BJD C L I NI C A L T R IA L British Journal of Dermatology Benefit–risk profile of tofacitinib in patients with moderate- to-severe chronic plaque psoriasis: pooled analysis across six clinical trials* B.E. Strober iD ,1,2 A.B. Gottlieb,3 P.C.M. van de Kerkhof,4 L. Puig iD ,5 H. Bachelez,6 E. Chouela,7 S. Imafuku,8 D. Thacßi,9 H. Tan,10 H. Valdez,10 P. Gupta,10 M. Kaur,11 V. Frajzyngier12 and R. Wolk10 1 Department of Dermatology, University of Connecticut Health Center, Farmington, CT, U.S.A. 2 Probity Medical Research, Waterloo, ON, Canada 3 New York Medical College at Metropolitan Hospital, New York, NY, U.S.A. 4 Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands 5 Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona Medical School, Barcelona, Spain 6 Sorbonne Paris Cite Universite Paris Diderot, Assistance Publique-H^opitaux de Paris, Service de Dermatologie, H^opital Saint-Louis, Paris, France 7 Universidad de Buenos Aires, Buenos Aires, Argentina 8 Department of Dermatology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan 9 Comprehensive Center for Inflammation Medicine, University Hospital Schleswig-Holstein, Campus L€ubeck, L€ubeck, Germany 10 Pfizer Inc., Groton, CT, U.S.A. 11 Pfizer Inc., Collegeville, PA, U.S.A. 12 Pfizer Inc., New York, NY, U.S.A. Linked Comment: Fleming. Br J Dermatol 2019; 180:13–14. Summary Correspondence Background Although existing psoriasis treatments are effective and well tolerated Robert Wolk. in many patients, there is still a need for new effective targeted treatment E-mail: robert.wolk@pfizer.com options. Tofacitinib is an oral Janus kinase inhibitor that has been investigated in patients with moderate-to-severe chronic plaque psoriasis. Accepted for publication 22 July 2018 Objectives To consider the benefits and risks of tofacitinib in patients with moder- ate-to-severe psoriasis. Funding sources Methods Data were pooled from one phase II, four phase III and one long-term exten- This study was funded by Pfizer Inc. sion study comprising 5204 patient-years of tofacitinib treatment. Efficacy end points included patients achieving Physician’s Global Assessments of ‘clear’ or ‘almost clear’, Conflicts of interest ≥ 75% and ≥ 90% reduction in Psoriasis Area and Severity Index (coprimary end Conflicts of interest statements can be found in the Appendix. points) and improvements in Dermatology Life Quality Index score, Hospital Anxiety and Depression Scale depression score and Itch Severity Item score, at weeks 16 and *Plain language summary available online 52. Safety data were summarized for 3 years of tofacitinib exposure. Results Tofacitinib 5 and 10 mg twice daily (BID) showed superiority over placebo DOI 10.1111/bjd.17149 for all efficacy end points at week 16, with response maintained for 52 weeks of continued treatment. Tofacitinib improved patients’ quality of life and was well tol- erated. Rates of safety events of interest (except herpes zoster) were similar to those in the published literature and healthcare databases for other systemic psoriasis therapies. Tofacitinib 10 mg BID demonstrated greater efficacy than 5 mg BID. Conclusions Tofacitinib has a benefit–risk profile in moderate-to-severe psoriasis consistent with that of other systemic treatments. What’s already known about this topic? • Psoriasis is a chronic, systemic inflammatory disease, which has a significant impact on patients’ health-related quality of life. © 2018 The Authors. British Journal of Dermatology British Journal of Dermatology (2019) 180, pp67–75 67 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 68 Tofacitinib benefit–risk profile in chronic plaque psoriasis, B.E. Strober et al. • Although several existing psoriasis treatments are efficacious and well tolerated in many patients, some patients require treatment switching, and a proportion of patients remain untreated or undertreated. • Potential challenges to the use of existing therapies include safety issues and lim- ited efficacy in some patients with conventional oral psoriasis treatments, incon- venience of topical treatments and the requirement for parenteral administration of biologics. What does this study add? • Consistent efficacy and a safety profile consistent with that seen in rheumatoid arthritis, psoriatic arthritis and ulcerative colitis were demonstrated for oral tofacitinib in patients with moderate-to-severe psoriasis. • Tofacitinib has a benefit–risk profile in patients with moderate-to-severe psoriasis that is consistent with that of other systemic psoriasis treatments. Psoriasis is a chronic, systemic inflammatory disease with a glo- Efficacy end points bal prevalence in the range of 1–3%.1–3 Several treatments are available for psoriasis that are effective and well tolerated in The main efficacy end points for the current analyses were the many patients.4,5 However, conventional systemic therapies are proportion of patients achieving Physician’s Global Assessment associated with limited efficacy in some patients,4 clinical (PGA) ratings of ‘clear’ or ‘almost clear’ and the proportion of response to biologics can decrease over time,6 and both types of patients achieving ≥ 75% reduction in Psoriasis Area and drugs have recognized safety issues.7,8 Consequently, some Severity Index (PASI 75) at weeks 16 and 52 of treatment patients with psoriasis switch between multiple treatments over (these were the coprimary end points at week 16 in the OPT their lifetime, and a significant proportion of patients remain Pivotal 1 and 2 studies). Other efficacy end points included untreated or undertreated.9 the proportions of patients achieving PASI 90; a score of ≤ 1 The treatment satisfaction of patients with psoriasis has on the Dermatology Life Quality Index (DLQI), indicating no been reported to be poor, but it is generally higher with bio- effect of skin disease on the patient’s life;20 a score of ≤ 1 on logical agents than with traditional therapies,9–11 due to the the Itch Severity Item (ISI), equating to ‘little or no itch’;21 a better efficacy of biologics.10,11 However, patients generally depression score of < 8 on the Hospital Anxiety and Depres- prefer oral to parenteral treatments.12 sion Scale (HADS), indicating no symptoms of depression;22 Tofacitinib is a Janus kinase inhibitor. In contrast to cur- ≥ 75% reduction in the Nail Psoriasis Severity Index (NAPSI rent biological therapies, tofacitinib is administered orally. 75) in patients with nail psoriasis at baseline; and change This analysis aimed to assess the benefit–risk profile of from baseline in body surface area affected by psoriasis. tofacitinib in patients with moderate-to-severe chronic plaque psoriasis by pooling the data from six clinical Safety end points trials.13–18 The incidence rates (IRs; numbers of patients with events per 100 patient-years) of serious infections, opportunistic infec- Patients and methods tions, herpes zoster, major adverse cardiovascular events (MACE), malignancy excluding nonmelanoma skin cancer Study design (NMSC), and NMSC were assessed. Treated infections that These analyses were based on pooled data from one phase II required parenteral antimicrobial therapy, required hospitaliza- double-blind randomized controlled trial (ClinicalTrials.gov tion or met other criteria that required the infection to be identifier NCT00678210),18 four phase III double-blind ran- reported as a serious adverse event (AE) were considered a domized controlled trials (collectively referred to as the index serious infection. Opportunistic infections, defined as infec- studies) (OPT Pivotal 1, NCT01276639;15 OPT Pivotal 2, tions that occur more frequently in immunocompromised NCT01309737;15 OPT Compare, NCT01241591;14 OPT individuals, also included disseminated herpes zoster and her- Retreatment, NCT01186744)13 and one open-label long-term pes zoster affecting nonadjacent or more than two adjacent extension study (NCT01163253).19 Further details of the study dermatomes. MACE was defined as the occurrence of a designs and treatments are provided in Table S1 (see Supporting myocardial infarction, cerebrovascular event or cardiovascular Information). death. Independent adjudication committees, blinded to British Journal of Dermatology (2019) 180, pp67–75 © 2018 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists. Tofacitinib benefit–risk profile in chronic plaque psoriasis, B.E. Strober et al. 69 treatment assignment, reviewed all potential opportunistic infections and all cardiovascular events. Results Patients Statistical analysis For efficacy analyses, 745, 741 and 373 patients were included who received tofacitinib 5 mg BID, tofacitinib Efficacy data 10 mg BID and placebo, respectively, in OPT Pivotal 1 and 2. Data from OPT Pivotal 1 and OPT Pivotal 2, up to week 52, The patient demographics and baseline disease characteristics were pooled for the efficacy analyses. The full analysis set have previously been reported for these patients and were bal- included all patients who were randomized and received at anced between the treatment groups.15 least one dose of study drug in either Pivotal study. For safety analyses during the 16-week placebo-controlled For dichotomized data, missing observations were set to period, the numbers of patients receiving at least one dose of nonresponders unless otherwise stated. The Cochran–Mantel– tofacitinib 5 mg BID, tofacitinib 10 mg BID and placebo were Haenszel approach to adjust the study effect was used to esti- 1123 (299 patient-years of exposure), 1120 (302 patient-years) mate the treatment difference among treatment groups at and 530 (136 patient-years), respectively. For safety analyses week 16 (before placebo-treated patients advanced to over 1 year, 1217 (801 patient-years) and 1219 (869 patient- tofacitinib). Statistical testing was based on normal approxima- years) patients received at least one dose of tofacitinib 5 mg and tion to the binomial proportions. No statistical analyses were 10 mg BID, respectively. For analyses of safety across all applied to data beyond week 16. tofacitinib-treated patients up to 3 years, 3623 patients were included (5204 patient-years of exposure), and 2915, 2362, 995 and 55 patients had received treatment with tofacitinib for Safety data at least 6 months, 1 year, 2 years and 3 years, respectively. Data from patients who received at least one dose of The demographic and other baseline characteristics for all tofacitinib, including all events through to 4 April 2014 tofacitinib-treated patients are shown in Table S3 (see Sup- (interim data for the long-term extension study), were consid- porting Information). The median DLQI score was 11, indicat- ered for the safety analyses. ing a very large effect of psoriasis on the patients’ quality of Safety data from the phase II and III studies were summa- life.23 rized for tofacitinib 5 mg and 10 mg twice daily (BID) over 16 weeks (vs. placebo) and over 1 year (no placebo arm; for Efficacy patients initially receiving placebo then advanced to tofacitinib at week 16, the data after week 16 were included). Safety data Based on pooled data from the OPT Pivotal 1 and 2 studies, were also summarized for combined tofacitinib exposure for significantly greater proportions of patients receiving up to 3 years in the index and long-term extension studies. tofacitinib 5 mg or 10 mg BID vs. placebo achieved a PGA of Total tofacitinib exposure data are presented for patients who ‘clear’ or ‘almost clear’ (440%, 591% and 100%, respec- received tofacitinib 10 mg BID for ≥ 80% of their study dura- tively; P < 0001) and PASI 75 (431%, 594% and 89%, tion (10-mg BID group) and for pooled tofacitinib doses respectively; P < 0001) at week 16 (Fig. 1a, b). Further (tofacitinib all). For patients who switched from placebo or improvements were seen with both tofacitinib doses up to etanercept to tofacitinib, a new baseline was established, with week 28. At week 52, ≥ 57% of patients who achieved a PGA the first day of tofacitinib treatment considered as day 1. response at week 16 and ≥ 66% of patients who achieved PASI To contextualize IRs for safety events, a systematic review 75 at week 16 maintained that response. of published randomized clinical trials and observational stud- The more stringent efficacy thresholds of PASI 90 and ies reporting AEs with other psoriasis treatments was under- NAPSI 75 were also achieved in more patients receiving tofaci- taken (Appendix S1 and Table S2; see Supporting tinib 5 mg or 10 mg BID than placebo at week 16 (PASI 90: Information). Additionally, data from the six tofacitinib clini- 222%, 391% and 30%, respectively; P < 0001; NAPSI 75: cal trials were benchmarked against two Pfizer-commissioned 169%, 281% and 68%, respectively; P < 0001) (Fig. 1c, comparison cohorts of patients with moderate-to-severe psori- d). At week 52, ≥ 65% of those who achieved PASI 90 at asis, derived from U.S. Medicare and Kaiser Permanente week 16 maintained that response. Northern California (KPNC) databases (Appendix S1). At week 16, a DLQI total score ≤ 1 and an ISI score ≤ 1 All clinical studies were conducted in compliance with the were achieved in significantly more patients receiving ethical principles originating in or derived from the Declara- tofacitinib 5 mg or 10 mg BID (DLQI: 277% and 443%, tion of Helsinki and with the International Council for Har- respectively; ISI: 430% and 609%, respectively) than placebo monisation Good Clinical Practice Guidelines. All (DLQI: 53%; ISI: 105%; P < 0001) (Fig. 1e, f). The propor- documentation was reviewed by the institutional review board tions of patients achieving a DLQI total score ≤ 1, and an ISI and/or independent ethics committee at each of the investiga- score ≤ 1 continued to increase to week 28. Of those patients tional centres. All patients provided written informed consent. who had a HADS depression score indicative of depression © 2018 The Authors. British Journal of Dermatology British Journal of Dermatology (2019) 180, pp67–75 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists. 70 Tofacitinib benefit–risk profile in chronic plaque psoriasis, B.E. Strober et al. Fig 1. Proportions of patients (mean  SE) achieving (a) Physician’s Global Assessment (PGA) response of ‘clear’ or ‘almost clear’, (b) ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75), (c) PASI 90, (d) ≥ 75% improvement in Nail Psoriasis Severity Index (NAPSI 75), (e) Dermatology Life Quality Index (DLQI) response and (f) Itch Severity Item (ISI) response (full analysis set, nonresponder imputation). aOf those patients with nail psoriasis at baseline, bof those patients with baseline DLQI > 1, cof those patients with baseline ISI > 1. **P < 00001 tofacitinib vs. placebo; ††P < 00001 tofacitinib 10 mg twice daily (BID) vs. tofacitinib 5 mg BID. P-values are shown at week 16 only (the time at which the main efficacy end points were collected across the various studies). (≥ 8) at baseline, a higher proportion receiving tofacitinib 5 showed greater efficacy than 5 mg BID in all subgroups, and mg BID (524%) or 10 mg BID (616%) compared with pla- the overall efficacy was lower in patients with baseline PASI cebo (358%) had a HADS depression score indicating they < 20, prior experience of systemic treatment and bodyweight were not depressed (< 8) at week 16 (Fig. S1; see Supporting ≥ 90 kg at baseline (Table 1). Information). Tofacitinib was efficacious in subgroups of patients with Safety moderate or severe disease, who had previous experience of systemic treatment or were systemic treatment naive, and who Safety data from patients with psoriasis receiving 16 weeks of had lower or higher bodyweight. Tofacitinib 10 mg BID treatment with tofacitinib 5 mg and 10 mg BID vs. placebo British Journal of Dermatology (2019) 180, pp67–75 © 2018 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists. Tofacitinib benefit–risk profile in chronic plaque psoriasis, B.E. Strober et al. 71 Table 1 Proportions of patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) with tofacitinib 10 mg twice daily (BID) vs. tofacitinib 5 mg BID by subgroup (full analysis set, nonresponder imputation) Week 16 Week 52 Tofacitinib 5 mg Tofacitinib 10 mg Tofacitinib 5 mg Tofacitinib 10 mg BID (n = 739) BID (n = 734) BID (n = 739) BID (n = 734) Baseline PASI < 20 386 (337–436) 571 (520–622) 365 (316–414) 497 (446–549) ≥ 20 475 (425–526) 617 (568–667) 444 (393–494) 541 (500–592) Previous systemic treatment No 570 (506–633) 700 (645–756) 542 (479–606) 642 (584–701) Yes 364 (322–406) 536 (491–581) 340 (299–381) 452 (407–496) Baseline weight < 90 kg 460 (413–508) 627 (580–673) 450 (402–497) 564 (517–612) ≥ 90 kg 391 (337–445) 551 (496–606) 343 (290–396) 459 (404–514) Values are the percentage (95% confidence interval). have been previously reported.15 During the placebo-con- The IR of malignancies excluding NMSC was similar between trolled period, AEs were reported in 606 (540%) patients patients receiving tofacitinib 5 mg and 10 mg BID. The IRs who received tofacitinib 5 mg BID, 660 (589%) who (95% CIs) for total exposure were 097 (064–140) and 100 received tofacitinib 10 mg BID and 267 (504%) who (075–131) for tofacitinib 10 mg BID and all tofacitinib doses, received placebo; 29 (26%), 35 (31%) and 26 (49%), respectively. No increase in the IR of malignancies excluding respectively, discontinued treatment due to AEs. NMSC was observed over time in patients treated with During 1 year of treatment with tofacitinib 5 mg and tofacitinib for up to 3 years. The IR of NMSC was higher in 10 mg BID, there were few dose-related differences in the IRs patients receiving tofacitinib 10 mg BID over 1 year compared for events of special interest. Although IRs for serious infec- with 5 mg BID (Table S4). The IRs (95% CIs) for total exposure tions, herpes zoster and NMSC were numerically greater with were 090 (058–133) and 074 (052–101) for tofacitinib 10 tofacitinib 10 mg BID than with 5 mg BID, the 95% mg BID and all tofacitinib doses, respectively. Of the adjudicated confidence intervals (CIs) overlapped (Table S4; see Support- cardiovascular events, 19 occurring in patients receiving tofaci- ing Information). tinib were considered to be MACE during the entire tofacitinib Across all tofacitinib-treated patients in the six clinical trials exposure, with no dose dependency observed over 1 year included in this analysis, the most frequently observed serious (Table S4). The IRs (95% CIs) for MACE over the total tofaci- infections were pneumonia (n = 16, 04%), herpes zoster tinib exposure were 032 (015–061) and 037 (022–057) (n = 8, 02%) and appendicitis (n = 7, 02%). There was no for tofacitinib 10 mg BID and all tofacitinib doses, respectively. association between the occurrence of serious infections and During the placebo-controlled phases of the psoriasis clinical cases of confirmed neutropenia or lymphopenia. Opportunistic trials analysed in this study, the IR of death for patients receiving infections were infrequent, with 12 infections adjudicated to tofacitinib was low and comparable with that observed in the be opportunistic, and no dose dependency was observed. Nine placebo treatment groups. Across all studies, there was a total of herpes zoster events, reported in eight of the 130 patients 10 deaths up to 30 days after discontinuation of tofacitinib, with herpes zoster (6%), were adjudicated to be opportunistic with an IR of 019 (95% CI 009–035). By comparison, there infections. Other opportunistic infections were listeria was one death in a patient receiving placebo (IR 073, 95% CI encephalitis, fungal pneumonia, herpes simplex meningitis 002–409) and no deaths reported in patients receiving etaner- and cryptococcal pneumonia, each reported in one patient, cept. Of note, only 335 patients received etanercept for up to and all of which resolved on anti-infective treatment. 12 weeks (747 patient-years of exposure) and only 530 Of the 130 cases of herpes zoster, > 90% were classified as patients received placebo for 12–16 weeks (136 patient-years of mild or moderate in severity. Most cases of herpes zoster exposure). Causes of death in patients receiving tofacitinib resolved with antiviral therapy without complication; eight included myocardial infarction (n = 4), cardiac arrest (n = 2), patients discontinued due to herpes zoster. Postherpetic neu- acute respiratory distress syndrome (n = 1), lung cancer (n = 1), ralgia (PHN) was reported by 10 (8%) of the tofacitinib-trea- hepatic failure (n = 1) and road traffic accident (n = 1). ted patients with herpes zoster, equating to 03% of all the Changes were seen in some laboratory parameters in tofacitinib-treated patients and an IR of 019 per 100 patient- patients receiving tofacitinib.13–15 Small, dose-dependent years. A higher IR for herpes zoster was observed in Asian decreases in haemoglobin, stable after 3 months of treatment (particularly Japanese) patients with psoriasis receiving and reversible on treatment withdrawal, were observed. Across tofacitinib: the IR (95% CI) over the total tofacitinib exposure all tofacitinib-treated patients in the six studies, the mean  for Asian patients was 575 (365–863), compared with 255 SE change from baseline to the last observation in haemoglo- (213–303) for the global population. bin levels was 034  002 g dL 1. Small mean decreases in © 2018 The Authors. British Journal of Dermatology British Journal of Dermatology (2019) 180, pp67–75 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists. 72 Tofacitinib benefit–risk profile in chronic plaque psoriasis, B.E. Strober et al. neutrophil counts were observed at week 4, gradually revert- term use are needed. The efficacy of tofacitinib in patients ing back towards baseline values after week 8, and generally with moderate-to-severe psoriasis has been demonstrated in stabilizing after month 4. Increases in lymphocyte counts were the extensive clinical development programme, with improve- seen at week 4, persisting through week 8, followed by slight ments observed for all clinical end points and quality of life. decreases through month 24. Across all tofacitinib-treated Together with safety data from 5204 patient-years of exposure patients, the mean change from baseline to the last observa- to tofacitinib, these findings suggest a benefit–risk profile for tion in neutrophil count was 004 9 109 cells L 1, and in tofacitinib in psoriasis that is consistent with those of other lymphocyte count it was 018 9 109 cells L 1. systemic treatments. Small, nonprogressive increases occurred in mean total Significant differences for tofacitinib vs. placebo were seen cholesterol, high-density lipoprotein (HDL) cholesterol, low- for all efficacy end points at week 16. A loss of efficacy was density lipoprotein (LDL) cholesterol and triglycerides, but seen in some patients after 28 weeks; the mechanism of action total : HDL cholesterol or LDL : HDL cholesterol ratios were for this is unknown, and a clinical response is maintained in unaffected. Across all tofacitinib-treated patients, the mean  many patients for up to 2 years.19 Improvements in nail psori- SE percentage changes from baseline to the last observation asis (reported to be nonresponsive to traditional psoriasis were 99  035% for total cholesterol, 120  057% for treatments),24,25 relief of itch within 2 days of treatment,14 LDL cholesterol, 125  040% for HDL cholesterol and 146 sustained improvements in quality of life, and improvements  113% for triglycerides. Small, dose-dependent median (in- in the HADS depression score were seen with both tofacitinib terquartile range) increases in aspartate aminotransferase doses. Tofacitinib 5 mg BID has consistently demonstrated (AST) and alanine aminotransferase (ALT) levels were superior efficacy to placebo, and tofacitinib 10 mg BID has observed over 1 year of treatment: 25 IU L 1 ( 10 to 70) shown additional efficacy compared with 5 mg BID.13–15 for AST and 20 IU L 1 ( 20 to 90) for ALT in the tofaci- Based on the results of OPT Compare (NCT01241591), tinib 5 mg BID group, and 30 IU L 1 ( 10 to 90) for AST tofacitinib 10 mg BID had similar efficacy to etanercept and 30 IU L 1 ( 30 to 110) for ALT in the tofacitinib 10 50 mg twice weekly (PASI 75: 636% and 585%, respec- mg BID group; they did not increase further on longer expo- tively; PGA response: 682% and 663%, respectively), sure. There were no confirmed cases of Hy’s law or drug- whereas 5 mg BID did not meet the noninferiority criteria induced liver injury. (PASI 75: 395%; PGA response: 471%).14 A meta-analysis IRs of safety events reported in published randomized con- conducted by Pfizer has shown the efficacy of tofacitinib 5 mg trolled trials and observational studies, and those reported in BID to be similar to those of oral methotrexate and etanercept the Pfizer-commissioned comparison cohorts (Medicare and 25 mg twice weekly, and numerically higher than with the KPNC) for other systemic psoriasis treatments, are summarized oral psoriasis therapies acitretin and apremilast.26 The meta- in Table 2, alongside data from the tofacitinib clinical pro- analysis also showed the efficacy of tofacitinib 10 mg BID to gramme. Detailed results are given in Figure S2 (see Support- be in the range of those of injectable tumour necrosis factor ing Information). antagonists (currently the most widely prescribed biological drugs for psoriasis), similar to that of ciclosporin, and greater than those of other oral treatments (apremilast, acitretin, oral Discussion methotrexate and fumarates).26,27 Despite a range of biological treatment options being available Tofacitinib demonstrated efficacy in subgroups defined by for plaque psoriasis, orally administered agents with clinically baseline PASI score, prior systemic treatment and bodyweight. meaningful efficacy and an acceptable safety profile with long- Lower efficacy was seen in patients with PASI baseline score Table 2 Incidence rate ranges (events per 100 patient-years) for safety events of interest reported in randomized controlled trials, observational studies, Pfizer-commissioned comparison cohorts (Medicare, KPNC) and the tofacitinib clinical trials Published Published Medicare comparison KPNC comparison Tofacitinib RCTsa observational studies cohort cohort allb Serious infections 0–455 083–262 NA 151–217 168 Herpes zoster 475 000–323 111–143 086–103 255 Malignancies (excluding NMSC) 0–769 054–29 050–129 075–115 100 NMSC 0–208 007–189 224–536 114–124 074 MACE 0–116 036–445c NA NA 037 KPNC, Kaiser Permanente Northern California; MACE, major adverse cardiovascular events; NA, not available; NMSC, nonmelanoma skin can- cer. aPublished randomized controlled trial (RCT) data refer to data from the full duration (typically 1 year) of clinical trials of agents other than tofacitinib (secukinumab, ustekinumab, adalimumab, etanercept, infliximab, apremilast and oral methotrexate); they do not include data from long-term extension phases. bIncludes data for combined tofacitinib exposure for up to 3 years in the index and long-term extension studies. cRange cited is for rates where definition of MACE included any death. When cardiovascular death only was included, the upper bound was 222 rather than 445 events per 100 patient-years. British Journal of Dermatology (2019) 180, pp67–75 © 2018 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists. Tofacitinib benefit–risk profile in chronic plaque psoriasis, B.E. Strober et al. 73 < 20, higher bodyweight and prior systemic treatment, as has The authors acknowledge some limitations of this study. been observed with biological therapy.28,29 The study included data from clinical trials, and the selection Tofacitinib 5 mg BID and 10 mg BID were generally well criteria for the trials were such that the study populations may tolerated, and safety events were similar to those reported not fully reflect the characteristics of patients seen in everyday with tofacitinib in rheumatoid arthritis, ulcerative colitis and clinical practice. The clinical trials included limited numbers psoriatic arthritis.30–34 Only one study is available comparing of patients and involved relatively short follow-up periods tofacitinib head to head with another psoriasis treatment,14 compared with the time course of a chronic disease like psori- and comparisons between treatments must therefore be inter- asis, and therefore estimates of rare safety events, such as preted cautiously. However, comparisons with data from pub- malignancies, may be less reliable than when long-term data lished studies and Pfizer-commissioned comparison cohorts are available. demonstrate that, with the exception of herpes zoster, rates of As psoriasis is a chronic disease, often occurring from an key safety events in the tofacitinib clinical trials analysed fall early age, over their lifetimes most patients will receive multi- within the range of rates for the same events across a range of ple therapies, with some not responding well to any; there is systemic psoriasis therapies. IRs for herpes zoster were gener- therefore an unmet need for new and effective treatment ally higher in the tofacitinib clinical trials in the comparison options with acceptable safety profiles. While the efficacy of cohorts, although there was some overlap in the CIs around tofacitinib is somewhat lower than that of some biological estimates for tofacitinib and ustekinumab in the Medicare psoriasis treatments, the efficacy of tofacitinib 10 mg BID is comparison cohort (Fig. S2d; see Supporting Information). comparable with that of etanercept 50 mg twice weekly.26 The rates were also higher than the majority of those in The safety profile of tofacitinib is generally comparable with published observational studies, but were lower than the esti- that of biologics, with the exception of the higher rates of her- mate for ustekinumab in one publication, and the 95% CIs pes zoster seen with tofacitinib. However, the parenteral admin- overlapped those around estimates for ciclosporin, infliximab, istration of biologics might be an issue for some patients. The oral methotrexate with biologics, acitretin with biologics and oral route of administration of tofacitinib is more convenient psoralen plus ultraviolet A (Fig. S2c; see Supporting Informa- and may be preferred by patients over subcutaneous injection or tion). The majority of cases of herpes zoster were nonserious, intravenous infusion;12,40,41 it also bypasses the risk of injec- were of mild or moderate severity and resolved on treatment. tion- or infusion-site-related AEs, one of the most frequently PHN was reported by 8% of patients receiving tofacitinib who reported AEs for biological therapies.42,43 experienced herpes zoster (IR for PHN: 02 per 100 patient- Overall, tofacitinib has a benefit–risk profile in patients with years); no published data on the rates of PHN in patients with moderate-to-severe plaque psoriasis consistent with those of psoriasis were found in the literature. other systemic psoriasis treatments, with significant improve- IRs of serious infections and herpes zoster were numerically ment in clinical signs and symptoms and an acceptable safety higher with tofacitinib 10 mg BID than with 5 mg BID; how- profile. ever, the IR of serious infections with tofacitinib 10 mg BID was below that reported in some observational studies for Acknowledgments tumour necrosis factor antagonists (Table S2), and the dose- dependent difference in the IR for herpes zoster was fairly The authors would like to thank Maryam Asgari and Charlie small (13%). Given the greater observed efficacy of the Quesenberry, principal investigators of the KPNC database higher dose of tofacitinib, the overall benefit–risk profile of cohort study, and Kevin Winthrop and Jeffrey Curtis, principal tofacitinib 10 mg BID is maintained and consistent with those investigators of the Medicare database cohort. This study was of other systemic treatments for moderate-to-severe psoriasis. supported by Pfizer Inc. Medical writing support under the In the global clinical studies in psoriasis, patients in Japan guidance of the authors was provided by Sandrine M. Dupre, were noted to show an increased incidence of herpes zoster PhD, and Carole Evans, PhD, at and on behalf of Complete compared with other patients, reflecting findings reported Medical Communications, Manchester, U.K., and was funded elsewhere.35 by Pfizer Inc., New York, NY, U.S.A., in accordance with the A number of changes in laboratory parameters were seen in Good Publication Practice (GPP3) guidelines.44 patients receiving tofacitinib in the psoriasis clinical trials analysed in this study, but they were reversible upon with- References drawal of tofacitinib. There were no indications that tofaci- tinib was associated with the safety issues that are seen with 1 Gelfand JM, Weinstein R, Porter SB et al. Prevalence and treatment oral methotrexate treatment, such as hepatic toxicity36–38 or of psoriasis in the United Kingdom: a population-based study. Arch Dermatol 2005; 141:1537–41. bone marrow suppression,37,39 or with the renal toxicity 2 Kurd SK, Gelfand JM. 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Patient preferences regarding Pharma, Lilly, MSD, Novartis, Pfizer Inc., Regeneron, Roche, rheumatoid arthritis therapies: a conjoint analysis. Am Health Drug Sandoz, Sanofi and Sun Pharma. H.B. has been an advisory Benefits 2016; 9:84–93. board member, speaker, consultant or investigator for AbbVie, 42 Farahnik B, Beroukhim K, Nakamura M et al. Anti-IL-17 agents for Amgen, Anaptysbio, Baxalta, Bayer, Boehringer Ingelheim, psoriasis: a review of phase III data. J Drugs Dermatol 2016; 15:311– 16. Celgene, Janssen, LEO Pharma, Lilly, MSD, Novartis, Pfizer 43 Sorenson E, Koo J. Evidence-based adverse effects of biologic Inc., Pierre Fabre, Sun Pharma and Takeda. E.C. has been a agents in the treatment of moderate-to-severe psoriasis: providing speaker, consultant or investigator for AbbVie, Galderma, Lilly, clarity to an opaque topic. J Dermatolog Treat 2015; 26:493–501. Merck, Novartis, Pfizer Inc. and Roche. S.I. has been a speaker 44 Battisti WP, Wager E, Baltzer L et al. Good Publication Practice for or consultant for AbbVie, Celgene, Janssen, Lilly, Maruho, communicating company-sponsored medical research: GPP3. Ann Novartis, Pfizer Inc. and Torii Yakuhin. D.T. has received Intern Med 2015; 163:461–4. research support from AbbVie, Almirall, Amgen, Astellas, Bio- gen Idec, Boehringer Ingelheim, Celgene, Dignity, Appendix GlaxoSmithKline, Janssen-Cilag, LEO Pharma, Lilly, MSD, Novartis, Pfizer Inc., Regeneron and Sandoz; has received Conflicts of interest: B.E.S. has been a consultant and advisory honoraria from AbbVie, Biogen Idec, Celgene, Janssen, LEO board member for AbbVie, Amgen, AstraZeneca, Boehringer Pharma, Novartis and Pfizer Inc.; has been a consultant for Ingelheim, Celgene, Cutanea-Maruho, Dermira, Janssen, LEO AbbVie, Celgene, Dignity, Galapagos, Novartis, Pfizer Inc. and Pharma, Lilly, Medac, Novartis, Pfizer Inc., Sun Pharma, UCB Xenoport; and has been on scientific advisory boards for Abb- and Valeant (honoraria for all); an investigator for AbbVie, Vie, Celgene, GlaxoSmithKline, Janssen, LEO Pharma, Lilly, Amgen, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Novartis, Pfizer Inc., Sandoz and Sanofi. H.T., H.V., P.G., V.F. Novartis, Janssen, Lilly, Merck, Pfizer Inc. and Sun Pharma and R.W. are employees and shareholders of Pfizer Inc. M.K. (payments to the University of Connecticut, not to B.E.S.) and was an employee of Pfizer Inc. at the time the studies were scientific director for the CORRONA Psoriasis Registry (con- conducted. sulting fee); and received grant support to the University of Connecticut for a fellowship programme from AbbVie and Supporting Information Janssen (payments to the University of Connecticut, not to B.E.S.). A.B.G. has been a consultant or advisory board mem- Additional Supporting Information may be found in the online ber for AbbVie, Aclaris, Actelion, Akros, Allergan, Amgen, version of this article at the publisher’s website: Amicus, Astellas, Baxalta, Beiersdorf, Bristol-Myers Squibb, Appendix S1 Contextualization of the findings. Canfite, Catabasis, Celgene, Centocor (Janssen), Coronado, Table S1 Details of the included studies. Crescendo Bioscience, CSL Behring Biotherapies for Life, Der- Table S2 Incidence rate (events per 100 patient-years) mipsor, Dermira, Genentech, GlaxoSmithKline, Incyte, Karyo- ranges reported in published randomized controlled trials. pharm, Kineta One, KPI Therapeutics, Lilly, Meiji Seika Table S3 Demographic and baseline characteristics of the Pharma Co., Mitsubishi Tanabe Pharma Development America, study patients (all studies). Novartis, Novo Nordisk, Pfizer Inc., Reddy Labs, Takeda, Table S4 Incidence rates (patients with events per 100 TEVA, UCB, Valeant, Vertex and Xenoport; and received patient-years) for safety events of interest in patients with pso- research or educational grants from Janssen Incyte. P.C.M.vdK. riasis treated with tofacitinib over 1 year in the phase III stud- has been a consultant for Abbott, Almirall, Amgen, Celgene, ies. Centocor, Galderma, Janssen-Cilag, LEO Pharma, Lilly, Mit- Fig S1. Proportions of patients with Hospital Anxiety and subishi, Novartis, Pfizer Inc., Philips and Sandoz; and an inves- Depression Scale (HADS) depression score < 8 at week 16 tigator for AbbVie, Amgen, Basilea, Janssen-Cilag, LEO among those with HADS depression score ≥ 8 at baseline. Pharma, Lilly, Pfizer Inc. and Philips. L.P. has been an advisory Fig S2. Incidence rates (events per 100 patient-years) in board member, speaker, consultant or investigator for AbbVie, observational studies and Pfizer-commissioned comparison Almirall, Amgen, Biogen, Boehringer Ingelheim, Janssen, LEO cohorts. © 2018 The Authors. British Journal of Dermatology British Journal of Dermatology (2019) 180, pp67–75 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.