Get your patient on Zilbrysq - Zilucoplan injection, Solution (Zilucoplan)

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) ] .

Before initiating ZILBRYSQ, obtain baseline lipase and amylase levels [see Warnings and Precautions (5.4) ] .

The recommended dosage of ZILBRYSQ is given once daily as a subcutaneous injection and is dependent on actual body weight (see Table 1 ).

• 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.

• 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.

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.

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 ZILBRYSQ and any potential adverse effects on the breastfed infant from ZILBRYSQ or from the underlying maternal condition.

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.

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) ] .

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.

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.

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.

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.

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.

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.

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.

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 ZILBRYSQ 0.3 mg/kg.

In Study 1 [see Clinical Studies (14) ], complement inhibition of 97.5% was observed by the end of the first week and sustained throughout the 12-week treatment period for gMG patients treated with the recommended dosage regimen of ZILBRYSQ.

Cardiac Electrophysiology

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

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

Absorption

Following single and multiple daily subcutaneous administration of ZILBRYSQ 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 ZILBRYSQ 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 [see Clinical Studies (14) ] , after daily repeated subcutaneous administration of ZILBRYSQ 0.3 mg/kg, plasma concentrations of zilucoplan were consistent, with steady state trough concentrations being reached by four weeks of treatment with ZILBRYSQ through twelve weeks.

Distribution

The mean volume of distribution at steady state was 3.51 L in the population pharmacokinetics analysis for adult patients with gMG. Zilucoplan and its 2 major metabolites are highly bound to plasma proteins (>99%).

Elimination

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

Metabolism

As a peptide, ZILBRYSQ 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 (<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 ZILBRYSQ 0.3 mg/kg in subjects with severe renal impairment (as defined by a creatinine clearance <30 mL/min estimated by 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 ZILBRYSQ 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.

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% (2/86) of patients treated with ZILBRYSQ developed anti-drug antibodies (ADA). A total of 9.3% (8/86) of ZILBRYSQ 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 ZILBRYSQ.

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.

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:

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:

• 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.