Summary Basis of Decision for Zilbrysq

Clinical Pharmacology

Zilucoplan (the medicinal ingredient in Zilbrysq) is a 15 amino acid, synthetic macrocyclic peptide. 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 vitro, zilucoplan was shown to bind to complement component 5 (C5) and inhibit its cleavage by C5 convertase into C5a and C5b. This inhibition results in a downregulation of the assembly and cytolytic activity of the membrane attack complex (C5b-9, MAC).

The clinical pharmacology package submitted for zilucoplan included reports from human pharmacodynamic and pharmacokinetic studies.

The pharmacodynamic effect of zilucoplan injection was analysed through the ability of inhibiting ex vivo, complement-induced sheep red blood cell lysis.

In the Phase II study in generalized myasthenia gravis, patients received Zilbrysq 0.3 mg/kg, Zilbrysq 0.1 mg/kg or a placebo daily for 12 weeks. There was rapid complement inhibition within 1 to 3 hours and at Week 12, complement inhibition was 95.7% in patients receiving Zilbrysq 0.3 mg/kg/day, compared to 81.8% in patients receiving Zilbrysq 0.1 mg/kg/day.

In the Phase III study in generalized myasthenia gravis, patients received Zilbrysq 0.3 mg/kg or placebo daily for 12 weeks. Similarly, complete complement inhibition of 97.5% could be seen from Week 1 through Week 12 with Zilbrysq.

This effect was maintained in the Phase III open-label extension study, where complement inhibition at Week 12 was 97.3% in patients who were treated with Zilbrysq in Phase II or Phase III studies, and 95.9% in patients who were treated with placebo in Phase I or Phase III studies and switched to Zilbrysq in the open-label extension.

Data from the Phase II and Phase III studies demonstrated rapid, complete and sustained complement inhibition with Zilbrysq 0.3 mg/kg/day.

Zilbrysq was evaluated in a thorough QT study where no meaningful effects on cardiac functions were found following administration of a supratherapeutic dose of zilucoplan. From a safety standpoint, Zilbrysq was generally safe and well-tolerated in all the studies evaluated as part of the clinical pharmacology package. No discernible safety concern patterns, including adverse reactions, laboratory or vital sign findings, were observed.

No clinical drug-drug interaction studies were performed with Zilbrysq. In all clinical studies, patients taking rituximab were excluded from the study. Rituximab is a monoclonal antibody that is used to treat certain types of cancer and rheumatoid arthritis. It has also been used in studies to treat myasthenia gravis. However, there is a potential inhibitory effect of zilucoplan on the complement-dependent effect of rituximab. Therefore, zilucoplan may reduce the complement-dependent pharmacodynamic effects of rituximab. For this reason, rituximab has been added to the drug interactions section of the Zilbrysq Product Monograph.

For further details, please refer to the Zilbrysq Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Zilbrysq for the sought indication in adults was supported by two double-blind, placebo-controlled efficacy and safety studies, MG0010 (pivotal study) and MG0009 (supportive study). Both studies were 12 weeks in duration, with the option to enter into an open-label extension study following study completion. In these studies, a total of 100 male and female participants received Zilbrysq at 0.3 mg/kg once daily and 15 participants received Zilbrysq at 0.1 mg/kg once daily (placebo: 103), using weight-bracketed dosing (this strategy resulted in a possible range of doses in MG0010 from 0.22 mg/kg/day to 0.42 mg/kg/day).

Participants in the pivotal Phase III study had an average age of about 53 years (range 19‑75 years). Participants were nearly 50% male and female.

Baseline disease characteristics, including age at disease onset, disease severity, duration of disease, prior myasthenia gravis crisis, and generalized myasthenia gravis refractory status were similar between treatment groups. Participants included in these studies were acetylcholine-receptor antibody positive, had a Myasthenia Gravis Foundation of America (MGFA) class of II-IV, had a Myasthenia Gravis-Specific Activities of Daily Living (MG-ADL) score of at least 6, and a Quantitative Myasthenia Gravis (QMG) score of at least 12 with a score of at least 2 in at least 4 items.

In the MG0010 pivotal study, the primary efficacy endpoint was a comparison of the change from baseline between treatment groups in Myasthenia Gravis-Specific Activities of Daily Living (MG-ADL) total score at Week 12. At the recommended 0.3 mg/kg/day dose of Zilbrysq, a numerical difference between the placebo group and the Zilbrysq group was already seen at Week 1. The effect of placebo and Zilbrysq stabilized after approximately 4 weeks with a steady difference up to Week 12. Study results showed there was a placebo-adjusted improvement (decrease) of -2.09 in the MG-ADL total score. In addition, all sensitivity analyses showed highly significant treatment difference between placebo and Zilbrysq of slightly more than two points, which has been found clinically relevant.

The key secondary endpoints in the MG0010 study were change from baseline at week 12 in Quantitative MG (QMG) total score, myasthenia gravis composite (MGC) total score, and Revised Myasthenia Gravis Quality of Life 15-Item Scale (MG-QOL15r) total score. These secondary endpoints further supported the efficacy of Zilbrysq with statistically significant results at 12 weeks. In the studied population, a change from baseline of ‑2.94 in QMG total score, -3.20 in the MGC total score and -2.49 in the MG‑QOL15r total score were observed.

The efficacy findings from the pivotal MG0010 study were supported by the 12-week randomized double-blind placebo-controlled dose-finding study, MG0009. This study evaluated two Zilbrysq doses: 0.1 mg/kg/day and 0.3 mg/kg/day. Efficacy endpoints were assessed as change from baseline at 12 weeks with QMG as the primary endpoint. The sample size was very limited, as 45 patients were randomized. The analysis of the primary endpoint was the comparison between the 0.3 mg/kg/day Zilbrysq group and the placebo group: the comparison versus the lower dose (0.1 mg/kg/day) and placebo was described as a secondary endpoint. Overall, a clinically significant change from baseline was observed in the primary endpoint with a mean difference between 0.3 mg/kg/day Zilbrysq and the placebo group of -2.8 points (p = 0.0538). Secondary endpoints also showed clinically meaningful changes.

The study duration for both efficacy studies, MG0010 and MG0009, were of shorter duration (12 weeks) compared to previously approved generalized myasthenia gravis treatments (24 to 26 weeks), making long-term efficacy more difficult to confirm. However, the long-term open label efficacy data suggest a sustained and, in some cases, increased positive effect.

Indication

The New Drug Submission for Zilbrysq was filed by the sponsor with the following proposed indication:

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

Health Canada approved the following indication:

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

For more information, refer to the Zilbrysq Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety evaluation of Zilbrysq in patients with generalized myasthenia gravis was based primarily on three clinical studies, MG0009, MG0010, and open-label extension study MG0011. At the time of data cut-off, 91 patients had been treated with Zilbrysq 0.3 mg/kg/day for more than a year.

The safety evaluation revealed that there was no increase in overall incidence of treatment-emergent adverse events (TEAEs) or severe TEAEs for Zilbrysq-treated patients compared to the placebo group (any TEAE: 78% vs 73.8%, respectively; Serious TEAEs: 16% vs 15.5%, respectively; Severe TEAEs: 14% vs 13.6%, respectively). The incidence of any TEAE decreased after the first month of treatment in both Zilbrysq treatment groups and placebo groups. In the open-label long-term treatment safety pool, the incidence of any TEAE over time was generally stable (i.e., no meaningful differences in incidence of TEAEs by duration of treatment). The number of TEAEs leading to discontinuation was low and similar across treatment groups in both the controlled studies and the open label extension.

Several important safety findings were identified during the review of the safety data, as follows

Meningococcal Infections

Meningococcal infections are the most important identified risk for C5 inhibition. For the other approved C5 inhibitors, there is a Serious Warnings and Precautions box for serious meningococcal infections, which may be fatal especially if not treated early. In the generalized myasthenia gravis studies with C5 inhibitors, all participants were required to be vaccinated against Neisseria Meningitidis (meningococcal infection) and/or to use prophylactic antibiotics. No meningococcal infections were reported in any of the clinical studies with Zilbrysq. In order to mitigate this risk, a Serious Warnings and Precaution Box is present in the Zilbrysq Product Monograph, in line with other C5 inhibitors. Zilbrysq in Canada is available as part of a controlled distribution program under which prescribers must enrol patients and confirm vaccination with meningococcal vaccine. Prescribers must also counsel patients about the risk of meningococcal infection and provide them with the patient/carer guide and patient safety card.

Hepatic/Biliary/Pancreatic Events

In the clinical studies, elevated amylase and lipase were observed, with one patient in the open-label extension discontinuing due to a pancreatic enzyme elevation. In the MG0010 pivotal study, 1 (1.1%) of 88 patients on placebo and 7 (8.1%) of 86 patients on 0.3 mg/kg/day Zilbrysq had high-lipase adverse events. In the long-term extension studies (MG0009 and MG0010), eight patients had nine high-lipase adverse events, and all were on 0.3 mg/kg/day Zilbrysq. In the 120-day safety follow-up data, 5 additional participants, none of whom had a pancreatic history, had adverse events of lipase elevation.

There were adverse events of elevated amylase in the pivotal study, reported in 5 (5.8%) patients in the Zilbrysq arm and 2 (2.3%) patients in the placebo arm. There was a single, isolated high-amylase adverse event in the pivotal study, and a single isolated high‑amylase adverse event in the long-term extension study.

Pancreatic adverse events did not occur during the 12-week placebo-controlled studies but did in the long-term extensions, where median time to onset was 180 days. Because of this delayed effect, proportions of participants experiencing pancreatic adverse events could not be compared to placebo. It does, however, appear that the incidence of acute pancreatitis in the open-label extension study was higher than expected for the general population. In the long-term extension there were 10 pancreatic events reported in 7 participants and 1 additional pancreatic event (chronic pancreatitis) was not reported as an adverse event but was an additional finding in one of these study participants. Of these, two had a prior history of having a pancreatic event. Overall, there were 4 participants with pancreatitis, 3 participants with pancreatic cysts, 2 participants with pancreas infection (infected pancreatic pseudocyst), and 2 participants with pancreatic mass/carcinoma. Two patients died of pancreatic adenocarcinoma within two months of diagnosis, one with and one without a pre-Zilbrysq history of a pancreatic condition. Although a prior pancreatic history increases the risk of future events, this does not exclude a contributory role of Zilbrysq. In the 120-day safety follow-up for the long-term extension study, another participant without a pancreatic history had a non-serious mild adverse event of pancreatic steatosis. Pancreatic events are serious and can be life-threatening. Since there are remaining uncertainties about the causality of Zilbrysq in pancreatic events, a precautionary approach was used when labeling for these possibly life-threatening conditions in the Zilbrysq Product Monograph.

Other Infections

In the MG0010 pivotal study, the overall incidence of non-serious infections was higher for Zilbrysq-treated patients than for placebo (22.1% vs 13.6%), which was driven by a higher incidence of upper respiratory tract infections (14.0% for Zilbrysq vs 6.8% for placebo), which is considered an adverse reaction for Zilbrysq and has been labeled in the Zilbrysq Product Monograph. This included nasopharyngitis and sinusitis. The incidence of urinary tract infection was slightly higher in the Zilbrysq group compared with the placebo group (8.1% vs 4.5%); this has also been labeled as an adverse drug reaction in the Zilbrysq Product Monograph.

Labeled Adverse Events

The incidence of injection site reactions was higher in the Zilbrysq treatment group than in the placebo group (26.7% vs 14.8%) in the MG0010 pivotal study. Diarrhea was observed in MG0010 pivotal study at a higher incidence compared to placebo (10.5% vs 2.3%, respectively). In the 120-day safety update a safety signal of morphea was identified due to the occurrence of 11 TEAEs of morphea in 10 study patients. These events have been labeled in the Zilbrysq Product Monograph along with increased blood eosinophils and immunogenicity.

For more information, refer to the Zilbrysq Product Monograph, approved by Health Canada and available through the Drug Product Database.

The review of the non-clinical pharmacology, toxicology and pharmacokinetic studies carried out with zilucoplan (the medicinal ingredient in Zilbrysq) did not identify any serious safety signals or efficacy issues. Overall, the non-clinical pharmacology, toxicology and pharmacokinetic studies support the approval of Zilbrysq for the recommended indication.

Zilucoplan effectively inhibited complement activation by interacting with complement component 5 (C5). This potent interaction inhibits the proteolytic cleavage of C5 into C5a and C5b, and consequently, the downstream assembly of the membrane attack complex (MAC or C5b-9), independently of the type of complement pathway that was activated. Zilucoplan also exhibited activity against the genetic C5 variants R588C/H, suggesting potential efficacy in patients with those genetic variants. Two metabolites of zilucoplan, namely RA103488 and RA106009, displayed in vitro pharmacological activity, although RA106009 was not detected in human plasma.

No pharmacologically or clinically relevant activity of zilucoplan was observed in vitro against a panel of 35 targets known to be associated with abuse liability.

Absorption studies compared oral, intravenous, and subcutaneous routes of administration in rats and intravenous and subcutaneous routes of administration in monkeys. Zilucoplan was absorbed with a time to peak concentration varying between 5 to 8 hours. The oral bioavailability was very low in rats (0.4%) and the subcutaneous bioavailability was reasonable in monkeys (70% to 87%).

Zilucoplan and its major metabolites were highly bound to plasma proteins regardless of the species. Zilucoplan widely distributed into the tissues throughout the body after single subcutaneous dose. Additionally, zilucoplan was quantifiable in brain microdialysate and in cerebrospinal fluid. Major metabolites of zilucoplan were not quantifiable in cerebrospinal fluid. Transplacental transfer of zilucoplan was very low (0.5% to 1.0%) and was not affected by the presence of human complement C5 in the maternal perfusate. Metabolite profiles varied slightly between species. Zilucoplan was mainly metabolized via hydrolysis, leading to the formation of at least 6 metabolites; up to 18 metabolites in human plasma. Two major metabolites were identified (RA102758 and RA103488). cytochrome P450 (CYP) 4F2 was identified to produce RA103488 as a product of ω‑oxidation of zilucoplan. Zilucoplan was extensively metabolized prior to elimination. The major route of excretion was feces and urine, with minor contribution of bile.

Zilucoplan and its major metabolites are unlikely to modulate major CYP enzymes. Zilucoplan and its metabolites are not substrates of drug transporters (P‑glycoprotein/breast cancer resistance protein/organic anion transporting polypeptide 1B1/3) and are unlikely to inhibit major efflux and uptake transporters.

The effect of zilucoplan was evaluated in the safety pharmacology core battery studies on central nervous system, cardiovascular, and respiratory function as well as on human Ether-à-go-go-related gene potassium channels. Overall, no serious safety signals were identified and no QT prolongation is expected.

Chronic toxicity studies showed transient and/or reversible findings (e.g., mononuclear cell infiltration, myofiber degeneration, hematological changes, local signs) that were associated with the drug. These signs were particularly present in the high dose group.

In a 39 week monkey study, early euthanasia was necessary for a few animals, including in the low, mid and high dose groups (i.e., 2, 4, and 6 mg/kg/day). Clinical examination showed several systemic effects, with a more severe extent in animals from the high dose of 6 mg/kg/day. At terminal euthanasia, epithelial tissue was affected in all treated groups at various locations such as tongue, esophagus, cervix, vagina, etc. The thymus was also affected with increased cellularity and/or lymphoid follicles formation. The bone marrow of females in the high dose group (6 mg/kg/day) were particularly affected, with lymphoid follicles formation and aggregates. Interestingly, at recovery euthanasia, most drug-associated findings were not observed but some of them, such as esophagus findings, were still reported.

The drug was detected in both the tear and saliva tests with dose proportionality, which suggested broad systemic distribution.

The local findings (i.e., scabs, dark/red foci, thickness) were expected with the route of administration and were corroborated by subcutaneous cell infiltration.

The highest dose that was considered tolerated in the 39-week study was 2 mg/kg/day (also corresponding to the 13-week monkey study no-observed-adverse-effect level). The exposure as measured by the area under the plasma concentration-time curve (AUC_0-t) was 541,000 ng*h/mL and the peak plasma concentration (C_max) was 32,250 ng/mL at Day 273. Therefore, based on study CL0529 that predicted an AUC of 275 ng*h/mL for a patient of 80 kg receiving a 32.4 mg dose (i.e., 0.4 mg/kg/day), the safety margin was 1.97.

Genotoxicity studies did not reveal any adverse effect of the drug. A carcinogenicity waiver has been granted to the sponsor based on the biology and pharmacology of Zilbrysq, as well as on the evaluation of the chronic toxicity studies and the reproductive and developmental studies.

Reproductive and development studies demonstrated that the drug did not elicit any adverse effect on male fertility. However, it should be noted that while the sperm maturation process stages were observed and deemed normal, no quantitative data was provided. Furthermore, no maternal toxicity, fetal development alteration, reproductive organ histopathology or spermatogenic developmental changes were observed.

For more information, refer to the Zilbrysq Product Monograph, approved by Health Canada and available through the Drug Product Database.

The quality (chemistry and manufacturing) information submitted for Zilbrysq has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at 5 ºC ± 3 ºC, and 3 months when stored at room temperature (up to 30 ºC) and protected from light.

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.