Clinical Trials

Date: 2016-11-14

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the American College of Rheumatology (ACR)/Association of Rheumatology Health Professionals (ARHP) Annual Meeting

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, Belgium, Canada, Croatia, Czech Republic, Germany, Hungary, India, Italy, Japan, Republic of Korea, Mexico, Poland, Portugal, Puerto Rico, Romania, Russian Federation, Slovakia, Spain, Taiwan, UK, USA

Trial details:

• The RAB-BUILD study aims to determine whether baricitinib 4 mg once daily is superior to placebo in the treatment of participants with moderately to severely active rheumatoid arthritis who have had inadequate response to or are intolerant to at least 1 conventional disease-modifying antirheumatic drug  and who have not received a biologic disease-modifying antirheumatic drug (DMARD).(NCT01721057)

Latest news:

• • On November 14, 2016, Eli Lilly and Incyte announced new data analyses of two phase 3 trials, RA-BUILD and RA-BEAM, showing that baricitinib treatment resulted in improvements in rheumatoid arthritis symptoms across a diverse population of patients with RA regardless of age, body mass index (BMI) and previous treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Findings were presented at the American College of Rheumatology (ACR)/Association of Rheumatology Health Professionals (ARHP) Annual Meeting in Washington DC, November 11-16, 2016. Results from a post-hoc analysis of the phase 3 RA-BUILD and RA-BEAM studies evaluating elderly patients found that age did not affect baricitinib's efficacy as measured by ACR20, Health Assessment Questionnaire-Disability Index (HAQ-DI), Disease Activity Score 28 C-Reactive Protein (DAS28-CRP) and Simplified Disease Activity Index (SDAI). At week 12, in the baricitinib 4 mg group, 67 percent of patients younger than 65 years and 68 percent of patients 65 years or older achieved an ACR20 response, meaning a 20 percent improvement across various aspects of RA. In the group that received placebo, 40 percent of patients younger than 65 years and 43 percent of patients 65 years or older achieved an ACR20 response. The percentage of patients reporting an adverse event (AE) was higher in patients 65 years or older. The overall rates of AEs, serious adverse events (SAEs), and serious infections were similar between patients treated with placebo and baricitinib in patients younger than 65 years and patients 65 years or older. Additional safety information regarding RA-BUILD and RA-BEAM are provided in the study description below. Results from a post-hoc analysis of the phase 3 RA-BUILD and RA-BEAM studies evaluating the effect of baseline BMI on the response to baricitinib in patients who had insufficient response to previous csDMARDs found that baricitinib improved clinical outcomes compared to placebo regardless of baseline BMI as measured by ACR20, ACR50, ACR70, DAS28-CRP, SDAI and Clinical Disease Activity Index (CDAI). The proportion of patients who reached low disease activity or remission, including progression in structural joint damage, improved compared to placebo across the different BMI groups.
• Proportion of patients in the low, middle and high BMI groups who achieved an ACR20 response were 68.4 percent, 68 percent and 64.7 percent, respectively. ACR50 and ACR70 responses (meaning a 50 percent and 70 percent improvement across various aspects of RA, respectively) were also improved compared to placebo across the BMI groups. As has been shown for other DMARDs, baricitinib treatment effect for patients with higher BMI was numerically smaller than for patients with lower BMI. Additional safety information regarding RA-BUILD and RA-BEAM are provided in the study description below. Results from a post-hoc analysis of the phase 3 RA-BUILD and RA-BEAM studies evaluating whether the number of previous csDMARD failures altered patients' response to baricitinib found that baricitinib demonstrated improvement in RA symptoms irrespective of the number of previous csDMARDs used or the present use of oral corticosteroids as measured by ACR20, ACR50, ACR70, radiographic progression, SDAI and DAS28-ESR.
• At week 12, in the baricitinib 4 mg groups that previously used methotrexate alone, methotrexate + 1 csDMARD and methotrexate + =2 csDMARDs, 67.9 percent, 67.3 percent and 66.9 percent of patients achieved an ACR20 response, respectively. ACR50 responses were also similar across the groups (42.5 percent, 42.9 percent and 39.2 percent, respectively) and ACR70 responses were 21.4 percent, 19.5 percent and 13.3 percent respectively. The rates of SAEs and discontinuation due to AEs were comparable regardless of the number of csDMARDs used and corticosteroid use. Additional safety information regarding RA-BUILD and RA-BEAM are provided in the study description below. The RA-BUILD study enrolled 684 patients with moderate-to-severe RA who previously had an inadequate response to, or were intolerant of, at least one csDMARD and had not received a biologic disease-modifying antirheumatic drug (bDMARD). Patients received either once-daily baricitinib (2 mg or 4 mg) or placebo, in addition to their background therapy. In RA-BUILD, the incidence of SAEs with baricitinib treatment, including serious infections, was similar to placebo. There were no gastrointestinal perforations in the study. A single case of tuberculosis was reported in a patient receiving baricitinib. The most common adverse events observed were consistent with previous studies of baricitinib in RA. Discontinuation rates due to adverse events were similar between treatment groups. RA-BEAM The 52-week RA-BEAM study randomized 1,307 patients who had active, moderate-to-severe RA, despite ongoing treatment with methotrexate. Patients were randomized to once-daily placebo (n=488), once-daily baricitinib 4 mg (n=487) or biweekly adalimumab 40 mg (n=330). All patients received background methotrexate. At week 24, patients taking placebo were crossed over to the baricitinib treatment group. In RA BEAM, compared to placebo, serious adverse events rates were similar for baricitinib and lower for adalimumab; serious infection rates were similar across groups. There were no cases of gastrointestinal perforations. One event of tuberculosis was reported in each of the baricitinib and adalimumab groups. The most common adverse events observed with baricitinib were nasopharyngitis and bronchitis. Discontinuations due to adverse events occurred with similar frequency across treatment groups.
• • On June 10, 2015, Eli Lilly and Incyte announced that five abstracts featuring data from three clinical studies and separate pharmacology studies for its investigational rheumatoid arthritis drug baricitinib will be presented at the 2015 annual meeting of the European League Against Rheumatism in Rome June 10-13. Lilly and Incyte previously released positive topline results for the RA-BEACON and RA-BUILD studies, both of which met their primary endpoint of ACR20 at 12 weeks as compared to placebo. Abstracts being presented are highlighted below : "Baricitinib, An Oral Janus Kinase (JAK)1/JAK2 Inhibitor, In Patients With Active Rheumatoid Arthritis (RA) And An Inadequate Response To TNF Inhibitors: Results Of The Phase 3 RA-BEACON Study" - M. Genovese
• "Baricitinib, an Oral JAK1/JAK2 Inhibitor, in Patients With Active Rheumatoid Arthritis and an Inadequate Response to cDMARDs: Results of the Phase 3 RA-BUILD Study" - M. Dougados
• "Effects Of Baricitinib On Multi Biomarker Disease Activity Scores And Their Components In A Phase 2b Study In Moderate-To-Severe Rheumatoid Arthritis Patients" - P. Taylor
• "Effects Of Baricitinib, An Oral JAK1/JAK2 Inhibitor, On Patient-Reported Outcomes From A Phase 3 Study In Patients Who Have Had An Inadequate Response To Tumor Necrosis Factor Inhibitors" - J.S. Smolen "Evaluation Of Potential Drug-Drug Interactions With Baricitinib" - C. Payne
• • On February 23, 2015, Eli Lilly and Incyte announce that baricitinib demonstrated a statistically significant improvement compared to placebo in a second consecutive Phase 3 trial in rheumatoid arthritis (RA). The RA-BUILD study included patients with moderately-to-severely active rheumatoid arthritis who had an inadequate response to, or were intolerant of, at least one conventional disease-modifying antirheumatic drug (cDMARD). The study met its primary endpoint of an improved ACR20 response rate compared to placebo after 12 weeks of treatment.
• Part of an extensive Phase 3 program testing baricitinib in more than 3,000 patients at different stages along the RA treatment continuum, the RA-BUILD study enrolled 684 patients with rheumatoid arthritis who previously had an inadequate response to, or were intolerant of, at least one cDMARD and had not received a biologic disease-modifying antirheumatic drug (bDMARD). Patients received either one of two doses of once-daily baricitinib or placebo, in addition to their background therapy.
• In RA-BUILD, the incidence of treatment-emergent adverse events and serious adverse events with baricitinib treatment, including serious infections, was similar to placebo. There were no opportunistic infections or gastrointestinal perforations in the study. A single case of tuberculosis was reported in a patient receiving baricitinib. The most common adverse events observed were consistent with previous studies of baricitinib in RA. Discontinuation rates due to adverse events were similar between treatment groups. A large majority of patients completing this 6-month trial opted to participate in a long-term extension study.
• Lilly and Incyte announced top-line results from the first Phase 3 trial of baricitinib, RA-BEACON, which also met its primary endpoint, in December 2014 and plan to present detailed data from both RA-BEACON and RA-BUILD at scientific meetings in 2015.
• 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 recently 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.

Is general: Yes