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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 RA2,8 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.

Study Duration Participant Inclusion Criteria Demographics Intervention Primary Outcomes Results
ORAL Solo12
(NCT00814307)
6 months Active RA patients with inadequate response to at least one DMARD (biologic or nonbiologic) n=611
Age: 49.7-52.4
Male: 13.3%
Duration of RA: 7.7-8.6 years
Baseline HAQ-DI: 1.50-1.53
Baseline DAS-28: 6.65-6.71
Tofacitinib 5 mg bid; Tofacitinib 10 mg bid; Placebo for 3 months then tofacitinib 5 mg or 10 mg bid ACR 20 response at month 3; DAS28-4 (ESR) <2.6 at month 3; HAQDI at month 3 (change from baseline) ARC 20 response rates were sig. higher (p<0.001) and HAQ-DI score were sig. improved in tofacitinib groups (p<0.001).
ORAL Step13
(NCT00960440)
6 months Moderate to severe RA patients with inadequate response to TNFα inhibitors n=399
Age: 54.4-55.4
Male: 16.7%-86.36%
Duration of RA: 11.3-13.0 years
Baseline HAQ-DI: 1.5-1.6
Baseline DAS-28: 6.4-6.5
Tofacitinib 5 mg bid; Tofacitinib 10 mg bid; Placebo for 3 months then tofacitinib 5 mg or 10 mg bid ACR 20 response at month 3; DAS28-4 (ESR) <2.6 at month 3; HAQDI at month 3 (change from baseline) ARC 20 response and HAQDI score were sig. improved in both tofacitinib groups (p<0.0001). DAS28-4 (ESR) score <2.6 was sig. with tofacitinib 5 mg (p=0.049) and 10 mg (p=0.011).
ORAL Standard14
(NCT00853385)
12 months Active RA patients receiving stable doses of methotrexate n=717
Age: 51.9-55.5
Male: 19.8%
Duration of RA: 6.9-9.0 years
Baseline HAQ-DI: 1.4-1.5
Baseline DAS-28: 6.3-6.6
Tofacitinib 5 mg bid; Tofacitinib 10 mg bid; Adalimumab 40 mg SC every 2 weeks; Placebo for 6 months then tofacitinib 5 mg or 10 mg bid ACR 20 response at month 6; DAS28-4 (ESR) <2.6 at month 6; HAQDI at month 3 (change from baseline) ARC 20 responses were sig. higher in treatment groups compared to placebo (p<0.001). Sig. changes from baseline in DAS28-4 (ESR) and HAQ-DI in the active treatment groups were seen over time (p≤0.05).
ORAL Sync15
(NCT00856544)
12 months Active RA patients with inadequate response to one or more DMARD n=792
Age: 50.8-53.3
Female: 20.85%
Duration of RA: 8.1-10.2 years
Baseline HAQ-DI: 1.24-1.45
Baseline DAS-28: 6.14-6.44
Tofacitinib 5 mg bid; Tofacitinib 10 mg bid; Placebo ACR 20 response at month 6; DAS28-4 (ESR) <2.6 at month 6; HAQDI at month 3 (change from baseline) ARC 20 response and HAQ-DI score were sig. improved in both tofacitinib groups (p<0.001). DAS28-4 (ESR) <2.6 was sig. in both tofacitinib groups (p=0.005).
ORAL Scan16
(NCT00847613)
24 months Active RA patients receiving background methotrexate n=797
Age: 52.0-53.7
Male: 14.3%
Duration of RA: 8.8-9.5 years
Baseline HAQ-DI: 1.23-1.41
Baseline DAS-28: 6.25-6.34
Tofacitinib 5 mg bid; Tofacitinib 10 mg bid; Placebo for 3 months then tofacitinib 5 mg or 10 mg bid ACR 20 response at month 6; DAS28-4 (ESR) <2.6 at month 6; HAQDI at month 3 (change from baseline); SHS at month 6 (change from baseline) ARC 20 response rates were sig. higher in both tofacitinib groups compared to placebo (p<0.0001). Sig. changes from baseline in DAS28-4 (ESR) and HAQ-DI were seen in the tofacitinib 10 mg group (p<0.0001).
ORAL Start17
(NCT01039688)
24 months Methotrexate naïve patients with active RA n=952
Age: 49.3-50.3
Male: 20.1%
Duration of RA: 2.7-3.4 years
Baseline HAQ-DI: 1.5
Baseline DAS-28: 6.5-6.6
Baseline TSS: 16.51-20.30
Tofacitinib 5 mg bid; Tofacitinib 10 mg bid; Methotrexate 10 mg per week with 5 mg increments every 4 weeks up to 20 mg per week Modified TSS at month 6; ACR 70 response at month 6 ARC 70 response rates were sig. higher in both tofacitinib groups compared with methotrexate (p<0.001). Change in modified TSS from baseline was sig. smaller in the tofacitinib groups (p≤0.05).
Long-Term Open Extension18
(NCT00413699, NCT00661661)
60 months Completed participation in a prior qualifying Phase I, II, or III study for RA n=4102
Mean age: 53.2
Male: 17.0%
Mean (max) duration: 531 (1844) days
Tofacitinib 5 mg or 10 mg bid + background DMARD; Tofacitinib 5 mg or 10 mg bid monotherapy Safety; ACR 20, ACR 50, ACR 70, DAS28-4 (ESR), HAQ-DI Safety consistent with Phase III; ACR response rates maintained, both DAS28-4 (ESR) decreased and mean HAQ-DI score improved at month 48.
Table 1. Summary of Phase III tofacitinib studies for rheumatoid arthritis
DMARD: Disease-modifying antirheumatic drug; TSS: Total sharp score; TNF: Tumor necrosis factor; SHS: Sharp/van der Heijde Score; HAQ-DI: Health Assessment Questionnaire Disability Index; ARC 20 or 70 response: American College of Rheumatology response (≥20% or ≥70% reduction in the number of both tender and swollen joints and ≥20% or ≥70% improvement in three of five of 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; DAS 28-4 (ESR): Disease Activity Score for 28 joint counts based on erythrocyte sedimentation rate; sig.: significant(ly).

ORAL Solo12 Placebo Tofacitinib 5 mg Tofacitinib 10 mg
TEAEs 55% 44% 48%
SAEs 5% 1% 2%
Discontinuation of study 4% 3% 2%
ORAL Step13 Placebo Tofacitinib 5 mg Tofacitinib 10 mg
TEAEs 57% 46% 49%
SAEs 5% 3% 3%
Discontinuation of study 5% 4% 5%
ORAL Standard14 Placebo Tofacitinib 5 mg Tofacitinib 10 mg Adalimumab 40 mg
TEAEs 40% 41% 40% 42%
SAEs 2% 5% 4% 3%
Discontinuation of study 2% 4% 4% 4%
ORAL Sync15 Placebo Tofacitinib 5 mg Tofacitinib 10 mg
TEAEs 62% 69% 68%
SAEs 4% 6% 6%
Discontinuation of study 2% 5% 8%
ORAL Scan16 Placebo Tofacitinib 5 mg Tofacitinib 10 mg
TEAEs 46% 48% 48%
SAEs 3% 4% 3%
Discontinuation of study 3% 4% 3%
ORAL Start17 Tofacitinib 5 mg Tofacitinib 10 mg Methotrexate 10 mg
TEAEs 80% 84% 79%
SAEs 11% 11% 12%
Discontinuation of study 11% 10% 13%
Long-Term Open Extension18 Tofacitinib 5 mg and 10 mg + DMARD Tofacitinib 5 mg and 10 mg monotherapy
TEAEs 56% 48%
SAEs 11% 10%
Discontinuation of study 8% 7%
Table 2. Safety and tolerability of tofacitinib in RA patients: results from Phase III trials
TEAEs: treatment-emergent adverse events
SAEs: serious adverse events
Discontinuation of study due to treatment-emergent adverse events

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.

Study Duration Participant Inclusion Criteria Demographics Intervention Primary Outcomes Results
OPT Retreatment5
(NCT01186744)
56 weeks ≥18 years old, diagnosed with chronic plaque psoriasis for ≥12 months, were candidates for systemic therapies or phototherapy, had a PASI score ≥12, PGA score of 3 or 4 and psoriasis involvement of ≥10% of total BSA n=666

Age: 18-83

Male: 68.8%

Duration of disease
(mean): 15.5 years
Initial treatment (24 weeks): tofacitinib 5 mg or 10 mg bid; Withdrawal (16 weeks): placebo or tofacitinib 5 mg or 10 mg bid; Retreatment (16 weeks): placebo or tofacitinib 5 mg or 10 mg bid PASI 75 response and a PGA rating of 'clear' or 'almost clear' Withdrawal period: sig. more patients maintained PASI 75 and PGA responses with both tofacitinib treatments vs. patients switched to placebo (p<0.0001). Retreatment: 48% and 52% and 72.5% and 64.2% of patients treated with placebo during withdrawal regained/ maintained PASI 75 and PGA response with tofacitinib 5 mg and 10 mg, respectively.
OPT Pivotal 14
(NCT01186744)
and OPT Pivotal 24
(NCT01309737)
52 weeks ≥18 years old, diagnosed with chronic plaque psoriasis for ≥12 months, were candidates for systemic therapies or phototherapy, had a PASI score ≥12, PGA score of 3 or 4 and psoriasis involvement of ≥10% of total BSA Pivotal 1, n=901
Age: 18-79
Male: 70.9%
Duration of disease (mean): 16.2 years
Average BSA affected: 25.2%

Pivotal 2, n=960
Age: 18-82
Male: 68.6%
Duration of disease (mean): 16.3 years
Average BSA
affected: 24.5%
Tofacitinib 5 mg bid;

Tofacitinib 10 mg bid;

Placebo for 16 weeks then switch to tofacitinib 5 mg or 10 mg bid
PASI 75 response and a PGA rating of 'clear' or 'almost clear' Sig. higher PASI 75 rates and PGA responses were seen with both tofacitinib treatments vs. placebo in both studies (p<0.001 for both studies).
OPT Compare6
(NCT01241591)
12 weeks ≥18 years old, diagnosed with psoriasis for ≥12 months, were candidates for systemic therapies or phototherapy, had a PASI score ≥12, PGA score of 3 or 4 and psoriasis involvement of ≥10% of total BSA, and had failed to respond to, had a contraindication to, or were intolerant to at least one conventional systemic therapy for psoriasis n=1101
Age: 18-81
Male: 70%
Duration of disease (mean): 17 years
Average BSA affected: 26.7%
Tofacitinib 5 mg bid;
Tofacitinib 10 mg bid;
Etanercept 50 mg
subcutaneously twice weekly;
Placebo
PASI 75 response and a PGA rating of 'clear' or 'almost clear' Sig. higher PASI 75 rates and PGA responses were seen with all active treatments (tofacitinib and etanercept) vs. placebo (p<0.0001).
OPT Extend
(NCT01163253)
≥18 years old, diagnosed with plaque psoriasis, complete participation in a qualifying tofacitinib clinical study ≥18 years old, diagnosed with psoriasis for ≥12 months, were candidates for systemic therapies or phototherapy, had a PASI score ≥12, PGA score of 3 or 4 and psoriasis involvement of ≥10% of total BSA, and had failed to respond to, had a contraindication to, or were intolerant to at least one conventional systemic therapy for psoriasis n=3200 (estimate) Tofacitinib 10 mg bid for first 3 months, then tofacitinib 5 mg bid or tofacitinib 10 mg bid at principal investigator's discretion Evaluate long-term safety and tolerability Ongoing
Table 3. Summary of Phase III tofacitinib studies for psoriasis
PASI 75 response: Psoriasis Area and Severity Index (the percentage of patients who have achieved a 75% or more reduction in their PASI score from baseline); PGA rating: Physician's Global Assessment rating of 'clear' or 'almost clear' (using a 5-point scale: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe); BSA: body surface area; sig.: significant(ly); bid: twice daily.

OPT Retreatment5 Tofacitinib 5 mg Tofacitinib 10 mg Placebo + Tofacitinib 5 mg Placebo + Tofacitinib 10 mg
TEAEs 59% 66% 50% 48%
SAEs 2% 4% 2% 1%
Discontinuation of study 3% 4% 0% 1%
OPT Pivotal 1,
OPT Pivotal 24
Study 1 Study 2
Placebo1 Tofacitinib 5 mg Tofacitinib 10 mg Placebo Tofacitinib 5 mg Tofacitinib 10 mg
TEAEs 50% 51% 61% 47% 56% 56%
SAEs 3% 2% 3% 1% 3% 1%
Discontinuation of study 6% 3% 3% 3% 4% 3%
OPT Compare6 Placebo Tofacitinib 5 mg Tofacitinib 10 mg Etanercept 50 mg
TEAEs 51% 55% 60% 57%
SAEs 5% 2% 2% 2%
Discontinuation of study 4% 1% 3% 3%
Table 4. Safety and tolerability of tofacitinib in psoriasis patients: results from Phase III trials
TEAEs: treatment-emergent adverse events; SAEs: serious adverse events; Discontinuation of study due to treatment-emergent adverse events

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.

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In this issue:

  1. Tofacitinib in the Treatment of Rheumatoid Arthritis and Chronic Plaque Psoriasis
  2. A Review of Guselkumab, an IL-23 Inhibitor, for Moderate-to-Severe Plaque Psoriasis
  3. Skin Treatments Introduced in 2016
  4. Update on Drugs and Drug News - March-April 2017