Selective JAK1 Inhibitor Research Articles

Real-world effectiveness of abrocitinib treatment in patients with difficult-to-treat atopic dermatitis.

Abrocitinib is a JAK-1 selective inhibitor registered for the treatment of moderate-to-severe atopic dermatitis (AD). Although efficacy and safety have been shown in phase 3 clinical trials, data on real-world patients with a treatment history of advanced systemics are scarce. The objective of the study was to evaluate the effectiveness and safety of abrocitinib treatment in patients with difficult-to-treat AD in daily practice. In this prospective observational single-centre study, all AD patients who started abrocitinib treatment in the context of standard care between April 2021 and December 2022 were included. Effectiveness was assessed using clinician- and patient-reported outcome measures. Adverse events were evaluated. Forty-one patients were included. The majority (n = 30; 73.2%) had failed (ineffectiveness) on other targeted therapies, including JAK inhibitors (n = 14, 34%) and biologics (n = 16, 39%). Abrocitinib treatment resulted in a significant decrease in disease severity during a median follow-up period of 25 weeks (IQR 16-34). Median EASI score at baseline decreased from 14.7 (IQR 10.4-25.4) to 4.0 (IQR 1.6-11.4) at last review (p < 0.001). Median NRS itch decreased from 7.0 (IQR 5-8) to 3.0 (IQR 1-2) at last review (p < 0.001). The most frequently reported AEs included gastrointestinal symptoms (27.6%), acne (20.7%) and respiratory tract infections (17.2%). 16 (39%) patients discontinued abrocitinib treatment due to ineffectiveness, AEs or both (41.2%, 41.2% and 11.8%, respectively). Abrocitinib can be an effective treatment for patients with moderate-to-severe AD in daily practice, including non-responders to other targeted therapies.

Discovery of N-(4-(Aminomethyl)phenyl)-5-methylpyrimidin-2-amine Derivatives as Potent and Selective JAK2 Inhibitors.

The JAK2V617F mutation leads to JAK2 autophosphorylation and activation of downstream pathways, eventually resulting in myeloproliferative neoplasms (MPNs). Selective inhibitors showed advantages in terms of side effects; therefore, there is an urgent need to develop novel selective JAK2 inhibitors for treating MPNs. In this study, we described a series of N-(4-(aminomethyl)phenyl)pyrimidin-2-amine derivatives as selective JAK2 inhibitors. Systematic exploration through opening the tetrahydroisoquinoline based on the previous lead compound 13ac led to the discovery of the optimal compound A8. Compound A8 showed excellent potency on JAK2 kinase, with an IC50 value of 5 nM, and inhibited the phosphorylation of JAK2 and its downstream signaling pathway. Moreover, A8 exhibited 38.6-, 54.6-, and 41.2-fold selectivity for JAK1, JAK3, and TYK2, respectively. Compared to the lead compound, A8 demonstrated much better metabolic stabilities, with a bioavailability of 41.1%. These findings suggest that A8 is a relatively selective JAK2 inhibitor, deserving to be developed for treating MPNs.

MAPK-negative feedback regulation confers dependence to JAK2V617F signaling.

Despite significant advances in developing selective JAK2 inhibitors, JAK2 kinase inhibitor (TKI) therapy is ineffective in suppressing the disease. Reactivation of compensatory MEK-ERK and PI3K survival pathways sustained by inflammatory cytokine signaling causes treatment failure. Concomitant inhibition of MAPK pathway and JAK2 signaling showed improved in vivo efficacy compared to JAK2 inhibition alone but lacked clonal selectivity. We hypothesized that cytokine signaling in JAK2V617F induced MPNs increases theapoptotic threshold that causes TKI persistence or refractoriness. Here, we show that JAK2V617F and cytokine signaling converge to induce MAPK negative regulator, DUSP1. Enhanced DUSP1 expression blocks p38 mediated p53 stabilization. Deletion of Dusp1 increases p53 levels in the context of JAK2V617F signaling that causes synthetic lethality to Jak2V617F expressing cells. However, inhibition of Dusp1 by a small molecule inhibitor (BCI) failed to impart Jak2V617F clonal selectivity due to pErk1/2 rebound caused by off-target inhibition of Dusp6. Ectopic expression of Dusp6 and BCI treatment restored clonal selectively and eradicated the Jak2V617F cells. Our study shows that inflammatory cytokines and JAK2V617F signaling converge to induceDUSP1, which downregulates p53 and establishes a higher apoptotic threshold. These data suggest that selectively targeting DUSP1 may provide a curative response in JAK2V617F-driven MPN.

First Approval of Pacritinib as a Selective Janus Associated Kinase-2 Inhibitor for the Treatment of Patients with Myelofibrosis.

In this short perspective, the chemical structure, physical properties, synthesis, mechanism of action, and pharmacokinetic profile of pacritinib are summarized. It is an orally bioavailable and isoform-selective JAK-2 inhibitor for treating patients with myelofibrosis.

Practical and Scalable Method for Manufacturing AZD4604, A Potent and Selective JAK1 Inhibitor

The development of a scalable process for the manufacture of a potent and selective JAK1 inhibitor intended for the inhaled treatment of asthma is described. The initial milligram-scale synthetic protocols were unsuitable for larger-scale synthesis, which led to a systematic evaluation of the reaction conditions to identify the optimized reaction conditions for the Suzuki/Buchwald–Hartwig coupling, deprotection of the tosyl group, chemoselective nitro-reduction, and developing mild conditions for the amide coupling of a sensitive amino acid. This work also highlights mitigating critical issues associated with the synthesis of poorly soluble compounds, slurry-to-slurry metal-catalyzed coupling protocols. The optimized amide coupling conditions using chiral amino acid produced the desired active pharmaceutical ingredient (API) in high overall yield and good high-performance liquid chromatography (HPLC) purity.

Effect of durable hematocrit control and minimal thrombotic risk in real-world polycythemia vera patients treated with ruxolitinib.

e19080 Background: Polycythemia Vera (PV) is a myeloproliferative neoplasm characterized by unregulated red blood cell production. Most patients (pts) harbor a JAK2 mutation and must have erythrocytosis or elevated red cell mass for diagnosis (DX). Pts are at increased risk of thrombosis. Current treatments include aspirin, therapeutic phlebotomy (TP), and cytoreductive therapy such as hydroxyurea (HU). In 2014, based on the RESPONSE study, ruxolitinib (rux), a selective JAK inhibitor, was approved for second line treatment after intolerance or inadequate response to HU. A recent real-world analysis of rux in PV showed durable hematocrit (HCT) control and decreased need for TP (Coltoff 2020). Despite emerging clinical reports, real-world data on HCT control, dose adjustment, and thrombotic risk with rux are extremely limited. Methods: A retrospective chart review from three centers was performed to evaluate PV pts treated with rux between Dec 2014 and Dec 2019. Pts age &lt;18 at rux start, who received rux through investigational studies, and/or who had myelofibrosis were excluded. Data cutoff was May 30, 2022. Results: 69 patients were identified. Median time from PV DX to rux start was 4.4 yrs (range 0.1 to 40.2), and median follow-up from start of rux was 3.3 yrs (range 0.1 to 6.3). Pt characteristics: 37 (54%) Male, 59 pts (86%) White, 4 (6%) Black, and 64 (93%) Non-Hispanic. The most common reasons for starting rux were HU intolerance (46%), uncontrolled platelet count (28%), and symptom burden (19%). Median time on rux was 2.4 yrs (range 0.1 to 6.3); 43 pts (62%) remained on rux at data cutoff. A total of 6 pts (9%) received less than 3 months of rux before discontinuation, 8 pts (12%) received less than 6 months of rux. 41% pts (27/66), did not have HCT control (HCT &lt;45%) within 1 month prior to rux start. Of evaluable pts, HCT control rates at 3 and 6 months were 88% (52/59) and 89% (47/53) respectively. Phlebotomy frequency in the 3-month periods before and after rux start were known for 48 pts; 21 (44%) experienced a decrease in phlebotomies within 3 months after initiation of rux, 20 (42%) remained stable, and 7 (16%) saw an increase (ranging from +1 to +3). Twelve pts (17%) required dose reductions/suspensions due to cytopenias. One pt experienced an acute pulmonary embolism while on rux (4.4 yrs after rux initiation). The pt was diagnosed with T cell lymphoma while on rux and the thrombotic event was attributed to lymphoma. This pt achieved HCT control on rux at 3 and 6 months. No arterial thromboses were observed. Conclusions: In this real-world analysis, rux was highly effective in controlling HCT in the vast majority of PV pts by 3 and 6 months. PV pts treated with rux rarely developed thrombosis. Rux was well tolerated, and few patients required dose reduction or discontinuation. [Table: see text]

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Currently there is no consensus on the treatment of relapsed/refractory (r/r) PTCL, and patient prognosis was poor. Golidocitinib is an orally available, JAK1-selective inhibitor currently being evaluated in a multinational, pivotal study in r/r PTCL (JACKPOT8 Part B, NCT04105010). Here we reported the primary analysis of efficacy and safety results of this study. Methods: PTCL patients who had relapsed from or had been refractory/intolerant to ≥1 (but ≤3) prior systemic therapy(ies) were enrolled to receive golidocitinib at 150 mg once daily until disease progression or pre-defined discontinuation criteria were met. The primary endpoint was CT-based objective response rate (ORR) assessed by an independent review committee (IRC) according to Lugano 2014 classification. The efficacy analysis set included patients whose pathological diagnosis of PTCL had been retrospectively confirmed by a central laboratory and who had at least one measurable lesions at baseline. The safety analysis set included all dosed patients. Results: As of 30 November 2022, a total of 104 patients with r/r PTCL were enrolled and dosed with golidocitinib. Baseline characteristics: median age was 58 yrs; 64.4% were male; 20.2% had baseline bone marrow involvement. Major subtypes included NOS (46.2%), AITL (15.4%) and ALCL (9.6%). The median prior lines of therapies were two. All of the patients had been treated with chemotherapies, and 48.1% had been treated with histone deacetylase inhibitors. By the data cut-off (DCO) date, a total of 80 patients had both IRC assessment and central pathology review results available, and thus were included in the efficacy analysis. Among them, 35 patients achieved tumor response (ORR = 43.8%), including 20 patients (25.0%) achieved complete responses. Tumor response was observed in various subtypes, including AITL (56.3%), NOS (45.7%), ALCL (11.1%) and others (44.4%). In patients who relapsed from HDAC inhibitor treatment, 54.8% achieved tumor response. With a median follow-up of 5.5 months for responders, the median duration of response (DoR) has not been reached. Golidocitinib was tolerated in patients with r/r PTCL. By the DCO date, the longest duration on treatment was 15.7 months (still responding). The most common ≥ grade 3 treatment-related adverse events (TRAEs) were hematological in nature, including neutrophil count decreased (26.0%), white blood cell count decreased (25.0%), platelet count decreased (16.3%) and lymphocyte count decreased (16.3%). TRAEs leading to dose interruption, reduction, and discontinuation were 37.5%, 5.8%, and 7.7%, respectively. The majority of TRAEs were reversible or clinically manageable. Conclusions: Golidocitinib demonstrated its potential as a novel targeted therapy for the treatment of r/r PTCL. The updated data will be presented at the conference. Encore Abstract—previously submitted to ASCO 2023 Keywords: aggressive T-cell non-Hodgkin lymphoma, molecular targeted therapies Conflicts of interests pertinent to the abstract W. Yu Employment or leadership position: Employed by Dizal Pharmaceutical

Golidocitinib in treating refractory or relapsed peripheral T-cell lymphoma: Primary analysis of the multinational pivotal study results (JACKPOT8).

7503 Background: Currently there is no consensus on the treatment of relapsed/refractory (r/r) PTCL, and patient prognosis was poor. Golidocitinib is an orally available, JAK1-selective inhibitor currently being evaluated in a multinational, pivotal study in r/r PTCL (JACKPOT8 Part B, NCT04105010). Here we reported the primary analysis of efficacy and safety results of this study. Methods: PTCL patients who had relapsed from or had been refractory/intolerant to ≥ 1 (but ≤ 3) prior systemic therapy(ies) were enrolled to receive golidocitinib at 150 mg once daily until disease progression or pre-defined discontinuation criteria were met. The primary endpoint was CT-based objective response rate (ORR) assessed by an independent review committee (IRC) according to Lugano 2014 classification. The efficacy analysis set included patients whose pathological diagnosis of PTCL had been retrospectively confirmed by a central laboratory and who had at least one measurable lesions at baseline. The safety analysis set included all dosed patients. Results: As of November 30, 2022, a total of 104 patients with r/r PTCL were enrolled and dosed with golidocitinib. Baseline characteristics: median age was 58 years old; 64.4% were male; 20.2% had baseline bone marrow involvement. Major subtypes included NOS (46.2%), AITL (15.4%) and ALCL (9.6%). The median prior lines of therapies were two. All of the patients had been treated with chemotherapies, and 48.1% had also been treated with histone deacetylase inhibitors. By the data cut-off (DCO) date, a total of 80 patients had both IRC assessment and central pathology review results available, and thus were included in the efficacy analysis. Among them, 35 patients achieved tumor response (ORR = 43.8%), including 20 patients (25.0%) achieved complete responses. Tumor response was observed in various subtypes, including AITL (56.3%), NOS (45.7%), ALCL (11.1%) and others (44.4%). In patients who relapsed from HDAC inhibitor treatment, 54.8% achieved tumor response. With a median follow-up of 5.5 months for responders, the median duration of response (DoR) has not been reached. Golidocitinib was tolerated in patients with r/r PTCL. By the DCO date, the longest duration on treatment was 15.7 months (still responding). The most common ≥ grade 3 treatment-related adverse events (TRAEs) were hematological in nature, including neutrophil count decreased (26.0%), white blood cell count decreased (25.0%), platelet count decreased (16.3%) and lymphocyte count decreased (16.3%). TRAEs leading to dose interruption, reduction, and discontinuation were 37.5%, 5.8%, and 7.7%, respectively. The majority of TRAEs were reversible or clinically manageable. Conclusions: Golidocitinib demonstrated its potential as a novel targeted therapy for the treatment of r/r PTCL. The updated data will be presented at the conference. Clinical trial information: NCT04105010 .

JAK2/STAT5 inhibition protects mice from experimental autoimmune encephalomyelitis by modulating T cell polarization

Multiple sclerosis (MS) has been considered as a T cell-mediated autoimmune disease. However, the signaling pathways regulating effector T cells in MS have yet to be elucidated. Janus kinase 2 (JAK2) plays a crucial role in hematopoietic/immune cytokine receptor signal transduction. Here, we tested the mechanistic regulation of JAK2 and the therapeutic potential of pharmacological JAK2 inhibition in MS. Both inducible whole-body JAK2 knockout and T cell-specific JAK2 knockout completely prevented the onset of experimental autoimmune encephalomyelitis (EAE), a widely used MS animal model. Mice with JAK2 deficiency in T cells exhibited minimal demyelination and minimal CD45+ leukocyte infiltration in the spinal cord, accompanied by a remarkable reduction of T helper cell type 1 (TH1) and type 17 (TH17) in the draining lymph nodes and spinal cord. In vitro experiments showed that disruption of JAK2 markedly suppressed TH1 differentiation and IFNγ production. The phosphorylation of signal transducer and activator of transcription 5 (STAT5) was reduced in JAK2 deficient T cells, while STAT5 overexpression significantly increased TH1 and IFNγ production in STAT5 transgenic mice. Consistent with these results, JAK1/2 inhibitor baricitinib or selective JAK2 inhibitor fedratinib attenuated the frequencies of TH1 as well as TH17 in the draining lymph nodes and alleviated the EAE disease activity in mice. Our findings suggest that overactive JAK2 signaling in T lymphocytes is the culprit in EAE, which may serve as a potent therapeutic target for autoimmune disease.

Synergistic activity of JAK2 and BCL-2 inhibition against B-cell acute lymphoblastic leukemia.

e22002 Background: Treatment of relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) remains a challenge particularly in patients who do not respond to traditional chemotherapy. The objective of this study was to assess the efficacy of fedratinib, a semi selective JAK2 inhibitor and venetoclax, a selective BCL-2 inhibitor, on a model of B-ALL using the human cell line RS4;11 in vitro and in vivo. While select studies have examined the efficacy of these drugs on hematologic disorders as single agents, data is lacking on whether these drugs work optimally as single agents or in combination. Methods: RS4;11 cells were treated with either vehicle (DMSO), single agent fedratinib or venetoclax, or the combination of both inhibitors for 48 and 72 hours. Live/dead discrimination was performed using flow cytometry and a 72-hour MTS assay to assess proliferation. Drug synergy was calculated using CompuSyn software to generate combination index (CI) scores, with a CI score less than 1 reflecting synergy. RS4;11 was then used in a cell line derived xenograft model using NSG mice. Peripheral blood was obtained via retroorbital bleeds on days +10 (engraftment), +21 (treatment start), and +35 (post treatment) to assess B-ALL disease burden. Mice were randomized to one of the following groups: untreated, single agent venetoclax, fedratinib, or combination therapy. Mice were treated for 14 days with 6.25 mg/kg venetoclax IP and 100 mg/kg fedratinib via gavage. Results: In vitro, the combination of 7.5 nM venetoclax and 700 nM fedratinib significantly increased cell death compared to single agent venetoclax (p = 0.0186) and fedratinib (p = 0.0035). Furthermore, the combination significantly decreased leukemia cell proliferation compared to single agent venetoclax (p = 0.0183) and fedratinib (p = &lt; 0.0001). Synergy between venetoclax and fedratinib was seen in combination (CI = 0.40517). In vivo, peripheral blood counts post treatment showed a significant decrease in leukemic burden in combination compared to both single agent venetoclax (p = 0.016770) and fedratinib (p = 0.00002). Flow cytometry analysis of peripheral blood also showed a significant increase in CD19 MFI expression in samples from mice that received either venetoclax or combination therapy. Conclusions: The combination of fedratinib and venetoclax synergistically combined to treat B-ALL in vitro. The combination also was effective at significantly reducing leukemic disease burden in a cell line derived xenograft model. Finally, the significant increase in CD19 MFI expression post treatment suggests this combination therapy may be useful as a bridge to other CD19 targeted cell therapies.

The mTOR kinase inhibitor everolimus synergistically enhances the anti‐tumor effect of the Janus kinase 1 (JAK1) inhibitor AZD4205 on Peripheral T cell lymphoma

Introduction: Peripheral T-cell lymphoma (PTCL) constitute a heterogenous group of non-Hodgkin lymphomas, which is distinguished by their aggressive courses and poor clinical outcomes. Multiple researches have indicated that the JAK/STAT pathway acts as an important role in the mechanism of TCL pathogenesis. Preliminary results from related clinical studies showed that JAK inhibitors have a high remission rate and durable response in PTCL patients. AZD4205 is a potent JAK1-selective inhibitor currently evaluated in phase II clinical studies in PTCLs, which could reduce the side effects caused by JAK2 blockade by selectively targeting JAK1. Therefore, the aim of this study is to explore the efficacy and appropriate combination regimen of the novel JAK1 inhibitor AZD4205 in PTCL and to decipher the underlying anti-tumor mechanism. Methods: We analyzed the expression of JAK/STAT pathway in PTCL tissues via bioinformatics analysis and IHC. In vitro cell viability was assessed by using Cell Titer-Glo Luminescent assay. Induction of cell apoptosis was measured by flow cytometry. Western blot was utilized to identify the influence of AZD4205 on the intracellular relevant signaling pathways. The effects of AZD4205 on the transcriptome of PTCL cells were analyzed via transcriptome sequencing technology. High-throughput compounds screening was applied to explore potential combination therapeutic targets of AZD4205. Tumor-bearing mouse models were established to validate the efficacy and safety of AZD4205 and the combination regimen. Results: High expression of phosphorylated JAK1 in PTCL tissues are potential poor prognostic factors. The JAK1 inhibitor AZD4205 inhibited the proliferation of PTCL cells and down-regulated the activation of JAK/STAT signaling pathway. In addition, AZD4205 induced apoptosis in PTCL cells, and showed anti-tumor effects in vivo. However, AZD4205 also induced adverse effects of hepatic impairment and dyslipidemia in vivo. Transcriptome sequencing analysis revealed that AZD4205 treatment upregulated the expression of mTOR pathway-related genes. Moreover, high-throughput screening assay showed that the mTOR inhibitor everolimus significantly enhanced the inhibitory efficacy of AZD4205. We further confirmed that AZD4205 combined with the mTOR inhibitor everolimus exerted synergistic anti-PTCL efficacy both in vitro and in vivo, and the combination regimen significantly reduced AZD4205-induced adverse effects. The RNA-seq results suggested that the combination treatment affected the cholesterol homeostasis pathway and a further validation of the combined anti-PTCL effect of mevastatin and AZD4205 was confirmed in mouse models. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Combination Therapies, Molecular Targeted Therapies No conflicts of interests pertinent to the abstract.

Upadacitinib as a Novel Treatment in Therapy Refractory Collagenous Colitis.

Microscopic colitis (MC) is an inflammatory disorder of the colon histologically subclassified into lymphocytic colitis (LC) and collagenous colitis (CC).1,2 Budesonide is an effective first-line treatment in both forms of MC. However treatment-refractory disease, particularly in CC, remains a challenging clinical problem.3,4 Janus kinase (JAK) inhibitors are novel small molecules approved for the management of ulcerative colitis that have a rational mechanistic basis for treatment of MC based on the role of interferon-γ in disease pathogenesis.5 One recent case report described the use of upadacitinib, a selective JAK1 inhibitor, in LC.6,7 However, to date no reports exist about the effectiveness of JAK inhibitors for refractory CC. Here, we describe a patient with refractory CC who rapidly achieved clinical remission on upadacitinib. The patient was a 75-year-old woman with a history of hypothyroidism who developed watery diarrhea (4-8 bowel movements per day, Bristol Stool Scale type 7) accompanied by fecal incontinence in 2014. She was diagnosed with CC based on colonoscopy with biopsies, after ruling out celiac disease and infectious etiologies. Treatment with budesonide, cholestyramine, bismuth subsalicylate, loperamide, and later prednisone 40 mg daily resulted in a slight decrease in stool frequency, but she continued to experience urgent liquid stools and fecal incontinence that greatly impaired her quality of life. She was next treated with dose-optimized adalimumab, vedolizumab, and ustekinumab without meaningful improvement (Figure 1). Because of her refractory symptoms, she was started on upadacitinib 45 mg daily, with achievement of clinical remission by Hjortswang criteria8 for the first time since diagnosis within 1 week of therapy initiation (Figure 1). After 8 weeks of induction dosing, she had 1 to 2 formed (Bristol Stool Scale type 3-5) bowel movements per day with complete resolution of urgency and incontinence. C-reactive protein decreased from 1.1 to <0.1 mg/dL and erythrocyte sedimentation rate from 7 to 3 mm/h. Monitoring labs showed an increase in her transaminases (alanine transaminase from 21 to 40 IU/L and aspartate transaminase from 19 to 40 IU/L) and a drop in hemoglobin (from 13.2 to 11.2 g/dL). Her upadacitinib dose was decreased to 30 mg, then 15 mg daily. On this dose she has remained in clinical remission with hemoglobin normalization and stable transaminases.

Upadacitinib for moderate to severe atopic dermatitis.

Atopic dermatitis is an inflammatory skin disease, theprevalence of which has increased in the last decade. It affects all age groups, with adult involvement being a major focus of interest in recent years. The unmet needs of the disease, such as pruritus, sleep quality impairment and eczematous skin lesions, have undergone a therapeutic revolution following the commercialization of drugs such as JAK inhibitors. Upadacitinib, a selective JAK1 inhibitor, has been positioned by both clinical trial results and those observed in clinical practice as the fastest and most effective drug in reducing both pruritus and Eczema Area and Severity Index and validated Investigator Global Assessment. Although the safety profile may be initially alarming, it is advisable to update the actual data in this regard for proper management. New perspectives for upadacitinib in nonatopic comorbidities such as psoriasis and alopecia areata are beginning to be described, and interest in learning more about its peculiarities is growing.

Discovery of C-5 Pyrazole-Substituted Pyrrolopyridine Derivatives as Potent and Selective Inhibitors for Janus Kinase 1.

Developing selective inhibitors for Janus kinase 1 (JAK1) is a significant focus for improving the efficacy and alleviating the adverse effects in treating immune-inflammatory diseases. Herein, we report the discovery of a series of C-5 pyrazole-modified pyrrolopyrimidine derivatives as JAK1-selective inhibitors. The potential hydrogen bond between the pyrazole group and E966 in JAK1 is the key point that enhances JAK1 selectivity. These compounds exhibit 10- to 20-fold JAK1 selectivity over JAK2 in enzyme assays. Compound 12b also exhibits excellent JAK1 selectivity in Ba/F3-TEL-JAK cellular assays. Metabolism studies and the results of the hair growth model in mice indicate that compound 12b may be a viable lead compound for the development of highly JAK1-selective inhibitors for immune and inflammatory diseases.

Advances in pharmacotherapy for ulcerative colitis: a focus on JAK1 inhibitors

Introduction Janus kinase (JAK) inhibitors are an emerging class of small-molecule drugs, providing targeted therapy for a variety of diseases, and have made their way into the treatment armamentarium of ulcerative colitis (UC) in recent years. Areas covered This review focuses on the pharmacokinetics, safety, and efficacy of selective JAK1 inhibitors in the treatment of moderate to severe UC. The PubMed database and clinicaltrials.gov were consulted using keywords – further expanded in the methods section. The search was focused on full text publications in English. No publication date restrictions were imposed. Expert opinion JAK1 inhibitors are small-molecule drugs used in the treatment of ulcerative colitis and other immune mediated inflammatory diseases. They are orally bioavailable and have a rapid mechanism of action and no immunogenicity. JAK inhibitors can be used for the management of both naïve patients and biological-experienced patients. Particular attention should be paid to elderly patients or those with cardiovascular or oncological risk factors, in whom JAK inhibitors should be recommended only if no alternatives are available. In addition, JAK inhibitors have the potential to be combined with other biological drugs or small molecules for the management of difficult-to-treat cases.

An evaluation of fedratinib for adult patients with newly diagnosed and previously treated myelofibrosis

ABSTRACT Introduction Myelofibrosis (MF) is a life-shortening myeloproliferative neoplasm that has multiple features such as clonal proliferation, fibrosis and splenomegaly. Until recently, ruxolitinib, a Janus Kinase (JAK) 1/2 inhibitor was the only targeted therapy approved for transplant-ineligible patients with MF and who require treatment for symptoms and/or splenomegaly. However, the discontinuation rate with ruxolitinib at 3 to 5 years is high and mostly due to loss of response or toxicity, and these patients had no subsequent treatment. Areas covered Fedratinib, a selective JAK2 inhibitor, was approved by the Food and Drug Administration (FDA) in August 2019 for the treatment of intermediate-2 or high-risk primary or secondary MF, regardless of prior JAK inhibitor treatment for the management of symptoms and splenomegaly. We discuss herein the development of fedratinib and its pharmacology and pharmacokinetics as well as the clinical development and the future directions. We used PubMed for the search of articles related to fedratinib and myelofibrosis. Expert Opinion Fedratinib provided a second-line treatment for patients with MF who failed or discontinued ruxolitinib. New combinations of JAK inhibitors with other targeted therapies are a must in order to improve the management of MF.

Huangkui capsule alleviates doxorubicin-induced proteinuria via protecting against podocyte damage and inhibiting JAK/STAT signaling.

Huangkui capsule (HKC), a Chinese patent medicine, has been widely used in China as adjuvant therapy for chronic kidney disease (CKD). It displays superior anti-proteinuria efficacy than losartan in patients with CKD at stages 1-2, however, the mechanism of HKC alleviating proteinuria has not been well elucidated. This study aims to confirm the therapeutic effect and investigate associated underlying mechanism of HKC against proteinuria by in vivo and in vitro experiments. We established a doxorubicin (DOX) induced proteinuria mouse model to evaluate kidney function by biochemical markers measurement and to observe histopathological alterations by hematoxylin and eosin (H&E), Masson's trichrome and Periodic Acid-Schiff (PAS)-stained sections of renal, respectively. Moreover, the expressions of Nephrin and Podocin were measured by immunohistochemistry (IHC) and western blotting analysis to investigate podocyte damage. Furthermore, we established Mouse Podocyte Clone-5 (MPC-5) injury model to identify the active components of HKC against podocyte damage by detecting the expressions of Nephrin, Podocin, and ZO-1 proteins. At last, the key protein levels of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway were assessed by western blotting analysis to explore the underlying mechanism of HKC against proteinuria. Our results showed that HKC administration for three consecutive weeks dose-dependently ameliorated both renal function and histopathological damages, elevated the expressions of Nephrin and Podocin, the pivotal molecules maintaining filtration function of the podocyte, indicating the promising protective effect against podocyte injury under DOX exposure. Consistently, in vitro experiments showed HKC administration effectively reversed the abnormal expressions of Nephrin and Podocin in MPC-5 cells treated with DOX, suggesting its protective effect against podocyte injury to maintain filtration barrier integrity. In addition, Hibifolin was identified as the most active ingredients in HKC, which suppressed upstream JAK2/STAT3 and PI3K/Akt pathway phosphorylation to maintain the structural and functional integrity of podocyte filtration barrier. Of note, AG490, a selective JAK2 inhibitor, was used to further affirm the role of Hibifolin involving in regulation JAK2/STAT3. Our study suggested that HKC may protect podocytes via JAK2/STAT3 and PI3K/Akt pathway to display its effects of ameliorating proteinuria.

Circulating miRNA-19b as a biomarker of disease progression and treatment response to baricitinib in rheumatoid arthritis patients through miRNA profiling of monocytes.

A number of studies have demonstrated a key role of miRNA isolated from cells, tissue or body fluids as disease-specific biomarkers of autoimmune rheumatic diseases including rheumatoid arthritis (RA) and systemic sclerosis (SSc). Also, the expression level of miRNA is changing during disease development, therefore miRNA can be used as biomarkers monitoring RA progression and treatment response. In this study we have investigated the monocytes-specific miRNA that could serve as potential biomarkers of disease progression observed in sera and synovial fluids (SF) in early (eRA) and advanced (aRA) RA and in RA patients before and 3 months after selective JAK inhibitor (JAKi) -baricitinib treatment. Samples from healthy control (HC) (n=37), RA (n=44) and SSc (n=10) patients were used. MiRNA-seq of HC, RA, and SSc monocytes was performed to find versatile miRNA present in different rheumatic diseases. Selected miRNAs were validated in body fluids in eRA (<2 years disease onset) and aRA (>2 years disease onset) and RA patients receiving baricitinib. Using miRNA-seq, we selected top 6 miRNA out of 95 that were significantly changed in both RA and SSc monocytes compared to HC. To identify circulating miRNA predicting RA progression, these 6 miRNA were measured in eRA and aRA sera and SF. Interestingly, miRNA (-19b-3p, -374a-5p, -3614-5p) were significantly increased in eRA sera vs HC and even further upregulated in SF vs aRA sera. In contrast, miRNA-29c-5p was significantly reduced in eRA sera vs HC and even further decreased in SF vs aRA sera. Kegg pathway analysis predicted that miRNA were involved in inflammatory-mediated pathways. ROC analysis demonstrated that miRNA-19b-3p (AUC=0.85, p=0.04) can be used as biomarker predicting JAKi response. In conclusion, we identified and validated miRNA candidates which were present simultaneously in monocytes, sera, SF and that can be used as biomarkers predicting joint inflammation and monitoring therapy response to JAKi in RA patients.

Efficacy and safety of selective JAK 1 inhibitor filgotinib in active rheumatoid arthritis patients with inadequate response to methotrexate: comparative study with filgotinib and tocilizumab examined by clinical index as well as musculoskeletal ultrasound assessment (TRANSFORM study): study protocol for a randomized, open-label, parallel-group, multicenter, and non-inferiority clinical trial

BackgroundAdministration of Janus kinase (JAK) inhibitors and biological disease-modifying antirheumatic drugs has dramatically improved even the clinical outcomes in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). Dysregulation of JAK-STAT pathways via overproduction of cytokines, such as interleukin-6, is involved in the pathogenesis of RA. Filgotinib is a selective JAK1 inhibitor pending approval for use in RA. By inhibition of the JAK-STAT pathway, filgotinib is effective in suppressing disease activity and preventing the progression of joint destruction. Similarly, interleukin-6 inhibitors such as tocilizumab also inhibit the JAK-STAT pathways by inhibition of interleukin-6 signaling. We present the protocol for a study that will evaluate whether the effectiveness of filgotinib monotherapy is non-inferior to that of tocilizumab monotherapy in RA patients with an inadequate response to MTX.MethodsThis study is an interventional, multicenter, randomized, open-label, parallel-group, and non-inferiority clinical trial with a 52-week follow-up. Study participants will be 400 RA patients with at least moderate disease activity during treatment with MTX. Participants will be randomized in a 1:1 ratio to administer filgotinib monotherapy or subcutaneous tocilizumab monotherapy switched from MTX. We will evaluate disease activity by measuring clinical disease activity indices and by using musculoskeletal ultrasound (MSUS). The primary endpoint is the proportion of patients who achieve an American College of Rheumatology 50 response at week 12. Secondary endpoints are changes from baseline in the MSUS scores. We will also comprehensively analyze serum levels of multiple biomarkers, such as cytokines and chemokines.DiscussionThe study results are expected to show the non-inferiority of the effectiveness of filgotinib monotherapy to that of tocilizumab monotherapy in RA patients with inadequate response to MTX. The strength of this study is its prospective evaluation of therapeutic efficacy using not only clinical disease activity indices, but also MSUS, which accurately and objectively evaluates disease activity at the joint level among patients drawn from multiple centers with a standardized evaluation by MSUS. We will evaluate the effectiveness of both drugs by integrating multilateral assessments—clinical disease activity indices, MSUS findings, and serum biomarkers.Trial registrationJapan Registry of Clinical Trials (https://jrct.niph.go.jp) jRCTs071200107. Registered on March 3, 2021. ClinicalTrials.gov NCT05090410. Registered on October 22, 2021.

Abrocitinib for the Treatment of Moderate-to-Severe Atopic Dermatitis.

Atopic dermatitis (AD) is ranked as the third most prevalent skin condition with a worldwide prevalence of 2.4%. Atopic dermatitis is a common form of eczema. It develops in infancy or childhood and continues into adulthood with symptoms ranging from mild to severe. Pruritis and inflammation are the hallmark symptoms of AD. Abrocitinib is a JAK1 selective inhibitor; inhibition results in a decreased interleukin (IL) 4 activation and decreased pruritis in a patient with AD. Abrocitinib is hepatically metabolized by multiple cytochrome P450 enzymes, and dose modification may be required when administered with concurrent medications. At least 6 JAK1 Atopic Dermatitis Efficacy and Safety (JADE) trials were conducted evaluating Investigator's Global Assessment and Eczema Area and Severity Index score for efficacy. All JADE trials showed abrocitinib 100 mg and 200 mg doses efficacious when compared with placebo. Common adverse reactions were related to gastrointestinal disturbances, headache, and acne. Serious adverse reactions to assess risk for include serious infections, malignancy, major adverse cardiovascular events, and venous thromboembolisms. Abrocitinib provides a valuable treatment option for patients with moderate-to-severe AD unresponsive to other therapies for those candidates without a high risk for significant adverse reaction associated with its use.