symptoms of overdosage are likely to be consistent with isatuximab's adverse effect profile and may therefore include significant infusion-site reactions, gastrointestinal disturbances, and may increase the risk of infection.

Treatment of overdose should involve careful monitoring of the patient and symptomatic and supportive measures as clinically indicated.

is contraindicated in patients with severe hypersensitivity to isatuximab-irfc or to any of its excipients.

Patients with severe hypersensitivity to isatuximab-irfc or to any of its excipients.

Premedicate with dexamethasone, acetaminophen, H2 antagonists, and diphenhydramine.

The recommended dosage of

SARCLISA is 10 mg/kg as an intravenous infusion.

See full prescribing information for

SARCLISA schedules of administration and drugs used in combination. 2.1 Recommended Dosage Administer pre-infusion medications.

SARCLISA should be administered by a healthcare professional, with immediate access to emergency equipment and appropriate medical support to manage infusion-related reactions if they occur.

The recommended dose of

SARCLISA is 10 mg/kg actual body weight administered as an intravenous infusion in combination with pomalidomide and dexamethasone or in combination with carfilzomib and dexamethasone, or in combination with bortezomib, lenalidomide, and dexamethasone.

SARCLISA dosing schedules are provided in

Tables and 2.

Table 1: SARCLISA Dosing Schedule in Combination with Pomalidomide and Dexamethasone or in Combination with Carfilzomib and Dexamethasone Cycles Dosing schedules Cycle 1 (28-day cycle) Days 1, 8, 15, and 22 (weekly) Cycle and beyond (28-day cycles) Days 1, 15 (every 2 weeks) Table 2: SARCLISA Dosing Schedule in Combination with Bortezomib, Lenalidomide, and Dexamethasone Cycles Dosing schedules Cycle 1 (42-day cycle) Days 1, 8, 15, 22, and 29 Cycles to 4 (42-day cycles) Days 1, 15, and 29 (every 2 weeks) Cycles to 17 (28-day cycles) Days and 15 (every 2 weeks) Cycles and beyond (28-day cycles) Day 1 (every 4 weeks) Treatment is repeated until disease progression or unacceptable toxicity.

SARCLISA is used in combination with pomalidomide and dexamethasone or in combination with carfilzomib and dexamethasone or in combination with bortezomib, lenalidomide, and dexamethasone.

For dosing instructions of combination agents administered with SARCLISA, see Clinical Studies and manufacturer's prescribing information.

Missed SARCLISA Doses If a planned dose of SARCLISA is missed, administer the dose as soon as possible and adjust the treatment schedule accordingly, maintaining the treatment interval. 2.2 Recommended Premedications and Antimicrobial Prophylaxis Recommended Premedications Administer the following premedications prior to SARCLISA infusion to reduce the risk and severity of infusion-related reactions: When administered in combination with SARCLISA and pomalidomide: Dexamethasone 40 mg orally or intravenously (or 20 mg orally or intravenously for patients ≥75 years of age).

When administered in combination with SARCLISA and carfilzomib: Dexamethasone 20 mg (intravenously on the days of SARCLISA and/or carfilzomib infusions, orally on day in cycle and beyond, and orally on day in all cycles).

When administered in combination with

SARCLISA, bortezomib, and lenalidomide: Dexamethasone 20 mg (intravenously on the days of SARCLISA infusions, orally on the other days).

Acetaminophen 650 mg to 1,000 mg orally (or equivalent).

H2 antagonist Diphenhydramine 25 mg to 50 mg orally or intravenously (or equivalent).

The intravenous route is preferred for at least the first 4 infusions.

The above recommended dose of dexamethasone (orally or intravenously) corresponds to the dose to be administered before infusion as part of the premedication and part of the backbone treatment.

Administer dexamethasone before

SARCLISA and pomalidomide, before SARCLISA and carfilzomib, and before SARCLISA, bortezomib, and lenalidomide administration.

Administer the recommended premedication agents to 60 minutes prior to starting a SARCLISA infusion.

Initiate antibacterial and antiviral prophylaxis (such as herpes zoster prophylaxis) if needed based on standard guidelines. 2.3 Dosage Modifications No dose reduction of SARCLISA is recommended.

Dose delay may be required to allow recovery of blood counts in the event of hematological toxicity.

For information concerning drugs given in combination with SARCLISA, see manufacturer's prescribing information. 2.4 Preparation Prepare the solution for infusion using aseptic technique as follows: Calculate the dose (mg) of required SARCLISA based on actual patient weight (measured prior to each cycle to have the administered dose adjusted accordingly) .

More than one

SARCLISA vial may be necessary to obtain the required dose for the patient.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Remove the volume of diluent from the 250 mL Sodium Chloride Injection, or 5% Dextrose Injection, diluent bag that is equal to the required volume of SARCLISA injection.

Withdraw the necessary volume of

SARCLISA injection from the vial and dilute by adding to the infusion bag of 0.9% Sodium Chloride Injection, or 5% Dextrose Injection.

Discard any unused portion left in the vial.

The infusion bag must be made of polyolefins (PO), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) with di-(2-ethylhexyl) phthalate (DEHP) or ethyl vinyl acetate (EVA).

Gently homogenize the diluted solution by inverting the bag.

Do not shake. 2.5 Administration Administer the infusion solution by intravenous infusion using an intravenous tubing infusion set (in PE, PVC with or without DEHP, polybutadiene [PBD], or polyurethane [PU]) with a 0.22 micron in-line filter (polyethersulfone [PES], polysulfone, or nylon).

The infusion solution should be administered for a period of time that will depend on the infusion rate.

Use prepared

SARCLISA infusion solution within 48 hours when stored refrigerated at 2°C to 8°C, followed by 8 hours (including the infusion time) at room temperature.

Do not administer

SARCLISA infusion solution concomitantly in the same intravenous line with other agents.

On the days where both

SARCLISA and carfilzomib are administered, administer dexamethasone first, followed by SARCLISA infusion, then followed by carfilzomib infusion.

Following dilution, administer the SARCLISA infusion solution intravenously at the infusion rates presented in Table 3.

Incremental escalation of the infusion rate should be considered only in the absence of infusion-related reactions.

Table 3: Infusion Rates of SARCLISA Administration Dilution Volume Initial Rate Absence of Infusion-Related Reaction Rate Increment Maximum Rate First infusion 250 mL 25 mL/hour For 60 minutes 25 mL/hour every 30 minutes 150 mL/hour Second infusion 250 mL 50 mL/hour For 30 minutes 50 mL/hour for 30 minutes then increase by 100 mL/hour 200 mL/hour Subsequent infusions 250 mL 200 mL/hour – – 200 mL/hour.

SARCLISA (isatuximab-irfc) injection is a clear to slightly opalescent, colorless to slightly yellow solution, essentially free of visible particulates, supplied as follows: One 100 mg/5 mL (20 mg/mL) single-dose vial in a carton: NDC 0024-0654-01 One 500 mg/25 mL (20 mg/mL) single-dose vial in a carton: NDC 0024-0656-01 Storage Store in a refrigerator at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light.

Do not freeze.

Do not shake.

Discard unused portion of solution.

All materials that have been utilized for dilution and administration should be disposed of according to standard procedures.

Store in a refrigerator at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light.

Do not freeze.

Do not shake.

SARCLISA can cause fetal harm when administered to a pregnant woman.

The assessment of isatuximab-irfc-associated risks is based on the mechanism of action and data from target antigen CD38 knockout animal models.

There are no available data on

SARCLISA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

Animal reproduction toxicity studies have not been conducted with isatuximab-irfc.

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, miscarriage, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

The combination of

SARCLISA and pomalidomide or lenalidomide is contraindicated in pregnant women because pomalidomide and lenalidomide may cause birth defects and death of the unborn child.

Refer to the pomalidomide or lenalidomide prescribing information on use during pregnancy.

Pomalidomide and lenalidomide are only available through a REMS program.

Fetal/neonatal reactions Immunoglobulin G1 monoclonal antibodies are known to cross the placenta.

Based on its mechanism of action, SARCLISA may cause depletion of fetal CD38-positive immune cells and decreased bone density.

Defer administration of live vaccines to neonates and infants exposed to SARCLISA in utero until a hematology evaluation is completed.

Data Animal data Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density which recovered 5 months after birth.

Data from studies using

CD38 knockout animal models also suggest the involvement of CD38 in regulating humoral immune responses (mice), feto-maternal immune tolerance (mice), and early embryonic development (frogs).

The safety and effectiveness of

SARCLISA in pediatric patients have not been established.

The safety and efficacy of

SARCLISA in combination with chemotherapy were assessed, but not established, in an open-label study (ACT15378, ISAKIDS, NCT03860844) in 62 pediatric patients aged 1.4 years to < 17 years with relapsed or refractory T-acute lymphoblastic leukemia (T-ALL), B-acute lymphoblastic leukemia (B-ALL), or acute myeloid leukemia (AML).

No new safety signals were observed in pediatric patients in this trial.

Body weight adjusted clearance at steady state and volume of distribution of isatuximab in pediatric patients were within the range of values that were observed in adults.

Of the total number of patients with relapsed or refractory multiple myeloma in clinical studies of SARCLISA, 56% (n=586) were 65 years of age and older, while 16% (n=163) were 75 years of age and older.

No overall differences in safety or effectiveness were observed between patients 65 years of age and older compared to younger patients, and other reported clinical experience has not identified differences in responses between the adults 65 years of age and older and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Of the total number of

SARCLISA-treated patients with newly diagnosed multiple myeloma in IMROZ, 72% (n=319) were less than 75 years of age and 28% (n=125) were 75 years of age and older.

The clinical trial did not enroll patients over age 80.

Adverse reactions occurring at a higher frequency in the SARCLISA arm (≥5%) in patients 75 years of age and older included neutropenia.

Adverse reactions leading to dose modifications in patients 75 years of age and older occurred at a higher frequency (≥5%) in the SARCLISA arm.

The hazard ratio for overall survival (OS) in patients 75 years of age and older was 1.25 [95% CI: 0.68 to 2.3.