Tofacitinib in the Treatment of Rheumatoid Arthritis and Chronic Plaque Psoriasis

Aditya K. Gupta, MD, PhD, FRCP(C)^1,2; Maria Cernea, PhD²; Charles W. Lynde, MD, FRCP(C)^1,3

¹University of Toronto Department of Medicine, Toronto, ON, Canada
²Mediprobe Research Inc., London, ON, Canada
³Lynde Institute for Dermatology, Markham, ON, Canada

Conflicts of Interest:
AKG has been a clinical trials investigator for Valeant Canada, Nuvolase, Bristol Meyers Squibb, Eli Lilly, Merck, Novartis, Janssen and Allergan. AKG has served as a speaker or consultant for Valeant Canada, Almirall, Janssen, Novartis, Sandoz, Moberg Pharma, and Bayer. CWL has been an investigator in clinical trials sponsored by Abbvie, Amgen, Boehringer Ingelheim, Celgene, Coherus, Dermira, Galderma, Innovaderm, Janssen, Eli Lilly, Leo Pharma, Merck, MSD, Medimmune, Novartis, Pfizer, Regeneron and Xoma. CWL has acted as an advisor or speaker, or received travel support, from Abbvie, Amgen, Boehringer, Celgene, Eli Lilly, Janssen, Leo-Pharma, Merck-Serono, MSD, Novartis, Pfizer, Sandoz, and Valeant. MC is a former employee of Mediprobe Research Inc. which conducts clinical trials under the supervision of AKG.

ABSTRACT
Tofacitinib is an oral immunosuppressant approved for the treatment of rheumatoid arthritis (RA) and is currently undergoing investigation (Phase III trials) for treating chronic plaque psoriasis. Tofacitinib inhibits Janus kinases (JAKs), which are essential for the signaling of multiple inflammatory pathways and have been implicated in the pathogenesis of RA and psoriasis. The efficacy and safety of tofacitinib in the treatment of RA and psoriasis have been demonstrated in Phase III trials. Across all studies, the efficacy of tofacitinib in alleviating symptoms of RA and psoriasis were superior to placebo. Moreover, treatment was generally well-tolerated, with the most frequently reported adverse events, for both RA and psoriasis, being nasopharyngitis and upper respiratory tract infection. As such, tofacitinib proves to be an effective therapeutic option for RA and a promising new therapy for psoriasis.

Key Words:
IL-17, interleukin-17, interleukin-17A, monoclonal antibody, chronic plaque psoriasis

Introduction

Tofacitinib (CP-690,550; trade name: Xeljanz®) is an oral immunosuppressant developed by Pfizer¹ that is currently approved for the treatment of rheumatoid arthritis (RA)^2,3 and is undergoing Phase III trials for the treatment of chronic plaque psoriasis.^4-6 Tofacitinib is a pan-Janus-activated kinase (JAK) inhibitor, which works by inhibiting JAK3, JAK1, and, to a lesser extent, JAK2.⁷ Members of the JAK family play a key role in the signaling pathways of multiple cytokines (e.g., tumour necrosis factor [TNF]), growth factors, and hormones.² Activation of these immune pathways involving JAKs have been implicated in the pathogenesis of RA^2,8 and psoriasis.⁹

Since its FDA approval in 2012, tofacitinib has demonstrated promising results in Phase III clinical trials by significantly reducing RA associated symptoms such as synovial inflammation and structural joint damage.¹⁰ Moreover, ongoing Phase III studies are demonstrating that tofacitinib could emerge as a valuable therapy for psoriasis.¹¹ The focus of this paper is to evaluate the efficacy and safety of tofacitinib in the treatment of RA and psoriasis by reviewing recent clinical trials.

Tofacitinib for Rheumatoid Arthritis

Phase III Trials

Six Phase III trials (belonging to the Oral Rheumatoid Arthritis triaLs [ORAL] series) have been conducted to assess the efficacy of tofacitinib in the treatment of RA in various patient groups.^12-17 A summary of the details from each Phase III trial and two long-term open extension trials¹⁸ can be found in Table 1. Three primary efficacy outcomes were similar between the five Phase III trials: 1) American College of Rheumatology (ACR) 20 ( ≥20% reduction in the number of both tender and swollen joints and ≥20% improvement in three of five other criteria: the patient’s assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician) response criteria; 2) changes from baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI; range of score 0-3, “no difficulty” to “unable to do”); and 3) percentage of patients with Disease Activity Score for 28 joint counts based on erythrocyte sedimentation rate (DAS28-4 [ESR]) of less than 2.6 (range 0-9.4). The sixth trial (ORAL Start) used the primary efficacy outcome of ARC 70 response and the modified total Sharp score (mTSS) from baseline. In the groups receiving tofacitinib treatment, ARC 20 or 70 (for the ORAL Start trial) response rates and the HAQ-DI scores were significantly higher compared to the placebo groups. Most studies also showed significant changes from baseline in the DAS28-4 (ESR) score in the tofacitinib group(s) compared to placebo and the ORAL Start trials showed that the change in mTSS from baseline was significantly smaller in the tofacitinib groups. The most common adverse event (AE) throughout the studies was upper respiratory tract infection. During the first 3 months of tofacitinib therapy, significant decreases in neutrophil counts and increases in low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol counts were observed compared to placebo groups. Safety and tolerability data for these studies are summarized in Table 2.

Data from Phase II and Phase III Trials

A study using pooled data from tofacitinib Phase II, Phase III and long-term extension studies was conducted to determine the rate of infection and all-cause mortality across studies in patients receiving tofacitinib monotherapy or tofacitinib in conjunction with methotrexate or other non-biologic disease-modifying antirheumatic drugs (DMARDs).¹⁹ The overall rate of serious infection in 4,789 patients was 3.09 events per 100 patientyears, with the overall rates of mortality and infection being similar in the tofacitinib groups and groups being treated with biological agents. A recent Phase II randomized control study was conducted to test the efficacy of tofacitinib monotherapy vs. placebo for the treatment of RA in Japanese patients.²⁰ Similar to the Phase III ORAL studies, dose-dependent decreases were observed in neutrophil and platelet counts, with a significant increase in low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and total cholesterol levels compare to placebo groups.²⁰ The significant decrease in neutrophil counts led to moderate-severe neutropenia in seven patients that was not life threatening.²⁰ Furthermore, 23.3% of patients across all groups had a decrease in absolute lymphocyte counts, however, this did not lead to an increase in severe infections.²⁰ Of note, RA patients from Asia may be at increased risk for herpes zoster when undergoing tofacitinib treatment. An open-label, longterm extension study of tofacitinib in Japanese patients reported herpes zoster in 19.3% of patients,²¹ while analysis of tofacitinib patients from the worldwide clinical program identified Asia as an enrollment center to be an independent risk factor for developing herpes zoster.²²

Another study conducted using data from the Phase III trial ORAL Step assessed patient-reported outcomes for tofacitinib.²³ Patients reported improvements in patient global assessment of disease activity (p<0.0001) and the physical and mental component of the Short Form 36 Health Survey version 2 scores (p<0.05) for both tofacitinib doses compared with placebo. Furthermore, improvements were more frequently reported by tofacitinib treated patients vs. placebo for pain (p<0.0001). The results are consistent with recently published data from the ORAL Solo trial, demonstrating statistically significant improvements in pain, Medical Outcome Survey (MOS) for Physical and Mental health, and Functional Assessment of Chronic Illness Therapy-Fatigue in patients receiving tofacitinib (5 mg or 10 mg) vs. placebo (p<0.0001 for all).²⁴

A systematic review of randomized Phase II and III controlled trials concluded that tofacitinib, at dosages of 5 mg and 10 mg twice daily, is effective in patients with active RA who show an inadequate response to methotrexate or DMARDs.²⁵ The ACR 20 response rates were significantly higher in the tofacitinib 5 mg and 10 mg groups than in the placebo groups in all studies. Moreover, the safety outcomes did not differ between the tofacitinib groups and placebo groups, with the exception of infection in the tofacitinib 10 mg group.

A systematic review of randomized Phase II and III controlled trials concluded that tofacitinib, at dosages of 5 mg and 10 mg twice daily, is effective in patients with active RA who show an inadequate response to methotrexate or DMARDs.²⁵ The ACR 20 response rates were significantly higher in the tofacitinib 5 mg and 10 mg groups than in the placebo groups in all studies. Moreover, the safety outcomes did not differ between the tofacitinib groups and placebo groups, with the exception of infection in the tofacitinib 10 mg group.

A meta-analysis of 10 randomized controlled studies evaluating the efficacy and safety of tofacitinib in patients with active RA showed that tofacitinib, at dosages of 5 mg and 10 mg twice daily, in combination with methotrexate, was the most effective therapy for active RA and was not associated with a significant risk for withdrawal due to AEs.²⁶

From an economic/societal perspective, studies conducted in Korea²⁷ and Brazil²⁸ showed that incorporating tofacitinib into the treatment regime or as a first-line therapy for patients with moderate to severe RA is a cost-effective alternative to the current standard of care.

Tofacitinib for Psoriasis

Phase II Trials (NCT00678210)

A 12 week, Phase IIb multicenter, randomized, double-blind, parallel-group, placebo-controlled trial was conducted to evaluate the efficacy and safety of various doses of oral tofacitinib (2 mg, 5 mg, or 15 mg twice daily) in 197 patients with moderate-tosevere psoriasis.²⁹ At week 12, Psoriasis Area and Severity Index 75 (PASI 75; the percentage of patients who have achieved a 75% or more reduction in their PASI score from baseline) responses were observed in 25% (2 mg; p<0.001), 40.8% (5 mg; p<0.0001), and 66.7% (15 mg; p<0.0001) of the patients in the tofacitinib groups compared with 2% in the placebo group. The most common AEs were upper respiratory tract infections, nasopharyngitis, and headache. Moreover, mild dose-dependent decreases in hemoglobin and neutrophil counts, and increased total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol occurred over the duration of treatment compared to placebo.²⁹ In this same study cohort, outcome questionnaires were completed by the patient³⁰ and showed that treatment with tofacitinib resulted in significant, dose-dependent improvements in several patient-reported outcomes compared with placebo. In the same study cohort, the efficacy of tofacitinib was evaluated in four body regions (head and neck, upper limbs, trunk, and lower limbs).³¹ Mean improvements in PASI 75 and body surface area (BSA) values were significantly improved with tofacitinib vs. placebo across all four body regions.

Data from the Phase IIb trial was also used to elucidate the correlation between pruritus (a severe and bothersome symptom of psoriasis which is not assessed by the PASI or Physician’s Global Assessment [PGA] rating of ‘clear’ or ‘almost clear’ using a 5-point scale: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe)³² and the clinical signs of psoriasis (erythema, induration and scaling).³³ This study showed that tofacitinib acts directly to improve patient-reported pruritus and this effect is independent from improvements in clinician-reported psoriasis severity signs.

Phase III Trials

A summary of the details for the Phase III psoriasis trials can be found in Table 3. The most common AEs were nasopharyngitis and upper respiratory tract infection. Safety and tolerability data for these studies are summarized in Table 4. Laboratory findings were similar to those reported for tofacitinib for the treatment of RA. Two additional Phase III trials are undergoing clinical investigation: NCT01163253 (OPT Extend) is in the process of recruiting participants and is a long-term open label extension study available to patients enrolled in a qualifying clinical study, while NCT01815424 has been concluded and investigated the efficacy of tofacitinib 5 mg and 10 mg in Asian patients; results have not yet been published.

Treatment Withdrawal & Retreatment Study (NCT01186744)

A Phase III, randomized, double-blind, parallel-group study was conducted to evaluate the efficacy of tofacitinib in three phases of treatment (OPT Retreatment).⁵ At the end of the initial treatment, patients were classified as treatment responders if they achieved both PASI 75 response and a PGA rating of ‘clear’ or ‘almost clear’. Responders entered the treatment-withdrawal period, and were re-randomized to placebo or their previous dose of tofacitinib. Patients who relapsed (defined as >50% reduction in the PASI improvement from baseline to week 24) entered the retreatment period. All remaining patients continued in the treatmentwithdrawal period before entering the retreatment period. In the retreatment period, patients who received placebo during treatment withdrawal were retreated with the same dose of tofacitinib that they received during the initial treatment period. After initial treatment, 33.5% and 55.2% of patients achieved both PASI 75 and PGA responses with tofacitinib 5 mg and 10 mg, respectively, and were eligible to enter the treatment withdrawal phase. At the end of the withdrawal period, a greater number of patients receiving tofacitinib 5 mg (56.2%) and 10 mg (62.3%) maintained a PASI 75 response compared to patients who were switched to placebo (23.3%, p=0.008 and 26.1% p<0.0001). Moreover, 92.3% and 93.0% of patients receiving tofacitinib 5 mg and 10 mg, respectively, did not relapse compared with 32.8% and 42.9% of those who were switched to placebo. At the end of the retreatment period, 63.0% and 73.8% of patients who continued to receive tofacitinib 5 mg and 10 mg during the treatmentwithdrawal period regained or maintained a PASI 75 response and 66.7% and 64.3% regained or maintained a PGA response. Moreover, 48.0% and 72.5% of the patients treated with placebo during the treatment-withdrawal period regained or maintained a PASI 75 response, and 52.0% and 64.2% regained or maintained a PGA response after 16 weeks of retreatment with tofacitinib 5 mg or 10 mg, respectively.

Pivotal Trials (NCT01276639 & NCT01309737)

Two similarly designed Phase III studies (OPT Pivotal 1, n=901 and OPT Pivotal 2, n=960) were conducted to evaluate the efficacy and safety of tofacitinib 5 mg and 10 mg twice daily.⁴ At Week 16, higher PASI 75 rates were observed in both tofacitinib groups vs. placebo (OPT Pivotal 1: 39.9%, 59.2% and 6.2% for tofacitinib 5 mg and 10 mg, and placebo; OPT Pivotal 2: 46.0%, 59.6% and 11.4%; all p<0.0001). Moreover, higher PGA ratings were seen in patients receiving tofacitinib 5 mg and 10 mg vs. placebo (OPT Pivotal 1: 41.9% and 59.2% vs 9.0%; OPT Pivotal 2: 46.0% and 59.1% vs. 10.9%; all p<0.0001).

Tofacitinib vs. Etanercept (NCT01241591)

A Phase III, randomized, multicenter, double-dummy, placebocontrolled trial compared the non-inferiority of tofacitinib with etanercept (50 mg) subcutaneously twice weekly or placebo (OPT Compare).⁶ At week 12, a greater number of patients receiving active treatment (39.5% for tofacitinib 5 mg, 63.6% for tofacitinib 10 mg, and 58.8% for etanercept) achieved PASI 75 responses compared to placebo (5.6%, p<0.0001 for all treatments vs. placebo). Moreover, a PGA response was achieved by 47.1%, 68.2%, 66.3%, and 15.0% of the patients in the tofacitinib 5 mg, 10 mg, etanercept and placebo groups (p<0.0001 for all treatments vs. placebo).

Conclusion

Numerous Phase II and Phase III trials have shown that tofacitinib is safe and effective in alleviating RA symptoms, relieving pain, and improving physical and mental health, either when used as monotherapy in patients who show inadequate responses to TNF inhibitors, methotrexate or DMARDs, or as combination therapy with methotrexate or DMARDs. In addition, tofacitinib has been shown to be effective in the treatment of chronic plaque psoriasis in Phase II and III clinical trials, with continuous therapy resulting in better treatment prognosis than intermittent therapy. Efficacy of tofacitinib was comparable to etanercept and superior to placebo in improving the clinical symptoms of psoriasis. Moreover, tofacitinib was also shown to improve pruritus, a common and troublesome symptom of psoriasis not typically assessed in clinical studies. These studies provide support for tofacitinib as an innovative and valuable oral systemic therapy for the treatment of RA and psoriasis.

References

1. Tofacitinib. Drugs R D. 2010;10(4):271-84.
2. Lundquist LM, Cole SW, Sikes ML. Efficacy and safety of tofacitinib for treatment of rheumatoid arthritis. World J Orthop. 2014 Sep;18;5(4):504-11.
3. Xeljanz® (tofacitinib citrate) tablet [Prescribing information]; revised February 2016. Pfizer Laboratories, New York, NY. Available from: http://labeling.pfizer.com/ShowLabeling.aspx?id=959. Accessed January 15, 2017.
4. Papp KA, Menter MA, Abe M, et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials. Br J Dermatol. 2015 Oct;173(4):949-61.
5. Bissonnette R, Iversen L, Sofen H, et al. Tofacitinib withdrawal and retreatment in moderate-to-severe chronic plaque psoriasis: a randomized controlled trial. Br J Dermatol. 2015 May;172(5):1395-406.
6. Bachelez H, van de Kerkhof PC, Strohal R, et al. Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial. Lancet. 2015 Aug 08;386(9993):552-61.
7. Ghoreschi K, Jesson MI, Li X, et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol. 2011 Apr 01;186(7):4234-43.
8. Malemud CJ. Intracellular signaling pathways in rheumatoid arthritis. J Clin Cell Immunol. 2013 Aug 19;4:160.
9. Palanivel JA, Macbeth AE, Chetty NC, et al. An insight into JAK-STAT signalling in dermatology. Clin Exp Dermatol. 2014 Jun;39(4):513-8.
10. Bannwarth B, Kostine M, Poursac N. A pharmacokinetic and clinical assessment of tofacitinib for the treatment of rheumatoid arthritis. Expert Opin Drug Metab Toxicol. 2013 Jun;9(6):753-61.
11. Chang BY, Zhao F, He X, et al. JAK3 inhibition significantly attenuates psoriasiform skin inflammation in CD18 mutant PL/J mice. J Immunol. 2009 Aug 01;183(3):2183-92.
12. Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012 Aug 09;367(6): 495-507.
13. Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013 Feb 09;381(9865):451-60.
14. van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012 Aug 09;367(6): 508-19.
15. Kremer J, Li ZG, Hall S, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2013 Aug 20;159(4):253-61.
16. van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013 Mar;65(3):559-70.
17. Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014 Jun 19;370(25):2377-86.
18. 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 May;41(5):837-52.
19. Cohen S, Radominski SC, Gomez-Reino JJ, et al. Analysis of infections and all-cause mortality in phase II, phase III, and long-term extension studies of tofacitinib in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014 Nov;66(11):2924-37.
20. Tanaka Y, Takeuchi T, Yamanaka H, et al. Efficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, randomized, phase 2 study. Mod Rheumatol. 2015 Jul;25(4):514-21.
21. Yamanaka H, Tanaka Y, Takeuchi T, et al. Tofacitinib, an oral Janus kinase inhibitor, as monotherapy or with background methotrexate, in Japanese patients with rheumatoid arthritis: an open-label, long-term extension study. Arthritis Res Ther. 2016 Jan 28;18:34.
22. Winthrop KL, Yamanaka H, Valdez H, et al. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014 Oct;66(10):2675-84.
23. Strand V, Burmester GR, Zerbini CA, et al. Tofacitinib with methotrexate in third-line treatment of patients with active rheumatoid arthritis: patientreported outcomes from a phase III trial. Arthritis Care Res (Hoboken). 2015 Apr;67(4):475-83.
24. Strand V, Kremer J, Wallenstein G, et al. Effects of tofacitinib monotherapy on patient-reported outcomes in a randomized phase 3 study of patients with active rheumatoid arthritis and inadequate responses to DMARDs. Arthritis Res Ther. 2015 Nov 04;17:307.
25. Song GG, Bae SC, Lee YH. Efficacy and safety of tofacitinib for active rheumatoid arthritis with an inadequate response to methotrexate or disease-modifying antirheumatic drugs: a meta-analysis of randomized controlled trials. Korean J Intern Med. 2014 Sep;29(5):656-63.
26. Lee YH, Bae SC, Song GG. Comparative efficacy and safety of tofacitinib, with or without methotrexate, in patients with active rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials. Rheumatol Int. 2015 Dec;35(12):1965-74.
27. Lee MY, Park SK, Park SY, et al. Cost-effectiveness of tofacitinib in the treatment of moderate to severe rheumatoid arthritis in South Korea. Clin Ther. 2015 Aug;37(8):1662-76 e2.
28. Ferreira CN, Rufino CS, Santana CF, et al. Assessment of tofacitinib for rheumatoid arthritis from the perspective of the Brazilian healthcare system. Value Health. 2015 Nov;18(7):A646.
29. Papp KA, Menter A, Strober B, et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study. Br J Dermatol. 2012 Sep;167(3):668-77.
30. Mamolo C, Harness J, Tan H, et al. Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, improves patient-reported outcomes in a phase 2b, randomized, double-blind, placebo-controlled study in patients with moderate-to-severe psoriasis. J Eur Acad Dermatol Venereol. 2014 Feb;28(2):192-203.
31. Menter A, Papp KA, Tan H, et al. Efficacy of tofacitinib, an oral janus kinase inhibitor, on clinical signs of moderate-to-severe plaque psoriasis in different body regions. J Drugs Dermatol. 2014 Mar;13(3):252-6.
32. Globe D, Bayliss MS, Harrison DJ. The impact of itch symptoms in psoriasis: results from physician interviews and patient focus groups. Health Qual Life Outcomes. 2009 Jul 06;7:62.
33. Bushmakin AG, Mamolo C, Cappelleri JC, et al. The relationship between pruritus and the clinical signs of psoriasis in patients receiving tofacitinib. J Dermatolog Treat. 2015 Feb;26(1):19-22.