Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Evaluating the Safety, Efficacy, and Therapeutic Potential of Momelotinib in the Treatment of Intermediate/High-Risk Myelofibrosis: Evidence to Date.

ABSTRACT: Myelofibrosis is a heterogeneous disorder with regard to both molecular pathogenesis and clinical phenotype, ranging from an initial fairly indolent condition in some through to an aggressive and debilitating scenario with profound constitutional symptoms, cytopenia frequently requiring transfusional support, and massive splenomegaly. Many advances have been made within the therapeutic arena, and an increasing array of novel agents are now available for disease management. Within this review, we focus on the current and predicted role of the JAK inhibitor momelotinib (Sierra Oncology) in myelofibrosis, with an emphasis on clinical trial evaluation, drug efficacyand safety, and discuss the suggested place in the therapeutic paradigm of myelofibrosis in 2020 and beyond.

SUBMITTER: Bassiony S

PROVIDER: S-EPMC7524184 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Evaluating the Safety, Efficacy, and Therapeutic Potential of Momelotinib in the Treatment of Intermediate/High-Risk Myelofibrosis: Evidence to Date.

Bassiony Sarah S Harrison Claire N CN McLornan Donal P DP

Therapeutics and clinical risk management 20200925

Myelofibrosis is a heterogeneous disorder with regard to both molecular pathogenesis and clinical phenotype, ranging from an initial fairly indolent condition in some through to an aggressive and debilitating scenario with profound constitutional symptoms, cytopenia frequently requiring transfusional support, and massive splenomegaly. Many advances have been made within the therapeutic arena, and an increasing array of novel agents are now available for disease management. Within this review, we ...[more]

PMID: 33061394

Similar Datasets

Evaluating the Safety and Efficacy of Nivolumab in Patients with Advanced Hepatocellular Carcinoma: Evidence to Date.

Project description:Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a dismal prognosis, especially when diagnosed at advanced stages. Surgical resection of the primary lesion, liver-directed therapies, and orthotropic liver transplantation are employed in localized disease depending upon the clinical status, underlying liver function, the size, and location of the liver lesions. Systemic therapy plays a critical role in the management of advanced HCC. Sorafenib had remained as the only United States Food and Drug Administration (US-FDA)-approved systemic therapeutic agent for approximately a decade since its approval in 2007, until the advent of immunotherapy and a better understanding of HCC molecular pathogenesis changed the landscape of advanced HCC management. Lenvatinib was approved as an alternative first-line agent, whereas regorafenib, nivolumab, pembrolizumab, ramucirumab, and cabozantinib were approved as second-line agents for HCC patients who could not tolerate or whose disease progressed on sorafenib. Nivolumab and pembrolizumab are the two immunotherapeutic agents that were conditionally approved by the US-FDA based on the encouraging results in Phase I/II trials. This review discusses the potential role of immunotherapy in advanced HCC with a special focus on nivolumab.

| S-EPMC6886547 | biostudies-literature

A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis.

Project description:Momelotinib, a small-molecule inhibitor of Janus kinase 1 and Janus kinase 2, has demonstrated efficacy in myelofibrosis patients with 300 mg, once-daily dosing. This open-label, non-randomized, phase 1/2 study evaluated the safety and therapeutic benefit of momelotinib with twice-daily dosing. A total of 61 subjects with primary myelofibrosis or post-polycythemia vera/post-essential thrombocythemia myelofibrosis with intermediate- or high-risk disease received momelotinib. A phase 1 dose escalation identified 200 mg twice daily as the optimal dose to be expanded in phase 2. The most frequent adverse events were diarrhea (45.9%), peripheral neuropathy (44.3%), thrombocytopenia (39.3%), and dizziness (36.1%), the latter primarily due to a first-dose effect. The response assessment according to the 2006 International Working Group criteria (?8 weeks duration at any time point) demonstrated spleen response by palpation of 72% (36/50) and anemia response of 45% (18/40). Spleen response by magnetic resonance imaging obtained at 24 weeks was 45.8% (27/59) for all subjects and 54.0% (27/50) for those with palpable splenomegaly at baseline. The symptoms of myelofibrosis were improved in most subjects. Cytokine analysis showed a rapid decline in interleukin-6 with momelotinib treatment, and a slower reduction in other inflammatory cytokines. In the subgroup of subjects with the JAK2V617F mutation at baseline (n=41), momelotinib significantly reduced the allele burden by 21.1% (median) at 24 weeks. These results provide evidence of tolerability and a potential therapeutic activity of momelotinib for subjects that support further evaluation in ongoing, phase 3 randomized trials. (clinicaltrials. gov identifier:01423058).

| S-EPMC5210237 | biostudies-literature

Evaluating the Therapeutic Potential of Zanubrutinib in the Treatment of Relapsed/Refractory Mantle Cell Lymphoma: Evidence to Date.

Project description:Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma characterized by an aggressive clinical course in the majority of patients. Despite recent improvements in outcomes, MCL remains incurable and a major therapeutic challenge. BTK inhibitors are the preferred treatment option for patients with relapsed/refractory MCL, including those unfit for chemotherapy or those with chemoresistant disease. In addition to ibrutinib and acalabrutinib, the FDA recently approved zanubrutinib for the treatment of patients with relapsed/refractory MCL based on the results of two Phase 2 clinical trials showing overall response rates of 85-87% with complete responses in 30-77% of patients. Compared with ibrutinib, zanubrutinib is more selective for BTK and has less off-target inhibition, which is thought to limit certain toxicities although direct comparative data are still lacking. This review article summarizes data from clinical trials of currently FDA-approved BTK inhibitors in MCL with a focus on zanubrutinib.

| S-EPMC7351990 | biostudies-literature

Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis

Project description:17 patients with myelofibrosis contributed paired research samples; the time points were pre-study and 12 weeks after commencing study treatment with CYT387.Gene expression analysis was investigated to study the effects of drug treatment. Additional analysis invesitigated differences in expression patterns in groups of anemia responders and non-responders following drug treatment. 34 samples representing 17 patients. Each patient submitted 1 pre-treatment sample and 1 post 12 weeks of treatment.

2013-01-14 | E-GEOD-40841 | biostudies-arrayexpress

Momelotinib therapy for myelofibrosis: a 7-year follow-up.

Project description:One-hundred Mayo Clinic patients with high/intermediate-risk myelofibrosis (MF) received momelotinib (MMB; JAK1/2 inhibitor) between 2009 and 2010, as part of a phase 1/2 trial (NCT00935987); 73% harbored JAK2 mutations, 16% CALR, 7% MPL, 44% ASXL1, and 18% SRSF2. As of July 2017, MMB was discontinued in 91% of the patients, after a median treatment duration of 1.4 years. Grade 3/4 toxicity included thrombocytopenia (34%) and liver/pancreatic test abnormalities (<10%); grade 1/2 peripheral neuropathy occurred in 47%. Clinical improvement (CI) occurred in 57% of patients, including 44% anemia and 43% spleen response. CI was more likely to occur in ASXL1-unmutated patients (66% vs 44%) and in those with <2% circulating blasts (66% vs 42%). Response was more durable in the presence of CALR type 1/like and absence of very high-risk karyotype. In multivariable analysis, absence of CALR type 1/like (HR 3.0; 95% CI 1.2-7.6) and presence of ASXL1 (HR 1.9; 95% CI 1.1-3.2) or SRSF2 (HR 2.4, 95% CI 1.3-4.5) mutations adversely affected survival. SRSF2 mutations (HR 4.7, 95% CI 1.3-16.9), very high-risk karyotype (HR 7.9, 95% CI 1.9-32.1), and circulating blasts ?2% (HR 3.9, 95% CI 1.4-11.0) predicted leukemic transformation. Post-MMB survival (median 3.2 years) was not significantly different than that of a risk-matched MF cohort not receiving MMB.

| S-EPMC5841331 | biostudies-literature

Momelotinib: an emerging treatment for myelofibrosis patients with anemia.

Project description:The suite of marked anemia benefits that momelotinib has consistently conferred on myelofibrosis (MF) patients stem from its unique inhibitory activity on the BMP6/ACVR1/SMAD and IL-6/JAK/STAT3 pathways, resulting in decreased hepcidin (master iron regulator) expression, higher serum iron and hemoglobin levels, and restored erythropoiesis. Clinical data on momelotinib from the phase 2 and the two phase 3 SIMPLIFY trials consistently demonstrated high rates of sustained transfusion-independence. In a recent phase 2 translational study, 41% of the patients achieved transfusion independence for ≥ 12 weeks. In the phase 3 trials SIMPLIFY-1 and SIMPLIFY-2, 17% more JAK inhibitor-naïve patients and two-fold more JAK inhibitor-treated patients achieved or maintained transfusion independence with momelotinib versus ruxolitinib and best available therapy (89% ruxolitinib), respectively. Anemia is present in approximately a third of MF patients at diagnosis, eventually developing in nearly all patients. The need for red blood cell transfusions is an independent adverse risk factor for both overall survival and leukemic transformation. Presently, FDA-approved medications to address anemia are lacking. Momelotinib is one of the prime candidates to durably address the critical unmet needs of MF patients with moderate/severe anemia. Importantly, momelotinib may have overall survival benefits in frontline and second-line MF patients. MOMENTUM is an international registration-track phase 3 trial further assessing momelotinib's unique constellation of anemia and other benefits in second-line MF patients; the results of the MOMENTUM trial are keenly awaited and may lead to regulatory approval of momelotinib.

| S-EPMC8772195 | biostudies-literature

Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis

2013-01-14 | GSE40841 | GEO

Safety and efficacy of frequency-domain optical coherence tomography in evaluating and treating intermediate coronary lesions.

Project description:AIM:To establish whether frequency-domain optical coherence tomography (FD-OCT) is safe and effective in the evaluation and treatment of angiographically-intermediate coronary lesions (ICL). METHODS:Sixty-four patients with 2-dimensional quantitative coronary angiography (2D-QCA) demonstrating ICL were included. OCT imaging was performed. According to predetermined OCT criteria, patients were assigned to either of 2 groups: OCT-guided percutaneous coronary intervention (PCI) or OCT-guided optimal medical therapy (OMT). The primary efficacy endpoint was to demonstrate the superiority and higher accuracy of FD-OCT compared to 2D-QCA in evaluating stenosis severity in patients with ICL. The primary safety endpoint was the incidence of 30-d major adverse cardiac events (MACE). Secondary endpoints included MACE at 12 mo and other clinical events. RESULTS:Analysis of the primary efficacy endpoint demonstrates that 2D-QCA overestimates the stenosis severity of ICL in both the OCT-guided PCI and OMT groups, proving FD-OCT to be superior to and more precise than 2D-QCA in treating this subset of lesions. The primary safety endpoint was fully met with the incidence of 30-d MACE being nil in both the OCT-guided PCI and OCT-guided OMT groups. Incidences of secondary endpoints were found to be low in both arms, the only exception being the relatively high incidence of recurrent episodes of angina which was, however, very similar in the 2 groups. CONCLUSION:FD-OCT is safe and effective in the evaluation and treatment of ICL. Larger studies are needed to firmly establish the efficacy and safety of FD-OCT in treating ICL across all coronary artery disease population subgroups.

| S-EPMC6259025 | biostudies-literature

Venetoclax: evidence to date and clinical potential.

Project description:The emergence of targeted therapy for patients with hematological diseases has permanently altered the therapeutic landscape. Immunochemotherapy regimes are now more and more being replaced by targeted therapies due to superior efficacy and better safety profiles. However, evolution and selection of subclones with continuous treatment leads to disease relapse and resistance toward these novel drugs. Venetoclax, the highly selective BCL-2 inhibitor (ABT-199), has an acceptable safety profile. To date, it has been approved for the treatment of first-line and relapsed/refractory chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, extension of indications can be expected in monotherapy and in combination regimens with promising outcomes in other hematological diseases. In this article, we describe the mechanism of action that stands behind the efficacy of venetoclax and provide a summary of available results from clinical trials.

| S-EPMC6788387 | biostudies-literature

Therapeutic Potential of the Ranibizumab Port Delivery System in the Treatment of AMD: Evidence to Date.

Project description:AbstractAge-related macular degeneration (AMD) is one of the leading causes of blindness in older adults worldwide. The advent of intravitreal neutralization of vascular endothelial growth factor (VEGF) has revolutionized the management of patients with neovascular AMD, but current anti-VEGF therapies carry a high threshold of patient burden. The ranibizumab port delivery system (PDS) is an implanted, refillable reservoir that continuously supplies the anti-VEGF medication ranibizumab directly into the vitreous, eliminating the need for frequent intravitreal injections. It has most recently been evaluated in the Phase II LADDER trial demonstrating the efficacy and safety of the PDS, with Phase III trials currently underway. This review presents both the promise and drawbacks of the PDS in the treatment of AMD from the current literature.

| S-EPMC7245454 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data