Phase I studies A phase I study revealed that<unk>  followed a bi-exponential disposition with a terminal half-life of 6–16 hours. There was no significant accumulation over the dose range of 3–36 mg per day. No interaction was found in rheumatoid arthritis patients taking methotrexate. The most common adverse event was headache but its incidence was similar to that when taking placebo (15.6% for<unk>  vs. 16.7% for placebo). An investigation into absorption and metabolism found that dosing after a high-fat meal had no effect on<unk>  total drug exposure over time (area under the curve or AUC). Inhibition of CYP3A by ketoconazole increased total AUC, indicating the importance of this metabolic route. Phase II studies Two phase IIb studies were initiated to study the efficacy and safety of<unk>  in patients with rheumatoid arthritis and one phase II study was initiated in patients with Crohn's disease. BALANCE I In the first study, 276 rheumatoid arthritis patients were recruited who had previously experienced inadequate response to anti–tumor necrosis factor (TNF) therapy and were currently on a stable dose of methotrexate. Patients were randomized to receive 3, 6, 12, or 18 mg twice daily or placebo. The primary endpoint was a 20% improvement in symptoms according to the American College of Rheumatology improvement criteria (ACR20). At the completion of the study it was found that response rates were significantly higher in those receiving<unk>  versus in those receiving placebo alone (36–42% and 22– 26%, respectively). Adverse events included headache, nausea, and infection but no infections were serious. BALANCE II In the second phase IIb study, 300 rheumatoid arthritis patients were recruited who have had an inadequate response to methotrexate. Patients were randomized to receive 3, 6, 12, or 18 mg twice daily or placebo. The primary endpoint was a 20% improvement in symptoms according to the American College of Rheumatology improvement criteria (ACR20). At the completion of the study it was found that response rates were significantly higher in those receiving<unk>  versus in those receiving placebo alone. (62%, 68%, 80%, 64%, and 76% for the 3, 6, 12, 18, and 24 mg doses, respectively) than with placebo (46%). Improvement in symptoms was rapid, with significant changes in disease scores by week 2. Adverse events were mild with infection being the most serious. One case of community-acquired pneumonia occurred at 12 mg. CELEST In this 16-week study, 220 patients were recruited with moderately to severely active Crohn's disease. Participants must have also experienced an inadequate response to or intolerance to Immunotherapy or TNF inhibitors. Patients were randomized to therapy with<unk>  at 3, 6, 12, 24 mg twice daily or 24 mg once daily for 16 weeks or placebo, followed by blinded extension therapy for 36 weeks. The co-primary endpoints were the proportion of patients who achieved clinical remission (soft stool frequency or daily abdominal pain score) at week 16 and endoscopic remission at week 12 or 16. Secondary endpoints included significant clinical response (≥30% reduction in symptoms) at week 16 and endoscopic response (≥25% decrease in symptoms) at week 12 or 16. At 16 weeks 22% of patients taking the 24 mg twice daily dose achieved endoscopic remission with<unk>  compared to 0% of patients taking placebo. 27% of patients taking the 6 mg twice daily dose achieved clinical remission compared to 11% of patients taking placebo. Adverse events did not appear to be dose-related. A single case of non-melanoma skin cancer was reported in the 24 mg twice daily group. Phase III studies Abbvie has planned a total of six phase III trials that will evaluate over 4,000 patients with moderate to severe rheumatoid arthritis. Two Phase III trials are planned studying participants with psoriatic arthritis and one in participants with ulcerative colitis. SELECT-COMPARE In SELECT-COMPARE 1629 patients with moderate to severe rheumatoid arthritis and inadequate response to methotrexate were randomized (2:2:1) to once-daily<unk>  15mg, placebo, or adalimumab 40mg, on stable background methotrexate. Primary endpoints were ACR20 and DAS28CRP<2.6 versus placebo at week 12; inhibition of radiographic progression was evaluated at week 26. The study was designed and powered to test for non-inferiority and superiority of<unk>  versus adalimumab clinically and functionally. At week 12, both primary endpoints were met for<unk>  versus placebo (p≤0.001). ACR20 was achieved by 71% versus 36%, and DAS28CRP<2.6 by 29% versus 6%.<unk>  was superior to adalimumab for ACR50, DAS28CRP≤3.2, ΔPain and ΔHAQDI. At week 26, more patients on<unk>  vs placebo or adalimumab achieved low disease activity or remission (p≤0.001). Radiographic progression was less and observed in fewer patients receiving<unk>  versus placebo (p≤0.001). Up to week 26, adverse events (AEs) including serious infections were comparable for<unk>  and adalimumab. The proportions of patients with serious AEs and AEs leading to discontinuation were highest for adalimumab; the proportion with herpes zoster and CPK elevations was highest for<unk> . Three malignancies, five MACE, and four deaths were reported, none on<unk> . Six venous thromboembolic events were reported placebo, one;<unk> , two; adalimumab, three.<unk>  was superior to placebo and adalimumab for improving signs, symptoms and physical function in RA patients on background methotrexate, and significantly inhibited radiographic progression versus placebo, while the overall safety profile was generally similar to adalimumab, except for higher rates of herpes zoster and CPK elevations on<unk> . SELECT-CHOICE SELECT-CHOICE was a phase III trial comparing<unk>  and abatacept in 612 people whose rheumatoid arthritis did not respond to biologic DMARDs. It compared their ability to reduce Disease Activity Score-28 with CRP (DAS-28 CRP), a measure of rheumatoid arthritis disease severity that includes number of tender and swollen joints, C-reactive protein level (a marker of inflammation), and overall health reported on a standardized scale. The trial found that after 12 weeks of treatment, people treated with<unk>  had lower DAS-28 CRP scores and a higher rate of remission. There was also a higher rate of serious and opportunistic infections, elevated liver enzymes, and thromboembolism in the<unk>  group.
Upadacitinib
Abrocitinib
Selpercatinib
Baricitinib
Erdafitinib
Oclacitinib
Dacomitinib
Axitinib