P1/2, N=84, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting | N=206 --> 84

P1, N=24, Recruiting, 35Pharma Inc | Phase classification: P1/2 --> P1

Summarized are traditional approaches to anemia management and the clinical trial efficacy and safety data that support momelotinib as an option in each setting from mild to severe anemia, including in the context of co-occurring thrombocytopenia. With the availability of momelotinib and other emerging therapies directed at anemia control, early treatment of anemia to avoid progression and support improvement in eligible patients with myelofibrosis should be a primary consideration.

Zilurgisertib exhibited a favorable pharmacokinetic profile amenable to once-daily dosing that can be administered without regard to food. Study results support further clinical development of zilurgisertib in patients.

P1/2, N=24, Recruiting, 35Pharma Inc | Not yet recruiting --> Recruiting | Phase classification: P1 --> P1/2 | Trial completion date: Apr 2027 --> Jul 2027 | Initiation date: Jul 2024 --> Oct 2024 | Trial primary completion date: Feb 2026 --> Dec 2026

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.

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.

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

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.

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.

P1, N=25, Recruiting, Mayo Clinic | N=18 --> 25 | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

P2, N=113, Active, not recruiting, Clementia Pharmaceuticals Inc. | Recruiting --> Active, not recruiting | Trial completion date: Aug 2029 --> Mar 2029

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.

P1, N=30, Not yet recruiting, 35Pharma Inc

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

P1/2, N=22, Completed, Incyte Corporation | Active, not recruiting --> Completed

Additionally, we explore the application of Momelotinib in other cancer types and investigate predictors for treatment success. Furthermore, we examine the utilization of Momelotinib in patients with liver and kidney failure.

While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis-related anemia, a negative prognostic factor for survival. This review describes momelotinib's mechanism of action, detailing how the JAK-STAT pathway is involved in myelofibrosis pathogenesis and ACVR1 inhibition decreases hepcidin, leading to improved erythropoiesis. Additionally, it summarizes the pivotal studies and data that informed the recommended dosage and risk/benefit assessment.

Grade 3/4 TRAE rates were 0% and 55.6%, with specific events being anemia (55.6%) and vertigo (11.1%) with ruxolitinib. Momelotinib was well tolerated, improved spleen and symptom responses, and reduced transfusion requirements in Japanese patients with JAKi-naïve MF.

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

Whereas the latter are usually addressed by the JAK1/2 inhibitors ruxolitinib and fedratinib, cytopenias often remain critical. 5 patients stopped treatment due to side effects (8%), 6 patients due to a worsening of clinical symptoms (10%). Taken together, the MoReLife analysis identifies momelotinib as potent and safe therapeutic option also for heavily pre-treated cytopenic MF patients under real world conditions.

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

P2, N=56, Not yet recruiting, GlaxoSmithKline

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

In patients with moderate-to-severe anemia and/or in need of RBC transfusions, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using anemia supportive therapies.

The MOMENTUM trial compared MMB to danazol in JAK inhibitor-treated MF patients with anemia, showing MMB's superior symptom relief and transfusion independence rates. Additionally, the SIMPLIFY-1 and SIMPLIFY-2 trials evaluated MMB in JAK inhibitor-naïve and experienced patients, respectively, confirming MMB's non-inferiority to ruxolitinib in spleen volume reduction and highlighting its benefits in transfusion requirements...These trials collectively suggest MMB as an effective treatment for MF, improving quality of life and offering a survival advantage for patients with anemia. Despite challenges, such as trial design limitations and adverse events, MMB represents a significant advancement in MF management, providing a new therapeutic option for a previously underserved patient population.

P1, N=24, Not yet recruiting, 35Pharma Inc

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.

Herein, a series of CRBN-directed JAK-targeting PROTACs were designed and synthesized utilizing a JAK1/JAK2 dual inhibitor-momelotinib as the warhead...Moreover, PROTAC 10c significantly suppressed JAK1 and its key downstream signaling. Together, compound 10c may serve as a novel lead compound for antitumor drug discovery.

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.

P1/2, N=20, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

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

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

P1/2, N=206, Recruiting, Incyte Corporation | N=100 --> 206 | Trial completion date: Apr 2024 --> Jun 2026 | Trial primary completion date: Apr 2024 --> Nov 2025

Momelotinib-approved for treatment of myelofibrosis in adults with anemia-and its major active metabolite, M21, were assessed as drug-drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple-dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single-dose rifampin), and a strong CYP3A4 inducer (multiple-dose rifampin). Momelotinib DDI perpetrator potential (multiple-dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively)...Safety findings were mild in this short-term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments.