Summary Basis of Decision for Uplizna

As outlined in the What steps led to the approval of Uplizna? section, the clinical review of the New Drug Submission for Uplizna was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .

Clinical Pharmacology

Uplizna is a CD19-directed cytolytic antibody drug. The precise mechanism by which inebilizumab (the medicinal ingredient in Uplizna) exerts its therapeutic effects in adult patients with neuromyelitis optica spectrum disorders (NMOSD) is unknown, but it is presumed to involve binding to CD19, a cell surface antigen present on pre-B and mature B-cells. Following cell surface binding to B lymphocytes, inebilizumab results in antibody dependent cellular cytotoxicity.

Based on observed concentration from the randomized control period (RCP) of the pivotal Study 1155, the pharmacokinetics of inebilizumab was characterized in patients with NMOSD following a 300 mg dose regimen administered intravenously. No pharmacokinetic data were collected during the open-label period of the study. The effects of potential covariates on the pharmacokinetics of inebilizumab in patients with NMOSD was assessed through a population pharmacokinetic analysis using pooled data from 213 patients (total of 1,617 samples) from Study 1155 and the two Phase I studies conducted in patients with systemic sclerosis (Study CP200) or multiple sclerosis (Study 1102).

Following intravenous administration of 300 mg inebilizumab on Day 1 and Day 15, the mean maximum concentration was 104 mcg/mL and 116 mcg/mL, respectively. The mean terminal half-life of inebilizumab was approximately 18 days and the mean cumulative change in the area under the concentration-time curve (AUC) was 3,130 mcg d/mL by week 26. The population analysis identified body weight as a significant covariate. Inebilizumab clearance increased with body weight. In NMOSD patients, about 20% exposure variability (AUC from Day 0 to Day 14 [AUC_0-14d] and cumulative AUC at 26 weeks) was observed between patients with lighter body weight (range: 38 to 57 kg) and heavier body weight (range: 78 to 148 kg). Anti-aquaporin-4 immunoglobulin G (AQP4-IgG) serostatus, age, gender, and race had no significant effect on inebilizumab pharmacokinetics. Despite variability due to the effect of body weight, the exposure-response analysis showed a flat relationship between exposure and efficacy (primary and key secondary endpoints) as well as safety (incidence of adverse events or serious adverse events). These findings support the proposed 300 mg fixed dose of inebilizumab for the treatment of NMOSD, and thus no dose adjustments are deemed necessary.

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

Clinical Efficacy

The efficacy of Uplizna as a monotherapy for the treatment of NMOSD in adult patients who are anti-AQP4-IgG seropositive was based on the results of Study 1155, a pivotal Phase II/III, multicentre, multinational, randomized, double-blind, placebo-controlled study. The study design consisted of two parts, a randomized control period (RCP) and an open-label period (OLP).

Study 1155 included patients who had experienced at least one acute NMOSD attack in the prior year or at least two attacks in the prior two years that required rescue therapy (e.g., steroids, plasma exchange, intravenous immunoglobulin), and had an Expanded Disability Severity Scale (EDSS) score of 7.5 or less (patients with an EDSS score of 8 were eligible as well if they were deemed capable of participating). The EDSS is a scale used to assess neurologic impairment in multiple sclerosis. The EDSS scale consists of seven functional system scores testing visual, brainstem, pyramidal, cerebellar, sensory, bowel and bladder, and cerebral, which are used to derive an EDSS score ranging from 0 (normal neurological exam) to 10 (death from multiple sclerosis).

Patients were excluded from the study if previously treated with immunosuppressant therapies within an interval specified for each such therapy. The use of immunosuppressants as background therapy for the prevention of a NMOSD relapse was prohibited during the RCP. The use of corticosteroids, whether oral or intravenous, was also prohibited during the blinded phase of the trial, with the exception of premedication for investigational treatment and treatment for a relapse.

The efficacy data reviewed for this submission focused primarily on anti-AQP4-IgG seropositive patients, given efficacy data on anti-AQP4-IgG seronegative patients are limited.

Study 1155 included 213 AQP4-IgG seropositive patients with NMOSD. During the RCP, 161 of the 213 patients received treatment with Uplizna (300 mg) and 52 patients received a placebo. Study treatment was administered as a 90-minute intravenous infusion via an infusion pump on Day 1 and Day 15 at the start of the RCP. This was followed by a single intravenous infusion (300 mg) dose every 6 months. Patients remained in the RCP for a maximum of 197 days if they did not experience a relapse. On completion of the RCP, patients were then given the option to enrol into an OLP. In the OLP patients who received Uplizna during the RCP received Uplizna on OLP Day 1 and placebo on OLP Day 15 then 300 mg Uplizna every 6 months. Patients who received a placebo during the RCP initiated treatment with Uplizna in the OLP.

All relapses experienced by patients during the RCP were assessed by a blinded and independent adjudication committee, who determined whether the relapse met protocol-defined criteria. Once the adjudicated relapse was confirmed, the patient was withdrawn from the RCP and offered the option to enrol into the OLP and initiate treatment with Uplizna following the administration of rescue therapy. Patients for whom the relapse was not confirmed by the adjudication committee continued in the RCP until Day 197, or until another attack occurred that was confirmed by the adjudication committee.

The OLP duration was a minimum of 12 months and a maximum of 3 years following entry of the last patient. Enrolled patients could choose to exit the OLP at any time for any reason, including seeking alternative treatment options, at which point they entered the 12-month safety follow-up period (unless consent was withdrawn).

The baseline demographic and disease characteristics were balanced across the two treatment groups. Of the patients, 52% of patients were White, 21% Asian, and 9% Black or African American. Females accounted for 94% of the study population. The mean age was 43 years (range 18 to 74 years). The overall mean EDSS score was 3.94. The overall number of relapses in the two years prior to randomization was two or more in 83% of the patients.

The primary efficacy endpoint in Study 1155 was the time (i.e., number of days) to onset of the first adjudicated NMOSD relapse on or before Day 197. Additional key secondary endpoint measures included worsening from baseline in EDSS at last visit during the RCP, change from baseline in low-contrast visual acuity binocular score measured by low-contrast Landolt C Broken Rings Chart at last visit during the RCP, cumulative total active magnetic resonance imaging lesions (new gadolinium-enhancing or new/enlarging T2 lesions) during the RCP, and the number of NMOSD-related in-patient hospitalizations. A patient was considered to have a worsening in EDSS score if one of the following criteria were met:

• Worsening of two or more points in EDSS score for patients with baseline score of 0;

• Worsening of one or more points in EDSS score for patients with baseline score of 1 to 5;

• Worsening of 0.5 points or more in EDSS score for patients with baseline score of 5.5 or more.

The results from Study 1155 showed that the time to onset of the first adjudicated relapse was significantly longer in patients treated with Uplizna compared to patients who received a placebo with a relative risk reduction of 77% (p <0.0001) in the AQP4-IgG seropositive population. The demonstrated reduction in adjudicated relapses was clinically meaningful and statistically significant. These results were supported by relevant sensitivity analyses.

Secondary endpoints, such as reduced incidence of EDSS worsening and decrease in annualized NMOSD-related hospitalization rate, also support the primary efficacy endpoint results.

In conclusion, the efficacy data assessed in this submission established the efficacy of Uplizna as monotherapy for the treatment of NMOSD in adult patients who are AQP4-IgG seropositive. The mechanism of action of Uplizna is distinct from other drugs currently authorized for this indication. Therefore, Uplizna constitutes an alternative treatment option for patients with NMOSD.

Indication

The New Drug Submission for Uplizna was filed by the sponsor with the following proposed indication, which Health Canada subsequently approved:

Uplizna (inebilizumab for injection) is indicated as monotherapy for the treatment of adult patients with neuromyelitis optica spectrum disorders (NMOSD) who are anti-aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive.

Treatment should be administered under the supervision of a qualified healthcare professional.

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

Clinical Safety

The clinical safety of Uplizna was assessed in a pivotal Phase II/III, multinational, multicentre, randomized, double-blind, placebo-controlled study (Study 1155). This study consisted of a 197-day RCP followed by an OLP of 12 months up to three years in duration.

Across both the RCP and OLP, 208 NMOSD patients who are anti-AQP4-IgG seropositive received one or more doses of Uplizna. Among these, 197 patients were exposed to Uplizna for at least 6 months and 189 patients were exposed to Uplizna for at least one year. Uplizna exposure in total was 667.5 person-years.

Across both the RCP and OLP, the most common adverse reactions occurring in ≥10% of patients with NMOSD AQP4-IgG seropositive who received Uplizna were urinary tract infection (27%), nasopharyngitis (21%), arthralgia (17%), upper respiratory tract infection (17%), headache (16%), back pain (13%), and infusion-related reaction (13%). The most common serious adverse reactions (occurring in at least 2% of patients) were infections (11%) (including urinary tract infections [4%] and pneumonia [2%]). There were six patients who had adverse events leading to permanent discontinuation from treatment. These adverse events were neutropenia, steroid withdrawal syndrome, hepatic steatosis, atypical pneumonia, pneumonia, liver function test increased, and myasthenia gravis.

Similar to other B cell-depleting therapies, Uplizna may increase the susceptibility to infections. In Study 1155, one patient died following the development of new brain lesions for which a definitive diagnosis could not be established. However, the differential diagnosis included progressive multifocal leukoencephalopathy, an opportunistic viral infection of the brain caused by the John Cunningham virus. The sample size and the duration of the clinical studies limit the ability to detect rare events. Malignancy is also a risk of immunomodulatory medicinal products. The risks are managed through appropriate labeling (Warnings and Precautions) in the approved Uplizna Product Monograph. Additionally, patient alert cards will be distributed by healthcare professionals and given to patients and their caregivers to inform them about the symptoms of serious infections. These include progressive multifocal leukoencephalopathy, viral reactivation, and opportunistic infections that may occur with Uplizna treatment. Patients are encouraged to seek medical attention promptly if they experience any of these symptoms. The sponsor will monitor adverse events of interest and will submit updates to Health Canada on a regular basis.

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity, where anti-drug antibodies may develop and could potentially neutralize the biological activity of inebilizumab (the medicinal ingredient in Uplizna). In Study 1155, 7.1% of patients who received Uplizna displayed treatment-emergent anti-drug antibodies that developed or significantly increased from baseline after administration of Uplizna. Although these data do not demonstrate an impact of anti-inebilizumab antibody development on the efficacy or safety of Uplizna in these patients, the available data are too limited to make definitive conclusions.

Overall, Uplizna was generally safe and well tolerated in adult patients with NMOSD who are anti-AQP4-IgG seropositive. Appropriate warnings and precautions are in place in the approved Uplizna Product Monograph to address the identified safety concerns.

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

As outlined in the What steps led to the approval of Uplizna? section, the review of the non-clinical component of the New Drug Submission for Uplizna was conducted as per Method 1 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Primary pharmacodynamic data support inebilizumab (the medicinal ingredient in Uplizna) binding to CD19 and inducing antibody-dependent cellular cytotoxicity and depletion of CD19+ B cells.

Toxicology studies were conducted in human CD19 transgenic mice at doses of 3 mg/kg and 30 mg/kg body weight once weekly. In these studies, inebilizumab administration resulted in B cell depletion in peripheral blood and lymphoid tissues, consistent with the expected pharmacological activity of inebilizumab. No adverse effects were observed in repeat-dose intravenous toxicity studies of up to 6 months in duration. However, repeated dosing using the subcutaneous route at the same dosages resulted in extensive skin lesions (ulcerations with inflammation) in some animals that necessitated early euthanasia for humane reasons. One animal also developed a bacterial infection within ulcerated skin. These findings are considered related to the immunosuppressive effects of inebilizumab.

Reduced fertility was observed following intravenous administration to males and females in a combined fertility and embryo-fetal development study. Although no teratogenic effects were observed, maternal exposure to inebilizumab resulted in the presence of inebilizumab in fetal serum and in a severe reduction in B cells in fetal peripheral blood and fetal liver at both doses.

Maternal exposure to inebilizumab in a pre- and post-natal development study also resulted in the presence of inebilizumab in offspring serum and a severe reduction in B cells in offspring peripheral blood, spleen, and bone marrow. This was accompanied by immunotoxicity in offspring at both maternal doses tested based on a reduction in immune response despite recovery of B cell levels, demonstrating impairment of normal B cell function.

The above findings indicate that inebilizumab crosses the placental barrier and/or it is also excreted in milk. Inebilizumab has a pharmacological effect in fetuses and an adverse effect in offspring at animal maternal exposures lower than the estimated human exposure.

Carcinogenicity and genotoxicity studies were not performed, which was considered acceptable and in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use: Preclinical safety evaluation of biotechnology-derived pharmaceuticals - Scientific guideline (ICH: S6[R1]).

All potential risks identified in toxicology studies, including findings of reduced fertility, post-natal developmental immunotoxicity in offspring, and transfer across the placental barrier, have been labelled in the Product Monograph.

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

The medicinal ingredient of Uplizna, inebilizumab, is an immunoglobulin G, subclass 1, kappa light chain (IgG1κ) human monoclonal antibody that specifically binds to CD19, a cell surface antigen present on pre-B and mature B-cell lymphocytes. Following cell surface binding to B lymphocytes, inebilizumab leads to the activation of effector cells and the induction of antibody-dependent cellular cytotoxicity activity, resulting in a depletion of CD19-positive B cells. It is thought these B cells play a key role in the pathogenesis of neuromyelitis optica spectrum disorders (NMOSD). Although the precise mechanism by which inebilizumab exerts its therapeutic effects in NMOSD is unknown, it is presumed to involve B-cell depletion and may also include the suppression of antibody secretion.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that inebilizumab consistently exhibits the desired characteristic structure and biological activity.

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable.

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

Drug Substance

The drug substance, inebilizumab, is produced in a mammalian cell line (Chinese Hamster Ovary) using recombinant deoxyribonucleic acid technology. The manufacture is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

The manufacturing process of the drug substance consists of a series of stages which include cell culture, pre-culture expansion, bioreactor production, harvesting, clarification, chromatography, viral inactivation, ultrafiltration, purification, and formulation. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use.

Development of the drug substance involved an initial pilot process that was used to manufacture non-clinical/toxicology lots. An increase in scale, and introduction of the master cell bank along with a minor change to the formulation resulted in the drug substance used in Phase I clinical studies. The drug substance used in Phase II and Phase III studies included another increase in manufacturing scale, introduction of the working cell bank, and optimization of the purification steps. Finally, the process was transferred from the clinical manufacturing site to a commercial facility and scaled up for the manufacturing of the commercial drug substance. Comparability data obtained through critical quality attribute testing, characterization, and forced degradation studies was provided between the drug substances manufactured by each process, demonstrating that the process changes did not negatively impact product quality.

Drug Product

Uplizna is supplied as a clear to slightly opalescent, colourless to slightly yellow sterile, preservative-free solution provided in a single-dose vial containing 100 mg inebilizumab in 10 mL solution. Following dilution in commercially available 0.9% sodium chloride, the product is intended for intravenous infusion.

The method of manufacturing and the controls used during the manufacturing process for the drug product are valid and considered to be adequately controlled within justified limits.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with ICH guidelines.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.

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 at 2º C to 8º C for Uplizna is considered acceptable.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.

Based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug substance and drug product manufacturing facilities were not deemed necessary.

Adventitious Agents Safety Evaluation

The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. The manufacturing process provides sufficient capacity to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Purification process steps designed to remove and inactivate viruses are adequately validated.

The excipients used in the formulation are not of animal or human origin.