PLACEBO-CONTROLLED EFFICACY AND SAFETY OF UPADACITINIB THROUGH ONE YEAR IN PATIENTS WITH NON-RADIOGRAPHIC AXIAL SPONDYLOARTHRITIS

BackgroundUpadacitinib (UPA), a Janus kinase inhibitor, was effective and well tolerated in patients (pts) with non-radiographic axial spondyloarthritis (nr-axSpA) through 14 weeks (wks) of treatment.[1]ObjectivesThis analysis assessed the efficacy and safety of UPA vs placebo (PBO) through 1 year.MethodsThe SELECT-AXIS 2 nr-axSpA study included a 52-wk randomized, double-blind, PBO-controlled period. Enrolled adults had a clinical diagnosis of active nr-axSpA fulfilling the 2009 ASAS classification criteria, objective signs of inflammation based on MRI sacroiliitis and/or elevated C-reactive protein, and an inadequate response to NSAIDs. One-third of pts had an inadequate response to biologic DMARDs. Pts were randomized 1:1 to UPA 15 mg once daily or PBO. Concomitant medications, including NSAIDs, had to be kept stable through wk 52. The study protocol outlined that pts who did not achieve ASAS20 at any two consecutive study visits between wks 24 to 52 should receive rescue therapy with NSAIDs, corticosteroids, conventional synthetic/biologic DMARDs, or analgesics. Cochran-Mantel-Haenszel (CMH) test with non-responder imputation incorporating multiple imputation (NRI-MI) was used to handle missing data and intercurrent events for binary efficacy endpoints. Mixed-effect model repeated measures (MMRM) was used to assess continuous efficacy endpoints. NRI was used for binary endpoints after rescue and as observed analysis excluding data after rescue for continuous endpoints. Treatment-emergent adverse events (TEAEs) are reported through wk 52.ResultsOf the 314 pts randomized, 259 (82%;UPA, n=130;PBO, n=129) completed wk 52 on study drug. More pts achieved an ASAS40 response with UPA vs PBO from wks 14 to 52 with a 20% treatment difference at wk 52 (63% vs 43%;nominal P <.001;Figure 1). The proportion of pts achieving ASDAS inactive disease with UPA remained higher than PBO at wk 52 (33% vs 11%;nominal P <.0001;Figure 1). Consistent improvements and maintenance of efficacy were also seen across other disease activity measures. Between wks 24 and 52, fewer pts on UPA (9%) than PBO (17%) received rescue therapy. A similar proportion of pts in each treatment group had a TEAE (Table 1). Infections were the most common TEAE;the rates of serious infections and herpes zoster were higher with UPA vs PBO, although no new serious infections were reported from wks 14 to 52. COVID-19 events were balanced between treatment groups. No opportunistic infections, malignancy excluding non-melanoma skin cancer, adjudicated major adverse cardiovascular events, inflammatory bowel disease, or deaths were reported. Two pts (1.3%) on PBO had adjudicated venous thromboembolic events.ConclusionUPA showed consistent improvement and maintenance of efficacy vs PBO through 1 year across multiple disease activity measures. No new safety risks were identified with longer-term UPA exposure. These results continue to support the benefit of UPA in pts with active nr-axSpA.Reference[1]Deodhar A, et al. Lancet. 2022;400(10349):369–379.Table 1.Safety through week 52Event, n (%)PBO (n = 157)UPA 15 mg QD (n = 156)Any AE103 (66%)107 (69%)Serious AE6 (3.8%)6 (3.8%)AE leading to D/C4 (2.5%)6 (3.8%)COVID-19-related AE22 (14%)24 (15%)Deaths00Infection60 (38%)68 (44%) Serious infection1 (0.6%)2 (1.3%) Herpes zoster1 (0.6%)5 (3.2%)Malignancy other than NMSC00NMSC1 (0.6%)0Hepatic disorder7 (4.5%)6 (3.8%)Neutropenia1 (0.6%)8 (5.1%)MACE (adjudicated)00VTE (adjudicated)2 (1.3%)a0Uveitisb3 (1.9%)2 (1.3%)Inflammatory bowel disease00aBoth patients had non-serious events of deep vein thrombosis in the lower limb with risk factors including obesity and prior deep vein thrombosis in one patient and concomitant COVID-19 infection in the other patient.bThree events of uveitis occurred in each treatment group (among n = 3 patients in the PBO group and n = 2 patients in the UPA group);two events in the PBO group and one in the UPA group occurred in patients with a history of uveitis.AcknowledgementsAbbVie funded this study and participated in the study design, res arch, analysis, data collection, interpretation of data, review, and approval of the . All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided by Julia Zolotarjova, MSc, MWC, of AbbVie.Disclosure of InterestsFilip van den Bosch Speakers bureau: AbbVie, Amgen, Galapagos, Janssen, Lilly, Merck, MoonLake, Novartis, Pfizer, and UCB., Consultant of: AbbVie, Amgen, Galapagos, Janssen, Lilly, Merck, MoonLake, Novartis, Pfizer, and UCB., Atul Deodhar Consultant of: AbbVie, Amgen, Aurinia, BMS, Celgene, GSK, Janssen, Lilly, MoonLake, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Bristol Myers Squibb, Celgene, GSK, Lilly, Novartis, Pfizer, and UCB, Denis Poddubnyy Speakers bureau: AbbVie, Biocad, BMS, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, MSD, Medscape, MoonLake, Novartis, Peervoice, Pfizer, Roche, Samsung Bioepis, and UCB, Consultant of: AbbVie, Biocad, BMS, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, MSD, Medscape, MoonLake, Novartis, Peervoice, Pfizer, Roche, Samsung Bioepis, and UCB, Grant/research support from: AbbVie, Lilly, MSD, Novartis, and Pfizer., Walter P Maksymowych Consultant of: AbbVie, BMS, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Novartis, Pfizer, and UCB, Employee of: Chief Medical Officer of CARE Arthritis Limited, Désirée van der Heijde Consultant of: AbbVie, Bayer, BMS, Cyxone, Eisai, Galapagos, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, and UCB, Employee of: Director of Imaging Rheumatology BV, Tae-Hwan Kim Speakers bureau: AbbVie, Celltrion, Kirin, Lilly, and Novartis., Mitsumasa Kishimoto Consultant of: AbbVie, Amgen, Asahi-Kasei Pharma, Astellas, Ayumi Pharma, BMS, Chugai, Daiichi Sankyo, Eisai, Gilead, Janssen, Lilly, Novartis, Ono Pharma, Pfizer, Tanabe-Mitsubishi, and UCB., Xenofon Baraliakos Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, and UCB, Consultant of: AbbVie, BMS, Chugai, MSD, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie and Novartis, Yuanyuan Duan Shareholder of: AbbVie, Employee of: AbbVie, Kristin D'Silva Shareholder of: AbbVie, Employee of: AbbVie, Peter Wung Shareholder of: AbbVie, Employee of: AbbVie, In-Ho Song Shareholder of: AbbVie, Employee of: AbbVie.

EFFICACY AND SAFETY OF ABBV-599 HIGH DOSE (ELSUBRUTINIB 60 MG AND UPADACITINIB 30 MG) AND UPADACITINIB MONOTHERAPY FOR THE TREATMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS: A PHASE 2, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL

BackgroundABBV-599 is a novel combination of elsubrutinib (ELS;a selective BTK inhibitor) and upadacitinib (UPA;a JAK inhibitor) that targets non-overlapping signaling pathways associated with systemic lupus erythematosus (SLE).ObjectivesTo report results from SLEek, a phase 2, randomized, placebo (PBO)-controlled, parallel-group, multicenter study evaluating efficacy and safety of ABBV-599 and UPA monotherapy in adults with moderately to severely active SLE (NCT03978520).MethodsPatients (pts) were randomized 1:1:1:1:1 to once daily (QD) ABBV-599 high dose (HD;ELS 60 mg + UPA 30 mg), ABBV-599 low dose (LD;ELS 60 mg + UPA 15 mg), ELS 60 mg, UPA 30 mg, or PBO. The primary endpoint was the proportion of patients at W24 achieving SLE Responder Index-4 (SRI-4) and steroid dose ≤ 10 mg QD;additional efficacy and safety endpoints through W48 are also reported. The pre-specified 2-sided alpha level was 0.1.Results341 patients were enrolled. After a planned interim analysis when 50% of pts reached W24, the ABBV-599LD and ELS 60 mg arms were discontinued for lack of efficacy (no safety concerns). Of 205 continuing pts (ABBV-599HD n = 68, UPA 30 mg n = 62, PBO n = 75), baseline characteristics were well balanced. The primary endpoint (proportion achieving SRI-4 and steroid dose ≤ 10 mg QD at W24 vs PBO) was met by ABBV-599HD and UPA 30 mg. Key secondary endpoints were also achieved at W48 in both groups (Table 1). Overall flares and time to first flare were substantially reduced in the ABBV-599HD and UPA 30 mg groups through W48 (Figure 1). Anti-double stranded DNA antibodies were significantly decreased with both treatments. TEAEs considered related to study drug were 42.6% ABBV-599HD, 32.3% UPA 30 mg, and 33.3% PBO. There were no malignancies or VTE. There were 3 non-fatal CV events (1 MI on PBO and 2 ruptured cerebral aneurysms [1 each on ABBV-599HD and UPA 30 mg]);all were assessed as unrelated to study drug by investigators. No new safety signals were observed beyond previously known data for UPA or ELS.ConclusionABBV-599HD (ELS 60 mg + UPA 30 mg) and UPA 30 mg demonstrated significant improvements in SLE disease activity and flares with acceptable safety through 48 weeks.Table 1.Key Endpoints at Week 48PBO (n = 75)ABBV-599HD (n = 68)UPA 30 mg (n = 62)SRI-4 and steroid dose ≤ 10 mg QD, n (%) [95% CI]a24 (32.0) [21.4, 42.6]33 (48.5) [36.7, 60.4]*27 (43.5) [31.2, 55.9]SRI-4, n (%) [95% CI]a24 (32.0) [21.4, 42.6]35 (51.5) [39.6, 63.3]*28 (45.2) [32.8, 57.5]+BICLA, n (%) [95% CI]a19 (25.3) [15.5, 35.2]33 (48.5) [36.7, 60.4]***33 (53.2) [40.8, 65.6]***LLDAS, n (%) [95% CI]a18 (24.0) [14.3, 33.7]27 (39.7) [28.1, 51.3]*31 (50.0) [37.6, 62.4]***Joint-Count 50 in patients with ≥ 6 affected joints at baseline, n/n (%) [95% CI]a26/59 (44.1) [31.4, 56.7]37/58 (63.8) [51.4, 76.2]*34/59 (57.6) [45.0, 70.2] +CLASI-50 in patients with baseline CLASI ≥ 10, n/n (%) [95% CI]a5/14 (35.7) [10.6, 60.8]6/12 (50.0) [21.7, 78.3]5/8 (62.5) [29.0, 96.0]*Change from baseline in steroid dose, mg, LS mean (SE)b−1.5 (0.5)−1.5 (0.5)−1.2 (0.5)SFI, events/patient-years (95% CI)c Overall flares2.8 (2.4, 3.3)1.5 (1.2, 1.9)***2.0 (1.6, 2.4)** Mild/moderate flares2.5 (2.1, 2.9)1.3 (1.0, 1.6)***1.9 (1.5, 2.3)* Severe flares0.3 (0.2, 0.5)0.2 (0.1, 0.3)0.2 (0.1, 0.3) +Time to first flare by SFI, days, median (Q1, Q3)c141 (57, NE)312 (114, NE)*311 (99, NE)**BILAG-based flare rate, estimated incidence ratec0.570.19*0.26Data are presented for the full analysis set.aMissing data imputed using NRI incorporating multiple imputation to handle missing data due to COVID 19.bMissing data imputed using MMRM.cObserved data w/o imputation.+P <.1;*P <.05;**P <.01, ***P <.001 vs PBO.ABBV-599HD, elsubrutinib 60 mg QD and UPA 30 mg QD;CLASI-50, ≥ 50% reduction in CLASI activity score;Joint-Count 50, ≥ 50% improvement in tender or swollen lupus joints;LLDAS, Lupus Low Disease Activity State;NE, not estimated;PBO, placebo;SFI, SELENA SLEDAI Flare Index;UPA, upadacitinib.AcknowledgementsAbbVie and the authors thank the patients who particip ted in the study and all study investigators for their contributions. Medical writing assistance, funded by AbbVie, was provided by Callie A S Corsa, PhD, of JB Ashtin.Disclosure of InterestsJoan T Merrill Consultant of: AbbVie, Alexion, Alumis, Amgen, Astra Zeneca, Aurinia, Bristol Myers Squibb, EMD Serono, Genentech, Gilead, GlaxoSmithKline, Lilly, Merck, Pfizer, Provention, Remegen, Sanofi, UCB, and Zenas, Grant/research support from: Astra Zeneca, Bristol Myers Squibb, and GlaxoSmithKline, Yoshiya Tanaka Speakers bureau: AbbVie, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Gilead, Lilly, Mitsubishi-Tanabe, and Pfizer, Grant/research support from: AbbVie, Asahi-Kasei, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, and Takeda., David d'cruz Consultant of: GlaxoSmithKline, Lilly, and UCB., Karina Vila Consultant of: AbbVie, Daniel Siri Grant/research support from: AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Gilead, Hoffman Laroche, Jansen, Lilly, and Sanofi, Xiaofeng Zeng: None declared, Kristin D'Silva Shareholder of: AbbVie, Employee of: AbbVie, Ling Cheng Shareholder of: AbbVie, Employee of: AbbVie, Thierry Sornasse Shareholder of: AbbVie, Employee of: AbbVie, Thao Doan Shareholder of: AbbVie, Employee of: AbbVie, Denise Kruzikas Shareholder of: AbbVie, Employee of: AbbVie, Alan Friedman Shareholder of: AbbVie, Employee of: AbbVie.