Moreover, JAKi therapy impaired Tfh cell differentiation in patients with ICI-T1DM. These studies highlight CD4 + Tfh cells as underrecognized but critical mediators of ICI-T1DM that may be targeted with JAKi to prevent this grave IrAE.

Most TNFi could be more effective than JAKi and IL-17i. The safety of the therapies is generally good. However, the efficacy and safety of TNFi/IL-17i/JAKi remains to be further analyzed in studies with larger sample size and longer follow-up times.

In turn, the results indicate that the anti-asthmatic action induced by the studied agents is not mediated by the generation of forkhead box protein 3-expressing CD4+ regulatory T cells. Clinical implication of the the results suggest that MMF and TFB may exert anti-asthmatic action, and thus they may be considered therapeutic options for the treatment of allergic asthma cases resistant to conventional/existing treatment.

P3, N=182, Recruiting, Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Not yet recruiting --> Recruiting

P2, N=70, Recruiting, Stanford University | Trial completion date: Nov 2024 --> Nov 2026 | Trial primary completion date: Nov 2024 --> Nov 2025

Angoline, a JAK/STAT3 pathway inhibitor, attenuated the effect of PKM2 overexpression on the efficacy of YJP. In conclusion, YJP can inhibit the activation of the JAK/STAT3 pathway by regulating PKM2, thereby inhibiting the malignant biological behavior of HeLa cells.

P1, N=48, Completed, Biora Therapeutics, Inc. | Recruiting --> Completed

Clinical trials and basic research have demonstrated the efficacy of JAK inhibitors in modulating these cytokine pathways and promoting melanocyte repigmentation. This review provides a comprehensive analysis of JAK inhibitors, exploring their mechanisms and latest applications in regulating cytokine and skin immune responses, aiming to optimize their use in vitiligo therapy.

These novel time-dependent transfusion burden analyses demonstrate that momelotinib is associated with anemia-related benefits in most patients and greater transfusion burden reduction versus comparators.

P=N/A, N=450, Recruiting, Humanitas Clinical and Research Center

P4, N=308, Not yet recruiting, University Hospital, Toulouse

P3, N=182, Not yet recruiting, Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

P1, N=40, Recruiting, Icahn School of Medicine at Mount Sinai | Trial completion date: Oct 2024 --> Jun 2025 | Trial primary completion date: Oct 2024 --> Jun 2025

P2, N=30, Active, not recruiting, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Recruiting --> Active, not recruiting

Recently, there has been increased efforts to optimize treatment with the development of highly selective JAK inhibitors, as well as use of combination agents to counter disease resistance through targeting aberrant signaling pathways. Treatment of MF patients with JAKi therapy can be challenging but the development of more potent and selective JAK inhibitors, as well as combination therapies, represent exciting treatment advances in this field.

In particular, the lipid paradox associated with RA highlights the complex relationship between RA treatments (MTX, JAKis, tumor necrosis factor (TNF) inhibitors, and interleukin (IL)-6 receptor inhibitors), inflammation, different lipid profiles, and CV risk. In the absence of contraindications and when MTX is tolerated, this commentary suggests the concomitant use of MTX and JAKis as a preferred option for optimizing CV protection in patients with RA.

P1, N=8, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: May 2024 --> May 2025

The JAK1/2 inhibitor, ruxolitinib, which increased the uSTAT5:pSTAT5 ratio, had similar effects on murine HSC function: it constrained HSC differentiation and proliferation, promoted HSC maintenance and upregulated transcriptional programs associated with stemness...Our results therefore reveal a previously unrecognized interplay between pSTAT5 and uSTAT5 in the control of HSC function and highlight JAK inhibition as a potential strategy for enhancing HSC function during ex vivo culture. Increased levels of uSTAT5 may also contribute to the failure of JAK inhibitors to eradicate myeloproliferative neoplasms.

Ruxolitinib and fedratinib can cause myelosuppression and are recommended for patients with myeloproliferative MF. Approval of 2 less myelosuppressive JAKi, pacritinib and momelotinib, provided essential treatment options for patients with severe thrombocytopenia and anemia, respectively...Judicious treatment decisions of JAKi can be made with in-depth understanding of the pivotal clinical trials on JAKi and their therapeutic attributes and should be guided by the dominant clinical manifestations and the type/degree of cytopenia(s). This article reviews our clinical approach to treatment with JAKi and their sequencing in MF patients by presenting 3 clinical vignettes.

We demonstrated that JAKi prevent GM-CSF-induced CEACAM1 expression in neutrophils, and JAKi-induced inhibition depends on their selectivity against JAK isoforms. These findings suggest that JAKi can modulate the expression of CEACAM1 in cytokine-activated neutrophils, thereby limiting their activation.

P2, N=30, Not yet recruiting, M.D. Anderson Cancer Center

In order to potentially increase clinical benefit for patients with MF, several novel agents are being partnered with ruxolitinib (RUX) with the ongoing hypothesis to augment greater measures of MF disease modification. The novel agents are either 'added-on' to RUX or as a combo in JAKi naïve patients. Also, the mutant-targeting era of therapies is now beginning with novel CALR-mutated, novel JAK2 V617F mutation-specific and type II JAK2i in the initial stages of drug development, representing a new approach to treatment.

P1/2, N=39, Not yet recruiting, University of Michigan Rogel Cancer Center

The JAK/signal transducers and activators of the transcription (STAT) signaling pathway mediate the downstream events involved in immune fitness, tissue repair, inflammation, apoptosis, and adipogenesis by binding various ligands, such as cytokines, growth hormones, and growth factors. The mutation or loss of JAK/STAT components is implicated in autoimmune diseases, thus inhibition of such pathways has been an important area of research in therapeutic development.1 In this review, we provide a comprehensive overview of the efficacy and safety of JAK inhibitors for the management of NIU, with evidence from current trials and case reports.

P1, N=32, Not yet recruiting, Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

P2, N=106, Completed, Celon Pharma SA | Recruiting --> Completed

P=N/A, N=1442, Completed, Aetion, Inc. | Active, not recruiting --> Completed | N=3000 --> 1442

P3, N=362, Active, not recruiting, LEO Pharma | Recruiting --> Active, not recruiting

P4, N=118, Recruiting, Beijing Children's Hospital; Beijing Children's Hospital, Capital Medical University, China

The surface modification of liposomes with the CD34 antibody, along with the inclusion of the SAR317461 and cytarabine (a common AML chemotherapeutic agent), is observed. Due to the high expression of CD34 on the surface of AML cells, the nanoliposome could target AML cells specifically, further achieving an effective treatment for AML through the synergistic effect of JAK2/STAT3 inhibitors and chemotherapeutic agents. The implementation of this project will provide more theoretical support and ideas for the clinical application of JAK/STAT3 inhibitors in malignant tumors and for overcoming chemotherapy resistance.

P2, N=20, Recruiting, Fred Hutchinson Cancer Center | Trial primary completion date: Aug 2024 --> Aug 2026

Upon loss of response to upadacitinib, JAK-2 inhibitor ruxolitinib provided clinical benefit in one of the cases, facilitating further tapering of glucocorticoids. This arena warrants further exploration through prospective studies of larger cohorts to delineate optimal management strategies.

Pacritinib (not approved in Japan) is suitable for MF patients with thrombocytopenia. JAK inhibitor selection and supportive care by ESA or danazol in lieu of transfusion should be considered. Many classes of drugs other than JAK inhibitors for myelofibrosis are under investigation.

The result suggested that CD4 interacts with JAK2 and that the CD4-JAK2 complex is stable. This study was able to identify a candidate inhibitor that warrants further examination and optimization and may potentially serve as a future MPN treatment.

P=N/A, N=150, Recruiting, Second Affiliated Hospital, School of Medicine, Zhejiang University

P=N/A, N=0, Withdrawn, Central Hospital, Nancy, France | N=20 --> 0 | Recruiting --> Withdrawn

Tofacitinib and filgotinib are approved for treating ulcerative colitis (UC), while upadacitinib is approved for UC and Crohn's disease. Ozanimod and etrasimod are S1PRMs approved for the treatment of UC, but they can cause side effects such as bradycardia, conduction disorder, and macular edema. Overall, JAK inhibitors and S1PRMs offer significant benefits in managing IBD, although their potential side effects require careful monitoring.

P3, N=320, Recruiting, Geron Corporation | Trial completion date: Apr 2027 --> Nov 2026 | Trial primary completion date: Apr 2027 --> Nov 2026

P2, N=258, Completed, LEO Pharma | Phase classification: P2b --> P2

P2, N=251, Completed, LEO Pharma | Phase classification: P2b --> P2

Amino pyrimidine-containing compound 6 and thiopheno[3,2-d]pyrimidine-containing compound 13 expressed admirable JAK3 inhibition activity with IC50 of 1.7 nM and 1.38 nM respectively. Our review will support the medicinal chemists in refining and directing the development of novel N-heterocyclic-based JAK inhibitors.

P=N/A, N=100, Recruiting, Central Hospital, Nancy, France | Not yet recruiting --> Recruiting | Trial completion date: Jun 2024 --> Sep 2024 | Trial primary completion date: Jun 2024 --> Sep 2024