The JAK family of intracellular, non-receptor tyrosine kinases is named the Janus kinase as they have two very similar phosphate transferring domains; one confers the kinase activity, and the other regulates it
The JAK family of intracellular, non-receptor tyrosine kinases are involved in the JAK-STAT signalling pathway, where they transduce cytokine mediated signals. The name was originally derived from ‘just another kinase’ but this was later re-rationalised to Janus kinase, after the Roman god with two faces, as they have two very similar phosphate transferring domains. One of these confers the kinase activity, and the other regulates it.
There are four kinases in the family – JAK1, JAK2, JAK3 and TYK2 – each with slightly different activities. Various drugs targeting the JAK family kinases are available and in development for a number of therapeutic indications, including Pfizer’s tofacitinib, which acts at JAK1 and JAK3, and is licensed for rheumatoid arthritis. Another kinase inhibitor, baricitinib, this time acting at JAK1 and JAK2, is being developed by Eli Lilly, in collaboration with Incyte who originally invented it, for the same indication.1 The drug also has potential in psoriasis and diabetic nephropathy.
In a Phase IIb trial, 301 patients with moderate to severe rheumatoid arthritis who did not respond to methotrexate treatment were given once-daily doses of 1, 2, 4 or 8mg baricitinib or placebo for 12 weeks.2 Those given the three highest doses continued to receive blind doses for a further 12 weeks, while those given placebo or 1mg were given 2mg twice daily or 4mg once a day for the second 12 weeks. Significantly more patients in the combined 4 and 8mg dose groups achieved an American College of Rheumatology 20% response compared with placebo after 12 weeks. This was maintained, or improved further, through to the end of the 24 weeks. Three treated patients developed a serious infection, but it was otherwise well tolerated.
Positive results have also been reported in several Phase III trials. In one, 527 patients with active rheumatoid arthritis who had not responded or were intolerant to at least one TNF inhibitor were randomised to receive 2 or 4mg baricitinib or placebo once a day for 24 weeks.3 The ACR20 response after 12 weeks was 55% for the 4mg group compared with 27% with placebo, and improvements in other scores were also seen, some as early as the first week. Treatment benefit was sustained through to 24 weeks with the 4mg dose, and the safety and tolerability profile was acceptable.
In another, 684 patients with active rheumatoid arthritis and an inadequate response or intolerability to at least one conventional disease modifying drug were given 2 or 4mg or placebo once a day for 24 weeks, with rescue treatment from week 16 for non-responders.4 The rescue rates were 9% for 2mg, 7% for 4mg and 24% for placebo, and the ACR20 response at week 12 was 62% at 4mg, and 40% with placebo. Again, improvements were seen in various other scores, and adverse event profiles were similar across all groups.
Positive results were also reported in a third Phase III trial via press release in September. Here, nearly 600 patients who had received little or no exposure to methotrexate were given 4mg baricitinib, baricitinib in combination with oral methotrexate once weekly, or weekly doses of methotrexate. According to ACR20 response, baricitinib was superior to methotrexate. Discontinuations were most common in those patients receiving the combination. The companies expect to announce results from a fourth Phase III trial in the near future.
1. J.G. Shi et al. J. Clin. Pharmacol. 2014, 54, 1354
2. E.C. Keystone et al. Ann. Rheum. Dis. 2015, 74, 333
3. M.C. Genovese et al. Ann. Rheum. Dis. 2015, 74 (Suppl. 2), 75
4. M. Dougados et al. Ann. Rheum. Dis. 2015, 74 (Suppl. 2), 79