Clinical Trials

Date: 2016-11-02

Type of information: Publication of results in a medical journal

phase: 3

Announcement: publication of results in Annals of the Rheumatic Diseases

Company: Eli Lilly (USA - IN) Incyte Corporation (USA - DE)

Product: baricitinib (LY3009104)

Action mechanism:

• kinase inhibitor/tyrosine kinase inhibitor/janus kinase inhibitor. Baricitinib is a once daily, oral, selective JAK1 and JAK2 inhibitor. There are four known JAK enzymes: JAK1, JAK2, JAK3 and TYK2. JAK-dependent cytokines have been implicated in the pathogenesis of a number of inflammatory and autoimmune diseases, suggesting that JAK inhibitors may be useful for the treatment of a broad range of inflammatory conditions. Baricitinib demonstrates approximately 100-fold greater potency of inhibition against JAK1 and JAK2 than JAK 3 in kinase assays.
• In December 2009, Lilly and Incyte announced an exclusive worldwide license and collaboration agreement for the development and commercialization of baricitinib and certain follow-on compounds for patients with inflammatory and autoimmune diseases. Baricitinib is currently in Phase 3 clinical development for rheumatoid arthritis and Phase 2 development for psoriasis and diabetic nephropathy.
• Lilly and Incyte are conducting four pivotal Phase 3 clinical trials of baricitinib in patients with moderately-to-severely active rheumatoid arthritis to support regulatory submission in most countries. An additional Phase 3 study was initiated to support clinical development in China. The clinical trial program includes a wide range of patients including those who are methotrexate naïve, inadequate responders to methotrexate, inadequate responders to conventional disease-modifying anti-rheumatic drugs, or inadequate responders to TNF inhibitors. Four of these five pivotal studies are expected to be completed by the end of 2015. Patients completing any of the five Phase 3 studies can enroll in a long-term extension study.

Disease: rheumatoid arthritis

Therapeutic area: Autoimmune diseases – Inflammatory diseases - Rheumatic diseases

Country: Argentina, Australia, Austria, Belgium, Canada, Croatia, Denmark, France, Germany, Greece, India, Israel, Italy, Japan, Republic of Korea, Mexico, The Netherlands, Poland, Puerto Rico, Spain, Switzerland, Turkey, UK, USA

Trial details:

• The purpose of this study is to determine whether baricitinib 4 milligram (mg) once daily is superior to placebo in the treatment of participants with moderately to severely active Rheumatoid Arthritis (RA) who have had an inadequate response to a tumor necrosis factor (TNF) inhibitor, despite ongoing treatment with conventional disease-modifying antirheumatic drugs (cDMARDs). (NCT01721044)

Latest news:

• • On November 2, 2016, Eli Lilly and Incyte announced that new data from RA-BEACON - a pivotal phase 3 study of baricitinib in the treatment of moderate-to-severe rheumatoid arthritis (RA) - showed baricitinib demonstrated significant improvement in patient-reported outcomes and health-related quality of life (HRQOL) measures, fatigue and pain compared with placebo. The results of the study were published in Annals of the Rheumatic Diseases. The global trial is part of the ongoing study of baricitinib, a once-daily oral medication currently under regulatory review for the treatment of moderate-to-severe RA.
• The RA-BEACON study included patients who had insufficient response or intolerance to previous treatment with biologic disease-modifying antirheumatic drugs (bDMARDs), including tumor necrosis factor (TNF) inhibitors. In these patients, treatment with baricitinib through 24 weeks significantly improved most patient-reported outcomes compared with placebo, and patients receiving baricitinib 4 mg showed the most rapid and greatest change. Previously, baricitinib has also shown significant clinical efficacy in these patients. HRQOL was assessed using the 36-Item Short Form Health Survey (SF-36), a patient-reported instrument that collects information in multiple domains, including physical function, bodily pain, general health, limitation in role, vitality and social functioning. The SF-36 reports physical and mental component scores. Results of the study showed that:
• At week 12, a clinically important improvement (?5) in the physical component score was achieved by 49 percent  of patients taking baricitinib 2 mg; 53 percent of patients taking baricitinib 4 mg; and 32 percent of patients in the placebo group. At week 24, a clinically important improvement (?5) in the physical component score was achieved by 39 percent of patients taking baricitinib 2mg; 45 percent of patients taking baricitinib 4 mg; and 21 percent of patients in the placebo group.
• At week 4, in patients treated with baricitinib (2 mg and 4 mg doses), the improvement in the physical component score of SF-36 was statistically significant compared to the improvement seen in the placebo group. This improvement was sustained through week 24 for both baricitinib doses.
• Both doses of baricitinib (2 mg and 4 mg) also significantly improved fatigue as early as week 4 compared to placebo, and the greater improvement compared to placebo was maintained throughout the study. The study also showed that baricitinib treatment resulted in significant reductions in the duration of morning joint stiffness as early as week 1 (for 4 mg dose) compared to placebo, and the greater improvement compared to placebo was maintained throughout the study. There were also significant improvements in physical functioning and pain in the baricitinib-treated groups at week 12 and week 24, compared with placebo.
• The differences in improvement in Patient's Global Assessment of Disease Activity and disability were evident as early as week 1 in the baricitinib-treated groups versus placebo. For patient's assessment of pain, only baricitinib 4 mg was shown to be statistically significantly different from placebo at week 1.
• The RA-BEACON study enrolled 527 patients who previously had failed at least one TNF inhibitor, and included 199 patients who also had received prior treatment with one or more non-anti-TNF biologic agents. Patients received baricitinib 4 mg (n=177) or 2 mg (n=174) or placebo (n=176) daily, in addition to their existing background therapies, for 24 weeks. Clinical efficacy and safety results from the RA-BEACON study were published earlier this year in the New England Journal of Medicine.[i]
• In RA-BEACON, through 24 weeks, 77 percent of patients on baricitinib 4 mg and 71 percent of patients on baricitinib 2 mg experienced treatment-emergent adverse events (AEs), compared to 64 percent of patients in the placebo group. Discontinuation rates due to AEs were 6 percent, 4 percent and 4 percent, respectively. The most common AEs reported for baricitinib-treated patients included headache, upper respiratory infections and nasopharyngitis. There were no cases of tuberculosis or gastrointestinal perforations. Rates of serious adverse events (SAEs) were 10 percent for baricitinib 4 mg, 4 percent for baricitinib 2 mg and 7 percent for placebo. One death was reported in the baricitinib 4 mg dose group (stroke). A large majority of patients completing this 6-month trial opted to participate in a long-term extension study.
• • On March 31, 2016, Eli Lilly and Incyte announced that detailed results of RA-BEACON — a pivotal phase 3 global study of baricitinib, a once-daily oral treatment currently under regulatory review for the treatment of moderate-to-severe rheumatoid arthritis (RA) — were publishe in the New England Journal of Medicine. The study met its primary endpoint of improved ACR 20 response for baricitinib compared with placebo at week 12. ACR 20 represents at least a 20 percent improvement across selected measures of disease activity. ACR 20 response rates were as follows (P?0.001 for each baricitinib dose versus placebo):
• 55 percent for baricitinib 4 mg 49 percent for baricitinib 2 mg 27 percent for placebo The RA-BEACON study enrolled 527 patients who previously had failed at least one tumor necrosis factor (TNF) inhibitor, and included 199 patients who also had received prior treatment with one or more non-anti-TNF biologic agents. Patients received baricitinib 2 mg or 4 mg or placebo daily, in addition to their existing background therapies, for 24 weeks. A statistically significant improvement in ACR 20 response rate with baricitinib versus placebo was observed as early as one week (P?0.01). ACR 50 and ACR 70 response rates were also significantly higher for baricitinib compared with placebo at week 12 (P?0.01).
• A significantly greater proportion of patients treated with baricitinib also achieved a DAS28-CRP score—a measure of RA disease activity—below 2.6 (indicating disease remission) at week 12 compared with patients receiving placebo. Additionally, a greater proportion of patients treated with baricitinib versus placebo achieved score improvements of at least 0.3 on the Health Assessment Questionnaire Disability Index (HAQ-DI)—a patient-reported assessment of physical function— at week 12.
• Significant improvements in ACR response rates, DAS28-CRP and HAQ-DI that were noted with baricitinib versus placebo at week 12 were maintained through week 24.
• Through 24 weeks, the rate of treatment-emergent adverse events (AEs) was higher for baricitinib 4 mg (77 percent) and baricitinib 2 mg (71 percent) than for placebo (64 percent). Discontinuation rates due to AEs were 6 percent, 4 percent and 4 percent, respectively. The most common adverse events reported for baricitinib-treated patients included headache, upper respiratory infections and nasopharyngitis. There were no opportunistic infections, cases of tuberculosis or gastrointestinal perforations. Rates of serious adverse events were 10 percent for baricitinib 4 mg, 4 percent for baricitinib 2 mg and 7 percent for placebo. One death was reported in the baricitinib 4 mg dose group (stroke).

Is general: Yes