Regeneron Lynozyfic page 6 of 6 4C (near Multiple Myeleoma) Serious adverse reactions occurred in 74% of patients who received LYNOZYFIC. Serious adverse reactions that occurred in >5% of patients included cytokine release syndrome (27%), pneumonia (13%), COVID-19 (7%), and acute kidney injury (5%). Fatal adverse reactions occurred in 7% of patients, and included sepsis (3.4%), chronic kidney disease (0.9%), pneumonia (0.9%), tumor lysis syndrome (0.9%), and encephalopathy (0.9%). Permanent discontinuation of LYNOZYFIC due to adverse reactions occurred in 16% of patients. Adverse reactions leading to discontinuation that occurred in at least 2 patients included sepsis, pneumonia, and encephalopathy. Dosage interruptions or delays of LYNOZYFIC due to adverse reactions occurred in 74% of patients. Adverse reactions which required a dosage interruption or delay in >10% of patients included neutropenia (29%), upper respiratory tract infection (18%), pneumonia (15%), and COVID-19 infection (11%). The most common adverse reactions (≥20%) were musculoskeletal pain, cytokine release syndrome, cough, upper respiratory tract infection, diarrhea, fatigue, pneumonia, nausea, headache, and dyspnea. The most common Grade 3 to 4 laboratory abnormalities (≥30%) were decreased lymphocyte count, decreased neutrophil count, decreased hemoglobin, and decreased white blood cell count. Table 7 summarizes the adverse reactions in LINKER-MM1. Table 7: Adverse Reactions (≥10%) in Patients With Relapsed or Refractory Multiple Myeloma Who Received LYNOZYFIC in LINKER-MM1 Adverse Reaction LYNOZYFIC (N=117) All Grades (%) Grade 3 or 4 (%) Musculoskeletal and connective tissue disorders Musculoskeletal pain* 53 3.4# Immune system disorders Cytokine release syndrome 46 0.9# Hypogammaglobulinemia 13 0.9# Respiratory, thoracic and mediastinal disorders Cough* 39 0 Dyspnea* 21 0.9# Nasal congestion 16 0 Infections and infestations Upper respiratory tract infection* 35 6# Pneumoniaa± 28 21 COVID-19 17 5 Urinary tract infections* 16 8# Sepsis 10 6 Gastrointestinal disorders Diarrhea 35 1.7# Nausea 23 0 Vomiting 19 0 Constipation 17 0 General disorders and administration site conditions Fatigue* 34 0 Edema* 19 0.9# Pyrexia 17 0 Nervous system disorders Headache* 22 0.9# Encephalopathy±,b 18 3.4 Sensory Neuropathy* 13 0.9 Metabolism and nutrition disorders Decreased appetite 15 0.9# Skin and subcutaneous tissue disorders Rashc 15 1.7# Psychiatric disorders Insomnia 13 0 Vascular disorders Hypertension 10 4.3# * Includes other related terms. # Only Grade 3 adverse reactions occurred. ± Includes fatal outcome. a Pneumonia includes atypical pneumonia, COVID-19 pneumonia, PJP, pneumonia, pneumonia cytomegaloviral, pneumonia fungal, pneumonia influenzal, and pneumonia viral. b Encephalopathy includes agitation, amnesia, cognitive disorder, confusional state, delirium, depressed level of consciousness, encephalopathy (including hyperammonemic and toxic encephalopathy), irritability, lethargy, memory impairment, mental status changes, somnolence, and excludes ICANS. c Rash includes dermatitis acneiform, dermatitis contact, drug eruption, erythema, rash, rash erythematous, rash maculo-papular, rash pruritic, and stasis dermatitis. Clinically significant adverse reactions that occurred in <10% of patients treated with LYNOZYFIC included IRR, motor dysfunction, febrile neutropenia, ICANS, CMV infection, and PML. Table 8: Select Laboratory Abnormalities (≥5% for Grade 3 or 4) That Worsened From Baseline in Patients With Multiple Myeloma Treated With LYNOZYFIC in LINKER-MM1 Laboratory Abnormalitya LYNOZYFIC (N=117)b All Grades (%) Grade 3 or 4 (%) Hematology Lymphocyte count decreased 97 92 Hemoglobin decreased 72 42 Platelet count decreased 64 19 White blood cell count decreased 63 31 Neutrophil count decreased 62 47 Chemistry Aspartate aminotransferase increased 61 10 Table 8: Select Laboratory Abnormalities (≥5% for Grade 3 or 4) That Worsened From Baseline in Patients With Multiple Myeloma Treated With LYNOZYFIC in LINKER-MM1 (continued) Laboratory Abnormalitya LYNOZYFIC (N=117)b All Grades (%) Grade 3 or 4 (%) Phosphorus decreased 55 24 Creatinine increased 47 7 Alanine aminotransferase increased 46 6 a Laboratory tests were graded according to NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) Version 5.0. b The denominator used to calculate the rate varied from 106 to 117 based on the number of patients with a baseline value and at least one post-treatment value. 7 DRUG INTERACTIONS 7.1 Effects of LYNOZYFIC on Other Drugs Certain CYP substrates Monitor for toxicity unless otherwise recommended in the Prescribing Information of certain CYP substrates where minimal changes in the concentration may lead to serious adverse reactions when used concomitantly with LYNOZYFIC. Linvoseltamab-gcpt causes the release of cytokines [see Clinical Pharmacology (12.2)] that may suppress cytochrome P450 (CYP) enzyme activity. Concomitant use with LYNOZYFIC increases CYP substrate exposure which may increase the risk of adverse reactions related to these substrates. Increased CYP substrate exposure is more likely to occur from initiation of the LYNOZYFIC step-up dosing schedule up to 14 days after the first 200 mg dose, and during and after CRS [see Warnings and Precautions (5.1)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on the mechanism of action, LYNOZYFIC may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of LYNOZYFIC in pregnant women to evaluate for a drug associated risk. No animal reproductive or developmental toxicity studies have been conducted with LYNOZYFIC. Linvoseltamab-gcpt causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. In addition, based on the finding of B-cell depletion in non-pregnant animals, linvoseltamab-gcpt can cause B-cell lymphocytopenia in infants exposed to linvoseltamab-gcpt in-utero. Human immunoglobulin (IgG) is known to cross the placenta after the first trimester of pregnancy; therefore, linvoseltamab-gcpt has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus. LYNOZYFIC is associated with hypogammaglobulinemia, therefore, assessment of immunoglobulin levels in newborns of mothers treated with LYNOZYFIC should be considered. 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. 8.2 Lactation Risk Summary There are no data on the presence of linvoseltamab-gcpt in human milk, the effects on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with LYNOZYFIC and for 3 months after the last dose. 8.3 Females and Males of Reproductive Potential LYNOZYFIC may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating treatment with LYNOZYFIC. Contraception Females Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of LYNOZYFIC. 8.4 Pediatric Use The safety and effectiveness of LYNOZYFIC have not been established in pediatric patients. 8.5 Geriatric Use Of the 117 patients with relapsed or refractory multiple myeloma who received LYNOZYFIC, 42 (36%) of patients were 65 to 74 years of age and 31 (26%) were 75 years of age and older [see Clinical Studies (14)]. No overall differences in safety or effectiveness were observed in patients 65 years of age and older, including patients 75 years of age and older, when compared with younger patients. 12 CLINICAL PHARMACOLOGY 12.6 Immunogenicity The observed incidence of anti-drug antibodies 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 linvoseltamab-gcpt. During treatment in LINKER-MM1 (evaluated through 30 months) [see Clinical Studies (14)], 1% (2/192) of LYNOZYFIC-treated patients developed anti-linvoseltamab-gcpt antibodies. Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of linvoseltamab products is unknown. Regeneron Pharmaceuticals, Inc. (Tarrytown, NY 10591) ©2025 Regeneron Pharmaceuticals, Inc. All rights reserved. US.LYN.25.05.0004 07/25
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