Oral Janus Kinase Research Articles

Pain and Inflammation as Mediators of Tofacitinib Treatment Effect on Fatigue in Patients with Ankylosing Spondylitis: A Mediation Analysis.

Tofacitinib is an oral Janus kinase inhibitor for treatment of ankylosing spondylitis (AS). Using mediation modelling, we describe interrelationships between fatigue, pain, morning stiffness, C-reactive protein (CRP) and tofacitinib treatment in patients with AS. Data from phase2 (NCT01786668)/phase3 (NCT03502616) studies of patients receiving tofacitinib 5mg twice daily (BID) or placebo were used. Initial models included treatment as the independent binary variable (tofacitinib 5mg BID versus placebo); fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F; modelA] or Bath AS Disease Activity Index [BASDAI] Q1 [modelB]) as the dependent variable; and pain (total back pain/nocturnal spinal pain [modelA] or pain measured by BASDAI Q2/3 [modelB]), morning stiffness (BASDAI Q5/6) and CRP as mediator variables. Pooled data from 370/371 patients were included in modelsA/B. Initial models demonstrated that tofacitinib treatment affects fatigue mainly indirectly via pain and morning stiffness. As a result, initial models were respecified to exclude direct treatment effect and the indirect effect via CRP. For respecified modelA, 44.0% of the indirect effect of tofacitinib treatment on fatigue was mediated via back pain/morning stiffness, 40.0% via morning stiffness alone and 16.0% via back pain alone (all P < 0.05). For respecified modelB, 80.8% of the indirect effect of tofacitinib treatment on fatigue was mediated via pain/morning stiffness and 19.2% via pain alone (both P < 0.05). In tofacitinib-treated patients with AS, improvements in fatigue were collectively mediated through combined treatment effects on morning stiffness and pain.

Baricitinib provides rapid and sustained improvements in absolute EASI and SCORAD outcomes in adults with moderate-to-severe atopic dermatitis

BackgroundBaricitinib is an oral selective Janus kinase 1/2 inhibitor approved for moderate-to-severe atopic dermatitis (AD) in adults.ObjectivesTo evaluate absolute Eczema Area and Severity Index (EASI) and SCORing of Atopic Dermatitis (SCORAD) outcomes over 16 weeks and to link disease severity categories to quality of life (QoL) improvements.MethodsThis post-hoc analysis included patients enrolled in Phase3 monotherapy (BREEZE-AD1/AD2) and topical corticosteroid (TCS) combination therapy (BREEZE-AD7) trials and analyzed baricitinib 2 and 4 mg vs. placebo. Categorical outcomes were analyzed using Fisher’s exact test.ResultsSignificantly more baricitinib-treated patients reached EASI ≤ 7 and SCORAD < 25 as early as week 1 in monotherapy and week 2 in TCS combination therapy, compared to placebo. Significant response vs. placebo was sustained until week 16 for EASI ≤ 7 (AD1/2 [p-value vs. placebo]: 2 mg = 19.9%, 4 mg = 25.4% [p = 0.001] and AD7: 2 mg = 40.4% [p = 0.087], 4 mg = 48.6% [p = 0.003]) and SCORAD < 25 (AD1/2: 2 mg = 12.2%, 4 mg = 19.4% [p = 0.001] and AD7: 2 mg = 30.3% [p = 0.025], 4 mg = 34.2% [p = 0.004]) severity categories. These effects were accompanied by rapid improvements in QoL.ConclusionBaricitinib-treated patients rapidly achieved recommended absolute EASI and SCORAD treatment outcomes which were sustained until week 16. Improvements in QoL were greater than EASI severity categories reflected, indicating that physician-assessed scores do not necessarily correlate with patients’ impression of AD severity.

Upadacitinib for moderate-to-severe atopic dermatitis: stratified analysis from three randomized phase 3 trials by key baseline characteristics.

Atopic dermatitis (AD) is a heterogeneous inflammatory skin disease with different clinical phenotypes based on factors such as age, race, comorbidities, and clinical signs and symptoms. The effect of these factors on therapeutic responses in AD has only been scarcely studied and not for upadacitinib. Currently, there is no biomarker predicting response to upadacitinib. Evaluate the efficacy of the oral Janus kinase inhibitor upadacitinib across patient subgroups (baseline demographics, disease characteristics, and prior treatment) in patients with moderate-to-severe AD. Data from phase 3 studies (Measure Up 1, Measure Up 2, and AD Up) were utilized for this post hoc analysis. Adults and adolescents with moderate-to-severe AD were randomized to receive once daily oral upadacitinib 15 mg, upadacitinib 30 mg, or placebo; patients enrolled in the AD Up study received concomitant topical corticosteroids. Data from the Measure Up 1 and Measure Up 2 studies were integrated. A total of 2584 patients were randomized. A consistently greater proportion of patients achieved at least 75% improvement in the Eczema Area and Severity Index, a 0 or 1 on the validated Investigator Global Assessment for Atopic Dermatitis, and improvement in itch (including an achievement of a reduction of ≥4; and score of 0/1 in Worst Pruritus Numerical Rating Scale) with upadacitinib compared with placebo at week 16, regardless of age, sex, race, body mass index, AD severity, body surface area involvement, history of atopic comorbidities or asthma, or previous exposure to systemic therapy or cyclosporin. Upadacitinib had consistently high skin clearance rates and itch efficacy across subgroups of patients with moderate-to-severe AD through week 16. These results support upadacitinib as a suitable treatment option in a variety of patients. ClinicalTrials.gov Identifiers: NCT03569293 (Measure Up 1), NCT03607422 (Measure Up 2), and NCT03568318 (AD Up).

Janus kinase inhibitors for alopecia areata: A narrative review.

The Janus kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway has been identified as a key player in the pathophysiology of alopecia areata and a potential target for therapy. Here, we give a narrative review of what is known about Janus kinase inhibitors in alopecia areata. Several clinical trials as well as smaller studies have demonstrated hair regrowth and remission with oral Janus kinase inhibitors therapy, even in patients who failed conventional treatment. Baricitinib is the only US FDA-approved treatment for alopecia areata but data for other oral Janus kinase inhibitors such as tofacitinib, ruxolitinib and ritlecitinib are also promising. Fewer clinical trials have investigated topical Janus kinase inhibitors for alopecia areata, with many of them terminated early due to unfavourable results. Overall, Janus kinase inhibitors are an efficacious addition to the therapeutic arsenal for treatment-refractory alopecia areata. Further work is needed to examine the effects of long-term usage of Janus kinase inhibitors, the efficacy of topical Janus kinase inhibitors, as well as to identify biomarkers that could predict differential therapeutic responses to the various Janus kinase inhibitors.

427 Long-term 4-year safety of upadacitinib in moderate-to-severe atopic dermatitis: results of an integrated analysis of phase 3 studies

Abstract Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by intense itch and eczematous skin lesions that can impact individuals at any age across any area of the body. There is a need for safe treatments for AD that provide rapid itch relief and skin clearance and that are suitable for long-term use. Upadacitinib is a selective, reversible oral Janus kinase 1 (JAK1) inhibitor, which is approved in multiple countries for the treatment of adolescents and adults with moderate-to-severe AD. The current analysis assessed the long-term safety for up to 4 years of upadacitinib 15 and 30 mg in adolescents and adults with moderate-to-severe AD, using integrated data from three ongoing global pivotal phase 3 studies. The Measure Up 1, Measure Up 2, and AD Up studies are ongoing pivotal phase 3, randomized, placebo-controlled, multicenter studies evaluating the safety and efficacy of upadacitinib 15 mg and upadacitinib 30 mg in adolescents and adults with moderate-to-severe AD. Patients were randomized 1 : 1 : 1 to receive oral upadacitinib 15 mg, upadacitinib 30 mg or placebo once daily alone (Measure Up 1 and Measure Up 2) or with concomitant topical corticosteroids (AD Up). At Week 16, patients receiving upadacitinib 15 or 30 mg during the double-blinded period continued their assigned treatment in the blinded extension (BE) period, whereas patients receiving placebo were re-randomized 1 : 1 to receive either upadacitinib 15 or 30 mg in the BE period (upadacitinib treatment for up to 260 weeks). A total of 2693 adults and adolescents (upadacitinib 15 mg, 1340; upadacitinib 30 mg, 1353) who received at least one dose of upadacitinib were included in the integrated analysis. Treatment-emergent adverse events of special interest (AESI) were analysed as exposure-adjusted rates per 100 patient-years (PY) for the entire treatment period to adjust for potentially different durations of follow-up. Upadacitinib was well tolerated by both adults and adolescents. For all patients, rates of AESIs were similar at the 1-year analysis and up to 4-year analysis for upadacitinib (15 mg/30 mg) for: serious infections, 2.3 and 2.2/2.8 and 2.8; opportunistic infections, 1.6 and 1.8/1.9 and 2.4; active tuberculosis, &amp;lt;0.1/&amp;lt;0.1 at both time points; herpes zoster, 3.5 and 3.1/5.2 and 5.8; nonmelanoma skin cancer (NMSC), 0.3 and 0.4/0.4 and 0.3; malignancy excluding NMSC, 0.1 and 0.4/0.5 and 0.3; and adverse events leading to death, 0 and 0/&amp;lt;0.1 and &amp;lt;0.1. Rates of adjudicated major adverse cardiovascular events (MACE) were 0.1 and &amp;lt;0.1/&amp;lt;0.1 and &amp;lt;0.1, and for venous thromboembolic events (VTE) were &amp;lt;0.1 for both doses at the 1-year analysis and up to 4-year analysis. Rates of gastrointestinal perforations were 0 for both doses at both timepoint analyses. Rates of serious infections remain low (&amp;lt;3.0 E/100 PY). Based on the integrated analysis of long-term safety data for up to 4 years, rates of AESIs remained low throughout a longer duration of treatment with upadacitinib 15 or 30 mg among adults and adolescents with moderate-to-severe AD. No new safety risks were observed. Findings of the current safety analysis continue to support a favorable benefit-risk profile of upadacitinib in the treatment of adults and adolescents with moderate-to-severe AD for up to 4 years of treatment.

425 Effect of upadacitinib on SCORAD intensity items: analysis from the Measure Up 1 and Measure Up 2 studies

Abstract Atopic dermatitis (AD) is a chronic, inflammatory disease characterized by typical clinical signs (erythema, edema/papulation, oozing/crusting, excoriation, lichenification and dryness) and prominent itch that can markedly impact a patient’s sleep and quality of life (QoL). Upadacitinib is a selective oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 vs. JAK2, JAK3 and tyrosine kinase 2. The SCORing Atopic Dermatitis (SCORAD) measure is a validated assessment tool that evaluates the extent of disease based on the area of the body affected, intensity of clinical signs of AD, and itch and sleeplessness due to AD. In this integrated post hoc analysis of the Measure Up 1 and Measure Up 2 studies, we compared the effects of upadacitinib (15 and 30 mg) vs. placebo on the intensity of the individual signs assessed by the SCORAD at Week 2 and Week 16. Measure Up 1 and Measure Up 2 are replicate phase 3 multicenter, randomized, double-blind studies comparing the safety and efficacy of upadacitinib 15 mg and upadacitinib 30 mg to placebo in adolescent and adult patients with moderate-to-severe AD. Patients were randomized to upadacitinib 15 mg, upadacitinib 30 mg or placebo orally once daily. All patients received additive-free, bland emollient twice daily for at least 7 days before baseline and during the study until week 16. The current study assessed the intensity of the six clinical signs assessed by the SCORAD (erythema, edema/papulation, oozing/crusting, excoriation, lichenification and dryness with a 4-level rating scale of none, mild, moderate and severe). The proportions of patients achieving resolution (i.e. an intensity rating of ‘none’) of each clinical sign at Week 2 and Week 16 were evaluated among patients with mild, moderate or severe intensity at baseline. Resolution rates were compared using the Mantel–Haenszel test. Missing data were handled using nonresponder imputation. A total of 1679 participants (placebo, 558; upadacitinib 15 mg, 557; upadacitinib 30 mg, 564) were included in the analysis of integrated data from the Measure Up 1 and Measure Up 2 studies. Differences in the proportion of patients achieving resolution for both upadacitinib doses (15 mg/30 mg) vs. placebo were observed at Week 2 (P &amp;lt; 0.0001) for erythema (3.1%/6.0% vs. 0.0%), edema/papulation (13.1%/16.6% vs. 1.3%), oozing/crusting (49.8%/59.1% vs. 15.6%), excoriation (26.9%/34.6% vs. 3.1%), lichenification (9.6%/13.5% vs. 1.4%) and dryness (8.6%/11.9% vs. 1.8%). Resolution rates were also higher with upadacitinib (15 mg/30 mg) vs. placebo at Week 16 (P &amp;lt; 0.0001) for erythema (22.2%/29.7% vs. 2.2%), edema/papulation (33.6%/42.8% vs. 4.9%), oozing/crusting (62.1%/72.0% vs. 20.5%), excoriation (43.3%/54.6% vs. 8.5%), lichenification (30.8%/40.7% vs. 5.2%) and dryness (28.7%/35.9% vs. 4.4%). Greater proportions of patients treated with upadacitinib 15 mg or upadacitinib 30 mg achieved resolution of erythema, edema/papulation, oozing/crusting, excoriation, lichenification or dryness compared with placebo at Week 2 and Week 16. Complete resolution of these clinical signs of AD may correspond to reductions in disease burden that translate to improved QoL. Consideration of the clinical signs of AD as assessed by the SCORAD may help inform physicians as they tailor their treatment choices specifically to the unique skin manifestations of each individual patient.

Baseline Body Surface Area and Itch Severity Define Response to Baricitinib in Patients with Moderate-to-Severe Atopic Dermatitis at Week 16.

Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by heterogeneous clinical phenotypes and high symptom burden, especially through itch. Baricitinib (BARI), an oral Janus Kinase 1/2 inhibitor, is approved in Europe, Japan, and other countries, for treatment of adults with moderate-to-severe AD who are candidates for systemic therapy. This post hoc analysis of a Phase 3 topical corticosteroid (TCS) combination therapy trial (BREEZE-AD7) aims to characterize patients who might benefit most from BARI. Classification and regression tree (CART) analysis was used to identify baseline predictors for patients treated with BARI 4-mg, who achieved≥75% improvement in Eczema Area and Severity Index (EASI75), or EASI75 or Itch Numerical Rating Scale (NRS)≥4-point improvement at week 16 (responders), versus non-responders. Subgroup efficacy analyses were performed based on identified predictor variables, combined with Itch NRS<7/≥7. Missing data were imputed as non-responder. Baseline body surface area (BSA) was identified by CART as strongest variable predicting response to BARI at week 16, with a cut-off around 40% (BSA≤40%). When combining BSA with itch severity, highest response rates were achieved by BARI patients with BSA≤40%/Itch NRS≥7 at baseline. In this subgroup, 69% and 58% of patients treated with BARI 4-mg achieved EASI75 and Itch NRS≥4-point response at week 16, respectively. While these response rates were 65% and 50% for BARI 4-mg patients with baseline BSA≤40%/Itch NRS<7, they were 33% and 11% in BSA>40%/Itch NRS<7, and 32% and 49% in BSA>40%/Itch NRS≥7 subgroups, respectively. Using a machine learning approach, patients with moderate-to-severe AD and a BSA affecting 10-40% and Itch NRS≥7 were characterized as likely to benefit most from BARI 4-mg TCS combination therapy. This was confirmed by subgroup analyses, which showed that these patients are most likely to show favorable response rates in improving AD signs and symptoms, specifically itch, after 16weeks of treatment.

Retrospective comparative study of the efficacy of JAK inhibitor (tofacitinib) in the treatment of systemic sclerosis-associated interstitial lung disease.

The oral Janus kinases inhibitor (JAKi) has improved the management of skin manifestations in systemic sclerosis (SSc), and our study aimed to explore the efficacy of non-selective JAKi tofacitinib in ameliorating interstitial lung disease (ILD) in the patients with SSc. The hospitalization data of the SSc-ILD patients from April 2019 to April 2021 were collected, and the changes of pulmonary function and the radiological findings in pulmonary high-resolution CT (HRCT) from the 9 patients who received tofacitinib for at least 6months and a matched group of 35 SSc-ILD patients treated with conventional immunosuppressants or glucocorticoids, were compared and analyzed. There were no significant differences in demographic data and clinical characteristics between the tofacitinib-treated group (tofa-group) and the matched group. However, in the tofa-group, the changes in serum lactate dehydrogenase (LDH) concentration and serum interleukin-6 levels were significantly lower than those in the matched group. Moreover, the tofa-group showed amelioration in decreased diffusing capacity of the lung for carbon monoxide (DLCO) (62.05 ± 9.47 vs. 66.61 ± 12.39, p = 0.046), reductions in ground-glass attenuation involvement (1.00 ± 0.86 vs. 0.33 ± 0.50, p = 0.024) and irregular pleural thickening (1.33 ± 0.50 vs. 0.67 ± 0.51, p = 0.004) in pulmonary HRCTs, alleviated modified Rodnan skin score (mRSS) of skin sclerosis (9.22 ± 3.81 vs. 7.11 ± 3.92, p = 0.048), and reduced HRCT scores of pulmonary fibrosis (15.00 ± 3.87 vs. 12.66 ± 4.92, p = 0.009). Logistic regression analysis showed that the involvement of ground-glass attenuation (OR 11.43) and the add-on therapy of tofacitinib (OR 9.98) were the relevant factors in the amelioration of HRCT. Our results indicate that the use of JAKi (tofacitinib) may be relevant to significant improvement of the sclerosis and early radiological abnormalities in SSc-ILD patients. Further studies are needed to confirm these findings and to explore its efficacy more precisely. Key Points • The currently available therapies for SSc-ILD have limited therapeutic benefits. • The add-on therapy of the oral JAK inhibitor is available in the real world. • The tofacitinib was promising in the improvement of the sclerosis and early radiological abnormalities in SSc-ILD patients.

Etiopathogenesis and Emerging Methods for Treatment of Vitiligo.

Vitiligo is an acquired chronic depigmenting disorder of skin. It is mostly asymptomatic and characterized by amelanotic macules and patches that affects 0.5% to 2% of the world's population. The etiology of vitiligo has not been clearly elucidated and multiple theories have been proposed regarding the causes of the disorder. Among the most prevalent theories, the genetic predisposition, oxidative stress theory, promotion of cellular stress and pathologic influence of lymphocytes T have been highlighted. As a result of increases in in-depth knowledge concerning the pathogenetic processes in vitiligo, we review the most recent information concerning its etiopathogenesis and treatment methods including topical and oral Janus kinase inhibitors, prostaglandins and their analogues, namely afamelanotide, Wnt/β-catenin-signaling agonists and cell-based therapies. Topical ruxolitinib has been registered for vitiligo treatment, whereas other agents as oral ritlecitinib, afamelanotide and latanoprost have been studied in ongoing clinical trials. New highly effective therapeutic strategies may be developed thanks to molecular and genetic studies.

A phase I study of ruxolitinib in combination with abemaciclib for patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.

TPS7086 Background: Patients (pts) with myelofibrosis (MF) have a reduced life-expectancy compared to age-matched controls. Several oral Janus Kinase (JAK) inhibitors such as ruxolitinib (RUX) have been approved by the US FDA based on improvements in symptom burden and spleen volume reduction compared to physician’s choice of best available therapy. However, duration of response to these agents is generally time-limited and treatment with JAK inhibitors is not considered to have disease-modifying potential. Additionally, median overall survival after RUX discontinuation is only 11-14 months. Thus, novel mechanism-based therapies for pts with disease progression on RUX are needed. JAK2 V617F mutations promote transition from G1 to S-phase of the cell cycle via increased expression of CDC25A, which is also upregulated in primary MPN patient samples. Additional cell cycle regulators such as CDK6 and Cyclin D have also been implicated in MF pathogenesis. Finally, we and others have shown that combination of the CDK4/6 inhibitors and RUX had synergistic effects in murine models of MF (Rampal et al., CCR 2021) providing the preclinical rationale for this trial. Methods: This multicenter, phase I dose-escalation trial (NCT05714072) evaluates the safety of RUX + the CDK4/6 inhibitor abemaciclib in pts with primary or secondary MF with intermediate-1/2 or high-risk disease by DIPSS who require treatment and had an inadequate response to RUX. Among the currently FDA-approved CDK4/6 inhibitors, abemaciclib was chosen for combination therapy due to less myelosuppressive effects compared with other CDK4/6 inhibitors. Inadequate response to RUX is defined by (I) palpable splenomegaly ≥5 cm below the left costal margin at study entry AND/OR (II) active MPN symptoms, as defined by the presence of one symptom score ≥5 or two symptom scores ≥3 using the screening MPN-SAF TSS. Following a conventional “3+3” dose-escalation design, pts will be treated with increasing doses of abemaciclib and stable doses of RUX (10mg or 15mg BID). The primary endpoint is to determine the maximum tolerated dose of RUX + abemaciclib. Secondary endpoints include measures of efficacy. Exploratory endpoints include changes in allele fraction of driver mutations, gene expression profiling, and clonal architecture to identify biomarkers of response, mechanisms of resistance, and to assess for any disease-modifying effects of the combination therapy. This trial is open to enrollment at Memorial Sloan Kettering Cancer Center and MD Anderson Cancer Center. Clinical trial information: NCT05714072 .

Impact of upadacitinib on the risk of digestive events in patients with rheumatoid arthritis: A systematic review and meta-analysis of randomized controlled trials

BackgroundUpadacitinib (UPA), an oral Janus kinase (JAK) inhibitor, is an effective treatment option for rheumatoid arthritis (RA), but its use has been associated with an increased risk of digestive events. This systematic review aimed to investigate the risk of digestive events in RA patients treated with UPA. MethodsSystematic searches of electronic databases (PubMed, Cochrane Library, and EMBASE) from inception to September 2022 were conducted to locate randomized controlled trials (RCTs) that compared UPA with control treatment and reported digestive events in RA patients. We pooled data using the random-effects model and meta-analysis was conducted by Stata software. ResultsTen RCTs met the inclusion criteria and were analyzed, with a total of 6103 patients. Compared with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), pooled analysis of 8 trials revealed no statistical difference in hepatic disorder (HD) risk and gastrointestinal (GI) perforation (GIP) risk ((OR = 1.16, 95% CI 0.86 to 1.56, I2 = 0.00%); OR = 4.49, 95% CI 0.56 to 35.93, I2 = 0.00%)). When we considered the influence of UPA on the grade of liver enzymes, the data indicated that grade 3 and 4 elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were infrequent. Additionally, a dose-dependent impact of UPA on the risks of HD was not observed. The results suggested no interaction by dose of drug, or indication for treatment of GIP risk. ConclusionOur results showed that RA patients receiving UPA compared with csDMARDs had no significant increased risk associated with digestive events. Further long-term research of emerging data is urgently needed to gain a better understanding of the association between UPA and digestive events in the RA population.

Upadacitinib Induction and Maintenance Therapy for Crohn’s Disease

BackgroundUpadacitinib, an oral selective Janus kinase (JAK) inhibitor, is under investigation for the treatment of Crohn’s disease.MethodsIn two phase 3 induction trials (U-EXCEL and U-EXCEED), we randomly assigned patients with moderate-to-severe Crohn’s disease to receive 45 mg of upadacitinib or placebo (2:1 ratio) once daily for 12 weeks. Patients who had a clinical response to upadacitinib induction therapy were randomly assigned in the U-ENDURE maintenance trial to receive 15 mg of upadacitinib, 30 mg of upadacitinib, or placebo (1:1:1 ratio) once daily for 52 weeks. The primary end points for induction (week 12) and maintenance (week 52) were clinical remission (defined as a Crohn’s Disease Activity Index score of <150 [range, 0 to 600, with higher scores indicating more severe disease activity]) and endoscopic response (defined as a decrease in the Simple Endoscopic Score for Crohn’s Disease [SES-CD; range, 0 to 56, with higher scores indicating more severe disease] of >50% from baseline of the induction trial [or for patients with an SES-CD of 4 at baseline, a decrease of ≥2 points from baseline]).ResultsA total of 526 patients underwent randomization in U-EXCEL, 495 in U-EXCEED, and 502 in U-ENDURE. A significantly higher percentage of patients who received 45-mg upadacitinib than those who received placebo had clinical remission (in U-EXCEL, 49.5% vs. 29.1%; in U-EXCEED, 38.9% vs. 21.1%) and an endoscopic response (in U-EXCEL, 45.5% vs. 13.1%; in U-EXCEED, 34.6% vs. 3.5%) (P<0.001 for all comparisons). At week 52 in U-ENDURE, a higher percentage of patients had clinical remission with 15-mg upadacitinib (37.3%) or 30-mg upadacitinib (47.6%) than with placebo (15.1%), and a higher percentage had an endoscopic response with 15-mg upadacitinib (27.6%) or 30-mg upadacitinib (40.1%) than with placebo (7.3%) (P<0.001 for all comparisons). Herpes zoster infections occurred more frequently in the 45-mg and 30-mg upadacitinib groups than in the respective placebo groups, and hepatic disorders and neutropenia were more frequent in the 30-mg upadacitinib group than in the other maintenance groups. Gastrointestinal perforations developed in 4 patients who received 45-mg upadacitinib and in 1 patient each who received 30-mg or 15-mg upadacitinib.ConclusionsUpadacitinib induction and maintenance treatment was superior to placebo in patients with moderate-to-severe Crohn’s disease. (Funded by AbbVie; U-EXCEL, U-EXCEED, and U-ENDURE ClinicalTrials.gov numbers, NCT03345849, NCT03345836, and NCT03345823.)

1-Year Comparative Effectiveness of Tofacitinib vs Ustekinumab for Patients With Ulcerative Colitis and Prior Antitumor Necrosis Factor Failure.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Real-world data comparing the effectiveness of tofacitinib to ustekinumab are limited. We compared 52-week outcomes of tofacitinib vs ustekinumab for UC after antitumor necrosis factor (anti-TNF) failure. In this retrospective cohort study, adults initiated tofacitinib or ustekinumab for UC after anti-TNF failure May 1, 2018 to April 1, 2021, at a US academic medical center. The primary outcome was steroid-free clinical remission (SFCR) at 12 and 52 weeks. The secondary outcome was drug survival (ie, time to drug discontinuation due to nonresponse). Adverse events (AEs) were also assessed. Sixty-nine patients initiated tofacitinib, and 97 patients initiated ustekinumab with median follow-up of 88.0 and 62.0 weeks, respectively. After inverse probability of treatment-weighted logistic and Cox regression, there was no association of tofacitinib vs ustekinumab with SFCR at 12 weeks (odds ratio, 1.65; 95% CI, 0.79-3.41), SFCR at 52 weeks (odds ratio, 1.14; 95% CI, 0.55-2.34), or drug survival (hazard ratio, 1.37; 95% CI, 0.78-2.37). Kaplan-Meier analysis demonstrated no separation in drug survival curves. Regression results were similar after excluding patients with prior tofacitinib or ustekinumab exposure. During available follow-up, 17 AEs were reported for tofacitinib (most commonly shingles, n = 4), and 10 AEs were reported for ustekinumab (most commonly arthralgia and rash, each n = 2). Two patients discontinued treatment due to AEs (1 tofacitinib for elevated liver enzymes, 1 ustekinumab for arthralgia). In a real-world UC cohort, tofacitinib and ustekinumab demonstrated similar effectiveness at 52 weeks. Adverse events were consistent with the known safety profiles of these agents.

The differential effects of upadacitinib treatment on skin rashes of four anatomical sites in patients with atopic dermatitis

BackgroundUpadacitinib is an oral Janus kinase (JAK) 1 inhibitor approved in Japan for moderate-to-severe atopic dermatitis (AD), and it provides a high therapeutic efficacy.ObjectivesWe compared the therapeutic effects of upadacitinib on skin rashes of individual anatomical sites, head and neck, upper limbs, lower limbs, and trunk in patients with AD.MethodsFrom August 2021 to December 2022, 65 Japanese patients with moderate-to-severe AD (aged ≥ 12 years) were treated with oral once daily upadacitinib 15 mg plus twice daily topical corticosteroids of moderate-to-strongest classes.ResultsThe eczema area and severity indexes (EASIs) of individual sites decreased significantly at weeks 4, 12, and 24 compared to those at week 0 in parallel to total (whole body) EASI. The achievement rates of EASI 75 at week 24 and of EASI 90 at week 12 of lower limbs were significantly higher than those of trunk. The percent reductions of EASI of lower limbs at weeks 12 and 24 were significantly higher than those of head and neck and of trunk.ConclusionsAmong the four anatomical sites, the treatment responsiveness to upadacitinib in lower limbs appeared the highest, while those in trunk and in head and neck appeared relatively lower.

Nine cases of chronic hand and foot eczema treated with baricitinib.

Chronic hand and foot eczema (CHFE) is a common inflammatory disorder that generally lasts for over 3 months. If it is intractable to topical agents, systemic immunomodulators can be considered; however, they are not suitable for long-term management because of their adverse effects. Baricitinib is an oral Janus kinase inhibitor that has been approved for the treatment of moderate-to-severe atopic dermatitis. However, its effect on CHFE has rarely been described. Herein, we report nine cases of recalcitrant CHFE that were treated with baricitinib after an inadequate response to low-dose ciclosporin. All patients had more than moderate improvement within 2-8 weeks without serious adverse effects.

Effects of filgotinib on semen parameters and sex hormones in male patients with inflammatory diseases: results from the phase 2, randomised, double-blind, placebo-controlled MANTA and MANTA-RAy studies

ObjectivesThe phase 2 MANTA and MANTA-RAy studies aimed to determine if the oral Janus kinase 1 preferential inhibitor filgotinib affects semen parameters and sex hormones in men with inflammatory diseases.MethodsMANTA...

P125 Long-term efficacy of baricitinib in patients with rheumatoid arthritis who have had inadequate response to csDMARDs: results from RA-BEYOND up to 7 years of treatment

Abstract Background/Aims Baricitinib (BARI), an oral selective Janus kinase 1/2 inhibitor, has demonstrated efficacy in patients (pts) with rheumatoid arthritis (RA) for up to 3 years (yrs) in a long-term extension (LTE) study RA-BEYOND. This analysis reports efficacy of BARI in csDMARD-IR pts in the completed LTE study (up to 7 yrs). Methods In RA-BUILD, csDMARD-IR pts were randomized 1:1:1 to BARI 4 mg, 2 mg, or placebo (PBO). Completers to week (wk) 24 could enter the LTE and received BARI 4 or 2 mg. In RA-BEAM, MTX-IR pts were randomized 1:1:1 to BARI 4 mg, adalimumab (ADA) 40 mg, or PBO. Completers to wk 52 received BARI 4 mg in the LTE. Pts with no response could be rescued after wk 16 in both studies. Data were analysed by treatment assigned at baseline in originating studies as observed up to time of stepdown (if applicable), study discontinuation or completion, whichever occurred earlier. Efficacy response rates (RR) were assessed as proportions of pts with observed data up to yr 7 (wk 364) for low-disease activity (LDA) (SDAI ≤ 11, DAS28-hsCRP ≤ 3.2, CDAI ≤ 10), remission (REM) (SDAI ≤ 3.3, DAS28-hsCRP &amp;lt; 2.6, CDAI ≤ 2.8, Boolean), and physical function (HAQ-DI ≤ 0.5). No formal statistical comparisons were conducted. Results Approximately 56%/25% of pts in BARI 4 mg, 80%/31% in BARI 2 mg, and 60%/25% in PBO from RA-BUILD remained active at yr 3/7; 59%/17% of pts in ADA, 54%/16% in BARI 4 mg, and 67%/14% in PBO from RA-BEAM remained active at year 3/7. SDAI and CDAI had comparable RR for LDA and REM (Table 1). DAS-28CRP LDA RR were similar to SDAI and CDAI, while REM RR were about twice those of SDAI and CDAI (Table 1). HAQ-DI ≤ 0.5 RR was achieved by 25-30% of BARI-treated pts from both trials and maintained to the end of LTE. Conclusion In observed data, BARI demonstrated maintained efficacy in treatment and maintenance of physical function of a csDMARDs-IR RA pt population up to 7 yrs. Disclosure R. Caporali: Consultancies; R. C. has been a consultant and/or speaker for: AbbVie, Amgen, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, Fresenius Kabi, Galapagos NV, Janssen, Merck Sharp &amp; Dohme, Novartis, Pfizer, Roche, Sandoz, and UCB Pharma. D. Aletaha: Grants/research support; D. A. has been a speaker for and/or has received research support from: AbbVie, Amgen, Eli Lilly and Company, Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, and Sobi. R. Sanmartí: Grants/research support; R. S. has been a speaker for and has received research support from: Eli Lilly and Company. T. Takeuchi: Grants/research support; T. T. has been a consultant and/or speaker for and/or has received research support from: AbbVie, Asahi Kasei Pharma, Astellas, AYUMI Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, DNA Chip Research, Eisai, Eli Lilly Japan K.K., Gilead Sciences, Janssen, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Sanofi, and UCB Pharma. D. Mo: Shareholder/stock ownership; D. M. is an employee and shareholder of: Eli Lilly and Company. E. Haladyj: Shareholder/stock ownership; E. H. is an employee and shareholder of: Eli Lilly and Company. L. Zaremba-Pechmann: Other; L. Z-P. is a contractor for: HaaPACS GmbH. P.C. Taylor: Grants/research support; P. C. T. has been a consultant for and/or has received research support from: AbbVie, Biogen, Celgene, Eli Lilly and Company, Fresenius Kabi, Galapagos NV, Gilead Sciences, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer, Roche, and Sanofi.

P107 Long-term efficacy of baricitinib in patients with rheumatoid arthritis with inadequate response to bDMARDs: results from RA-BEYOND up to 6.9-years of treatment

Abstract Background/Aims Baricitinib (BARI), an oral selective Janus kinase 1/2 inhibitor, is approved for treatment of adults with moderately-to-severely active rheumatoid arthritis (RA). BARI demonstrated efficacy in patients (pts) with RA who have inadequate response to biologic disease-modifying antirheumatic drugs (bDMARD-IR) in a 24-week (wk) phase 3 study, RA-BEACON. BARI efficacy was evaluated up to 3 years (yrs) of treatment in a long-term extension (LTE) study, RA-BEYOND. This analysis reports long-term efficacy of BARI 4 mg and 2 mg in bDMARD-IR pts in the completed study RA-BEYOND. Methods In RA-BEACON, pts were randomized 1:1:1 to BARI 4 mg, 2 mg, or PBO; pts with no response could be rescued after wk 16. Completers to wk 24 could enter with BARI 4 or 2mg RA-BEYOND for up to 360 wks (6.9 yrs). LTE data were analysed by treatment assigned at baseline in RA-BEACON as observed up to time of stepdown (if applicable), study discontinuation, or study completion, whichever occurred earlier. Efficacy response rates (RR) were assessed as proportions of pts with observed data up to wk 360 for low-disease activity (LDA) (SDAI ≤ 11, DAS28-hsCRP ≤ 3.2, CDAI ≤ 10), remission (REM) (SDAI ≤ 3.3, DAS28-hsCRP &amp;lt; 2.6, CDAI ≤ 2.8, Boolean), and physical functioning (HAQ-DI ≤ 0.5). No formal statistical comparisons were conducted. Results 156, 152, and 140 pts entered the LTE (4 mg, 2 mg, and PBO, respectively). Pts in BARI 4 and 2 mg arms had higher LDA and REM RR vs PBO at LTE entry (wk 24). PBO-treated pts achieved comparable RR to pts in the BARI 4 mg arm by wk 48 (24 wks after switch to BARI 4 mg) and up to wk 360. Of pts enrolled to RA-BEYOND, approx. 50% in BARI 4 mg, 65% in 2 mg and 61% in PBO remained active at wk 156; 17%, 26% and 26% at wk 360, respectively. SDAI LDA RR were 47%/70% and 61%/74% for pts treated with BARI 4 mg and 2 mg, at wk 156 (yr 3)/ 360 (yr 6.9), respectively; SDAI REM RR were 15%/26% and 26%/26% for BARI 4 mg and 2 mg, at wk 156/360, respectively. SDAI and CDAI had comparable RR. DAS-28CRP LDA RR were similar to SDAI and CDAI, while REM RR were about twice those of SDAI and CDAI. HAQ-DI ≤ 0.5 RR was 15%/26% (BARI 4 mg), 21%/15% (BARI 2mg), and 9%/3% (PBO) at 3/6.9 yrs. Conclusion In observed data, BARI maintained efficacy and normative physical function bDMARD-IR population up to 6.9 yrs (360 wks). Disclosure R. Caporali: Consultancies; R. C. has been a consultant and/or speaker for: AbbVie, Amgen, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, Fresenius Kabi, Galapagos NV, Janssen, Merck Sharp &amp; Dohme, Novartis, Pfizer, Roche, Sandoz, and UCB Pharma. D. Aletaha: Grants/research support; D. A. has been a speaker for and/or received research support from: AbbVie, Amgen, Eli Lilly and Company, Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, and Sobi. R. Sanmartí: Grants/research support; R. S. has been a speaker for and received research support from: Eli Lilly and Company. T. Takeuchi: Grants/research support; T. T. has been a consultant and/or speaker for and/or received research support from: AbbVie, Asahi Kasei Pharma, Astellas, AYUMI Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, DNA Chip Research, Eisai, Eli Lilly Japan K.K., Gilead Sciences, Janssen, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Sanofi, and UCB Pharma. D. Mo: Shareholder/stock ownership; D. M. is an employee and shareholder of: Eli Lilly and Company. E. Haladyj: Shareholder/stock ownership; E. H. is an employee and shareholder of: Eli Lilly and Company. L. Zaremba-Pechmann: Other; L. Z-P. is a contractor for: HaaPACS GmbH. P.C. Taylor: Grants/research support; P. C. T. has been a consultant for and/or received research support from: AbbVie, Biogen, Celgene, Eli Lilly and Company, Fresenius Kabi, Galapagos NV, Gilead Sciences, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer, Roche, and Sanofi.

P111 Exploratory Analysis of Filgotinib Safety Data in Patients With Moderately to Severely Active Rheumatoid arthritis and an Increased Risk of Cardiovascular Events: Data From Phase 2 and 3 Clinical Trials

Abstract Background/Aims The safety profile of filgotinib (FIL), a second-generation oral Janus kinase (JAK) 1 preferential inhibitor approved in Europe, Japan, and the UK for treatment of rheumatoid arthritis (RA) has been reported. In patients (pts) with active RA aged ≥50y with ≥1 cardiovascular (CV) risk factor, treated with the pan-JAK inhibitor tofacitinib, data from an interventional post-marketing study (NCT02092467) suggested a higher risk of major adverse cardiovascular events (MACE) and malignancies compared with TNF inhibitors. No data are available from a similar prospective study with FIL. This post hoc exploratory analysis aimed to describe the incidence of MACE and malignancies in a subgroup of pts with RA from the FINCH and DARWIN clinical trials, receiving FIL 200 mg (FIL200) and FIL 100 mg (FIL100). Methods Exploratory analysis of adverse events of special interest are reported using integrated FIL RA data from phase 2 (NCT01668641, NCT01894516), phase 3 (NCT02889796, NCT02873936, NCT02886728), and the long-term extension (LTE) studies DARWIN 3 (NCT02065700) and FINCH 4 (NCT03025308), in a pt population at higher risk of CV events similar to ORAL-SURVEILLANCE,1 namely, aged ≥50y with ≥1 CV risk factor (history of dyslipidemia, diabetes or CV disease; hypertension, ischemic vascular conditions, peripheral vascular disease, extra-articular manifestations of RA; or current smokers). All pts met ACR criteria for functional class I-III. Censored exposure-adjusted incidence rates (EAIRs)/100 pt-years of exposure for MACE, venous thromboembolism (VTE), malignancies excluding nonmelanoma skin cancer (NMSC), NMSC, (serious) infections, and deaths were determined. Data were as of Jan 11, 2022 (DARWIN 3) and Jan 31, 2022 (FINCH 4). Analyses were performed on an ad hoc interim analysis data set without additional cleaning. Results The higher-risk population included 1484 pts: mean age 62.1y (536 [36.1%] aged ≥65y), 291 (22.5%) current smokers, and 904 (60.9%) received background MTX; baseline (BL) MTX use was higher in the FIL100 vs FIL200 group (66.6% vs 54.6%); other BL demographics were balanced. Numerically higher EAIRs for malignancies (excluding NMSC), NMSC, serious infections, and deaths were observed for pts receiving FIL200 vs FIL100; 95% confidence intervals overlapped. For MACE and VTE, incidence is considered similar for both doses. The risk of experiencing MACE, malignancies excluding NMSC, and NMSC over time with FIL100 or FIL200 will be described. Conclusion In this RA population at higher risk of CV events, the incidence of MACE and VTE was similar for both doses. A numerically higher incidence of malignancies (excluding NMSC), NMSC, serious infections, and deaths was observed in the high- vs low-dose group. Limitations included population selection bias, low event numbers, and the post hoc nature of the analysis. The ongoing LTE and real-world studies in RA will continue to investigate the safety of FIL in these populations. Disclosure M.H. Buch: Honoraria; MHB has recieved funding (Paid to her host institution) fromAbbVie, Galapagos, Gilead, Pfizer, Eli Lilly, Merck-Serono, Roche, UCB. G.R. Burmester: Honoraria; AbbVie, Galapagos, Lilly, MSD, Pfizer, Roche, UCB, Janssen, Gilead Sciences, Inc. X. Mariette: Honoraria; AstraZeneca, Bristol Myers Squibb, Galapagos, GSK, Novartis, Pfizer. C. Charles-Schoeman: Honoraria; AbbVie, Bristol Myers Squibb (BMS), Pfizer, Regeneron-Sanofi, Gilead. V. Rajendran: Other; Employee of Galapagos NV. P. Stiers: Other; Employee of Galapagos NV. A. Cerani: Other; Employee of Galapagos NV. P. Van Hoek: Other; Employee of Galapagos NV. K. Van Beneden: Other; Employee of Galapagos NV. Y. Tanaka: Honoraria; Lilly, AbbVie, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Pfizer, Mitsubishi Tanabe, GlaxoSmithKline, Asahi Kasei, Takeda, Astellas, Janssen, Novartis, Sanofi, UCB, YL Biologics, MSD, Ono, T. H. Schulze-Koops: Honoraria; AbbVie, Galapagos, Lilly, Pfizer. R. Westhovens: Honoraria; Celltrion, Galapagos, Gilead. E. Favalli: Honoraria; AbbVie, BMS, Celltrion, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, UCB.

Abstract CT242: A phase I study of ruxolitinib in combination with abemaciclib for patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis

Abstract Introduction: Patients (pts) with primary and secondary myelofibrosis (MF) have a reduced life expectancy. While several oral Janus Kinase (JAK)-1/2 inhibitors such as ruxolitinib (RUX) have demonstrated improvements in symptom burden and spleen volume reduction compared to physician choice of best available therapy leading to their approval by the US FDA, responses to these agents are generally time-limited. Additionally, these agents are not considered to be disease-modifying and survival in pts after RUX discontinuation is poor with a median survival of 11-14 months. Thus, novel mechanism-based therapies for pts with suboptimal response or progression on RUX are needed. Preclinical Rationale: JAK2 V617F mutations promote transition from G1 to S-phase of the cell cycle via increased expression of CDC25A in preclinical models and CDC25A expression is upregulated in primary MPN patient samples. Additional cell cycle regulators such as CDK6 and Cyclin D also play a role in MF pathogenesis and drive myeloproliferation. Finally, combination of the CDK4/6 inhibitor ribociclib and RUX demonstrated reduction in spleen and liver size when compared to RUX alone in murine models, suggesting synergy (Rampal et al., CCR 2021). Methods: This multicenter, phase I dose-escalation trial evaluates the safety of RUX + the CDK4/6 inhibitor abemaciclib in pts with primary or secondary MF with intermediate-1/2 or high-risk disease by DIPSS who require treatment and had an inadequate response to RUX. An inadequate response will be defined by (I) palpable splenomegaly ≥5 cm below the left costal margin at study entry AND/OR (II) active MPN symptoms [presence of 1 symptom score ≥5 or 2 symptom scores ≥3 using the screening MPN-SAF TSS. This study follows a conventional “3+3” dose-escalation design, in which pts on a stable dose of RUX (10mg or 15mg BID) with sufficient baseline platelet and absolute neutrophil count will be treated with increasing doses of abemaciclib. Abemaciclib was chosen due to less myelosuppression compared with other CDK4/6 inhibitors. The pre-study dose of ruxolitinib will be maintained to determine the maximum tolerated dose of the combination of RUX+ abemaciclib. The primary endpoint is to determine the safety and tolerability, and to identify the recommended phase II dose of abemaciclib in MF pts on a stable dose of RUX. Secondary endpoints include overall response rate, progression-free and overall survival, and duration of response per the modified International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and the European Leukemia Net (ELN) 2013 consensus definitions. Correlative studies are planned to identify biomarkers predictive of response to RUX + abemaciclib, mechanisms of resistance (e.g., MAP kinase pathway activation), and any disease-modifying effects of combination therapy. Citation Format: Jan P. Bewersdorf, Srdan Verstovsek, Andriy Derkach, Lucia Masarova, Naveen Pemmaraju, Eytan M. Stein, Michael Mauro, Raajit Rampal, Prithviraj Bose. A phase I study of ruxolitinib in combination with abemaciclib for patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT242.