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Tofacitinib in the treatment of Indian patients with rheumatoid arthritis: A post hoc analysis of efficacy and safety in Phase 3 and long‐term extension studies over 7 years

Abstract Objectives Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We characterized tofacitinib efficacy/safety in Indian vs rest of the world (ROW; excluding India) RA patients. Methods Efficacy data were pooled for disease‐modified antirheumatic drug (DMARD) inadequate responders from Phase (P)3 studies. For Indian patients, ORAL Solo and ORAL Scan; ROW (excluding India), these studies plus ORAL Step, ORAL Sync, and ORAL Standard. Safety data also included ORAL Start (P3; methotrexate‐naïve) and ORAL Sequel (long‐term extension [LTE] study; data cut‐off March 2017) for Indian patients, and these studies plus A3921041 (LTE study; Japanese study) for ROW. Efficacy outcomes at months 3/6: American College of Rheumatology (ACR)20/50/70; Disease Activity Score in 28 joints, erythrocyte sedimentation rate remission/low disease activity; change from baseline in Health Assessment Questionnaire‐Disability Index. Incidence rates (IRs; patients with events/100 patient‐years) for adverse events of special interest (AESIs) were assessed throughout. Descriptive data underwent no formal comparison. Results One‐hundred‐and‐ninety‐seven Indian and 3879 ROW patients were included. Compared with ROW patients, Indian patients were younger, had lower body mass index, shorter RA duration, and higher baseline disease activity; most Indian patients were non‐smokers and all were biologic DMARD (bDMARD)‐naïve. Month 3 ACR20 rates with tofacitinib 5 mg twice daily/10 mg twice daily/placebo were 67.4%/82.1%/40.9% (India) and 59.0%/66.1%/28.2% (ROW), and month 6 rates were 76.2%/92.1%/88.9% (India) and 69.0%/74.2%/66.5% (ROW). Month 3/6 improvements in other outcomes were generally numerically greater with tofacitinib vs placebo, and similar in both populations. Compared with ROW, Indian patients had numerically fewer AEs/serious AEs, and similar IRs for discontinuations due to AEs and AESIs, except that tuberculosis (TB) IR was higher in Indian (IR = 1.21; 95% CI 0.49, 2.49) vs ROW patients (IR = 0.17; 95% CI 0.11, 0.25). Conclusions Tofacitinib efficacy/safety were similar in both populations, except TB IR, which was higher in Indian patients but in line with those in bDMARD‐treated RA patients from high‐risk countries (IR = 0.00‐2.56; TB IR >0.05 [World Health Organization]). Limitations included the small Indian population and baseline differences between populations.


| INTRODUC TI ON
Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune disease characterized by inflammation of the articular synovium, joint damage, deformity, and progressive disability, and carries a significant burden of morbidity and economic impact. 1,2 RA has an estimated global prevalence of 0.24%. 3 However, RA receives a low level of economic support in low-to-middle income countries, such as India where age-/gender-adjusted RA prevalence is reported to be 0.34% (95% confidence interval [CI] 0.08-0.79). 4,5 The Asia-Pacific League of Associations for Rheumatology acknowledges that treatment of RA in Asia-Pacific regions should be considered independently from the rest of the world (ROW), due to potential differences in disease prevalence/manifestation, treatment response, increased prevalence of certain infections (eg, tuberculosis [TB], hepatitis B/C) and country-specific challenges with respect to healthcare resources. 6 Filling existing gaps in our understanding of treatment responses in these countries may help to inform clinical practice.
India is among 30 countries considered to have a high TB burden, and has some of the highest global rates of TB (incidence rate [IR] = 0.2 per 100 patient-years 7 ) and latent TB infection. 8 India also accounts for 23% and 36% of the global and regional burden of pneumonia, respectively. 9 Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of RA. The clinical development program for tofacitinib includes data from 7061 patients, representing 22 875 patient-years of exposure up to 9.5 years. 10 While tofacitinib long-term extension (LTE) studies have included Asia-Pacific patients, 11-14 understanding of tofacitinib efficacy/safety in India is restricted to a post hoc analysis conducted in 8 Asia-Pacific countries (China, India, Japan, Korea, Malaysia, the Philippines, Taiwan, and Thailand; total N = 1464). 15 Efficacy outcomes for tofacitinib in this post hoc analysis of data pooled from Phase 2/3 studies were comparable with, or slightly higher than, those in global studies. Greater improvements with tofacitinib vs placebo were observed in disease activity and health status (measured by Health Assessment Questionnaire-Disability Index [HAQ-DI]) after 3 months, which persisted to 24 months.
Safety outcomes (based on pooled data from Phase 2/3/LTE studies) were generally comparable with those seen in global patients; however, the infection incidence (including TB) was higher in Asia-Pacific patients. 15 In this post hoc analysis, we characterized tofacitinib efficacy and safety in Indian patients with RA, vs patients from ROW (all patients excluding Indian patients).
Full study details have been reported previously (summarized in Table S1). Briefly, patients were ≥18 years of age, with a diagnosis of active RA based on the American College of Rheumatology (ACR) 1987 revised criteria, 23  In Phase 3 studies, patients were randomized to receive tofacitinib 5 or 10 mg twice daily or placebo, either alone or with background conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Patients receiving placebo advanced to tofacitinib 5 or 10 mg twice daily at month 3 or month 6. Patients in LTE studies initiated treatment with tofacitinib 5 or 10 mg twice daily, with dose adjustments permitted at the discretion of the investigator.
All studies were conducted in compliance with the Declaration

| Statistical analysis
Efficacy analyses were based on the full analysis set, which included all patients who received ≥1 dose of study drug for whom data were available from ≥1 post-baseline assessment.  All analyses were based on observed cases without imputation for missing data. No multiplicity adjustment was made for any comparisons.

| Efficacy at months 3 and 6
ACR20, ACR50, and ACR70 response rates for the Indian population are shown in Figure 1A-C respectively; ACR20, AC50, and ACR70 response rates for the ROW population are shown in Figure 1D  respectively ( Figure 2F).

| Safety
Safety data from pooled Phase 3/LTE studies are summarized in  Step advanced in a blinded manner to tofacitinib 5 or 10 mg b.i.d. at month 3; placebo-treated non-responders (defined as patients not achieving ≥20% reduction from baseline in swollen and tender joint counts) in ORAL Scan, ORAL Sync, and ORAL Standard advanced in a blinded manner to tofacitinib 5 or 10 mg b.i.d. at month 3; remaining placebo-treated patients advanced at month 6; efficacy analyses were based on observed cases without imputation for missing data. b.i.d., twice daily; CI confidence interval; DAS28-4(ESR), Disease Activity Score in 28 joints, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire-Disability Index; ROW, rest of the world; SE, standard error

| D ISCUSS I ON
In this post hoc analysis, we present a comprehensive characteri-  Tofacitinib treatment duration, y, mean (SD)      Abnormality is defined as a count of <2×1000/mm 3 .

TA B L E 3 (Continued)
there is an increased short-term risk of hospitalization for VTEs in patients initiating bDMARDs, compared with MTX, 32 although other studies have found no association between bDMARD use and risk of VTE 33 ; therefore, the evidence for bDMARD use as a risk factor for VTE has not been confirmed.
Previously identified risk factors for ILD in patients with RA include older age, male gender, smoking status, disease activity, and high levels of serum rheumatoid factor (RF+) and antibodies against cyclic citrullinated peptide (anti-CCP+). 34 [49][50][51][52] and the risk of some AEs has also been shown to differ in csDMARD-IR vs bDMARD-IR patients receiving tofacitinib. 53 However, conversely, rates of AESI were similar in both populations, despite Indian patients being younger, having no prior bDMARD experience, shorter disease duration, and higher baseline disease activity, compared with the ROW population. It is also possible that there were differences in undertreatment or delayed treatment between the two populations, which may confound interpretation of these results. It is also important to note that the sample size and patient exposure in the Indian population were smaller than in the ROW population, and 95% CIs were wide, limiting our ability to discern differences (numerical or otherwise) between populations.
Also, all analyses were descriptive in nature, only general trends are described, and no formal statistical analyses were carried out.
In conclusion, the efficacy of tofacitinib in Indian patients with RA was similar to that in ROW patients. These results help provide insight into the benefit: risk profile of tofacitinib in Indian patients with RA.  (6), 461-464).

DATA AVA I L A B I L I T Y S TAT E M E N T
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