Sign Out
Pharmacology: Pharmacodynamics: Mechanism of action: Spesolimab is a humanised antagonistic monoclonal immunoglobulin G1 (IgG1) antibody blocking human IL36R signalling. Binding of spesolimab to IL36R prevents the subsequent activation of IL36R by cognate ligands (IL36 α, β and γ) and downstream activation of pro-inflammatory and pro-fibrotic pathways. IL-36R signalling is differentiated from TNF-α, integrin and IL-23 inhibitory pathways by directly and simultaneously blocking both inflammatory and pro-fibrotic pathways. Genetic human studies have established a strong link between IL36R signalling and skin inflammation.
Pharmacodynamic effects: Following treatment with SPEVIGO in patients with GPP, reduced levels of C-reactive protein (CRP), interleukin (IL)-6, T helper cell (Th1/Th17) mediated cytokines, keratinocyte-mediated inflammation, neutrophilic mediators, and proinflammatory cytokines were observed in serum and skin at week 1 compared to baseline and was associated with a decrease in clinical severity. These reductions in biomarkers became more pronounced at the last measurement at week 8 in Effisayil 1.
Clinical efficacy and safety: A randomised, double-blind, placebo-controlled study (Effisayil-1) was conducted to evaluate the clinical efficacy and safety of SPEVIGO in adult patients with flares of Generalized Pustular Psoriasis (GPP), as diagnosed per European Rare And Severe Psoriasis Expert Network (ERASPEN) criteria, regardless of IL36RN mutation status. Patients were randomised if they had a flare of GPP 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 sub score of at least 2 (mild), and at least 5% of body surface area (BSA) 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 sub score of 0 (indicating no visible pustules) at Week 1 after treatment. 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. Additional secondary endpoints at Week 4 were the proportion of patients with a 75% reduction in the Psoriasis Area and Severity Index for Generalized Pustular Psoriasis (GPPASI 75), and patient-reported outcomes including change from baseline in Pain Visual Analog Scale (VAS) score, change from baseline in Psoriasis Symptom Scale (PSS) score, and change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue score.
A total of 53 patients were randomised (2:1) to receive a single intravenous dose of 900 mg SPEVIGO (n= 35) or placebo (n=18). 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 SPEVIGO, resulting 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, 6 patients (4 SPEVIGO arm; 2 placebo arm) received rescue treatment with a single 900 mg dose of intravenous SPEVIGO for reoccurrence of a flare after Day 8.
The study population consisted of 32% men and 68% women. 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 sub score of 3 (43%) or 4 (36%), and patients had a GPPGA total score of 3 (81%) or 4 (19%). 24.5% of patients had been previously treated with biologic therapy for GPP.
At Week 1, there was a statistically significant difference in the proportion of patients achieving a GPPGA pustulation sub score of 0 (indicating no visible pustules) and GPPGA total score of 0 or 1 (clear or almost clear skin) in the SPEVIGO arm compared with placebo (see Table 1).
Click on icon to see table/diagram/imageIn patients randomized to SPEVIGO, pustular clearance (GPPGA pustulation sub score of 0) was achieved as early as one day after treatment in 11.4% (4/35) of patients. The effect of up to two doses of SPEVIGO on GPPGA pustulation sub score and GPPGA total score was sustained until Week 12 (see Figures 1 and 2).
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageThe results of the primary and key secondary endpoints were consistent across subgroups including sex, age, race, GPPGA pustulation sub score at baseline, GPPGA total score at baseline, mutation status in IL36RN, and irrespective of any GPP treatment prior to randomization.
At Week 4, 16 patients (46%) randomized to SPEVIGO achieved a GPPASI 75.
In patients randomized to SPEVIGO, improvements in the pain VAS score, PSS score (measuring symptoms of pain, redness, itching, and burning), and FACIT Fatigue score were observed at Week 4 (median change from baseline: -22.45, -2.00 and 3.00, for the pain VAS score, PSS score, and FACIT Fatigue score, respectively).
Pharmacokinetics: A population pharmacokinetic model was developed based on data collected from healthy subjects, patients with GPP and patients with other diseases. After a single i.v. dose of 900 mg, the population PK model-estimated AUC0-∞ (95% CI) and Cmax (95% CI) in a typical ADA-negative patient with GPP were 4750 (4510, 4970) μg·day/mL and 238 (218, 256) μg/mL, respectively.
Distribution: Based on the population pharmacokinetic analysis, the typical volume of distribution at steady state was 6.4 L.
Biotransformation: The metabolic pathway of spesolimab has not been characterized. As a humanized IgG1 monoclonal antibody, spesolimab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.
Elimination: In the linear dose range (0.3-20 mg/kg), based on the population PK model, spesolimab clearance (95% CI) in a typical GPP patient without ADA, weighing 70 kg was 0.184 (0.175, 0.194) L/day. The terminal-half-life was 25.5 (24.4, 26.3) days.
Linearity/non-linearity: At low doses, spesolimab exhibited target-mediated drug disposition (TMDD) kinetics after single i.v. dose administration. At doses from 0.01 to 0.3 mg/kg, both clearance (CL) and terminal half-life were dose dependent, and systemic exposure (AUC) increased more than dose proportionally with dose.
The saturation of the nonlinear elimination pathway occurred at about 0.3 mg/kg as spesolimab AUC increased approximately linearly with dose from 0.3 to 20 mg/kg, and CL and terminal half-life were independent of dose.
Elderly/Gender/Race: Based on population pharmacokinetic analyses, age, gender and race do not have an effect on the pharmacokinetics of spesolimab.
Hepatic and renal impairment: As a monoclonal antibody, spesolimab is not expected to undergo hepatic or renal elimination. No formal trial of the effect of hepatic or renal impairment on the pharmacokinetics of spesolimab was conducted.
Population PK analysis did not identify mild hepatic impairment or mild or moderate renal impairment as having an influence on the systemic exposure of spesolimab.
Body weight: Spesolimab concentrations were lower in subjects with higher body weight. The impact of body weight on spesolimab plasma concentrations is not expected to be clinically meaningful.
Paediatric population: The pharmacokinetics of spesolimab in paediatric patients has not yet been studied.
Drug-Drug Interactions (studies): No formal drug interactions studies have been conducted with spesolimab. Population PK analyses indicated that concomitant use of immunosuppressants or oral corticosteroids did not have a direct impact on the pharmacokinetics of spesolimab.
Toxicology: Preclinical safety data: Pre-clinical data reveal no special hazard for humans.
Repeat dose toxicology studies were conducted in mice using a surrogate, mouse specific anti-IL36R monoclonal antibody by twice weekly intravenous injection for 26 weeks at a dose (50 mg/kg) that was 5 fold higher than the dose that was protective in an experimental mouse colonic inflammation model. No adverse changes in body weight, food consumption or clinical observations were noted at this dose. No adverse effects on clinical pathology parameters including haematology, immunophenotyping, clinical chemistry and histopathology, including lymphoid tissues, have been observed.
The binding specificity of spesolimab to human tissues was evaluated in a tissue cross-reactivity study. No unexpected tissue binding was observed.
Developmental and Reproductive Toxicity: Pre-clinical studies conducted in mice using a surrogate antibody directed towards murine IL-36R do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development or fertility, at intravenous doses up to 50 mg/kg twice weekly.
Genotoxicity: Genotoxicity studies have not been conducted with spesolimab.
Carcinogenicity: Carcinogenicity and mutagenicity studies have not been conducted with spesolimab.
Continue with Google