Nipocalimab

IMAAVY is a neonatal Fc receptor blocker indicated for the treatment of: generalized myasthenia gravis (gMG) in adult and pediatric patients 12 years of age and older who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive. ( 1.1 ) warm autoimmune hemolytic anemia (wAIHA) in adult and pediatric patients 12 years of age and older currently or previously treated with corticosteroids. ( 1.2 )

1.1 Generalized Myasthenia Gravis (gMG) IMAAVY is indicated for the treatment of generalized myasthenia gravis (gMG) in adult and pediatric patients 12 years of age and older who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive.

1.2 Warm Autoimmune Hemolytic Anemia (wAIHA) IMAAVY is indicated for the treatment of warm autoimmune hemolytic anemia (wAIHA) in adult and pediatric patients 12 years of age and older currently or previously treated with corticosteroids.

Injection: colorless to slightly brownish, clear to slightly opalescent solution available as: 300 mg/1.62 mL (185 mg/mL) in a single-dose vial 1,200 mg/6.5 mL (185 mg/mL) in a single-dose vial Injection: 300 mg/1.62 mL (185 mg/mL) in a single-dose vial ( 3 ) Injection: 1,200 mg/6.5 mL (185 mg/mL) in a single-dose vial ( 3 )

IMAAVY is contraindicated in patients with a history of serious hypersensitivity reaction to nipocalimab-aahu or any of the excipients in IMAAVY. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions (5.2) ] . IMAAVY is contraindicated in patients with a history of serious hypersensitivity reaction to nipocalimab-aahu or to any of the excipients in IMAAVY. ( 4 )

Infections: Delay administration of IMAAVY to patients with an active infection. Monitor for signs and symptoms of infection in patients treated with IMAAVY. If serious infection occurs, administer appropriate treatment and consider withholding IMAAVY until the infection has resolved. ( 5.1 ) Hypersensitivity Reactions: Angioedema, anaphylaxis, rash, urticaria, and eczema have occurred in patients treated with IMAAVY. If a hypersensitivity reaction occurs, discontinue the infusion and institute appropriate therapy. ( 5.2 ) Infusion-Related Reactions: If a severe infusion-related reaction occurs, discontinue the infusion and initiate appropriate therapy; consider the risks and benefits of readministering. If a mild to moderate infusion-related reaction occurs, may rechallenge with close clinical observation, slower infusion rates, and pre-medication. ( 5.3 )

5.1 Infections IMAAVY may increase the risk of infection [see Adverse Reactions (6.1) ] . In gMG Study 1 [see Clinical Studies (14.1) ] , 42 (43%) out of 98 patients treated with IMAAVY reported 71 events of infection. Across gMG Study 1 (double-blind period) and its extension study (open label-period), out of 186 patients treated with IMAAVY, 132 (71%) patients reported 360 events of infection and serious infections were reported in 7% of patients treated with IMAAVY. In the wAIHA Study (double-blind period), 35 (45%) out of 78 patients treated with IMAAVY reported 52 events of infection [see Clinical Studies (14.2) ] . Across the wAIHA Study (double-blind period) and its extension study (open label-period), out of 113 patients treated with IMAAVY, 80 (71%) patients reported 184 events of infection and serious infections were reported in 12% of patients treated with IMAAVY. Delay IMAAVY administration in patients with an active infection until the infection is resolved. During treatment with IMAAVY, monitor for clinical signs and symptoms of infection. If serious infection occurs, administer appropriate treatment and consider withholding IMAAVY until the infection has resolved. Latent Viral Infections Patients treated with IMAAVY may be at an increased risk of activation of latent viral infections, such as herpes zoster [see Adverse Reactions (6.1) ] . In the extension period of gMG Study 1, there were 2 patients with serious adverse reactions related to Epstein-Barr virus (EBV) infection, and 1 of these patients had fatal complications. Patients who screened positive for hepatitis were excluded from gMG Study 1. Follow standard vaccination guidelines [see Dosage and Administration (2.1) ]. Immunization The safety of immunization with live vaccines and the immune response to vaccination during treatment with IMAAVY are unknown. Because IMAAVY causes a reduction in IgG levels, vaccination with live vaccines is not recommended during treatment with IMAAVY. Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of treatment with IMAAVY.

5.2 Hypersensitivity Reactions In clinical trials, hypersensitivity reactions, including angioedema, anaphylaxis, rash, urticaria, and eczema were observed in patients treated with IMAAVY. In gMG Study 1 and the wAIHA Study, hypersensitivity reactions were mild or moderate. In gMG Study 1, all hypersensitivity reactions occurred within one hour to 2 weeks of administration. In the wAIHA Study, 76% of hypersensitivity reactions occurred within 2 weeks of administration [see Adverse Reactions (6.1) ] . In gMG Study 1, one patient experienced a hypersensitivity reaction (urticaria) that led to treatment discontinuation. Management of hypersensitivity reactions depends on the type and severity of the reaction. Monitor the patient during treatment with IMAAVY and for 30 minutes after the administration is complete for clinical signs and symptoms of hypersensitivity reactions [see Dosage and Administration (2.5) ] . If a hypersensitivity reaction occurs during administration, discontinue IMAAVY infusion and institute appropriate supportive measures if needed. IMAAVY is contraindicated in patients with a history of serious hypersensitivity to nipocalimab-aahu or any of the excipients of IMAAVY [see Contraindications (4) ] .

5.3 Infusion-Related Reactions In clinical trials, infusion-related reactions, including headache, influenza-like illness, rash, nausea, fatigue, dizziness, chills, and erythema were observed in patients treated with IMAAVY. In gMG Study 1 and the wAIHA Study, infusion-related reactions were mild to moderate in severity. In gMG Study 1, all infusion-related reactions occurred within one hour to 2 days of administration. In the wAIHA Study, 89% of infusion-related reactions occurred within 2 days of administration [see Adverse Reactions (6.1) ] . Monitor patients during treatment with IMAAVY and for 30 minutes after each infusion [see Dosage and Administration (2.5) ] . If a severe infusion-related reaction occurs, discontinue IMAAVY infusion and initiate appropriate therapy. Consider the risks and benefits of readministering IMAAVY following a severe infusion-related reaction. If a mild to moderate infusion-related reaction occurs, patients may be rechallenged with close clinical observation, slower infusion rates, and pre-medication.

The following clinically significant adverse reactions are described elsewhere in the labeling Infections [see Warnings and Precautions (5.1) ] Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] Infusion-related Reactions [see Warnings and Precautions (5.3) ] The most common adverse reactions (≥10%) in patients with gMG treated with IMAAVY were respiratory tract infections, peripheral edema, and muscle spasms. ( 6.1 ) The most common adverse reactions (≥10%) in patients with wAIHA treated with IMAAVY were peripheral edema, diarrhea and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults with gMG In gMG Study 1 and its extension study, the safety of IMAAVY was evaluated in 186 patients with gMG who received at least one dose of IMAAVY. Of those patients, 168 patients were exposed to IMAAVY every 2 weeks for at least 6 months, and 140 patients were exposed for at least 12 months. In gMG Study 1, 98 adult patients with gMG received IMAAVY 15 mg/kg every two weeks (after 30 mg/kg initial dose) [see Clinical Studies (14.1) ]. Of these 98 patients, approximately 67% were female, 67% were White, 29% were Asian, and 10% were of Hispanic or Latino ethnicity. The mean age at study entry was 53 years (range 20 to 81). Adverse reactions reported in gMG Study 1 in at least 5% of patients treated with IMAAVY and more frequently than placebo, are summarized in Table 3. The most common adverse reactions (reported in at least 10% of patients treated with IMAAVY) were respiratory tract infection, peripheral edema, and muscle spasms. Table 3: Adverse Reactions (≥ 5%) of Patients Treated with IMAAVY and More Frequently than in Placebo in gMG Study 1 Adverse Reaction IMAAVY N=98 % Placebo N=98 % Includes the following reported in patients treated with IMAAVY: Infection Respiratory tract infection COVID-19 (and other related terms), pneumonia, bronchitis, pneumonia bacteria 18 13 Urinary tract infection other related terms 6 3 Herpes zoster and Herpes simplex 6 2 Oral infection glossitis, oral candidiasis, pericoronitis, pulpitis dental, tooth abscess, tooth infection 5 3 Peripheral edema 12 2 Muscle spasm 12 3 Hypersensitivity reaction angioedema, dermatitis atopic, eczema, gingival swelling, rash (and other related terms), urticaria 8 7 Abdominal pain 8 3 Back pain 8 5 Pyrexia 7 1 Diarrhea 7 3 Cough 7 3 Anemia 6 4 Dizziness 5 1 Nausea 5 2 Hypertension 5 2 Insomnia 5 2 Infections In gMG Study 1 and its extension study, infections that occurred in patients treated with IMAAVY (n=186) included upper respiratory tract infection (46%), respiratory tract infection (28%; including pneumonia, bronchitis, COVID-19), urinary tract infection (15%), herpes (8%; including herpes simplex, herpes zoster, herpes zoster oticus), influenza (8%), oral infection (8%; including candidiasis and dental infections), and skin infection (7%; including cellulitis). Two (1%) cases of infections (cellulitis and urinary tract infection) led to discontinuation of IMAAVY [see Warnings and Precautions (5.1) ] . Hypersensitivity Reactions In gMG Study 1 and its extension study, out of 186 patients treated with IMAAVY, 30 (16%) patients experienced hypersensitivity reactions, which occurred within one hour to two weeks of administration. One patient experienced hypersensitivity reaction (urticaria) that required discontinuation of IMAAVY [see Warnings and Precautions (5.2) ] . Infusion-Related Reactions In gMG Study 1 and its extension study, out of 186 patients treated with IMAAVY, 20 (11%) patients experienced infusion-related reactions, which occurred within one hour to 2 days of administration. No patients experienced infusion-related reaction that required discontinuation of IMAAVY [see Warnings and Precautions (5.3) ] . Laboratory Findings Lipids In gMG Study 1 (N=98), patients treated with IMAAVY had elevations from normal to high of fasting total cholesterol ( ≥ 240 mg/dL) and LDL cholesterol ( ≥ 160 mg/dL) (24% and 11% of patients, respectively). In gMG Study 1, these changes from baseline peaked at Week 4, then decreased and plateaued by Week 24 to mean increases of 14 mg/dL and 7 mg/dL, respectively. Five percent of patients treated with IMAAVY had decreases from normal to low of fasting HDL cholesterol (<40 mg/dL). Pediatric Patients 12 Years of Age and Older with gMG In a 24-week, single arm study (gMG Study 2), evaluating the safety of IMAAVY in 7 pediatric patients age 12 to 16 years with gMG who were AChR positive, adverse reactions were consistent with those observed in adult patients with gMG [see Use in Specific Populations (8.4) ] . Adults with wAIHA The safety of IMAAVY in patients with wAIHA was evaluated in 113 adult patients with wAIHA who received at least one dose of IMAAVY. Of these patients, 84 patients received IMAAVY for at least 6 months, and 49 patients received IMAAVY for at least 12 months. The median duration of treatment was 44 weeks. In the double-blind phase of the wAIHA Study, 78 patients received IMAAVY across the dose regimens evaluated in the study [see Clinical Studies (14.2) ]. Adverse reactions that occurred in the wAIHA Study in at least 5% of patients treated with IMAAVY are summarized in Table 4. The most common adverse reactions (reported in at least 10% of patients treated with IMAAVY) were peripheral edema, diarrhea, and pyrexia. Table 4: Adverse Reactions (≥ 5%) of Patients Treated with IMAAVY and More Frequently than in Placebo in the wAIHA Study Adverse Reaction IMAAVY N=78 % Placebo N=39 % Peripheral edema Includes Edema peripheral, Edema and Generalized edema. 12

2.6 Diarrhea 12 8 Pyrexia 10

2.6 Dizziness 9 8 Infection Urinary tract infection Includes Urinary tract infection, Pyelonephritis and Urinary tract infection bacterial. 9 5 Headache 6 5 Additional Clinically Relevant Adverse Reactions occurring in ≤5% of patients Pneumonia (5% with IMAAVY; 5% with placebo) Nausea (3.8% with IMAAVY; 2.6% with placebo) Insomnia (1.3% with IMAAVY; 0% with placebo) Infections In the wAIHA Study and its extension study, infections that occurred in patients treated with IMAAVY (n=113) included upper respiratory tract infection (34%), respiratory tract infection (33%), urinary tract infection (12%), gastroenteritis (5%). Three (2.7%) cases of infections (pneumonia, salmonella sepsis and spontaneous bacterial peritonitis) led to discontinuation of IMAAVY [see Warnings and Precautions (5.1) ] . Hypersensitivity Reactions In the wAIHA Study and its extension study, out of 113 patients treated with IMAAVY, 9 (8%) patients experienced hypersensitivity reactions [see Warnings and Precautions (5.2) ] . Infusion-Related Reactions In the wAIHA Study and its extension study, out of 113 patients treated with IMAAVY, 12 (11%) patients experienced infusion-related reactions. One patient in the wAIHA Study discontinued IMAAVY due to an infusion-related reaction (back pain) [see Warnings and Precautions (5.3) ] . Laboratory Findings Lipids In the double-blind phase of the wAIHA Study (N=78), 2.3% of patients treated with IMAAVY had elevations from normal to high of fasting total cholesterol ( ≥ 240 mg/dL) and LDL cholesterol remained <160 mg/dL for all patients at Week 24. These changes from baseline peaked between Week 4 and Week 12, then decreased and plateaued by Week 24 to mean increases in fasting total cholesterol of 6 mg/dL and fasting LDL of 4.2 mg/dL. Of the patients treated with IMAAVY, 12% had fasting HDL cholesterol of <40 mg/dL.

Closely monitor for reduced effectiveness of medications that bind to the human neonatal Fc receptor. When concomitant long-term use of such medications is essential for patient care, consider discontinuing IMAAVY and using alternative therapies. ( 7.1 )

7.1 Effect of IMAAVY on Other Drugs Concomitant use of IMAAVY with medications that bind to the human neonatal Fc receptor (FcRn) (e.g., immunoglobulin products, monoclonal antibodies, or antibody derivates containing the human Fc domain of the IgG subclass) may lower systemic exposures and reduce effectiveness of such medications. Closely monitor for reduced effectiveness of medications that bind to the human neonatal Fc receptor. When concomitant long-term use of such medications is essential for patient care, consider discontinuing IMAAVY, and using alternative therapies [see Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary There are limited data on the use of IMAAVY in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There was no evidence of direct adverse effects on fetal development following administration of nipocalimab-aahu to pregnant monkeys; however, adverse effects on the placenta were associated with fetal loss at both doses tested (see Data ) . The 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 outcomes. In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There is a pregnancy safety study for IMAAVY. If IMAAVY is administered during pregnancy, or if a patient becomes pregnant while receiving IMAAVY, healthcare providers should report IMAAVY exposure by contacting Janssen at 1-800-526-7736 or www.IMAAVY.com Clinical Considerations Fetal/Neonatal Adverse Reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Because IMAAVY reduces maternal serum IgG concentration and impedes placental IgG transfer to the fetus, passive immunity in the infant may be reduced for 6 months or more; therefore: Monitor for the development of serious infection. Effectiveness of vaccines may be reduced. Consider the risks and benefits prior to administering live vaccines to infants exposed to IMAAVY in utero . Data Animal Data Intravenous administration of nipocalimab-aahu (0, 100, or 300 mg/kg) to pregnant monkeys weekly from the end of organogenesis (gestation day 45) through parturition resulted in placental ischemia, associated with fetal loss and decreased levels of immunoglobulin (IgG) in the offspring at both doses tested. IgG levels in offspring returned to normal levels and no adverse effects on immune function were evident by 6 months after birth. Mean systemic exposures achieved at the doses tested were 5- and 24-times the population PK model simulated mean steady state exposure at the recommended human maintenance dose for gMG (15 mg/kg) and 5.5- and 28-times the population PK model simulated mean steady state exposure at the recommended human maintenance dose for wAIHA (30 mg/kg) on an AUC basis.

8.2 Lactation Risk Summary Nipocalimab-aahu is excreted in human colostrum and breastmilk based on limited data from an investigational study of 13 pregnant women administered nipocalimab-aahu during pregnancy where colostrum and breastmilk was assessed in the first 8 days after birth. There are insufficient data on the effect of IMAAVY in the breastfed infant. There are no data on the effect of nipocalimab-aahu on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for IMAAVY, and any potential adverse effects on the breastfed infant from IMAAVY, or from the underlying maternal condition.

8.4 Pediatric Use gMG The safety and effectiveness of IMAAVY for the treatment of gMG have been established in pediatric patients 12 years of age and older. Use of IMAAVY in pediatric patients for this indication is supported by evidence from an adequate and well-controlled trial in adults with additional pharmacokinetic and safety data in pediatric patients who are 12 years of age and older [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ] . Safety and effectiveness of IMAAVY for the treatment of gMG in pediatric patients below the age of 12 years have not been established. wAIHA The safety and effectiveness of IMAAVY for the treatment of wAIHA have been established in pediatric patients 12 years of age and older currently or previously treated with corticosteroids. Use of IMAAVY in pediatric patients for the treatment of wAIHA is supported by evidence from an adequate and well-controlled trial in adults with additional pharmacokinetic data in pediatric patients who are 12 years of age and older [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.2) ] . Safety and effectiveness of IMAAVY for the treatment of wAIHA in pediatric patients below the age of 12 years have not been established .

8.5 Geriatric Use There were 86 patients 65 years of age and older in the clinical studies for gMG (n=37) and wAIHA (n=49) [see Clinical Studies (14) ] . Of the total number of IMAAVY-treated patients in gMG, 12 were 65 to 74 years of age and 6 were 75 to 84 years of age. Of the total number of IMAAVY-treated patients in wAIHA, 19 were 65 to 74 years of age and 12 were 75 to 84 years of age. Clinical studies of IMAAVY did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger adult patients.

Nipocalimab-aahu is a human IgG1 monoclonal antibody that binds to neonatal Fc receptor (FcRn), resulting in the reduction of circulating IgG levels.