Clinical Trials

Date: 2017-02-15

Type of information: Publication of results in a medical journal

phase: 3

Announcement: publication of results in The New English Journal of Medicine

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, Belgium, Canada, China, Croatia, Czech Republic, France, Germany, Greece, Hungary, Japan, Republic of Korea, Latvia, Lithuania, Mexico, Poland, Portugal, Puerto Rico, Romania, Russian Federation, Slovakia, Slovenia, South Africa, Spain, Switzerland, Taiwan, UK, USA, Netherlands

Trial details:

• RA-BEAM  is a pivotal phase 3 study of baricitinib in the treatment of moderate-to-severe rheumatoid arthritis. The purpose of the study is to determine whether baricitinib is superior to placebo in the treatment of participants with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate. Part of a larger Phase 3 program of more than 3,000 rheumatoid arthritis patients at various points in the rheumatoid arthritis  treatment continuum, RA-BEAM enrolled more than 1,300 patients who were randomized to one of three treatment groups: 4 mg oral once-daily baricitinib on background methotrexate, 40 mg injectable every-other-week adalimumab on background methotrexate placebo on background methotrexate.(NCT01710358)

Latest news:

• • On February 15, 2017, Eli Lilly and Incyte Corporation announced additional detailed results from RA-BEAM  were published in the New England Journal of Medicine. This publication includes supplementary data, which show that starting as early as week 8, and sustained through week 52, a higher proportion of patients taking baricitinib achieved ACR50 and ACR70 response - composite scores that represent at least 50 percent and 70 percent improvement, respectively, in multiple components of rheumatoid arthritis disease activity - compared to adalimumab (Humira®*). These improvements were statistically significant compared to adalimumab at weeks 12, 20, 28, 32 and 40. At week 52, both ACR50 and ACR70 rates were higher in the baricitinib group compared to adalimumab, although only ACR 50 was statistically significant.
• A significantly higher proportion of patients taking baricitinib had low disease activity, assessed by the 28-joint Disease Activity Score (using high-sensitivity C reactive protein [DAS28-CRP]), Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) scores, compared to adalimumab at weeks 12 and 52.
• Through the 52-week period, serious adverse event rates were 8 percent for baricitinib and 4 percent for adalimumab. Patients stopping therapy due to adverse events from baseline through week 52 were 7 percent for baricitinib and 4 percent for adalimumab. Major adverse cardiovascular events (MACE) were reported in less than 1 percent of patients in both the baricitinib and adalimumab groups (baseline through 52 weeks). A total of 5 deaths were reported in the study (1 placebo, 2 baricitinib, 1 adalimumab and 1 placebo rescued to baricitinib).
• • 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 9, 2016, Eli Lilly and Incyte announced that in two phase 3 trials patients with rheumatoid arthritis treated with baricitinib reported significant improvements in quality of life symptoms and other patient-reported outcomes compared to methotrexate or adalimumab (Humira®). Patients with rheumatoid arthritis also reported improvement in productivity at work. In these studies, significant improvements in patient-reported measures, including pain, physical function, tiredness and morning joint stiffness, were observed as early as one week after initial treatment with baricitinib. These findings were presented  at the Annual European Congress of Rheumatology (EULAR 2016) in London. In the phase 3 RA-BEAM trial, where all patients received background methotrexate therapy: At 12 weeks, 75 percent of patients treated with baricitinib reported clinically meaningful improvement in physical function compared with 71 percent of patients on adalimumab (p=0.302). Clinically meaningful improvement was defined as an improvement in HAQ-DI score of =0.22. At 24 weeks, 73 percent of patients treated with baricitinib reported clinically meaningful improvement in physical function compared with 64 percent of patients on adalimumab (p < 0.05). At 52 weeks, 68 percent of patients treated with baricitinib reported clinically meaningful improvement in physical function compared with 58 percent of patients on adalimumab (p < 0.01). At 52 weeks, baricitinib was also associated with significant improvement in pain, and clinically meaningful improvement in fatigue and the physical health components of quality of life compared with adalimumab. An analysis of the phase 3 trials found that in each study, patients taking baricitinib have less impairment in work productivity and daily activities compared to patients taking the comparator. Physical function was measured using the patient-reported HAQ-DI questionnaire that assesses the ability of a patient to perform daily activities like dressing, eating, walking, grip, etc. Quality of life assessment was made by using the Medical Outcomes Study 36-Item Short Form Health Survey Version 2 Acute, or SF-36, which is a patient-reported survey that measures overall health quality based on physical and psychological functioning.
• •  On October 14, 2015, Eli Lilly and Incyte announced positive topline results of RA-BEAM. The study met its primary objective of demonstrating superiority compared to placebo after 12 weeks of treatment based on ACR20 response - a standard clinical measure that represents at least a 20 percent improvement in rheumatoid arthritis disease activity. Baricitinib was also superior to adalimumab on key secondary objectives of ACR20 response and improvement in DAS28-hsCRP score after 12 weeks of treatment. Following 24 weeks of treatment, baricitinib was superior to placebo in preventing progressive radiographic structural joint damage. These treatment benefits with baricitinib observed at 12 and 24 weeks were maintained through 52 weeks of therapy.
• 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. Rates of treatment-emergent adverse events, including infections, were higher for baricitinib and adalimumab compared to placebo. The most common adverse events observed with baricitinib were nasopharyngitis and bronchitis. Discontinuations due to adverse events occurred with similar frequency across treatment groups. A large majority of patients completing this trial opted to participate in a long-term extension study. Lilly and Incyte announced top-line results in December 2014 for the first Phase 3 trial of baricitinib, RA-BEACON, and in February 2015 for the second, RA-BUILD. Data from these studies were presented at the EULAR annual scientific congress in June 2015 . Topline results of the third Phase 3 trial, RA-BEGIN, were announced in September 2015 and will be presented at the American College of Rheumatology annual scientific congress in November. The companies plan to submit detailed data from RA-BEAM and other Phase 3 studies for presentation at scientific meetings and publication in peer-reviewed journals in 2015 and 2016.

Is general: Yes