Sutimlimab-Jome

1 INDICATIONS AND USAGE ENJAYMO is a classical complement inhibitor indicated for the treatment of hemolysis in adults with cold agglutinin disease (CAD). ( 1 ) Cold Agglutinin Disease ENJAYMO (sutimlimab-jome) is indicated for the treatment of hemolysis in adults with cold agglutinin disease (CAD).

2 DOSAGE AND ADMINISTRATION Vaccinate against encapsulated bacteria at least two weeks prior to treatment. ( 2.1 ) Weight-based dosage weekly for two weeks then every two weeks: For patients weighing 39 kg to less than 75 kg: 6,500 mg by intravenous infusion. ( 2.2 ) For patients weighing 75 kg or more: 7,500 mg by intravenous infusion. ( 2.2 ) See Full Prescribing Information for important preparation and administration instructions. ( 2.2 , 2.3 ) 2.1 Recommended Vaccinations for Encapsulated Bacterial Infections Vaccinate patients against encapsulated bacteria, including Streptococcus pneumoniae and Neisseria meningitidis (serogroups A, C, W, Y and B), according to current Advisory Committee on Immunization Practices (ACIP) recommendations at least 2 weeks prior to initiation of ENJAYMO [see Warnings and Precautions (5.1) ]. If urgent ENJAYMO therapy is indicated in a patient who is not up to date with vaccines for Streptococcus pneumoniae and Neisseria meningitidis administer these vaccines as soon as possible. 2.2 Recommended Dosage Regimen The recommended dosage of ENJAYMO for patients with CAD is based on body weight. For patients weighing 39 kg to less than 75 kg, the recommended dose is 6,500 mg and for patients weighing 75 kg or more, the recommended dose is 7,500 mg. Administer ENJAYMO intravenously weekly for the first two weeks, with administration every two weeks thereafter. Administer ENJAYMO at the recommended dosage regimen time points, or within two days of these time points. If a dose is missed, administer as soon as possible; thereafter, resume dosing every two weeks. If the duration after the last dose exceeds 17 days, administer ENJAYMO weekly for two weeks, with administration every two weeks thereafter. 2.3 Preparation and Administration ENJAYMO is for intravenous infusion only. Each vial of ENJAYMO is intended for single dose only. ENJAYMO can either be used as an undiluted or diluted preparation. Undiluted preparation of ENJAYMO Use aseptic technique to prepare ENJAYMO as follows: Remove ENJAYMO from the refrigerator. To minimize foaming, do not shake ENJAYMO. Inspect vials visually for particulate matter and discoloration prior to administration. ENJAYMO solution is a clear to slightly opalescent and colorless to slightly yellow liquid. Do not administer if discolored or if other foreign particulate matter is present. Withdraw the calculated volume of ENJAYMO from the appropriate number of vials based on the recommended dosage (see Table 1 ) and add to an empty infusion bag. Prior to administration, allow the infusion solution to adjust to room temperature (59°F to 77°F (15°C to 25°C). Refer to Table 1 for infusion rate. The infusion should be administered over 1 hour. Administer ENJAYMO infusion solution only through a 0.2 micron in-line filter with a polyethersulfone (PES) membrane. The infusion catheter and tubing should be primed with the dosing solution immediately before infusion and flushed immediately following completion of the infusion with a sufficient quantity (approximately 20 mL) of sterile 0.9% Sodium Chloride Injection, USP. If the ENJAYMO infusion solution is not used immediately, store refrigerated at 36°F to 46°F (2°C to 8°C). Once removed from refrigeration, allow the ENJAYMO infusion solution to adjust to room temperature 59°F to 77°F (15°C to 25°C) and administer within 8 hours. Total time from the time of preparation, including refrigeration, adjustment to room temperature and the expected infusion time should not exceed 36 hours. In-line infusion warmers may be used, do not exceed a temperature of 104°F (40°C). No incompatibilities have been observed between ENJAYMO infusion solution and infusion bags made of Di-(2-ethylhexyl)phthalate (DEHP) plasticized polyvinyl chloride (PVC), Ethyl Vinyl Acetate (EVA) and polyolefin (PO); administration sets made of DEHP-plasticized PVC, DEHP-free polypropylene (PP) and polyethylene (PE); and vial adapters made of polycarbonate (PC) and acrylonitrile-butadiene-styrene (ABS). Table 1: Infusion Reference Table for ENJAYMO (undiluted) Body Weight Range Dose Number of ENJAYMO Vials Needed ENJAYMO Volume Maximum Infusion Rate Greater than or equal to 39 kg to less than 75 kg 6,500 mg 6 130 mL 130 mL/hour Patients with cardiopulmonary disease may receive the infusion over 120 minutes. 75 kg or greater 7,500 mg 7 150 mL 150 mL/hour Diluted preparation of ENJAYMO Use aseptic technique to prepare ENJAYMO as follows: Remove ENJAYMO from the refrigerator. To minimize foaming, do not shake ENJAYMO. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ENJAYMO solution is a clear to slightly opalescent and colorless to slightly yellow solution. Do not administer if discolored or if foreign particulate matter is present. Withdraw the calculated volume of ENJAYMO from the appropriate number of vials based on the recommended dosage (see Table 1 ). Dilute the calculated volume with 0.9% Sodium Chloride Injection, USP to a total volume of 500 mL. Refer to Table 2 for infusion rate. Administer the infusion over 1 to 2 hours depending on the patient's body weight. Administer ENJAYMO infusion solution only through a 0.2 micron in-line filter with a polyethersulfone (PES) membrane. Prime the infusion tubing with the dosing solution immediately before infusion and flush immediately following completion of the infusion with a sufficient quantity (approximately 20 mL) of 0.9% Sodium Chloride Injection, USP. If the ENJAYMO infusion solution is not used immediately, store refrigerated at 36°F to 46°F (2°C to 8°C). Once removed from refrigeration, allow the ENJAYMO infusion solution to adjust to room temperature 59°F to 77°F (15°C to 25°C) and administer within 8 hours. Total time from the time of preparation, including refrigeration, adjustment to room temperature and the expected infusion time should not exceed 36 hours. In-line infusion warmers may be used; do not exceed a temperature of 104°F (40°C). No incompatibilities have been observed between ENJAYMO infusion solution and infusion bags made of Di-(2-ethylhexyl)phthalate (DEHP) plasticized polyvinyl chloride (PVC), Ethyl Vinyl Acetate (EVA) and polyolefin (PO); administration sets made of DEHP-plasticized PVC, DEHP-free polypropylene (PP) and polyethylene (PE); and vial adapters made of polycarbonate (PC) and acrylonitrile-butadiene-styrene (ABS). Table 2: Infusion Reference Table for ENJAYMO (diluted in 0.9% Sodium Chloride Injection, USP) Body Weight Range Dose Number of ENJAYMO Vials Needed ENJAYMO Volume Volume of NaCl Diluent Total Volume Maximum Infusion Rate 39 kg to less than 70 kg 6,500 mg 6 130 mL 370 mL 500 mL 250 mL/hour 70 kg to less than 75 kg 6,500 mg 6 130 mL 370 mL 500 mL 500 mL/hour Patients with cardiopulmonary disease may receive the infusion over 120 minutes. 75 kg or greater 7,500 mg 7 150 mL 350 mL 500 mL 500 mL/hour Slow or stop the infusion in case of infusion reaction during ENJAYMO administration. Monitor the patient for at least two hours following completion of the initial infusion for signs or symptoms of an infusion and/or hypersensitivity reaction. Monitor the patient for one hour following completion of subsequent infusions for signs or symptoms of an infusion reaction.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Serious Infections [see Warnings and Precautions (5.1) ] Infusion-Related Reactions [see Warnings and Precautions (5.2) ] Risk of Autoimmune Disease [see Warnings and Precautions (5.3) ] Recurrent Hemolysis After ENJAYMO Discontinuation [see Warnings and Precautions (5.4) ] Most common adverse reactions in the CADENZA study (Part A) (incidence ≥18%) are rhinitis, headache, hypertension, acrocyanosis, and Raynaud's phenomenon. The most common adverse reactions in the CARDINAL study (incidence ≥25%) are urinary tract infection, respiratory tract infection, bacterial infection, dizziness, fatigue, peripheral edema, arthralgia, cough, hypertension, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344 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. The safety of ENJAYMO in patients with a confirmed diagnosis of CAD was evaluated in a placebo-controlled study (CADENZA) in Part A (n=42) followed by an open-label single-arm study in Part B (n=39) and an open-label single-arm study (CARDINAL) (n=24) [see Clinical Studies (14) ] . The median duration of treatment exposure to ENJAYMO was 104 weeks (patients randomized to ENJAYMO in CADENZA Part A) and 93 weeks (patients randomized to placebo in CADENZA Part A) and 143 weeks for CARDINAL. CADENZA (Part A) Serious adverse reaction occurred in 2/22 (9%) patients who received ENJAYMO. Serious adverse reactions included Raynaud's phenomenon (n=1) and febrile infection (n=1). Permanent discontinuation of ENJAYMO due to an adverse reaction occurred in 2/22 (9%) patients. Adverse reactions which resulted in permanent discontinuation of ENJAYMO included Raynaud's phenomenon (n=1), acrocyanosis (n=1), and infusion related reactions (n=1). Dosage interruptions of ENJAYMO due to an adverse reaction occurred in 3/22 patients. Adverse reactions which required dosage interruption included nasopharyngitis (n=1) and infusion related reaction (n=1), including pruritis (n=1) and chest discomfort (n=1). The most common adverse reactions (≥18%) reported in the CADENZA study were rhinitis, headache, hypertension, acrocyanosis, and Raynaud's phenomenon. Table 3: Adverse Reactions (≥10%) in Patients Who Received ENJAYMO with a Difference Between Arms of >5% Compared to Placebo in the CADENZA Study (Part A) Adverse Reactions ENJAYMO (N=22) Placebo (N=20) Headache 5 (23%) 2 (10%) Hypertension 5 (23%) 0 Rhinitis 4 (18%) 0 Acrocyanosis 4 (18%) 0 Raynaud's phenomenon 4 (18%) 0 CARDINAL Serious adverse reactions occurred in 10/24 (42%) patients who received ENJAYMO. The most common adverse reaction (>5%) was acrocyanosis (n=2). A fatal adverse reaction of pneumonia klebsiella occurred in one patient who received ENJAYMO. Permanent discontinuation of ENJAYMO due to an adverse reaction occurred in 2/24 (8%) patients. Adverse reactions which resulted in permanent discontinuation of ENJAYMO included pneumonia klebsiella (n=1) and acrocyanosis (n=2). Dosage interruptions of ENJAYMO due to an adverse reaction occurred in 7/24 patients. Adverse reactions which required dosage interruption included pneumonia, COVID-19 pneumonia, abdominal pain upper, urinary tract infection bacterial, urosepsis, acrocyanosis, viral infection, blood creatinine increased and infusion-related reaction. The most common adverse reaction (≥25%) reported in the CARDINAL study were urinary tract infection, respiratory tract infection, bacterial infection, dizziness, fatigue, peripheral edema, arthralgia, cough, hypertension, and nausea. Table 4: Adverse Reactions (≥15%) in Patients Receiving ENJAYMO in the CARDINAL Study Adverse Reaction/Body System n (%) (N=24) Please note: if a subject has multiple events in a grouped term the subject is only counted once. The following terms were combined for the analysis: INFECTIONS AND INFESTATIONS Urinary tract infection Urinary Tract Infection includes cystitis, urosepsis 9 (38%) Respiratory tract infection Respiratory tract infection includes upper respiratory tract infection, bronchitis, lower respiratory tract infection, COVID-19 pneumonia 6 (25%) Bacterial infection Bacterial infection includes Escherichia urinary tract infection, urinary tract infection bacteria, cystitis bacterial, Escherichia sepsis, pneumococcal sepsis, pneumonia klebsiella, streptococcal sepsis, wound infection staphylococcal 6 (25%) Nasopharyngitis 5 (21%) Viral infection Viral infection includes oral herpes, herpes zoster, respiratory tract infection viral, viral upper respiratory tract infection, Herpes simplex viraemia 5 (21%) NERVOUS SYSTEM DISORDERS Dizziness Dizziness includes dizziness postural and vertigo 7 (29%) Headache 5 (21%) GENERAL DISORDERS Fatigue Fatigue includes asthenia, malaise, mental fatigue 8 (33%) Peripheral edema Peripheral edema includes peripheral swelling 6 (25%) Pyrexia 5 (21%) MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia 6 (25%) VASCULAR DISORDERS Hypertension Hypertension includes, blood pressure increased, essential hypertension 6 (25%) Acrocyanosis 5 (21%) GASTROINTESTINAL DISORDERS Nausea 6 (25%) Abdominal pain Abdominal pain includes abdominal pain upper, abdominal tenderness 5 (21%) RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Cough Cough includes productive cough 6 (25%) INJURY, POISONING AND PROCEDURAL COMPLICATIONS Infusion-related reaction Infusion related reaction includes stress cardiomyopathy, feeling cold (All occurred within 24 hours of start of ENJAYMO infusion) 4 (17%)

12.3 Pharmacokinetics Following administration of the approved weight-based recommended dosages, the exposure of sutimlimab-jome increases proportionally over a dosage range of 60 mg/kg to 100 mg/kg by intravenous infusion (0.3 to 1.5 times the maximum approved recommended dosage based on 75 kg body weight). Steady state was achieved by Week 7 after starting sutimlimab-jome treatment, with an accumulation ratio of less than 2. Distribution Sutimlimab-jome binds to C1s in the serum. The volume of distribution at steady state was approximately 5.8 L in patients with CAD. Elimination The terminal elimination half-life and clearance varies at different doses due to target-mediated drug disposition at lower sutimlimab-jome concentrations. The terminal elimination half-life (t 1/2β ) of sutimlimab-jome is 21 days with a clearance (CL) of approximately 0.14 L/day at the approved recommended dosage. Metabolism Sutimlimab-jome is a protein. It is generally recognized that antibodies are metabolized by degradation into small peptides and individual amino acids. Specific Populations No clinically significant differences in the pharmacokinetics of sutimlimab-jome were observed based on sex, age (19 to 88 years of age), ethnicity (Japanese, non-Japanese), and mild to moderate renal impairment (30 to 89 mL/min/1.73 m 2 measured by estimated glomerular filtration rate [eGFR]). The effects of severe renal impairment and hepatic impairment on the pharmacokinetics of sutimlimab-jome are unknown. Body weight Population pharmacokinetic analysis shows that sutimlimab-jome AUC at steady-state decreased up to 40% for a patient weighing 110 kg following the 7.5 g dose and increased up to 170% for a patient weighing 40 kg following the 6.5 g dose as compared with a patient weighing 70 kg following the 6.5 g dose. The effect of body weight on pharmacokinetics has been integrated in the recommended dose regimen tiered by body weight.