Summary Basis of Decision for Saphnelo

As described above, the review of the clinical component of the New Drug Submission for Saphnelo was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Anifrolumab, the medicinal ingredient in Saphnelo, is a human immunoglobulin G1 kappa monoclonal antibody that binds with high specificity and affinity to the interferon (IFN) alpha and beta receptor subunit 1 (IFNAR1). This binding inhibits type I IFN signalling which blocks the biologic activity of type I IFNs. Anifrolumab also induces the internalization of IFNAR1, thereby reducing the levels of cell surface IFNAR1 available for receptor assembly. Blockade of receptor-mediated type I IFN signalling inhibits IFN responsive gene expression as well as downstream inflammatory and immunological processes.

Type I IFNs play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Most adult patients with SLE (approximately 60-80%) express elevated levels of type I IFN inducible genes which are associated with increased disease activity and severity.

The clinical pharmacology of Saphnelo was assessed in: a Phase I study that included a first-in-human single ascending dose and multiple ascending dose phase; a single Phase II study with one open-label extension study; and two Phase III studies together with an ongoing placebo-controlled extension. A single population pharmacokinetic and exposure-response model of Saphnelo in adult SLE patients was derived from data from the Phase II and Phase III studies.

The Phase I study CP180 was conducted in adult subjects with scleroderma. In the single ascending dose (SAD) phase, study participants were dosed intravenously (60 minute infusion) with Saphnelo by weight in a dose-escalation manner at dose levels from 0.1-20 mg/kg (~6.5 to 1,300 mg assuming a 65 kg average weight). The multiple ascending dose (MAD) cohort was dosed four times at dose levels of 0.3, 1.0, and 5.0 mg/kg, with the intravenous infusions given over 60 minutes once a week for a total treatment duration of 4 weeks. The top MAD dose corresponds to ~325 mg Saphnelo (assuming a 65 kg average weight).

The pharmacokinetic data from the SAD phase of the study suggested that there is a non-dose proportional increase in the area under the concentration time curve from time 0 to infinity (AUC_inf), driven by saturation of target-mediated drug disposition (TMDD) mechanisms at doses ≥10 mg/kg. An increase in half-life (t_1/2) was also apparent with increasing dose due to TMDD. The pharmacodynamic data showed a robust decrease in type I IFN gene signature following both single (>0.3 mg/kg) and multiple (>1.0 mg/kg) doses, consistent with the mechanism of action of anifrolumab. 

Study 1013 was a Phase II, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group study with a primary objective of evaluating the efficacy of Saphnelo compared to placebo in subjects with chronic, moderately-to-severely active SLE with an inadequate response to standard of care treatment for SLE after 24 weeks of treatment.

The pharmacokinetic data from this study demonstrated a dose-proportional increase in the maximum concentration (C_max) between the 300 and 1,000 mg doses, with a more than dose-proportional increase in trough concentration (C_trough). Following multiple administrations of Saphnelo, effective steady-state was achieved by Day 84 following dosing every 4 weeks. As expected, given the greater-than-dose-proportional increase in C_trough, the accumulation ratio for C_trough at both Day 169 (2.49) and Day 365 (3.06) was higher than C_max (1.36 and 1.56 respectively) at the 300 mg dose with dosing every 4 weeks. In addition, a time-dependent decrease in clearance was also observed (~8.4% over 1 year of treatment) which also contributes to the larger accumulation ratio measured by C_trough compared with C_max.

The population-pharmacokinetic model for anifrolumab was built upon data from SLE patients enrolled in the Phase II study 1013 and the Phase III studies 04 and 05. The model was externally validated using data from Study 04 before that data was included in the final population-pharmacokinetic model. The most appropriate structural model to describe the population-pharmacokinetic profile of anifrolumab consisted of a two compartment model with parallel first-order elimination kinetics and TMDD. This model was appropriately parameterized and consistent with the known physiological characteristics of anifrolumab elimination. The population-pharmacokinetic model accurately predicted the biphasic nature of anifrolumab clearance and larger than dose-proportional increases in exposure that were directly observed in the clinical studies. Only body weight and IFN gene activity level (high/low) were significant covariates on anifrolumab exposure, with increasing exposure observed at lower body weight and/or with low IFN gene activity.

An 85% decrease in type I IFN gene levels was observed 28 days after initiation of anifrolumab treatment, consistent with its mechanism of action. This was maintained throughout the dosing period and recovered following cessation of dosing. No dose dependence in type I IFN gene inhibition was observed between the 300 mg every 4 weeks and the 1,000 mg every 4 weeks dosing regimens. The exposure-response model for anifrolumab suggests that efficacy plateaus at exposure levels consistent with 300 mg dosing. No imbalance in the incidence of herpes zoster or infusion reactions and hypersensitivity was observed at anifrolumab exposures correlating with either 150 mg or 300 mg dosing.

The immunogenicity data suggest that the incidence of anti-anifrolumab antibodies (anti-drug antibodies [ADAs]) was low following multiple dosing for up to 52 weeks. However, uncertainties regarding the false positive rate of the ADA assay, both at baseline and during anifrolumab dosing, precludes any firm conclusions to be drawn at this time regarding the immunogenic profile of anifrolumab. The limitations of the immunogenicity data have been included in the Product Monograph for Saphnelo.

The clinical pharmacology data support the use of Saphnelo for the recommended indication. For further details, please refer to the Saphnelo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Saphnelo in patients with SLE was evaluated in two pivotal Phase III studies (Study 05 and 04) and one Phase II study (Study 1013). All three studies were multicentre, randomized, double-blind, and placebo-controlled with a 52-week treatment period. Patients were diagnosed with SLE according to the American College of Rheumatology (1997) classification criteria.

Study Design

Each study enrolled patients who were ≥18 to <70 years of age with moderate to severe, active, autoantibody positive disease, with an SLE Disease Activity Index 2000 (SLEDAI-2K) score ≥6 points, organ level involvement based on British Isles Lupus Assessment Group (BILAG) assessment (BILAG-2004 level A disease in ≥1 organ system or BILAG-2004 level B disease in ≥2 organ systems), and a Physician’s Global Assessment (PGA) score ≥1, despite receiving standard SLE therapy consisting of either one or any combination of oral corticosteroids, antimalarials and/or immunosuppressants at baseline. Patients continued to receive their existing SLE therapy at stable doses during the clinical trials, with the exception of oral corticosteroids (prednisone or equivalent) where tapering was a component of the protocol. Patients who had severe active lupus nephritis or severe active central nervous system lupus were excluded. The use of other biologic agents and cyclophosphamide were not permitted during the clinical trials; patients receiving other biologic therapies were required to complete a wash-out period of at least 5 half-lives prior to enrolment. All three studies were conducted in North America, Europe, South America and Asia. Of the population studied, 93% were female, 60% were White, 13% were Black/African American, and 10% were Asian. Patients had a mean age of 41 years (range: 18 to 69).

In all studies, patients received Saphnelo or placebo, administered by intravenous infusion, every 4 weeks. In the pivotal Study 05, 457 patients were randomized (1:2:2) to receive Saphnelo 150 mg, 300 mg, or placebo, whereas for the pivotal Study 04, 362 patients were randomized (1:1) to receive Saphnelo 300 mg or placebo. The efficacy of Saphnelo was assessed based on clinical response at Week 52 using the composite endpoints of the BILAG-based Composite Lupus Assessment (BICLA) and the SLE Responder Index (SRI-4). The primary endpoint for both pivotal studies was improvement in disease activity evaluated at Week 52 as measured by SRI-4 (in Study 05) and BICLA (in Study 04). Both studies evaluated the efficacy of Saphnelo 300 mg versus placebo; a dose of Saphnelo 150 mg was also evaluated for dose-response in Study 05. In both pivotal studies, key secondary endpoints of important clinical relevance included but were not limited to the maintenance of oral corticosteroid reduction and annualized flare rate.

In the supportive Study 1013, 305 patients were randomized (1:1:1) to receive Saphnelo 300 mg, 1,000 mg, or placebo. The pre-specified analyses at Week 52 were SRI-4 and BICLA response. Data from this study provided important supportive information, given inconsistencies that were observed in the Phase III study results.

Study Results

In the pivotal Study 05, the pre-specified primary endpoint of improvement in disease activity evaluated at Week 52 as measured by SRI-4 did not demonstrate a statistically significant treatment benefit. Based on a post-hoc analysis using the same definition for restricted medication thresholds as in Study 04, 49% of patients in the Saphnelo 300 mg treatment group and 43% of patients in the placebo group achieved an SRI-4 response with a risk difference of 6% (95% confidence interval [CI]: -4.2, 16.2). These results were inconsistent with those observed in Study 04 and Study 1013 where SRI-4 response was a pre-specified analysis. In the pivotal Study 04, 56% of patients in the Saphnelo 300 mg treatment group and 37% of patients in the placebo group achieved an SRI-4 response with a risk difference of 18% (95% CI: 8.1%, 28.3%). In the supportive Study 1013, 63% of patients in the Saphnelo 300 mg treatment group and 39% of patients in the placebo treatment group achieved an SRI-4 response with a risk difference of 24% (95% CI: 10.9%, 37.2%).

In Study 04, the pre-specified primary endpoint was improvement in disease activity evaluated at Week 52 as measured by BICLA response. The results of the study demonstrated that 48% of patients in the Saphnelo 300 mg treatment group compared to 32% of patients in the placebo group achieved a BICLA response at Week 52 with a risk difference of 16.3% (95% CI: 6.3%, 26.3%). In Study 05 and Study 1013, BICLA response was a pre-specified analysis and consistent results were observed. In Study 05, based on a post-hoc analysis using the same definition for restricted medication thresholds as in Study 04, 47% of patients in the Saphnelo group and 30% of patients in the placebo group achieved a BICLA response at Week 52 with a risk difference of 17% (95% CI: 7.2%, 26.8%). In Study 1013, 53.5% of patients in the Saphnelo 300 mg treatment group and 25% in the placebo group achieved a BICLA response with a risk difference of 28% (95% CI: 15.3%, 41.5%).

A key secondary endpoint of the pivotal studies was the maintenance of oral corticosteroid reduction. In Studies 04 and 05, during weeks 8-40, patients with a baseline oral corticosteroid dose of ≥10 mg/day were required to taper their dose to ≤7.5 mg/day, unless there was worsening disease activity. In Study 04, of the 47% (total number [n] = 70) of patients with a baseline oral corticosteroid use ≥10 mg/day, 52% of patients in the Saphnelo 300 mg group and 30% in the placebo group were able to reduce their oral corticosteroid use by at least 25% to ≤7.5 mg/day at Week 40. This was maintained through to Week 52 for a difference of 21.2% (95% CI 6.8, 35.7). Based on a post-hoc analysis using the same definition for restricted medication thresholds as in Study 04, a consistent trend in favour of Saphnelo 300 mg was also observed in Study 05 (50% vs. 33%; difference: 16% [95% CI 3.4, 29.8]). Although Study 1013 did not include a mandatory requirement to taper oral corticosteroid dose, 56% of patients in the Saphnelo 300 mg and 27% of patients the placebo group were able to reduce their use to ≤7.5 mg/day by Week 52.

Another key secondary endpoint of the pivotal studies was treatment effect on the annualized flare rate. In Study 04, the annualized flare rate was 0.43 in the Saphnelo 300 mg group and 0.64 in the placebo group (rate ratio: 0.67 [95% CI: 0.48, 0.94]). In Study 05, the annualized flare rate in the Saphnelo group was 0.60 and 0.72 in the placebo group (rate ratio: 0.83 [95% CI: 0.60, 1.14]). In Study 1013, the rate ratio between the Saphnelo 300 mg group and placebo was 0.73 [95% 0.44, 1.20]. Therefore, a favourable treatment effect was consistently observed on the annualized flare rate across the clinical studies.

Indication

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

Saphnelo (anifrolumab injection) is indicated as an add-on therapy for the treatment of adult patients with moderate to severe systemic lupus erythematosus (SLE).

To ensure safe and effective use of the product, Health Canada approved the following indication:

Saphnelo (anifrolumab for injection) is indicated in addition to standard therapy for the treatment of adult patients with active, autoantibody positive, systemic lupus erythematosus (SLE).

The safety and efficacy of Saphnelo have not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. Use of Saphnelo is not recommended in these situations.                   

Overall Analysis of Efficacy

Overall, a favourable treatment effect was observed for Saphnelo. Despite the positive results, several important limitations were noted. The pivotal Study 05 failed to demonstrate a statistically significant treatment benefit with respect to the pre-specified primary endpoint of SRI-4 response at Week 52. Furthermore the treatment effect observed in Study 05 using SRI-4 was not consistent with other measures of disease activity (i.e., BICLA response). There were also inconsistencies with the magnitude of effect seen for SRI-4 response in Study 05 as compared to the results observed in Study 04 and Study 1013. In addition, due to errors made in the protocol regarding restricted medication thresholds, the results reviewed were based primarily on a post-hoc analysis using the same restriction medication rules used in Study 04 for consistency. The primary endpoint in Study 04 was amended from SRI-4 to BICLA response at Week 52 following review of the results from Study 05. Although this amendment occurred prior to un-blinding the results, it occurred after results from Study 05 became available, and is therefore considered data-driven from a statistical point of view. Finally, Study 1013 was a Phase II study and was not designed as a pivotal study. As such, the endpoints were not adequately controlled for multiplicity of testing.

While each study contained limitations, based on the totality of evidence, a favourable trend in treatment effect was consistently observed across studies for several clinically meaningful endpoints including the SRI-4 response rate at Week 52, the BICLA response rate at Week 52, the effect on concomitant corticosteroid treatment, and the effect on SLE flares. For more information, refer to the Saphnelo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Saphnelo was evaluated based on data from Study 05, Study 04 and Study 1013, and their longer-term extension studies. The design of these studies is described in the Clinical Efficacy section. Patients who completed either Study 05 or Study 04 were eligible to enroll into the ongoing longer-term extension Study 09. Patients who completed Study 1013 were eligible to enroll into the longer-term extension Study 1145. In all, the safety of Saphnelo at a dose of 150 mg, 300 mg, and 1,000 mg has been characterized in 837 patients with SLE for up to 4 years as of the database cut-off of March 19, 2020.

From the 52-week controlled clinical study period, 459 patients were exposed to at least one 300 mg intravenous dose of Saphnelo compared to 466 patients in the placebo control group. Adverse events were reported in 86.9% of patients receiving Saphnelo and 79.4% of patients receiving placebo. The proportion of patients with serious adverse events was not different in a clinically meaningful way, with 11.8% for Saphnelo and 16.7% for placebo. The most commonly reported (≥5%) treatment-emergent adverse events during treatment for patients receiving Saphnelo versus  (vs.) placebo, respectively, included nasopharyngitis (16.3% vs. 9.4%), upper respiratory tract infection (15.5% vs. 9.7%), urinary tract infection (12.0% vs. 13.5%), bronchitis (9.8% vs. 4.3%), infusion related reaction (9.4% vs. 7.1%), headache (8.1% vs. 9.7%), herpes zoster (6.1% vs. 1.3%), back pain (5.2% vs. 4.3%), sinusitis (5.2% vs. 5.2%) and cough (5.0% vs. 3.2%). Imbalances that were observed in the clinical development program including infections, herpes zoster, and hypersensitivity have been labelled under the Warnings and Precautions section in the Saphnelo Product Monograph. As well, treatment-emergent adverse events that occurred more frequently in patients treated with Saphnelo 300 mg compared to placebo at 52 weeks, have been captured in the Adverse Reactions section of the Saphnelo Product Monograph. 

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs], which have the potential to neutralize the biological activity of the drug). In the Phase II and III studies, neither the development of ADAs nor neutralizing antibodies (nAbs) appeared to be associated with infusion or hypersensitivity reactions; however, definitive conclusions regarding the effect of immunogenicity on safety could not be reliably made due to the limited number of patients who tested positive for ADAs (6/352; 1.7%) and nAb (1/351; 0.3%) against anifrolumab in the Phase III studies, as well as ongoing uncertainties regarding the ADAs. The limitations of the immunogenicity data have been included in the Saphnelo Product Monograph.

Infections and malignancy were important class-based potential risks due to the mechanism of action of anifrolumab. In patients treated with Saphnelo vs. placebo, infections were reported more frequently (69.7% vs. 55.4%), but not serious infections (4.8% vs. 5.6%). Fatal infections occurred in 0.4% of Saphnelo patients compared to 0.2% of those who received placebo. In patients treated with Saphnelo vs. placebo, the reported rates of malignancies excluding non-melanoma skin cancers (0.7% vs. 0.6%) and malignant neoplasms including non-melanoma skin cancers (1.2% vs. 0.6%) did not differ between the treatment groups in a clinically meaningful way. Based on the available data at the time of authorization of Saphnelo, the effect of anifrolumab exposure on the development of malignancies is not known. The longer-term risk of malignancy with prolonged anifrolumab exposure will be addressed in a 5-year post-authorization safety study. Overall, these risks have been appropriately communicated in the Saphnelo Product Monograph and through routine and non-routine pharmacovigilance.

Given that SLE primarily affects women, and with the disease being most active during child-bearing age, the risk of anifrolumab exposure to pregnant and breastfeeding women was considered important for the risk analysis for Saphnelo. However, there is limited available data due to the exclusion criteria set out in the clinical trials. The use of Saphnelo in pregnant and breastfeeding women has been included as missing information in the Risk Management Plan and the limitation of the available data has been appropriately communicated in the Saphnelo Product Monograph. The sponsor will also be conducting a pregnancy post-authorization safety study to address the use of Saphnelo in pregnant women.

Based on the available clinical data at the time of authorization, the safety profile of Saphnelo was considered acceptable. The observed increased risk of infections, including herpes zoster, hypersensitivity and infusion-related reactions, will be managed post-market through additional labelling and post-market pharmacovigilance. Appropriate warnings and precautions are in place in the approved Saphnelo Product Monograph to address the identified safety concerns. For more information, refer to the Saphnelo Product Monograph, approved by Health Canada and available through the Drug Product Database.