Highlights

Indications and usage

Zilucoplan is indicated for the treatment of generalized myasthenia gravis in adult patients who are anti-acetylcholine receptor (AChR) antibody positive.

Dosage and administration

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 before initiation of zilucoplan.

If urgent zilucoplan 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 zilucoplan must enroll in the zilucoplan REMS.

Recommended testing before initiating zilucoplan

Before initiating zilucoplan, obtain baseline lipase and amylase levels.

Recommended dosage

The recommended dosage of zilucoplan 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

Preparation instructions

Zilucoplan prefilled syringes can be stored in a refrigerator in the original carton. Zilucoplan 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 one zilucoplan prefilled syringe out of the refrigerator and place it on a clean, flat surface. Allow zilucoplan to reach room temperature out of direct sunlight (30 to 45 minutes). Do not heat or place in the microwave.

• Immediately return the carton with the other prefilled syringes to the refrigerator.

If stored at room temperature.

• Remove one zilucoplan prefilled syringe from the carton.

• Do not return zilucoplan to the refrigerator after it has been stored at room temperature.

Visually inspect zilucoplan for particulate matter and discoloration before administration. Zilucoplan 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. Zilucoplan does not contain preservatives; unused portions of the drug remaining in the syringe should be discarded.

Each prefilled syringe is single-dose only.

Administration instructions

Zilucoplan is intended for use under the guidance and supervision of a healthcare professional. Patients may self-inject zilucoplan after training in subcutaneous injection technique. Provide proper training to patients and caregivers on the subcutaneous injection technique of zilucoplan according to the “Instructions for Use.”

Administer zilucoplan 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 zilucoplan in the upper, outer arm should be performed by a caregiver.

When using zilucoplan prefilled syringes, inject the full contents of the single-dose prefilled syringe.

Discard the zilucoplan 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 one dose per day.

Dosage forms and strengths

Injection: 16.6 mg/0.416 mL, 23 mg/0.574 mL, or 32.4 mg/0.81 mL of zilucoplan as a clear to slightly opalescent, colorless solution in single-dose prefilled syringes.

Contraindications

Zilucoplan is contraindicated for initiation in patients with an unresolved serious Neisseria meningitidis infection.

Warnings and precautions

Serious meningococcal infections

Zilucoplan, 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 zilucoplan 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 before administering the first dose of zilucoplan, according to current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations, considering the duration of zilucoplan 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 zilucoplan 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 zilucoplan. The benefits and risks of treatment with zilucoplan, 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 the 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 them 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 interrupting zilucoplan in patients who are undergoing treatment for serious meningococcal infection, depending on the risks of interrupting treatment in the disease being treated.

Zilucoplan is available only through a restricted program under a risk evaluation and mitigation strategy (REMS).

Zilucoplan REMS

Zilucoplan is available only through a restricted program under a risk evaluation and mitigation strategy called zilucoplan REMS because of the risk of serious meningococcal infections.

Further information is available at www.ZILBRYSQREMS.com or 1-877-414-8353.

Other infections

Serious infections with Neisseria species (other than Neisseria meningitidis), including disseminated gonococcal infections, have been reported in patients treated with complement inhibitors.

Zilucoplan 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 zilucoplan are at an increased risk of infections due to these organisms, even if they develop antibodies following vaccination.

Pancreatitis and other pancreatic conditions

Pancreatitis and pancreatic cysts have been reported in patients treated with zilucoplan.

During the open-label extension studies, seven (3.3%) patients experienced pancreatic events, including four (1.9%) patients with pancreatitis and three (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 zilucoplan compared to no patients on placebo, and adverse reactions of increased amylase were reported in four (4.7%) patients treated with zilucoplan 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 zilucoplan compared to no patients on placebo.

Patients should be informed of this risk before starting zilucoplan. Obtain lipase and amylase levels at baseline before starting treatment with zilucoplan. Discontinue zilucoplan in patients with suspected pancreatitis and initiate appropriate management until pancreatitis is ruled out or has resolved.

Adverse reactions

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

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 zilucoplan 0.3 mg/kg in clinical studies in generalized myasthenia gravis. 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 generalized myasthenia gravis, 86 patients received zilucoplan 0.3 mg/kg. 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 zilucoplan and more frequently than placebo. The most common adverse reactions (reported in at least 10% of patients treated with zilucoplan) were injection site reactions, upper respiratory tract infections, and diarrhea.

Table 2. Adverse Reactions in at least 5% of Patients Treated with Zilucoplan and More Frequently than in Patients who Received Placebo in Study 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 zilucoplan.

Adverse laboratory changes in clinical trials. Additional laboratory abnormalities included transient elevations of blood eosinophils, which were of uncertain clinical significance.

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 1 year after start of treatment and were mild to moderate in severity. One patient discontinued zilucoplan because of morphea.

Use in specific populations

Pregnancy

Risk summary. There are no available data on zilucoplan 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.

All pregnancies have a background risk of birth defects, 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.

Lactation

Risk summary. There are no data on the presence of zilucoplan in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for zilucoplan and any potential adverse effects on the breastfed infant from zilucoplan or from the underlying maternal condition.

Pediatric use

Safety and effectiveness in pediatric patients have not been established.

Geriatric use

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

Clinical pharmacology

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 a reduction in C5b-9 deposition at the neuromuscular junction.

Pharmacodynamics

In a placebo-controlled Phase 2 study, patients received zilucoplan 0.3 mg/kg or 0.1 mg/kg for 12 weeks. There was a dose-dependent inhibition of complement. Complement inhibition, as represented by inhibition of sheep red blood cell (sRBC) lysis, was 89.1% within 3 hours after the first administration and 94.9% after the 12-week treatment period in patients receiving zilucoplan 0.3 mg/kg.

In Study 1, a 97.5% complement inhibition was observed by the end of the first week and sustained throughout the 12-week treatment period for patients with generalized myasthenia gravis treated with the recommended dosage regimen of zilucoplan.

Cardiac electrophysiology. At a dose two times the maximum approved recommended dose, zilucoplan does not cause clinically significant QTc interval prolongation.

Pharmacokinetics

The population pharmacokinetics (PK) analysis showed that zilucoplan PK was not time-dependent. Following single daily subcutaneous administration of zilucoplan (0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg, and 0.4 mg/kg) in healthy subjects, the increase in peak plasma concentration was approximately dose proportional, and the increase in area under the curve was less than dose proportional.

Absorption. Following single and multiple daily subcutaneous administration of zilucoplan 0.3 mg/kg in healthy subjects, zilucoplan reached peak plasma concentration generally between 3 to 6 hours post-dose. Following daily subcutaneous dosing of zilucoplan 0.3 mg/kg for 14 days in healthy subjects, both the peak plasma concentration and exposure (AUC tau) increased by approximately 3-fold.

In Study 1, after daily repeated subcutaneous administration of zilucoplan 0.3 mg/kg, plasma concentrations of zilucoplan were consistent, with steady-state trough concentrations being reached by 4 weeks of treatment with zilucoplan through 12 weeks.

Distribution. The mean volume of distribution at steady state was 3.51 L in the population pharmacokinetics analysis for adult patients with generalized myasthenia gravis. Zilucoplan and its two major metabolites are highly bound to plasma proteins (greater than 99%).

Elimination. The mean plasma terminal half-life of zilucoplan was approximately 172 hours (7 to 8 days).

Metabolism. As a peptide, zilucoplan is expected to be degraded into small peptides and amino acids via catabolic pathways.

In plasma, two major metabolites, RA103488 and RA102758, were detected. The metabolite RA103488, formed mainly because of cytochrome CYP450 4F2, has pharmacological activity similar to zilucoplan but is present at a much lower concentration compared to zilucoplan. The metabolite RA102758, formed by protease-mediated degradation, is pharmacologically inactive. The AUCs of both metabolites were approximately 10% of the parent AUC. The contribution of RA103488 to pharmacological activity is, therefore, expected to be low.

Excretion. Excretion of zilucoplan and its metabolite in urine and feces was negligible (less than 1% of the dose).

Specific populations.

Age, sex, and race. A population pharmacokinetics analysis assessing the effects of age, sex, and race did not suggest any clinically significant impact of these covariates on zilucoplan exposures.

Patients with renal impairment. A dedicated clinical study compared the pharmacokinetics of a single subcutaneous dose of zilucoplan 0.3 mg/kg in subjects with severe renal impairment (as defined by a creatinine clearance less than 30 mL/min estimated by the Cockcroft-Gault formula) to that of matched healthy subjects with normal renal function. A decrease in zilucoplan exposure (AUC 0-inf) of 13% was observed. This change in zilucoplan exposures is not expected to be clinically significant. No dose adjustment is required in patients with renal impairment.

Patients with hepatic impairment. A dedicated clinical study compared the pharmacokinetics of a single subcutaneous dose of zilucoplan 0.3 mg/kg in subjects with moderate hepatic impairment (as indicated by a Child-Pugh category of moderate [score of 7 to 9]) to that of matched healthy subjects with normal hepatic function. A decrease in zilucoplan exposure (AUC 0-inf) of 24% was observed. This change in zilucoplan exposures is not expected to be clinically significant. No dose adjustment is required in patients with mild or moderate hepatic impairment. The pharmacokinetics of zilucoplan in patients with severe hepatic impairment have not been studied.

Drug interactions. Clinical drug interaction studies have not been performed with zilucoplan.

In vitro studies have shown that zilucoplan is not a substrate of major cytochrome P450 (CYP) enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A) or transporters (P-gp, BCRP, OATP1B1, and OATP1B3). Based on the results from in vitro drug interaction testing, clinically relevant interactions between zilucoplan and substrates of CYP enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A, and 4F), uridine diphosphoglucuronosyl transferases (UGTs; 1A1, 1A3, 1A4, 1A6, 1A9, 2B7, and 2B15), and transporters (P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, MATE2-K, OCT1, and OCT2) is unlikely.

Immunogenicity

As with all therapeutic peptides, there is a potential for immunogenicity. The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies or of other products. The sensitivity of the assay is not known, although ADA was detectable in the tested samples.

In up to 12 weeks of treatment in Study 1, 2.3% (2 of 86) of patients treated with zilucoplan developed anti-drug antibodies (ADA). A total of 9.3% (8 of 86) of zilucoplan-treated patients developed anti-polyethylene glycol (anti-PEG) antibodies. Because of the low occurrence of anti-drug antibodies and anti-PEG antibodies, the available data are too limited to make definitive conclusions regarding immunogenicity and its effect on pharmacokinetics, pharmacodynamics, safety, or efficacy of zilucoplan.

Nonclinical toxicology

Carcinogenesis, mutagenesis, impairment of fertility

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 a 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 those in humans at the maximum recommended human dose of 32.4 mg/day.

Clinical studies

The efficacy of zilucoplan for the treatment of generalized myasthenia gravis in adult patients who are anti-AChR antibody positive was established in a 12-week, multicenter, randomized, double-blind, placebo-controlled study (Study 1; NCT04115293).

Study 1 enrolled patients who met the following criteria at screening:

A total of 174 patients were enrolled in Study 1 and were randomized 1:1 to receive either zilucoplan 0.3 mg/kg (n=86) or placebo (n=88) once daily by subcutaneous injection. Baseline characteristics were similar between treatment groups. Patients had a mean age of 53.0 years and a mean time since diagnosis of 9 years. Fifty-seven percent of the patients were female, 74% were White, 12% were Asian, 8% were Black, 1% were American Indian or Alaska Native, and 6% did not have race reported. The mean baseline MG-ADL total score was 10.6 (range 6 to 19).

At baseline, approximately 85% of patients in each group received cholinesterase inhibitors, 63% received steroids, and 51% received non-steroidal immunosuppressive therapies at stable doses.

The primary efficacy endpoint was a comparison of the change from baseline between treatment groups in the MG-ADL scale total score after 12 weeks of treatment. The MG-ADL assesses the impact of generalized myasthenia gravis on the daily functions of eight signs or symptoms that are typically affected in generalized myasthenia gravis. Each item is assessed on a four-point scale, where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function. A total score ranges from 0 to 24, with the higher scores indicating more impairment.

The efficacy of zilucoplan was also measured using the Quantitative Myasthenia Gravis (QMG) total score, which is a 13-item categorical grading system that assesses muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness. A total possible score ranges from 0 to 39, where higher scores indicate more severe impairment.

Other secondary endpoints included the proportion of patients with improvements of at least 3 and 5 points in the MG-ADL total score and QMG total score, respectively, at week 12 without rescue therapy.

At week 12, treatment with zilucoplan demonstrated a statistically significant improvement from baseline compared to placebo for MG-ADL total score and QMG total score (see Table 3 and Figure 1 in the Clinical studies section of the DAILYMED drug label information).

The proportion of MG-ADL responders with at least a 3-point improvement at week 12 was greater for zilucoplan (73.1%) compared to placebo (46.1%) (p<0.001). The proportion of QMG responders with at least a 5-point improvement was also greater for zilucoplan (58%) compared to placebo (33%) (p = 0.0012). The proportion of clinical responders at higher response thresholds was consistently greater for zilucoplan compared to placebo.

How supplied/storage and handling

How supplied

Zilucoplan (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 half-inch needle, a needle safety guard, and a needle cover. The zilucoplan prefilled syringe components are not made with natural rubber latex.

Zilucoplan is available as follows:

Storage and handling

Pharmacy before dispensing. Store zilucoplan 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 the pharmacist are summarized in Table 4.

Table 4. After Dispensing Storage Conditions

Patient counseling information

Advise the patients andcaregivers to read FDA-approved patient labeling.

Serious meningococcal infection. Advise patients of the risk of serious meningococcal infection. Inform patients of the need to complete or update meningococcal vaccinations at least 2 weeks before receiving the first dose of zilucoplan or receive antibacterial drug prophylaxis if zilucoplan 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 zilucoplan therapy.

Inform patients that vaccination may not prevent serious meningococcal infection and that they should seek immediate medical attention if the following signs or symptoms occur:

Inform patients that they will be given a Patient Safety Card for zilucoplan that they should carry with them at all times and for 2 months following treatment with zilucoplan. This card describes symptoms that, if experienced, should prompt the patient to seek medical evaluation immediately.

Zilucoplan REMS. Zilucoplan is available only through a restricted program called zilucoplan REMS.

Inform the patient of the following notable requirements:

Other infections. Counsel patients about 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. 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 zilucoplan. 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 zilucoplan.

Administration. Provide training to patients and caregivers on the proper technique for subcutaneous injection.

Instruct patients to inject the full dose of zilucoplan.

Instruct patients or caregivers in the technique of needle and syringe disposal.

Remind patients if they forget to take their dose of zilucoplan 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 one dose per day.

Medication guide

See the Medication guide section of the DAILYMED drug label information.