Regulatory Decision Summary for Rystiggo

The purpose of this submission is to seek market authorization for Rystiggo (rozanolixizumab injection) for the treatment of generalized myasthenia gravis (gMG) in adult patients.

The submission was reviewed using the international review work-sharing model with the ACCESS Consortium between Switzerland, Australia, and Canada. Swissmedic led the review of the non-clinical and clinical data provided in the submission. Health Canada’s assessment was based on a peer review of Swissmedic’s primary assessment.

Myasthenia gravis (MG) is a rare and chronic autoimmune neuromuscular disease whereby pathogenic IgG antibodies attack proteins located in the postsynaptic membrane of the neuromuscular junction. Generalized MG (gMG) is characterized by muscle weakness that leads to difficulties in mobility, speech, swallowing, and vision, as well as impaired respiratory function and extreme fatigue.

The efficacy of Rystiggo for the treatment of generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive was established in Study MG0003, a randomized, double-blind, placebo-controlled study. The enrolled study population was restricted to those patients on stable doses of conventional MG therapies and being considered for additional treatment. In total, 200 patients were randomized 1:1:1 to receive a weight-tiered fixed dose of rozanolixizumab equivalent to approximately 7mg/kg (n = 66) or approximately 10 mg/kg (n = 67), or placebo (n = 67). In this study, patients received a single treatment cycle, defined as 1 dose administered weekly for a period of 6 weeks, followed by an 8-week observation period.

The primary efficacy endpoint was the change from baseline in MG-ADL total score at Day 43. Key secondary efficacy endpoints included change from baseline to Day 43 in MG-C and QMG scores. Rozanolixizumab (for both weight-tiered fixed doses approximating 7 mg/kg and 10 mg/kg) was superior to placebo for the primary and key secondary endpoints; the results were statistically significant and considered clinically meaningful.

The indication proposed by the sponsor initially was broad and did not include the requirement for gMG patients to be anti-AChR or -MuSK antibody positive. The recommended indication has been restricted to these patients to reflect the target population studied in the gMG clinical development program for Rystiggo. This approach is consistent with other products authorized for the treatment of gMG.

Evidence to support repeated cyclic treatment was obtained from an open-label extension study where subsequent treatment cycles were initiated based on worsening gMG symptoms. A consistent treatment response following administration of subsequent cycles of Rystiggo was observed.

Regarding the safety profile of Rystiggo, pivotal Study MG0003 provides placebo-controlled safety data from a single treatment cycle. Of 200 enrolled subjects, 67 received placebo, 64 received rozanolixizumab (RLZ) ≈7 mg/kg, and 69 received RLZ ≈10 mg/kg. Common adverse reactions associated with Rystiggo treatment included: headaches, diarrhea, nausea, abdominal pain, upper respiratory tract infections, rash, arthralgia, pyrexia, and injection site reactions. These risks have been labelled in the product monograph (PM) and will be monitored through pharmacovigilance activities. There is some evidence of an overall increased risk of serious/severe adverse events following treatment with the ≈10mg/kg vs. ≈7mg/kg dose. For this reason, the weight-tiered fixed dose of rozanolixizumab equivalent to ≈7mg/kg is the recommended dose posology for marketing authorization.

Rozanolixizumab is intended for chronic long-term repeated cyclic treatment. The safety of repeated treatment cycles was assessed using data from MG0003 and MG0007 combined. Given the frequent dose switches occurring during study MG0007, the results of both ≈7mg/kg and ≈10 mg/kg dose regimens were also combined to represent the RLZ total dose group. Generally, it was observed that the incidence of adverse events did not appear to decrease with repeated cyclic treatment; and the safety profile appears consistent between MG0003 placebo-controlled data and Pool S2. The additional risk of drug-induced aseptic meningitis was identified and6 deaths were reported, three of which occurring in a context of pneumonia (infection). Given the mechanism of action of rozanolixizumab (i.e. increased risk of infection), causality cannot be ruled out. Both aseptic meningitis and the occurrence of serious infections, including the occurrence of fatal infections, have been labelled in the Product Monograph and will be monitored through enhanced pharmacovigilance activities. Additionally, a worldwide retrospective observational study is planned to address all safety concerns.

The safety database for Rystiggo is considered sufficient to support authorization in the intended population and at the intended dosing regimen; overall, the safety experience with Rystiggo supports an acceptable risk profile. However, owing to the rarity of the disease and lack of long-term data, uncertainties in the safety profile remain. These uncertainties have been adequately addressed through a combination of labelling and/or through routine and enhanced pharmacovigilance activities in the post-market setting.

Overall, the benefit-risk profile of Rystiggo in adult patients with gMG who are who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive is considered favourable.

An updated Risk Management Plan (RMP) for Rystiggo was reviewed by Health Canada and considered acceptable.

The chemistry and manufacturing information submitted for Rystiggo 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 Product Monograph were considered to be acceptable.

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