Vonjo (pacritinib)

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.

The primary objective of treatment in myelofibrosis (MF) is prolongation of life, which is currently accomplished only by allogeneic hematopoietic stem cell transplantation (AHSCT). Pacritinib and fedratinib provide alternative options in the presence of severe thrombocytopenia or ruxolitinib-resistance/intolerance, respectively. Splenectomy remains a viable option for drug-resistant symptomatic splenomegaly and cytopenia.

This review summarizes novel and promising treatments for anemia in myelofibrosis including transforming growth factor-β inhibitors luspatercept and KER-050, JAK inhibitors momelotinib, pacritinib, and jaktinib, BET inhibitors pelabresib and ABBV-744, antifibrotic PRM-151, BCL2/BCL-XL inhibitor navitoclax, and telomerase inhibitor imetelstat. Standard approaches to treat myelofibrosis-related anemia have limited efficacy and are associated with toxicity. New drugs have shown positive results in myelofibrosis-associated anemia when used alone or in combination.

P1/2, N=26, Not yet recruiting, Douglas Tremblay

Background: Prior to the approval of ropeginterferon alfa-2b-njft (ropeginterferon) in November 2021, the alternatives to hydroxyurea for the treatment of polycythemia vera (PV) included Janus Kinase inhibitors (JAKi) and older versions of recombinant interferon-alpha (rIFNα). This study examined FAERS reports to detect disproportional reporting odds of drug-associated AEs severity and SOCs in four PV treatments: ropeginterferon, ruxolitinib, interferon alfa-2a, and pacritinib. Ropeginterferon had a significant ROR for non-serious AEs. Peginterferon alfa-2a demonstrated a significant ROR for SAEs.

The role of the JAK/Signal transducer and activator of transcriptions (STAT) pathway in MF has led to the recent approval of three different JAK2 inhibitors (ruxolitinib, pacritinib, and fedratinib) for MF treatment. Our studies showed high sensitivity of MF cell lines to tagraxofusp as a single agent, which is expected given phase 2 results demonstrated clinical efficacy of single-agent tagraxofusp in R/R MF (Yacoub et al. ASH 2021). In addition, synergism was observed in combination with JAK inhibitors.

Despite the current standard of care, the JAK1/2 inhibitor (JAKi) ruxolitinib (RUX), a significant unmet need remains for patients (pts) with MF, due to lack of response or JAKi resistance... JAK2V617F mutant cell lines HEL ( TP53M113K), UKE-1 ( TP53WT), MUTZ-8 ( TP53WT), and JAK2WT ELF-153 ( TP53I251N) cells were treated with SEL alone or in combination with RUX, pacritinib (PAC), momelotinib (MMB), pelabresib (PELA), or navitoclax (NAV)... In a panel of MPN-derived cells with or without JAK2V617F, SEL showed single-agent antiproliferative activity, and synergism with other MF therapeutics at clinically achievable concentrations through regulation of XPO1, JAK/STAT signaling, and apoptosis/senescence regulators. In addition to positive Phase 1 clinical data in pts with JAKi-naïve MF who received SEL with RUX, these preclinical data support synergistic activity between SEL and other MF therapies, suggesting the potential for SEL as a backbone for novel treatment combinations for MF.

P1/2, N=50, Recruiting, National Cancer Institute (NCI) | Trial completion date: Nov 2023 --> Nov 2024 | Trial primary completion date: Nov 2023 --> Nov 2024

Interestingly, pacritinib exhibited synergistic effects when combined with temsirolimus and sunitinib, but antagonistic effects when combined with doxorubicin, in a panel of RCC cell lines. Mechanistic studies indicated that the inhibition of JAK2, but not IRAK, was the main contributor to the anti-RCC activity of pacritinib. Our study is the first to demonstrate that pacritinib shows promise as a treatment option for RCC and underscores the therapeutic potential of targeting the JAK2/STAT signalling pathway in RCC.

Thrombocytopenia is both prognostic of poor outcomes and predictive of treatment intolerance with the JAK1/2 inhibitor ruxolitinib, which exacerbates cytopenias. Of 117 patients randomized to pacritinib (75 from PERSIST-2, 42 from PAC203), 16% (n=19) experienced HI-P on study (as defined in methods). Additionally, 14 of the 19 HI-P patients had sustained platelet improvement over ≥12 weeks). By contrast, only 5% (4/77) of patients on BAT achieved HI-P response prior to end of study treatment.

In cytopenic MF patients from PERSIST-2, TI-R on pacritinib was associated with BMF improvement. Though these results are based on a small sample size, they contrast with recent data suggesting no correlation between BMF reduction and TI-R on the JAK1/2 inhibitors momelotinib and ruxolitinib (Oh ST, et al. Blood 2022; 140 (Supp 1):821-23).

Introduction: Three Janus kinase 2 (JAK2) inhibitors (JAKinibs) have been approved by the FDA for the treatment of myelofibrosis (MF): ruxolitinib, fedratinib, and pacritinib; a fourth one, momelotinib, is currently under FDA review. JAKinibs clinically evaluated for treatment of MF exhibit distinct kinase inhibition profiles and cellular activities. Amongst the agents tested in this study, ruxolitinib was the most potent and selective JAK2 inhibitor. At concentrations several fold above clinically relevant concentrations, ruxolitinib had no observable effects on the health of cells not reliant on JAK/STAT mediated signaling.

FDA-approved JAKi for the treatment of MF include ruxolitinib, fedratinib, and pacritinib. CALR-1 mutation is the most important risk factor for both drug survival and longevity without AHSCT, in momelotinib-treated patients with MF. Such information might help identify MF patients who might benefit from treatment with momelotinib and in whom AHSCT might be deferred or not.

Background: Pacritinib is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that demonstrated symptom benefit measured by TSS (v2.0, excluding tiredness) vs best available therapy (BAT) in PERSIST-2, which enrolled cytopenic myelofibrosis patients with platelets ≤100×109/L. In cytopenic myelofibrosis patients enrolled in PERSIST-2, having a reduction of TSS≥10% on full-dose PAC was associated with OS benefit – a finding that has not been noted with other JAK inhibitors to date. By contrast, this association was not found with BAT, (82% of these patients received ruxolitinib). Thus, reductions in TSS in patients treated with PAC were associated with an OS benefit.

JAK inhibition can reduce GM-CSF signaling, which contributes to CMML pathobiology; ruxolitinib has been clinically evaluated in CMML demonstrating promising, but insufficient clinical activity. Modulation of biomarkers of disease activity with treatment including GM-CSF dependent STAT5 phosphorylation, MAPK, and PI3K signaling will be analyzed. We will also evaluate changes in mutational and cytogenetic burden with treatment as well as at baseline to identify predictive biomarkers of response.

Optional treatment of ruxolitinib or pacritinib, may be added for patients whose SVR is <10% at week 12 or <35% at week 24 when compared to baseline; and the choice of ruxolitinib or pacritinib will be considered based on platelet count. Primary secondary endpoints are safety, TSS50 at week 24, anemia response at week 24, overall survival, and overall response rate. Efficacy and safety assessments will also be performed on patients who receive optional add-on treatment.

Hydroxyurea was the most commonly used drug in patients with MF prior to the approval of ruxolitinib (RUX), a first-in-class Janus kinase 1/2 inhibitor (JAKi) that is widely approved for symptomatic patients with MF. In addition to RUX, the JAKis fedratinib and, more recently, pacritinib have also been approved by the US Food and Drug Administration... In patients with MF, RUX was the most commonly used agent in all lines of therapy. The greatest reduction in duration of MF treatment occurred from 1L to 2L. Most patients remained on 1L therapy through Week 24 and did not initiate 2L therapy until Week 156.

We performed comparative studies to evaluate the activity of pacritinib and the covalent BTK-inhibitors ibrutinib and zanubrutinib on mutated MYD88 relevant pro-survival signaling, as well as proliferation and survival in MYD88 mutated cell lines and primary MYD88-mutated WM cells...Lastly, pacritinib alone and combined with venetoclax induced high levels of apoptosis in BTKCys481Ser expressing covalent BTK-inhibitor resistant MYD88 mutated WM and ABC DLBCL lymphoma cells... Pacritinib more broadly extinguishes mutated MYD88 pro-survival signaling cascades (Fig 1.) and demonstrates high levels of apoptotic activity in mutated MYD88 WM and ABC DLBCL cells versus selective covalent BTK-inhibitors. Pacritinib also synergizes with covalent BTK- and BCL2 inhibitors and can overcome covalent BTK-inhibitor resistance related to mutated BTKCys481. Our studies provide a framework for investigating pacritinib in MYD88 mutated lymphomas.

Introduction: Our phase I graft-versus-host disease (GVHD) prevention trial of pacritinib (recommended phase II dose: 100mg po BID day 0 to +70, dose level 2) plus sirolimus (8-14ng/ml) and tacrolimus (3-7ng/ml) (PAC/SIR/TAC) demonstrated the regimen was safe and free of pan-JAK myelosuppression after allogeneic hematopoietic cell transplantation (alloHCT). While PAC/SIR/TAC successfully reduced pSTAT3, increased pSTAT5, and suppressed Th1 and Th17 cells, the regimen did not reduce acute GVHD risk. Completed phase II and III trials testing tocilizumab (anti-IL-6 monoclonal antibody, ACTRN12612000726853, ACTRN12614000266662) and now PAC reveal a biologic disconnect between effective IL-6/JAK2/pSTAT3 axis blockade and a disappointing lack of clinical improvement in acute GVHD prevention. We surmise uncontrolled T cell Aurora kinase A activity contributed to acute GVHD via CD28 costimulation in this trial.

P1/2, N=40, Completed, H. Lee Moffitt Cancer Center and Research Institute | Active, not recruiting --> Completed

P1, N=60, Active, not recruiting, CTI BioPharma | Trial primary completion date: Aug 2023 --> Dec 2023

P1, N=32, Recruiting, CTI BioPharma | Trial completion date: Dec 2023 --> May 2024 | Trial primary completion date: Sep 2023 --> May 2024

Pacritinib inhibited ACVR1 with greater potency (half-maximal inhibitory concentration [IC50] = 16.7 nM; Cmax:IC50 = 12.7) than momelotinib (IC50 = 52.5 nM; Cmax:IC50 = 3.2), fedratinib (IC50 = 273 nM; Cmax:IC50 = 1.0), or ruxolitinib (IC50 > 1000; Cmax:IC50 < 0.01). Among patients on PERSIST-2 who were not TI at baseline based on Gale criteria, a significantly greater proportion became TI on pacritinib compared to best available therapy (37% vs. 7%, P=0.001), and significantly more had a ≥50% reduction in transfusion burden (49% vs. 9%, P<0.0001). These data indicate that the anemia benefit of the JAK2/IRAK1 inhibitor pacritinib may be a function of potent ACVR1 inhibition.

P2, N=65, Not yet recruiting, National Cancer Institute (NCI)

However, early JAK inhibitors (ruxolitinib and fedratinib) are often associated with cytopenias, particularly thrombocytopenia and anemia, which limit their tolerability. To address these complications, pacritinib has been developed and recently approved for patients with thrombocytopenia, while momelotinib is in development for those with anemia...In the near future, MF treatment strategies will involve selecting the most suitable JAK inhibitor based on individual patient characteristics and prior therapy. Ongoing and future clinical trials are crucial for advancing the field and expanding therapeutic options for MF patients.

P2, N=100, Recruiting, University of Michigan Rogel Cancer Center | Trial completion date: Mar 2028 --> Nov 2028 | Trial primary completion date: Mar 2025 --> Nov 2027

This manuscript, describing the pharmacological aspects of eleven anticancer novel drug therapies approved by the FDA, shall serve as a helpful document for cancer patients, concerned academicians, researchers, and clinicians, especially oncologists.

Finally, the JAK2/IRAK1 dual inhibitor Pacritinib exhibited strong activities against pC ALK- ALCL where the IL-1R pathway is hyper-activated in the cell line and xenograft mouse model. Thus, our studies revealed critical insights into the essential roles of the IL-1R pathway in pC ALCL, and provided opportunities for developing novel therapeutic strategies.

P2, N=100, Recruiting, University of Michigan Rogel Cancer Center | Not yet recruiting --> Recruiting

Aims: To assess whether inhibition of NF-κB and/or JAK/STAT signaling can attenuate the inflammatory state and reverse the MF-like phenotype in an aged miR-146a -/- mouse model, using either (a) the JAK1/2 inhibitor ruxolitinib (RUX), (b) the NF-κB pathway inhibitor, through IKKα/β, BMS-345541 (BMS), (c) RUX+BMS, or (d) the dual JAK2/IRAK1 inhibitor pacritinib (PAC). In an aging-associated MF-like murine model without driver mutations, NF-κB inhibitors, either alone or incombination with JAK inhibitors, as well as dual-acting inhibitors, reduced inflammatory cytokines and splenomegaly, reversed thrombocytopenia and improved BM fibrosis. The combination therapy (RUX+BMS) produced BM aplasia and worsened anemia, whereas the dual inhibitor (PAC) improved or stabilized hematologic parameters. Bone Marrow Fibrosis, Myelofibrosis, NF- B, Myeloproliferative disorder

In this in vivo MF-like model, particularly useful to study the inflammatory component of MF without driver mutations, dual JAK2+IRAK1 inhibition, with inhibitors such as pacritinib, prevents the development ofthrombocytopenia, splenomegaly, extramedullary hematopoiesis and BM fibrosis, postulated as a potential modifier of the natural course of these diseases. The improvement of inflammatory symptoms in MF patients receiving pacritinib, which does not inhibit JAK1, could be explained by inhibition of the NF-κB pathway through IRAK1. Bone Marrow Fibrosis, Myeloproliferative disorder, Myelofibrosis, NF- B