Sutimlimab

12.1 Mechanism of Action Sutimlimab-jome is an immunoglobulin G (IgG), subclass 4 (IgG4) monoclonal antibody (mAb) that inhibits the classical complement pathway (CP) and specifically binds to complement protein component 1, s subcomponent (C1s), a serine protease which cleaves C4. Sutimlimab-jome does not inhibit the lectin and alternative pathways. Inhibition of the classical complement pathway at the level of C1s prevents deposition of complement opsonins on the surface of RBCs, resulting in inhibition of hemolysis in patients with CAD.

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

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