Summary Basis of Decision for Rystiggo

Clinical Pharmacology

Rozanolixizumab is a humanized immunoglobulin G (IgG) 4 monoclonal antibody that binds to neonatal Fc receptor (FcRn). It decreases serum concentrations of IgG and pathogenic IgG autoantibodies by inhibiting the binding of IgG to FcRn, a receptor that normally protects IgG from intracellular degradation and recycles IgG back to the cell surface.

Rozanolixizumab exhibited non-linear pharmacokinetics. Following subcutaneous administration, rozanolixizumab exposure increased in a greater than dose-proportional manner over a dose range of 1 mg/kg to 20 mg/kg (more than two times the maximum recommended dose of approximately 7 mg/kg). Peak plasma levels are achieved after approximately 2 days in healthy subjects. After subcutaneous administration, the absolute bioavailability of rozanolixizumab was estimated at approximately 70% based on a population pharmacokinetic analysis. Rozanolixizumab is expected to be metabolized via catabolic pathways, similarly to endogenous IgG. The non-linear pharmacokinetics observed for rozanolixizumab was attributed to target-mediated drug disposition due to binding to the FcRn. This accelerates the clearance of rozanolixizumab and other IgG antibodies, and therefore the half-life of rozanolixizumab is concentration dependent and cannot be calculated. Rozanolixizumab plasma concentrations were undetectable within one week after dosing.

Results of a population pharmacokinetic analysis indicated that increasing body weight is correlated with decreased rozanolixizumab exposure. To mitigate this effect, the recommended doses are adjusted based on body weight categories. No dose adjustment is needed based on age, sex, race, renal impairment, or hepatic impairment.

Due to the mechanism of action of rozanolixizumab, exposures of concomitantly administered IgG-based drugs and Fc–peptide fusion proteins may be decreased. This risk has been addressed in the Product Monograph for Rystiggo.

After one treatment cycle of six weekly doses of rozanolixizumab, 26.9% (42/156) of patients developed anti-drug antibodies (ADAs) and 10.3% (16/156) had neutralizing antibodies (NAbs). Upon reinitiating therapy, the proportion of patients who developed ADAs and NAbs increased to 61.4% (35/57) and 43.9% (25/57), respectively. The development of NAbs was associated with a 24% decrease in overall plasma exposure of rozanolixizumab. While the data were limited, there was no apparent impact of immunogenicity on efficacy. The rate for certain events (e.g., dyslipidemia, upper respiratory tract infections, and dyspnea) was at least two times higher in patients with ADAs than in patients without ADAs.

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

Clinical Efficacy

Data from the Phase III pivotal Study MG0003 provided evidence of the clinical efficacy of Rystiggo in patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive. The enrolled study population was limited to patients on stable doses of conventional myasthenia gravis therapies, who were being considered for additional treatment (Myasthenia Gravis Foundation of America [MGFA] Clinical Classification Class II to IVa; Myasthenia Gravis Activities of Daily Living [MG-ADL] total score ≥3; Quantitative Myasthenia Gravis [QMG] score ≥11). Two hundred patients were randomized 1:1:1 to receive a weight-tiered dose of rozanolixizumab equivalent to approximately 7 mg/kg (66 patients), approximately 10 mg/kg (67 patients), or placebo (67 patients). In this study, patients received a single treatment cycle, defined as one dose administered weekly for a period of 6 weeks, followed by an 8-week observation period.

Efficacy was primarily assessed at Day 43 (one week following the end of the treatment period with Rystiggo). The primary efficacy endpoint was the change from baseline to Day 43 in the MG-ADL total score. The MG-ADL scale, an established endpoint for measuring treatment benefit in patients with gMG, assesses the impact of gMG on daily function according to 8 signs/symptoms with the total score ranging from 0 to 24. Key secondary efficacy endpoints included the change from baseline to Day 43 in the Myasthenia Gravis Composite (MG-C) score and the QMG score. The MG-C total score measures symptoms and signs of gMG based on physician examination and patient history, with the total score ranging from 0 to 50. The QMG total score is a 13-item categorical grading system that assesses muscle weakness, with the total score ranging from 0 to 39. Changes of at least 2 points on the MG-ADL scale and at least 3 points in the MG-C and QMG scores are considered clinically meaningful.

For both weight-tiered doses approximating 7 mg/kg and 10 mg/kg, rozanolixizumab was superior to placebo for the primary and key secondary endpoints. The results are both statistically significant and clinically meaningful. The MG-ADL least squares mean change from baseline to Day 43 was -0.784 in the placebo group, -3.370 in the group that received approximately 7 mg/kg (difference versus placebo: -2.586 [95% confidence interval (CI): -4.091, -1.249]). The analysis of the key secondary endpoints, the least squares mean change in MG-C and QMG scores, showed consistent results providing supportive evidence of treatment benefit.

Rystiggo is intended for repeated cyclic treatment based on clinical evaluation. The frequency of rozanolixizumab treatment cycles is therefore expected to vary by patient. In Study MG0007, an open-label extension study which enrolled patients from Study MG0003, subsequent treatment cycles were initiated based on worsening gMG symptoms (defined as, for example, an increase of 2.0 points on the MG-ADL scale or 3 points on the QMG scale). In total, 157 patients were treated in Study MG0007. At Cycle 1, 80 patients were assigned to receive approximately 7 mg/kg, and 77 patients were assigned to receive approximately 10 mg/kg, however, dose switches were permitted throughout the study.

The median number of treatment cycles received through the course of this study was 6 (ranging from 1 to 17) and the median time in the study was 24.2 months. Data from Study MG0007 demonstrated clinically relevant improvements (reductions from baseline) consistently across several measures of efficacy (the MG-ADL, MG-C, and QMG) following repeated cyclic treatment. The onset of effect and magnitude of treatment effect observed after repeated cyclic treatment is consistent with that observed in the pivotal Study MG0003. These results therefore provide supportive evidence of a positive treatment benefit following repeated cyclic treatment with Rystiggo. While these results support an overall favourable treatment benefit, they are based on a limited sample size and the examination of individual-level data reveals variability in the treatment response. Therefore, the Product Monograph includes the requirement for close monitoring during treatment.

Rystiggo is meant to be administered over time. The pivotal Study MG0003 was designed to evaluate efficacy and safety of an initial treatment cycle relative to placebo. Additional cycles were administered in an open-label extension Study MG0007, which was ongoing at the time the NDS was submitted. Interim data were submitted, which were challenging to interpret due to a significant number of patients who rolled over into the open-label extension study from the pivotal study and had their dose modified. There were limited data from patients who were exclusively treated with the approximately 7 mg/kg dosing regimen, which was proposed for market authorization. Therefore, the benefit-risk profile of Rystiggo could not be adequately characterized.

Health Canada reviewed this NDS as part of the Access Consortium, with the Swiss Agency for Therapeutic Products (Swissmedic) as the lead reviewer. To address the deficiency of information, Swissmedic requested additional data following the completion of the open-label extension study (MG0007). However, during the Canadian regulatory review process, new data and/or missing documents cannot be requested. Therefore, an NOD was issued, as it enabled Health Canada to accept the new data and continue the review process alongside the other Access partners.

Indication

Sponsor's proposed indication	Health Canada-approved indication
Rystiggo (rozanolixizumab injection) is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients.	Rystiggo (rozanolixizumab injection) is indicated for the treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive.

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

Clinical Safety

The pivotal study, MG0003, provided placebo-controlled safety data from a single treatment cycle (i.e., 6 subcutaneous infusions of Rystiggo, administered weekly) followed by an 8-week no-treatment observation period. Of the 200 enrolled patients, 67 patients received placebo, 64 patients received a dose approximating 7 mg/kg, and 69 patients received a dose approximating 10 mg/kg. The median exposure time to Rystiggo was 36 days (consistent with the dosing regimen), and was balanced across treatment groups. The majority of patients in all treatment groups received all 6 infusions. No deaths were reported in the study.

Overall the incidence of treatment-emergent adverse events (TEAEs) was similar in the groups receiving approximately 7 mg/kg and approximately 10 mg/kg (approximately 82%), and lower in the placebo group (approximately 67%). A trend was observed that the incidences of serious TEAEs, severe TEAEs, and TEAEs leading to permanent and/or temporary discontinuation were the highest in the group receiving approximately 10 mg/kg. Therefore, there is some evidence of an overall increased risk of serious/severe adverse events following treatment with the dose approximating 10 mg/kg compared to the dose approximating 7 mg/kg.

Adverse reactions reported in at least 5% of patients treated with Rystiggo (total dose group) and at a greater frequency than placebo included: headaches, diarrhea, nausea, abdominal pain, upper respiratory tract infections, rash, arthralgia, pyrexia, and injection site reactions. With respect to serious TEAEs, none were reported in more than a single patient with the exception of myasthenia gravis/myasthenic gravis crisis (i.e., the underlying medical condition).

The safety profile of a single treatment cycle of Rystiggo, consisting of 6 weekly doses of approximately 7 mg/kg or approximately 10 mg/kg, was characterized in Study MG0003. No major safety issues were detected which cannot be appropriately managed and/or mitigated.

The safety of repeated treatment cycles was assessed by analyzing pooled data (Pool S2) from the pivotal study, MG003 (Rystiggo data only), and the open-label extension study, MG0007. Due to the permitted dose switches that occurred during Study MG0007, the results from the groups assigned to receive approximately 7 mg/kg and approximately 10 mg/kg were also combined. As such, the safety profile of Rystiggo beyond one treatment cycle was characterized in the total dose group. The pooled data included 188 patients, with 93.1% of patients reporting TEAEs. Six deaths were reported: three due to pneumonia, one due to cardiac failure related to endocarditis, one due to myocardial infarction, and one due to small cell lung cancer. All six deaths were assessed as not related to treatment with Rystiggo. It is, however, important to note that three of the six deaths occurred in the context of pneumonia (infection), and given the mechanism of action of rozanolixizumab (i.e., increased risk of infection), causality cannot be ruled out. The Product Monograph for Rystiggo therefore addresses the occurrence of serious infections, including the occurrence of fatal infections.

Generally, the incidence of TEAEs did not appear to change with repeated cyclic treatment. The safety profiles were consistent between the placebo-controlled data in the pivotal study (one treatment cycle) and the pooled data from the pivotal and open-label extension studies (multiple treatment cycles). Analysis of the pooled data confirmed that several adverse events were reported at higher incidence in patients treated with Rystiggo compared to placebo: headaches (including serious and/or severe headaches), infections (including serious infections), hypersensitivity reactions (rash, angioedema), aseptic meningitis, gastrointestinal disturbances (diarrhea, nausea, abdominal pain), injection site reactions, and arthralgia. In addition to routine pharmacovigilance activities, the sponsor has agreed to enhanced monitoring of the risks listed above and has committed to conducting a worldwide retrospective observational study to address all safety concerns.

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

In vitro primary pharmacodynamic studies demonstrated that rozanolixizumab binds to the neonatal Fc receptor (FcRn) with high affinity and inhibits FcRn-mediated immunoglobulin G (IgG) recycling and transcytosis.

Toxicology studies with rozanolixizumab were conducted in cynomolgus monkeys. In all studies, a reduction in circulating total IgG concentrations (expected pharmacological response) was observed following the administration of rozanolixizumab, including in pregnant females and their infants (at birth, as a result of the impaired maternal IgG transfer). Reduced immune IgG response to antigen challenge in a T-dependent antibody response (TDAR) assay was also observed, but only in repeat-dose toxicity studies. The findings did not lead to adverse effects but suggest an increased risk of infection with rozanolixizumab administration.

No adverse effects were observed in a 13-week repeat-dose toxicity study. The no-observed-adverse-effect level (NOAEL) in this study was 150 mg/kg administered every three days subcutaneously or intravenously (exposures of 64-fold and 91-fold the human exposure at the maximum recommended human dose, respectively). In contrast, in a 26-week repeat-dose toxicity study in which animals were administered 150 mg/kg every three days subcutaneously, anti-drug antibody (ADA)-associated immune complex disease was observed in two animals. The inflammatory response in one of the animals was determined to be adverse based on adverse histopathological findings, and therefore, a NOAEL could not be determined for this study. Immunogenicity in non-clinical species, however, does not necessarily translate to humans.

Maternal exposure to rozanolixizumab in the enhanced pre- and postnatal development study resulted in an increase in prenatal loss and in a reduction in mean female infant body weight during the postnatal period. As a result, a NOAEL for the developmental toxicity of rozanolixizumab could not be determined. A reduction in circulating total IgG concentrations was also observed at birth in infants whose mothers had maintained significant exposure to rozanolixizumab. This indicated inhibition of maternal IgG transfer across the placenta, and therefore, inhibition of passive immunization of fetuses/infants. Some drug transfer across the placental barrier was observed, as low concentrations of rozanolixizumab were detected in infants at birth (but not thereafter).

Carcinogenicity and genotoxicity studies were not performed, which was considered acceptable and in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Rystiggo. Considering the intended use of Rystiggo, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

Characterization of the Drug Substance

Rozanolixizumab is a recombinant humanized immunoglobulin G4 (IgG4) monoclonal antibody directed against the neonatal Fc receptor (FcRn), expressed in genetically engineered Chinese hamster ovary (CHO) cells. It is indicated for the treatment of generalized myasthenia gravis in adult patients. Rozanolixizumab specifically binds FcRn to block IgG binding to FcRn. Without rozanolixizumab, IgG antibodies are internalized through endocytosis, and bind to FcRn within endosomes at acidic pH. The IgG antibodies are subsequently re-released from the cell. Rozanolixizumab binds to FcRn, and the complex is internalized into endosomes, competitively inhibiting IgG binding to FcRn within endosomes. This leads to sorting of IgG into lysosomes, where free IgG is degraded.

Detailed characterization studies were performed to provide assurance that rozanolixizumab consistently exhibits the desired characteristic structure and biological activity. The quality attributes examined included primary and higher order structure, molecular weight, size heterogeneity, charge heterogeneity, post-translational modifications, oligosaccharide profiling, and biological function.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

Rozanolixizumab is manufactured by recombinant deoxyribonucleic acid (DNA) technology in CHO cells which have been genetically engineered to express the drug substance. A cell culture is initiated from a single vial from the working cell bank and allowed to expand through a fed-batch process. The drug substance is harvested and purified through a series of centrifugation, chromatographic and filtration steps. The drug substance is formulated and then filtered into bags, and stored at ≤-60 °C. Potential viruses are inactivated and removed using low pH inactivation and virus filtration.

Manufacturing of the drug product involves thawing and pooling the formulated drug substance and sterile filling into vials. The vials are stoppered and sealed, visually inspected, and stored at 2 °C to 8 °C.

The data submitted have demonstrated that the drug substance and drug product manufacturing processes are capable of consistently manufacturing rozanolixizumab drug substance and drug product of acceptable quality, and a drug product that consistently meets the label claim.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of the rozanolixizumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The drug substance and drug product manufacturing processes are controlled by process parameters and in-process controls/tests with defined operating ranges, action limits, and acceptance criteria. The criticality of each of these was appropriately defined, and based on risk assessments, process characterization studies, and previous experience gained during development. The analytical methods were appropriately validated or complied with relevant pharmacopeia standards. Appropriate specifications have been defined for drug substance and drug product release and stability. Overall, the control strategy ensures suitable product quality for rozanolixizumab drug substance and drug product over the lifetime of the product.

A review of the viral clearance studies completed by the Therapeutic Goods Administration of Australia demonstrated minimal risk of exposure to viral adventitious agents or endogenous agents for patients.

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. No risk factors were identified for potential release of N-nitrosamines for the rozanolixizumab manufacturing process, equipment or facilities for the drug substance or drug product, or from the container closure systems. Confirmatory testing for N-nitrosamines in the rozanolixizumab drug product is therefore not considered necessary.

Rystiggo is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 36-month shelf life is acceptable when Rystiggo is stored at 5 °C ± 3 °C and protected from light. Additional storage and disposal instructions are included in the Product Monograph for Rystiggo.

Facilities and Equipment

Based on risk assessment scores determined by Health Canada, on-site evaluations (OSEs) were not recommended for the drug substance or drug product manufacturing sites.

Adventitious Agents Safety Evaluation

Adventitious agents are excluded from the process stream through careful selection of raw materials and the manufacturing process. The potential retrovirus-like particle (RVLP) load in the unprocessed bulk was used in combination with the maximum dose and the viral clearance data to estimate the potential worst-case potential RVLP contamination. Adventitious agents are excluded from the process stream through the careful selection of raw materials and control of the manufacturing process. The potential load of retrovirus-like particles (RVLPs) in the unprocessed bulk was assessed using the maximum dose and viral clearance data and was determined to be within safe limits under worst-case conditions.

The biologic raw materials originate from sources with no or minimal risk of transmissible spongiform encephalopathy agents or other human pathogens.