:https://journals.lww.com/ijd/fulltext/2026/01000/topical_tofacitinib_for_atopic_dermatitis__.7.aspx
Topical Tofacitinib for Atopic Dermatitis – Outcomes from Randomized Phase 3 Clinical Trial: First Approval
Chaturvedi, Alok R.1; Zaveri, Hemant G.1; Patel, Dhaval V.1; Tof-O in AD Trial Investigators
Author Information
Indian Journal of Dermatology 71(1):p 44-50, Jan–Feb 2026. | DOI: 10.4103/ijd.ijd_197_24
Open
Abstract
Background:
The Janus kinase (JAK) enzyme plays a crucial role in the pathophysiology of atopic dermatitis (AD). The United States Food and Drug Administration (USFDA) has recently granted approval for three JAK inhibitors intended for AD treatment. These comprise topical Ruxolitinib, oral Abrocitinib, and Upadacitinib. In alignment with these advancements, we developed a topical formulation of Tofacitinib, a JAK inhibitor, and evaluated its potential in mild-to-moderate AD, which has been recently approved on the basis of a phase 3 clinical trial.
Aims and Objectives:
The present trial was conducted to evaluate the efficacy and safety of tofacitinib ointment 2% w/w (Tof-O) versus pimecrolimus cream 1% w/w (Pim-C) in adult patients with mild-to-moderate AD.
Materials and Methods:
In this prospective, open-label, multicenter phase 3 trial, 184 patients with mild-to-moderate AD were randomized (1:1) to receive either Tof-O or Pim-C for 4 weeks. The efficacy evaluations included percent change in Eczema Area and Severity Index (EASI) score, percentage of patients achieving EASI 50, 75, and 90% improvement, change in validated Investigator Global Assessment (vIGA-AD) score, change in affected percentage body surface area (BSA), and change in pruritus using numeric scale. Safety and tolerability were assessed by laboratory parameters, physical examination, and adverse events (AEs).
Results:
Tof-O significantly (P < 0.05, mean: 1.9709, CI: −4.3327, 8.2745) improved EASI score from baseline after 4 weeks of treatment; the improvement was comparable to Pim-C. Both treatment groups also demonstrated a significant (P < 0.05) increase in the percentage of patients achieving EASI 50, 75, and 90, along with significant (P < 0.05) improvements in vIGA-AD scores, affected BSA, and pruritus from baseline after 4 weeks of treatment. There were no significant changes observed in laboratory values and other safety parameters in both groups.
Conclusion:
Tof-O demonstrated favourable safety and efficacy in mild-to-moderate AD patients following 4 weeks of treatment.
Trial Registration:
Clinical Trial Registry-India (CTRI). CTRI/2022/07/044136 [Registered on: 19/07/2022] Trial Registered Prospectively.
URL:
https://ctri.nic.in/Clinicaltrials/showallp.php?mid1=71771&EncHid=&userName=tofacitinib%20ointment.
Type of Trial:
Interventional.
Introduction
Atopic dermatitis (AD), also known as eczema, is a chronic, inflammatory, non-communicable, relapsing skin condition with eczematous nature, characterized by itchy, red, and inflamed skin.[1] According to a recent study published in the Indian Journal of Dermatology,[2] AD affects about 10% of adults and ~20% of children in high-income nations, with limited evidence available for India. In India, AD is often underdiagnosed and undertreated due to socioeconomic status, with many patients relying on traditional or alternative therapies rather than seeking medical treatment. This can lead to delayed diagnosis and poor disease management, which can have a significant impact on quality of life.[3]
The immuno-inflammatory responses in AD patients are believed to be mediated through Janus kinases (JAKs) and subsequent activation of signal transducers and activators of transcription (STATs). These key transcription factors influence the production and release of several cytokines, including interleukin (IL)-4, IL-5, IL-13, and IL-31, which play significant roles in the pathogenesis of AD.[4] Inhibition of the JAK/STAT pathway disrupts transcription of genes responsible for pro-inflammatory cytokines associated with AD pathogenesis, reduces immune-inflammatory responses, providing relief and thereby making it a promising avenue for AD treatment.[5,6]
The USFDA has recently approved two orally administered JAK inhibitors, Abrocitinib and Upadacitinib, for treating adults with refractory moderate to severe AD.[7] The oral JAK inhibitors have limitations due to safety-related issues; hence, topical formulation of JAK inhibitors might offer advantages over oral administration by delivering the drug directly to the affected skin, accelerating the onset of action, and reducing the potential for systemic AEs.[8] To date, the USFDA has approved only one topically administered JAK inhibitor, Ruxolitinib (1.5%), for managing mild-to-moderate AD in both paediatric and adult patients.[9] Furthermore, topical Delgocitinib (0.5%), another JAK inhibitor developed by Nakagawa and colleagues (a group of researchers from Japan), has received approval in Japan for AD treatment.[10] Notably, a phase 2a clinical trial led by Bissonnette and colleagues[11] demonstrated the favourable efficacy, safety, and tolerability of Tofacitinib ointment compared to a vehicle control in AD patients.
In line with these developments, we have developed a topical Tofacitinib 2% w/w ointment (Tof-O), and conducted a phase 3 randomized clinical trial to explore the therapeutic potential of Tof-O in the management of mild-to-moderate AD patients. To the best of our knowledge, we are the first to receive regulatory approval for the manufacturing and marketing of the world’s first topical Tofacitinib for the treatment of mild-to-moderate AD patients.
Materials and Methods
Trial design and patients’ selection criteria
This was a prospective, multicenter, randomized, open-label, two-arm, parallel-group, active-controlled, phase 3 clinical trial conducted at a total of 14 sites in India, from 31 July 2022 to 28 January 2023. The key inclusion criteria were patients of either sexes, aged between 12–60 years diagnosed with mild-to-moderate AD using Hanifin diagnostic criteria,[12] AD patients with 5–20% treatable body surface area (BSA) and baseline validated Investigator Global Assessment (vIGA-AD) score of 2 (mild) or 3 (moderate). The exclusion criteria were current and past history of other skin conditions that requires frequent hospitalizations and/or continued treatment for skin infections and have clinically unstable AD or having consistent requirement for either oral, or parenteral (including topical) corticosteroids to manage AD signs and symptoms, history of eczema herpeticum and recurrent herpes zoster infection within 12 months and already treated with phototherapy, systemic immunosuppressants, cytostatic drugs, systemic corticosteroid, oral JAK inhibitors, monoclonal antibody, leukotriene antagonists, systemic antibiotics, herbal medications, or topical therapy with unknown properties or known beneficial effects for AD within 14 days to 1 month before randomization.
Sample size determination
The sample size calculation was based on a literature review of the use of tofacitinib ointment and pimecrolimus cream. Assuming a common standard deviation of 50% and an expected maximum allowable mean difference of 26% between the two treatment groups, with a null difference of 0.10, a significance level of 0.05, and 90% power, a minimum of 80 subjects per arm (total N = 160) was required. Accounting for a potential 15% dropout rate, a total of 184 subjects were planned for randomization in a 1:1 ratio to receive either Tof-O or Pimecrolimus Cream 1% w/w (Pim-C).
Treatment protocol
The eligible patients (N = 184) were randomized (1:1) to receive either Tof-O or Pim-C treatment twice daily for a period of 28 days to affected areas, except those on the hair-bearing scalp. Any new lesions of AD observed on treatment-eligible areas, including groin or genitals, during the trial period, were also treated with the trial medication. Patients were instructed to continue to treat all treatment-eligible areas, regardless of clearing or improvement, and not to bath or shower for at least 4 h after application of the trial medication.
Trial outcomes and assessments
The primary efficacy outcome was the percent change in Eczema Area and Severity Index (EASI) score, total score from baseline after completion of 4 weeks of treatment. The secondary efficacy outcomes were percentage of patients achieving vIGA-AD of 0 or 1 with a 2-point improvement following 2 and 4 weeks of treatment, percentage of patients achieving ≥50%, ≥75%, and ≥90% improvement in EASI after 2 and 4 weeks of treatment, change in affected %BSA after 2 and 4 weeks of treatment from baseline, and change in patient’s assessment of pruritus using numeric scale after 2 and 4 weeks of treatment (0 – no itch, 1 – mild itch, 2 – moderate itch, and 3 – severe itch).
For safety assessments, patients were monitored for the occurrence of any adverse events throughout the trial period. The changes in clinical laboratory parameters (haematology, clinical biochemistry, and routine urine analysis) at baseline and end of trial, vitals, and physical exams were also evaluated throughout the trial.
Statistical analysis
The random allocation sequence was generated by a biostatistician using computer-generated randomization. Based on a comparison of two studied arms using Pearson’s Chi-square statistic with a normal approximation, the eligible patients (N = 184) were randomized in 1:1 ratio. All continuous data were summarized with descriptive statistics (number of subjects, mean, standard deviation, minimum, median, and maximum), while categorical data were summarized as frequency and percentage. All efficacy variables were analyzed on the full analysis set (FAS), while safety variables were analyzed on the safety set. FAS is defined as all randomized patients who topically received at least one dose of trial medication with no protocol violation and have undergone at least one efficacy evaluation. The safety set is defined as all randomized patients who topically received at least one dose of trial medication. The primary efficacy endpoint was analyzed using a linear mixed model for repeated measures (MMRM) between treatments with no imputation for missing data. Least squares (LS) means, along with SE, were calculated for each treatment group and the mean difference and P value between treatments. The percentage of patients with a vIGA-AD of clear (0) or almost clear (1) with a ≥2-point improvement from baseline was analyzed by using the Cochran-Mantel-Haenszel (CMH) test. The percentage of patients achieving EASI ≥50, 75, and 90% response was analyzed using the CMH approach. Furthermore, changes in %BSA affected at the end of weeks 2 and 4 relative to baseline were analyzed by using the MMRM model. Additionally, improvement on pruritus score after weeks 2 and 4 was analyzed using a non-parametric test (log-rank test). Descriptive statistics were provided for all safety data. All statistical analysis was performed using SAS version 9.4 (SAS Institute Inc., NC, USA).
Results
Patient demographics and baseline characteristics
A total of 194 potential patients were screened in the trial, of which 184 patients met elgibility criteria. Eligible patients (N = 184) were randomly assigned (1:1) to either Tof-O (n = 92) or Pim-C (n = 92) group. Of 184 enrolled patients, 172 patients completed the trial, and 12 patients were prematurely discontinued or withdrawn from the trial. The safety was assessed for all the enrolled patients (safety population), and the efficacy was assessed for the FAS population. The patient disposition is shown in Figure 1.
Figure 1:
The CONSORT flow diagram
The baseline demographic and disease characteristics were evenly distributed among the two treatment groups, as demonstrated in Table 1. The majority of patients were male (63%), with an average age of 34.5 years (ranging from 12.0 to 59.0). Of the total 184 patients, 37 (20.1%) of patients had mild AD, and 147 (79.9%) of patients had moderate AD as assessed by vIGA-AD score. At baseline, the overall mean EASI total score was 9.34 (range: 1.2–32.2). The mean percentage of affected BSA was 8.1, and the mean pruritus severity score was 1.89 (range: 1–3). These characteristics were well balanced across treatment groups.
Table 1:
Patient demographics and baseline disease characteristics presented for FAS
Efficacy
Both Tof-O and Pim-C treatments significantly reduced the EASI score after 4 weeks (P < 0.001). Tof-O lowered the score from 9.94 to 3.32, while Pim-C reduced it from 8.76 to 3.04. The percent reduction in EASI score was −41.64% and −43.61% for Tof-O and Pim-C, respectively. This reduction was comparable between treatment groups. After 2 weeks of treatment with Tof-O, 30.3%, 8.9%, and 2.2% of patients showed 50%, 75%, and 90% improvement in EASI, respectively. Similarly, after 4 weeks, 73%, 44.4%, and 20% of patients showed 50%, 75%, and 90% improvement in EASI, respectively. Interestingly, the percentage of participants achieving EASI 75 was numerically higher in Tof-O compared to Pim-C at both week 2 (8.9% vs. 5.4%) and week 4 (44.4% vs. 43.5%). Additionally, EASI 90 was also higher for Tof-O at week 4 (20.0% vs. 16.3%), while it was comparable between the two groups at week 2 [Table 2]. However, the differences between the groups were statistically nonsignificant for all EASI improvements.
Table 2:
Efficacy parameters
At week 2, 5.6% and at week 4, 44.9% of patients treated with Tof-O achieved a vIGA-AD score of 0 or 1 with a 2-point improvement. The improvement in vIGA-AD score after Tof-O treatment was comparable to Pim-C treatment at week 2. Impressively, the improvement in vIGA-AD score in Tof-O-treated patients was numerically higher than Pim-C (44.9% vs. 33.7%) at week 4; however, the difference was statistically nonsignificant (P = 0.122) [Table 2]. The 28-day treatment with Tof-O significantly (P < 0.0001) reduced %BSA affected at the end of weeks 2 and 4 from baseline with percentage reduction of −1.78% and −2.82%, respectively. Similar reduction was observed with the Pim-C group (−2.00% and −3.10% at weeks 2 and 4, respectively), suggesting non-inferiority of Tof-O to Pim-C. The Tof-O treatment also showed significant (P < 0.0001) reduction in pruritus at weeks 2 and 4 compared to baseline. The reduction in pruritus scale was −0.56 at week 2 and −1.04 at week 4 in the Tof-O group. The reduction in pruritus in patients who received Tof-O was comparable with patients who received Pim-C [Table 2].
Safety
A total of seven treatment-emergent adverse events (TEAEs) were reported during the trial. Among these, five in Tof-O include pyrexia (n = 2), rash (n = 1), application site pruritus (n = 1), and eczema (n = 1), while two in the Pim-C group, mainly pyrexia, were reported (observed). Of seven AEs, one AE (application site eczema) was marked as probable/likely, while another AE (application site pruritus) was marked as possible. All reported adverse events (AEs) were mild (grade 1) in nature and resolved in due course, with no deaths and no serious adverse events (SAEs) being documented. There were no clinically significant changes observed in laboratory evaluation, physical examination, and vital signs during the trial period. No patient discontinued from the trial due to AE. Overall, the safety profile of the Tof-O was found to be favourable, with no major safety concerns reported, indicating that the novel ointment formulation Tof-O was safe and well-tolerated in patients with mild-to-moderate AD.
Discussion
The novel Tof-O was not only effective in improving symptoms in patients with mild-to-moderate AD, we believe that the findings of this trial may hold clinical importance and would be of interest to clinicians in India and globally for the following reasons: First, the existing treatment options such as topical corticosteroids (TCSs) and calcineurin inhibitors (TCIs) are unsuitable for use on sensitive areas like faces, groin, and genital parts and thereby hampers managing symptoms in these specific area.[13-15] The Tof-O provides a promising solution and thus enabling targeted application to these challenging areas. Second, the trial also demonstrates that Tof-O is noninferior to Pim-C, which is a first-line treatment for mild-to-moderate AD. This suggests that Tof-O might offer an alternative first-line treatment for AD patients. Further, the safety profile of Tof-O was favourable, with no SAEs reported. The favourable safety profile of Tof-O is an added advantage given that some of the current treatments for AD have significant safety concerns.[8,15,16]
The current trial showed that JAK inhibition with Tof-O in the studied population with mild-to-moderate AD demonstrated improvement in efficacy parameters over 4 weeks compared to baseline data, with no major safety concerns. Herein, we evaluated the change in EASI score at week 4 from baseline in mild-to-moderate AD patients following Tof-O topical treatment. EASI scoring, a widely used method to evaluate the effectiveness of treatment for AD, involves the assessment of four major signs of AD, which are erythema, oedema/papulation, excoriation, and lichenification.[12] Tof-O significantly (P < 0.0001) improved the EASI score from baseline after 4 weeks of treatment, which is attributed to the reduction in the severity of these four signs of AD. Our findings are in line with a previous trial of Bissonnette and colleagues, which showed that percentage changes in EASI score from baseline data were significantly higher in the tofacitinib ointment group at week 4.[11]
Additionally, it is also evident from the results that the majority of patients had 50% improvement in EASI, and a considerable number of patients had 75% and 90% improvement in EASI. This highlights the efficacy of Tof-O in improving the EASI score for the majority of the participants after 4 weeks of treatment. The observed improvement in EASI was aligned with already established Pim-C therapy. Notably, these outcomes are consistent with the findings from the phase 2a trial led by Bissonnette and co-authors, where ~90%, ~62%, and ~42% of patients achieved EASI 50, 75, and 90, respectively.[11] Further, the vIGA-AD scoring is one of the widely used methods to assess the overall severity of lesions of AD patients.[17] The results of this trial showed that Tof-O treatment showed a 2-point improvement in vIGA-AD score for 44.9% of patients, indicating improvement in AD severity in the majority of the patients at week 4. Nonetheless, achieving a 2-point improvement in vIGA-AD score could have significant clinical implications in measuring clinical outcomes and severity of AD, leading to improved disease management and better quality of life for patients.[17]
Given that pruritus is the most prevalent symptom in AD patients, primarily due to the overexpression of IL-4 and IL-13, targeting JAK signalling may mitigate pruritus.[18] In the present trial, after 2 and 4 weeks of treatment, AD patients exhibited a significant reduction in pruritic conditions from baseline, attributable to the inhibitory effects of Tof-O on JAK signalling. Importantly, this improvement in pruritus aligns with the efficacy demonstrated by the Pim-C treatment arm.
Moreover, Tof-O treatment not only improved the signs and symptoms of AD patients, but it also reduced the affected %BSA of AD patients. In this trial, we enrolled AD patients with 5–20% affected BSA. There was a reduction of − 1.78% and − 2.82% at week 2 and 4, respectively, in the affected %BSA of AD patients who received Tof-O treatment. Apart from a promising efficacy profile, Tof-O was also found safe and well-tolerated in mild-to-moderate AD patients during 4 weeks of treatment. All the AEs reported during the trial were mild in nature and resolved in due course. No patient discontinued due to AEs or required discontinuation of treatment. Additionally, no systemic abnormality was observed as assessed by laboratory investigations, PE, and vital signs.
While our trial provided promising results regarding the efficacy and safety of Tof-O, it is important to acknowledge certain limitations that should be considered. The open-label design and absence of a placebo (control) arm introduce an inherent constraint. Further, the trial may not have had a sufficiently long follow-up period to capture potential long-term serious AEs. Therefore, additional long-term studies with a placebo arm, larger sample sizes, extended follow-up periods, and comprehensive adverse event monitoring are needed to further investigate the efficacy and safety of Tof-O along with the occurrence of any potential long-term serious AEs.
Conclusion
In a nutshell, the JAK inhibition by Tof-O resulted in significant improvement in efficacy parameters, including EASI, vIGA-AD, pruritus, and %BSA affected, without any major safety concerns. Overall, it can be concluded that Tof-O treatment is safe and effective in mild-to-moderate AD patients and has promising applicability to manage the AD condition of patients in real-world practice.
Author contributions
ARC, HGZ, DVP: Contributed to conception and design of the trial, acquisition and interpretation of data, critically revised the manuscript for important intellectual content, as well as approved the contents of the manuscript. All Tof-O in AD principal investigators: Conducted the clinical trial, involved in the acquisition of data. All authors made substantial contributions to this trial and agree to be accountable for all aspects of the work.
Ethical approval statement
The trial was conducted after approval from the Institutional Ethical Committee (IEC), associated with each respective clinical trial site. This trial is prospectively registered on the Clinical Trial Registry of India (CTRI) with registration numbers CTRI/2022/07/044136 (Registered on: 19 July 2022). The trial was conducted in accordance with approved protocol, the ethical principles of International Conference on Harmonization (ICH) E6 (R2) guideline on Good Clinical Practice (GCP), Declaration of Helsinki (Fortaleza, Brazil, October 2013), and any other applicable regulatory authorities. All participants provided a written informed consent form to participate in the trial.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
This trial was funded by Intas Pharmaceuticals Ltd., Ahmedabad, Gujarat, India.
Conflict of interest
This study was financially supported by Intas Pharmaceuticals Ltd., Gujarat, India. The sponsor was involved in the study design; however, data collection, analysis, and interpretation were conducted independently at respective study sites under the supervision of the principal investigator, ensuring an unbiased assessment of results. The authors declare that they have no financial or non-financial conflicts of interest related to this trial.
Disclosure
Dr. Alok Chaturvedi, Dr. Hemant Zaveri, and Dr. Dhaval Patel are employees of Intas Pharmaceuticals Limited, Ahmedabad, India.
Consent for publication
Consent for publication was obtained from all authors, the participants, or legally authorized representatives involved in this trial.
Availability of data and materials (data sharing statement)
The clinical trial data are available upon reasonable request to the corresponding author.
인도직구 미녀와탈로
구글에 미녀와탈모
토파타스 연고
토파타스 크림
토파타스 직구
토파타스 미녀와탈모