Zilucoplan

Zilucoplan, a complement inhibitor, is a 15 amino-acid, synthetic macrocyclic peptide. The molecular formula of zilucoplan is C 172 H 278 N 24 O 55 in free acid form and its molecular weight is 3562.23 Daltons (free acid form). The chemical name for zilucoplan sodium is: acetyl‐[L-lysyl 1 -L-valyl 2 -L-glutamyl 3 -L-arginyl 4 -L phenylalanyl 5 -L aspartyl 6 ]- N -methyl L-aspartyl 7 -L tert-leucyl 8 -L tyrosyl 9 -L-7-azatryptophyl 10 -L glutamyl 11 -L-tyrosyl 12 -L prolyl 13 -L cyclohexylglycyl 14 -[L-lysyl 15 , N ε -palmitoyl-γ-L-glutamyl-(1-amino-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69,72-tetracosaoxapentaheptacontan-75-oyl)], cyclic (Lactam 1-6), tetra sodium. The primary structure for zilucoplan sodium is shown below: ZILBRYSQ injection is a sterile, clear to slightly opalescent, colorless, preservative-free, buffered solution of zilucoplan (as zilucoplan sodium) for subcutaneous injection, in single-dose prefilled syringes. The solution pH is between 6.5 and 7.5. ZILBRYSQ is supplied in three dose strengths containing 16.6 mg /0.416 mL, 23 mg /0.574 mL, and 32.4 mg/0.81 mL of zilucoplan free acid equivalent to 17 mg, 23.6 mg, and 33.2 mg of zilucoplan sodium, respectively. Additionally, each mL of the solution contains dibasic sodium phosphate, anhydrous (4.11 mg); monobasic sodium phosphate, monohydrate (2.9 mg); sodium chloride (4.42 mg); and water for injection. Chemical Structure

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 )

16.1 How Supplied ZILBRYSQ (zilucoplan) injection prefilled syringe contains a sterile, preservative-free, clear to slightly opalescent, colorless solution. Each single-dose prefilled syringe consists of a 1 mL glass syringe with a 29-gauge ½ inch needle, a needle safety guard, and a needle cover. The ZILBRYSQ prefilled syringe components are not made with natural rubber latex. ZILBRYSQ is available as follows: NDC Carton Pack Size Strength Plunger Color 50474-990-80 28 single-dose prefilled syringes (4 cartons each containing 7 syringes for a total of 28 syringes) 16.6 mg/0.416 mL RUBINE RED 50474-991-80 28 single-dose prefilled syringes (4 cartons each containing 7 syringes for a total of 28 syringes) 23 mg/0.574 mL ORANGE 50474-992-80 28 single-dose prefilled syringes (4 cartons each containing 7 syringes for a total of 28 syringes) 32.4 mg/0.81 mL DARK BLUE 16.2 Storage and Handling Pharmacy Prior to Dispensing Store ZILBRYSQ prefilled syringes refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton until dispensing. Do not freeze. Storage for Patients or Caregivers After Dispensing Storage conditions after dispensing by pharmacist are summarized in Table 4: Table 4: After Dispensing Storage Conditions Temperature Refrigeration 2°C to 8°C (36°F to 46°F) Room Temperature Up to 30°C (86°F) Time Period Until expiration date on the carton Up to 3 months after removing from refrigerator or until expiration date on the carton, whichever occurs first Do not freeze. Store ZILBRYSQ prefilled syringes in the original carton to protect them from light until time of use. ZILBRYSQ prefilled syringes may be stored at room temperature in the original carton for a single period of up to 3 months. When storing ZILBRYSQ prefilled syringes at room temperature, write the date removed from the refrigerator in the space provided on the carton and discard if not used within 3 months or if the expiration date has passed, whichever occurs first. Do not return ZILBRYSQ to the refrigerator after it has been stored at room temperature. ZILBRYSQ does not contain a preservative; discard any unused portion.

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.

ZILBRYSQ is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection [see Warnings and Precautions (5.1) ] . ZILBRYSQ is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection. ( 4 )

Other Infections: Use caution when administering ZILBRYSQ to patients with any other systemic infection. ( 5.3 ) Pancreatitis and pancreatic cysts have been reported in patients treated with ZILBRYSQ. Discontinue ZILBRYSQ in patients with suspected pancreatitis and initiate appropriate management until pancreatitis is ruled out or has resolved. ( 5.4 ) 5.1 Serious Meningococcal Infections ZILBRYSQ, a complement inhibitor, increases a patient's susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (septicemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of ZILBRYSQ treatment is contraindicated in patients with unresolved serious Neisseria meningitidis infection. Complete or update meningococcal vaccination (for serogroups A, C, W, Y and B) at least 2 weeks prior to administration of the first dose of ZILBRYSQ, according to current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of ZILBRYSQ therapy. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. 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 meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including ZILBRYSQ. The benefits and risks of treatment with ZILBRYSQ, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by Neisseria meningitidis . Vaccination does not eliminate the risk of meningococcal infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of ZILBRYSQ in patients who are undergoing treatment for serious meningococcal infection, depending on the risks of interrupting treatment in the disease being treated [ see Contraindications (4) ] . ZILBRYSQ is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) [see Warnings and Precautions (5.2) ] . 5.2 ZILBRYSQ REMS ZILBRYSQ is available only through a restricted program under a REMS called ZILBRYSQ REMS, because of the risk of serious meningococcal infections [see Warnings and Precautions (5.1) ] . Notable requirements of the ZILBRYSQ REMS include the following: Prescribers must enroll in the REMS. Prescribers must counsel patients about the risk of serious meningococcal infection. Prescribers must provide the patients with the REMS educational materials. Prescribers must assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y, and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of ZILBRYSQ. Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently and the patient is not up to date with meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of ZILBRYSQ. Pharmacies that dispense ZILBRYSQ must be certified in the REMS and must verify prescribers are certified. Patients must receive counseling from the prescriber about the need to receive meningococcal vaccines per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of meningococcal infection. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 2 months following treatment discontinuation with ZILBRYSQ. Further information is available at www.ZILBRYSQREMS.com or 1-877-414-8353. 5.3 Other Infections Serious infections with Neisseria species (other than Neisseria meningitidis ), including disseminated gonococcal infections, have been reported in patients treated with complement inhibitors. ZILBRYSQ blocks terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections caused by Neisseria meningitidis but also Streptococcus pneumoniae , Haemophilus influenzae , and to a lesser extent, Neisseria gonorrhoeae . Administer vaccinations for the prevention of Streptococcus pneumoniae infection according to ACIP recommendations. Patients receiving ZILBRYSQ are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination. 5.4 Pancreatitis and Other Pancreatic Conditions Pancreatitis and pancreatic cysts have been reported in patients treated with ZILBRYSQ. During the open-label extension studies, seven (3.3%) patients experienced pancreatic events, including 4 (1.9%) patients with pancreatitis and 3 (1.4%) with pancreatic cysts. In the 3-month, double-blind Study 1, adverse reactions of increased lipase were reported in six (6.9%) patients treated with ZILBRYSQ compared to no patients on placebo, and adverse reactions of increased amylase were reported in four (4.7%) patients treated with ZILBRYSQ compared to one (1.1%) patient on placebo. Lipase levels exceeded three times the upper limit of normal in six (7%) patients after being started on ZILBRYSQ compared to no patients on placebo. Patients should be informed of this risk before starting ZILBRYSQ. Obtain lipase and amylase levels at baseline before starting treatment with ZILBRYSQ. Discontinue ZILBRYSQ in patients with suspected pancreatitis and initiate appropriate management until pancreatitis is ruled out or has resolved.

Advise the patients and/or caregivers to read FDA-approved patient labeling (Medication Guide and Instructions for Use) . Serious Meningococcal Infection Advise patients of the risk of serious meningococcal infection [see Warnings and Precautions (5.1) ] . Inform patients of the need to complete or update meningococcal vaccinations at least 2 weeks prior to receiving the first dose of ZILBRYSQ or receive antibacterial drug prophylaxis if ZILBRYSQ treatment must be initiated immediately and they have not been previously vaccinated. Inform patients of the requirement to be revaccinated according to current ACIP recommendations for meningococcal infection while on ZILBRYSQ therapy. Inform patients that vaccination may not prevent serious meningococcal infection and to seek immediate medical attention if the following signs or symptoms occur: fever fever and a rash fever with high heart rate headache with nausea or vomiting headache and a fever headache with a stiff neck or stiff back confusion muscle aches with flu-like symptoms eyes sensitive to light Inform patients that they will be given a Patient Safety Card for ZILBRYSQ that they should carry with them at all times and for 2 months following treatment with ZILBRYSQ. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation. ZILBRYSQ REMS ZILBRYSQ is available only through a restricted program called ZILBRYSQ REMS [see Warnings and Precautions (5.2) ]. Inform the patient of the following notable requirements: Patients must receive counseling about the risk of serious meningococcal infections. Patients must receive written educational materials about this risk. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 2 months following treatment with ZILBRYSQ. Patients must be instructed to complete or update meningococcal vaccines for serogroups A, C, W, Y, and B per ACIP recommendations as directed by the prescriber prior to treatment with ZILBRYSQ. Patients must receive antibiotics as directed by the prescriber if they are not up to date with meningococcal vaccines and have to start ZILBRYSQ right away. Other Infections Counsel patients of the increased risk of infections, particularly those due to encapsulated bacteria, especially Neisseria species. Advise patients of the need for vaccination against meningococcal infections according to current medical guidelines [see Warnings and Precautions (5.3) ] . Counsel patients about gonorrhea prevention and advise regular testing for patients at risk. Advise patients to report any new signs and symptoms of infection. Pancreatitis and Other Pancreatic Conditions Inform patients that pancreatitis and pancreatic cysts have been reported in patients taking ZILBRYSQ. Inform patients that persistent abdominal pain, sometimes severe or radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to contact their healthcare provider if these symptoms occur to determine if they should discontinue ZILBRYSQ [see Warnings and Precautions (5.4) ] . Pregnancy Registry Advise patients that there is registry that monitors outcomes in patients with Myasthenia Gravis, including women exposed to ZILBRYSQ during pregnancy and/or breastfeeding [see Use in Specific Populations (8.1) ]. Administration Provide training to patients and caregivers on proper subcutaneous injection technique. Instruct patients to inject the full dose of ZILBRYSQ [see Medication Guide and Instructions for Use ] . Instruct patients or caregivers in the technique of needle and syringe disposal [see Instructions for Use ]. Remind patients if they forget to take their dose of ZILBRYSQ to inject their dose as soon as they remember. They should then take their next dose at the appropriate scheduled time. They should not take more than 1 dose per day.

Carcinogenesis Studies to assess the carcinogenic potential of zilucoplan have not been conducted. Mutagenesis Zilucoplan was not genotoxic in in vitro (Ames and chromosomal aberration) and in vivo (rat micronucleus) assays. Impairment of Fertility Subcutaneous administration of zilucoplan (0, 1, 2, or 4 mg/kg/day) to male monkeys resulted in testicular germ cell depletion/degeneration at all doses at the end of the 13-week dosing period and after the 8-week recovery period, indicating lack of reversibility. A no-effect dose for testicular germ cell degeneration was not identified. At the lowest dose tested, plasma exposures (AUC) were similar to that in humans at the maximum recommended human dose of 32.4 mg/day.

Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZILBRYSQ during pregnancy. Patients or healthcare providers may contact UCBCares at 1-844-599-CARE (2273) or email ucbcares@ucb.com, so that information about the exposure of ZILBRYSQ during pregnancy and/or breastfeeding can be collected. Risk Summary There are no available data on ZILBRYSQ use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Administration of zilucoplan to pregnant monkeys resulted in increases in embryofetal death at maternal exposures similar to those in humans at therapeutic doses (see Animal Data ) . All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background rate of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Subcutaneous administration of zilucoplan (0, 1, 2, or 4 mg/kg/day) to pregnant monkeys throughout gestation resulted in an increase in embryofetal death at all doses, in the absence of maternal toxicity. A no effect dose for adverse developmental effects in monkeys was not identified. The lowest dose tested was associated with maternal exposures (AUC) similar to that in humans at the maximum recommended human dose of 32.4 mg/day. Data from an ex vivo human placental transfer model demonstrated transfer of zilucoplan into the fetal compartment at a rate of 0.5% at a steady state plasma concentration of 10 µg/mL zilucoplan, which corresponds to a therapeutic dose of 0.3 mg/kg. The clinical significance of these data in human pregnancies is unknown.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of ZILBRYSQ did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger adult patients.

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.