JAK Inhibitors Research Articles

Kinase-Bench: Comprehensive Benchmarking Tools and Guidance for Achieving Selectivity in Kinase Drug Discovery.

Developing selective kinase inhibitors remains a formidable challenge in drug discovery because of the highly conserved structural information on adenosine triphosphate (ATP) binding sites across the kinase family. Tailoring docking protocols to identify promising kinase inhibitor candidates for optimization has long been a substantial obstacle to drug discovery. Therefore, we introduced "Kinase-Bench," a pioneering benchmark suite designed for an advanced virtual screen, to improve the selectivity and efficacy of kinase inhibitors. Our comprehensive data set includes 6875 selective ligands and 422,799 decoys for 75 kinases, using extensive bioactivity and structural data from the ChEMBL database and decoys generated by the Directory of Useful Decoys-Enhanced version. Our benchmarking sets and retrospective case studies were designed to provide useful guidance in discovering selective kinase inhibitors. We employed a Glide High-Throughput Virtual Screen and Standard Precision complemented by three scoring functions and customized protein-ligand interaction filters that target specific kinase residue interactions. These innovations were successfully implemented in our virtual screen efforts targeting JAK1 inhibitors, achieving selectivity against its family member, TYK2. Consequently, we identified novel potential hits: Compound 2 (JAK1 IC50: 980.5 nM, TYK2 IC50: 4.5 μM) and the approved pan-AKT inhibitor Capivasertib (JAK1 IC50: 275.9 nM, TYK2 IC50: 10.9 μM). Using the Kinase-Bench protocol, both compounds demonstrated substantial JAK1 selectivity, making them strong candidates for further investigation. Our pharmaceutical results underscore the utility of tailored virtual screen protocols in identifying selective kinase inhibitors with substantial implications for rational drug design. Kinase-Bench offers a robust toolset for selective kinase drug discovery with the potential to effectively guide future therapeutic strategies effectively.

Ruxolitinib Treatment Ameliorates Clinical, Immunological, and Transcriptomic Aberrations in Patients with STAT3 Gain-of-Function Disease

BackgroundSTAT3 gain-of-function (GOF) disease presents with lymphoproliferation, autoimmunity, and failure to thrive. While JAK inhibitors have alleviated symptoms, their effects on disease pathogenesis remain unclear. ObjectiveWe prospectively investigated the clinical, immunological, and transcriptomic responses of four STAT3 GOF patients under long-term ruxolitinib treatment. MethodsWe conducted clinical and immunological evaluations at baseline and after ruxolitinib treatment at 3, 8, 12, and over 12 months. Our assessments included circulating T follicular helper cells (cTFH), regulatory T (Treg) cells, cytokine levels, and proliferation assays. Furthermore, we investigated the transcriptomic changes with treatment and conducted T-cell receptor sequencing. ResultsRuxolitinib achieved substantial control over the clinical manifestations. Post-treatment evaluations demonstrated a notable increase in naive CD4+ and CD8+ T cell populations, alongside a significant reduction in effector memory T cells. Additionally, there was a decrease in cTFH cells and double-negative T cells. Treg cell percentages and their canonical markers, already reduced before treatment, further declined with ruxolitinib. The treatment did not alter IFN-γ, IL-17A, IL-10, IL-4 cytokine productions of CD4+ T cells. Importantly, ruxolitinib effectively normalized the previously dysregulated transcriptome profile in peripheral blood mononuclear cells, bringing it closer to that of healthy controls. This normalization was most striking in the downregulation of STAT3-targeted genes, interferon-related genes, myeloid cell activation, and cytotoxic effector CD8+ T-cell genes, with effects persisting for up to 12 months. Self-reactive T-cell indices based on TCR repertoire analysis revealed potential auto-reactive cell clones in the patient samples. ConclusionRuxolitinib reversed cellular and transcriptomic signatures, enhancing our understanding of the disease's pathophysiology and highlighting essential immunological markers for precise monitoring.

Current Evidence on Safety of JAK Inhibitors in Pregnancy and Lactation

Current Evidence on Safety of JAK Inhibitors in Pregnancy and Lactation

Molecular Docking and Molecular Dynamics Simulation of New Potential JAK3 Inhibitors.

JAK3 kinase inhibitor has become an effective means to treat tumors and autoimmune diseases. In this study, molecular docking and molecular dynamics simulation were used to study the theoretical interaction mechanism between 1-phenylimidazolidine-2-one molecules and JAK3 protein. The results of molecular docking showed that the six 1-phenylimidazolidine-2-one derivatives obtained by virtual screening were bound to the ATP pocket of JAK3 kinase, which were competitive inhibitors of ATP, and were mainly bound to the pocket through hydrogen bonding and hydrophobic interaction. Further, MM/GBSA based on molecular dynamics simulation sampling was used to calculate the binding energy between six molecules and the JAK3 kinase protein. Subsequently, the binding energy was decomposed into the contribution of each amino acid residue, of which Leu905, Lys855, Asp967, Leu956, Tyr904, and Val836 were the main energycontributing residues. Among them, the molecule numbered LCM01415405 can interact with the specific amino acid Arg911 of JAK3 kinase, suggesting that the molecule may be a selective JAK3 kinase inhibitor. The root-mean-square fluctuation (RMSF) of JAK3 kinase pocket residues during molecular dynamics simulation showed that the combination of six new potential small molecule inhibitors with JAK3 kinase could reduce the flexibility of JAK3 kinase pocket residues. These findings reveal the mechanism of 1-phenylimidazolidine-2-one derivatives on JAK3 protein and provide a relatively solid theoretical basis for the development and structural optimization of JAK3 protein inhibitors.

Comment on: "Hepatitis B reactivation in PsA patients: an SLR and meta-analysis for IL-17, IL-23 and JAK inhibitors": reply.

Comment on: "Hepatitis B reactivation in PsA patients: an SLR and meta-analysis for IL-17, IL-23 and JAK inhibitors": reply.

Repression of JAK2-STAT1 and PD-L1 by CEP-33779 ameliorates the LPS-induced decline in phagocytic activity of alveolar macrophages and mitigates lung injury in mice

BackgroundThe role of the JAK2-STAT1/PD-L1 pathway in the phagocytic activity of alveolar macrophages (AMs) during LPS-induced acute lung injury in mice remains poorly understood. This study aims to explore whether the JAK2-STAT1/PD-L1 pathway is upregulated on AMs in LPS-induced mice acute lung injury and to further explore the impact of the JAK2-specific inhibitor CEP-33779 on the LPS-induced impairment of AMs phagocytic activity and lung injury.MethodsALI was induced in mice via intratracheal administration of LPS, followed by intragastric administration of JAK2 inhibitor CEP-33779 suspension. Immunohistochemistry was conducted to assess PD-L1 expression in lung tissue, as well as p-JAK2, p-STAT1, and PD-L1 expression on AMs in bronchoalveolar lavage fluid (BALF) using immunofluorescence. Levels of TNF-α and IL-6, as well as protein concentration in BALF, were measured using enzyme-linked immunosorbent assay and Bicinchoninic acid assays, respectively. Hematoxylin-eosin staining and lung injury score were employed to evaluate pathological changes in mouse lungs. Total cell count in BALF was determined using a cell counter. Furthermore, western blot and immunofluorescence was conducted to assess the effect of JAK2 and STAT1 inhibitor on JAK2-STAT1 pathway activation and PD-L1 expression, while confocal microscopy with latex beads rabbit IgG FITC complex was used to observe MH-S cells phagocytic ability.ResultsThe study revealed that LPS stimulation triggered the activation of the JAK2-STAT1 pathway and an upregulation of PD-L1 on AMs in both LPS-induced acute lung injury mice and MH-S cell lines. Moreover, treatment with the JAK2 and STAT1 inhibitor effectively reduced the activation of JAK2-STAT1 signaling, downregulated PD-L1 expression on AMs in BALF from LPS-induced ALI mice and LPS-stimulated MH-S cells, and significantly improved the LPS-induced reduction in phagocytic activity in MH-S cells. Most notably, CEP-33779 treatment significantly mitigated the pulmonary inflammatory response and lung injury in mice with LPS-induced ALI.ConclusionsCollectively, these findings imply that the JAK2-STAT1 pathway plays a role in the upregulation of PD-L1, which in turn is associated with the diminished phagocytic activity in LPS-induced AMs as well as lung injury. Furthermore, our study highlights that CEP-33779 treatment can effectively improve the reduced phagocytic activity of AMs and relieve lung injury induced by LPS through suppression of the JAK2-STAT1/PD-L1 pathway.

PERSISTENCE, EFFECTIVENESS, AND SAFETY OF UPADACITINIB IN CROHN'S DISEASE AND ULCERATIVE COLITIS IN REAL LIFE: RESULTS FROM A SPANISH NATIONWIDE STUDY (UREAL STUDY): Upadacitinib for IBD.

Real-world data on the effectiveness of upadacitinib for inflammatory bowel disease (IBD) are limited. To assess upadacitinib persistence, effectiveness, and safety in a real-world scenario. Retrospective multicentre study of IBD patients who received upadacitinib before 31st December 2022 and at least 12 weeks before the recruitment date. Clinical effectiveness was assessed based on partial Mayo score for ulcerative colitis (UC) and Harvey-Bradshaw index for Crohn's disease (CD). We included 100 patients (68 with CD, and 32 with UC). Patients had previously received a median of four advanced therapies. Twenty-three discontinued the treatment (median follow-up 7.6 months). CD (vs. UC) (Hazard Ratio[HR] 3.7;95%Confidence Interval (CI):1.04-12.9), and age below 40 years at upadacitinib initiation (HR 2.4;95%CI:1.0-5.8) were associated with treatment discontinuation in multivariable analysis. Clinical remission for IBD was achieved in 59% of patients at week 8, 64% at week 12, and 42% at week 52. The proportion of patients with UC previously exposed to tofacitinib (n=25) who achieved clinical remission was 78% at week 12, and 50% at week 52. Factors associated with clinical remission at week 12 were UC diagnosis (Odds Ratio[OR] 4.6;95%CI:1.3-17), mild or moderate activity at baseline (OR 8;95%CI:1.1-56) and not smoking (OR 4.4;95%CI:1.5-13). Dose escalation recaptured remission in 60% of patients with relapse. Eighty percent of patients with active immune-mediated diseases or extraintestinal manifestations improved with upadacitinib. Forty-three patients reported adverse events, 11 of them serious. Upadacitinib is effective and safe for treating highly refractory IBD patients, even in previously treated with JAK inhibitors.

Self-assembled Lipid Nanoparticles for Killing Triple Negative Breast Cancer Cells.

Triple negative breast cancers (TNBCs) lacking estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) on their cell surfaces are highly aggressive, difficult-to-treat and often relapse. Herein, we report on the self-assembled lipid nanoparticles (LNPs) of two new pegylated lipopeptides for killing TNBCs (MDA-MB-231). The pegylated lipopeptides were synthesized by conjugating an n-hexadecyl hydrophobic tail to one end of a (PEG)27 unit the other distal end of which was covalently grafted with two previously reported tumor targeting RGDK- and CGKRK- peptides. The SEM images of the self-assembled LNPs formed upon dissolution of the pegylated lipopeptides in aqueous medium revealed formation of spherical aggregates. The degree of cellular uptake for the self-assembled LNPs formed by the pegylated CGKRK-lipopeptide were found to be significantly higher than that for the self-assembled LNPs formed by the pegylated RGDK-lipopeptide in MCF-7, MDA-MB-231, HEK-293 and HFF cells. Notably, about 60 % TNBCs (MDA-MB-231 cells) were killed upon treatment with commercially available potent JAK2 inhibitor (WP 1066) loaded LNPs of the pegylated RGDK-lipopeptide. Contrastingly, the same treatment killed only about 20 % non-cancerous HEK-293 cells. The self-assembled pegylated LNPs described herein open the door for undertaking preclinical studies in animal models for TNBCs.

Preclinical efficacy of CDK7 inhibitor–based combinations against myeloproliferative neoplasms transformed to AML

AbstractRising blast percentage or secondary acute myeloid leukemia (sAML) transformation in myeloproliferative neoplasms (MPNs) leads to JAK inhibitor (JAKi) therapy resistance and poor survival. Here, we demonstrate that treatment with the CDK7 inhibitor (CDK7i) SY-5609 depletes phenotypically characterized post-MPN sAML stem/progenitor cells. In cultured post-MPN sAML SET2 and HEL as well as patient-derived (PD) post-MPN sAML cells, SY-5609 treatment inhibited growth and induced lethality while sparing normal cells. RNA-sequencing analysis after SY-5609 treatment demonstrated reduced messenger RNA (mRNA) expression of MYC, MYB, CDK4/6, PIM1, and CCND1 but increased mRNA levels of CDKN1A and BCL2L1. Mass spectrometry of SY-5609–treated MPN-sAML cells also demonstrated reduced c-Myc, c-Myb, PIM1, and CDK4/6 but increased p21, caspase 9, and BAD protein levels. CRISPR-mediated CDK7 depletion also reduced the viability of HEL cells. CyTOF analysis of SY-5609–treated PD post-MPN sAML stem/progenitor cells showed reduced c-Myc, CDK6, and PU.1 but increased protein levels of CD11b, p21, and cleaved caspase 3. Cotreatment with SY-5609 and ruxolitinib was synergistically lethal in HEL, SET2, and PD post-MPN sAML cells. A CRISPR screen in SET2 and HEL cells revealed BRD4, CBP, and p300 as codependencies with SY-5609 treatment. Accordingly, cotreatment with SY-5609 and the BETi OTX015 or pelabresib or with the CBP/p300 inhibitor GNE-049 was synergistically lethal in MPN-sAML cells (including those exhibiting TP53 loss). Finally, in the HEL-Luc/GFP xenograft model, compared with each agent alone, cotreatment with SY-5609 and OTX015 reduced post-MPN sAML burden and improved survival without inducing host toxicity. These findings demonstrate promising preclinical activity of the CDK7i-based combinations with BETi or HATi against advanced MPNs, including post-MPN sAML.

Mechanobullous form of epidermolysis bullosa acquisita: Insights into disease mechanisms as inferred by response to rituximab, but not to JAK inhibitors

AbstractEpidermolysis bullosa acquisita (EBA) is a rare autoimmune blistering disease associated with IgG autoantibodies directed against type VII collagen. Different clinical forms have been described, including the classical mechanobullous variant resembling epidermolysis bullosa dystrophica, which is typically treatment‐resistant. We here describe a 67‐year‐old patient with a mechanobullous EBA characterized by trauma‐induced blisters on her hands and feet for 9 months. Despite treatments with oral prednisolone, topical steroids or calcineurin inhibitors, doxycycline, ciclosporin, and baracitinib, no improvement was observed. The patient went into complete remission only after administration of rituximab with no lesions off therapy at the 10‐month follow up. Our observation suggests that inflammatory cytokines are not primarily responsible for skin blistering and fragility in mechanobullous EBA. The effectiveness of rituximab provides some insights into the major direct role of autoantibodies in mediating dermo‐epidermal separation in this variant of EBA.

Impact of Therapeutic Inertia on Patient-Reported Outcomes in Moderate-to-Severe Atopic Dermatitis: A 12-Month Longitudinal Study from the TARGET-DERM AD Registry

Background: Therapeutic inertia, the delay or reluctance to modify treatment when goals are unmet, is a significant challenge in managing chronic diseases, including atopic dermatitis (AD). This inertia can lead to suboptimal disease control and affect patient outcomes. Objectives: This study evaluates the effect of therapeutic inertia on patient-reported outcomes (PROs) in moderate-to-severe AD patients undergoing systemic treatment over 3 to 12 months. Methods: We analyzed longitudinal data from the TARGET-DERM AD registry, which includes 3,457 patients with moderate-to-severe AD from 39 centers across the U.S. and Canada. Eligible patients had documented patient-reported outcomes (PROs) at the initiation of systemic therapy and at subsequent 3-month intervals up to 12 months of follow-up. We assessed the proportion of patients not meeting treatment targets based on expert consensus. Patients had a validated Investigator Global Assessment (vIGA-AD) score of 3 or more at initiation of either an advanced systemic therapy (AST) such as biologics or JAK inhibitors or a conventional systemic therapy (CST) such as cyclosporine, methotrexate, or prednisone. PROs were evaluated at 3-month intervals up to 12 months, assessing achievement against the predefined treatment targets. PRO measures included Worst-Itch (PROMIS Itch-Severity), POEM, PO-SCORAD, NRS-sleep, and NRS-pain with specific moderate and optimal target levels established for each. Itch-Severity (range: 0–10; moderate target: ≥4-point reduction, optimal target: score ≤1), POEM (range: 0-28; moderate target: ≥4-point reduction, optimal target: score ≤2), PO-SCORAD (range: 0-103; moderate target: score ≤24; optimal target: score ≤10), NRS-sleep and NRS-pain (range: 0-10; moderate target: reduction ≥3-points; optimal target: score ≤1). Results: Out of 2107 patients with moderate-to-severe AD, 445 qualifying participants were included (63.8% adult, 62.0% female, 45.4% Non-Hispanic White, mean age of 31 years). Most patients (88.8%) initiated AST, with dupilumab being the most common (86.5%). At 6 months, significant proportions of AST-treated patients failed to reach moderate and optimal targets for itch (67% and 79%, respectively), POEM (46% and 69%), and NRS-sleep (59% and 47%). By 12 months, these figures were similar, with 66% and 88% failing to meet itch targets, 53% and 73% failing to meet POEM targets, and 62% and 45% failing to meet NRS-sleep targets, respectively. A similar pattern was observed for other PROs. CST-treated patients exhibited similar trends. Conclusions: The study highlights the profound impact of therapeutic inertia on the quality of life of patients with moderate-to-severe AD. Despite systemic therapy, a considerable proportion failed to meet treatment targets over a 12-month period, underscoring the need for more proactive and responsive treatment strategies in AD management.

Isolation and identification of patient-derived liver cancer stem cells and development of personalized treatment strategies

BackgroundLiver cancer stem cells (LCSCs) are thought to drive the metastasis and recurrence, however, the heterogeneity of molecular markers of LCSCs has hindered the development of effective methods to isolate them.MethodsThis study introduced an effective approach to isolate and culture LCSCs from human primary liver cancer (HPLC), leveraging mouse embryonic fibroblasts (MEFs) as feeder cells in conjunction with using defined medium. Isolated LCSCs were further characterized by multiple approaches. Transcriptome sequencing data analysis was conducted to identify highly expressed genes in LCSCs and classify different subtypes of liver cancers.ResultsTotal sixteen cell strains were directly isolated from 24 tissues of three types of HPLC without sorting, seven of which could be maintained long-term culture as colony growth on MEFs, which is unique characteristics of stem cells. Even 10 of cloned cells formed the tumors in immunodeficient mice, indicating that those cloned cells were tumorgenic. The histologies and gene expression pattern of human xenografts were very similar to those of HPLC where these cloned cells were isolated. Moreover, putative markers of LCSCs were further verified to all express in cloned cells, confirming that these cells were LCSCs. These cloned LCSCs could be cryopreserved, and still maintained the feature of colony growth on MEFs after the recovery. Compared to suspension culture as conventional approach to culture LCSCs, our approach much better maintained stemness of LCSCs for a long time. To date, these cloned cells could be cultured on MEFs over 12 passages. Moreover, bioinformatics analysis of sequencing data revealed the gene expression profiles in LCSCs, and liver cancers were classified into two subtypes C1 and C2 based on genes associated with the prognosis of LCSCs. Patients of the C2 subtype, which is closely related to the extracellular matrix, were found to be sensitive to treatments such as Cisplatin, Axitinib, JAK1 inhibitors, WNT-c59, Sorafenib, and RO-3306.ConclusionIn summary, this effective approach offers new insights into the molecular landscape of human liver cancers, and the identification of the C2 subtype and its unique response to the treatment pave the way for the creation of more effective, personalized therapeutic strategies.

Characterizing Lipid Changes and Use of Lipid-Lowering Medications in Patients With Alopecia Areata Treated With Baricitinib: Integrated Results From the BRAVE-AA1 and -AA2 Clinical Trials

Introduction. Elevations in total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) can occur with baricitinib treatment, consistent with a class effect of JAK inhibitors. In this analysis, we characterized changes in lipid levels and use of lipid-lowering medication among patients with severe alopecia areata (AA) treated with baricitinib through 152-weeks of treatment. Methods. Two integrated datasets from the BRAVE-AA1 (NCT03570749) and BRAVE-AA2 (NCT03899259) trials were analyzed: 1. Extended BARI AA includes patients treated with continuous baricitinib 2 mg (N=383) and 4 mg (N=565) from baseline and censored at dose change: 2. ALL BARI AA (N=1303) includes data for patients who received ≥1 dose of baricitinib at any time. Outcomes included abnormal changes in lipid parameters, mean change from baseline in lipids, and concomitant use of lipid-lowering medications. Results. At time of enrollment, 43% of patients had hypercholesterolemia. Incidence rates for categorical increases in total cholesterol (TC; ≥240mg/dL), LDL-C (≥130 mg/dL), and HDL-C (>60 mg/dL) were 11.8, 13.3, and 12.9 per 100 patients-years of exposure, respectively in the ALL BARI AA dataset. In the Extended BARI AA the mean maximal increase in lipids (mg/dL) for baricitinib 4 mg was 20.9 for TC, 12.4 for LDL-C, and 8.5 for HDL-C. Changes occurred early and stabilized by one year for TC and LDL-C and by 12 weeks for HDL-C. 6.1% (n=79) of patients in the ALL BARI AA dataset used lipid-lowering medication at baseline; post-baseline, 3.9% (n=51) discontinued this medication and 4.7% (n=61) initiated lipid lowering medication. No patients discontinued baricitinib treatment due to treatment-emergent adverse events related to hyperlipidemia. Conclusions. Elevations in TC, LDL-C, and HDL-C, but not triglycerides were associated with baricitinib treatment in patients with AA, consistent with a class effect of JAK inhibitors. The relatively low use of lipid-lowering medications at baseline despite the prevalence of hypercholesterolemia may reflect undermanagement of this condition in the population. Notably, the mean maximal magnitude of increase in lipid levels on baricitinib was modest. Initiation of lipid-lowering medication was infrequent, and no patients discontinued due to lipid abnormalities.

Efficacy of JAK-JANUS Kinase Inhibitors as Mono Therapy and in Combination with Methotrexate in Active Rheumatoid Arthritis

Objective: To compare the efficacyof Janus kinase inhibitors as mono therapy and in combination with methotrexate in patients with active rheumatoid arthritis. Study Design: Quasi-experimental study. Place and Duration of Study: Department of Medicine, Combined Military Hospital, Hospital Multan, Pakistan, from Nov 2022 to Oct 2023. Methodology: A total of 1194 patients aging 18 years or above with active rheumatoid arthritis and taking Tofacitinab (5 mg twice daily) were included in this study. In Group-A patients were continued with oral Tofacitinab (5 mg twice daily) while patients in Group-B were added oral methotrexate (15–25 mg per week). The study’s primary outcome was set as the number of patients achieving ACR50 at 6 months of the treatment. Secondary outcomes were the patients achieving ACR70, low disease activity (SDAI ≤11), remission (SDAI ≤3.3) and response of ≥0.22 in HAQ-D index at 6 months follow up. Results: The Mean±SD of age in this study was 51.66±9.36 years. The female gender was 72.61% of total population while males were 27.39%. The results of the primary outcomes of the study show a statistically significant difference between Group-A and Group-B (39.20% Vs 44.72 respectively, p=0.05) proving the combination therapy to be more effective than monotherapy. Among secondary end points, significantly more patients achieved ACR 70 rate, SDAI ≤11 and SDAI ≤3.3 in Group-B compared to Group-A, however, no statistically significant difference was present regarding achieving ≥0.22 response at HAQ-D index. Conclusion: The combination of a JAK inhibitor with methotrexate is more effective in the treatment of

Worldwide Clinical and Real-World Exposure to Baricitinib

Introduction: Baricitinib (BARI), an oral selective JAK inhibitor, is approved in many geographies for adults with rheumatoid arthritis or alopecia areata and for patients as young as age 2 years with atopic dermatitis or juvenile idiopathic arthritis. It is also approved in the US for hospitalized patients with COVID-19 infection. We report the worldwide clinical trial and real-world exposure to BARI across a range of diseases, ages and racial backgrounds. Methods: Real-world patient exposure estimates were calculated based on total mg sold, average daily dose, and average length of therapy as reported to regulatory agencies through the cumulative timeframe ending Jan. 31, 2024. Clinical trial exposures were based on actual exposures from completed trials through Feb. 13, 2024, and estimates were made for ongoing blinded trials based on the enrolment/randomization schemes Results: In the real-world setting, an estimated 1,836,600 patients have been exposed to the following BARI doses: 1 mg, ~2,000 (0.1%); 2 mg, ~524,900 (28.6%); 4 mg, ~1,309,600 (71.3%). Of these estimated exposures, ~ 57% were for COVID-19 with the remaining for all other indications combined. Across 59 clinical trials (completed and ongoing), an estimated 14,660 subjects (548 healthy volunteers and 14,112 patients) have received BARI since June 2008. Exposures from completed studies include 10,276 patients (62% female), 399 of whom were <18 yrs of age (≤1 month, N=4; 1 month - ≤2 yrs, N=24; >2 - ≤12 yrs, N=111; >12 - ≤18 yrs, N=260), 8820 were >18 to ≤65 yrs, 1027 were >65 yrs, and 30 had age unknown. An additional 467 adolescent and pediatric patients down to the age of 2 have been treated with BARI for atopic dermatitis in an ongoing clinical trial, bringing the total number of patients <18 years of age to 866 across dermatologic, rheumatologic, other autoimmunologic, and acute infectious diseases (excluding alopecia areata for which there is an ongoing pediatric trial). Clinical trial exposures by racial and ethnic background are as follows: Asian, N=2,491; Black, N=450; Caucasian, N=6,237; other, N=496; multiple, N=135; unknown, N=467. Conclusion: There has been extensive real-world exposure to BARI across indications and populations, and BARI is a well-studied molecule in clinical trials, across varied disease states, racial populations and ages. Since average daily dose and length of therapy may vary over time, real-world exposures are only an estimate of total patients receiving BARI. Exposures in clinical trials include patients as young as less than 1 month of age up to patients over the age of 65 years. While these exposures do not indicate efficacy or safety, they provide data to establish the overall profile of the drug and can inform on its performance over time across a variety of populations.

Long-Term Maintenance of Optimal Treatment Targets for Skin and Itch Outcomes With Upadacitinib in Moderate-to-Severe Atopic Dermatitis: 140-Week Results From the Phase 3 Measure Up 1 and 2 Studies

Introduction: Despite undergoing prolonged systemic therapy, many patients with moderate-to-severe atopic dermatitis (AD) do not achieve optimal targets for skin and itch outcomes as defined by Aiming High in Eczema/AD (AHEAD) recommendations (eg, ≥90% improvement from baseline in Eczema Area and Severity Index [EASI 90] and Worst Pruritus Numerical Rating Scale [WP-NRS] score of 0/1 [no/minimal itch]). We evaluated long-term maintenance of optimal treatment targets with upadacitinib, an oral selective JAK inhibitor approved for moderate-to-severe AD in adolescents and adults. Methods: This 140-week interim analysis included adolescents and adults with moderate-to-severe AD who were randomized at baseline to upadacitinib 15 mg (UPA15) or 30 mg (UPA30) in the ongoing, phase 3, double-blind Measure Up 1 and 2 studies. Assessments included the proportion of patients (at the population level) who maintained EASI 90, WP-NRS 0/1, or simultaneous achievement of EASI 90 + WP-NRS 0/1 responses from week 16 (end of the placebo-controlled period) onwards. Data are reported as observed cases with no imputation for missing data. Results: Among patients who achieved EASI 90 at week 16 (UPA15, n=298; UPA30, n=384), EASI 90 was maintained by 79.8% (UPA15) and 83.7% (UPA30) at week 52, 76.7% (UPA15) and 83.0% (UPA30) at week 100, and 74.0% (UPA15) and 84.2% (UPA30) at week 140. Of patients achieving WP-NRS 0/1 at week 16 (UPA15, n=193; UPA30, n=281), WP-NRS 0/1 was maintained by 69.4% (UPA15) and 72.0% (UPA30) at week 52, 65.6% (UPA15) and 68.4% (UPA30) at week 100, and 62.3% (UPA15) and 66.0% (UPA30) at week 140. Of patients simultaneously achieving EASI 90 + WP-NRS 0/1 at week 16 (UPA15, n=156; UPA30, n=243), maintenance was achieved by 68.1% (UPA15) and 70.8% (UPA30) at week 52, 62.7% (UPA15) and 66.5% (UPA30) at week 100, and 58.7% (UPA15) and 64.4% (UPA30) at week 140. Among patients who did not maintain optimal outcomes, most still achieved clinically meaningful responses. Conclusion: Most patients maintained optimal skin and itch outcomes through 140 weeks of upadacitinib treatment, demonstrating its potential to provide sustained long-term disease control in atopic dermatitis.

Clinical and Immune Effects of Peri-Transplantation JAK Inhibition for Myelofibrosis.

Despite the introduction of JAK inhibitors, allogeneic hematopoietic cell transplant remains the only potentially curative treatment for patients with myelofibrosis but has considerable treatment-related complications. Whether the incorporation of JAK inhibition into the transplant algorithm leads to improved outcomes is still unclear. Here, we analyzed different transplant platforms in myelofibrosis patients undergoing a first transplant, comparing immune profiles and outcomes of (1) 33 patients continuing JAK inhibition at start of conditioning until stable engraftment (PERI-group), (2) 38 patients receiving JAK inhibition prior to transplant until start of conditioning (PRE-group), and (3) 38 patients that had never received JAK inhibition (NON-group). Patients in the PERI-group showed significantly higher early B-cell recovery as well as significantly increased late recovery of gamma-delta T cells and NK cells. We observed excellent neutrophil and platelet engraftment (100% for both) in the PERI-group and no hematotoxic effects or increased rates of infections following peri-transplant JAK inhibition. Cumulative incidence of acute graft-versus-host disease (GvHD) grade II-IV at day 100 after transplant was 15% in the PERI-group versus 29% in the PRE-group versus 34% in the NON-group. Cumulative incidence of relapse at 1 year after transplant was 9% in the PERI-group compared with 16% in the PRE-group and 18% in the NON-group. In conclusion, peri-transplant JAK inhibition was feasible with promising engraftment and acute GvHD rates, though deserves further investigation.

JAK inhibitor adverse event profiles in dermatology patients: the experience of two academic medical centers.

JAK inhibitors (JAKi) are increasingly being utilized for both FDA-approved and off-label treatments in dermatology. However, JAKi carry a black box warning concerning major side effects, including serious infections, cardiovascular events, thrombosis, malignancy, and mortality. Given that there is an absence of large-scale studies examining the adverse event (AE) profile of multiple JAKi for dermatologic conditions in real-world settings, our study aimed to bridge this gap by evaluating AEs of dermatology patients on oral JAKi at two academic medical centers.

Rosacea Fulminans following Initiation of Deucravacitinib.

Rosacea fulminans developed in a middle-aged caucasian man 10 days after initiating Deucravacitinib for chronic plaque psoriasis. The painful papulopustular eruption resolved without scarring after discontinuation of deucravacitinib, and treatment with a short-course of oral prednisolone. This case is notable as it is the first reported instance of rosacea fulminans linked to the use of a JAK inhibitor.

Prevention of liver metastasis via the pharmacological suppression of AMIGO2 expression in tumor cells

AMIGO2 adheres to liver endothelium and induces liver metastasis. We revealed that genetically altering AMIGO2 expression in tumor cells affects their liver metastatic potential, depending on the AMIGO2 expression level. The aim of this study was to prevent liver metastasis by pharmacologically suppressing AMIGO2 expression. For screening, we used the mouse LV12 cells because of their affinity to adhere to liver endothelium and metastasize the liver owing to elevated AMIGO2 expression. Of the 285 compounds tested, 17 reduced AMIGO2 mRNA expression. We subsequently screened for compounds that inhibited tumor cell adhesion to liver endothelium and identified five compounds that inhibit three signaling pathways (MEK, JAK, and JNK). Treatment with these compounds inhibited liver metastasis of LV12 cells. Next, we used clinically available signal inhibitors (MEK inhibitor trametinib, JAK inhibitor ruxolitinib, and JNK inhibitor SP600125), and found that ruxolitinib inhibits AMIGO2 expression more stably. Furthermore, ruxolitinib inhibited the adhesion of LV12 cells to liver endothelium and suppressed liver metastasis. Using the MKN45 gastric cancer cells, we confirmed that ruxolitinib could prevent liver metastasis of human cancer cells. These results demonstrate that pharmacological inhibition of AMIGO2 expression in tumor cells is a promising novel strategy to prevent and control liver metastasis.