Summary Basis of Decision for Spevigo

Clinical Pharmacology

Spesolimab is a humanized antagonistic monoclonal immunoglobulin G1 (IgG1) antibody that blocks interleukin-36 (IL-36) signalling by binding to the IL-36 receptor (IL‑36R). This prevents the activation of the IL-36R by cognate ligands (IL-36α, IL-36β, and IL-36γ) and the downstream activation of proinflammatory and profibrotic pathways. There is evidence that suggests a link between IL‑36R signalling and skin inflammation, however the precise mechanism of how decreased IL-36R signalling is linked to the treatment of skin in generalized pustular psoriasis (GPP) patients is not clear.

A population pharmacokinetic (PK) model was developed based on pooled spesolimab plasma concentration data from healthy patients, patients with GPP, and patients with other diseases. In anti-drug antibody (ADA)-negative GPP patients treated with the proposed single intravenous dose of 900 mg of Spevigo, the population PK model-estimated area under the concentration-time curve from zero to infinity (AUC_0-∞) and maximum concentration (C_max) were 4,750 µg·day/mL (95% confidence interval [CI]: 4,510, 4,970) and 238 µg/mL (95% CI: 218, 256), respectively.

In the pivotal clinical study (EFFISAYIL-1/1368-0013, described in the Clinical Efficacy section), ADAs were detected in 46% of Spevigo‑treated GPP patients, with a median onset time of 2.3 weeks post dose. The plasma concentration of spesolimab was significantly decreased for most patients who had ADA titer values greater than 4,000.

Based on the population PK analysis, the typical volume of distribution at steady state was 6.4 L.

Spesolimab AUC increased approximately dose proportionally within the dose range of 0.3 to 20 mg/kg with clearance and terminal half-life independent of dose.

The population modelling analysis indicated that at a dose range of 0.3 to 20 mg/kg, in a typical GPP patient weighing 70 kg without ADA formation, spesolimab clearance was 0.184 L/day (95% CI: 0.175, 0.194) and the terminal half-life 25.5 days (range: 24.4, 26.3).

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

Clinical Efficacy

The proposed indication for Spevigo is supported by clinical data from the pivotal Phase II study (EFFISAYIL-1/1368-0013) and supportive data from three Phase I and II studies (1368-0011, 1368-0025, and 1368-0027). All studies were conducted in patients with generalized pustular psoriasis (GPP).

The EFFISAYIL-1 study was a randomized, double-blind, placebo-controlled study conducted to evaluate the clinical efficacy and safety of Spevigo in adult patients with flares of GPP. Patients were randomized if they had a flare of moderate-to-severe intensity as defined by a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) total score (which ranges from 0 [clear] to 4 [severe]) of at least 3 (moderate), presence of fresh pustules (new appearance or worsening of pustules), GPPGA pustulation subscore of at least 2 (mild), and at least 5% of body surface area covered with erythema and the presence of pustules. Patients were required to discontinue systemic and topical therapy for GPP prior to receiving study drug.

The primary endpoint of the study was the proportion of patients with a GPPGA pustulation subscore of 0 (indicating no visible pustules) at Week 1. The key secondary endpoint of the study was the proportion of patients with a GPPGA total score of 0 or 1 (clear or almost clear skin) at Week 1.

Fifty-three patients were randomized to receive a single intravenous dose of 900 mg Spevigo (total number [n] = 35) or placebo (n = 18) during the double-blind phase of the study. Patients in either treatment arm who still experienced flare symptoms at Week 1 were eligible to receive a single intravenous dose of open‑label 900 mg of Spevigo. This resulted in 12 patients (34%) in the Spevigo arm receiving a second dose of Spevigo and 15 patients (83%) in the placebo arm receiving one dose of Spevigo on Day 8. In addition, six patients (four in the Spevigo arm and two in the placebo arm) received rescue treatment with a single 900 mg dose of intravenous Spevigo for reoccurrence of a flare beyond Day 8.

Of the patients who were randomized to participate in the study, 32% were male and 68% were female. The mean age was 43 (range: 21 to 69) years; 55% of patients were Asian and 45% were Caucasian. Most patients included in the study had a GPPGA pustulation subscore of 3 (43%) or 4 (36%). Eighty-one percent of patients had a GPPGA total score of 3 (81%) and 19% of patients had a GPPGA total score of 4. Thirteen of 53 (24.5%) patients had been previously treated with biologic therapy for GPP.

The efficacy of Spevigo was demonstrated in the target patient population. Spevigo was superior to placebo for all tested endpoints. For the primary endpoint, the proportion of patients achieving a GPPGA pustulation subscore of 0 at Week 1 was higher in the Spevigo group (54.3% [19 of 35 patients]) than in the placebo group (5.6% [1 of 18 patients]). This resulted in a statistically significant risk difference between Spevigo and placebo of 48.7% (one-sided p = 0.0004). Similarly, for the key secondary endpoint, the proportion of patients achieving a GPPGA total score of 0 or 1 at Week 1 was higher in the Spevigo group (42.9% [15 of 35 patients]) than in the placebo group (11.1% [2 of 18 patients). This also resulted in a statistically significant risk difference between Spevigo and placebo of 31.7% (one-sided p = 0.0118).

The effect of Spevigo on clearing pustules and achieving clear or almost clear skin for all skin manifestations seen in the primary analysis was consistent across prespecified sensitivity analyses and the prespecified subgroups, thereby demonstrating the robustness of the efficacy assessment. The results of the pivotal study were clinically meaningful and statistically significant. The onset of efficacy was rapid and was sustained over the entire 12‑week observation period. The effect of Spevigo on the skin lesions was supported by the efficacy shown for the patient-reported outcomes, including the Pain Visual Analogue Scale (VAS) score, the Psoriasis Symptom Scale (PSS) score, and the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score; these endpoints were also included in the hierarchical testing strategy, and all reached statistical significance versus placebo. Compared with the natural history of GPP flares when treated with available therapies, the results of the EFFISAYIL-1 Study demonstrated that Spevigo provides a substantial and clinically meaningful improvement in patients presenting with a GPP flare.

Indication

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

Spevigo (spesolimab for injection) is indicated for the treatment of flares in adult patients with generalized pustular psoriasis.

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

Clinical Safety

The clinical safety of Spevigo in GPP patients was primarily assessed from data derived from the pivotal, placebo-controlled EFFISAYIL-1 study described in the Clinical Efficacy section.

Through Week 1, the most frequent adverse events that occurred in 5% or more of patients, and at a higher rate in the Spevigo group as compared to the placebo group, were: asthenia and fatigue; headache; pruritus and prurigo; infusion site hematoma and bruising; and urinary tract infection. Overall, the most frequently reported adverse event among patients treated with Spevigo was infection. During the 1-week placebo-controlled period in EFFISAYIL-1, infections were reported in 17.1% of patients treated with Spevigo compared with 5.6% of patients treated with placebo. Serious infection (urinary tract infection) was reported in one patient (2.9%) in the Spevigo group and no patients in the placebo group. Infections observed in clinical trials with spesolimab were generally mild to moderate with no distinct pattern regarding pathogen or type of infection. Two cases of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome were reported in patients who were treated with Spevigo. In both reported DRESS cases, there was a close temporal association to a GPP flare, which can share many of the same signs and symptoms as DRESS, as well as to the use of possible trigger concomitant medications, which are plausible alternative causes. Of note, among approximately 750 patients exposed to Spevigo during clinical development, Guillain-Barré syndrome (GBS) was reported in three patients who received various doses of Spevigo in clinical studies for other indications. A certain diagnosis of GBS could not be verified in any of the cases. There is no indication from the available literature at this time that inhibition of the interleukin-36 pathway is linked to an increased risk of treatment-emergent peripheral neuropathy. Based on recommendations following analysis of the safety data, the risks of infection, DRESS, and peripheral neuropathy, have been appropriately addressed in the Spevigo 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). The impact of ADAs on safety of flare re-treatment with Spevigo is unclear, as ADAs generally did not develop until after treatment and resolution of a flare. Based on the submitted data, it was not possible to draw meaningful conclusions regarding the impact of ADAs on safety during re-treatment of subsequent flares with Spevigo.

A high-level review of three supportive studies (Study 1368-0011, a Phase I pharmacokinetic and proof of concept study in 7 patients, Study 1368-0027 [an ongoing, Phase II maintenance study], and Study 1368-0025 [an ongoing, Phase II open-label extension study]) did not indicate any new safety signals. One potential important difference that may lead to an increased risk of adverse events was the frequency of administration of Spevigo in the pivotal clinical study versus its potential use in the post-market setting. In the pivotal study, a single open-label rescue treatment with Spevigo could be administered after Week 1 to Week 12 with a maximum of three total doses during the study. In the post-market setting, there is potential for multiple, repeat dosing due to GPP reoccurrence. The Warnings and Precautions section of the Spevigo Product Monograph includes information regarding the limited safety data available for re-treatment with Spevigo for a subsequent flare. The unknown effect of immunogenicity on the efficacy and safety of Spevigo after repeat dosing, have also been addressed in the Spevigo Product Monograph.

Based on the data evaluated, no significant safety concerns were identified that would preclude the authorization of the Spevigo for the treatment of flares in adult patients with GPP. Appropriate warnings and precautions are in place in the approved Spevigo Product Monograph to address the identified safety concerns. Risk mitigation measures also include relevant pharmacovigilance activities.

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

The non-clinical data submitted demonstrated spesolimab binding to the interleukin-36 receptor (IL-36R) and spesolimab-mediated inhibition of the IL-36R pathway in cultured human skin cells. Spesolimab lacks pharmacologic activity in non-human species; therefore, a mouse surrogate antibody (BI 674304) was developed. The binding and functional studies were repeated in appropriate tissues with BI 674304. In two mouse models of skin inflammation, BI 674304 treatment reduced ear inflammation in mice in a moderate manner. In a 26-week repeat-dose toxicity study with a 4-week recovery period, mice were administered BI 674304 at doses of 10 or 50 mg/kg body weight given by intravenous (IV) injection two times per week. Two deaths occurred in the high-dose group due to complications from infection that was attributed to the test article.

In an embryo-fetal development study, pregnant mice were administered BI 674304 at doses of 10 or 50 mg/kg body weight by IV bolus injection during gestation. One dam in the low-dose group died, but the cause of death was not determined. Increased resorption rates were reported in dams in the low- and high-dose groups.

In a fertility and early embryonic development study, male and female mice were administered BI 674304 at doses of 10 or 50 mg/kg body weight by IV bolus injection two times per week prior to and during mating. Females were also dosed during gestation every three days up to gestation day (GD) 12. Two females, one in the low-dose group and another in the high-dose group died; the causes of death were not determined. No effects were observed in animal fertility or early embryonic development. A no-observed-adverse-effect level (NOAEL) of 50 mg/kg body weight was determined.

In a prenatal and postnatal developmental study, female mice were administered BI 674304 at doses of 10, or 50 mg/kg body weight by IV bolus injection two times per week from GD 6 to lactation day 18. The F1 offspring were mated on postnatal day (PND) 80 to 84. One neonate died on PND 0. This animal had fused right medial and right lateral liver lobes, abdominal distension, large stomach, and malpositioned kidneys. It was uncertain if the developmental findings were related to the test article. One F1 female from the maternal low-dose group died. No cause of death was identified. No effects were observed in animal fertility or early embryonic development. The NOAEL for this study was 50 mg/kg body weight.

In all three reproductive and developmental toxicity studies, the serum BI 674304 concentration levels in dams were low compared to those achieved in mice from other repeat-dose toxicity studies given the same IV doses with similar frequency. Therefore, the results should be interpreted with caution. The incidence of unscheduled deaths reported in the developmental and reproductive toxicity (DART) studies falls within the range of historical controls for the test facility. It is recommended to avoid use of Spevigo in pregnancy which further mitigates any uncertainty related to the DART findings.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Spevigo Product Monograph. Appropriate warnings and precautionary measures are in place to address the identified safety concerns. In view of the intended use of Spevigo, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

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

Characterization of the Drug Substance

Spesolimab is a humanized antagonistic monoclonal immunoglobulin G1 (IgG1) antibody directed against human interleukin‑36 receptor (IL‑36R). Spesolimab has been engineered with two-point mutations in the fragment crystallizable (Fc) region to reduce binding to Fcγ receptors and Fc-mediated effector functions. Binding of spesolimab to IL-36R blocks the binding of human IL-36 ligands (α, β and γ) to IL‑36R, thereby preventing downstream activation of proinflammatory and profibrotic pathways linked to flares associated with generalized pustular psoriasis (GPP).

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

The drug substance manufacturing process has been optimized and scaled up during development. The process changes introduced at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

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

The drug substance, spesolimab, is produced by recombinant deoxyribonucleic acid (rDNA) technology in a mammalian cell expression system (Chinese hamster ovary [CHO] cell line). The final cell culture is harvested, clarified, and subsequently purified using a series of chromatographic and viral inactivation steps. Following purification, the bulk drug substance is filtered into the drug substance containers.

The manufacturing process of the drug product consists of a series of stages which include thawing and dilution of the drug substance followed by bioburden reduction, sterile filtration, and aseptic filling into 10 mL glass vials. Spevigo is supplied as a concentrate for solution for intravenous infusion. In addition to the medicinal ingredient, each vial of product contains the following excipients: arginine hydrochloride, glacial acetic acid, polysorbate 20, sodium acetate trihydrate, sucrose, and water for injection.

The materials used in the manufacture of the drug substance and drug product (including materials derived from biological sources) are considered suitable and/or meet standards appropriate for their intended use. None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of spesolimab with the excipients is supported by the stability data provided.

Changes to the manufacturing process and formulation made throughout the development are considered acceptable upon review.

Control of the Drug Substance and Drug Product

Process design and process control elements were appropriately defined and classified according to their criticality. The manufacturing process is considered to be adequately controlled within justified limits.

The proposed release and stability specifications follow International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines and include assays for identity, quantity, biological activity, purity and impurities, safety and compendial requirements as per ICH guidelines. The drug substance and drug product are tested against suitable reference standards. Analytical procedures are validated and in compliance with ICH guidelines.

Spevigo 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 Spevigo is stored between 2 °C to 8 °C, protected from light.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facility and equipment 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 (OSE) of the drug substance and drug product manufacturing facilities was not deemed necessary.

Both sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The spesolimab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

Materials of biological origin are properly sourced and tested. The biologic raw materials originate from sources with no or minimal risk of transmissible spongiform encephalopathy agents or other human pathogens.

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