OP0115\u2005EFFICACY AND SAFETY OF ABBV-3373, A NOVEL ANTI-TNF GLUCOCORTICOID RECEPTOR MODULATOR ANTIBODY DRUG CONJUGATE, IN PATIENTS WITH MODERATE TO SEVERE RHEUMATOID ARTHRITIS DESPITE METHOTREXATE THERAPY: A PHASE 2A PROOF OF CONCEPT STUDY

Abstract

ABBV-3373 is a novel antibody drug conjugate composed of adalimumab (ADA) linked to a proprietary and highly potent glucocorticoid receptor modulator (the anti-inflammatory payload) currently evaluated for the treatment of rheumatoid arthritis (RA).To assess the efficacy and safety of ABBV-3373 vs ADA in RA patients (pts).This was a 24-week (wk) randomized, double-blind, double-dummy, active-controlled Phase 2a study of intravenously (IV)-administered ABBV-3373 100 mg (for 12 wks followed by placebo [PBO] for 12 wks) vs subcutaneous injections of ADA 80 mg every other wk (for 24 wks) in pts on background methotrexate. The primary endpoint was the change from baseline (BL) in DAS28(CRP) at Wk 12. Pre-planned statistical methods incorporating pre-specified historical ADA data both alone (pre-specified success criterion, 2-sided P ≤0.1) and supplemented with in-trial ADA data (pre-specified success criterion, probability >95%) were used to achieve adequate statistical power with a reduced trial size. Assay sensitivity was evaluated through construction of a synthetic PBO arm by propensity score matching, using individual pt-level PBO data from 3 recent sponsor-run trials of similar populations and trial settings. Secondary endpoints at Wk 12 included 1) mean change from BL in CDAI, SDAI, DAS28(ESR), HAQ-DI; 2) proportion of pts achieving DAS28(CRP)≤3.2, ACR20/50/70 responses, HAQ-DI≤-0.22. Continuous and categorical efficacy variables were analyzed using mixed effect model repeated measurements and Cochran-Mantel-Haenszel test, respectively; non-responder imputation was applied to missing categorical data. Treatment-emergent adverse events were summarized through Wk 12.A total of 48 pts were randomized and treated (ABBV-3373: 31; ADA: 17); 46 pts (96%) completed 12 wks of study treatment. BL demographics and disease characteristics were indicative of established RA and similar among the 2 treatment arms and the synthetic PBO arm. ABBV-3373 demonstrated significant improvement in mean DAS28(CRP) at Wk 12 vs the pre-specified historical ADA (-2.65 vs -2.13; P=0.022) and numerically greater improvement vs the combined in-trial and historical ADA arm (-2.65 vs -2.29; probability 90%; Figure). Comparable improvements in disease activity and targets were observed for ABBV-3373 and in-trial ADA. Assay sensitivity was supported by the fact that both ABBV-3373 and ADA arms were superior to synthetic PBO (P<0.001). For secondary endpoints, greater efficacy was observed with ABBV-3373 vs historical ADA; ABBV-3373 was predicted with 79-99% probability to be better than ADA based on the combined in-trial and historical ADA data. 2 serious infections were reported with ABBV-3373 (pneumonia, upper respiratory tract infection) and none with ADA through Wk 12 (Table). 1 event of anaphylactic shock reaction was reported with ABBV-3373. After increasing the duration of IV administration from 3 min to 15-30 min, no similar events were observed.Table 1.Treatment Emergent Adverse Events up to Week 12Event, n (%)ADA(N = 17)ABBV-3373(N = 31)Adverse event (AE)12 (70.6)11 (35.5)AE with reasonable possibility of being drug related$3 (17.6)2 (6.5)Severe AE01 (3.2)Serious AE04 (12.9) #AE leading to Discontinuation of Study Drug1 (5.9)1 (3.2)Serious infections02 (6.5)Opportunistic infection excluding Tuberculosis00Allergic Reactions Including Hypersensitivity, Angioedema, and Anaphylaxis2 (11.8) &1 (3.2) ^Systemic glucocorticoid events00All deaths00$As assessed by investigator. #Serious AEs: 1 non-cardiac chest pain, 1 pneumonia, 1 upper respiratory tract disease and 1 anaphylactic shock. &1 Type I hypersensitivity, 1 Pruritus ^1 Anaphylactic shockThese data demonstrate the clinical efficacy of ABBV-3373 and its potential to provide improved outcomes for RA pts compared to ADA. The safety profile of ABBV-3373 was generally similar to ADA.AbbVie and the authors we thank the patients, trial sites, and investigators who participated in this clinical trial. AbbVie, Inc was the trial sponsor, contributed to trial design, data collection, analysis & interpretation, and to writing, reviewing, and approval of final version. No honoraria or payments were made for authorship. The authors thank Yang Yang of AbbVie Inc for supporting the statistical analysis and data reporting. Medical writing support was provided by Ramona Vladea, PhD of AbbVie, Inc.Frank Buttgereit Consultant of: AstraZeneca, AbbVie, Grünenthal, Horizon Pharma, Pfizer, and Roche, Grant/research support from: AbbVie, Horizon Pharma, Pfizer, and Roche, Jacob Aelion Grant/research support from: AbbVie, Amgen, AstraZeneca, BMS, Celgene, Eli Lilly, Galapagos/Gilead, Genentech, GlaxoSmithKline, Horizon, Janssen, Mallinckrodt, Nektar, Nichi-Iko, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis, Selecta, UCB, Bernadette Rojkovich: None declared, Anna Zubrzycka-Sienkiewicz Consultant of: Astellas and Roche, Grant/research support from: AbbVie, Astellas, Galapagos NV, Gilead Sciences, Janssen, Lilly, Mabion, Pfizer, Roche, and UCB SA, Timothy Radstake Shareholder of: AbbVie, Employee of: AbbVie, Su Chen Shareholder of: AbbVie, Employee of: AbbVie, Dilek Arikan Shareholder of: AbbVie, Employee of: AbbVie, Hartmut Kupper Shareholder of: AbbVie, Employee of: AbbVie, Howard Amital Consultant of: Abbvie, Janssen, Novartis, Roche, Perrigo, Pfizer, Neopharm, Elly Lilly, Gilead, Sanofi, Teva and Rafa, Grant/research support from: Yansen, Pfizer