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Novel TYK2-Inhibitor for the Treatment of Plaque Psoriasis

Novel TYK2-Inhibitor for the Treatment of Plaque Psoriasis

doctors

Drs Rothstein and Rosmarin of Tufts Medical Center in Boston, MA, are studying oral agents that inhibit tyrosine kinase 2 as a potential treatment for plaque psoriasis. 

As our understanding of the immunepathogenesis of psoriasis has expanded, so has our armamentarium of treatment options. Treatments for psoriasis range from topical steroids and phototherapy to small-molecule oral medicines and biologic agents. Even with the advent of highly effective biologics, however, some patients still have difficult-to-control disease and some patients prefer taking a pill to injections or infusions. This has led to continued research efforts into the study of novel small-molecule inhibitors to provide effective results with minimized deleterious side effects.1 

BMS-986165 is one such novel oral agent that inhibits tyrosine kinase 2 (TYK2).2 A recent phase 2 study demonstrated the efficacy and tolerability of BMS-986165 in patients with moderate to severe plaque psoriasis.3 Based on this data, BMS-986165 is a promising future therapeutic agent for patients with plaque psoriasis.

Tyrosine Kinase 2: A Janus Kinase

Psoriasis pathogenesis is characterized by keratinocyte hyperplasia due to immunologic dysregulation. In particular, psoriasis is driven by a predominant TH17 immune response with elevated levels of cytokines including IL-17, IL-23, tumor necrosis factor-α, and IL-22, all of which are known to play important roles in psoriasis pathogenesis.4,5 The Janus kinase (JAK) and signal transducers and activators of transcription (STAT) pathway is required for molecular signaling in the TH17 axis, making JAK molecules an attractive target for psoriasis drug development.6,7  

There are 4 members of the JAK family—JAK1, JAK2, JAK3, and TYK2. Genome-wide association studies have linked the TYK2 gene to psoriasis susceptibility,8 and TYK2 gene impairment confers protection against the development of psoriasis and other autoimmune diseases.9 By examining mouse models deficient in TYK2 and selectively inhibiting TYK2 in mice and human cells, researchers have demonstrated that TYK2 activity is required for the signaling of IL-12, IL-23, and type I interferons.10-13 Therefore, blocking TYK2 activity inhibits the major downstream signaling effects of IL-12 and IL-23, ultimately interrupting many of the cellular processes that contribute to the formation of psoriatic lesions. This mechanism of action is similar to that of the widely used psoriasis biologic agent ustekinumab (Stelara), which is a human monoclonal antibody that binds the p40 subunit of IL-23 and IL-12.14,15

Commercially available JAK inhibitors that are FDA approved include tofacitinib (Xeljanz), ruxolitinib (Jakafi), and baricitinib (Olumiant) (Table).7 JAK inhibitors are currently in development to treat a broad range of inflammatory disorders including atopic dermatitis, alopecia areata, connective tissue disease, and vitiligo.16 These JAK inhibitors have minimal effect on TYK2 function and are not approved for the treatment of plaque psoriasis. TYK2 inhibitors have a narrower spectrum of activity compared with other JAK inhibitors, and therefore may be associated with a more desirable safety profile.17

table

BMS-986165 is a novel oral medication that inhibits TYK2 by stabilizing the pseudokinase domain of the protein.18 Compared with other JAK inhibitors, BMS-986165 has a selective mechanism of action, avoiding inhibition of the other JAKs.12 Currently, there are no TYK2 inhibitors approved by the FDA for therapeutic use.

BMS-986165 Clinical Trial Results

A phase 1 trial of BMS-986165 demonstrated that the drug was overall safe and well-tolerated in healthy participants, with no serious adverse events reported.19 The results of a large-scale phase 2, double-blind, randomized, controlled trial of BMS-986165 in 267 adult patients with moderate to severe plaque psoriasis was recently published in the New England Journal of Medicine.3 Patients were randomized to the drug at doses of 3-mg every other day, 3-mg daily, 3-mg twice daily, 6-mg twice daily, 12-mg daily, or to placebo. The primary endpoint was an achievement of a 75% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12 (PASI 75). Secondary endpoints included rates of achievement of PASI 90 and PASI 100.

At the end of 12 weeks, the percentage of patients who achieved a PASI 75 were 7% on placebo, 9% with 3-mg every other day dosing (P=.49), 39% with 3-mg daily dosing (P<.001), 69% with 3-mg twice daily dosing (P<.001), 67% with 6-mg twice daily dosing (P<.001), and 75% with 12-mg daily dosing (P<.001). These PASI 75 results are comparable to those of existing biologic agents. The percentages of patients who achieved a PASI 90 were 2%, 7%, 16%, 44%, 44%, and 43%, respectively. Complete skin clearance (PASI 100) was achieved in 0%, 2%, 0%, 9%, 18%, and 25% of patients, respectively. Seventy-five percent of biologic naïve and 63% of previous biologic users in the 3 highest dosing groups achieved a PASI 75 at 12 weeks. Patients in the 3-mg twice daily and above dosing groups achieved higher rates of normal or near normal Dermatology Life Quality Index scores compared with patients in the groups receiving lower doses and placebo.3 

The most common adverse events observed were nasopharyngitis, headache, diarrhea, nausea, and upper respiratory tract infections. One patient in the 3-mg daily group was diagnosed with melanoma in situ. The percentage of patients in active treatment groups who discontinued the drug due to adverse events was 2% to 7% across all treatment groups compared with 4% in the placebo group. The development of mild to moderate acne was observed at higher rates in participants in the active treatment groups (9% in patients taking 12-mg daily) compared with 0% in the placebo group, which the researchers postulated may be due to inhibition of cytokines in the pilosebaceous unit that normally target acne-causing bacteria. Acne may be a class-effect of the JAK inhibitors. There were no significant changes in laboratory values (complete blood count, liver function tests, lipids, creatinine, or immunoglobulins) from baseline to week 12 in patients receiving the drug.3 This is noteworthy given that alterations in these laboratory values are known side effects of other JAK inhibitors, although larger studies are needed to better characterize the side-effect profile.

Future Outlook

By blocking the action of TYK2, BMS-986165 inhibits the downstream signaling effects of cytokines IL-12, IL-23, and type I interferons, resulting in the clinical improvement of psoriatic plaques. BMS-986165 demonstrated high rates of improvement in adults with moderate to severe plaque psoriasis, with 75% of patients in the 12-mg daily dosing group achieving the primary endpoint of PASI 75 at 12 weeks, and 9% to 25% of patients in the higher dosing groups achieving PASI 100 skin clearance at 12 weeks. The side-effect profile was overall favorable with no significant impact on patient laboratory values, and patients in the higher dosing groups experienced statistically significant improvement in their quality of life.3 

The phase 2 clinical trial data suggest that BMS-986165 is an effective and well-tolerated new oral agent for the treatment of moderate to severe plaque psoriasis. Given the high rates of efficacy observed in this phase 2 clinical trial, a phase 3 clinical trial program is currently enrolling patients with moderate to severe plaque psoriasis.20 With time, BMS-986165 may become a preferred therapeutic option for our psoriasis patients. 

Dr Rothstein is a dermatology resident with the department of dermatology at Tufts Medical Center in Boston, MA.

Dr Rosmarin is a dermatologist with the department of dermatology at Tufts Medical Center in Boston, MA.

 

Disclosures: Dr Rothstein reports no relevant financial relationships.

Dr Rosmarin has been a consultant for AbbVie, Celgene, Dermavant, Janssen, Lilly, Novartis, Pfizer, and Regeneron Pharmaceuticals, Inc; received research support from AbbVie, Bristol-Myers Squibb, Celgene, Dermira, Incyte, Janssen, Lilly, Merck, Novartis, Pfizer, and Regeneron Pharmaceuticals, Inc; and was a paid speaker for AbbVie, Celgene, Janssen, Lilly, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc, and Sanofi.

References

1. Cline A, Cardwell LA, Feldman SR. Advances in treating psoriasis in the elderly with small molecule inhibitors. Expert Opin Pharmacother. 2017;18(18):1965-1973. doi:10.1080/14656566.2017.1409205

2. Bristol-Myers Squibb’s novel, oral, selective TYK2 inhibitor delivered significant skin, clearance in patients with moderate to severe plaque psoriasis in phase 2 trial [news release]. Princeton, NJ: Bristol-Myers Squibb; September 12, 2018. https://news.bms.com/press-release/bristolmyers/bristol-myers-squibbs-novel-oral-selective-tyk2-inhibitor-delivered-signi. Accessed January 20, 2019. 

3. Papp K, Gordon K, Thaci D, et al. Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis. N Engl J Med. 2018;379(14):1313-1321. doi:10.1056/NEJMoa1806382

4. Lowes MA, Kikuchi T, Fuentes-Duculan J, et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol. 2008;128(5):1207-1211. doi:10.1038/sj.jid.5701213

5. Jeon C, Sekhon S, Yan D, Afifi L, Nakamura M, Bhutani T. Monoclonal antibodies inhibiting IL-12, -23, and -17 for the treatment of psoriasis. Hum Vaccin Immunother. 2017;13(10):2247-2259. doi:10.1080/21645515.2017.1356498

6. Murray PJ. The JAK-STAT signaling pathway: Input and output integration. J Immunol. 2007;178(5):2623-2629.

7. Di Lernia V, Bardazzi F. Profile of tofacitinib citrate and its potential in the treatment of moderate-to-severe chronic plaque psoriasis. Drug Des Devel Ther. 2016;10:533-539. doi:10.2147/DDDT.S82599

8. Strange A, Capon F, Spencer CC, et al; Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet. 2010;42(11):985-990. doi:10.1038/ng.694

9. Dendrou CA, Cortes A, Shipman L, et al. Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity. Sci Transl Med. 2016;8(363):363ra149. doi:10.1126/scitranslmed.aag1974

10. Karaghiosoff M, Neubauer H, Lassnig C, et al. Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity. 2000;13(4):549-560.

11. Shaw MH, Boyartchuk V, Wong S, et al. A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity. Proc Natl Acad Sci USA. 2003;100(20):11594-11599.

12. Sohn SJ, Barrett K, Van Abbema A, et al. A restricted role for TYK2 catalytic activity in human cytokine responses revealed by novel TYK2-selective inhibitors. J Immunol. 2013;191(5):2205-2216. doi:10.4049/jimmunol.1202859

13. Ishizaki M, Muromoto R, Akimoto T, et al. Tyk2 is a therapeutic target for psoriasis-like skin inflammation. Int Immunol. 2014;26(5):257-267. doi:10.1093/intimm/dxt062

14. Kim HJ, Lebwohl MG. Biologics and psoriasis: The beat goes on. Dermatol Clin. 2019;37(1):29-36. doi:10.1016/j.det.2018.07.004.

15. Stelara [package insert]. Horsham, PA: Janssen Biotech, Inc; 2018.

16. Ciechanowicz P, Rakowska A, Sikora M, Rudnicka L. JAK-inhibitors in dermatology. Current evidence and future applications [published online November 15, 2018]. J Dermatolog Treat. doi:10.1080/09546634.2018.1546043

17. He X, Chen X, Zhang H, Xie T, Ye XY. Selective Tyk2 inhibitors as potential therapeutic agents: A patent review (2015-2018) [published online January 22, 2019]. Expert Opin Ther Pat. doi:10.1080/13543776.2019.1567713

18. Gillooly K, Zhang Y, Yang X, et al. BMS-986165 is a highly potent and selective allosteric inhibitor of Tyk2, blocks IL-12, IL-23 and type I interferon signaling and provides for robust efficacy in preclinical models of systemic lupus erythematosus and inflammatory bowel disease. Presented at: 2016 ACR/ARHP Annual Meeting; Washington, DC; November 11-16, 2016. Abstract 11L.

19. Catlett I, Aras U, Liu Y, et al. A first-in-human, study of BMS-986165, a selective, potent, allosteric small molecule inhibitor of tyrosine kinase 2. Ann Rheum Dis. 2017;76(Supple2):859. doi:10.1136/annrheumdis-2017-eular.3809

20. Bristol-Myers Squibb. An investigational study to evaluate experimental medication BMS-986165 compared to placebo and a currently available treatment in participants with moderate to severe plaque psoriasis (POETYK-PSO-1). https://clinicaltrials.gov/ct2/show/NCT03624127. NCT03624127. Accessed January 29, 2019.

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