Monica Luchi

Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate.

Objectives To investigate baricitinib (LY3009104, formerly INCB028050), a novel, oral inhibitor of JAK1/JAK2 in patients with moderate to severe rheumatoid arthritis (RA) despite treatment with methotrexate. Methods In this phase IIb study, 301 patients were randomised 2:1:1:1:1 to receive once daily doses of placebo or 1, 2, 4 or 8 mg baricitinib for 12 weeks. Patients assigned to 2, 4 and 8 mg baricitinib continued blinded treatment for an additional 12 weeks. Patients assigned to placebo or 1 mg baricitinib were reassigned to 2 mg twice daily or 4 mg once daily baricitinib between weeks 12–24. The primary endpoint was the proportion of patients in the combined 4 and 8 mg groups achieving an American College of Rheumatology 20% (ACR20) response versus placebo at week 12. Results Significantly more patients in the combined baricitinib 4 and 8 mg groups compared with placebo achieved an ACR20 response at week 12 (76% vs 41%, p<0.001). At week 12, significant differences versus placebo were also observed in patients achieving ACR50, ACR70 and remission as measured by Disease Activity Score for 28-joint counts, Clinical Disease Activity Index and Simplified Disease Activity Index. Patients receiving 2, 4, or 8 mg baricitinib maintained or improved in all measures through 24 weeks. Similar proportions of patients experienced at least one adverse event in the placebo and baricitinib groups. Serious infections developed in three patients receiving baricitinib. No cases of tuberculosis, herpes zoster, opportunistic infections or deaths were reported. Dose-dependent decreases in haemoglobin were observed with baricitinib. Conclusions Baricitinib improved the signs and symptoms of RA in methotrexate inadequate responders with active disease. Baricitinib was well tolerated with no unexpected safety findings through week 24. Trial registration number NCT01185353.

A randomized, double-blind, placebo-controlled, dose-escalation study of the safety and efficacy of INCB039110, an oral janus kinase 1 inhibitor, in patients with stable, chronic plaque psoriasis

Abstract Background: Chronic plaque psoriasis is partially mediated by elevation of proinflammatory cytokines, including several within the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Objective: To evaluate the safety and efficacy of the oral selective JAK1 inhibitor INCB039110 in stable, chronic plaque psoriasis. Methods: This was a phase 2, randomized, double-blind, placebo-controlled, dose-escalation study of INCB039110 (100 mg once daily, 200 mg once daily, 200 mg twice daily and 600 mg once daily) for 28 days. The primary endpoint was mean percent change from baseline in the static Physician Global Assessment (sPGA) at day 28. The protocol was institutional review board approved. Results: Of 50 patients, 48 completed the study. At day 28, mean percent reduction from baseline in sPGA was 22.2% for INCB039110 100 mg once daily (p  =  0.270 vs. placebo), 29.4% for 200 mg once daily (p  =  0.118), 35.2% for 200 mg twice daily (p  =  0.053), 42.4% for 600 mg once daily (p  =  0.003) and 12.5% for placebo. Across groups, 11.1% to 45.5% achieved an sPGA score of 1 versus 0% for placebo. INCB039110 was generally well tolerated; the most common treatment-emergent adverse event was nasopharyngitis (18.4%). Conclusion: INCB039110 produced significant improvements in sPGA, demonstrating proof of concept in chronic plaque psoriasis.

LB0005 12-week results of a phase 2B dose-ranging study of LY3009104 (INCB028050), an oral JAK1/JAK2 inhibitor, in combination with traditional dmards in patients with rheumatoid arthritis

Background LY3009104 (LY) is a novel, oral inhibitor of the JAK1/JAK2 signalling pathway known to be important in the pathobiology of rheumatoid arthritis (RA). Objectives To compare efficacy and safety of LY versus placebo (PBO) in patients (pts) with moderate to severe RA with inadequate response to methotrexate (MTX). Methods In this Phase 2b, 24-week randomized, double-blind, PBO-controlled study, pts with active RA on stable MTX were randomized 2:1:1:1:1 to receive either PBO or 1 of 4 once-daily LY doses (1, 2, 4, or 8 mg) for 12 weeks. The primary endpoint to evaluate the efficacy of LY was assessed by the combined proportion of pts in the 4-mg and 8-mg dose groups who achieved an ACR20 response compared to PBO over 12 weeks. Results Of the 301 pts randomized and treated, 76% of the combined 4- and 8-mg (75% of the 4-mg and 78% of the 8-mg dose) groups achieved ACR20 responses compared with 41% of PBO-treated pts (p ≤.001) by the end of 12 weeks. Similarly, greater proportions of pts achieved disease remission as judged by DAS28-CRP in the 4-mg (37%) and 8-mg (22%) dose groups compared to PBO (4%; Table 1). Onset of efficacy was rapid for ACR20, ACR50, ACR70, and DAS28-CRP, with statistically significant differences seen from Week 2 onwards. A greater percentage of pts achieved the MCID for the HAQ-DI in the 4-mg (60%) and 8-mg (67%) dose groups compared to PBO (41%) at week 12. Most adverse events (AEs) were mild. A similar rate of infections was observed in PBO (12%) and combined LY (14%) groups representing the most common treatment emergent AE. No deaths or opportunistic infections occurred in the active treatment groups. One pt taking PBO was diagnosed with an opportunistic infection of toxocariasis. Serious AEs were reported in 6 pts (2 in PBO; 3 in 2-mg; 1 in 8-mg). Decreases in hemoglobin, small increases in serum creatinine, and increases in LDL and HDL were seen (Table 2). Pt demographics across treatment groups were similar (83% female, mean age 51 years, mean duration of RA 5–7 years, HAQ-DI, 1.02–1.31; DAS28 [ESR], 6.0–6.6). Table 1. Endpoints PBO 1 mg LY 2 mg LY 4 mg LY 8 mg LY 4+8 mg LY (N=98) (N=49) (N=52) (N=52) (N=50) (N=102) % ACR20† 41 57* 54 75** 78** 76** % ACR50† 10 31* 17 35** 40** 37** % ACR70† 2 12* 8 23** 20** 22** DAS28-CRP†§ –1.0 –1.5* –1.4* –2.2** –2.1** N/A % DAS28 <2.6† 4 14* 15* 37** 22** N/A †Non-responder imputation and 1-sided p-value (Fisher’s exact test); §2-sided p-value from LY dose vs PBO (ANCOVA: treatment is a fixed factor and baseline is a covariate [LS mean change, LOCF]); *p<0.05; **p≤0.001 vs. PBO. Table 2. Mean (SD) Change from Baseline; 12 Weeks PBO 4 mg LY 8 mg LY Hemoglobin (g/dL) –0.14 (0.62) –0.15 (0.80) –0.57 (0.92) Neutrophil count (103/mm3) –0.03 (1.52) –0.30 (1.79) –0.68 (2.06) Creatinine (mg/dL) 0.01 (0.08) 0.11 (0.36) 0.09 (0.27) HDL cholesterol (mg/dL) 0.92 (11.57) 7.55 (13.40) 7.25 (13.92) LDL cholesterol (mg/dL) –4.4 (25.06) 9.5 (30.29) 12.0 (23.36) Conclusions Clinical efficacy of LY against PBO was demonstrated in this Phase 2b study of LY in combination with background MTX in pts with moderate to severe RA. LY was well tolerated. No new safety signals were detected when compared to previously conducted studies with LY. Disclosure of Interest E. Keystone Grant/Research support from: Abbott Laboratories, Amgen Inc, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, Centocor Inc, F.Hoffman-La Roche Inc, Genzyme Inc, Merck, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, UCB, Consultant for: Abbott Laboratories, AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company, Centocor Inc, F.Hoffman-La Roche Inc, Genentech Inc, Merck, Nycomed, Pfizer Pharmaceuticals, UCB, Speakers Bureau: Abbott Laboratories, Bristol-Myers Squibb Company, F.Hoffman-La Roche Inc, Merck, Pfizer Pharmaceuticals Inc, UCB, Amgen, Janssen Inc., P. Taylor Grant/Research support from: AstraZeneca, Merck, UCB, Celgene, Consultant for: Eli Lilly & Co, Celgene, UCB, Novartis, Merck, NovoNordisk, Abbott, Pfizer, AstraZeneca, Roche, Takeda, M. Genovese Grant/Research support from: Lilly, Pfizer, Rigel, AstraZeneca, Consultant for: Lilly, Pfizer, Rigel, AstraZeneca, Vertex, Biogen-Idec, Astellas, D. Schlichting Shareholder of: Eli Lilly & Co, Employee of: Eli Lilly & Co, S. Beattie Shareholder of: Eli Lilly & Co, Employee of: Eli Lilly & Co, C. Gaich Shareholder of: Eli Lilly & Co, Employee of: Eli Lilly & Co, R. Fidelus Gort Employee of: Incyte Corp., M. Luchi Shareholder of: Incyte Corp., Employee of: Incyte Corp., W. Macias Shareholder of: Eli Lilly & Co, Employee of: Eli Lilly & Co

JAK inhibition for the treatment of rheumatoid arthritis: a new era in oral DMARD therapy

Introduction: In rheumatoid arthritis (RA) there is a significant medical need for safe and effective oral disease-modifying anti-rheumatic drugs (DMARDs) for patients who respond inadequately to methotrexate, the first-line therapy in RA. Oral agents targeting Janus-associated kinases (JAKs) are the most promising new agents in clinical development. This review describes the preclinical and clinical activities of the most advanced JAK inhibitors with different JAK selectivity profiles. Areas covered: This review first describes the current treatment landscape and the pathophysiology of RA. Role for cytokines in the disease pathogenesis followed by significance of JAK/STAT pathway in cytokine signaling are discussed. Available chemical description and enzymatic data on the most advanced JAK inhibitors in clinical development are provided. Preclinical and clinical results that are publicly available are summarized. Review of literature was conducted using National Library of Medicine (NLM) database, ‘PubMed’. In addition, all publicly disclosed data from companies that are developing the JAK inhibitors was researched to obtain the most up-to-date information of the compounds discussed in this report. Expert opinion: Emerging clinical results demonstrate that JAK inhibition is a validated new mechanism for the development of oral DMARD agents that is likely to join the armamentarium against RA in the near future.