An Open-label, Phase IIa Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Oral GB2064 (a LOXL2 Inhibitor) in Participants With Myelofibrosis (MF)

This study is an open label, phase IIa trial in subjects with Myelofibrosis

开始日期2021-06-09

申办/合作机构

Galecto Biotech ApS

[+1]

NCT02852551 / Completed临床1期

A Phase 1, Randomised, Placebo-Controlled, Ascending Single and Multiple Dose Safety, Tolerability, Pharmacokinetic and Food Effect Study of PAT-1251 in Healthy Adult Subjects

A single-center, randomized, placebo-controlled study consisting of both a single ascending dose (SAD) and a multiple ascending dose (MAD) portion to evaluate the safety, tolerability, pharmacokinetics and effect of food using PAT-1251 orally administered to healthy subjects

开始日期2016-07-01

申办/合作机构

PharmAkea, Inc.

100 项与 GB-2064 相关的临床结果

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100 项与 GB-2064 相关的转化医学

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100 项与 GB-2064 相关的专利（医药）

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项与 GB-2064 相关的文献（医药）

bioRxiv : the preprint server for biology

LOXL2 inhibition ameliorates pulmonary artery remodeling in pulmonary hypertension

作者: Gadkari, Mahin ; Brady, Travis ; Nandakumar, Kavitha ; Shimoda, Larissa A. ; Wang, Huilei ; Steppan, Jochen ; Poe, Alan ; Santhanam, Lakshmi ; Pak, Lydia ; Berkowitz, Dan E.

Abstract:

Background:

Conduit pulmonary arterial stiffening and the resultant increase in pulmonary vascular impedance has emerged as an important underlying driver of pulmonary arterial hypertension (PAH). Given that matrix deposition is central to vascular remodeling, we evaluated the role of the collagen crosslinking enzyme lysyl oxidase like 2 (LOXL2) in this study.

Methods and Results:

Human pulmonary artery smooth muscle cells (PASMCs) subjected to hypoxia showed increased LOXL2 secretion. LOXL2 activity and expression were markedly higher in primary PASMCs isolated from pulmonary arteries of the rat Sugen 5416 + hypoxia (SuHx) model of severe PH. Similarly, LOXL2 protein and mRNA levels were increased in pulmonary arteries (PA) and lungs of rats with PH (SuHx and monocrotaline (MCT) models). Pulmonary arteries (PAs) isolated from rats with PH exhibited hypercontractility to phenylephrine and attenuated vasorelaxation elicited by acetylcholine, indicating severe endothelial dysfunction. Tensile testing revealed a a significant increase in PA stiffness in PH. Treatment with PAT-1251, a novel small-molecule LOXL2 inhibitor, improved active and passive properties of the PA ex vivo. There was an improvement in right heart function as measured by right ventricular pressure volume loopsin-vivowith PAT-1251. Importantly PAT-1251 treatment ameliorated PH, resulting in improved pulmonary artery pressures, right ventricular remodeling, and survival.

Conclusion:

Hypoxia induced LOXL2 activation is a causal mechanism in pulmonary artery stiffening in PH, as well as pulmonary artery mechanical and functional decline. LOXL2 inhibition with PAT-1251 is a promising approach to improve pulmonary artery pressures, right ventricular elastance, cardiac relaxation, and survival in PAH.

New & Noteworthy:

Pulmonary arterial stiffening contributes to the progression of PAH and the deterioration of right heart function. This study shows that LOXL2 is upregulated in rat models of PH. LOXL2 inhibition halts pulmonary vascular remodeling and improves PA contractility, endothelial function and improves PA pressure, resulting in prolonged survival. Thus, LOXL2 is an important mediator of PA remodeling and stiffening in PH and a promising target to improve PA pressures and survival in PH.

项与 GB-2064 相关的新闻（医药）

2024-05-03

·GlobeNewswire-Health Care

Galecto Announces First Patient Dosed in an Investigator-Initiated Phase 2 Trial of GB1211 in Combination with Pembrolizumab

May 01, 2024 -- Galecto, Inc. (NASDAQ: GLTO), a clinical-stage biotechnology company focused on the development of novel treatments for cancer and fibrosis, today announced that the first patient has been enrolled in an investigator-initiated Phase 2 trial to evaluate GB1211, Galecto’s first-in-class, oral small molecule galectin-3 inhibitor candidate, at the Earle A. Chiles Research Institute (EACRI), a division of Providence Cancer Institute in Portland, Oregon, USA. Under the direction of Providence investigators Dr. Brendan Curti and Dr. William Redmond, the study aims to evaluate the safety and efficacy of GB1211 at a dose of 100mg twice daily in combination with pembrolizumab for the treatment of metastatic malignant melanoma (MM) and head and neck squamous cell carcinoma (HNSCC). Drs. Curti and Redmond received an R01 Research Project Grant award from the National Cancer Institute, National Institutes of Health, for their investigator-initiated Phase 2 trial. Galecto has committed to supply GB1211 for the trial. Galectin-3 is overexpressed in many cancers, including melanoma and HNSCC. Increased galectin-3 expression in tumors is linked to tumor growth, invasiveness and metastatic potential. Furthermore, increased levels of galectin-3 in the tumor microenvironment can cause checkpoint inhibitor resistance by blocking the binding of the checkpoint inhibitor antibodies, pembrolizumab and atezolizumab (Tecentriq®), to their respective targets. Preclinical data has shown that GB1211 has the ability to reduce galectin-3 associated interference with immune checkpoint inhibition (ICI), thus alleviating galectin-3-specific ICI resistance. In the fourth quarter of 2023, Galecto reported topline results from its Phase 1b/2a GALLANT-1 clinical trial evaluating GB1211 twice daily in combination with atezolizumab for the first-line treatment of non-small cell lung cancer (NSCLC). Galecto reported that investigator-assessed objective tumor responses (defined as partial responses per RECIST criteria 1.1) were observed in three of five patients (60%) who received the recommended Phase 2 dose level of GB1211 100 mg for at least three weeks. Historically, response rates of only 22–38% have been observed with atezolizumab monotherapy in the first-line treatment of advanced NSCLC, suggesting a potential benefit of adding GB1211 to ICI. Dr. Brendan Curti, Medical Director, Providence Melanoma Program, and EACRI Member and Robert W. Franz Endowed Chair for Clinical Research, said, “Our ability to perform bench-bedside research is a great strength of the Providence Cancer Institute. The insights from Dr. Redmond’s lab about how to use galectin inhibitors to alter the tumor microenvironment and promote anti-tumor activity, as well as our initial observations in patients, provide a robust rationale for our phase II clinical trial in patients with melanoma and HNSCC.” Dr. William Redmond, Member and Director, EACRI Immune Monitoring Lab, and co-principal investigator for the trial, stated, “We have published a significant amount of data on the important role of galectin-3 in creating immune suppression within the tumor microenvironment. We are excited to start this study in melanoma and HNSCC patients to potentially counteract ICI resistance and increase the efficacy of ICI by combining GB1211 and pembrolizumab.” “We are excited that the Providence Cancer Institute and Drs. William Redmond and Brendan Curti have initiated this trial. Dr. Redmond is a world-leading expert on the role of galectin-3 in cancer and ICI resistance and has demonstrated how galectin inhibition can be used to enhance tumor treatment,” stated Dr. Hans Schambye, CEO of Galecto. “Following the encouraging topline results from the GALLANT-1 trial that we reported in the fourth quarter of 2023, we look forward to exploring potential synergies with another leading ICI, pembrolizumab. This new trial marks a significant stride towards exploring GB1211's potential to enhance the effectiveness of ICI in various cancer indications.” The randomized, double-blind placebo-controlled, investigator-initiated Phase 2 trial will evaluate whether the addition of GB1211 increases the response rate of pembrolizumab in metastatic melanoma and HNSCC patients. The study will employ a fixed dose of GB1211 in conjunction with the standard therapeutic dose of pembrolizumab in patients with unresectable or metastatic MM or recurrent or metastatic HNSCC progressing during or after platinum-containing chemotherapy. In addition to monitoring for toxicity and clinical response, biospecimens will be obtained to assess immunologic measures relevant to galectin biology and T-cell checkpoint inhibition. Tumor volume will be assessed by immune response RECIST criteria (iRECIST criteria 1.1). It is anticipated that early data from this trial could be available as early as 2025. Increased galectin-3 expression in tumors is linked to tumor growth, invasiveness, and metastatic potential. In the tumor tissue, galectin-3 supports the creation of fibrosis, tumor proliferation, metastasis, and immune avoidance. Preclinical data announced at the 2022 ASCO Annual Meeting furthermore suggest that galectin-3 can enhance PD-1 and PD-L1 binding and avert the interference of anti-PD-1/anti-PD-L1 therapies by blocking the binding of the antibodies to their respective targets. GB1211 is specifically designed to counter these anti-checkpoint inhibitor effects of galectin-3. GB1211 demonstrated an anti-cancer effect and antifibrotic activity in multiple preclinical models and has successfully completed a Phase 1 trial in 78 healthy volunteers. In the Phase 1 trial, GB1211 was well-tolerated and exhibited dose-dependent pharmacokinetics. Galecto is a clinical stage company incorporated in the U.S. that is developing small molecule-based inhibitors of galectin-3 and LOXL2. Galecto has multiple Phase 2 clinical opportunities in fibrosis and cancer, including (i) an orally active LOXL2 inhibitor (GB2064) for the treatment of myelofibrosis; (ii) an orally active galectin-3 inhibitor (GB1211) for the treatment of liver cirrhosis; and (iii) an orally active galectin-3 inhibitor (GB1211) in combination with a checkpoint inhibitor for various oncology indications. Providence Cancer Institute of Oregon, a part of Providence St. Joseph Health, offers the latest in cancer services, including diagnostic, treatment, prevention, education, support and internationally renowned research. Providence Cancer Institute is home to the Earle A. Chiles Research Institute, a world-class research facility located within the Robert W. Franz Cancer Center in Portland, Oregon, and is a recognized leader in the field of cancer immunotherapy since 1993. Learn more at www.providence.org/ORcancer. The content above comes from the network. if any infringement, please contact us to modify.

免疫疗法临床结果ASCO会议

2023-12-22

·GlobeNewswire-Health Care

Topline Results from MYLOX-1 Trial Demonstrate Reduction in Fibrosis of the Bone Marrow in Patients with Myelofibrosis

Galecto, Inc. (NASDAQ: GLTO), a clinical stage biotechnology company focused on the development of novel treatments for fibrosis and cancer, today announced positive topline results from a Phase 2a trial of GB2064 for the treatment of myelofibrosis (the “MYLOX-1 trial”, NCT04679870). The MYLOX-1 trial dosed a total of 18 myelofibrosis patients, of which 11 (61%) patients had previously received janus kinase inhibitor (JAKi) therapy with ruxolitinib, with eight of those patients being refractory and three being intolerant to JAKi therapy. Six out of ten evaluable myelofibrosis patients who received GB2064 monotherapy for at least six months experienced a ≥ 1-grade reduction in collagen fibrosis of the bone marrow, an improvement suggesting that GB2064 could impact the progression of the disease and be disease-modifying. Fibrosis is a key disease mechanism of myelofibrosis that destroys bone marrow function. Reducing fibrosis is required to slow the progression of the disease. Bone marrow biopsies taken during the study showed that GB2064 penetrated the bone marrow and could exert its anti-fibrotic effect directly in the disease compartment. Furthermore, GB2064 demonstrated target engagement systemically by binding to LOXL2 in plasma. All six patients who experienced a > 1-grade reduction in bone marrow fibrosis score also showed stable hematological parameters, including hemoglobin, white blood cell count and platelets. At six months of treatment, one patient obtained a ≥35% reduction in spleen volume, two patients reduced their Total Symptom Score (TSS) by more than 50% and one patient had an anemia response. Four of these patients have entered the extension phase of the study due to the clinical benefit derived from GB2064 as evaluated by the treating physician, with one patient receiving treatment for more than 30 months. Professor Claire Harrison, Guy’s and St Thomas’ NHS Foundation Trust, and Chair of the Safety Review Committee for the MYLOX-1 trial, commented, “It is exciting and encouraging to see that the data from the MYLOX-1 trial affirms the safety and effectiveness of LOXL-2 inhibition in the challenging landscape of myelofibrosis. I am especially intrigued by the unique observed improvements in bone marrow collagen fibrosis, showcasing the targeted impact on a crucial aspect of this relentless disease.” GB2064 showed a generally acceptable tolerability profile in the MYLOX-1 trial. Eighteen patients were dosed with GB2064 monotherapy in the MYLOX-1 trial. Eight patients completed treatment in the core phase of the MYLOX-1 trial and ten patients discontinued treatment due to an adverse event or disease progression. The most commonly observed treatment-related adverse events were gastrointestinal in nature and were manageable in most patients with standard therapy. The only treatment-related serious adverse event was a case of fall, which was assessed as possibly related to GB2064 by the investigator. Dr. Hans Schambye, President and Chief Executive Officer of Galecto, commented, “We believe that the topline results from the MYLOX-1 trial reaffirm the anti-fibrotic activity observed in the intermediate assessment of the trial announced in September 2022. We are very excited with the proof of principle achieved with GB2064, showcasing its strong anti-fibrotic impact in a very challenging patient population. The encouraging topline results from the MYLOX-1 trial reinforce our confidence in GB2064's potential as a transformative therapy for various cancers and a range of fibrotic diseases, but we will not make any decisions relating to funding additional trials with GB2064 until we complete our previously announced strategic alternative process.” The MYLOX-1 trial was a Phase 2, open-label, single-arm study in myelofibrosis patients who were ineligible, refractory, or intolerant to JAKi therapy. These patients have a progressive disease with poor quality of life, high mortality rates and very limited treatment options. Patients received GB2064 orally at a dose of 1000mg twice daily for nine months and undergo bone marrow biopsies at the beginning of the trial and again at months 3, 6 and 9. The primary endpoint of the MYLOX-1 trial was to assess the safety and tolerability of GB2064. Apart from evaluating the safety and tolerability of GB2064, key secondary objectives of the MYLOX-1 trial were to evaluate hematological parameters as well as the direct anti-fibrotic activity of GB2064 by blocking lysyl oxidase-like 2 (LOXL2) in an indication that allows for repeated tissue biopsies. Myelofibrosis is a hematological cancer that causes fibrosis of the bone marrow and disrupts the body’s normal production of blood cells, which can lead to multiple negative impacts and a significantly reduced quality of life and mortality. The bone marrow is destroyed by fibrosis, forcing out the production of blood components and aggravating symptoms, including anemia, thrombocytopenia, leukocytosis, and spleen enlargement. JAKi therapy is the current standard of care for patients with myelofibrosis; however, these therapies do not address the core of the underlying disease biology and have not shown a consistent effect on fibrosis, biomarkers of disease modification, or overall survival. GB2064, a potentially first-in-class, oral, lysyl oxidase-like 2 (LOXL2) inhibitor candidate, is in development for the treatment of fibrotic diseases and cancer. LOXL2 is an enzyme that plays a key role in myelofibrosis and contributes to the fibrotic progression of the disease. LOXL2 catalyzes the cross-linking of collagen, forming the backbone of fibrosis. The molecular target for GB2064 is LOXL2, an enzyme that plays a central role in the crosslinking of collagen in tissue fibrosis and is involved in multiple types of fibrotic diseases, including myelofibrosis. In contrast to previous attempts to inhibit LOXL2 with a monoclonal antibody, GB2064 is designed to completely inhibit the LOXL2 enzymatic activity. Galecto is a clinical stage company incorporated in the U.S. that is developing small molecule-based inhibitors of galectin-3 and LOXL2. Galecto has multiple Phase 2 clinical opportunities in fibrosis and cancer, including (i) an orally active LOXL2 inhibitor (GB2064) for the treatment of myelofibrosis; (ii) an orally active galectin-3 inhibitor (GB1211) for the treatment of liver cirrhosis; and (iii) an orally active galectin-3 inhibitor (GB1211) in combination with a checkpoint inhibitor for various oncology indications. The content above comes from the network. if any infringement, please contact us to modify.

临床2期临床结果

2023-12-22

·FierceBiotech

Galecto posts myelofibrosis data as search for savior continues, investors shrug

Fibrosis affects the production of blood cells, leading to anemia, weakness and fatigue. Galecto is giving potential buyers and investors more data to chew over. Three months into a review of strategic alternatives, the biotech has posted topline results from a phase 2a clinical trial of a potential treatment for the bone marrow cancer myelofibrosis. Boston-based Galecto laid off 70% of its staff and began looking for a buyer in September. The review followed the phase 2 failure of an inhaled treatment for idiopathic pulmonary fibrosis. While looking for a way out of its predicament, the biotech continued to track patients in a phase 2a trial of another drug candidate, the LOXL2 inhibitor GB2064. Galecto posted topline data from the trial after the market closed Thursday. The study dosed 18 people with myelofibrosis, including 11 who had previously received Incyte’s JAK inhibitor Jakafi. Ten patients discontinued treatment because of an adverse event or disease progression. Six of the 10 evaluable patients who received the drug candidate for at least six months had a one-grade or greater reduction in collagen fibrosis of the bone marrow. Fibrosis affects the production of blood cells, leading to anemia, weakness and fatigue. Galecto presented the finding as evidence that “GB2064 could impact the progression of the disease and be disease-modifying.” The six patients with reduced fibrosis had stable hematological parameters, including hemoglobin, white blood cell count and platelets. One patient had a 35% or greater reduction in spleen volume. Two people experienced a 50% or greater reduction on a symptom scale. Four patients have entered the extension stage of the study. In a statement, Galecto CEO Hans Schambye said the study showed a “strong anti-fibrotic impact in a very challenging patient population.” However, the biotech will defer decisions on funding more trials of GB2064 until it has completed its strategic alternative process. Investors appeared unsure what to make of the data. After spiking in the immediate aftermath of the news, Galecto’s share price fell 3% to 61 cents in pre-market trading.

临床2期临床结果临床失败

100 项与 GB-2064 相关的药物交易

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04679870 (MYLOX-1, GlobeNewswire) 人工标引	临床2期	原发性骨髓纤维化	18	GB2064	鹽憲獵顧鏇夢襯鏇鹽構(顧鬱獵齋餘製衊鬱範糧) = 顧範窪淵獵壓齋餘壓積糧簾鬱繭網蓋獵鬱製鏇 (糧壓願構網繭選鏇鏇繭 )	积极	2023-12-21
NCT04679870 (Mylox-1, ASH2022) 人工标引	临床2期	原发性骨髓纤维化	16	GB-2064 1000 mg	艱鹽鏇網襯醖艱鹽齋窪(襯繭願襯鹽廠鹹鏇膚夢) = No significant safety concerns were observed at a dose of 1000 mg BID to date. 積窪獵積鹹憲簾膚醖遞 (糧膚糧遞願餘構壓鏇夢 )	积极	2022-11-15