Richard G Langley’s research while affiliated with Dalhousie University and other places

Bimekizumab has a favourable safety profile and has demonstrated rapid and superior efficacy, compared with placebo, adalimumab, ustekinumab, and secukinumab, in treating psoriasis. A previous study demonstrated the safe and effective subcutaneous self-injection of 320 mg bimekizumab via two 1 mL (2 × 160 mg) doses using safety syringe (SSy) or auto-injector (AI) devices. Delivery of 320 mg bimekizumab via a single 2 mL self-injection could lead to an improved treatment experience for patients. We describe the results from four studies. Two self-injection experience studies (DV0002 [n = 38] and DV0006 [n = 89], sub-studies of the phase 3 study BE BRIGHT [NCT03598790]) assessed the safe and effective self-administration of bimekizumab at week 8 and baseline, as well as patient self-injection experience and pain, in patients with moderate to severe plaque psoriasis using the 2 mL SSy or AI. Additionally, we report on two bioequivalence studies (UP0068 [n = 71] and UP0119 [n = 121]) that describe pharmacokinetic profiles for two 1 mL injections and a single 2 mL injection, delivered by SSy or AI devices in healthy participants. All patients were able to administer safe and effective self-injections at baseline and week 8 using the different 2 mL devices, except one patient that administered an incomplete dose as a result of injection site pain that was mild. Overall, bimekizumab was generally well tolerated and all adverse device effects reported were mild and did not lead to discontinuation. Patients reported a positive self-injection experience with low pain scores (all ≤ 12.0/100). Bioequivalence was demonstrated for bimekizumab between a single 2 mL injection and two 1 mL injections, using both the SSy and AI. The 2 mL SSy and AI devices offer patients with moderate to severe plaque psoriasis two different safe and effective options for the delivery of bimekizumab, empowering individuals to select a device on the basis of personal preference. Graphical abstract available for this article. ClinicalTrials.gov identifier, NCT03766685.

Introduction: Achieving and maintaining skin clearance is key for patients with psoriasis.1,2 However, loss of disease control over time is often seen with biologics; therefore, evaluating whether high efficacy levels are maintained at every visit in the long term is important.3 Here, we assess whether bimekizumab (BKZ)-treated patients, who achieved complete skin clearance (PASI 100; 100% improvement in Psoriasis Area and Severity Index) after 16 weeks, maintained BSA (body surface area) ≤1% and PASI 90/75 (≥90/75% improvement in PASI) responses at every visit over 4 years. Procedure/study: Data were pooled from the 52/56-week BE VIVID/BE SURE/BE READY trials and their 144-week open-label extension (OLE) BE BRIGHT.4–7 Included patients received BKZ 320 mg every 4 weeks (Q4W) to Week16, then Q4W or Q8W into the OLE; all received BKZ Q8W from Week100/104 or next scheduled visit. Dose groups were pooled for all analyses. Proportions of patients achieving PASI 100 at Week16 who maintained BSA ≤1%/PASI 90/PASI 75 at every subsequent study visit (29/30 further visits [study-dependent]) up to Year4 (Week196/200) are reported. Proportions who maintained their response at every visit except at most 1 and at most 2 are also reported. Patients discontinuing treatment due to lack of efficacy/treatment-related adverse events were considered non-responders at subsequent timepoints; last observation carried forward was used for other missing data (mNRI-LOCF). Results: Of 989 BKZ-randomized patients, 62.7% achieved PASI 100 at Week16 (non-responder imputation). 503 Week16 PASI 100 responders received continuous BKZ and entered the OLE. Among these patients, BSA ≤1%, PASI 90, and PASI 75 responses were maintained at every study visit from Week16–Year4 by 69.4%, 80.9%, and 93.0% of patients, respectively (at every visit except at most 1: 79.5%, 87.5%, and 95.2%; at every visit except at most 2: 84.1%, 91.8%, and 96.8%). Conclusion: High proportions of Week16 PASI 100 responders maintained BSA ≤1%/PASI 90/PASI 75 at every visit through 4 years. The vast majority maintained these responses at every visit except at most 2 visits through 4 years. Funding: UCB. Medical writing support: Costello Medical.

Introduction: Tralokinumab, a monoclonal antibody that specifically neutralizes interleukin-13, is indicated for the treatment of moderate-to-severe atopic dermatitis (AD) in patients ≥12 years of age. ECZTEND (NCT03587805) is an open-label extension study evaluating the long-term safety and efficacy of tralokinumab in patients with moderate-to-severe AD. Interim analyses previously demonstrated the benefit-risk profile of tralokinumab in patients followed up to 3.5 years in ECZTEND; here, we present the final study results. Methods: Patients completing any of 9 parent trials (ECZTRA 1-8 and the TraSki investigator-initiated study) were able to enter ECZTEND. Patients in ECZTEND received tralokinumab 300 mg every other week, with topical corticosteroids and/or calcineurin inhibitors allowed. The primary objective of ECZTEND was to assess safety of tralokinumab treatment from baseline up to Week 268. Secondary objectives were to assess efficacy, including proportions of patients achieving Investigator’s Global Assessment score of 0 or 1 (IGA 0/1; clear/almost clear skin) or ≥75% improvement in Eczema Area and Severity Index (EASI-75) from parent trial baseline, and quality of life (QoL) measures up to Week 248. Results: In total, 1672 patients were treated with tralokinumab for up to 5.1 years in ECZTEND. Median exposure was 2.6 years, with 4466.2 total patient years of exposure. Maximum tralokinumab exposure, including the parent trial period, was 6.1 years. In ECZTEND, exposure-adjusted incidence rate (IR) of patients with ≥1 treatment-emergent adverse event (AE) was 114.3, which was lower than the initial 16-week treatment period of the parent trials (IR=424.8 for tralokinumab; IR=475.3 for placebo). Over 5 years of ECZTEND, serious AEs were reported in 9.0% of patients (IR=3.54). AEs that led to permanent discontinuation of treatment occurred in 4.5% of patients (IR=1.71). The most frequently reported AEs (≥5% of patients) were nasopharyngitis (22.2%), dermatitis atopic (21.4%), coronavirus infection (17.9%), upper respiratory tract infection (8.8%), headache (6.8%), and conjunctivitis (6.2%). Pre-defined AEs of special interest (eye disorders, skin infections requiring systemic treatment, eczema herpeticum, malignancies) were observed at rates similar to, or lower than, the initial treatment period of the parent trials. At Week 248, response rates (95% CI) for IGA 0/1 and EASI-75 were 66.7% (56.1-75.8) and 92.9% (85.3-96.7), respectively. Additionally, itch, sleep, and QoL improvements were sustained at levels equivalent to no-to-mild disease throughout ECZTEND. Conclusions: Long-term use of tralokinumab, up to 1 year in parent trials plus up to 5 years in ECZTEND, was well-tolerated with no new safety signals identified in patients aged 12 and up with moderate-to-severe AD. Tralokinumab treatment demonstrated robust long-term efficacy with sustained improvements in AD signs, symptoms, and QoL.

Background Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by eczematous skin lesions and pruritus. There is an unmet need for effective first-line systemic treatments with good safety profiles, particularly oral medications. Orismilast is a novel first-in-class oral phosphodiesterase 4 (PDE4) B/D inhibitor under investigation for the treatment of moderate-to-severe AD. Objectives To evaluate the optimal dose, efficacy and safety of twice-daily orismilast in patients with moderate-to-severe AD. Methods This 16-week, multicentre randomized placebo-controlled phase IIb dose-ranging study (NCT05469464) included patients from 48 centres in Europe and the USA. Adults with moderate-to-severe AD were given (1 : 1 : 1 : 1) orismilast 20 mg, 30 mg or 40 mg, or placebo, twice daily. The primary endpoint was percentage change in Eczema Area and Severity Index (EASI); the secondary endpoints (all at week 16) included achievement of a score of clear (0) or almost clear (1) with ≥ 2-point improvement on the Investigator Global Assessment (IGA 0/1); achievement of a Peak Pruritus Numerical Rating Scale (PP-NRS) reduction of ≥ 4 points; and achievement of a reduction in EASI of 75%, 90% and 100% from baseline. Results Overall, 233 patients were randomly assigned to orismilast 20 mg (n = 58), 30 mg (n = 61), 40 mg (n = 59) or placebo (n = 55). At week 16, reductions in EASI (percentage points) from baseline to week 16 were seen across orismilast groups and placebo (P > 0.05 for orismilast vs. placebo). Significantly more patients achieved IGA 0/1 with a ≥ 2-point improvement with orismilast 20 mg and 40 mg compared with placebo (P < 0.05). Significantly greater proportions of patients achieving a ≥ 4-point reduction in PP-NRS were demonstrated with orismilast at week 2. The safety profile was consistent with that of the PDE4 class, with no major safety concerns reported. Conclusions These data support the clinical relevance of selective PDE4B/D inhibition with orismilast, potentially offering a convenient, novel oral therapy for the treatment of AD.

Introduction: Psoriasis is a chronic disease where loss of response to biologic therapies over time is commonly observed; studying long-term efficacy of new treatments is important.1 Maintenance of high responses to bimekizumab (BKZ) has been reported through 3 years (yrs) in patients with moderate to severe plaque psoriasis.2 This study evaluates the maintenance of clinical responses over 4 years among patients with moderate to severe plaque psoriasis who achieved complete or near-complete skin clearance after 16 weeks (wks) of BKZ treatment and entered the BE BRIGHT open-label extension. Responses were compared over 4 years between all patients who were randomized to BKZ and continued to receive bimekizumab (320 mg every 4 wks [Q4W] or Q8W) in the open-label extension, and those who received the BKZ dosing regimen that is approved for most patients: BKZ 320 mg Q4W to Wk 16 followed by 320 mg Q8W. Methods: Patients completing the 52-wk BE VIVID or 56-wk BE SURE/BE READY phase 3 trials could enter the BE BRIGHT open-label extension (OLE).2–5 Maintenance of PASI90/PASI100 (≥90%/100% improvements from baseline in Psoriasis Area and Severity Index) to Yr4 (OLE Wk144) was assessed in Wk16 responders. Analyzed patients were randomized to BKZ 320 mg Q4W to Wk16, received BKZ Q4W or Q8W until OLE entry, then BKZ Q4W or Q8W dependent on PASI response/prior dose (BKZ Total); the subset who received BKZ Q4W/Q8W/Q8W (initial/maintenance/OLE) were also analyzed. All received BKZ Q8W from OLE Wk48 or at their next scheduled visit. Patients who discontinued due to lack of efficacy/treatment-related adverse events were considered non-responders; multiple imputation was used for all other missing data (modified non-responder imputation). Results: Of 989 BKZ-randomized patients, 87.5% achieved PASI90 and 62.7% PASI100 at Wk16 (non-responder imputation). 693 Wk16 PASI90 and 503 PASI100 responders entered the OLE (BKZ Total); 186 and 147, respectively, received BKZ Q4W/Q8W/Q8W. 87.7%/73.3% of Wk16 PASI90/PASI100 responders maintained their responses to Yr4 (BKZ Total). In the Q4W/Q8W/Q8W subset, 89.0%/76.7% maintained their responses to Yr4. Conclusions: Among Wk16 responders, high efficacy responses were sustained through 4 yrs of BKZ treatment, including patients who received the approved Q4W/Q8W/Q8W dosing regimen.