Other Jakinibs

Ruxolitinib is a Jakinib approved by the FDA to treat myelofibrosis and polycythemia vera. Ruxolitinib was evaluated in a randomized controlled phase 2a trial in patients with RA.2 Patients treated with ruxolitinib were more likely to achieve ACR20, ACR50, or ACR70 than patients taking placebo. The ruxolitinib arm also showed greater improvement in HAQ-DI scores after 4 weeks.2 “Ruxolitinib, which has significant activity toward JAK1/JAK2, may ultimately join tofacinitib [as a treatment for RA],” Dr Malemud said.

Baricitinib inhibits JAK1 and JAK2 and is under consideration by the FDA for moderate to severe RA. A randomized phase 3 trial compared baricitinib with placebo or adalimumab in approximately 1300 patients with active RA who had an inadequate response to methotrexate.11 


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At week 12 of the 52-week trial, patients taking baricitinib were significantly more likely than patients taking placebo or adalimumab to have an ACR20 response.11 At week 24, patients taking baricitinib had significantly less radiographic evidence of joint damage progression than patients taking placebo. 

However, the rate of adverse events, including infection, was significantly higher in the baricitinib and adalimumab arms than in the placebo arm. Baricitinib was also associated with decreased neutrophil counts and increased creatinine and low-density lipoprotein cholesterol levels.11

Decernotinib, which is highly selective for JAK3, is another Jakinib being studied for RA. In a phase 2b trial, patients with an inadequate response to methotrexate were randomly assigned to decernotinib or placebo for 24 weeks.12 

Decernotinib was associated with significantly better ACR20 responses, which the investigators said was similar to the response observed in trials of tofacitinib and baricitinib. The safety profile of decernotinib was like that observed with tofacitinib and other Jakinibs.12

Filgotinib, peficitinib, ABT-494, and INCB039110 are other investigational oral Jakinibs evaluated in phase 2 trials in patients with RA.2 Filgotinib and ABT-494 inhibit JAK1 and JAK2 but have far greater affinity for JAK1.2 Peficitinib inhibits all 4 JAKs, but its inhibition of JAK2 is mild. INCB039110 is highly selective for JAK1 but also inhibits JAK2 and JAK3. All these investigational drugs were found to be superior to placebo.

Dr Malemud predicts the use of JAK inhibitors in patients with RA will grow over time. “That’s because JAK1/JAK2/JAK3 represent a ‘common’ thread that links pro-inflammatory cytokines such as IL-6 and interferon-gamma to chronic inflammation,” he said. 

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References

1. Thomas S, Fisher KH, Snowden JA, et al. Methotrexate is a JAK/STAT pathway inhibitor. PLoS ONE. 2015;10(7):e0130078. doi:10.1371/journal.pone.0130078

2. Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT signaling as a target for inflammatory and autoimmune disease: current and future prospects. Drugs. 2017;77(5):521-546. doi:10.1007/s40265-017-0701-9

3. Malemud CJ. Suppression of pro-inflammatory cytokines via targeting of STAT-responsive genes. In: El-Shemy H, ed. Drug Discovery. Rijeka, Croatia: InTech Publishing; 2013: pp 373-411.

4. Malemud CJ. Apoptosis resistance in rheumatoid arthritis synovial tissue. Special Issue: Immune Response and Apoptosis. J Clin Cell Immunol. 2011;S3:006.

5. Malemud CJ. Chondrocyte apoptosis in rheumatoid arthritis: is preventive therapy possible? Immunotherapy (Los Angel). 2015;1:102.

6. Nakayamada S, Kubo S, Iwata S, et al. Recent progress in JAK inhibitors for the treatment of rheumatoid arthritis. BioDrugs. 2016;30:407-419.

7. Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367:495-507.

8. Xeljanz® [package insert]. Pfizer Labs: NY, NY; 2016.

9. Wollenhaupt J, Silverfield J, Lee EB, et al. Safety and efficacy of tofacitinib, an oral Janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J Rheumatol. 2014;41:837-852.

10. Cohen SB, Tanaka Y, Mariette X, et al. Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials [published online January 31, 2017]. Ann Rheum Dis.  doi:10.1136/annrheumdis-2016-210457

11. Taylor PC, Keystone EC, ver Heijde DV, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017;376:652-662.

12. Gadina M, Schwartz DM, O’Shea JJ. Decernotinib: a next-generation Jakinib. Arthritis Rheumatol. 2016;68:31-34.

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