Heidi S. Camp

Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate.

To evaluate the efficacy and safety of ABT‐494, a selective JAK‐1 inhibitor, in patients with moderate‐to‐severe rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX).

A Phase IIb Study of ABT‐494, a Selective JAK‐1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti–Tumor Necrosis Factor Therapy

To compare the efficacy and safety of ABT‐494, a novel selective JAK‐1 inhibitor, with placebo in patients with moderate‐to‐severe rheumatoid arthritis (RA) and an inadequate response or intolerance to at least 1 anti–tumor necrosis factor (anti‐TNF) agent.

A Randomized Phase 2b Study of ABT-494, a Selective JAK1 Inhibitor in Patients with Rheumatoid Arthritis and an Inadequate Response to Methotrexate.

To evaluate the efficacy and safety of ABT‐494, a selective JAK‐1 inhibitor, in patients with moderate‐to‐severe rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX).

A Phase 2b Study of ABT-494, a Selective JAK1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-TNF Therapy.

To compare the efficacy and safety of ABT‐494, a novel selective JAK‐1 inhibitor, with placebo in patients with moderate‐to‐severe rheumatoid arthritis (RA) and an inadequate response or intolerance to at least 1 anti–tumor necrosis factor (anti‐TNF) agent.

Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial

BACKGROUND Upadacitinib is a selective inhibitor of Janus kinase 1 and was efficacious in phase 2 studies in patients with moderate-to-severe rheumatoid arthritis. We aimed to assess the efficacy of upadacitinib in patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). METHODS This study is a double-blind, placebo-controlled trial at 150 sites in 35 countries. We enrolled patients aged 18 years or older with active rheumatoid arthritis for 3 months or longer, who had received csDMARDs for at least 3 months with a stable dose for at least 4 weeks before study entry, and had an inadequate response to at least one of the following csDMARDs: methotrexate, sulfasalazine, or leflunomide. Using interactive response technology, we randomly assigned patients receiving stable background csDMARDs (2:2:1:1) to receive a once-daily extended-release formulation of upadacitinib 15 mg or 30 mg, or placebo, for 12 weeks. Patients, investigators, and the funder were masked to allocation. After 12 weeks, patients taking placebo received 15 mg or 30 mg of upadacitinib once daily, according to the prespecified randomisation assignment. The primary endpoints were the proportion of patients at week 12 who achieved 20% improvement in American College of Rheumatology criteria (ACR20), and a 28-joint disease activity score using C-reactive protein (DAS28[CRP]) of 3·2 or less. We did efficacy analyses in the full analysis set of all randomly assigned patients who received at least one dose of study drug, and used non-responder imputation for assessment of the primary outcomes. This study is registered with ClinicalTrials.gov, number NCT02675426. FINDINGS Between Dec 17, 2015, and Dec 22, 2016, 1083 patients were assessed for eligibility, of whom 661 were recruited and randomly assigned to receive upadacitinib 15 mg (n=221), upadacitinib 30 mg (n=219), or placebo (n=221). All patients received at least one dose of study drug, and 618 (93%) completed 12 weeks of treatment. At week 12, ACR20 was achieved by 141 (64%; 95% CI 58-70) of 221 patients receiving upadacitinib 15 mg and 145 (66%; 60-73) of 219 patients receiving upadacitinib 30 mg, compared with 79 (36%; 29-42) of 221 patients receiving placebo (p<0·0001 for each dose vs placebo). DAS28(CRP) of 3·2 or less was met by 107 (48%; 95% CI 42-55) patients receiving upadacitinib 15 mg and 105 (48%; 41-55) patients receiving upadacitinib 30 mg, compared with 38 (17%; 12-22) patients receiving placebo (p<0·0001 for each dose vs placebo). Adverse events were reported in 125 (57%) of 221 patients receiving upadacitinib 15 mg, 118 (54%) of 219 patients receiving upadacitinib 30 mg, and 108 (49%) of 221 patients receiving placebo. The most frequently reported adverse events (≥5% of patients in any group) were nausea (16 [7%] of 221 in the upadacitinib 15 mg group; three [1%] of 219 in the upadacitinib 30 mg group; and seven [3%] of 221 in the placebo group), nasopharyngitis (12 [5%]; 13 [6%]; and nine [4%]), upper respiratory tract infection (12 [5%]; 12 [5%]; and nine [4%]), and headache (nine [4%]; seven [3%]; and 12 [5%]). More infections were reported for upadacitinib (64 [29%] of 221 patients receiving 15 mg and 69 [32%] of 219 patients receiving 30 mg) versus placebo (47 [21%] of 221 patients). There were three herpes zoster infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, and one [<1%] in the upadacitinib 30 mg group) and one primary varicella zoster virus infection (one [<1%] in the upadacitinib 30 mg group), two malignancies (both in the upadacitinib 30 mg group), one adjudicated major adverse cardiovascular event (in the upadacitinib 30 mg group), and five serious infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, three [1%] in the upadacitinib 30 mg group). No deaths were reported during the trial. INTERPRETATION Patients with moderately to severely active rheumatoid arthritis who received upadacitinib (15 mg or 30 mg) in combination with csDMARDs showed significant improvements in clinical signs and symptoms. FUNDING AbbVie Inc.

In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494)

BackgroundAnti-cytokine therapies such as adalimumab, tocilizumab, and the small molecule JAK inhibitor tofacitinib have proven that cytokines and their subsequent downstream signaling processes are important in the pathogenesis of rheumatoid arthritis. Tofacitinib, a pan-JAK inhibitor, is the first approved JAK inhibitor for the treatment of RA and has been shown to be effective in managing disease. However, in phase 2 dose-ranging studies tofacitinib was associated with dose-limiting tolerability and safety issues such as anemia. Upadacitinib (ABT-494) is a selective JAK1 inhibitor that was engineered to address the hypothesis that greater JAK1 selectivity over other JAK family members will translate into a more favorable benefit:risk profile. Upadacitinib selectively targets JAK1 dependent disease drivers such as IL-6 and IFNγ, while reducing effects on reticulocytes and natural killer (NK) cells, which potentially contributed to the tolerability issues of tofacitinib.MethodsStructure-based hypotheses were used to design the JAK1 selective inhibitor upadacitinib. JAK family selectivity was defined with in vitro assays including biochemical assessments, engineered cell lines, and cytokine stimulation. In vivo selectivity was defined by the efficacy of upadacitinib and tofacitinib in a rat adjuvant induced arthritis model, activity on reticulocyte deployment, and effect on circulating NK cells. The translation of the preclinical JAK1 selectivity was assessed in healthy volunteers using ex vivo stimulation with JAK-dependent cytokines.ResultsHere, we show the structural basis for the JAK1 selectivity of upadacitinib, along with the in vitro JAK family selectivity profile and subsequent in vivo physiological consequences. Upadacitinib is ~ 60 fold selective for JAK1 over JAK2, and > 100 fold selective over JAK3 in cellular assays. While both upadacitinib and tofacitinib demonstrated efficacy in a rat model of arthritis, the increased selectivity of upadacitinib for JAK1 resulted in a reduced effect on reticulocyte deployment and NK cell depletion relative to efficacy. Ex vivo pharmacodynamic data obtained from Phase I healthy volunteers confirmed the JAK1 selectivity of upadactinib in a clinical setting.ConclusionsThe data presented here highlight the JAK1 selectivity of upadacinitinib and supports its use as an effective therapy for the treatment of RA with the potential for an improved benefit:risk profile.

OP0035 Upadacitinib as monotherapy: a phase 3 randomised controlled double-blind study in patients with active rheumatoid arthritis and inadequate response to methotrexate

Background Upadacitinib (UPA), an oral JAK inhibitor, showed efficacy in rheumatoid arthritis (RA) patients (pts) with an inadequate response to csDMARDs or bDMARDs on continuing stable csDMARD(s).1 2 Objectives Safety and efficacy of switching to UPA 15 mg or 30 mg monotherapy vs continuing methotrexate (MTX) as a blinded study drug was evaluated in pts with inadequate response to MTX (MTX-IR). Methods Pts with active RA (TJC ≥6, SJC≥6, hsCRP ≥3 mg/L) on stable MTX were enrolled and randomised 1:1:1 in a double-blind manner to once-daily (QD) UPA 15 mg or 30 mg monotherapy or to continue MTX (cMTX) at their prior stable dose. At BL, all pts discontinued prior MTX without washout and received PBO (for pts on UPA) or MTX at prior dose (cMTX) as blinded study drug. The primary endpoints at Week (Wk) 14 were the proportion of pts achieving ACR20, and the proportion achieving DAS28-CRP≤3.2 (NRI). Results 648 pts were randomised, all received study drug; 598 (92.3%) completed 14 wks. BL demographics and disease characteristics were generally similar across arms. Both primary endpoints were met (p<0.001); at Wk 14, a significantly greater proportion of pts receiving UPA monotherapy (15 mg and 30 mg) vs cMTX achieved ACR20 (67.7% and 71.2% vs 41.2%), and DAS28-CRP≤3.2 (44.7% and 53.0% vs 19.4%) (table 1). All key secondary endpoints also showed UPA 15 and UPA 30 monotherapy to be superior to cMTX, including ACR50 (41.9% and 52.1% vs 15.3%), ACR70 (22.6% and 33.0% vs 2.8%), DAS28-CRP<2.6 (28.1% and 40.5% vs 8.3%), ΔHAQ-DI (−0.65 and −0.73 vs −0.32). ΔSF-36 PCS and ΔMorning Stiffness data are also shown (table 1). The proportion of pts achieving CDAI≤10 was significantly greater with UPA 15 and 30 vs cMTX (34.6% and 46.5% vs 24.5%). Adverse events (AEs) were reported at similar frequencies across arms; serious AEs were numerically higher in UPA 15 but similar between cMTX and UPA 30 (table 1). Numerically more infections were reported in cMTX and UPA 30 vs UPA 15. One serious infection each was reported in UPA 15 and cMTX, and none in UPA 30. Herpes zoster was more frequent in UPA 30 vs UPA 15 or cMTX. 3 malignancies (1 in cMTX and 2 in UPA 15) and 3 adjudicated MACE (1 in UPA 15 and 2 in UPA 30) were reported. One adjudicated pulmonary embolism was reported (UPA 15) in a pt with known risk factors (BMI 36; on oestrogen therapy). One death (haemorrhagic stroke due to ruptured aneurysm) was reported in UPA 15. No TB, renal dysfunction or GI perforation was reported. Rates and types of laboratory abnormalities were consistent with prior UPA RA studies to date.Abstract OP0035 – Table 1 Conclusions In this MTX-IR study population, switching to UPA as monotherapy at 15 mg and 30 mg QD showed significant improvements in RA signs and symptoms vs continuing MTX. Numerically higher responses were observed for UPA 30 mg vs 15 mg, particularly for more stringent efficacy criteria. Safety observations were similar to those in prior UPA studies. References [1] Burmester, et al. Arth Rheum2017;69:S10. [2] Genovese, et al. Arth Rheum2017;69:S10. Acknowledgements AbbVie: Study sponsor, study design, data collection, analysis and interpretation, writing, review, approval of final. Medical writing:Naina Barretto of AbbVie Disclosure of Interest J. Smolen Grant/research support from: AbbVie, Consultant for: AbbVie, S. Cohen Grant/research support from: Abbvie, Gilead, Eli Lilly,Pfizer, Consultant for: Abbvie, Gilead, Eli Lilly,Pfizer, P. Emery Grant/research support from: Pfizer, MSD, AbbVie, Bristol-Myers Squibb, UCB, Roche, Novartis, Samsung, Sandoz and Lilly., Consultant for: Pfizer, MSD, AbbVie, Bristol-Myers Squibb, UCB, Roche, Novartis, Samsung, Sandoz and Lilly., W. Rigby: None declared, Y. Tanaka Grant/research support from: Mitsubishi-Tanabe, Takeda Ltd, BMS, Chugai Ltd, Astellas Inc, AbbVie GK, MSD K.K., Daiichi Sankyo Ltd, Pfizer Japan Inc., Kyowa Hakko Kirin, Ltd, Eisai., Ltd, Ono, Ltd, Speakers bureau: Daiichi Sankyo Ltd, Astellas Pharma Inc, Pfizer Japan Inc., Mitsubishi-Tanabe, BMS, Chugai Ltd, YL Biologics, Eli Lilly Japan KK, Sanofi KK, Janssen KK, UCB Japan, Ltd, Y. Zhang Shareholder of: AbbVie, Employee of: AbbVie, A. Friedman Shareholder of: AbbVie, Employee of: AbbVie, A. Othman Shareholder of: AbbVie, Employee of: AbbVie, H. Camp Shareholder of: AbbVie, Employee of: AbbVie, A. Pangan Shareholder of: AbbVie, Employee of: AbbVie

OP0036 A phase 3 randomised, placebo-controlled, double-blind study of upadacitinib (ABT-494), a selective jak-1 inhibitor, in patients with active rheumatoid arthritis with inadequate response to conventional synthetic dmards

Background Upadacitinib (UPA) is an oral, selective JAK-1 inhibitor in development for the treatment of patients (pts) with moderate to severe rheumatoid arthritis (RA) and other immune-mediated diseases. Methods This Phase 3 study in pts with inadequate response (IR) to csDMARDs included a double-blind placebo (PBO)-controlled period (Period 1, reported here), during which pts were randomised 1:1:1 to receive once-daily (QD) extended-release formulation of UPA at 15 mg or 30 mg, or PBO for 12 weeks (wks). The primary efficacy endpoints were the proportion of pts who achieved an ACR20 response and the proportion who achieved DAS28-CRP low disease activity (LDA,≤3.2) at Wk 12, using non-responder imputation (NRI). Results Of 661 pts who were randomised, all received study drug, and 618 (93.5%) completed Period 1. At baseline, demographics and disease characteristics were similar across arms. The study met all primary and key secondary endpoints with p values<0.001 for both doses. At Wk 12, significantly more pts receiving UPA 15 mg and 30 mg QD vs PBO achieved an ACR20 response (63.8% and 66.2% vs 35.7%, p<0.001), and DAS28-CRP LDA (48.4% and 47.9% vs 17.2%, p<0.001) (table 1). Onset of action was rapid with significantly more pts in both UPA arms achieving ACR20 at Wk 1 vs PBO. At Wk 12, significantly more pts met ACR50 and ACR70 in the UPA 15 mg (38% and 20.8%) and 30 mg QD arms (43.4% and 26.5%) vs PBO (14.9% and 5.9%). Significantly more patients receiving UPA 15 mg and 30 mg QD vs PBO achieved DAS28-CRP<2.6 (30.8% and 28.3% vs 10%, p<0.001)] and CDAI-LDA (40.3% and 42% vs 19%, p<0.001), and pts receiving UPA at both doses experienced significantly greater improvements in DAS28-CRP, HAQ-DI, morning stiffness and FACIT-F vs PBO (p<0.001). Adverse events (AEs) and serious AEs were numerically higher with UPA than PBO (table 1). The overall incidence of infection was higher for UPA 15 mg and 30 mg QD vs PBO, but few were serious infections. There were 4 cases of herpes zoster/Varicella Zoster Virus infection (1 on PBO). Asymptomatic CPK elevations were only reported for patients on UPA. Two malignancies and 3 adjudicated cardiovascular events were reported. No PE/DVT were reported. There were no deaths, cases of TB or GI perforations. Types and frequency of laboratory abnormalities were similar to findings in Phase 2 studies with UPA.Abstract OP0036 – Table 1 Conclusions The efficacy of UPA at 15 mg and 30 mg QD vs PBO was demonstrated in this csDMARD-IR study population. The most notable responses were observed in the more stringent endpoints of LDA (by either DAS28-CRP or CDAI) and ACR70. The safety and tolerability profile was consistent with observations in the Phase 2 studies with UPA. Acknowledgements AbbVie and the authors thank the patients, study sites and investigators who participated in this clinical trial. AbbVie, Inc was the study sponsor, contributed to study design, data collection, analysis and interpretation, and to writing, reviewing, and approval of final version. Medical writing support was provided by Naina Barretto, PhD, of AbbVie, Inc. Disclosure of Interest G. Burmester Consultant for: AbbVie Inc., Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB., Speakers bureau: AbbVie Inc., Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB., J. Kremer Shareholder of: Corona, Grant/research support from: AbbVie Inc, Consultant for: AbbVie Inc., BMS, Genentech, Gilead, GSK, Eli Lilly and Pfizer, Employee of: Corona, F. van den Bosch Consultant for: AbbVie Inc., Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer and UCB, Speakers bureau: AbbVie Inc., Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer and UCB, Y. Li Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, Y. Zhou Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, A. Othman Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, A. Pangan Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, H. Camp Shareholder of: AbbVie Inc, Employee of: AbbVie Inc,