Rates Of Treatment-emergent Adverse Events Research Articles

Integrated safety analysis of filgotinib in patients with moderate-to-severe rheumatoid arthritis over a treatment duration of up to 8.3 years

ObjectivesTo update the long-term safety profile of filgotinib, a Janus kinase-1 preferential inhibitor, in patients with moderate-to-severe rheumatoid arthritis.MethodsData from seven trials were integrated (NCT01888874, NCT01894516, NCT02889796, NCT02873936, NCT02886728, NCT02065700...

A randomized, double-blinded, phase 2 trial of EDP1815, an oral immunomodulatory preparation of Prevotella histicola, in adults with mild-to-moderate plaque psoriasis

BackgroundPsoriasis is a chronic inflammatory skin disease. EDP1815 is an oral, gut-restricted preparation of non-live Prevotella histicola, the first of a new immunomodulatory therapeutic class targeting the small intestine to generate systemic anti-inflammatory responses.ObjectiveTo evaluate safety and efficacy of EDP1815 in mild-to-moderate psoriasis in a proof-of-concept study.MethodsA phase 2, multicenter, randomized, double-blinded, placebo-controlled, parallel-group study with a 16-week treatment period and up to 24 weeks of follow-up. Participants were randomized to receive 1, 4, or 10 capsules daily.ResultsEDP1815 was well tolerated with comparable rates of treatment-emergent adverse events to placebo, and no drug-related serious adverse events. Clinically meaningful responses to EDP1815, defined as at least 50% reduction in Psoriasis Area and Severity Index (PASI-50) at week 16, were observed in all 3 cohorts, statistically significant in the 1-capsule (29.7%; P = 0.048) and 4-capsule (31.9%; P = 0.022) groups, compared with placebo (12.1%). Among EDP1815-treated PASI-50 responders at week 16, 60% (18/30) maintained or improved off-treatment responses at week 40.LimitationsContinued off-treatment improvement past 16 weeks shows potential for greater therapeutic benefit that was not assessed.ConclusionEDP1815 was well-tolerated with a placebo-like safety profile, and had meaningful efficacy outcomes in psoriasis, validating this novel immunomodulatory approach.Clinical trial registrationhttps://www.clinicaltrials.gov/search?term=NCT04603027, identifier NCT04603027.

The Right Formula for Acne: Importance of Vehicle Formulation in Tazarotene 0.045% Lotion Design, Application, Tolerability, and Efficacy

The vehicles used for topical dermatological treatments can significantly contribute to treatment effects while also delivering ingredients to maintain skin barrier function and reduce irritation. Tazarotene 0.045% lotion was developed using proprietary polymeric emulsion technology to provide uniform and efficient delivery of the active ingredient as well as improved safety and tolerability compared to higher-dose tazarotene formulations. The lotion vehicle additionally provides rapid and sustained improvements in moisturization and skin barrier function with patient-friendly application and cosmetic properties. Compared with trifarotene 0.005% cream, tazarotene 0.045% lotion demonstrated ∼30% greater spreadability and a lower potential for irritation. In clinical trials and investigator-initiated studies, tazarotene 0.045% lotion demonstrated efficacy in the treatment of facial and truncal acne and improved skin oiliness. Facial acne improvements were similar among study participants grouped by sex, race, ethnicity, or age. In a head-to-head study, efficacy was comparable to tazarotene 0.1% cream with approximately half the rate of treatment-emergent adverse events. Tazarotene 0.045% lotion is a beneficial acne treatment option for patients of varying ages, races, ethnicities, and skin types, delivered in a formulation that can be easily used on the face, back, and chest.

An “Inclisiran First” Strategy vs Usual Care in Patients With Atherosclerotic Cardiovascular Disease

BackgroundMost patients with atherosclerotic cardiovascular disease fail to achieve guideline-directed low-density lipoprotein cholesterol (LDL-C) goals. Twice-yearly inclisiran lowers LDL-C by ∼50% when added to statins. ObjectivesThis study evaluated the effectiveness of an “inclisiran first” implementation strategy (adding inclisiran immediately upon failure to reach LDL-C <70 mg/dL despite receiving maximally tolerated statins) vs representative usual care in U.S. patients with atherosclerotic cardiovascular disease. MethodsVICTORION-INITIATE, a prospective, pragmatically designed trial, randomized patients 1:1 to inclisiran (284 mg at days 0, 90, and 270) plus usual care (lipid management at treating physician’s discretion) vs usual care alone. Primary endpoints were percentage change in LDL-C from baseline and statin discontinuation rates. ResultsWe randomized 450 patients (30.9% women, 12.4% Black, 15.3% Hispanic); mean baseline LDL-C was 97.4 mg/dL. The “inclisiran first” strategy led to significantly greater reductions in LDL-C from baseline to day 330 vs usual care (60.0% vs 7.0%; P < 0.001). Statin discontinuation rates with “inclisiran first” (6.0%) were noninferior vs usual care (16.7%). More “inclisiran first” patients achieved LDL-C goals vs usual care (<70 mg/dL: 81.8% vs 22.2%; <55 mg/dL: 71.6% vs 8.9%; P < 0.001). Treatment-emergent adverse event (TEAE) and serious TEAE rates compared similarly between treatment strategies (62.8% vs 53.7% and 11.5% vs 13.4%, respectively). Injection-site TEAEs and TEAEs causing treatment withdrawal occurred more commonly with “inclisiran first” than usual care (10.3% vs 0.0% and 2.6% vs 0.0%, respectively). ConclusionsAn “inclisiran first” implementation strategy led to greater LDL-C lowering compared with usual care without discouraging statin use or raising new safety concerns. (A Randomized, Multicenter, Open-label Trial Comparing the Effectiveness of an “Inclisiran First” Implementation Strategy to Usual Care on LDL Cholesterol [LDL-C] in Patients With Atherosclerotic Cardiovascular Disease and Elevated LDL-C [≥70 mg/dL] Despite Receiving Maximally Tolerated Statin Therapy [VICTORION-INITIATE]; NCT04929249)

Bimekizumab safety in moderate to severe plaque psoriasis: Rates of hepatic events and changes in liver parameters over 2 years in randomized phase 3/3b trials

Patients with psoriasis are at increased risk of liver function abnormalities. Explore rates of hepatic treatment-emergent adverse events (TEAEs) and changes in liver parameters in bimekizumab-treated patients with psoriasis. Data are reported from 5 phase 3/3b trials over 2years. Hepatic TEAEs, laboratory elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST), and changes in clinical markers of liver fibrosis (Fibrosis-4 [FIB-4] Index and AST to Platelet Ratio Index [APRI]) are reported. TEAEs are presented using exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY). 2186 patients received ≥1 bimekizumab dose. Over 2years, the EAIR of hepatic TEAEs was 3.5/100 PY and did not increase from first to second year. 2-year EAIRs of ALT/AST elevations >3x and >5x the upper limit of normal were 2.3 and 0.6/100 PY; rates were similar to placebo, adalimumab, secukinumab, and ustekinumab during controlled study periods. FIB-4 and APRI scores did not increase through 2years, regardless of fibrosis risk at baseline. Obesity, diabetes, dyslipidemia, chronic alcohol consumption, and medication changes are confounding factors for hepatic dysfunction. Rates of hepatic adverse events (AEs) with bimekizumab were consistent through 2years; incidences of transaminase elevations were similar to comparators during phase 3/3b controlled study periods.

Menopausal symptom management: Fezolinetant's varied doses provide effective relief for vasomotor symptoms in women - A meta-analysis of 3291 participants.

Menopause represents the physiological transition when a woman's reproductive period ends associated with a variety of symptoms, including vasomotor symptoms, such as night sweats and hot flashes. This systematic review and meta-analysis aimed to assess the effectiveness and safety of oral Fezolinetant for treating vasomotor symptoms associated with menopause. Five electronic databases were searched from their inception until May 2023. Via the Cochrane risk of bias tool, two reviewers assessed the studies' quality. The primary outcomes were a decrease in VMSs frequency and severity and safety outcomes at 4 and 12 weeks. Data were extracted and then analyzed using RevMan software. This meta-analysis included six trials with a total of 3291 women that compared Fezolinetant to a placebo in the treatment of menopausal VMSs. After 4 and 12 weeks of therapy, fezolinetant at 30 mg QD or 45 mg QD substantially decreased the frequency and severity of VMSs per 24 hours compared to placebo. Fezolinetant at 90 mg BID, 30 mg QD, or 45 mg QD did not show a significant difference in the rate of treatment-emergent adverse events (TEAEs), headache, and TEAEs leading to permanent discontinuation compared to placebo. Fezolinetant proves to be a successful and well-tolerated remedy for menopausal women suffering from VMSs. Notably, the 45 mg daily dosage over 12 weeks exhibited significant efficacy. Nonetheless, extensive future trials are necessary to ascertain its long-term safety, effectiveness, and relative potency compared to alternative VMS treatments like hormone therapy.

Long-term Efficacy and Safety Following Switch Between Upadacitinib and Adalimumab in Patients with Rheumatoid Arthritis: 5-Year Data from SELECT-COMPARE.

This study aimed to describe the long-term efficacy and safety of upadacitinib and adalimumab through 228weeks following immediate switch to the alternate therapy with a different mechanism of action (MoA) in patients with rheumatoid arthritis (RA) not achieving treatment goals with their initial randomized therapy in the ongoing phase3 SELECT-COMPARE study. Patients with non-response or incomplete response to initially prescribed upadacitinib 15mg once daily or adalimumab 40mg every other week were switched to the alternate therapy by week26. Efficacy was evaluated through 228weeks post-switch using validated outcome measures, including Clinical Disease Activity Index (CDAI) low disease activity (LDA; ≤ 10)/remission (≤ 2.8); 28-joint Disease Activity Score based on C-reactive protein ≤ 3.2/< 2.6; ≥ 20%/50%/70% improvement in American College of Rheumatology (ACR) response criteria; and change from baseline in ACR core components. Data are reported as observed. Safety was assessed by treatment-emergent adverse events (TEAEs) through week264. Of patients initially randomized to upadacitinib and adalimumab, 38.7% and 48.6%, respectively, switched to the alternate therapy by week26. Clinically relevant improvements in all efficacy measures were observed through 228weeks post-switch and were generally similar between groups, with small numeric differences mostly in favor of switching to upadacitinib. CDAI remission was achieved by 32.7% and 28.6% of initial non-responders, and 27.5% and 27.3% of incomplete responders, while CDAI LDA was achieved by 76.9% and 72.9% of non-responders, and 72.5% and 72.7% of incomplete responders switching to upadacitinib and to adalimumab, respectively. TEAE rates were similar between groups, although herpes zoster infection, lymphopenia, and creatine phosphokinase elevation were more frequent when switching to upadacitinib. No new safety signals were identified. Switching to a different MoA may provide long-term benefit to patients with RA not achieving treatment goals with their initial therapy, with acceptable safety profiles. NCT02629159.

Batoclimab vs Placebo for Generalized Myasthenia Gravis

Myasthenia gravis (MG) is caused by autoantibodies that disrupt the neuromuscular junction. The neonatal fragment crystallizable receptor (FcRn) antagonists, efgartigimod and rozanolixizumab, reduce immunoglobulin G (IgG) level in the circulation and alleviate symptoms in patients with generalized MG. To examine the efficacy and safety profile of batoclimab, a monoclonal IgG1 antibody, in patients with generalized MG. This was a multicenter randomized clinical trial conducted from September 15, 2021, to June 29, 2022, at 27 centers in China. Adult patients 18 years or older with generalized MG were screened, and those who were antibody positive were enrolled. Eligible patients received batoclimab or matching placebo in addition to standard of care. Each treatment cycle consisted of 6 weekly subcutaneous injections of batoclimab, 680 mg, or matching placebo followed by 4 weeks of observation. A second treatment cycle was conducted in patients who required continuing treatment. The primary outcome was sustained improvement, as defined by a 3-point or greater reduction in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score from baseline for 4 or more consecutive weeks in the first cycle in individuals who were positive for acetylcholine receptor or muscle-specific kinase antibodies. A total of 178 adult patients with generalized MG were screened, 132 were randomly assigned, 131 tested positive for antibodies, and 1 tested negative for antibodies. A total of 132 patients (mean [SE] age, 43.8 [13.6] years; 88 women [67.2%]) were enrolled. The rate of sustained MG-ADL improvement in the first cycle in antibody-positive patients was 31.3% (20 of 64) in the placebo group vs 58.2% (39 of 67) in the batoclimab group (odds ratio, 3.45; 95% CI, 1.62-7.35; P = .001). The MG-ADL score diverged between the 2 groups as early as week 2. The mean (SE) maximum difference in MG-ADL score reduction occurred 1 week after the last dose (day 43, 1.7 [0.3] in the placebo group vs 3.6 [0.3] in the batoclimab group; group difference, -1.9; 95% CI, -2.8 to -1.0; nominal P < .001). The rates of treatment-related and severe treatment-emergent adverse events in patients were 36.9% (24 of 65) and 7.7% (5 of 65) in the placebo group vs 70.1% (47 of 67) and 3.0% (2 of 67) in the batoclimab group, respectively. Batoclimab increased the rate of sustained MG-ADL improvement and was well tolerated in adult patients with generalized MG. Clinical effects and the extent of IgG reduction were similar to those previously reported for efgartigimod and rozanolixizumab. Future studies of large sample size are needed to further understand the safety profile of batoclimab. ClinicalTrials.gov Identifier: NCT05039190.

Long-term safety of Ixekizumab in adults with psoriasis, psoriatic arthritis, or axial spondyloarthritis: a post-hoc analysis of final safety data from 25 randomized clinical trials

BackgroundWe report long-term, end-of-study program safety outcomes from 25 randomized clinical trials (RCTs) in adult patients with psoriasis (PsO), psoriatic arthritis (PsA), or axial spondyloarthritis (axSpA) [including ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA)] who received ≥ 1 dose of Ixekizumab (IXE) over 5 years (PsO) or up to 3 years (PsA, axSpA).MethodsThis integrated safety analysis consists of data from patients who received any dose of IXE, across 25 RCTs (17 PsO, 4 PsA, 4 axSpA). Rates of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and selected adverse events (AEs) of interest were analyzed for all pooled studies by years of therapy and overall, through March 2022. Results were reported as exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) overall and at successive year intervals.ResultsSix thousand eight hundred ninety two adult patients with PsO, 1401 with PsA, and 932 with axSpA (including AS and nr-axSpA), with a cumulative IXE exposure of 22,371.1 PY were included. The most commonly reported TEAE across indications was nasopharyngitis (IRs per 100 PY: 8.8 (PsO), 9.0 (PsA), 8.4 (axSpA)). SAEs were reported by 969 patients with PsO (IR 5.4), 134 patients with PsA (IR 6.0), and 101 patients with axSpA (IR 4.8). Forty-five deaths were reported (PsO, n = 36, IR 0.2; PsA, n = 6, IR 0.3; axSpA, n = 3, IR 0.1). TEAEs did not increase during IXE exposure: IRs per 100 PY, PsO: 88.9 to 63.2 (year 0–1 to 4–5), PsA: 87 to 67.3 (year 0–1 to 2–3), axSpA: 82.1 to 55.4 (year 0–1 to > = 2). IRs per 100 PY of discontinuation from IXE due to AE were 2.9 (PsO), 5.1 (PsA), and 3.1 (axSpA). IRs per 100 PY of injection site reactions were 5.9 (PsO), 11.6 (PsA) and 7.4 (axSpA); Candida: 1.9 (PsO), 2.0 (PsA), and 1.2 (axSpA); depression, major adverse cerebro-cardiovascular events and malignancies: ≤ 1.6 across all indications. Adjudicated IRs per 100 PY of inflammatory bowel disease were ≤ 0.8 across indications (0.1 [PsO]; 0.1 [PsA]; 0.8 [axSpA]).ConclusionsIn this integrated safety analysis, consisting of over 22,000 PY of exposure, the long-term safety profile of IXE was found to be consistent with previous, earlier reports, with no new safety signals identified.Trial registrationNCT registration numbers for RCTs included in this integrated analysis can be found in Additional File 1.

510 - Dupilumab is efficacious in patients with prurigo nodularis regardless of stable use of topical corticosteroids and topical calcineurin inhibitors: pooled results from two phase 3 trials (LIBERTY-PN PRIME and PRIME2)

Abstract Introduction Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by severely itchy skin nodules, which substantially affects quality of life. Although topical treatments are frequently prescribed, these therapies are limited by insufficient demonstrated evidence for efficacy, and/or associated side effects. Objectives This study reports the effect of dupilumab on pruritus, skin lesions, and quality of life in patients with PN, with or without stable use of topical corticosteroids (TCS) and/or topical calcineurin inhibitors (TCI), in an analysis of pooled data from two phase 3 trials. Materials &amp; Methods LIBERTY-PN PRIME (NCT04183335) and PRIME2 (NCT04202679) were two randomized, double-blind, placebo-controlled, 24-week studies. Adults with PN inadequately controlled by topical prescription therapies, or for whom those therapies are inadvisable, were randomized 1:1 to dupilumab 300 mg every 2 weeks or matched placebo. “Stable use” was defined as maintaining the same medicine (low-to-medium potency TCS and/or TCI) during the study, with the same frequency of treatment (once or twice daily) as from 2 weeks prior to screening. Efficacy was assessed from baseline to Week 24 through the Worst Itch Numerical Rating Scale (WI-NRS; scored 0–10; high scores represent a poorer outcome), and the Investigator’s Global Assessment for PN-Stage score (IGA PN-S; scored 0–4; high scores represent a poorer outcome). Impact on Health-Related Quality of Life (HRQoL) was assessed through the Dermatology Life Quality Index questionnaire (DLQI; 10 questions scored 0–3 with a maximum score of 30; high scores represent poorer HRQoL). Results 311 patients were randomized (dupilumab/placebo n = 153/158), including 182 patients with stable use of TCI/TCS (dupilumab/placebo N = 91/91) and 129 patients without (dupilumab/placebo N = 62/67). Baseline demographics and disease characteristics were well balanced in both subgroups. At Week 24, significantly more patients treated with dupilumab with or without stable use of TCI/TCS achieved a ≥ 4-point improvement in WI-NRS (59.3%/58.1%) vs placebo (13.2%/26.9% [nominal P &amp;lt; 0.0001/P &amp;lt; 0.0001]). The proportion of patients achieving an IGA PN-S score of 0 or 1 at Week 24 was also significantly higher in the dupilumab group for patients with or without stable use of TCI/TCS (48.4%/43.5%), vs placebo (11.0%/25.4% [nominal P &amp;lt; 0.0001/P = 0.0319]). The positive impact of dupilumab treatment on HRQoL was greater, for patients with and without a stable use of TCI/TCS vs placebo, as suggested by the mean change from baseline in DLQI at Week 24 (−12.9/−11.9 vs −5.5/−7.1 [nominal P &amp;lt; 0.0001/P &amp;lt; 0.0001], respectively). Although the placebo response was higher for patients without stable use of TCI/TCS, the effect of dupilumab treatment was comparable in the two subgroups. Treatment-emergent adverse events (TEAEs) occurred with similar rates in dupilumab-treated patients with or without stable use of TCI/TCS (59.3%/60.7%), compared with placebo (53.3%/47.8%). Patients with or without stable use of TCI/TCS had similar rates of severe TEAEs in the dupilumab groups (2.2%/4.9%) and placebo groups (3.3%/4.5%). Conclusion Dupilumab treatment improves itch, skin lesions, and quality of life in patients with PN, with an acceptable safety profile, with little to no influence from concomitant treatment with topical therapies (TCI/TCS).

501 - Efficacy and safety of upadacitinib in a phase 2 randomized, double-blind, dose-ranging study of adults with extensive non-segmental vitiligo

Abstract Introduction &amp; Objectives Janus kinase (JAK) inhibition is a promising approach for the treatment of vitiligo. Here, we report the clinical efficacy and safety of upadacitinib (UPA), an oral JAK inhibitor, in a phase 2b multicenter, randomized, double-blind, placebo-controlled study of adults with extensive non-segmental vitiligo (NSV). Materials &amp; Methods Eligible patients were aged 18–65 years with NSV, a Facial Vitiligo Area Scoring Index (F-VASI) of ≥0.5, and a Total Vitiligo Area Scoring Index (T-VASI) of ≥5 at baseline. This 52-week study (NCT04927975) comprised 2 periods. In period 1, patients were randomly assigned to once daily UPA 22 mg (UPA22), UPA 11 mg (UPA11), UPA 6 mg (UPA6), or placebo (PBO) for 24 weeks of treatment. In a 28-week blinded extension (period 2), patients receiving UPA during period 1 continued their respective regimens; patients who received PBO in period 1 were pre-assigned to either UPA11 or UPA22. Clinical efficacy endpoints evaluated through week 36 included percent change from baseline (%CFB) in F-VASI (week 24, primary endpoint), reductions from baseline in F-VASI of ≥50% (F-VASI 50) and ≥75% (F-VASI 75), %CFB in T-VASI, and reduction from baseline in T-VASI of ≥50% (T-VASI 50). Safety data as of January 13, 2023 (data cutoff date) are presented. Results Of the 185 patients enrolled in period 1, 165 (89.2%) continued to period 2. At baseline, 68% of patients had extensive vitiligo (T-VASI &amp;gt; 10), and 71% had active vitiligo. At week 24, the %CFB in F-VASI was greater with UPA11 (−35.6%) and UPA22 (−34.0%) vs PBO (−14.4%; nominal P = .005 and P = .013, respectively). A greater proportion of patients achieved F-VASI 50 and F-VASI 75 with UPA11 (38.3%, 19.1%) and UPA22 (39.5%, 14.0%) vs PBO (10.9%, 2.2%; nominal P &amp;lt; .05 for both doses and for both endpoints). Likewise, the %CFB in T-VASI was greater with UPA11 (−17.3%) and UPA22 (−20.7%) vs PBO (−6.4%; nominal P = .026 and P = .005, respectively). A higher percentage of patients achieved T-VASI 50 with UPA22 (11.6%) than with PBO (2.2%; nominal P = .027). UPA efficacy continued to improve through week 36, with %CFB in F-VASI for UPA6, UPA11, and UPA22 of −20.8%, −44.9% and −47.7%, respectively. At week 36, F-VASI 50 was achieved with UPA6, UPA11, and UPA22 by 34.2%, 54.3% and 61.5% of patients and F-VASI 75 by 15.8%, 40.0%, and 30.8%, respectively. At week 36, %CFB in T-VASI for UPA6, UPA11 and UPA22 were −24.3%, −32.0% and −37.6%, with 10.5%, 20.0% and 19.2% of patients, respectively, achieving T-VASI 50. Treatment-emergent adverse event (TEAE) rates were generally similar with UPA and PBO in period 1 (most common TEAEs: COVID-19, acne, fatigue, and headache) and were similar across treatment arms in period 2. One death adjudicated as undetermined/unknown cause and deemed by the investigator to have no reasonable possibility of being related to study drug occurred in the UPA22 group (period 1). One adjudicated event of nonfatal ischemic stroke occurred with UPA11 (period 2). There were no adjudicated events of venous thromboembolism, gastrointestinal perforation, or events of opportunistic infection, active tuberculosis, or malignancy. Conclusion Treatment with UPA for 24 weeks resulted in greater improvements vs PBO in the clinical outcomes of adults with extensive NSV. Observed clinical efficacy continued to improve through week 36 with UPA treatment. UPA was generally well tolerated, with no new safety signals ­identified.

SUBCUTANEOUS INFLIXIMAB (CT-P13 SC) DOSE ESCALATION AS AN OPTION FOR MANAGING THE LOSS OF RESPONSE IN INFLAMMATORY BOWEL DISEASE POST HOC ANALYSIS OF LIBERTY-UC AND LIBERTY-CD STUDY

Abstract INTRODUCTION Dose escalation of IV infliximab is an option for inflammatory bowel disease (IBD) patients who lose response after induction therapy. However, as yet, there is limited data for CT-P13 subcutaneous (SC) infliximab (CT-P13 SC) dose escalation in IBD patients. AIMS &amp; METHODS The aim of the post hoc analysis was to evaluate the efficacy, safety, and immunogenicity of treatment with CT-P13 SC dose escalation in patients who initially responded but then lost response according to the loss of response (LOR) criteria in LIBERTY-UC and LIBERTY-CD studies, which were conducted in parallel over 54 weeks. Patients with moderately to severely active UC and CD were treated with 3 doses of infliximab IV 5mg/kg as induction therapy. Clinical responders at Week 10 were randomized (2:1) to receive either CT-P13 SC 120 mg or placebo every 2 weeks as maintenance therapy. From Week 22, the patients who received CT-P13 SC 120 mg every 2 weeks and who met LOR criteria were permitted to escalate the dose to CT-P13 SC 240 mg (double injection [2 shots] of CT-P13 SC 120 mg) every 2 weeks. RESULTS A total of 294 and 231 patients were randomized to CT-P13 SC 120mg in UC and CD study, each. Among them, dose escalation from CT-P13 SC 120 mg to CT-P13 SC 240 mg prior to Week 54was more common in UC than CD [27.6% (81/294) vs 16.9% (39/231)]. Of dose-escalated patients, 74.1% (60/81) and 51.3% (20/39) received their first dose of CT-P13 SC 240 mg at Week 22 in the UC and CD studies, respectively. In both UC and CD studies, patients showed improvement in terms of clinical remission [In UC, 24.7% (20/81), In CD, 53.8% (21/39)] or endoscopic response [In CD, 28.2% (11/39)] after dose escalation. Compared to the first dose escalation visits, patients who escalated the dose had almost a half, statistically significant, reduction in modified Mayo score in UC and CDAI score in CD at Week 54. (Table 1). The incidence rate of treatment-emergent adverse events (TEAEs) in the maintenance period of both studies was comparable between patients with and without dose escalation. [In UC, 72.8% (67/92) vs 65.2% (133/204), In CD, 71.1% (32/45) vs 72.5% (140/193)]. Among these, TEAEs of infection were as follows [In UC, 27.2% (25/92) vs 28.4% (58/204), In CD, 35.6% (16/45) vs 30.1% (58/193)]. In both studies, rates of anti-drug antibody (ADA) positive conversion up to Week 54 showed no difference in patients with and without dose escalation as follows [In UC, ADA 55.7% (49/88) and 67.3% (134/199), respectively. In CD, ADA 68.2% (30/44) and 64.4% (121/188), respectively]. CONCLUSION Dose escalation of CT-P13 SC from 120 mg to 240 mg every 2 weeks may be effective in restoring efficacy. Safety profiles including immunogenicity results were generally comparable between patients with or without dose escalation. No new safety concerns were found after dose escalation.

P658 Safety and efficacy of MH002, an optimized live biotherapeutic product, for the treatment of mild to moderate ulcerative colitis: a first-in-disease, double-blind, randomized clinical trial

Abstract Background Treatment options for patients with mild to moderate ulcerative colitis (UC) failing 5-ASA are limited. MH002 is an optimized consortium of 6 non-pathogenic, well-characterized commensal bacteria with immune modulating, wound healing and gut barrier protective effects. This study evaluated the safety, efficacy, and mechanistic effects of MH002 in mild to moderate UC. Methods In this 2:1-randomized, double-blind, placebo-controlled first-in-disease study (EudraCT 2020-001355-33), 45 patients with mild to moderate active UC (Modified Mayo Score [MMS] =4-8 but including Mayo Endoscopic Sub-score [MES] ≥2) received treatment with 400mg MH002 or placebo (PBO) once daily for 8 wks. Full colonoscopies with biopsies were performed at baseline and wk8, biopsies and endoscopy videos were scored by blinded central readers. The primary endpoint was the rate of treatment-emergent adverse events (TEAEs). Exploratory efficacy endpoints included clinical remission (MMS ≤2 with all sub-scores ≤1 and rectal bleeding sub-score =0), endoscopic improvement (MES ≤1), and UC-100 and biomarker normalisation (C-reactive protein [CRP] ≤5mg/L, faecal calprotectin [FCP] ≤250mg/kg). Changes from baseline (CFBL) in MES and stool consistency (Bristol Stool Form Scale) were also evaluated. Results MH002 was safe and well tolerated: a TEAE was reported in 11/31 (35%) patients with MH002 and in 8/14 (57%) with PBO. Most TEAEs were mild and unrelated to study treatment. Early discontinuations (7/45; 16%) occurred similarly in both groups. At wk8, patients achieved clinical remission, endoscopic improvement, and biomarker improvements at higher rates with MH002 vs PBO (Table 1). Clinical remission rates were 14% for MH002 vs 7% for PBO (Per-protocol Set [PPS]: 18% vs 0%). Significant differences in favour of MH002 over PBO were seen in the CFBL for MES at wk8 (P=0.05, 1-sided Wilcoxon) and for stool consistency at wk2 (P=0.0057, 1-sided Student t). In total, 14/45 (31%) and 36/42 (86%) patients had elevated CRP and FCP levels at baseline, resp. Of these, more patients treated with MH002 achieved normalisation at wk8 (CRP: 60% vs 25%; FCP: 36% vs 15%). Decreases in FCP and stool consistency with MH002 were observed as early as wk2 and were greater than with PBO through wk8 (Fig 1). Conclusion MH002 treatment was safe and well tolerated and resulted in clinically meaningful improvements in disease activity and inflammatory parameters. MH002 therefore represents a promising new treatment for mild to moderate UC patients insufficiently controlled with 5ASA. These results warrant further development in a phase 2/3 study.

DOP53 Long-term Efficacy and Safety of Risankizumab in Patients With Moderate to Severe Crohn's Disease up to 3 Years of Treatment: Results From the FORTIFY Open-Label Long-term Extension

Abstract Background The ongoing FORTIFY maintenance open-label extension (OLE) substudy evaluates the long-term efficacy and safety of risankizumab (RZB), a p19 interleukin-23 inhibitor, for treatment of moderate to severe Crohn’s disease (CD). Here, we report 2-year results of FORTIFY OLE. Methods The FORTIFY (NCT03105102) OLE enrolled patients (pts) who completed 52-wks maintenance dosing in the FORTIFY substudies or RZB phase 2 OLE.1,2 All pts received 180 mg subcutaneous (SC) RZB every 8 wks (Q8w), starting at wk56, except for pts who had prior rescue therapy (single 1200mg intravenous [IV] RZB dose then 360mg SC Q8w) who continued 360mg SC Q8w in the OLE. Pts with inadequate response (increased symptoms plus objective marker of inflammation) during the OLE could receive rescue therapy as described above. Pooled data from both treatment groups (RZB 180 mg &amp; 360 mg SC) were assessed. Clinical outcomes were evaluated every 24 wks (endpoint definitions in Figure footnote). Endoscopy was performed every 96 wks. Results are reported as observed. Efficacy data for pts receiving rescue therapy in the OLE were included up to rescue initiation. Safety was assessed through the cutoff date of 05MAR2023. As this trial is ongoing, most patients have not reached the wk152 study visit. Any treatment-emergent adverse events (TEAEs) reported on or after the first dose in the OLE were analysed. Results As of the cutoff date, 1147 pts entered the OLE, of which 203 (17.6%) pts received rescue therapy during the OLE. Clinical response and remission rates were generally maintained with RZB from wks 56 to 152 (CD activity index [CDAI] clinical response, 85.8% to 86.5%, respectively; enhanced clinical response, 88.6% to 89.2%; CDAI clinical remission, 68.5% to 77.6%; stool frequency/abdominal pain score clinical remission, 64.4% to 71.0%) (Figure). At wks 56 and 152, respectively, rates of endoscopic response were 53.4% and 74.2%, endoscopic remission were 37.5%, and 58.9%, and ulcer-free endoscopy were 31.0% and 50.0%. There were no new trends for exposure-adjusted rates of TEAEs, and rates of adjudicated major cardiovascular adverse events, malignancies, serious infections and hepatic events remained stable with no new safety risks identified. There were no events of active tuberculosis, serious hypersensitivity, or adjudicated anaphylactic reaction. Three deaths occurred during the OLE (see Table footnote), all assessed by investigators as unrelated to study drug. Conclusion Pts receiving long-term RZB maintenance therapy in FORTIFY demonstrated sustained clinical and endoscopic efficacy with at least 3 years of treatment. The safety profile is consistent and supports long-term RZB treatment. 1doi: 10.1093/ecco-jcc/jjab093 2doi: 10.1016/S0140-6736(22)00466-4.

Roflumilast foam 0.3% for adolescent and adult patients with seborrheic dermatitis: A randomized, double-blinded, vehicle-controlled, phase 3 trial

BackgroundThe topical phosphodiesterase 4 inhibitor roflumilast has been studied in several dermatologic conditions. ObjectiveRoflumilast foam 0.3% is being investigated as a topical treatment for seborrheic dermatitis (SD). MethodsIn this phase 3, double-blinded trial, patients with SD were randomly assigned (2:1 ratio) to once-daily roflumilast foam 0.3% or vehicle foam for 8 weeks. The primary efficacy outcome was Investigator Global Assessment (IGA) Success at week 8, defined as IGA of 0 (Clear) or 1 (Almost Clear) plus ≥2-point improvement from baseline. Safety was also assessed. Results79.5% of roflumilast-treated and 58.0% of vehicle-treated patients met the primary endpoint (P < .001); statistically significant differences in IGA Success also favored roflumilast at week 2 (roflumilast: 43.0%; vehicle: 25.7%; P < .001) and week 4 (roflumilast: 73.1%; vehicle: 47.1%; P < .001). Roflumilast was well-tolerated with a low rate of treatment-emergent adverse events. LimitationsStudy limitations include the 8-week treatment period for this chronic condition. ConclusionsOnce-daily roflumilast foam was superior to vehicle in leading to IGA of Clear or Almost Clear plus ≥2-point improvement from baseline at 8 weeks in patients with SD. Longer trials are needed to determine durability and safety of roflumilast foam in SD.

Analysis of patients (pts) with unresectable hepatocellular carcinoma (uHCC) and Child–Pugh (CP)-B liver function treated with regorafenib in routine clinical practice in the observational REFINE study.

452 Background: Pts with HCC and compromised liver function are typically excluded from clinical trials. The REFINE real-world study (NCT03289273) assessed a more varied pt population treated with regorafenib than the phase 3 RESORCE trial.1 Median overall survival (OS) in REFINE was 13.2 months and treatment-emergent adverse events (TEAEs) were consistent with RESORCE. We present a subgroup analysis of outcomes in pts from REFINE with CP-B liver function. Methods: REFINE is an international, prospective observational study of pts with uHCC for whom the decision to treat with regorafenib according to the local health authority approved label was made by their physician before enrollment. The primary endpoints were safety (Medical Dictionary for Regulatory Activities v25) and dose modifications due to drug-related TEAEs. Secondary endpoints included OS and duration of treatment (DoT). Results: Of 1005 evaluable pts, 123 (12%) were classified as CP-B at study entry, with most being CP-B7 (Table). Of the CP-B pts, 40/123 (9%), 9/123 (18%), and 58/123 (15%) initiated regorafenib at 160 mg, 120 mg, and 80 mg, per day, respectively. Median DoT with regorafenib was 2.3 months in CP-B pts and 3.7 months in the overall cohort. Incidence rates of TEAEs in CP-B pts and the overall cohort were similar (93% and 92%) and TEAEs were drug-related in 70% and 74% of pts, respectively. Grade 3–4 TEAEs occurred in 41% of CP-B pts and 39% of the overall cohort and were drug-related in 27% and 26% of pts, respectively. Serious TEAEs were observed in 48% of CP-B pts and 37% of the overall cohort, and were drug-related in 11% and 9% of pts, respectively. Drug-related TEAEs led to less frequent dose modifications in CP-B pts than in the overall cohort (28% vs 37%), but more frequent permanent discontinuations (28% vs 16%). Median OS in CP-B pts was 6.3 (95% confidence interval [CI] 4.9, 7.8) months and in CP-B7 pts was 6.7 (95% CI 5.1, 8.7) months. Conclusions: In REFINE, pts with uHCC and CP-B liver function had similar rates of grade 3–4 TEAEs, but a higher occurrence of serious TEAEs due to underlying cirrhosis led to more frequent permanent discontinuations in CP-B pts. Median OS in CP-B7 pts was comparable with OS in CP-B pts overall. The evaluation of prognostic models to identify CP-B pt subgroups who may benefit from regorafenib treatment is a subject for further research. 1. Kim YJ, ILCA 2022. [Table: see text]

Overview of the Safety Profile From Efgartigimod Clinical Trials in Participants With Diverse IgG-Mediated Autoimmune Diseases

Background Efgartigimod is a first-in-class, human immunoglobulin-G (IgG) Fc fragment that inhibits the neonatal Fc receptor (FcRn) and outcompetes endogenous IgG binding. FcRn inhibition by efgartigimod is a rational therapeutic option for IgG-mediated autoimmune disorders, including immune thrombocytopenia (ITP). Aims To determine the safety profile of efgartigimod for a variety of IgG-mediated autoimmune disorders, including ITP. Methods Intravenous efgartigimod safety was assessed in a phase 3 (ADVANCE) trial in ITP. It was also evaluated in generalized myasthenia gravis (gMG) in phase 2 and 3 (ADAPT) trials and a 3-year open-label extension (ADAPT+) along with an open-label phase 2 trial in pemphigus. Varying dosing regimens of efgartigimod (10-25 mg/kg) were used, including cyclical (gMG) and continuous weekly dosing (ITP, pemphigus). Results Across all indications and doses studied, efgartigimod demonstrated a consistent safety profile, with comparable treatment emergent adverse event (TEAE) rates to placebo (ADVANCE 93.0% efgartigimod vs. 95.6% placebo; ADAPT 77.4% efgartigimod vs. 84.3% placebo; 85% of participants in open label pemphigus study). Most TEAEs across studies were mild to moderate in severity. Discontinuation rates due to adverse events were low across studies (3.5% efgartigimod vs. 2.2% placebo in ADVANCE; 3.6% efgartigimod vs. 3.6% placebo in ADAPT; 3% in pemphigus). No increase in TEAE incidence rates or infections with repeated efgartigimod cycles (up to 19) in ADAPT+ was observed. In ADVANCE, no thromboembolic TEAEs were reported. Efgartigimod did not impair participant ability to generate new specific IgG responses to non-live vaccines, regardless of the timing of vaccinations however, there were transient reductions in specific IgG titers observed. Conclusions Efgartigimod was generally well tolerated across indications and doses studied. Most TEAEs, including infections, were mild or moderate in severity and did not increase in frequency with recurrent dosing. Non-live vaccine responsiveness was preserved. There were no thromboembolic events in those treated for ITP.

Cognitive and psychiatric adverse events during adjunctive cenobamate treatment in phase 2 and phase 3 clinical studies

ObjectiveCognitive and psychiatric adverse events in patients with epilepsy are important determinants of therapeutic outcomes and patient quality of life. We assessed the relationship between adjunctive cenobamate treatment and selected cognitive and psychiatric treatment-emergent adverse events (TEAEs) in adults with uncontrolled focal epilepsy. MethodsThis was a retrospective analysis of pooled populations of patients with focal epilepsy from two phase 2, randomized, double-blind clinical trials; two open-label extensions (OLEs) of those trials; and a long-term, open-label, phase 3 safety study. Occurrence of cognitive and psychiatric TEAEs in patients treated with adjunctive cenobamate or placebo during double-blind treatment were evaluated. Exposure-adjusted incidence rates of the cognitive and psychiatric TEAEs, defined as the number of TEAEs per patient-year of treatment, during up to 7 years of long-term adjunctive cenobamate treatment, were determined in the pooled OLE and phase 3 patient populations. ResultsThe pooled randomized trials resulted in a population of 442 patients treated with cenobamate (100 mg/day: n = 108; 200 mg/day: n = 223; 400 mg/day: n = 111) and 216 placebo-treated patients. The combined open-label studies resulted in pooled populations of cenobamate-treated patients ranging from n = 1690 during Year 1 to n = 103 during Year 7. Among cenobamate-treated (all doses) and placebo-treated patients during double-blind treatment, cognitive TEAEs were reported by ≤ 1.9 % (range, 0 %-1.9 %) and ≤ 0.5 % (range, 0 %-0.5 %), respectively, and psychiatric TEAEs by ≤ 3.6 % (range, 0 %-3.6 %) and ≤ 3.2 % (range, 0 %-3.2 %), respectively. During up to 7 years of open-label adjunctive cenobamate treatment, exposure-adjusted incidence rates of cognitive and psychiatric TEAEs were < 0.018 and < 0.038 events per patient-year, respectively. Discontinuation of adjunctive cenobamate due to cognitive or psychiatric TEAEs assessed in this study during double-blind or open-label treatment occurred in ≤ 0.3 % and ≤ 1.7 % of patients, respectively. ConclusionsCognitive and psychiatric TEAEs were reported by similar numbers of cenobamate- and placebo-treated patients during double-blind adjunctive cenobamate treatment (< 4 % of patients), and exposure-adjusted incidence rates of these TEAEs remained low during open-label cenobamate treatment for up to 7 years. Treatment discontinuations due to these TEAEs were rare. The results of this post-hoc analysis indicate that adjunctive cenobamate treatment exhibits a low incidence of cognitive or psychiatric TEAEs in patients with uncontrolled focal seizures.

Comparison of survival outcomes between olaparib and niraparib maintenance therapy in BRCA-mutated, newly diagnosed advanced ovarian cancer

IntroductionThis multicenter retrospective cohort study aimed to compare survival outcomes and adverse events between maintenance therapy with two poly (ADP-ribose) polymerase (PARP) inhibitors, olaparib and niraparib, in patients with BRCA-mutated, newly diagnosed advanced epithelial ovarian cancer (EOC) who responded to platinum-based chemotherapy. MethodsWe enrolled stage III-IV EOC patients with germline and/or somatic BRCA1/2 mutations that had received maintenance therapy with olaparib or niraparib. A 3:1 propensity score matching was conducted using two variables: residual disease size and the presence of germline variants. The primary outcome was progression-free survival (PFS), and the secondary outcomes were time to first subsequent therapy (TFST), overall survival (OS), and treatment-emergent adverse events (TEAEs). ResultsIn the propensity score-matched analysis, 80 patients who received olaparib and 31 patients who received niraparib were matched (3:1). In the propensity score-matched cohort, median PFS with olaparib vs. niraparib was not reached vs 31.5 months (HR, 1.08; 95% CI, 0.47–2.52; p = 0.854). The median TFST was not reached vs 31.8 months (HR, 1.20; 95% CI, 0.51–2.81; p = 0.682), and neither olaparib nor niraparib reached the median OS (HR, 0.42; 95% CI, 0.01–17.61; p = 0.649). In terms of the incidence rates of any-grade hematologic or non-hematologic TEAEs, higher rates of thrombocytopenia (p = 0.021) and neutropenia (p = 0.011) were observed in the niraparib group. ConclusionAdvanced EOC patients with BRCA1/2 mutations exhibited no significant difference in OS between olaparib and niraparib, indicating the need to consider individualized strategies for selecting PARP inhibitors based on adverse event profiles.

Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline–trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial

New treatments with new mechanisms are urgently needed for people with schizophrenia. Xanomeline is a dual M1 and M4-preferring muscarinic receptor agonist that does not block D2 dopamine receptors, unlike all currently approved treatments for schizophrenia. Xanomeline-trospium (KarXT) combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium chloride with the goal of ameliorating xanomeline-related adverse events associated with peripheral muscarinic receptors. The EMERGENT-2 trial aimed to assess the efficacy and safety of KarXT in people with schizophrenia experiencing acute psychosis. EMERGENT-2 was a randomised, double-blind, placebo-controlled, flexible-dose, 5-week, inpatient, phase 3 trial in people with schizophrenia. Participants were adults aged 18-65 years with a diagnosis of schizophrenia who had a recent worsening of psychosis warranting hospital admission, a Positive and Negative Syndrome Scale (PANSS) score of 80 or higher, and a Clinical Global Impression-Severity score of 4 or higher. The participants were recruited from 22 inpatient sites in the USA, and were randomly assigned (1:1) to KarXT or placebo twice per day. Participants randomly assigned to KarXT received 50 mg xanomeline and 20 mg trospium twice per day for the first 2 days and then 100 mg xanomeline and 20 mg trospium twice per day for days 3-7. Beginning on day 8, KarXT dosing was flexible with an optional increase to 125 mg xanomeline and 30 mg trospium twice per day and the option to return to 100 mg xanomeline and 20 mg trospium based on tolerability. The primary endpoint was change from baseline to week 5 in PANSS total score. Efficacy analyses used the modified intention-to-treat population (all randomly assigned participants who received at least one trial medication dose and had at least one post-baseline PANSS assessment). Least squares mean change from baseline, SE, and least squares mean difference between the KarXT and placebo groups at week 5, along with the 95% CI and two-sided p values were calculated for the primary and secondary continuous efficacy endpoints. Safety analyses included all participants receiving at least one trial medication dose and used descriptive statistics. This trial is registered with ClinicalTrials.gov (NCT04659161). From Dec 16, 2020, to April 13, 2022, of 407 people who were screened, 252 participants meeting enrolment criteria were randomly assigned to the KarXT (n=126) or placebo (n=126). Baseline PANSS total scores were 98·3 (KarXT; n=126) and 97·9 (placebo; n=125). The trial met the primary endpoint with a mean change from baseline to week 5 in PANSS total score that favoured KarXT (-21·2 points, SE 1·7) versus placebo (-11·6 points, 1·6; least squares mean difference -9·6; 95% CI -13·9 to -5·2; p<0·0001, Cohen's d effect size=0·61). All secondary endpoints were also met, and favoured KarXT versus placebo (p<0·05). The most common adverse events with KarXT versus placebo were constipation (27 [21%] vs 13 [10%]), dyspepsia (24 [19%] vs 10 [8%]), headache (17 [14%] vs 15 [12%]), nausea (24 [19%] vs seven [6%]), vomiting (18 [14%] vs one [1%]), hypertension (12 [10%] vs one [1%]), dizziness (11 [9%] vs four [3%]), gastro-oesophageal reflux disease (eight [6%] vs zero [0%]), and diarrhoea (seven [6%] vs four [3%]). Treatment-emergent adverse event rates of extrapyramidal motor symptoms (KarXT, zero [0%] vs placebo, zero [0%]), akathisia (one [1%] vs one [1%]), weight gain (zero [0%] vs one [1%]), and somnolence (six [5%] vs five [4%]) were similar between the KarXT and placebo groups, as were adverse event-related discontinuation rates (nine [7%] vs seven [6%]). In the EMERGENT-2 trial, KarXT was effective in reducing positive and negative symptoms and was generally well tolerated. These results support the potential for KarXT to represent a new class of effective and well tolerated antipsychotic medicines based on activating muscarinic receptors, not the D2 dopamine receptor-blocking mechanism of all current antipsychotic medications. Results from additional trials, including the identical EMERGENT-3 trial and the 52-week, open-label EMERGENT-4 and EMERGENT-5 trials, will provide additional information on the efficacy and safety of KarXT in people with schizophrenia. Karuna Therapeutics.