Crovalimab

12.1 Mechanism of Action Crovalimab-akkz is a monoclonal antibody that specifically binds with high affinity to the complement protein C5, inhibiting its cleavage into C5a and C5b, preventing the formation of the membrane attack complex (MAC). Crovalimab-akkz inhibits terminal complement-mediated intravascular hemolysis in patients with PNH.

1 INDICATIONS AND USAGE PIASKY is indicated for the treatment of adult and pediatric patients 13 years and older with paroxysmal nocturnal hemoglobinuria (PNH) and body weight of at least 40 kg. PIASKY is a complement C5 inhibitor indicated for the treatment of adult and pediatric patients 13 years and older with paroxysmal nocturnal hemoglobinuria (PNH) and body weight of at least 40 kg ( 1 )

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for instructions on preparation, dosage, and administration. ( 2.2 , 2.3 , 2.4 , 2.5 ) Start with one loading dose administered by intravenous infusion, followed by 4 additional loading doses administered by subcutaneous injection. Then administer a maintenance dose every 4 weeks by subcutaneous injection. For patients switching from another complement inhibitor, the first loading dose of PIASKY should be administered no sooner than the time of the next scheduled complement inhibitor administration. See Full Prescribing Information for considerations when switching from another C5 inhibitor. Administer doses based on the patient's actual body weight ( 2.2 ) 2.1 Recommended Vaccination and Prophylaxis for Meningococcal Infection Vaccinate patients for meningococcal infection (serogroups A, C, W, Y and B) according to current ACIP recommendations at least 2 weeks prior to initiation of PIASKY [see Warnings and Precautions (5.1) ] . If urgent PIASKY therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Healthcare providers who prescribe PIASKY must enroll in the PIASKY REMS [see Warnings and Precautions (5.2) ]. 2.2 Recommended Dosage Regimen The recommended dosage regimen consists of one loading dose administered by intravenous (IV) infusion (on Day 1), followed by four additional weekly loading doses administered by subcutaneous (SUBQ) injection (on Days 2, 8, 15, and 22). The maintenance dose starts on Day 29 and is then administered every 4 weeks by subcutaneous injection. Administer doses based on the patient's actual body weight, as shown in Table 1 . Table 1 PIASKY Dosage Regimen Based on Body Weight Body Weight ≥ 40 kg to < 100 kg ≥ 100 kg IV = intravenous, SUBQ = subcutaneous Loading Dose Day 1 Day 2, 8, 15, 22 1,000 mg (IV) 340 mg (SUBQ) 1,500 mg (IV) 340 mg (SUBQ) Maintenance Dose Day 29 and Q4W Q4W=every 4 weeks thereafter 680 mg (SUBQ) 1,020 mg (SUBQ) The dosing schedule is allowed to occasionally vary within 2 days of the scheduled administration day (except at Day 1 and Day 2). If this occurs, the subsequent dose should be administered according to the regular schedule. Modification of the maintenance dose is required if the patient's body weight changes to become consistently greater than or lower than 100 kg during the course of therapy. 2.3 Recommended Timing for Switching to PIASKY from Another C5 Inhibitor Healthcare providers should consider the benefits of the timing of switching C5 inhibitors vs. the risks of Type III hypersensitivity reactions [see Warnings and Precautions (5.3) ] . For patients switching from another C5 inhibitor (e.g., eculizumab or ravulizumab), the first intravenous loading dose of PIASKY should be administered no sooner than the time of the next scheduled complement inhibitor administration. The administration of the additional subcutaneous loading doses and maintenance doses of PIASKY should follow as per the schedule shown in Table 1 . 2.4 Delayed or Missed Dose If an entire planned dose or part of a planned dose of PIASKY is missed, administer the missed dose or remainder of the missed dose as soon as possible before the day of the next scheduled dose. Then administer the next dose on the regularly scheduled dosing day. Do not administer two doses or more than the prescribed dose on the same day to make up for a missed dose. 2.5 Preparation and Administration Each vial of PIASKY is for one-time use in only one patient. PIASKY is administered as an intravenous infusion (first dose) and as a subcutaneous injection (subsequent doses). Only healthcare providers should administer PIASKY. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. PIASKY is clear to opalescent, and an almost colorless to brownish-yellow solution. PIASKY should be discarded if the medicine looks cloudy, discolored, or has particles in it. Preparation of Intravenous Infusion Use aseptic technique to prepare PIASKY for intravenous administration. PIASKY must be diluted and administered as an intravenous infusion over 60 minutes ± 10 minutes (1,000 mg) or 90 minutes ± 10 minutes (1,500 mg). PIASKY solution must be diluted in 0.9% Sodium Chloride Injection prior to administration. A 0.2 micron in-line filter must be used with the infusion set during administration. A dedicated infusion line must be used during intravenous administration. Only dilute PIASKY in 0.9% Sodium Chloride Injection. Dilution of Intravenous Infusion Withdraw the required volume of PIASKY from the vial (see Table 2 ) using a sterile syringe and dilute into the infusion bag. Use multiple vials to meet the required volume of PIASKY to be added to the infusion bag. Discard any unused portion l

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the label: Serious Meningococcal Infection [see Warnings and Precautions (5.1) ] Type III Hypersensitivity Reactions Related to Drug-Target-Drug Complexes [see Warnings and Precautions (5.3) ] Other Infections [see Warnings and Precautions (5.4) ] Infusion- and Injection-Related Reactions [see Warnings and Precautions (5.5) ] The most common adverse drug reactions (incidence ≥10%) were infusion-related reaction, respiratory tract infection, viral infection, and Type III hypersensitivity reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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. Patients Who are Complement Inhibitor-Naïve The data described below reflect exposure of 204 patients with PNH who were complement inhibitor-naïve and who were randomized in COMMODORE 2 to receive PIASKY (n = 135) or eculizumab (n = 69) at the recommended dosing regimen for 24 weeks [see Clinical Studies (14) ] . Serious adverse reactions occurred in 6% of patients receiving PIASKY in the COMMODORE 2 study, including epistaxis and pneumonia, which occurred in 2 patients each, and infusion related reaction, pyelonephritis, COVID-19, and hypovolemic shock which were reported in 1 patient each. Table 4 lists adverse reactions that occurred at a rate of 5% or more among patients randomized to PIASKY treatment for 24 weeks in the COMMODORE 2 study. The most common adverse reactions (≥10%) in patients treated with PIASKY were infusion related reaction, respiratory tract infection, and viral infection. Table 4 Adverse Reactions Reported In 5% or More of Complement-Inhibitor Naïve Patients with PNH Randomized to PIASKY in COMMODORE 2 Adverse reactions PIASKY (N = 135) % ECULIZUMAB (N = 69) % Infusion-related reaction 16 13 Respiratory tract infection Grouped terms. Diarrhea includes diarrhea and diarrhea infectious. Headache includes headache and migraine. Injection-related reaction includes injection related reaction and injection site reaction. Respiratory tract infection includes nasopharyngitis, pharyngitis, rhinitis, rhinitis allergic, upper respiratory tract infection and pneumonia. Viral infection includes viral infection, COVID-19, influenza, herpes virus infection and oral herpes. 13 20 Viral infection 11 7 Hyperuricemia 8 9 Headache 8 6 Diarrhea 7 1 Injection-related reaction Injection-related reactions are only expected to occur in the PIASKY arm as eculizumab is not given by subcutaneous injection 6 0 Patients Previously Treated with a Complement C5 Inhibitor The data described below reflect exposure of 86 patients with PNH who received PIASKY (n=44) or eculizumab (n=42) at the recommended dosing regimen for 24 weeks in COMMODORE 1, an open-label, active-controlled, multicenter study conducted in patients switching from eculizumab. The median age was 47 years (range: 21 to 85); 52% were female, and race included White (73%), Asian (19%), unknown (5%), and Black/African-American (3%). The population ethnicities were 17% Hispanic or Latino and 76% not Hispanic or Latino. Serious adverse reactions in COMMODORE 1 were reported in 3 patients (7%) with PNH receiving PIASKY. Serious adverse reactions included pneumonia, nasopharyngitis, and urinary tract infection, which occurred in 1 patient each. Table 5 lists adverse reactions that occurred at a rate of 5% or more among patients randomized to PIASKY treatment for 24 weeks in the COMMODORE 1 study. The most common adverse reactions (≥10%) in patients treated with PIASKY were viral infections, respiratory tract infection, Type III hypersensitivity reaction, infusion-related reaction, peripheral edema, and headache. Table 5 Adverse Reactions Reported In 5% or More of Complement-Inhibitor Treated Patients with PNH Randomized to PIASKY in COMMODORE 1 Adverse reactions PIASKY (N = 44) % ECULIZUMAB (N = 42) % Viral infection Grouped terms Fatigue includes fatigue, malaise and asthenia. Injection-related reaction includes injection related reaction and injection site reaction. Rash includes rash and skin exfoliation. Peripheral edema includes edema peripheral and peripheral swelling. Respiratory tract infection includes respiratory tract infection, nasopharyngitis, pneumonia and upper respiratory tract infection. Viral infection includes viral infection, influenza, COVID-19, and respiratory syncytial virus infection 23 21 Respiratory tract infection 18 5 Type III hypersensitivity reaction Type III immune complex mediated reaction is only expected to occur in the PIASKY arm as patients in the eculizumab arm did not change C5 inh

7. DRUG INTERACTIONS PIASKY binds different epitopes on C5 compared to eculizumab and ravulizumab, which can lead to the formation of DTDCs when patients switch between PIASKY and either eculizumab or ravulizumab. These DTDCs comprise one or more units of C5 bound to both PIASKY and to eculizumab or ravulizumab. These DTDCs are expected to be cleared within approximately 8 weeks (in the case of eculizumab) or longer (in the case of ravulizumab) and can result in Type III hypersensitivity reactions [see Warnings and Precautions (5.3) , Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] .