Zilucoplan

12.1 Mechanism of Action Zilucoplan binds to the complement protein C5 and inhibits its cleavage to C5a and C5b, preventing the generation of the terminal complement complex, C5b-9. The precise mechanism by which zilucoplan exerts its therapeutic effect in generalized myasthenia gravis is unknown but is presumed to involve reduction of C5b-9 deposition at the neuromuscular junction.

1 INDICATIONS AND USAGE ZILBRYSQ is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive. ZILBRYSQ is a complement inhibitor indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive. ( 1 )

2 DOSAGE AND ADMINISTRATION Obtain baseline amylase and lipase. ( 2.2 ) For subcutaneous injection only. ( 2.3 ) Recommended dosage ( 2.3 ): Body Weight Once Daily Dosage Plunger Rod Color of Prefilled Syringe Less than 56 kg 16.6 mg RUBINE RED 56 kg to less than 77 kg 23 mg ORANGE 77 kg and above 32.4 mg DARK BLUE See Full Prescribing Information for instructions on dosage, preparation, and administration. ( 2.4 , 2.5 ) 2.1 Recommended Vaccination and Prophylaxis for Meningococcal Infection Vaccinate patients against meningococcal infection (serogroups A, C, W, Y, and B) according to current ACIP recommendations at least 2 weeks prior to initiation of ZILBRYSQ [see Warnings and Precautions (5.1) ] . If urgent ZILBRYSQ 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 [see Warnings and Precautions (5.1) ] . Healthcare providers who prescribe ZILBRYSQ must enroll in the ZILBRYSQ REMS [see Warnings and Precautions (5.2) ] . 2.2 Recommended Testing Before Initiating ZILBRYSQ Before initiating ZILBRYSQ, obtain baseline lipase and amylase levels [see Warnings and Precautions (5.4) ] . 2.3 Recommended Dosage The recommended dosage of ZILBRYSQ is given once daily as a subcutaneous injection and is dependent on actual body weight (see Table 1 ). Table 1: Total Daily Dosage by Body Weight Range Body Weight Once Daily Dosage Plunger Rod Color of Prefilled Syringe Less than 56 kg 16.6 mg RUBINE RED 56 kg to less than 77 kg 23 mg ORANGE 77 kg and above 32.4 mg DARK BLUE 2.4 Preparation Instructions ZILBRYSQ prefilled syringes can be stored in a refrigerator in the original carton. ZILBRYSQ can also be stored at room temperature in the original carton for up to 3 months or until the expiration date, whichever occurs first. If stored in the refrigerator: Before injecting, take 1 ZILBRYSQ prefilled syringe out of the refrigerator and place it on a clean, flat surface. Allow ZILBRYSQ to reach room temperature out of direct sunlight (30 to 45 minutes). Do not heat or place in microwave. Immediately return the carton with the other prefilled syringes to the refrigerator. If stored at room temperature: Remove 1 ZILBRYSQ prefilled syringe from the carton. Do not return ZILBRYSQ to the refrigerator after it has been stored at room temperature. Visually inspect ZILBRYSQ for particulate matter and discoloration prior to administration. ZILBRYSQ is a clear to slightly opalescent, colorless solution. Do not use if the solution contains visible particles, is cloudy, or if foreign particulate matter is present. ZILBRYSQ does not contain preservatives; unused portions of drug remaining in the syringe should be discarded. Each prefilled syringe is single-dose only. 2.5 Administration Instructions ZILBRYSQ is intended for use under the guidance and supervision of a healthcare professional. Patients may self-inject ZILBRYSQ after training in subcutaneous injection technique. Provide proper training to patients and/or caregivers on the subcutaneous injection technique of ZILBRYSQ according to the "Instructions for Use" [see Instructions for Use ] . Administer ZILBRYSQ subcutaneously into areas of the abdomen, thighs, or back of the upper arms that are not tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks. Rotate injection sites for each administration. Administration of ZILBRYSQ in the upper, outer arm should be performed by a caregiver. When using ZILBRYSQ prefilled syringes, inject the full contents of the single-dose prefilled syringe. Discard ZILBRYSQ prefilled syringe after use. Do not reuse. Instruct the patient that the daily dose should be administered at approximately the same time each day. If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time. Do not administer more than 1 dose per day.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Serious Meningococcal Infections [see Warnings and Precautions (5.1) ] Other Infections [see Warnings and Precautions (5.3) ] Pancreatitis and Other Pancreatic Conditions [see Warnings and Precautions (5.4) ] The most common adverse reactions (≥10%) in patients with gMG were injection site reactions, upper respiratory tract infection, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 844-599-2273 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. A total of 212 patients were treated with ZILBRYSQ 0.3 mg/kg in clinical studies in gMG. Of these, 137 patients were exposed for at least 6 months, and 87 were exposed for at least 1 year. In a placebo-controlled study (Study 1) in patients with gMG, 86 patients received ZILBRYSQ 0.3 mg/kg [see Clinical Studies (14) ] . Of these 86 patients, approximately 61% were female, 77% were White, 8% were Asian, and 8% were of Hispanic or Latino ethnicity. The mean age at study entry was 52.6 years (range 21 to 75 years). Table 2 summarizes the adverse reactions reported in at least 5% of patients treated with ZILBRYSQ and more frequently than placebo. The most common adverse reactions (reported in at least 10% of patients treated with ZILBRYSQ) were injection site reactions, upper respiratory tract infections, and diarrhea. Table 2: Adverse Reactions in at least 5% of Patients Treated with ZILBRYSQ and More Frequently than in Patients who Received Placebo in Study 1 Adverse Reaction ZILBRYSQ 0.3 mg/kg (n=86) % Placebo (n=88) % Injection site reactions 29 16 Upper respiratory tract infections 14 7 Diarrhea 11 2 Urinary tract infection 8 5 Nausea or vomiting 8 7 Lipase increased 7 0 Amylase increased 5 1 Pancreatic Events In addition to increases in amylase and lipase observed in Study 1, pancreatic events, including pancreatitis and pancreatic cysts have been observed in patients taking ZILBRYSQ [see Warnings and Precautions (5.4) ] . Adverse Laboratory Changes in Clinical Trials Additional laboratory abnormalities included transient elevations of blood eosinophils, which were of uncertain clinical significance. 6.2 Postmarketing Experience Adverse Reactions from Observational Studies Morphea In the open-label extension studies, which included 213 patients, morphea was observed in 10 (5%) patients; most cases had a time to onset longer than one year after start of treatment and were mild to moderate in severity. One patient discontinued ZILBRYSQ because of morphea.