Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis

BACKGROUND Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. METHODS We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12. RESULTS In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P<0.001 for all comparisons of ixekizumab with placebo). In the UNCOVER-1 and UNCOVER-2 trials, among the patients who were randomly reassigned at week 12 to receive 80 mg of ixekizumab every 4 weeks, 80 mg of ixekizumab every 12 weeks, or placebo, an sPGA score of 0 or 1 was maintained by 73.8%, 39.0%, and 7.0% of the patients, respectively. Patients in the UNCOVER-3 trial received continuous treatment of ixekizumab from weeks 0 through 60, and at week 60, at least 73% had an sPGA score of 0 or 1 and at least 80% had a PASI 75 response. Adverse events reported during ixekizumab use included neutropenia, candidal infections, and inflammatory bowel disease. CONCLUSIONS In three phase 3 trials involving patients with psoriasis, ixekizumab was effective through 60 weeks of treatment. As with any treatment, the benefits need to be weighed against the risks of adverse events. The efficacy and safety of ixekizumab beyond 60 weeks of treatment are not yet known

Atypical presentation of adenosquamous carcinoma: A case report

Cutaneous adenosquamous carcinoma is a rare malignant neoplasm that is more aggressive than conventional squamous cell carcinoma. The typical clinical presentation is an indurated papule or plaque on the head and neck of elderly patients. The authors report the case of a 52-year-old man with a right scrotal and inguinal tumour measuring 10 cm × 15 cm that had progressed over the past 2 years. The histological examination was compatible with adenosquamous carcinoma. Metastatic inguinal and pelvic lymph nodes were identified. This case demonstrates an atypical presentation of a rare tumour. Adenosquamous carcinoma is more aggressive than conventional squamous cell carcinoma, and prompt diagnosis is important

Olumacostat glasaretil (DRM01) for the treatment of acne vulgaris: Primary results from the DRM01-ACN02 phase 2b randomized controlled trial

Background: Sebum production, a critical factor in acne pathophysiology, is not addressed by available topical therapies. Olumacostat glasaretil (OG) inhibits acetyl coenzyme A carboxylase, a key regulator of the synthesis of sebum lipid components. This phase 2b trial assessed the safety and efficacy of OG gel in patients (pts) with facial acne vulgaris. Methods: DRM01-ACN02 (NCT02431052) was a randomized, double-blind, vehicle (VEH)-controlled, dose-ranging, 12-week (wk) trial. Eligible pts were adults with facial acne vulgaris (≥20 inflammatory acne lesions [IALs], ≥20 non-inflammatory acne lesions [NIALs], and an Investigator Global Assessment [IGA] score of 3 or 4). Pts were randomized 2:2:2:1:1 to receive OG 4% once daily (QD), OG 7.5%-QD, OG 7.5% twice daily (BID), VEH-QD, or VEH-BID. Primary efficacy endpoints were IAL and NIAL counts, and IGA response rate (≥2-point improvement from baseline [BL]) at Wk12. MCMC multiple imputation was used to impute missing values in the ITT population. Significance was calculated vs combined VEH group using ANCOVA model (IAL, NIAL count) and Cochran-Mantel-Haenszel test (IGA response). Results: 420 pts were randomized to receive OG 4%-QD, OG 7.5%-QD, OG 7.5%-BID, VEH-QD or VEH-BID; BL characteristics were similar. Significantly greater IAL and NIAL count reductions from BL were reported in OG groups vs combined VEH group at Wk12, with improvements seen from Wk4; highest efficacy was observed in the 7.5%-BID group (OG 7.5%-BID vs combined VEH: Wk4: IAL: -9.2 [-33.7%] vs -7.2 [-26.7%], P = .107; NIAL: -8.6 [-22.7%] vs -6.8 [-16.5%], P = .283; Wk12: IAL: -15.0 [-55.6%] vs -10.7 [-40.0%], P = .001; NIAL: -17.5 [-47.8%] vs -9.3 [-28.7%], P \u3c .001). Clinically meaningful changes were observed in acne severity, with IGA response rate greater in all OG-treated groups than in combined VEH groups (OG 7.5%-BID vs combined VEH: Wk4: 4.1% vs 2.3%, P = .495; Wk12: 25.9% vs 9.8%, P = .004). Adverse events (AEs) occurred in 20.8%, 25.7% and 27.7% vs 19.2% and 26.0% of pts treated with OG 4%-QD, OG 7.5%-QD, and OG 7.5%-BID vs VEH-QD and VEH-BID, respectively. The most common AEs were nasopharyngitis, upper respiratory tract infection and application site pruritus. Conclusions: OG-treated pts had reduced IAL and NIAL counts, and improved IGA scores, compared to VEH-treated pts from Wk4, with 7.5%-BID dosing producing the greatest response in all primary endpoints. OG gel was well tolerated at all tested doses during the 12-wk treatment period. Commercial support: This study was funded by Dermira, Inc. All costs associated with development of this poster were funded by Dermira, Inc

Olumacostat Glasaretil (DRM01) for the Treatment of Acne Vulgaris: Primary Results from the DRM01-ACN02 Phase 2b Randomized Controlled Trial

Background: Sebum production, a critical factor in acne pathophysiology, is not addressed by available topical therapies. Olumacostat glasaretil (OG) inhibits acetyl coenzyme A carboxylase, a key regulator of the synthesis of sebum lipid components. This phase 2b trial assessed the safety and efficacy of OG gel in patients (pts) with facial acne vulgaris. Methods: DRM01-ACN02 (NCT02431052) was a randomized, double-blind, vehicle (VEH)-controlled, dose-ranging, 12-week (wk) trial. Eligible pts were adults with facial acne vulgaris (≥20 inflammatory acne lesions [IALs], ≥20 non-inflammatory acne lesions [NIALs], and an Investigator Global Assessment [IGA] score of 3 or 4). Pts were randomized 2:2:2:1:1 to receive OG 4% once daily (QD), OG 7.5%-QD, OG 7.5% twice daily (BID), VEH-QD, or VEH-BID. Primary efficacy endpoints were IAL and NIAL counts, and IGA response rate (≥2-point improvement from baseline [BL]) at Wk12. MCMC multiple imputation was used to impute missing values in the ITT population. Significance was calculated vs combined VEH group using ANCOVA model (IAL, NIAL count) and Cochran-Mantel-Haenszel test (IGA response). Results: 420 pts were randomized to receive OG 4%-QD, OG 7.5%-QD, OG 7.5%-BID, VEH-QD or VEH-BID; BL characteristics were similar. Significantly greater IAL and NIAL count reductions from BL were reported in OG groups vs combined VEH group at Wk12, with improvements seen from Wk4; highest efficacy was observed in the 7.5%-BID group (OG 7.5%-BID vs combined VEH: Wk4: IAL: -9.2 [-33.7%] vs -7.2 [-26.7%], P = .107; NIAL: -8.6 [-22.7%] vs -6.8 [-16.5%], P = .283; Wk12: IAL: -15.0 [-55.6%] vs -10.7 [-40.0%], P = .001; NIAL: -17.5 [-47.8%] vs -9.3 [-28.7%], P \u3c .001). Clinically meaningful changes were observed in acne severity, with IGA response rate greater in all OG-treated groups than in combined VEH groups (OG 7.5%-BID vs combined VEH: Wk4: 4.1% vs 2.3%, P = .495; Wk12: 25.9% vs 9.8%, P = .004). Adverse events (AEs) occurred in 20.8%, 25.7% and 27.7% vs 19.2% and 26.0% of pts treated with OG 4%-QD, OG 7.5%-QD, and OG 7.5%-BID vs VEH-QD and VEH-BID, respectively. The most common AEs were nasopharyngitis, upper respiratory tract infection and application site pruritus. Conclusions: OG-treated pts had reduced IAL and NIAL counts, and improved IGA scores, compared to VEH-treated pts from Wk4, with 7.5%-BID dosing producing the greatest response in all primary endpoints. OG gel was well tolerated at all tested doses during the 12-wk treatment period. Commercial support: This study was funded by Dermira, Inc. All costs associated with development of this poster were funded by Dermira, Inc

Use of Systemic Therapies for Treatment of Psoriasis in People Living with Controlled HIV: Inference-Based Guidance from a Multidisciplinary Expert Panel

Abstract Background People living with human immunodeficiency virus (PLHIV) have a similar prevalence of psoriasis as the general population, though incidence and severity correlate with HIV viral load. Adequately treating HIV early renders the infection a chronic medical condition and allows PLHIV with a suppressed viral load (PLHIV-s) to live normal lives. Despite this, safety concerns and a lack of high-level data have hindered the use of systemic psoriasis therapies in PLHIV-s. Objectives We aim to provide a structured framework that supports healthcare professionals and patients discussing the risks and benefits of systemic psoriasis therapy in PLHIV-s. Our goal was to address the primary question, are responses to systemic therapies for the treatment of psoriasis in PLHIV-s similar to those in the non-HIV population? Methods We implemented an inference-based approach relying on indirect evidence when direct clinical trial data were absent. In this instance, we reviewed indirect evidence supporting inferences on the status of immune function in PLHIV. Recommendations on systemic treatment for psoriasis in PLHIV were derived using an inferential heuristic. Results We identified seven indirect indicators of immune function informed by largely independent bodies of evidence: (1) functional assays, (2) vaccine response, (3) life expectancy, (4) psoriasis manifestations, (5) rate of infections, (6) rate of malignancies, and (7) organ transplant outcomes. Conclusions Drug-related benefits and risks when treating a patient with systemic psoriasis therapies are similar for non-HIV patients and PLHIV with a suppressed viral load and normalized CD4 counts. Prior to initiating psoriasis treatment in PLHIV, HIV replication should be addressed by an HIV specialist. Exercise additional caution for patients with a suppressed viral load and discordant CD4 responses on antiretroviral therapy