Baricitinib for the Treatment of Moderate to Severe Rheumatoid Arthritis, United States of America
Baricitinib is the first once-daily oral selective JAK1 and JAK2 inhibitor for the treatment of moderate to severe active rheumatoid arthritis (RA).
The drug was discovered by Incyte. Eli Lilly will handle the development and commercialisation under an exclusive worldwide license and collaboration agreement signed between the companies in December 2009.
Under the agreement, Incyte will receive milestone-based and global regulatory payments, including $35m for new drug application (NDA) submission and $100m for drug approval from Eli Lilly and will be eligible for royalties on global net sales of the drug.
Eli Lilly submitted the NDA of Baricitinib for the treatment of RA to the US Food and Drug Administration (FDA) for approval on 19 January 2016. If approved by the FDA, Baricitinib will be the only once daily oral drug for the treatment of rheumatoid arthritis.
The Phase III trials to evaluate the efficacy and safety of Baricitinib are ongoing in Europe and the UK.
Rheumatoid arthritis is an autoimmune disease that results from the immune system attacking the body's own tissues. It is characterised by inflammation, pain, swelling, stiffness, loss of function and gradual destruction of joints. It can affect any joint, although it most commonly affects those in the wrist and fingers, and can affect other body parts such as the eyes, mouth and lungs.
Rheumatoid arthritis often starts in middle age and is most common in older people, more in women than men. The defined cause for the disease is unknown, but it is assumed that genes, environment and hormones might be responsible for the disease.
Baricitinib's mechanism of action
Baricitinib is a Janus kinase inhibitor, which functions by inhibiting the activity of selective JAK1 and JAK2 enzymes, interfering with the JAK-STAT signalling pathway.
Cytokines, which plays a major role in regulating cell growth and immune response, function by binding and activating type I and type II cytokine receptors, which depend upon the JAK family of enzymes for signal transduction.
JAK inhibitor drugs inhibit the activity of the Janus kinase enzymes and Janus kinase phosphorylate-activated cytokine receptors and block the cytokine signalling.
Phosphorylated cytokine receptors produce the STAT transcription factors and modulate gene transcription and inhibit immune-pathogenesis.
Clinical trials on Baricitinib
The NDA was submitted to the FDA based on results obtained from four Phase III clinical trials namely RA-BEACON in December 2014, RA-BUILD in February 2015, RA-BEGIN study in September 2015 and RA-BEAM study in October 2015.
RA-BEACON included RA patients, who showed inadequate responses to traditional disease modifying anti-rheumatic drugs (DMARDs). The second Phase III trial RA-BUILD included RA patients who did not show any distinct response to biological therapies.
The RA-BEGIN study included patients who had a defined or no prior treatment with methotrexate and were unaware of other traditional or biological disease modifying anti-rheumatic drugs (DMARDs).
The study, aimed at evaluating Baricitinib's safety and efficacy, enrolled approximately 600 patients, who were randomised to one of the three study arms, once-weekly oral methotrexate monotherapy or 4mg once-daily oral Baricitinib monotherapy or 4mg once-daily Baricitinib in combination with once-weekly oral methotrexate.
The trial demonstrated non-inferiority of Baricitnib monotherapy to methotrexate monotherapy based on ACR20 response after 24 weeks of treatment. Baricitinib was also found to be superior to methotrexate based on the ACR20 response.
The fourth Phase III trial RA-BEAM was conducted to demonstrate the safety and efficacy of Baricitinib along with methotrexate in RA patients, compared to a placebo for 24 weeks or adalimumab, an anti-inflammatory drug, for 52 weeks.
The studies enrolled more than 1,300 patients, who were randomised to 4mg oral-once daily Baricitinib with methotrexate or 40mg injectable every other week, adalimumab with methotrexate or placebo with methotrexate.
It demonstrated Baricitinib's superiority over a placebo after 12 weeks and 24 weeks based on the ACR20 response in preventing the progressive radiographic structural joint damage.
Baricitinib was also found to be superior to adalimumab in demonstrating response and improvement in DAS28-hsCRP score (disease activity score calculator in rheumatoid arthritis patients) after 12 weeks. The benefits of treatment with Baricitinib were observed and evaluated at 12 weeks, 24 weeks and 52 weeks of therapy.
The fifth Phase III study on Baricitinib was initiated in China in 2014 and is ongoing. The trial includes patients who are naive to methotrexate, inadequate responders to methotrexate, conventional disease-modifying anti-rheumatic drugs (DMARDs) or to tumour necrosis factor (TNF) inhibitors.