title: 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.
abstract: 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).
  
  
  
  Three hundred RA patients receiving stable doses of MTX were randomly assigned equally to receive immediate-release ABT-494 at 3, 6, 12, or 18 mg twice daily, 24 mg once daily, or placebo for 12 weeks. The primary efficacy end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12, as determined using the last observation carried forward method.
  
  
  
  At week 12, the proportion of ACR20 responses was higher with ABT-494 (62%, 68%, 80%, 64%, and 76% for the 3, 6, 12, 18, and 24 mg doses, respectively) than with placebo (46%) (using nonresponder imputation) (P < 0.05 for the 6, 12, and 24 mg doses). There was a significant dose-response relationship among all ABT-494 doses (P < 0.001). The proportions of patients achieving ACR50 and ACR70 responses were significantly higher for all ABT-494 doses (except the 12 mg dose for the ACR70 response) than for placebo, as were changes in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP). Rapid improvement was demonstrated by significant differences in ACR20 response rates and changes in the DAS28-CRP for all doses compared with placebo at week 2 (the first postbaseline visit). The incidence of adverse events was similar across groups; most were mild, and infections were the most frequent. One serious infection (community-acquired pneumonia) occurred with ABT-494 at 12 mg. There were dose-dependent increases in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, but the LDL cholesterol:HDL cholesterol ratios were unchanged through week 12. Mean hemoglobin levels remained stable at lower doses, but decreases were observed at higher doses.
  
  
  
  This study evaluated a broad range of doses of ABT-494 in RA patients with an inadequate response to MTX. ABT-494 demonstrated efficacy, with a safety and tolerability profile similar to that of other JAK inhibitors.
authors.affiliation: Stanford University School of Medicine, Palo Alto, California.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Genovese
authors.affiliation: Medical University of Vienna and Hietzing Hospital, Vienna, Austria.
authors.forename: Josef S
authors.initials: JS
authors.lastname: Smolen
authors.affiliation: Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weinblatt
authors.affiliation: Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Gerd R
authors.initials: GR
authors.lastname: Burmester
authors.affiliation: AbbVie Deutschland, Ludwigshafen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Meerwein
authors.affiliation: AbbVie, North Chicago, Illinois.
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Camp
authors.affiliation: AbbVie, North Chicago, Illinois.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: AbbVie, North Chicago, Illinois.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Othman
authors.affiliation: AbbVie, North Chicago, Illinois.
authors.forename: Nasser
authors.initials: N
authors.lastname: Khan
authors.affiliation: AbbVie, North Chicago, Illinois.
authors.forename: Aileen L
authors.initials: AL
authors.lastname: Pangan
authors.affiliation: AbbVie, North Chicago, Illinois.
authors.forename: Steven
authors.initials: S
authors.lastname: Jungerwirth
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D002097:C-Reactive Protein / Q000276:immunology; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006261:Headache / Q000139:chemically induced; D006454:Hemoglobins / Q000378:metabolism; D006562:Herpes Zoster / Q000139:chemically induced; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000139:chemically induced; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D010612:Pharyngitis / Q000139:chemically induced; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D006454:Hemoglobins; D006575:Heterocyclic Compounds, 3-Ring; D047428:Protein Kinase Inhibitors; C000613732:upadacitinib; D002097:C-Reactive Protein; D053613:Janus Kinase 1; D008727:Methotrexate