Small Molecule JAK Inhibitor Research Articles

Off-label use of Baricitinib improves moderate and severe atopic dermatitis in China through inhibiting MAPK and PI3K/Akt/mTOR pathway via targeting JAK-STAT signaling of CD4+ cells.

As an inflammatory disease with a disrupted immune system, cytokine disorders in atopic dermatitis (AD) are closely related to the abnormal activation of JAK-STAT signal pathway. The critical relevance of the JAK-STAT signaling pathway to the pathogenesis of AD provides a strong rationale for JAK inhibitor research. Baricitinib, a small-molecule oral JAK inhibitor, has been proven to inhibit JAK-STAT signaling in a variety of diseases, including AD. It is currently available in China for off-label use. However, its efficacy in China and its mechanism are rarely reported. In our study, we found that the immune status of patients with moderate and severe AD was hyperactive. Among the 49 known immunotherapy targets, JAK1 and JAK2 genes on lymphocytes of AD patients were significantly upregulated, which was closely related to the symptom severity in moderate and severe AD patients. Baricitinib can improve immune hyperresponsiveness and clinical symptoms in moderate and severe AD by inhibiting the activation of Th2 cell subsets and the secretion of Th2-type cytokines through MAPK, mTOR and PI3K-Akt signaling pathways, providing an important theoretical basis for clinical off-label use of Baricitinib to treat moderate and severe AD.

Safety and Effectiveness of Tofacitinib in Treating Polyarticular Course Juvenile Idiopathic Arthritis.

Polyarticular course juvenile idiopathic arthritis (pcJIA) is a form of arthritis that affects at least five joints at a time and presents before the age of 16. Its most common symptoms are pain, swelling, redness, and a limited range of motion, making it incredibly difficult for patients diagnosed to function in daily life. Historically, the leading treatment options have consisted of non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs) such as methotrexate. However, these drugs have serious toxic side effects associated with long-term use in addition to being ineffective in refractory cases. Recently, small molecule biologics have emerged as an alternate treatment to pcJIA. Tofacitinib is a small molecule JAK inhibitor that blocks the JAK/STAT cascade and decreases the transcription of genes responsible for immune function. We conducted a risk-benefit analysis to determine the viability of tofacitinib as a treatment for pcJIA. In our review, we found the side effect profile of tofacitinib to be relatively mild, with many of the serious adverse side effects occurring in those immunocompromised and those with impaired renal and hepatic metabolism. Overall, we have determined that tofacitinib has the potential to be effective in reducing flare-ups and lowering erythrocyte sedimentation rate (ESR) in immunocompetent patients with pcJIA. Additionally, our review has found that tofacitinib has the potential to be effective in patients who are refractory to traditional treatment. However, large-scale clinical trials are needed to determine if this effect holds true in younger pediatric populations, as limited data surrounds this demographic.

Identification of HHT-9041P1: A novel potent and selective JAK1 inhibitor in a rat model of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic systemic disease associated with long-term disability and premature mortality. If left untreated, it can seriously affect patients’ quality of life. The JAK-STAT signal transduction process is known to affect the occurrence and development of RA, and small molecule JAK inhibitors, such as tofacitinib, have been identified as treatments for RA. However, tofacitinib is a non-selective JAK inhibitor that was found to be associated with dose-limiting tolerability and safety issues, such as anemia in phase 2 dose-ranging studies. Therefore, we developed a selective JAK1 inhibitor, HHT-9041P1, to overcome target-related adverse reactions. We used enzyme and cytokine potency assays in vitro as well as the collagen-induced arthritis (CIA) model in vivo to explore the efficacy and mechanism. In vitro, HHT-9041P1 was diluted (0.017 nM–1 mM) in DMSO) and mixed with JAK1, JAK2, JAK3 or TYK2 kinases for use in the respective assays for inhibitory activity and selectivity evaluation. Fresh human PBMCs were activated and incubated with 100 ng/mL cytokine IL-6 or 20 ng/mL GM-CSF for use in the investigation of the immune mechanism. In vivo, HHT-9041P1 (1 mg/kg, 3 mg/kg and 10 mg/kg) was administered by oral gavage twice daily to CIA model Lewis rats from Day 8 to Day 29 for paw swelling and arthritis score evaluation. At the end of the experiment, the rats were sacrificed before collection of the hind ankle joint, spleen and blood for analysis of inflammation, arthritis phenotypes, inflammatory cytokine expression and Th1 cell proportions. As expected, HHT-9041P1 showed 10-fold greater selectivity for JAK1 over JAK2, and 23-fold greater selectivity over JAK3 in cellular assays. The high selectivity of HHT-9041P1 was also validated by in vivo safety studies. HHT-9041P1 demonstrated significant efficacy in a rat model of collagen-induced arthritis (CIA) and was associated with reduced helper T Cell 1 (Th1) cell differentiation. HHT-9041P1 also exhibited excellent pharmacokinetics properties. Thus, HHT-9041P1 was identified as a candidate for clinical development with many options for the treatment of RA.

De novo design of dual-target JAK2, SMO inhibitors based on deep reinforcement learning, molecular docking and molecular dynamics simulations

Triple-negative breast cancer (TNBC) and HER2-positive breast cancer are particularly aggressive and the effectiveness of current therapies for them is limited. TNBC lacks effective therapies and HER2-positive cancer is often resistant to HER2-targeted drugs after an initial response. The recent studies have demonstrated that the combination of JAK2 inhibitors and SMO inhibitors can effectively inhibit the growth and metastasis of TNBC and HER2-positive drug resistant breast cancer cells. In this study, deep reinforcement learning was used to learn the characteristics of existing small molecule inhibitors of JAK2 and SMO, and to generate a novel library of small molecule compounds that may be able to inhibit both JAK2 and SMO. Subsequently, the molecule library was screened by molecular docking and a total of 7 compounds were selected out as dual inhibitors of JAK2 and SMO. Molecular dynamics simulations and binding free energies showed that the top three compounds stably bound to both JAK2 and SMO proteins. The binding free energies and hydrogen bond occupancy of key amino acids indicate that A8976 and A10625 has good properties and could be a potential dual-target inhibitor of JAK2 and SMO.

S718 One-Year Comparative Effectiveness of Ustekinumab vs Tofacitinib for Ulcerative Colitis After Anti-Tumor Necrosis Factor Failure

S718 One-Year Comparative Effectiveness of Ustekinumab vs Tofacitinib for Ulcerative Colitis After Anti-Tumor Necrosis Factor Failure

S1023 Assessment of Health-Related Quality of Life and Patient-Reported Outcomes With Tofacitinib Treatment Stratified by Age in Patients From the OCTAVE Ulcerative Colitis Clinical Program

S1023 Assessment of Health-Related Quality of Life and Patient-Reported Outcomes With Tofacitinib Treatment Stratified by Age in Patients From the OCTAVE Ulcerative Colitis Clinical Program

S798 Indirect Effects of Tofacitinib on Work Productivity in Patients with Ulcerative Colitis: A Mediation Analysis Between Work Productivity and the Inflammatory Bowel Disease Questionnaire

Introduction: Tofacitinib is an oral small molecule JAK inhibitor for the treatment of UC. Tofacitinib induction treatment has been shown to improve work productivity in patients (pts) with UC. However, it is unknown whether improvements in work productivity are fully explained by changes in the Inflammatory Bowel Disease Questionnaire (IBDQ) or if other factors not captured by these changes contribute. Methods: We evaluated the interrelationship between IBDQ domains (bowel, emotional, social, and systemic) and Work Productivity and Activity Impairment-UC (WPAI-UC) components (overall work productivity loss and activity impairment) among pts in the Phase 3, 8-week induction studies that evaluated tofacitinib as induction therapy for UC (OCTAVE Induction 1&2; NCT01465763; NCT01458951). A mediation model used IBDQ domains as mediators of the treatment effect on WPAI-UC components as outcomes. Work productivity loss and activity impairment can be viewed as complementary outcomes covering work and other daily activities, respectively. Analyses used all available pooled data from Week 8 in pts receiving tofacitinib/placebo. Results: There were 490 and 1,083 pts available for analysis in the models assessing work productivity loss and activity impairment, respectively. For the models evaluating work productivity loss (Figure a) and activity impairment (Figure b), the effects of tofacitinib were fully mediated via IBDQ domains; the largest effects were via the IBDQ social domain, which represented 57.4% and 58.4% of the effects of tofacitinib on work productivity loss and activity impairment, respectively (Figure a and Figure b, respectively). The impact of tofacitinib via the IBDQ emotional domain did not affect work productivity loss or activity impairment. Conclusion: This analysis suggests that the effects of tofacitinib induction therapy on work productivity loss and activity impairment in pts with UC were fully mediated via IBDQ bowel, social, and systemic domains. These findings provide insights into the interrelationship between IBDQ domains and WPAI-UC and may help inform healthcare providers on the impact of UC therapies on pts' work and leisure activities.Figure 1.: Summary of indirect (mediated through IBDQ domains) effects of tofacitinib vs placebo on the a) work productivity loss and b) activity impairment WPAI-UC components as a percentage of the total treatment effect. The WPAI-UC is a self-administered six-item questionnaire that generates four metrics: absenteeism (work time missed), presenteeism (impairment whilst working), productivity loss (overall work impairment from the combination of absenteeism and presenteeism), and activity impairment (non-work activity impairment). WPAI-UC component scores are expressed as percentages, with a higher percentage indicating greater impairment and less productivity. The IBDQ evaluates disease-related quality of life by 32 items over four domains: bowel (total domain score ranges from 10 to 70), emotional (total domain score ranges from 12 to 84), social (total domain score ranges from 5 to 35), and systemic (total domain score ranges from 5 to 35). For the total score (ranges from 32 to 224) and each domain, a higher score indicates a better quality of life. IBDQ, Inflammatory Bowel Disease Questionnaire; WPAI-UC, Work Productivity and Activity Impairment-Ulcerative Colitis

S775 Major Cardiovascular Adverse Events by Baseline Cardiovascular Risk Stratification in Patients With Ulcerative Colitis Treated With Tofacitinib: Data From the OCTAVE Clinical Program

S775 Major Cardiovascular Adverse Events by Baseline Cardiovascular Risk Stratification in Patients With Ulcerative Colitis Treated With Tofacitinib: Data From the OCTAVE Clinical Program

P1004: EFFECT AND MOLECULAR MECHANISM OF TQ05105, A NOVEL SMALL MOLECULE INHIBITOR OF JAK2 IN MYELOPROLIFERATIVE NEOPLASM

Background: The JAK2V617F gene mutation leads to upregulation of the JAK/STAT signaling pathway, which causes excessive bone marrow cell proliferation, elevated inflammatory cytokines, constitutional symptoms and shortened survival in myeloproliferative neoplasms (MPN) patients. The JAK1/2 kinase inhibitor ruxolitinib can dramatically improve disease-related symptoms, but side effect such as anemia and thrombocytopenia limit its use in a substantial proportion of patients. Several JAK2 kinase inhibitor III Clinical trials have yielded unsatisfactory outcomes recently. TQ05105 is a new small molecule inhibitor that targets JAK2 kinase. Aims: We aim to investigate the effect and molecular mechanism of TQ05105 on MPN cell lines and mouse models. Methods: We systematically measured the function of TQ05105 in MPN cell lines, including UKE1 and SET2 cells, by performing proliferation, apoptosis and colony-forming assays. RT-PCR and inflammatory factor multi-assay kit was used to detect the secretion of inflammatory factors such as TNF-α, IL-1β, MCP-1 in mRNA level and protein level respectively. CFU-E and BFU-E assays were performed on MPN cell lines and primary cells. In vivo, TQ05105 was evaluated in JAK2V617F Jak2V617F transplant mouse model and MPL515 retroviral mouse model. Mice were orally administrated with placebo, 25 mg/kg (bid) and 50 mg/kg (bid) every day for 4 weeks. Flow cytometry analysis was performed to determine the proportion of different hematopoietic progenitor cell populations. In addition, HE staining and Gomori staining was used to detect the changes in the spleen and bone marrow. Results: In UKE1 and SET2 cell lines, TQ05105 can inhibit the proliferation and induced cell apoptosis, notably reduce the expression of cytokines, including TNF-α, IL-1 and MCP-1. According to Western blot results, the phosphorylation of JAK/STAT signaling pathway associated proteins JAK2, STAT3 and STAT5 were significantly suppressed by TQ05105. Furthermore, compared to the control group, TQ05105 can strongly limit the ability of UKE1 cell lines, SET2 cell lines and primary cells from MPN patients (PMF, PV, ET) to form BFU-E and CFU-GM. TQ05105 can striking reduce mouse spleen volume, along with favorable impact on leukocyte and erythrocyte counts in Jak2V617F transplant mouse model. The proportion of stem and progenitor cells, especially CMPs and MEPs, was considerably reduced in mice after treatment with TQ05105. HE staining showed remarkably Spleen response such as recovering structure, reduced infiltration of erythrocytes and suppressed proliferation of megakaryocytes. MPLW515L retroviral mouse model recapitulated the feature of myelofibrosis, application of TQ05105 in this model resulted in reduction of the spleen volume, extramedullary hematopoiesis, leukocyte and platelets count, bone marrow fibrosis and decreased fraction of CMPs and MEPs. Summary/Conclusion: TQ05105, as a novel small molecule JAK2 inhibitor, can inhibit cell proliferation, induce cell apoptosis and decrease inflammatory cytokines by affecting the JAK/STAT signaling pathway. In vivo experiments further proved that TQ05105 can reduce spleen size and improve disease-related symptoms of MPN, indicating that it is a promising therapeutic drug for MPN.

Tofacitinib Response in Ulcerative Colitis (TOUR): Early Response After Initiation of Tofacitinib Therapy in a Real-world Setting.

Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Using a novel electronic reporting tool, we aimed to prospectively describe the onset of tofacitinib efficacy during induction therapy in a real-world study. Patient-reported outcome data (PROs) including the simple clinical colitis activity index (SCCAI), PRO Measurement Identification Systems (PROMIS) measures, and adverse events were collected daily for the first 14 days and at day 28 and 56. Paired t tests and P for trend were utilized to compare changes in SCCAI over time. Bivariate analyses and logistic regression models were performed to describe response (SCCAI <5) and remission (SCCAI ≤2) by clinical factors. Of all included patients (n = 96), 67% had failed ≥2 biologics, and 61.5% were on concomitant steroids. Starting at day 3, PROs showed significant and persistent decline of the mean SCCAI (-1.1, P < 000.1) including significantly lower SCCAI subscores for stool frequency (-0.3; P < .003), bleeding (-0.3; P < .0002) and urgency (-0.2; P < .001). Steroid-free remission at day 14, 28, and 56 was achieved in 25%, 30.2%, and 29.2% of patients, respectively. Neither prior biologics nor endoscopic severity were independently predictive of response or remission in multivariate models. Numeric improvements in all PROMIS measures (anxiety, depression, social satisfaction) were seen through day 56. Rates of discontinuation due to adverse events were low. In this prospective real-world study, tofacitinib resulted in a rapid and persistent improvement in UC disease activity PROs. The safety findings were consistent with the established safety profile of tofacitinib.

Real-world characteristics, treatment experiences and corticosteroid utilisation of patients treated with tofacitinib for moderate to severe ulcerative colitis

BackgroundTofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. We aimed to describe the real-world treatment experience and corticosteroid utilisation of patients treated with tofacitinib in a US claims database.MethodsPatients with a UC diagnosis who initiated tofacitinib, vedolizumab or tumour necrosis factor inhibitor (TNFi) treatment between May 2018 and July 2019 were identified from the Optum Research Database. Demographic and clinical characteristics of patients who initiated tofacitinib, vedolizumab or TNFi were described. Oral corticosteroid use prior to and following tofacitinib initiation was evaluated. Tofacitinib adherence (proportion of days covered) and continuation was assessed for 6 months following initiation. Analyses were descriptive and stratified by prior biologic use (naïve, 1 or ≥ 2; minimum of 12 months prior to tofacitinib initiation).ResultsAmong patients initiating tofacitinib (N = 225), mean age was 45.6 (SD 16.5) years and 50.2% were female. Of these, 43 (19.1%) patients were biologic-naïve and 182 (80.9%) had prior biologic use (92 [40.9%], 1 prior biologic; 90 [40.0%], ≥ 2 prior biologics). Among patients with 1 prior biologic, 82.6% were previously treated with a TNFi. Among patients with ≥ 2 prior biologics, 54.4% were previously treated with vedolizumab and a TNFi, 16.7% with two TNFi and 28.9% with ≥ 3 prior biologics. In the 6 months prior to tofacitinib initiation, 65.8% of patients had received oral corticosteroids (74.4%, 60.9% and 66.7% for biologic-naïve, 1 and ≥ 2 prior biologics, respectively). The proportion of patients with ongoing oral corticosteroid use 3–6 months after tofacitinib initiation decreased to 13.3% (9.3%, 18.5% and 10.0% for biologic-naïve, 1 and ≥ 2 prior biologics, respectively), and 19.6% of patients discontinued oral corticosteroid use during the 6 months after tofacitinib initiation. Overall, tofacitinib adherence, as determined by the mean proportion of days covered during the 6-month follow-up, was 0.7 (median 0.8). During the 6-month follow-up, 84.9% of patients continued tofacitinib.ConclusionsAmong patients with UC initiating tofacitinib, the majority had prior biologic use. Tofacitinib adherence was high, discontinuation was low and oral corticosteroid utilisation decreased irrespective of prior biologic use. Further research with longer follow-up and a larger sample size is required.

Association of C-reactive Protein and Partial Mayo Score With Response to Tofacitinib Induction Therapy: Results From the Ulcerative Colitis Clinical Program.

Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). These post hoc analyses assessed associations between C-reactive protein (CRP), partial Mayo score (PMS), and efficacy outcomes during tofacitinib induction in UC. Patients received tofacitinib 10mg twice daily (BID) in an 8-week, phase 2 induction study and 2 identical, 8-week, phase 3 induction studies (OCTAVE Induction 1&2); induction nonresponders (IndNR) received an additional 8 weeks of tofacitinib 10mg BID in an open-label, long-term extension study. Associations between CRP and PMS, and efficacy outcomes (clinical response, clinical remission, endoscopic improvement, and endoscopic remission) were analyzed using univariate and multivariable logistic regression and receiver operating characteristic curves. Changes from baseline in the logarithm of CRP ([log]CRP) and PMS at week 4 were associated with clinical response at week 8 (univariate: per unit, odds ratio [OR], 0.55 [95% confidence interval (CI), 0.48-0.62]; and 0.42 [0.37-0.47], respectively). Among IndNR, change from baseline in PMS at week 8 was associated with clinical response at week 16 (univariate: per unit, OR, 0.59; 95% CI, 0.46-0.75). C-reactive protein at week 4 (area under the curve [AUC] > 0.6) and PMS at weeks 2 and 4 (AUC, > 0.7) generally exhibited predictive value for week 8 efficacy outcomes. Patients who achieved clinical response at week 8 had larger decreases in CRP and PMS at week 4 than patients who did not. IndNR who achieved clinical response at week 16 with extended tofacitinib induction had a larger decrease in PMS at week 8 vs those who did not. ClinicalTrials.gov:NCT00787202;NCT01465763;NCT01458951;NCT01470612.

The efficacy and safety of Janus kinase inhibitors in patients with atopic dermatitis: A systematic review and meta-analysis

To the Editor: Current treatments may not satisfactorily relieve symptoms of atopic dermatitis (AD), especially severe AD.1Leung D.Y. Guttman-Yassky E. Assessing the current treatment of atopic dermatitis: unmet needs.J Allergy Clin Immunol. 2017; 139: S47-S48Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Janus kinase inhibitors (JAKis) are increasingly being used in the treatment of AD, with both topical (ruxolitinib cream) and oral (upadacitinib and abrocitinib) versions recently receiving US Food and Drug Administration approval for this indication.2Kim B.S. Sun K. Papp K. Venturanza M. Nasir A. Kuligowski M.E. Effects of ruxolitinib cream on pruritus and quality of life in atopic dermatitis: results from a phase 2, randomized, dose-ranging, vehicle- and active-controlled study.J Am Acad Dermatol. 2020; 82: 1305-1313Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar We systematically review the efficacy and safety of JAKis among existing randomized, double-blinded, and placebo-controlled clinical trials of JAKis for the treatment of AD. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and registered in PROSPERO (CRD42020188514). We searched electronic databases (Embase, PubMed, and Cochrane Central Register of Controlled Trials) from their inception to September 16, 2021. We also searched unpublished clinical trials at ClinicTrials.gov. The search strategies and methods are provided in Supplementary Materials (available via Mendeley at https://data.mendeley.com/datasets/89x8s56p5z/2). We initially identified 1209 records from all 4 databases, as summarized in Supplementary Fig 1 (available via Mendeley at https://data.mendeley.com/datasets/89x8s56p5z/2). Of these, a total of 25 studies were finally included in the meta-analysis, including 8 studies on topical JAKis and 17 on oral JAKis. There were 9931 participants, consisting of 2383 involved in studies on topical JAKis and 7548 in studies on oral JAKis. Four kinds of topical JAKis (tofacitinib ointment, delgocitinib ointment, delgocitinib cream, and ruxolitinib cream) were applied, and 5 kinds of oral JAKis (baricitinib, abrocitinib, ASN002, SHR0302, and upadacitinib) were given at varying dosages. The detailed characteristics of the included studies are summarized in Supplementary Table I (available via Mendeley at https://data.mendeley.com/datasets/89x8s56p5z/2). We also assessed the risk of bias, as summarized in Supplementary Fig 2 (available via Mendeley at https://data.mendeley.com/datasets/89x8s56p5z/2) and Supplementary Table II (available via Mendeley at https://data.mendeley.com/datasets/89x8s56p5z/2). Overall, compared with placebos, the use of JAKis showed a significant improvement in the lesion score and pruritus: Eczema Area and Severity Index score (standard mean difference [95% CI], −0.79 [−0.97 to −0.61]; P < .00001); investigators’ global assessment score (odds ratio [OR] [95% CI], 5.08 [3.78-6.82]; P < .00001); and pruritus numerical rating scale (standard mean difference [95% CI], −0.49 [−0.67 to −0.32]; P < .00001) (Supplementary Table III [available via Mendeley at https://data.mendeley.com/datasets/89x8s56p5z/2] and Supplementary Figs 3 to 5 [available via Mendeley at https://data.mendeley.com/datasets/89x8s56p5z/2]). Although no significant adverse effects (AEs) were found for the topical JAKis, the oral JAKis showed an increased risk of at least 1 AE (OR [95% CI], 1.23 [1.11-1.36]; P < .0001) and the following most frequently reported AEs: gastrointestinal disorders (OR [95% CI], 2.49 [1.84-3.37]; P < .00001), nasopharyngitis (OR [95% CI], 1.23 [1.04-1.46]; P = .02), and headache (OR [95% CI], 1.57 [1.23-2.00]; P = .0003) (Supplementary Table IV, available via Mendeley at https://data.mendeley.com/datasets/89x8s56p5z/2). No malignancy or death was reported. Previous systematic reviews have reported that herpes zoster and serious infections are common in JAKi treatment.3Olivera P.A. Lasa J.S. Bonovas S. Danese S. Peyrin-Biroulet L. Safety of Janus kinase inhibitors in patients with inflammatory bowel diseases or other immune-mediated diseases: a systematic review and meta-analysis.Gastroenterology. 2020; 158: 1554-1573Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 4Bechman K. Subesinghe S. Norton S. et al.A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis.Rheumatology (Oxford). 2019; 58: 1755-1766Crossref PubMed Scopus (140) Google Scholar, 5Khoo J.K. Barnes H. Key S. Glaspole I.N. Östör A.J. Pulmonary adverse events of small molecule JAK inhibitors in autoimmune disease: systematic review and meta-analysis.Rheumatology (Oxford). 2020; 59: 2217-2225Crossref PubMed Scopus (17) Google Scholar However, these were infrequent in our systematic review. Creatine phosphokinase level elevations were mentioned in baricitinib and upadacitinib treatments: even though patients with creatine phosphokinase level elevation were asymptomatic, the incidence and relationship with JAKi therapy remain to be further investigated. Undoubtedly, long-term follow-up trials are needed for better assessing the safety profile. In conclusion, this systematic review and meta-analysis showed that JAKis are a promising treatment option for AD. Because of the higher risk of gastrointestinal disorders, nasopharyngitis, and headache during oral JAKi treatments, more attention should be paid to the AEs of patients treated with oral JAKis. Further studies with long follow-up in different conditions will be needed to fully elucidate the safety profile of the different JAKis. None disclosed.

Exploring binding interaction of baricitinib with bovine serum albumin (BSA): multi-spectroscopic approaches combined with theoretical calculation

Baricitinib (BRT) is an orally administered small molecule JAK inhibitor, which mainly inhibits JAK-1 and JAK-2. And it is used to treat autoimmune diseases such as rheumatoid arthritis (RA), atopic dermatitis and systemic lupus erythematosus. In this paper, the interaction between BRT and bovine serum albumin (BSA) was studied by fluorescence spectroscopy, UV spectrophotometry, fourier transform infrared spectroscopy (FT-IR) and molecular docking approaches. It has been proved that the fluorescence quenching mechanism of BSA in the mutual complexation process of BRT and BSA was a static quenching. The number of binding sites (n) of BRT-BSA complex was about 1. The binding site was located at site II of BSA and its binding constant was about 5.01 × 103 M−1 at 298 k. It is indicated that there was a weak binding between BRT and BSA. By analyzing the sign and magnitude of the free energy change (ΔG0), enthalpy change (ΔH0) and entropy change (ΔS0), it can be found that the complexation process of BRT and BSA is spontaneous and enthalpy-driven. Van der Waals forces and hydrogen bonds play a critical part in the complexation process of BRT with BSA. Based on synchronous fluorescence and three-dimensional fluorescence, it was found that the microenvironment around the residues of Tyr and Trp of BSA had no significant change after binding to BRT. FT-IR and molecular docking studies confirmed that the secondary structure of protein changed during the complexation of BRT with BSA. Experimental results showed that the addition of some metal ions (Ca2+, Zn2+, Cu2+ and Co2+) significantly increased the binding interaction of BRT with BSA. This study is helpful to further evaluate the pharmacological characteristics of BRT and provides an important reference for the design of new drugs.

P607 Efficacy and safety of tofacitinib in Ulcerative Colitis patients with extraintestinal manifestations in OCTAVE Open

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Data from OCTAVE Induction 1&amp;2 and OCTAVE Sustain demonstrated that a history of extraintestinal manifestations (EIMs) was shown not to influence the efficacy of tofacitinib 10 mg twice daily (BID).1 We explored the efficacy and safety of tofacitinib in patients (pts) with and without a history of EIMs in the open-label, long-term extension study, OCTAVE Open. Methods Efficacy and safety (treatment-emergent serious adverse events of interest) data from OCTAVE Open (NCT01470612) were analysed by history of EIMs. Tofacitinib dose in OCTAVE Open was based on baseline remission status; pts in remission received tofacitinib 5 mg BID; all others received 10 mg BID. The frequency of pre-defined prior and active EIMs at OCTAVE Open baseline (peripheral arthritis [PA]; sacroiliitis; ankylosing spondylitis [AS]; myopathy; pyoderma gangrenosum; erythema nodosum; scleritis, episcleritis; uveitis, iritis; oral ulcer/stomatitis; and thromboembolic disorder) and new occurrences of EIMs at Month (M)36, or at early termination, were evaluated in pts with non-missing data. Results In OCTAVE Open, 113/935 (12.1%) had EIMs at baseline (7/174 [4.0%] tofacitinib 5 mg BID; 106/761 [13.9%] tofacitinib 10 mg BID). Pts with EIMs were more likely to be female (61.1%), have a total Mayo score of ≥3 (93.8%) at OCTAVE Open baseline and have disease duration ≥6 years (60.2%), prior tumour necrosis factor inhibitor failure (61.9%), prior immunosuppressant treatment (86.7%) or corticosteroid use (54.0%) at induction study baseline, compared to those without EIMs (38.8%, 78.7%, 49.6%, 50.9%, 74.5% and 43.9%, respectively). There was no consistent trend in the proportions of pts with and without EIMs at baseline who met the OCTAVE Open efficacy endpoints (Table 1). Tofacitinib 5 and 10 mg BID had comparable safety in pts with or without EIMs at baseline (Table 2). In pts with EIMs at baseline, the most frequent active EIMs were PA (51/113 [45.1%]), sacroiliitis (6/113 [5.3%]), oral ulcer/stomatitis (5/113 [4.4%]), myopathy (4/113 [3.5%]) and AS (4/113 [3.5%]). At M36, 4/428 [0.9%] had new occurrences of PA and there were no new occurrences of sacroiliitis (0/468 [0%]), oral ulcer/stomatitis (0/460 [0%]), myopathy (0/469 [0%]) or AS (0/469 [0%]). Conclusion The presence or absence of a history of EIMs at baseline did not impact the long-term efficacy and safety of tofacitinib in pts with UC. New occurrences of EIMs were infrequent. Reference 1. Rubin DT et al. Therap Adv Gastroenterol 2021; 14: 1–12.

P286 Sustained improvement in health-related quality of life outcomes in patients with Ulcerative Colitis with long-term tofacitinib treatment in the open-label extension study, OCTAVE Open

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Tofacitinib induction and maintenance therapy has previously been shown to improve health-related quality of life (HRQoL) outcomes. Here, we present HRQoL data from patients (pts) with UC who received tofacitinib 5 or 10 mg twice daily (BID) in the Phase 3 open-label, long-term extension (OLE) study (OCTAVE Open; NCT01470612), up to Month (M)72. Methods Proportions of pts with an Inflammatory Bowel Disease Questionnaire (IBDQ) total score ≥170, and EuroQol-5D (EQ-5D) and Short Form-36 Health Survey (SF-36) scores were analysed up to M72 in 4 subpopulations in the OLE study: ‘maintenance remitters’ completed OCTAVE Sustain in remission and received tofacitinib 5 mg BID in the OLE study; in contrast, ‘maintenance treatment failures’ (induction responders who experienced treatment failure), ‘maintenance non-remitters’ and ‘induction non-responders (IndNR)’ received tofacitinib 10 mg BID in the OLE study (Figure 1). Data were analysed for each subpopulation overall and stratified by prior tumour necrosis factor inhibitor (TNFi) failure, prior immunosuppressant failure and baseline corticosteroid use. Results Baseline demographics and clinical characteristics for each subpopulation are shown in Table 1. Among the 163 maintenance remitters, HRQoL outcomes were maintained up to M72: 80.0% of pts had an IBDQ total score ≥170 (Figure 1); changes from baseline in EQ-5D scores up to M72 and SF-36 scores up to M33 were minimal (eg M72 EQ-5D utility score -0.07 [standard deviation 0.10]; M33 SF-36 physical functioning score -1.3 [8.3]). Among pts continuing long-term tofacitinib treatment, improvement in IBDQ total score was maintained/achieved by M2 (first post-baseline assessment), and was stable up to M72, with maintenance treatment failures and IndNR subpopulations experiencing the largest improvements from baseline (Figure 1). Similar trends were observed for improvement in EQ-5D and SF-36 scores. Improvements in HRQoL outcomes were independent of prior TNFi failure, prior immunosuppressant failure or baseline corticosteroid use, eg in maintenance remitters with prior TNFi failure, 90.9% of pts had IBDQ total score ≥170 at M60 vs 88.9% of pts without prior TNFi failure. Conclusion Sustained beneficial effects in HRQoL were observed among pts continuing long-term tofacitinib treatment in OCTAVE Open. In maintenance remitters, improvements in all HRQoL outcomes were maintained with tofacitinib therapy. In pts who entered the OLE study not in remission and received tofacitinib 10 mg BID, HRQoL improvements were observed within the first 2 months, and were maintained up to M72, regardless of treatment history including prior TNFi failure.

OP38 Tofacitinib for the treatment of Ulcerative Colitis: An integrated summary of safety data from the global OCTAVE and RIVETING clinical trials

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib were evaluated in randomised, placebo-controlled Phase (P)2 (NCT00787202) and P3 (NCT01465763; NCT01458951; NCT01458574) studies, an open-label, long-term extension (OLE) study (NCT01470612) and an ongoing P3b/4 study (NCT03281304). We report updated tofacitinib safety analyses from the tofacitinib UC clinical programme, with inclusion of a 6-month interim analysis of data from the P3b/4 study, up to 7.8 years of tofacitinib exposure. Methods This analysis included 1157 patients (pts) receiving tofacitinib 5 or 10 mg BID from completed P2/P3/OLE studies, and the ongoing P3b/4 study (as of 20 Feb 2020; Overall+P3b/4 Cohort). Proportions and incidence rates (IRs; unique pts with events/100 pt-years [PY] of exposure) were evaluated for deaths and adverse events (AEs) of special interest. Opportunistic infections (OIs), malignancies, major adverse cardiovascular events (MACE) and gastrointestinal perforations were adjudicated. Results Table 1 shows demographics and clinical characteristics. In the Overall+P3b/4 Cohort, 1157 pts received ≥1 dose of tofacitinib 5 or 10 mg BID; 955 (83%) received a predominant dose of 10 mg BID; 397/1157 (34.3%) pts had received tofacitinib for &amp;gt;4.1 years. Median treatment duration was 623 (range, 1–2850) days (2999.7 PY of exposure). Table 2 shows safety data for AEs of special interest in the Overall+P3b/4 Cohort. IRs (95% confidence intervals) for all tofacitinib doses: deaths, 0.23 (0.09, 0.46); serious infections, 1.69 (1.26, 2.21); herpes zoster (non-serious and serious), 3.30 (2.67, 4.04); OIs, 1.03 (0.70, 1.46); malignancies (excluding non-melanoma skin cancer [NMSC]), 0.84 (0.55, 1.24); NMSC, 0.73 (0.45, 1.10); MACE, 0.29 (0.13, 0.55); deep vein thrombosis, 0.03 (0.00, 0.18); pulmonary embolism, 0.19 (0.07, 0.42); and gastrointestinal perforations, 0.10 (0.02, 0.28). IRs for AEs of special interest were similar to prior Overall Cohort analyses.1 Conclusion The safety profile of tofacitinib in pts with UC from the tofacitinib UC clinical programme was generally consistent with that of other UC therapies, including biologics, with the exception of herpes zoster.2 IRs for AEs of special interest have remained stable over an extended period of time (up to 7.8 years) with inclusion of final data from the OLE study and an interim analysis of data from the P3b/4 study.1,3

P563 Association between smoking status and the efficacy and safety of tofacitinib in patients with Ulcerative Colitis: Data from the tofacitinib clinical programme

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib were evaluated in randomised, placebo-controlled Phase (P)2 (NCT00787202) and P3 (NCT01465763; NCT01458951; NCT01458574) studies, an open-label, long-term extension (OLE) study (NCT01470612) and an ongoing P3b/4 study (NCT03281304). Ex-smokers have an increased risk of UC, but the response to therapy in these patients (pts) has not been previously evaluated. We assessed the impact of smoking status on the efficacy and safety of tofacitinib in the UC clinical programme. Methods Efficacy endpoints and adverse events (AEs) were evaluated by smoking status (ever smokers [current and ex-smokers] and never smokers) in P2 (safety only)/P3/OLE/P3b/4 studies. Efficacy endpoints were summarised by treatment allocation; pt characteristics and AEs were summarised by tofacitinib predominant dose. Results This analysis included 1156 pts (ever smokers, n=416 [36.0%; current smokers, n=59 (5.1%); ex-smokers, n=357 (30.9%)]; never smokers, n=740 [64.0%]; Table 1). Compared with never smokers, ever smokers were older and more likely to have a prior history of myocardial infarction, diabetes mellitus, or ischaemic or coronary heart disease. The proportion of pts achieving efficacy endpoints was generally similar across tofacitinib treatment groups regardless of smoking status (Table 2). AEs were reported in 88.7% of ever smokers and 83.8% of never smokers. Overall, 60.6% of ever smokers had an infection, specifically 10.8% had herpes zoster (non-serious and serious), 12.0% had a Clostridioides difficile infection and 19.5% had a lower respiratory tract infection; corresponding values for each AE among never smokers were 53.1%, 6.8%, 8.5% and 11.4% (Table 1). Major adverse cardiovascular events were reported in 1.0% of ever smokers and 0.7% of never smokers; thromboembolic events were reported in 1.0% of ever smokers and 0.9% of never smokers. Malignancies (excl. non-melanoma skin cancer [NMSC]) occurred in 2.5% of ever smokers and 1.5% of never smokers; NMSC occurred in 3.7% and 1.0%, respectively. In total, 0.6% of never smokers had colorectal cancer and there were no cases in ever smokers. Conclusion The efficacy and safety of tofacitinib were generally similar in ever smokers and never smokers. This study is limited by the combined analysis of current and ex-smokers and unknown factors such as the degree of smoking and the time between smoking cessation and UC diagnosis. These data are consistent with previous reports in the general population and pts with UC.1,2

P056 Local nanocarrier delivery of JAK1 siRNA for IBD treatment: an in vivo mouse model

Abstract Background Janus Kinases (JAK), including JAK1, JAK2, JAK3 and TYK2, have garnered increasing interest as therapeutic targets for several chronic inflammatory diseases such as inflammatory bowel disease (IBD). Although oral small molecule JAK inhibitors are being used in the clinics as an effective treatment for moderate-to-severe ulcerative colitis, nonethelessthey can lead to severe systemic immunosuppression, which is associated with an increased risk of infections. Our project aimed to develop a nanomedicine that induced JAK1 mRNA degradation within the intestinal mucosa with little systemic distribution. Methods The NEWDEAL project (H2020) developed both potent small interfering RNAs (siRNA) specific for JAK1 (siJAK1) or TNF (siTNF), and lipid nanoparticles (CL40) as nano-vectors. Their biodistribution in a mice colitis model was analyzed using labeled AF488-siJAK1 complexed to CL40 and given intrarectally (IR) for 3 consecutive days. In vivo cellular uptake was determined by FACS analysis. To induce colitis, C57/Bl6 mice received 2.5% dextrate sulfate sodium (DSS) in drinking water for 5 days. To determine efficacy of siRNAs, mice started DSS on day 0 and received IR administrations of siRNAs alone or complexed with CL40 nanoparticles on days -3, -2, -1, 1, 3, 5 and 7. On day 9, mice were sacrificed and disease activity index (DAI), histological score, fecal inflammatory markers and qPCR of targeted genes were analyzed. Results Colonic phagocytic cells - such as macrophages, neutrophils and monocytes - are the main targets cells of the siRNA-CL40 nanocomplexes following IR administration. A small percentage of cells in the draining lymph nodes captured siRNA CL40 nanocomplexes, remaining almost undetectable in spleen. This suggests a localized effect of the siRNA nanocomplexes after IR administration. While siJAK1-alone effectively reduced JAK1 mRNA expression in the distal colon, it did not improve intestinal inflammation induced by administering DSS. siTNF-CL40 treatment, though not siTNF-alone, significantly decreased intestinal inflammation in the DSS colitis model of treated mice, revealing significant protection from weight loss, lower histological scores, and reduced production of fecal lipocalin. Conclusion In summary, these results show that despite effectively reducing JAK1 mRNA expression, siJAK1 administration does not ameliorate colitis in a DSS mice model. However, we showed that a locally delivered siTNF-nanocomplex has the capacity to improve clinical, macroscopic and histological symptoms as well as fecal biomarkers in DSS colitic mice. We conclude not only that siRNA-CL40 target delivery is a good therapeutic strategy, but also that siTNF-CL40 is effective in locally treating intestinal inflammation.

P477 Rectal bleeding and stool frequency improvement with tofacitinib retreatment in patients with Ulcerative Colitis after treatment interruption: Results from OCTAVE Open

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Patients may require retreatment following treatment interruption for reasons such as adverse events or pregnancy.1 In the tofacitinib UC clinical programme, patients who responded to tofacitinib 10 mg BID during induction, and experienced treatment failure whilst receiving placebo during maintenance (OCTAVE Sustain) and subsequently received tofacitinib 10 mg BID in the open-label, long-term extension (OLE) study (OCTAVE Open; NCT01470612), comprised the retreatment subpopulation. The efficacy and safety of tofacitinib in the retreatment subpopulation have previously been reported.1 Here, we evaluated patient-reported outcomes to assess rectal bleeding and stool frequency improvement in the retreatment subpopulation in OCTAVE Open. Methods The following efficacy endpoints based on the Mayo subscores were analysed in the overall retreatment subpopulation and by prior tumour necrosis factor inhibitor (TNFi) failure status: rectal bleeding improvement (≥1 point decrease in rectal bleeding subscore [RBS] from OLE study baseline), and stool frequency improvement (≥1 point decrease in stool frequency subscore [SFS] from OLE study baseline), up to Month (M)6 in the OLE study (full analysis set, non-responder imputation). Changes from baseline in partial Mayo score (PMS), RBS and SFS at M1, by M2 clinical response status, were also analysed (as observed). Results In OCTAVE Open, 101 patients were included in the retreatment subpopulation, of which 46 (45.5%) had prior TNFi failure. Overall, at M1 and M6 of OCTAVE Open, 83.2% and 76.2% of patients had rectal bleeding improvement, respectively (Figure 1). Corresponding values for stool frequency improvement were 70.3% and 75.2%. At most time points, rates of rectal bleeding and stool frequency improvements were similar in patients with and without prior TNFi failure. Mean decrease from baseline in PMS, RBS and SFS at M1 was similar in patients with and without a clinical response at M2 (Figure 2). Conclusion In this post hoc analysis, in patients with UC who had loss of response after 8–52 weeks of treatment interruption, retreatment with tofacitinib 10 mg BID resulted in rectal bleeding and stool frequency improvement in the majority of patients by M1, which was maintained to M6, regardless of prior TNFi failure status. Reference 1. Panés J et al. J Crohns Colitis 2021. Epub ahead of print.