Blenrep (Page 4 of 6)

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

The immunogenicity of BLENREP was evaluated using an electrochemiluminescence (ECL)-based immunoassay to test for anti-belantamab mafodotin antibodies. In clinical studies of BLENREP, 2/274 patients (<1%) tested positive for anti-belantamab mafodotin antibodies after treatment. One of the 2 patients tested positive for neutralizing anti-belantamab mafodotin antibodies following 4 weeks on therapy. Due to the limited number of patients with antibodies against belantamab mafodotin-blmf, no conclusions can be drawn concerning a potential effect of immunogenicity on pharmacokinetics, efficacy, or safety.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its mechanism of action, BLENREP can cause fetal harm when administered to a pregnant woman, because it contains a genotoxic compound (the microtubule inhibitor, MMAF) and it targets actively dividing cells [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. Human immunoglobulin G (IgG) is known to cross the placenta; therefore, belantamab mafodotin-blmf has the potential to be transmitted from the mother to the developing fetus. There are no available data on the use of BLENREP in pregnant women to evaluate for drug-associated risk. No animal reproduction studies were conducted with BLENREP. Advise pregnant women of the potential risk to a fetus.

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 outcome. 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.

Data

Animal Data: Animal reproductive or developmental toxicity studies were not conducted with belantamab mafodotin-blmf. The cytotoxic component of BLENREP, MMAF, disrupts microtubule function, is genotoxic, and can be toxic to rapidly dividing cells, suggesting it has the potential to cause embryotoxicity and teratogenicity.

8.2 Lactation

Risk Summary

There is no data on the presence of belantamab mafodotin-blmf in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with BLENREP and for 3 months after the last dose.

8.3 Females and Males of Reproductive Potential

BLENREP can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating BLENREP.

Contraception

Females: Advise women of reproductive potential to use effective contraception during treatment and for 4 months after the last dose.

Males: Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with BLENREP and for 6 months after the last dose [see Nonclinical Toxicology (13.1)].

Infertility

Based on findings in animal studies, BLENREP may impair fertility in females and males. The effects were not reversible in male rats, but were reversible in female rats [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of BLENREP in pediatric patients have not been established.

8.5 Geriatric Use

Of the 218 patients who received BLENREP in DREAMM-2, 43% were aged 65 to less than 75 years and 17% were aged 75 years and older. Clinical studies of BLENREP did not include sufficient numbers of patients aged 65 and older to determine whether the effectiveness differs compared with that of younger patients. Keratopathy occurred in 80% of patients aged less than 65 years and 73% of patients aged 65 years and older. Among the patients who received BLENREP at the 2.5-mg/kg dose in DREAMM-2 (n = 95), keratopathy occurred in 67% of patients aged less than 65 years and 73% of patients aged 65 years and older. Clinical studies did not include sufficient numbers of patients 75 years and older to determine whether they respond differently compared with younger patients.

8.6 Renal Impairment

No dose adjustment is recommended for patients with mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] 30 to 89 mL/min/1.73m2 as estimated by the Modification of Diet in Renal Disease [MDRD] equation) [see Clinical Pharmacology (12.3)].

The recommended dosage has not been established in patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2) or end-stage renal disease (ESRD) with eGFR <15 mL/min/1.73 m2 not on dialysis or requiring dialysis [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤upper limit of normal [ULN] and aspartate aminotransferase (AST) >ULN or total bilirubin 1 to ≤1.5 × ULN and any AST).

The recommended dosage of BLENREP has not been established in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST) [see Clinical Pharmacology (12.3)].

11 DESCRIPTION

Belantamab mafodotin-blmf is a B-cell maturation antigen (BCMA)-directed antibody and microtubule inhibitor conjugate. Belantamab mafodotin-blmf is an antibody conjugate composed of 3 components: 1) afucosylated, humanized immunoglobulin G1 monoclonal antibody covalently linked to 2) the microtubule inhibitor MMAF via 3) a protease-resistant maleimidocaproyl linker.

The antibody is produced in a mammalian cell line (Chinese Hamster Ovary) using recombinant DNA technology and the microtubule inhibitor and linker are produced by chemical synthesis. Approximately 4 molecules of mafodotin are attached to each antibody molecule. The molecular weight of belantamab mafodotin-blmf is approximately 152 kDa. Belantamab mafodotin-blmf has the following structure:

Belantamab mafodotin-blmf chemical structure
(click image for full-size original)

BLENREP (belantamab mafodotin-blmf) for injection is a sterile, preservative-free, white to yellow, lyophilized powder in a single-dose vial for reconstitution and further dilution prior to intravenous use. BLENREP is supplied as 100 mg per vial and requires reconstitution with 2 mL of Sterile Water for Injection, USP, to obtain a concentration of 50 mg/mL. Each mL of reconstituted solution contains belantamab mafodotin-blmf (50 mg) and the inactive ingredients, citric acid (0.42 mg), disodium edetate dihydrate (0.019 mg), polysorbate 80 (0.2 mg), trehalose dihydrate (75.6 mg), and trisodium citrate dihydrate (6.7 mg). The pH of the reconstituted solution is 6.2.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Belantamab mafodotin-blmf is an antibody-drug conjugate (ADC). The antibody component is an afucosylated IgG1 directed against BCMA, a protein expressed on normal B lymphocytes and multiple myeloma cells. The small molecule component is MMAF, a microtubule inhibitor. Upon binding to BCMA, belantamab mafodotin-blmf is internalized followed by release of MMAF via proteolytic cleavage. The released MMAF intracellularly disrupts the microtubule network, leading to cell cycle arrest and apoptosis.

Belantamab mafodotin-blmf had antitumor activity in multiple myeloma cells and mediated killing of tumor cells through MMAF-induced apoptosis, as well as by tumor cell lysis through antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).

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