Regulatory Decision Summary for Zilbrysq

This New Drug Submission (New Active Substance) was filed to obtain market authorization for Zilbrysq (zilucoplan injection) for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive.

The sponsor consented to information sharing between Health Canada and health technology assessment organizations as part of an aligned review pathway.

The new active substance Zilbrysq (zilucoplan injection) is a 15-amino acid macrocyclic peptide, which has been shown to inhibit complement activation in non-clinical studies.

Evidence to support the proposed indication was provided by two randomized, double-blind, placebo-controlled, safety and efficacy studies (MG0009 and MG0010). Both studies were 12 weeks in duration, with the option to enter into an open-label extension study following completion of the main study. In these studies, a total of 100 male and female participants received Zilbrysq at 0.3 milligrams per kilogram (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 to 0.42 mg/kg). Participants 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 (MG) crisis, and generalized myasthenia gravis (gMG) refractory status were similar between treatment groups.

In the main study, MG0010, the primary efficacy endpoint was the between-groups difference in change in Myasthenia Gravis-Specific Activities of Daily Living (MG-ADL) total score between baseline and Week 12. The key secondary endpoints were Quantitative Myasthenia Gravis (QMG), myasthenia gravis composite (MGC), and Revised Myasthenia Gravis Quality of Life 15-Item Scale (MG-QOL15r) scores. At the recommended 0.3 milligrams per kilogram per day (mg/kg/day) dose of Zilbrysq, there was a placebo-subtracted improvement (decrease) of -2.09 in the MG-ADL total score. This was supported by the results of the key secondary endpoints of placebo-subtracted improvement (decrease) of -2.94 in QMG score. MGC and MGQOL15r also showed similar trends in favor of Zilbrysq. Efficacy results from the supportive study, MG0009, confirmed the efficacy findings of study MG0010 (placebo-subtracted values of -2.3 and -2.2 for the primary and key secondary endpoints, respectively). These studies showed an acceptable level of efficacy and results were in line with the documented efficacy of other recently marketed gMG treatments. The study duration for both efficacy studies were of shorter duration (12 weeks) compared to previously approved gMG treatments (24-26 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.

The most common treatment-emergent adverse events (TEAEs) in the Zilbrysq treatment arms of the two controlled studies were injection site reactions, upper respiratory tract infection, urinary tract infection, diarrhea, and increased lipase and amylase levels. Long-term safety of Zilbrysq was assessed in the open-label extension study (MG0011) which enrolled 199 patients and demonstrated a similar safety profile to what was observed in the controlled studies.

Pancreatitis and other effects of Zilbrysq such as pancreatic cysts and pseudocysts with and without infection were seen in the human studies. This was consistent with the histologic findings and lipase (and amylase) elevations seen in the nonclinical studies. Additionally, two subjects died two months after diagnosis of advanced pancreatic adenocarcinoma (one with a history of pancreatitis and the other without). This risk has been adequately labelled in the Product Monograph (PM).

Other events that have been labelled include increased risk of infections, such as respiratory and urinary tract infections, injection site reactions, morphea, blood eosinophils increased and the potential for immunogenicity.

As with other complement (C5) inhibitors, the main safety concern is infection with encapsulated organisms such as Neisseria species (e.g., particularly N. meningitidis for C5 targeting therapy). Therefore, wording similar to that of other C5 inhibitors has been included in the Serious Warnings and Precautions Box in the label, as well as making Zilbrysq available as part of a controlled distribution program where prescribers must enrol patients and confirm vaccination with meningococcal vaccine.

A Risk Management Plan for Zilbrysq was reviewed by Health Canada and considered acceptable. Risks have been communicated in the approved PM and will continue to be monitored post market as outlined in the Risk Management Plan, with routine and non-routine pharmacovigilance activities.

The 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. Following review and requested revisions, the final labelling and PM were considered to be acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Zilbrysq 40mg/mL oral solution for the approved indication when used under the conditions of use recommended in the approved PM. Therefore, a Notice of Compliance was recommended.

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