Vonjo (pacritinib)

BCWM.2 cells also showed remarkable sensitivity to the B-cell lymphoma 2 inhibitor venetoclax and the Janus kinase 2/Interleukin-1 receptor-associated kinase 1 inhibitor pacritinib, underscoring their utility for identification of pharmacologically active agents. BCWM.2 represents a novel myeloid differentiation primary response 88-mutated, 6q-deleted cell line with distinct genomic features for in vivo and in vitro studies for WM.

P1, N=20, Not yet recruiting, University of Kansas Medical Center | Trial primary completion date: Dec 2025 --> Dec 2026

Mechanistic studies revealed that while pacritinib inhibited the phosphorylation of JAK, STAT3, and IRAK1 in esophageal carcinoma cells, it is the suppression of the JAK/STAT3 pathway, rather than IRAK1, that is responsible for the synergistic effect with carboplatin. Our findings indicate that pacritinib possesses potent anti-tumor activity in esophageal carcinoma and enhances the efficacy of carboplatin through the suppression of JAK/STAT3 signaling, warranting further clinical investigation.

The discovery of the JAK2 V617F mutation prompted the development of JAK inhibitors (JAKi) including the first-in-class JAK1/JAK2 inhibitor ruxolitinib and subsequent approval of fedratinib, pacritinib, and momelotinib. Selective JAK2 V617F inhibitors and targeting of mutant CALR by immunotherapy are the most intriguing and promising approaches. This review focuses on approved and experimental treatments for MF, highlighting their biological background.

P1, N=15, Recruiting, Washington University School of Medicine | Not yet recruiting --> Recruiting

P1/2, N=44, Recruiting, The University of Texas Health Science Center at San Antonio | Not yet recruiting --> Recruiting

P3, N=399, Recruiting, Swedish Orphan Biovitrum | Trial completion date: Dec 2025 --> Jul 2027 | Trial primary completion date: Jun 2025 --> Dec 2026

P2, N=78, Not yet recruiting, Swedish Orphan Biovitrum

P1/2, N=44, Not yet recruiting, The University of Texas Health Science Center at San Antonio | Initiation date: Sep 2024 --> Jan 2025

P1, N=15, Not yet recruiting, Washington University School of Medicine | Trial completion date: Oct 2028 --> Jan 2029 | Initiation date: Oct 2024 --> Jan 2025 | Trial primary completion date: Nov 2026 --> Feb 2027

Additionally, pacritinib preventive treatment reduced COL1A1 production in an in vitro model mimicking JAK2-driven fibrosis. These findings highlight that dual inhibition of JAK2/IRAK1 with pacritinib, by delaying or attenuating the myelofibrotic progression, could be a potential modifier of the natural course of MPN.

P2, N=6, Terminated, Medical College of Wisconsin | Trial completion date: May 2027 --> Oct 2024 | Active, not recruiting --> Terminated; After 6 patients were enrolled, it was determined that only patients with STAT5 activation were having a biochemical response to pacritinib treatment.

P1, N=10, Not yet recruiting, City of Hope Medical Center

Current therapeutic strategies include JAK inhibitors like Ruxolitinib, which target the JAK-STAT pathway, alongside supportive treatments such as blood transfusions, erythropoiesis-stimulating agents and developing combinatorial approaches...Recently approved JAK inhibitors, including Fedratinib, Pacritinib, and Momelotinib, have expanded the therapeutic landscape...These technologies elucidate the role of the spleen in MF, highlighting its transformation into a site of abnormal hematopoietic activity, fibrotic changes, and immune cell infiltration, functioning as a "tumor surrogate." By profiling diverse cell populations and molecular alterations within the BM and spleen, SRT facilitates a deeper understanding of MF pathophysiology, helping identify novel therapeutic targets and biomarkers. Ultimately, integrating spatial transcriptomics into MF research promises to enhance diagnostic precision and therapeutic innovation, addressing the multifaceted challenges of this disease.

In patients with myelofibrosis and platelets ≤ 100 × 109/L, achieving SVR on pacritinib, but not BAT (including ruxolitinib), was associated with significant OS benefit, suggesting that pacritinib may offer a unique survival advantage in patients with myelofibrosis and thrombocytopenia who achieve any SVR. Trial Registration: ClinicalTrials.gov number: NCT02055781.

Interestingly, pacritinib, but not other JAK inhibitors such as ruxolitinib, upadacitinib, or filgotinib, acted synergistically with lenvatinib in HCC cells. Immunohistochemical analysis of tumor sections revealed that pacritinib reduced Ki67 staining and phosphorylated IRAK1. Our findings suggest that pacritinib may be a promising therapeutic option for the treatment of advanced HCC, particularly in patients who have developed resistance to lenvatinib.

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.

In this work, additional effort was applied to design new BIBR1532-based analogues with potential inhibitory activity against telomerase and acting as multitarget antitumor candidates to overcome the resistance problem...Compound 4l represented a very promising JAK1 inhibitory potential with a 0.46-fold change, compared to that of pacritinib reference standard (0.33-fold change). Besides, it showed a superior STAT3-inhibitory potential with a 0.22-fold change compared to sorafenib (0.33-fold change). Additionally, compound 4l downregulated TLR4 protein expression by 0.81-fold change compared to that of resatorvid (0.29-fold change)...Remarkably, compound 4l led to prominent reductions in tumor size and mass. Concurrent enhancements in biochemical, hematologic, histopathologic, and immunohistochemical parameters further confirmed the suppression of angiogenesis and inflammation, elucidating additional mechanisms by which compound 4l exerts its anticancer effects.

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.

P2, N=65, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

P1, N=15, Not yet recruiting, Washington University School of Medicine

Our phase I graft-versus-host disease (GVHD) prevention trial of JAK2 inhibitor, pacritinib, (recommended phase II dose: 100mg po BID day 0 to +70) plus sirolimus and tacrolimus (PAC/SIR/TAC) demonstrated the regimen was safe and free of pan-JAK myelosuppression after allogeneic hematopoietic cell transplantation (alloHCT). The cumulative incidence of grade II-IV acute GVHD by day +100 with PAC/SIR/TAC was similar to historic SIR/TAC values (46 v 43%). While PAC/SIR/TAC suppressed pSTAT3 and Th1/Th17 cells, the regimen did not improve acute GVHD prevention.

P1/2, N=44, Not yet recruiting, The University of Texas Health Science Center at San Antonio

Pacritinib demonstrates consistent efficacy in patients with MF regardless of baseline platelet and hemoglobin counts.

P1, N=29, Completed, CTI BioPharma | Recruiting --> Completed

P1/2, N=26, Recruiting, Douglas Tremblay | Not yet recruiting --> Recruiting | Initiation date: Jan 2024 --> Sep 2024

Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells...The Entrectinib-Pacritinib combination suppressed orthotopic growth of HER2-positive Trastuzumab-refractory breast cancer xenografts and basal patient-derived xenograft (PDXs), reduced tumoral SOX2 and MYC, and induced apoptosis in both mouse models. The Entrectinib-Pacritinib combination inhibited overall metastatic burden, and brain and bone metastases of intracardially inoculated TNBC cells without toxicity. Together, our results demonstrate for the first time that co-inhibition of TrkA and JAK2 synergistically suppresses breast cancer growth and metastasis, thereby providing preclinical evidence that supports future clinical evaluations.

Ruxolitinib, fedratinib, momelotinib, and pacritinib are FDA-/EMA-approved JAK inhibitors effective in relieving symptoms in MPN patients but show variable clinical profiles due to poor JAK selectivity. Inhibitors differed in their JAK isoform selectivity and potency for erythropoietin signaling, but their general cytokine inhibition signatures in blood cells were comparable. Structural data indicate that high potency and moderate JAK2 selectivity can be obtained by targeting the front pocket of the adenosine 5'-triphosphate-binding site.

P2, N=118, Recruiting, Karyopharm Therapeutics Inc | Not yet recruiting --> Recruiting

We searched and reviewed clinical trial reports on the monotherapy of 13 FLT3 inhibitors, including sorafenib, lestaurtinib, midostaurin, gilteritinib, quizartinib, sunitinib, crenolanib, tandutinib, cabozantinib, pexidartinib, pacritinib, famitinib, and TAK-659 in patients with hematological and solid malignancies before May 31, 2023...The ORRs of FLT3 inhibitors in hematologic malignancies and solid tumors were 40.8% and 18.8%, respectively, indicating FLT3 inhibitors were more effective for hematologic malignancies than for solid tumors. In addition, time to maximum plasma concentration (Tmax) in these FLT3 inhibitors ranged from 0.7-12.0 hours, but the elimination half-life (T1/2) range was highly variable, from 6.8 to 151.8 h. FLT3 inhibitors monotherapy has shown significant anti-tumor effect in clinic, and the effectiveness may be further improved through combination medication.

Various IRAK1 inhibitors, including Pacritinib and Rosoxacin, show therapeutic potential against malignancies and inflammatory diseases...Additionally, the emergence of selective IRAK1 degraders, such as JNJ-101, provides a novel strategy by targeting the scaffolding function of IRAK1. Thus, the evolving landscape of IRAK1-targeted approaches provides promising avenues for increasingly safe and effective therapeutic interventions for various diseases.

P1, N=20, Not yet recruiting, University of Kansas Medical Center

P1, N=24, Recruiting, Fox Chase Cancer Center | Not yet recruiting --> Recruiting

Furthermore, tailoring treatment with currently available JAK inhibitors (such as ruxolitinib or fedratinib) does not modify the natural history of the disease and has important limitations, including cytopenias...Specifically, we tested the JAK1/2 inhibitor, ruxolitinib; the NF-κB inhibitor via IKKα/β, BMS-345541; both inhibitors in combination; or a dual inhibitor of both pathways (JAK2/IRAK1), pacritinib...Additionally, combined treatment reduced both COL1A1 and IL-6 production in an in vitro model mimicking JAK2-driven fibrosis. In conclusion, NF-κB inhibition reduces, in vitro and in vivo, disease burden and BM fibrosis, which could provide benefits in myelofibrosis patients.

P2, N=25, Recruiting, University of Washington | Trial completion date: Nov 2024 --> Nov 2026 | Trial primary completion date: Nov 2024 --> Nov 2026

P1/2, N=160, Not yet recruiting, National Cancer Institute (NCI)

Finally, pacritinib suppressed KSHV viral IL-6-induced human IL-6 and IL-10 production in peripheral blood mononuclear cells, which may model an important step in KSHV-MCD pathogenesis. These results suggest that pacritinib warrants testing for the treatment of KSHV-MCD and PEL.

Combining ADCT-602 + pacritinib was beneficial in ADCT-602-resistant cells. Chidamide increased CD22 expression on B-cell tumor surfaces, increasing ADCT-602 activity. These data support clinical testing of ADCT-602 in R/R B-ALL (NCT03698552) and CD22-positive hematological cancers.

P1, N=60, Completed, CTI BioPharma | Active, not recruiting --> Completed

P2, N=6, Active, not recruiting, Medical College of Wisconsin | Recruiting --> Active, not recruiting

P1, N=24, Not yet recruiting, Fox Chase Cancer Center

Among the approved JAK inhibitors (ruxolitinib, fedratinib, momelotinib, and pacritinib) for MF, momelotinib and pacritinib are preferably used in cytopenic patients; both agents are potent ACVR1 inhibitors that suppress hepcidin expression via the BMP6/ACVR1/SMAD pathway and restore iron homeostasis/erythropoiesis...Zilurgisertib (ACVR1 inhibitor) and DISC-0974 (anti-hemojuvelin monoclonal antibody) are evaluated in early phase clinical trials in patients with MF and anemia. Luspatercept (ACVR2B ligand trap) is assessed in transfusion-dependent MF patients in a registrational phase 3 trial. Approved ACVR1 inhibitors and novel agents in development are poised to improve the outcomes of anemic MF patients.