Accepted Manuscript. Tofacitinib: A jak of all trades. Kristin E. Burke, Ashwin N. Ananthakrishnan

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1 Accepted Manuscript Tofacitinib: A jak of all trades Kristin E. Burke, Ashwin N. Ananthakrishnan PII: S (19) DOI: Reference: YJCGH To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 26 December 2018 Please cite this article as: Burke KE, Ananthakrishnan AN, Tofacitinib: A jak of all trades, Clinical Gastroenterology and Hepatology (2019), doi: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Tofacitinib: A jak of all trades Kristin E Burke 1, Ashwin N Ananthakrishnan 1 Word count: 1,427 1 Division of Gastroenterology, Massachusetts General Hospital Conflicts of Interest: A.N.A is supported by funding from the US National Institutes of Health, Crohn s and Colitis Foundation, Pfizer, and the Chleck Family Foundation. Correspondence: Ashwin N Ananthakrishnan, MD, MPH Massachusetts General Hospital Crohn s and Colitis center 165 Cambridge Street, 9 th Floor Boston, MA Phone: Fax: aananthakrishnan@mgh.harvard.edu 1

3 Inflammatory bowel diseases affect an estimated 2 million individuals in the United States and lead to considerably morbidity. 1, 2 Fortunately, over the past two decades, our options to effectively treat them have expanded with the availability of biologic therapy, including monoclonal antibodies to tumor necrosis factor α, anti-integrins, and anti-interleukin 12/23 antibody therapy. Together, these biologics improved our ability to heal the intestine and restore normal quality of life. 3-5 However, two important limitations of these biologics include a need for parenteral administration and immunogenicity. Most biologics elicit production of anti-drug antibodies which are associated with increased drug clearance, and reduced efficacy and durability of treatment. An alternate promising avenue of therapy has been small molecule inhibitors of various inflammatory signaling pathways. The first such drug approved for the treatment of ulcerative colitis (UC) is tofacitinib, a non-selective inhibitor of janus kinase (JAK) enzymes 1, 2, and 3. 6 In May 2018, it was approved by the Food and Drug Administration for treatment of moderate to severely active ulcerative colitis and has been a welcome addition, with the benefits of oral administration and lack of immunogenicity. Three publications in this issue of Clinical Gastroenterology and Hepatology highlight the safety and potential novel uses of this drug. Sandborn et al. present an integrated safety analysis of tofacitinib in the phase 2 (induction) and phase 3 (induction and maintenance) trials and the open-label long-term extension studies 7. The analysis included 1,157 patients, contributing 1,613 person- years with a median treatment duration of 1.4 years (range years). Over three-quarters of the cohort received 10mg BID of tofacitinib. Overall adverse events (AE), serious AE, and treatment discontinuation due to AE were similar across all three treatment groups. Serious infections were infrequent but were more common with tofacitinib (0.9%) than placebo (0%) (incidence ratio 2

4 2.0, 95% CI ). Importantly, there was a dose dependent increase in risk of herpes zoster (HZ) which occurred at a frequency of 0.5% in placebo compared to 1.5% with tofacitinib 5mg BID and 5% with 10mg BID. This is consistent with prior observations from the tofacitinib trials in IBD and rheumatoid arthritis, the latter of which showed a further increase in risk when tofacitinib was combined with other immunosuppressive agents. 8 One mechanism proposed for the increase in risk observed with tofacitinib and other non-selective JAK inhibitors has been disruption of JAK-STAT signaling and production of type I and type II interferons important for suppressing viral reactivation 9. Elevations were also noted in both the LDL and HDL components of the lipid panel, but there was no alteration in the HDL/LDL ratio and cardiac events were very infrequent and unrelated to drug. Thus, while the overall safety signals are reassuring, the increased risk of HZ infection is an important take-away for practicing clinicians. Patients with IBD are at a higher risk for HZ when compared to healthy controls In an analysis from Korea, patients with IBD aged 50 years had a similar absolute risk of HZ as healthy individuals at 60 years of age. 11 Additional risk factors for HZ are older age, non-white race, and immunosuppression particularly with corticosteroids. 8, 12, 13 Studies have reported inadequate rates of vaccination against HZ in patients with IBD with only one-fifth of patients eligible for vaccination (age > 60 years) receiving the vaccine 14. Vaccination significantly reduces the risk of HZ from 7 events/1000 person-years to 4/1000 person-years 15. Thus far, availability of only a live-attenuated HZ vaccine (Zostavax ), contraindicated during or while anticipating immunosuppression, limited wider use. Fortunately, with the introduction of the inactivated recombinant zoster vaccine (RZV) (Shingrix ), we now have the tools to more effectively attenuate the risk of HZ in IBD patients, particularly in the context of initiating 3

5 tofacitinib. Differing from the live-attenuated version, RZV is administered as two intramuscular doses 2 to 6 months apart and has a greater than 90% efficacy in reducing shingles with a sustained efficacy over a 4-year follow-up. 16 The Advisory Committee on Immunization Practice (ACIP) recommends vaccination with RZV in all adults 50 years and older (irrespective of prior receipt of varicella vaccine, history of chicken pox or the live-vaccine), and in patients with a prior history of herpes zoster, chronic medical conditions, and patients on low-dose immunosuppression the latter two of which would include the sizeable majority of patients with IBD. Whether routine vaccination is indicated in all patients initiating tofacitinib in unclear, but certainly those age 50 and older should receive vaccination and consideration should be given in younger individuals with other risk factors for HZ. Newer, selective JAK inhibitors that are on the horizon may not be associated with increased HZ risk and may thus represent safer options however, results of larger ongoing trials are awaited. Two research correspondences in this issue of CGH also present intriguing novel indications for tofacitinib in patients with IBD. Berinstein and colleagues present a case series describing the use of tofacitinib in the management of acute severe ulcerative colitis (ASUC) 17. Treatment of this highly morbid complication of UC has relied on the use of corticosteroids, infliximab, or cyclosporine for nearly two decades with no effective new options and no secular improvement in rates of therapy failure or need for surgery. This case series describes 4 patients with ASUC who were deemed to be at high risk of failing corticosteroid monotherapy based on Truelove and Witts criteria on presentation. All 4 patients received 10mg TID of tofacitinib for 9 doses. Three patients also received concomitant intravenous (IV) steroid therapy. Of these, three patients were able to avoid colectomy during the index hospitalization. One patient who required 4

6 surgery for medical failure remained symptomatic after 7 days of IV steroids prior to receiving tofacitinib. Only two patients remained on tofacitinib long-term. Recent analysis of the Phase 3 trial data demonstrated that an improvement in clinical symptoms could be discerned as early as 3-7 days after initiation of tofacitinib. 18 With that background, this novel use of tofacitinib is intriguing. However, there are key obvious limitations to this case series. Three of four included patients had not actually failed steroid therapy and were only classified as likely to fail (though this projected probability ranged from 10-85%). As 3 patients received concomitant steroids, whether the improvement can be attributed to tofacitinib or steroids (or possibly both) cannot be determined. In addition, only 2 remained on tofacitinib for maintenance and thus medium- and long-term benefit may actually be from other maintenance medications. The above limitations notwithstanding, this study inspires a line of future investigation. If (a big IF ) the benefit of tofacitinib in this clinical setting can be confirmed in other studies, it has the potential to change how we manage patients with UC. Rather than the traditional model of assessing response after 3-7 days of IV steroid therapy, one can consider initiating tofacitinib upfront on day 1 in patients, allowing the attractive option of an oral maintenance agent that can be continued upon discharge from the hospital. In the interim, given the proven efficacy of infliximab and cyclosporine for steroid refractory ulcerative colitis, these should remain the first-line therapies for steroid-failure in ASUC. Tofacitinib also cannot be recommended as a third-line salvage in patients who have already failed rescue therapy due to the concern for risk of infections and serious morbidity. 19 At this time, given the exceedingly limited data and the number of unanswered questions about the robustness of efficacy, use of tofacitinib in ASUC should be encouraged only in selected patients, and preferably in the context of a research study or clinical trial. 5

7 The second research correspondence is a series of 3 patients by Kochar et al. with refractory pyoderma gangrenosum 20. All 3 patients had failed biologic therapy and intralesional corticosteroids and were initiated on tofacitinib for arthritis symptoms (5mg BID) in addition to the pyoderma. All 3 patients responded; 2 healed, and 1 patient required a dose increase to 10mg BID. Immunochemistry staining from biopsies of two patients demonstrated strong staining of various phosphorylated JAK/STAT molecules. This was the first report of using tofacitinib to treat pyoderma and is a useful option to consider in patients failing biologic therapies. In summary, tofacitinib is a welcome addition to our options to manage patients with moderate to severe UC. However, clinicians should be aware of the specific safety risks this may pose and optimize health maintenance, particularly monitoring lipid levels and vaccinating against HZ. While there may be novel uses of tofacitinib beyond the approved indications and patient settings, this should be examined carefully in research settings, ideally with comparator groups and denominators to truly define the magnitude of benefit. Stay tuned! References 1. Fumery M, Singh S, Dulai PS, et al. Natural History of Adult Ulcerative Colitis in Population-based Cohorts: A Systematic Review. Clin Gastroenterol Hepatol 2018;16: e3. 2. Dahlhamer JM, Zammitti EP, Ward BW, et al. Prevalence of Inflammatory Bowel Disease Among Adults Aged >/=18 Years - United States, MMWR Morb Mortal Wkly Rep 2016;65: Beaugerie L, Kirchgesner J. Balancing Benefit vs Risk of Immunosuppressive Therapy for Individual Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol Ma C, Panaccione R, Fedorak RN, et al. Heterogeneity in Definitions of Endpoints for Clinical Trials of Ulcerative Colitis: A Systematic Review for Development of a Core Outcome Set. Clin Gastroenterol Hepatol 2018;16: e13. 6

8 5. Narula N, Alshahrani AA, Yuan Y, et al. Patient-Reported Outcomes and Endoscopic Appearance of Ulcerative Colitis: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med 2017;376: Sandborn WJ, Panes J, D'Haens GR, et al. Safety of Tofacitinib for Treatment of Ulcerative Colitis, Based on 4.4 Years of Data From Global Clinical Trials. Clin Gastroenterol Hepatol Winthrop KL, Curtis JR, Lindsey S, et al. Herpes Zoster and Tofacitinib: Clinical Outcomes and the Risk of Concomitant Therapy. Arthritis Rheumatol 2017;69: Colombel JF. Herpes Zoster in Patients Receiving JAK Inhibitors For Ulcerative Colitis: Mechanism, Epidemiology, Management, and Prevention. Inflamm Bowel Dis 2018;24: Khan N, Patel D, Trivedi C, et al. Overall and Comparative Risk of Herpes Zoster With Pharmacotherapy for Inflammatory Bowel Diseases: A Nationwide Cohort Study. Clin Gastroenterol Hepatol 2018;16: e Chang K, Lee HS, Kim YJ, et al. Increased Risk of Herpes Zoster Infection in Patients With Inflammatory Bowel Diseases in Korea. Clin Gastroenterol Hepatol 2018;16: e Long MD, Martin C, Sandler RS, et al. Increased risk of herpes zoster among patients with inflammatory bowel disease. Aliment Pharmacol Ther 2013;37: Gupta G, Lautenbach E, Lewis JD. Incidence and risk factors for herpes zoster among patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2006;4: Khan N, Trivedi C, Kavani H, et al. Frequency of Herpes Zoster Vaccination Among Inflammatory Bowel Disease Patients. Inflamm Bowel Dis Khan N, Trivedi C, Kavani H, et al. Efficacy of Live Attenuated Herpes Zoster Vaccine in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med 2015;372: Berinstein JA, Steiner CA, Regal RE, et al. Efficacy of Induction Therapy with Highintensity Tofacitinib in 4 Patients with Acute Severe Ulcerative Colitis. Clin Gastroenterol Hepatol Hanauer S, Panaccione R, Danese S, et al. Tofacitinib Induction Therapy Reduces Symptoms Within 3 Days for Patients With Ulcerative Colitis. Clin Gastroenterol Hepatol 2019;17: Narula N, Fine M, Colombel JF, et al. Systematic Review: Sequential Rescue Therapy in Severe Ulcerative Colitis: Do the Benefits Outweigh the Risks? Inflamm Bowel Dis 2015;21: Kochar B, Herfarth N, Mamie C, et al. Tofacitinib for the Treatment of Pyoderma Gangrenosum. Clin Gastroenterol Hepatol