European Journal of Cardiovascular Medicine

Plaque psoriasis is a chronic inflammatory disease.It affects both the physical health and the quality of life of the patient [1].Psoriasis is a global disease that affects approximately 2-4% of Europeans.The North American population was also affected [2].

The prevalence of psoriasis is generally low in India, in Taiwan [3], 0.3% in South Korea [4], and 0.47% in mainland China [5]).However, disease symptoms, therapeutic effects,Adverse events (AEs) have been observed in clinical trials.Comparing the Asian population with other regions, therefore, it isEvaluation of psoriasis treatment is especially important in this area[6].

Tofacitinib is an oral Janus kinase inhibitor. Effectiveness andSafety of tofacitinib 5 mg and 10 mg twice daily (BID) in patientswith moderate to severe chronic plaque psoriasis. It was shown in phase 2 trials [7] and global phase 3 trials [8-11]for periods up to 56 weeks, and in long-term development studies.Efficacy and safety endpoints were reported over 24 monthsExposure of more than 33 months has been reported [11]. Efficiency and safetyTofacitinib has also been studied in several immune-mediated diseases, Inflammatory diseases including rheumatoid arthritis (RA) [12-17], psoriatic arthritis, ankylosing spondylitis [18], Crohn's disease [19]ulcer disease

Colitis [20,21].

Here, we report the efficacy and safety of tofacitinib and placebo for the treatment of moderate to severe chronic plaque psoriasisamong rural patients in Central India.

Patients were enrolled from the patients attending dermatology OPD I a tertiary teaching hospital in Central India from 2022 to 2024. Patient inclusion andexclusion criteria were similar to those of previous global studies[10,11].

Briefly, patients were aged 18 years with a diagnosis of plaquetype psoriasis for 12 months at screening, covering 10% of theirbody surface area (BSA), with a Psoriasis Area and Severity Index(PASI) score 12 and Physician’s Global Assessment (PGA) score of‘moderate’ or ‘severe’ at baseline.

Study design:

This was arandomized, double-blind, placebocontrolled, parallel-group study carried outbetween January 2022 and January 2024. A computergenerated randomization schedule was developed by Pfizer and anautomated telephone/web-based interactive response system wasused to assign patients 2:2:1:1 to receive tofacitinib 5 mg BID,tofacitinib 10 mg BID, placebo advanced to tofacitinib 5 mg BID, orplacebo advanced to tofacitinib 10 mg BID. At Week 16, patientsinitially receiving placebo were automatically advanced to theirpre-determined tofacitinib dose. Patients were treated up to Week52. Patients, investigators, and the sponsor were blinded to studytreatment. Placebo was provided as oral tablets matching those oftofacitinib.

The study was reviewed by the institutional review board andindependent ethics committees of each study center, and wasconducted in accordance with the International Conference onHarmonisation guidelines on Good Clinical Practice and applicablelocal regulatory requirements and laws. Patients providedinformed consent prior to study participation.

Outcomes:

The primary endpoints were the proportion of patientsachieving a PGA response (PGA of ‘clear’ or ‘almost clear’ on a5-point scale: 0 = clear; 4 = severe), and the proportion of patientsachieving 75% improvement from baseline PASI (PASI75 response) at Week 16.

Key secondary endpoints included: % change from baseline(CFB) in BSA at Week 16; proportion of patients achieving 90%improvement from baseline PASI (PASI90) at Week 16; CFB inDermatology Life Quality Index (DLQI) total score at Week 16; PGAresponse at Week 4; PASI75 at Week 4; CFB in DLQI at Week 4; %CFB in Nail Psoriasis Severity Index (NAPSI) at Week 16 amongpatients with nail psoriasis at baseline; and the proportion ofpatients maintaining PGA, PASI75, or PASI90 responses at Week 52,among those with a corresponding Week 16 response. Other

secondary endpoints included the median time to achieve PGA orPASI75 responses up to Week 16, and PGA or PASI75 responses ateach study visit through Week 52.

Safety was assessed through spontaneous reporting of AEs,physical examinations, and clinical laboratory tests. AEs of specialInterests have been described, including: serious, opportunistic andherpes zoster infection; Malignancy; major adverse cardiovascular events (MACE); and gastrointestinal perforations.

Statistical analysis:

A sample size of 70 patients per group was determinedto give 94% power to achieve a statistical significance level of 0.05 using a two-sided test to compare tofacitinib 5 mg and10 mg BID vs placebo for both primary endpoints. Data were analyzed for the full analysis set: all randomizedPatients who received 1 dose of study drug. All binary data,including primary endpoints, analyzes were performed using Cochranemantel-Haenszl statistics, adjusting for site effect, with non-responder imputation for missing data. To preserve the overall type IFor primary analysis, a step-down approach was used for errorSuperiority vs placebo in the following order: with PGA response10 mg BID; PASI75 response with 10 mg BID; PGA response with5 mg BID; PASI75 response with 5 mg BID. Statistical significanceA claim was made for a given endpoint at a given dose only if previouslyThe end point in the sequence met the significance requirements (p 0.05;two-sided). A Breslow-Day test was performed to verifyHomogeneity of odds ratios across screening sites.

ContinuousVariables were analysed using observed data with a mixed effects repeated measuresmodel from which least squares. The mean of the difference from placebo was derived.

Of the 266 randomized patients, 244 (91.7%) completed Week16 (tofacitinib 5 mg BID, n = 84 [95.5%]; 10 mg BID, n = 83 [92.2%];placebo, n = 77 [87.5%]; Fig. S1), and 231 (86.8%) completed Week52. Patient demographics and baseline characteristics weresimilar across treatment groups, with the exception that theplacebo group included higher proportions of patients with severedisease and biologic-naïve patients vs the tofacitinib groups(Table 1).

At Week 16, tofacitinib demonstrated superior efficacy vsplacebo for both primary endpoints. PGA response was achieved by52.3% and 75.6% of patients receiving tofacitinib 5 mg and 10 mgBID, respectively, vs 19.3% with placebo (both p < 0.0001;.

PASI75 was achieved by 54.6% and 81.1% of patients receivingtofacitinib 5 mg and 10 mg BID vs 12.5% with placebo (bothp < 0.0001). There was no significant difference in oddsratio across (pooled) investigator sites for PGA response (BreslowDay test: 5 mg BID, p = 0.50; 10 mg BID, p = 0.69) or PASI75(Breslow-Day test: 5 mg BID, p = 0.37; 10 mg BID, p = 0.51). Themedian time to response was 8 weeks for both PGA and PASI75responses with tofacitinib 10 mg BID, and 14 and 16 weeks,respectively, with tofacitinib 5 mg BID. Both PGA andPASI75 responses were generally sustained from Week 16 throughWeek 52 with tofacitinib 5 mg and 10 mg BID.Based on the step-down testing procedure, patients receivingtofacitinib 10 mg BID achieved significant differences from placebo(all p < 0.025) for all of the tested key secondary efficacy endpoints(Table 2). Patients in the tofacitinib 5 mg BID group achievedsignificant differences from placebo (all p < 0.025) for %CFB in BSAat Week 16, PASI90 response at Week 16, CFB in DLQI at Week 16,and PGA response at Week 4 (Table 2).

Weeks 0–16From baseline to Week 16, 64.8%, 67.8%, and 48.9% of patientsreceiving tofacitinib 5 mg BID, 10 mg BID, and placebo, respectively,had treatment-emergent AEs of all causality (Table 3). Twopatients receiving tofacitinib 5 mg BID experienced serious AEs(SAEs); no SAEs were reported in patients receiving tofacitinib10 mg BID or placebo. The numbers of discontinuations due to AEswere similar between treatment groups.

From baseline to Week 52, patients receiving tofacitinib 5 mgand 10 mg BID had similar rates of treatment-emergent AEs anddiscontinuations due to AEs (all causality); the placebo totofacitinib groups also had generally similar rates of AEs fromWeek 16 to Week 52 (Table 3). Four patients receiving tofacitinib5 mg BID, two receiving tofacitinib 10 mg BID, and one patient whoadvanced to tofacitinib 10 mg BID from placebo had SAEs.

The most common treatment-emergent AEs in the groups wereUpper respiratory tract infection, nasopharyngitis, hyperlipidemia,and increased blood cholesterol.

Two serious infections (bronchopneumonia, tofacitinib 10 mgBID; urinary tract infection, tofacitinib 5 mg BID) and twoMalignant (metastatic small-cell lung cancer, tofacitinib10 mg BID; Metastatic lung adenocarcinoma, tofacitinib 5 mgBID) were reported (Table 3); Both patients with malignant diseaseWere current or former smokers.

NoPatients had confirmed hemoglobin levels <10.0 g/dL. A small initialThe mean increase in creatine phosphokinase was more than 52 sustainedweeks; No patient had confirmed creatine phosphokinase >10 xUpper limit of normal (ULN). A small mean increase from baseline inLow-density lipoprotein cholesterol (LDL-c) and high-density lipoproteinlipoprotein cholesterol (HDL-c) was observed; There was noChange in mean LDL-c/HDL-c ratio. is confirmed inAspartate or alanine aminotransferase 3 x ULN were notedIn three patients who received tofacitinib 5 mg B.I.D.

Indian patients with psoriasis represent a distinct population and show differences in disease activity andTreatment outcomes compared to other regions [6]. So, thatIt is important to investigate potential efficacy and safetyPsoriasis treatment especially in these patients.

In this study, patients in rural areas in Central India with moderate to severe psoriasis, both tofacitinib 5 mg and10 mg BID was superior to placebo in primary efficacy End points, PGA and PASI75 responses at week 16. PGA and PASI75 Responses were maintained at week 16 in most patients(73.6–84.9%) by week 52. In addition, tofacitinib 10 mg BID

All were superior to placebo for key secondary endpoints, where as To facitinib 5 mg BID was superior to placebo for %CFB in BSA, PASI90, and CFB in DLQI at week 16, and PGA response at week 4.Tofacitinib 10 mg BID had a rapid onset of effect and showed Greater efficacy vs 5 mg BID.

Although no direct comparison can be made, more generallyPGA and PASI75 response rates were observed with tofacitinib5 mg and 10 mg BID compared to similar doses globallyPsoriasis studies [8-11]. This pattern is consistent with the results of a

A regional Japanese study of tofacitinib [22], and several reportsbiological agents [6]. Higher response rates in East Asian populationsmay be due to differences in patient characteristics, inclLess body weight, less duration of disease, less previous usecompared to biological therapies, and higher baseline disease severitywith a global clinical study population [6]. Patients in this studyGenerally had lower body mass index than globaltofacitinib includes psoriasis trials and more biologicspatients [8-10].

In this study, tofacitinib had an overall safety profilegenerally consistent with global studies [8-11]. This is compared to AE rates of particular interestreported in global studies [8-11].

Two errors were reported, one of which was resolvedmortality in smokers. Research

reported in clinical trials of tofacitinib in patientsIncludes 5671 RA patients, up to 72 monthsexposure, indicating the overall incidence rate (IR);Standard IR (SIR; Comparison and Surveillance, Epidemiology, and End Results Program) and types of disorders, mostIn most cases, lung cancer becomes stable over time as it increases

effect of tofacitinib; Patients treated with tofacitinib had SIRsin the expected range for moderate to severe RA patients[23].

Limitations of this study include the lack of a placebo armWeek 16 and no comparator control arm is activeduring the course. Plus 52 weeks of trainingthe duration and size of the study population was sufficient to demonstrateCommon AEs, accurate estimates of rare frequencies orRare AEs or prolonged delays (eg malignancy orcardiovascular AE) may require larger sample sizes and longer follow-upterms; Long-term safety data for a global study of tofacitinibpublished in Toshbayaz [11] and 8 months to 33 monthsYear in RA [24]. The results of this study are applied to Indian rural patients.In summary, tofacitinib demonstrated efficacy over placeboPatients with moderate to severe psoriasis in 16 weeks in Central India;Continued through the 52^ndweek. SAE is rarecompared with no unexpected safety results. Previous tofacitinib studies in global populations.

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