Exposure-adjusted Incidence Rates 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...

Real-world outcomes of ponatinib treatment in 724 patients with CML and Ph+ ALL: a post-marketing surveillance study with a special interest in arterial occlusive events in Japan.

In September 2016, ponatinib was approved in Japan for the treatment of patients with chronic myeloid leukemia with resistance/intolerance to prior tyrosine kinase inhibitors and patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia. We conducted a post-marketing all-case surveillance to study the safety and efficacy of ponatinib in clinical practice, focusing on arterial occlusive events. Data from 724 patients were collected for 2years from the initiation of ponatinib. The arterial occlusive events were reported in 6.49% (47/724) with an exposure-adjusted incidence rate of 6.8/100 person-years. The risks associated with arterial occlusive events were age and comorbidities including hypertension and diabetes. At 104weeks, the cumulative major molecular response rate in patients with chronic-phase chronic myeloid leukemia was 67.2% and the complete cytogenetic response in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia was 80.0%. Furthermore, the estimated 1-year overall survival rate was 98.5% for chronic-phase chronic myeloid leukemia and 68.6% for Philadelphia chromosome-positive acute lymphoblastic leukemia. This surveillance demonstrated that ponatinib has a favorable safety and efficacy profile in Japanese patients and also showed the necessity of closely monitoring arterial occlusive events in older adults and patients with predisposing factors for atherosclerosis.

P163 Low uveitis rates in patients with axial spondyloarthritis treated with bimekizumab: pooled results from phase 2b/3 trials

Abstract Background/Aims Acute anterior uveitis (‘uveitis’) is a common extra musculoskeletal manifestation of axial spondyloarthritis (axSpA). Interleukin (IL)-17 has been implicated in uveitis pathogenesis; however, inhibition of IL-17A alone may not be optimal for uveitis management. We report the incidence of uveitis following IL-17A and IL17F inhibition with bimekizumab (BKZ) in patients with axSpA. Methods Data were pooled for patients randomised to placebo (PBO) or BKZ 160mg every 4 weeks (Q4W) in the double-blind treatment period (DBTP) of the phase (ph)3 studies BE MOBILE 1 (NCT03928704; non-radiographic axSpA) and 2 (NCT03928743; radiographic axSpA [i.e. ankylosing spondylitis]). Data were also pooled for all patients treated with BKZ in BE MOBILE 1, BE MOBILE 2, BE MOVING (NCT04436640; open-label extension [OLE] of BE MOBILE 1 and 2), the ph2b study BE AGILE (NCT02963506; r-axSpA) and its OLE BE AGILE 2 (NCT03355573; data cut-off 4 July 2022). Uveitis events were identified using the preferred terms “autoimmune uveitis,” “iridocyclitis,” “iritis” and “uveitis,” and are reported as exposure adjusted incidence rates (EAIRs) per 100 patient-years (PY) for all patients who received ≥1 BKZ dose. Results Baseline characteristics of the axSpA study populations are shown in the Table. In the DBTP of BE MOBILE 1 and 2, uveitis events occurred in 11/237 (4.6%; EAIR/100 PY [95% CI]: 15.4 [7.7, 27.5]) and 2/349 (0.6%; 1.8 [0.2, 6.7]) patients randomised to PBO and BKZ (percentage difference [95% CI]: 4.1 [1.7, 7.6]), respectively. In 45 PBO-randomised (19.0%) and 52 BKZ-randomised (14.9%) patients with history of uveitis, uveitis occurred in 20.0% (EAIR/100 PY [95% CI]: 70.4 [32.2, 133.7]) and 1.9% (6.2 [0.2, 34.8]) of patients, respectively. In the ph2b/3 pool (N = 848) total BKZ exposure was 2,034.4 PY and 130 (15.3%) patients had history of uveitis. Uveitis occurred in 25 (2.9%; EAIR/100 PY [95% CI]: 1.2 [0.8, 1.8]) and 14 (10.8%; 4.6 [2.5, 7.7]) patients overall and with history of uveitis, respectively. All uveitis events were mild/moderate; one led to discontinuation. Conclusion Incidence of uveitis was lower to Week 16 in patients with axSpA randomised to BKZ 160mg Q4W versus PBO and remained low at 1.2/100 PY in the largest ph2b/3 pool. Disclosure M. Rudwaleit: Consultancies; AbbVie, Eli Lilly, Novartis and UCB Pharma. Member of speakers’ bureau; AbbVie, Boehringer Ingelheim, Chugai, Eli Lilly, Janssen, Novartis, Pfizer and UCB Pharma. M.A. Brown: Consultancies; Clementia, Grey Wolf Therapeutics, Incyte, Ipsen, Pfizer, Regeneron and Xinthera. Member of speakers’ bureau; Novartis and Pfizer. Grants/research support; UCB Pharma. F. van Gaalen: Grants/research support; Jacobus Stichting, Novartis, Stichting ASAS, Stichting Vrienden van Sole Mio and UCB Pharma. Other; fees from Novartis; personal fees from AbbVie, BMS, Eli Lilly and MSD. N. Haroon: Consultancies; AbbVie, Eli Lilly, Janssen, Novartis and UCB Pharma. L.S. Gensler: Consultancies; AbbVie, Acelyrin, Eli Lilly, Fresenius Kabi, Janssen, Novartis, Pfizer and UCB Pharma. Grants/research support; Novartis and UCB Pharma paid to institution. C. Fleurinck: Other; Employee of UCB Pharma. A. Marten: Other; Employee of UCB Pharma. U. Massow: Other; Employee of UCB Pharma. N. de Peyrecave: Other; Employee of UCB Pharma. T. Vaux: Other; Employee of UCB Pharma. K. White: Shareholder/stock ownership; UCB Pharma. Other; Employee of UCB Pharma. A. Deodhar: Consultancies; AbbVie, BMS, Eli Lilly, Janssen, MoonLake, Novartis, Pfizer and UCB Pharma. Member of speakers’ bureau; Janssen, Novartis and Pfizer. Grants/research support; AbbVie, BMS, Celgene, Eli Lilly, MoonLake, Novartis, Pfizer and UCB Pharma. D. McGonagle: Consultancies; AbbVie, Celgene, Janssen, Merck, Novartis, Pfizer and UCB Pharma. Honoraria; AbbVie, Celgene, Janssen, Merck, Novartis, Pfizer and UCB Pharma. Member of speakers’ bureau; AbbVie, Celgene, Janssen, Merck, Novartis, Pfizer and UCB Pharma. Grants/research support; AbbVie, Celgene, Janssen, Merck and Pfizer. I. van der Horst-Bruinsma: Consultancies; Abbvie, Eli Lilly, MSD, Novartis and UCB Pharma. Other; unrestricted grants received for investigator-initiated studies from AbbVie, MSD, Pfizer and UCB Pharma; fees received for lectures from AbbVie, BMS, MSD and Pfizer.

P123 Safety and efficacy of filgotinib, an update from the DARWIN 3 phase 2 long-term extension with a maximum of 8.2 years of exposure

Abstract Background/Aims DARWIN 3 (NCT02065700) is a long-term extension (LTE) study assessing the safety and efficacy of filgotinib (FIL) in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). In the DARWIN 1 (NCT01888874) and DARWIN 2 (NCT01894516) parent studies, patients received FIL in combination with MTX or FIL monotherapy, respectively. To provide an update on the safety and efficacy of FIL 200 mg (FIL200) in patients with RA, with or without MTX, with a maximum of 8.2 years of exposure. Methods Patients completing the DARWIN 1 and DARWIN 2 phase 2 studies could enter DARWIN 3, receiving FIL200[PE1] +/-MTX. The proportion of patients experiencing treatment-emergent adverse events (TEAEs) were reported, comprising data from both the parent and LTE studies. Efficacy was assessed from LTE baseline using the American College of Rheumatology (ACR) 20/50/70 criteria and DAS28-CRP, up to 264 weeks. Low disease activity and remission were defined as DAS28-CRP ≤3.2 and <2.6, respectively. Results In total, 739 patients were enrolled in DARWIN 3. In the FIL + MTX vs FIL monotherapy groups, TEAEs were reported for 90.9% and 92.1% of patients, respectively (Table). The most common TEAE was infection. In both treatment groups, eight patients had a TEAE leading to death (1.6% and 3.3%, respectively). Exposure-adjusted incidence rates, censored at time of first event for major adverse cardiovascular event, venous thromboembolism, herpes zoster, infections, serious infections, non-melanoma skin cancer (NMSC), malignancies excluding NMSC, gastrointestinal perforations and TEAEs leading to death, will be reported. Through five years, ACR20/50/70 responses were maintained in 86.3%/66.7%/50.7% of the FIL + MTX group and 90.8%/74.8%/51.4% of the FIL monotherapy group, respectively (observed data). DAS28-CRP low disease activity and remission rates (non-responder imputation) at DARWIN 3 baseline were 46.1%/40.1% (FIL + MTX) and 29.6%/24.8% (FIL monotherapy). At Week 264, the proportion of patients achieving low disease activity and remission were 34.0%/34.3% (FIL + MTX) and 27.0%/24.8% (FIL monotherapy). Conclusion With a maximum of 8.2 years of exposure in patients with RA, the FIL safety profile is similar between the background MTX and monotherapy treatment arms. Both arms show sustained efficacy over time. Disclosure P. Emery: Consultancies; Consultant of: AbbVie, AstraZeneca, BMS, Boehringer-Ingelheim, Galapagos, Gilead, Lilly, Novartis, Pfizer, Roche, and Samsung. Member of speakers’ bureau; y Speakers bureau: AbbVie, AstraZeneca, BMS, Boehringer-Ingelheim, Galapagos, Gilead, Lilly, Novartis, Pfizer, and Samsung. Grants/research support; Grant/research support from: AbbVie, BMS, Lilly, Novartis, Pfizer, Roche, and Samsung. R. Westhovens: Consultancies; Celltrion, Galapagos, and Gilead,. Member of speakers’ bureau; Celltrion, Galapagos, and Gilead. R.H.E. Alten: Consultancies; AbbVie, Amgen, Biogen, BMS, Celltrion, Gilead, Janssen, Lilly, Medac, MSD, Mylan, Novartis, Pfizer, Roche, Sandoz, SanofiGenzyme, UCB, and VIATRIS. L. Dagna: Consultancies; AbbVie, Amgen, AstraZeneca, Biogen, Boehringer-Ingelheim, BMS, Celltrion, Eli Lilly & Company, Galapagos, GlaxoSmithKline, Janssen, Kiniksa Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi-Genzyme,. Grants/research support; AbbVie, BMS, Celgene, GlaxoSmithKline, Janssen, Kiniksa, Merck Sharp & Dohme, Mundipharma Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi-Genzyme, and SOBI,. A. Kavanaugh: Consultancies; Amgen, AbbVie, BMS, Pfizer, UCB, Janssen, Novartis, and Pfizer. K.L. Winthrop: Consultancies; AbbVie, AstraZeneca, BMS, Eli Lilly & Company, Galapagos, Gilead, GlaxoSmithKline, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB. Grants/research support; BMS and Pfizer. J. Barry: Corporate appointments; Galapagos. Shareholder/stock ownership; Galapagos. R. Besuyen: Corporate appointments; Galapagos. Shareholder/stock ownership; Galapagos. C. Corallo: Corporate appointments; Galapagos. Shareholder/stock ownership; Galapagos. C. Watson: Corporate appointments; Galapagos. Shareholder/stock ownership; Galapagos. N. Martin: Consultancies; Galapagos. M. Genovese: Corporate appointments; Gilead Sciences. Shareholder/stock ownership; Gilead Sciences. A.J. Spindler: None. M. Stanislavchuk: Grants/research support; Amgen, AstraZeneca, Celgene, Eli Lilly, Galapagos, Gilead, Human Genome, Janssen, MSD, Nichi-Iko, Pfizer, and Roche. M. Greenwald: Grants/research support; AbbVie, Aclaris, Galapagos, Janssen, Lilly, and Nimbus.

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.

Evolocumab Treatment in Pediatric Patients With Homozygous Familial Hypercholesterolemia: Pooled Data From Three Open-Label Studies.

Pediatric patients with homozygous familial hypercholesterolemia (HoFH) have an increased risk of atherosclerotic cardiovascular disease and difficulty meeting low-density lipoprotein cholesterol (LDL-C) goals. In this post hoc analysis, we evaluated pooled safety and efficacy data from 3 studies in pediatric patients with HoFH treated with the PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibody inhibitor evolocumab. Patients with HoFH aged 10 to 17 years received treatment with open-label evolocumab 420 mg subcutaneously monthly or biweekly in the TAUSSIG, RAMAN, or HAUSER-OLE clinical studies. All patients received background statins with or without ezetimibe. Study duration ranged from 12 to 260 weeks. The primary end point was treatment-emergent adverse events per 100 patient-years. Efficacy end points were changes from baseline to week 12 in lipids and PCSK9. Of the 39 patients in the pooled analysis, 69.2% were males, median age was 13.0 years, and 79.5% (31/39) had genotyped HoFH with LDLR pathogenic variants. Overall, median exposure to evolocumab was 18.2 (Q1, Q3: 3.0, 18.5) months. Treatment-emergent adverse events with an exposure-adjusted patient incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%) per 100 patient-years. Exposure-adjusted patient incidence of serious treatment-emergent adverse events was 13.3% per 100 patient-years. Excluding 4 patients receiving lipoprotein apheresis, week 12 median percentage change from baseline in LDL-C was -2.9% (Q1, Q3: -21.7, 1.5); however, 42.9% (15/35) of patients achieved ≥15% reduction in LDL-C from baseline. Residual LDLR (LDL receptor) activity was not associated with a reduction in LDL-C. In this pooled data analysis from 3 studies in pediatric patients with HoFH, evolocumab was well tolerated, with no new safety signals reported. These safety findings are consistent with findings from previous studies of evolocumab. Patients showed marked variability in LDL-C reduction. Results from this pooled analysis support guidelines suggesting a trial of PCSK9 inhibitor therapy regardless of estimated residual LDLR function. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01624142, NCT03403374, and NCT02624869.

Cardiovascular events reported in patients with B-cell malignancies treated with zanubrutinib

AbstractFirst-generation Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has been associated with an increased risk of cardiovascular toxicities. Zanubrutinib is a more selective, next-generation BTK inhibitor. In this analysis, incidence rates of atrial fibrillation, symptomatic (grade ≥2) ventricular arrhythmia, and hypertension were evaluated in a pooled analysis of 10 clinical studies with zanubrutinib monotherapy in patients (N = 1550) with B-cell malignancies and a pooled analysis of head-to-head studies comparing zanubrutinib with ibrutinib (ASPEN cohort 1; ALPINE). Among the 10 studies, most patients (median age, 67 years) were male (66.3%) and had CLL/SLL (60.5%). Overall incidence and exposure-adjusted incidence rates (EAIR) for atrial fibrillation, symptomatic ventricular arrhythmia, and hypertension were lower with zanubrutinib than ibrutinib. Despite a similar prevalence of preexisting cardiovascular events in ASPEN and ALPINE, atrial fibrillation/flutter incidence rates (6.1% vs 15.6%) and EAIR (0.2 vs 0.64 persons per 100 person-months; P < .0001) were lower with zanubrutinib than with ibrutinib. Symptomatic ventricular arrhythmia incidence was low for both zanubrutinib (0.7%) and ibrutinib (1.7%) with numerically lower EAIR (0.02 vs 0.06 persons per 100 person-months, respectively) for zanubrutinib. The hypertension EAIR was lower with zanubrutinib than ibrutinib in ASPEN but similar between treatment arms in ALPINE. The higher hypertension EAIR in ALPINE was inconsistent with other zanubrutinib studies. However, fewer discontinuations (1 vs 14) and deaths (0 vs 6) due to cardiac disorders occurred with zanubrutinib versus ibrutinib in ALPINE. These data support zanubrutinib as a treatment option with improved cardiovascular tolerability compared with ibrutinib for patients with B-cell malignancies in need of BTK inhibitors. These trials were registered at www.ClinicalTrials.gov as # NCT03053440, NCT03336333, NCT03734016, NCT04170283, NCT03206918, NCT03206970, NCT03332173, NCT03846427, NCT02343120, and NCT03189524.

Deucravacitinib in Plaque Psoriasis: 3-year Safety and Efficacy Results from the Phase 3 POETYK PSO-1 and PSO-2 Trials

Introduction: Deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, is approved in the US, EU, and other countries for treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy. Deucravacitinib was superior to placebo and apremilast in the POETYK PSO-1 (NCT03624127) and PSO-2 (NCT03611751) parent trials in moderate to severe plaque psoriasis. The POETYK long-term extension (LTE; NCT04036435) trial enrolled patients completing PSO-1/PSO-2. We report deucravacitinib safety and efficacy for up to 3 years (Week 148; through cutoff 6/15/2022).&#x0D; Methods: PSO-1/PSO-2 randomized patients 1:2:1 to oral placebo, deucravacitinib 6 mg QD, or apremilast 30 mg twice daily. At Week 52, patients enrolled in the LTE received open-label deucravacitinib 6 mg QD. Safety was evaluated in patients receiving ≥1 deucravacitinib dose using exposure-adjusted incidence rate per 100 person-years (EAIR/PY). Efficacy outcomes (PASI 75/90; sPGA 0/1) were analyzed using modified nonresponder imputation (mNRI) in patients receiving continuous deucravacitinib from Day 1 of the parent trial and treated in the LTE.&#x0D; Results: Of 1519 patients who received ≥1 deucravacitinib dose (3294.3 PY cumulative exposure), 513 received continuous deucravacitinib from Day 1 in PSO-1/PSO-2 and were treated in the LTE. EAIRs/100 PY were comparable, or decreased, between the 2-year and 3-year cumulative periods, respectively, for AEs (154.4, 144.8), serious AEs (6.1, 5.5), discontinuations due to AEs (2.8, 2.4), herpes zoster (0.7, 0.6), malignancies (0.9, 0.9), major adverse cardiovascular events (0.4, 0.3), venous thromboembolism (0.1, 0.1), and deaths (0.4, 0.3). Response rates were maintained at Week 148 by mNRI (PASI 75, 73.2%; PASI 90, 48.1%; sPGA 0/1, 54.1%).&#x0D; Conclusion: Deucravacitinib maintained a consistent safety profile and durable efficacy for up to 3 years.

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.

496 - Conjunctivitis does not increase with longer duration of lebrikizumab exposure in patients with moderate-to-severe atopic dermatitis

Abstract IntroductionIntegrated safety data for lebrikizumab (LEB) treatment in moderate-to-severe atopic dermatitis (AD) has been previously published. Conjunctivitis and keratitis were identified as adverse events (AEs) of special interest in the AD ­program. Objectives Further characterize patient-reported conjunctivitis and keratitis AEs in LEB clinical trials for AD. Methods Data from adult and adolescent patients were analyzed in 2 groups: a) LEB 250mg every 2 weeks (LEBQ2W, N=783) vs placebo (PBO, N=404), weeks 0-16 (PC 0-16wk) from 4 clinical trials (ADvocate1, ADvocate2, ADhere, Phase 2b study); and b) patients who received at least one dose of LEB (ALL-LEB, N=1720) from 8 clinical trials (ADvocate1, ADvocate2, ADhere, ADore, ADjoin (ongoing), ARBAN, TREBLE, Phase 2b study). Conjunctivitis and keratitis refer to cluster definitions defined by MedDRA preferred terms conjunctivitis, allergic conjunctivitis, bacterial conjunctivitis, viral conjunctivitis, giant papillary conjunctivitis; and keratitis, atopic keratoconjunctivitis, allergic keratitis, ulcerative keratitis, vernal keratoconjunctivitis, respectively. Exposure adjusted incidence rates (IR) are provided as per 100 patient-years. Results In PC 0-16wk, at baseline, similar proportions of LEB (21.5%) and PBO (19.3%) patients had medical history (MH) of conjunctivitis. Of ALL-LEB, 22.2% had MH of conjunctivitis; of those with conjunctivitis or keratitis AE, 40% had MH of conjunctivitis. In PC 0-16wk, conjunctivitis cluster was reported by 8.5% (IR:30.6) LEBQ2W vs 2.5% (IR:8.9) PBO; keratitis cluster was reported by 0.6% (IR:2.2) and 0.3% (IR:0.9) of patients, respectively. All conjunctivitis and keratitis events in PC 0-16wk were mild or moderate in severity; 5 events (3 conjunctivitis, 2 keratitis) led to treatment discontinuation (LEBQ2W) vs 1 conjunctivitis event (PBO). ALL-LEB treatment duration ranged from 1 dose to 100 weeks. In ALL-LEB, conjunctivitis cluster was reported by 10.6% (IR:12.2), with the majority being mild or moderate (10.3%) and 0.3% severe. Keratitis was reported by 0.5% (IR:0.6), with 1 severe event of vernal keratoconjunctivitis. Conjunctivitis and keratitis events resulted in 17 (1.0%) and 3 (0.2%) treatment discontinuations, respectively. Similar proportions of adult (11.3%; 0.6%) and adolescent (8.3%; 0.3%) patients reported conjunctivitis and keratitis events. The majority were reported within first 16 weeks of treatment. ConclusionsConjunctivitis is an AE reported by LEB-treated patients. Patients with MH of conjunctivitis may have higher risk of developing treatment-emergent conjunctivitis or keratitis. Most events were mild or moderate in severity, did not lead to treatment discontinuation, were reported within first 16 weeks of treatment, and IR did not increase with longer duration of exposure.

DOP16 Safety of long-term ozanimod treatment for up to 4 years in patients with moderately to severely active Ulcerative Colitis: an interim analysis of the True North open-label extension

Abstract Background The 52-week, phase 3 True North (TN) study (NCT02435992) demonstrated the efficacy and safety of ozanimod (OZA), a highly selective sphingosine 1-phosphate receptor 1 and 5 modulator, in patients (pts) with moderately to severely active ulcerative colitis (UC). A prior analysis reported the long-term safety of up to 3 y of OZA in the ongoing TN open-label extension (OLE; NCT02531126; from TN baseline to OLE Week [W] 94). This analysis presents the cumulative long-term safety of OZA in TN and the TN OLE for an additional year (up to OLE W142). Methods The TN study design has been previously described. This analysis included all TN pts who entered the OLE from TN (clinical nonresponders at W10, lost response during maintenance, or completed maintenance at W52). Safety assessments were reported from the first dose of OZA either in TN or OLE up to OLE W142. Lab abnormalities, including absolute lymphocyte count (ALC) reductions, were reported. Exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) were calculated for all treatment-emergent adverse events (TEAEs). Results A total of 823 pts entered the TN OLE (average age: 41.7 y; 59% male); 62% had left-sided UC disease. Total PY exposure to OZA at OLE W142 was 2536 y. Overall, the cumulative safety assessments did not significantly change with an additional year of OZA exposure from OLE W94 to W142 (Table). A decrease in EAIRs per 100 PY was observed in overall TEAEs (85.5 vs 87.6) and serious TEAEs (7.0 vs 7.4) at OLE W142 vs OLE W94, respectively. Notably, with an additional year of OZA exposure, TEAEs leading to treatment discontinuation remained at 2.5 EAIR/100 PY, and there were no new cases of bradycardia or atrioventricular block. One new TEAE each of herpes zoster, macular oedema, cystoid macular oedema, myocardial ischaemia, pulmonary embolism, and deep vein thrombosis were noted. COVID-19 TEAEs increased at OLE W142 (n=103; EAIR: 4.3/100 PY) from OLE W94 (n=66; EAIR: 3.0/100 PY). Reductions in ALC &amp;lt;500 cells/mm3 were common in the OLE (OLE W94, 54.0%; OLE W142, 56.1%); few pts had ALC &amp;lt;200 cells/mm3 (OLE W94, 5.3%; OLE W142, 6.5%), but these pts had no serious infections. No serious hepatic safety events were observed. One new death due to adenocarcinoma, which was unrelated to OZA, was reported. Conclusion The ongoing safety profile of OZA is consistent with previous analyses, with no new safety signals identified compared with previous UC analyses. Long-term use of OZA representing 2536 PYs of exposure continues to be well tolerated in pts with moderately to severely active UC.

P1009 Efficacy and safety of 4 years of continuous ozanimod treatment: an interim analysis of the True North open-label extension study

Abstract Background The phase 3 True North (TN) study demonstrated the efficacy and safety of ozanimod (OZA) over 52 wk in patients (pts) with moderately to severely active ulcerative colitis (UC); the ongoing TN open-label extension (OLE) is assessing long-term efficacy and safety. This interim analysis of the TN OLE assessed pts with up to ~4 y of continuous OZA treatment. Methods Clinical responders after 52 wk of continuous OZA treatment (0.92 mg/d) during TN who subsequently entered the TN OLE were included in this analysis. Data were analysed up to OLE Week (W) 142, representing up to ~4 y of continuous OZA treatment. Symptomatic response (≥1-point and ≥30% decrease from baseline [BL] in the combined 6-point rectal bleeding subscore [RBS] + stool frequency subscore [SFS] and ≥1-point decrease in RBS or absolute RBS ≤1) and symptomatic remission (RBS=0 and SFS ≤1 [and ≥1-point decrease from BL SFS]) were evaluated from OLE W5 through OLE W142. Clinical remission, clinical response, endoscopic improvement, and corticosteroid (CS)-free remission were evaluated at OLE W46, W94, and W142. Endpoints were evaluated using observed case (OC) and nonresponder imputation (NRI) analyses. Adverse events were monitored throughout TN and the OLE. Results In all, 131 pts entered the OLE after achieving clinical response on OZA at W52 in TN. At the data cutoff, 87.0% of pts completed OLE W46, 71.8% completed OLE W94, and 64.1% completed OLE W142. Most (67.9%) pts had left-sided UC disease, 23.7% had concomitant CS use at TN BL, and 32.1% had prior exposure to tumour necrosis factor inhibitors. Symptomatic response and symptomatic remission were observed in 100.0% and 84.4% of pts, respectively, at OLE W5 in the OC analysis (93.1% and 78.6%, respectively, in the NRI analysis). By OLE W142, symptomatic response and symptomatic remission rates were 98.7% and 88.3%, respectively, in the OC analysis and 58.0% and 51.9%, respectively, in the NRI analysis. Rates of clinical and endoscopic endpoints during the OLE are shown in Figure 1A (OC) and 1B (NRI). Of note, 65.3% of TN W52 clinical responders achieved clinical remission and CS-free remission at OLE W142 in the OC analysis (35.9% in the NRI analysis). With this additional year of follow-up in the OLE, there were no new cases of bradycardia, third-degree atrioventricular block, hypertension, herpes zoster, or macular oedema, and no clinically meaningful change in malignancy exposure-adjusted incidence rates (Table). No serious hepatic events occurred. Conclusion Clinical responders after 1 y on OZA sustained response for an additional 3 y and achieved clinical remission with continuous OZA exposure. OZA is a safe, tolerable, and durable therapy for pts with UC.

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.

Incidence of New-Onset Inflammatory Bowel Disease, Oral and Gastrointestinal Candidiasis, Herpes Zoster, Pulmonary Tuberculosis, and Major Cardiovascular Events in Patients with Moderate-to-Severe Psoriasis Exposed to Biologics.

The multicenter, retrospective cohort study was aimed at examining adverse events in biologic-treated patients with moderate-to-severe psoriasis by using a real-world database. Thus, we analyzed exposure-adjusted incidence rates for new-onset inflammatory bowel disease (IBD), oral and gastrointestinal candidiasis, pulmonary tuberculosis, herpes zoster, and major cardiovascular events (MACEs) in biologic-treated patients with moderate-to-severe psoriasis. Overall, 2085 patients were found to have been exposed to tumor necrosis factor (TNF)-α, interleukin (IL)-12/23, IL-17, and IL-23 inhibitors (n = 463, 540, 635, and 447, respectively). No patient developed new-onset IBD. The incidence rates of oral and gastrointestinal candidiasis were comparable between patients treated with IL-23 and IL-17 inhibitors (5.6 and 5.3 per 1000 PY, respectively). None treated with IL-17 or IL-23 inhibitors reported pulmonary tuberculosis. The incidence rate of herpes zoster was the highest in patients treated with TNF-α inhibitors (17.0 per 1000 PY), followed by IL-17, IL-23, and IL-12/23 inhibitors (13.3, 7.8, and 2.7 per 1000 PY, respectively). MACEs were not reported in patients treated with IL-17 inhibitors but were reported in those treated with TNF-α, IL-23, and IL-12/23 inhibitors (incidence: 5.6, 3.8, and 1.8 per 1000 PY, respectively). The study indicated favorable safety profiles of biologics in Korean patients with moderate-to-severe psoriasis.

Safety and Tolerability of Inclisiran forTreatment of Hypercholesterolemia in7 Clinical Trials.

Inclisiran is a small interfering RNA agent to lower low-density lipoprotein cholesterol. The purpose of this study was to provide reliable evidence to date on the long-term safety profile of inclisiran. This post hoc analysis comprised patients treated with 300mg inclisiran sodium or placebo in the completed (ORION-1, -3, -5, -9, -10, and -11) and ongoing (ORION-8) trials. Exposure-adjusted incidence rates and Kaplan-Meier estimates of cumulative incidence of reported treatment-emergent adverse events (TEAE), abnormal laboratory measurements, and incidence of antidrug antibodies were analyzed. This analysis included 3,576 patients treated with inclisiran for up to 6 years and 1,968 patients treatedwith placebo for up to 1.5 years, with 9,982.1 and 2,647.7 patient-years of exposure, respectively. Baseline characteristics were balanced between groups. Kaplan-Meier analyses showed that TEAEs that were serious or led to discontinuation; hepatic, muscle, and kidney events; incident diabetes; and elevations of creatine kinase or creatinine accrued at a comparable rate between groups for up to 1.5 years, with similar trends continuing for inclisiran beyondthis period. Numerically fewer major cardiovascular events reported as TEAEs occurred with inclisiran during this period. Treatment-induced antidrug antibodies were uncommon with inclisiran (4.6%), with few of these persistent (1.4%) and not associated with greater incidence of TEAEs leading to study drug discontinuation or serious TEAEs. Long-term treatment with inclisiran was well tolerated in a diverse population, without new safety signals, supporting the safety of inclisiran in patients with dyslipidemia.

Short-term risk and long-term incidence rate of infection and malignancy with IL-17 and IL-23 inhibitors in adult patients with psoriasis and psoriatic arthritis: a systematic review and meta-analysis.

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022363127.

Cumulative Review of Hypertension in Patients with Chronic Lymphocytic Leukemia (CLL) and Other Hematologic Malignancies Treated with Acalabrutinib

Background: Patients (pts) with CLL have a high rate of comorbidities, including cardiovascular disease (CVD). Comorbid CVD is correlated with higher mortality in this pt population. Hypertension (HTN) is the most common concurrent CVD in pts with CLL and is associated with development of complications such as stroke and heart failure. The incidence of new or worsening HTN in treatment-naive CLL pts receiving placebo within the CLL12 trial was 8.3% over a 69.3-month observation period (Langerbeins et al. Hematol Oncol. 2023). New and/or worsening HTN has been observed in pts with CLL treated with Bruton tyrosine kinase inhibitor (BTKi) therapy. Studies have shown new or worsening HTN with ibrutinib (7−30%) and zanubrutinib (11−20%) (Christensen et al. Expert Rev Hematol. 2022). Acalabrutinib (acala), a selective, second-generation BTKi, demonstrated a lower rate of HTN (8.6%) vs ibrutinib (22.8%) in the head-to-head ELEVATE-RR study at a median follow-up of 40.9 months (Byrd et al. J Clin Oncol. 2021). Here, we performed a cumulative analysis of new or worsening HTN from the acala global development program and compared these data against real-world prevalence and incidence of HTN for pts with CLL prior to treatment initiation using claims data. Methods: Safety reports of new or worsening HTN were obtained from 11 clinical trials with acala (the safety database analysis comprised 2034 pts from studies in CLL [86.3%] and mantle cell lymphoma [6.1%], with the remainder from other B-cell malignancies). The clinical trials analyzed included therapy with acala (monotherapy or in combination with obinutuzumab) and active comparator groups (described in Table 1). Using the narrow Standardized MedDRA Query and the related MedDRA preferred terms for “HTN,” exposure-adjusted incidence rates in events/100 person-years were determined, and as a comparison, HTN prevalence was assessed at median treatment exposure for acala monotherapy. HTN prevalence (proportion of pts with HTN 6 months before treatment initiation) and incidence rates (number of new cases of HTN per 100 person-years during the 5 years before any treatment initiation) were also assessed based on ICD-10 codes from 3 adjudicated closed claims databases (Optum, MarketScan, and IQVIA). Results: In the claims database analysis, prevalence of HTN ranged from 47.3% to 66.1% in pts with TN CLL prior to treatment initiation. HTN prevalence with acala monotherapy at median treatment exposure (45.5 months) was 55.7%. Exposure-adjusted incidence rates of HTN were analyzed from 11 clinical trials; 1225 pts received acala monotherapy (947 pts with CLL), 223 pts received acala + obinutuzumab (all pts with CLL), 264 pts received ibrutinib as a comparator (all pts with CLL), and 322 pts received other comparators (all pts with CLL). Among the 1225 pts treated with acala monotherapy, 165 pts (147 with CLL) experienced a treatment-emergent adverse event of HTN (median age 66 years; 66.1% [n=109] male; 59.4% [n=98] with history of HTN at baseline). The exposure-adjusted incidence rates of HTN with acala monotherapy (3.844) and acala + obinutuzumab (3.926) were similar to that of other comparators (4.788 [excluding ibrutinib]) ( Table 1). In the ELEVATE-RR study specifically (subgroup of the current analysis), the exposure-adjusted incidence rate of HTN with acala (3.053) was approximately one-third that of ibrutinib (8.590). The exposure-adjusted incidence rate of HTN in pts treated with acala monotherapy without history of HTN was 3.239. Conclusions: Our data showed that HTN is a common comorbidity in pts with CLL as demonstrated in the claims database and clinical trial database analyses where 59.4% of pts who experienced HTN with acala monotherapy had history of HTN at baseline. The incidence rates of new or worsening HTN with acala monotherapy and acala + obinutuzumab were low (3.844 and 3.926, respectively). This is supported by similar incidence proportion of new or worsening HTN in pts receiving placebo (8.3%) from CLL12 (median follow-up 69.3 months) and acala monotherapy (8.9%) from ELEVATE-TN (median follow-up 58.2 months; Sharman et al. EHA. 2022), and similar HTN prevalence at median treatment exposure vs before treatment initiation in claims databases. Our analysis, conducted predominantly in patients with CLL, suggests that acala monotherapy did not worsen pre-existing HTN or increase the risk of new-onset HTN.

Sustained Efficacy and Safety with Asciminib (ASC) after Almost 4 Years of Median Follow-up from Ascembl, a Phase 3 Study of ASC Vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) after ≥2 Prior Tyrosine Kinase Inhibitors (TKIs): An End of Study Treatment (EOS Tx) Update, Including Results from Switch Population

CONCLUSIONS CML requires chronic therapy, emphasizing the need for Txs that are characterized by high, durable efficacy and a low adverse event (AE) burden. ASC, the first BCR::ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), demonstrated significantly superior efficacy and better safety/tolerability compared with BOS in pts with CML-CP who received ≥2 prior TKIs in the phase 3 ASCEMBL study. Major molecular response (MMR) rate was 25.5% with ASC vs 13.2% with BOS at wk 24, meeting the primary objective, and 37.6% vs 15.8% at wk 96, meeting the key secondary objective. Despite the longer duration of exposure to ASC, safety/tolerability remained consistently better with ASC vs BOS, with fewer all-grade and grade ≥3 AEs and AEs leading to Tx discontinuation observed. After a median follow-up of 3.7 y, we report EOS Tx results from ASCEMBL (cutoff: March 22, 2023). We also report the first available data from pts who experienced Tx failure on BOS and switched to ASC. Adults (aged ≥18 y) with CML-CP after ≥2 prior TKIs, with intolerance or lack of efficacy per 2013 ELN recommendations were randomized 2:1 to receive either ASC 40 mg twice daily or BOS 500 mg once daily. Pts who met Tx failure criteria per 2013 ELN while on BOS could switch to ASC and were analyzed separately. Pts who discontinued BOS due to intolerance could not switch. EOS will occur 5 y from when the last enrolled pt received first Tx dose. A total of 233 pts were randomized to ASC (n=157) or BOS (n=76). The most common reason for discontinuation was lack of efficacy in 40 (25.5%) pts on ASC and 28 (36.8%) on BOS. At the time of EOS Tx cutoff, Tx with ASC and BOS was ongoing in 77 (49.4%) and 8 (10.5%) pts, respectively; pts deriving benefit from study Tx at EOS TX, per investigator assessment, continued receiving posttrial access. MMR rate at wk 156 continued to be higher with ASC (33.8%) than with BOS (10.5%) (Figure 1). The difference after adjusting for baseline (BL) major cytogenetic response was 23.2%(95% CI, 13.1%-33.2%; 2-sided P&amp;lt;.001). The BCR::ABL1IS ≤1% rate at wk 156 in pts without this level of response at BL also continued to be higher with ASC (43.0%) than with BOS (11.1%). Despite the longer median duration (range) of exposure to ASC (156.0 [0.1-256.3] wk) vs BOS (30.5 [1.0-239.3] wk), safety/tolerability of ASC continued to be better compared with BOS and were consistent with previous analyses. Two new pts had AEs leading to Tx discontinuation since the wk 96 cutoff (1 pt on ASC reported pregnancy; 1 pt on BOS reported diarrhea), and rates remained lower with ASC vs BOS (8.3% vs 27.6%). The most frequent (≥10%) grade ≥3 AEs with ASC vs BOS were thrombocytopenia (22.4% vs 9.2%), neutropenia (18.6% vs 14.5%), diarrhea (0% vs 10.5%), and increased alanine aminotransferase (0.6% vs 14.5%). Most AEs occurred within the first 6 months (Figure 2). Exposure-adjusted incidence rates of arterial occlusive events (AOEs) with ASC decreased since the wk 96 cutoff, from 3.0 to 2.2 per 100 pt-y, and no new AOEs occurred with ASC, indicating that the risk of AOEs did not increase over time. Among pts who discontinued Tx due to lack of efficacy or disease progression, no new mutations occurred since the wk 96 cutoff. Of 28 pts who discontinued BOS for lack of efficacy, 25 switched to ASC. Almost all switch pts (96%) had BL BCR::ABL1IS &amp;gt;10% prior to switch. No switch pts achieved MMR at or by wk 48 post switch. However, at wk 48, 24% achieved BCR::ABL1IS ≤10% and 8% achieved BCR::ABL1IS ≤1%. The safety profile of ASC in switch pts was consistent with that in pts receiving ASC in the randomized period. Most frequent (≥10%) grade ≥3 AEs were neutropenia (32.0%) and thrombocytopenia (24.0%). AEs leading to Tx discontinuation occurred in 8.0% of switch pts. With almost 4 y of follow-up in ASCEMBL, ASC continued to show greater efficacy and better safety/tolerability than BOS in pts with CML-CP after ≥2 prior TKIs. The robust safety profile of ASC was sustained through each analysis in ASCEMBL (wk 24, wk 96, and EOS Tx), confirming that pts receiving ASC can maintain a high level of response and continue Tx without experiencing late-emerging AEs. Results in the switch population support the use of ASC early in the Tx paradigm. ASCEMBL EOS Tx results continue to strongly support ASC as the therapy of choice for pts with suboptimal responses and/or intolerance to ≥2 prior TKIs, allowing more pts to remain on Tx and achieve their Tx goals without needing to switch.

Deucravacitinib in Plaque Psoriasis: 3-Year Safety and Efficacy Results From the Phase 3 POETYK PSO-1 and PSO-2 Trials

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in the US, EU, and other countries for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy. Deucravacitinib was superior to placebo and apremilast in the POETYK PSO-1 (NCT03624127) and PSO-2 (NCT03611751) parent trials in moderate to severe plaque psoriasis. The POETYK long-term extension (LTE; NCT04036435) trial enrolled patients who completed PSO-1/PSO-2. We report safety and efficacy of deucravacitinib for up to 3 years (Week 148; through cutoff 6/15/2022).&#x0D; Methods: PSO-1/PSO-2 randomized patients 1:2:1 to oral placebo, deucravacitinib 6 mg once daily (QD), or apremilast twice daily. At Week 52, patients enrolled in the LTE received open-label deucravacitinib 6 mg QD. Safety was evaluated in patients who received ≥1 dose of deucravacitinib using exposure-adjusted incidence rate per 100 person-years (EAIR/PY). Efficacy outcomes (≥75%/≥90% reduction from baseline in Psoriasis Area and Severity Index [PASI 75/90]; static Physician Global Assessment score of 0 [clear] or 1 [almost clear] with a ≥2-point improvement from baseline [sPGA 0/1]) were analyzed using modified nonresponder imputation (mNRI) in patients who received continuous deucravacitinib treatment from Day 1 of the parent trial and were treated in the LTE.&#x0D; Results: Of 1519 patients who received ≥1 dose of deucravacitinib (3294.3 PY cumulative exposure), 513 patients received continuous deucravacitinib treatment from Day 1 in PSO-1/PSO-2 and were treated in the LTE. EAIRs/100 PY were comparable, or decreased, between the 2-year and 3-year cumulative periods, respectively, for AEs (154.4, 144.8), serious AEs (6.1, 5.5), discontinuations due to AEs (2.8, 2.4), herpes zoster (0.7, 0.6), malignancies (0.9, 0.9), major adverse cardiovascular events (0.4, 0.3), venous thromboembolism (0.1, 0.1), and deaths (0.4, 0.3). Response rates were maintained at Week 148 by mNRI (PASI 75, 73.2%; PASI 90, 48.1%; sPGA 0/1, 54.1%).&#x0D; Conclusion: Deucravacitinib maintained a consistent safety profile and durable efficacy for up to 3 years.

Deucravacitinib, an Oral, Selective, Allosteric Tyrosine Kinase 2 Inhibitor, in Moderate to Severe Plaque Psoriasis: Evaluation of Creatine Phosphokinase Elevations in the Phase 3 POETYK PSO-1 and PSO-2 Trials

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in the US, EU, and other countries for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy. In the phase 3 POETYK PSO-1 (NCT03624127) and POETYK PSO-2 (NCT03611751) trials, deucravacitinib was significantly more efficacious than placebo or apremilast and was well tolerated. This pooled safety analysis of POETYK PSO-1 and PSO-2 assessed changes from baseline in creatine phosphokinase (CPK) levels and CPK elevations and rhabdomyolysis adverse events (AEs) in patients receiving placebo, deucravacitinib, or apremilast.&#x0D; Methods: Patients with moderate to severe plaque psoriasis were randomized 1:2:1 to oral placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily. Shifts from baseline in severity grade (Common Terminology Criteria for Adverse Events [CTCAE] version 5) of CPK levels were analyzed. Elevated CPK and rhabdomyolysis adverse events (AEs) were reported.&#x0D; Results: The pooled population included 1683 patients (placebo, n=419; deucravacitinib, n=842; apremilast, n=422). At baseline, the proportions of patients with grade ≥1 CPK levels were comparable (placebo, 6.3%; deucravacitinib, 5.9%; apremilast, 7.4%). During Weeks 0-16, worsening of CPK levels by &gt;1 CTCAE grade from baseline occurred at similar rates in patients receiving placebo (2.2%), deucravacitinib (2.5%), and apremilast (1.4%). Most deucravacitinib-treated patients maintained their baseline CPK CTCAE grade or shifted to a lower grade through Week 52. Elevated CPK AEs were reported in 1.2% (placebo), 2.7% (deucravacitinib), and 0.7% (apremilast) of patients through Week 16. Exposure-adjusted incidence rates (EAIRs) of elevated CPK AEs through Week 52 were comparable across treatments (placebo, 4.5/100 person-years [PY]; deucravacitinib, 4.7/100 PY; apremilast, 3.6/100 PY). Two deucravacitinib-treated patients (0.2/100 PY) and 1 apremilast-treated patient (0.4/100 PY) discontinued due to AEs of asymptomatic elevated CPK. Two deucravacitinib-treated patients had rhabdomyolysis with potential inciting events, one of which was associated with CPK elevation.&#x0D; Conclusion: Most deucravacitinib-treated patients maintained their baseline CPK grade or shifted to a lower grade through Weeks 16 and 52. The EAIR of CPK elevation AEs were comparable across treatment groups over 52 weeks.