Galectin Therapeutics Inc. (GALT)

[Glycobio]

Scientists, medical researchers statements about GALT.

Galectins as a therapeutic target is a very exciting frontier in medicine. I see some uninformed posts here from non-experts. Why not instead take a closer look at what the scientists and medical researchers are saying. Here's a compilation of very recent statements from the research community.

Dr. Lawitz has over 300 publications to include publications in the New England Journal of Medicine, Lancet, Gastroenterology, Hepatology, and Journal of Hepatology. In addition, Dr. Lawitz serves on the editorial board of Lancet, Gastroenterology, American Journal of Gastroenterology, Gastroenterology & Clinical Gastroenterology, Hepatology, Journal of Hepatology, and Therapeutic Advances in Gastroenterology.

"Belapectin represents a new therapeutic mechanism for treating patients with NASH cirrhosis. A previously reported Phase 2 trial of belapectin enrolled 162 patients with portal hypertension who had a hepatic venous pressure gradient (HVPG) equal to or greater than six millimeters of mercury and compensated NASH cirrhosis. In the 54 patients with mild portal hypertension, defined as an HVPG of less than 10 millimeters of mercury at baseline, the patients on placebo had an increase in their HVPG of 26%, while those in the belapectin treatment group saw a reduction in their HVPG of 2 to 3%."

"In addition, this trial demonstrated that in subjects without esophageal varices at baseline, belapectin had a statistically significant reduction in the absolute and percentage change in HVPG. In a post hoc analysis, it was also seen that patients with no varices at baseline, who were then administered the placebo, developed varices at a higher rate than those treated with belapectin. Taken together, these data from the prior trial support the evaluation of belapectin in a Phase 2b/Phase 3 clinical trial to evaluate the use of belapectin in the reduction of incidence of new varices in patients with NASH cirrhosis who have yet to develop esophageal varices."

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Recent paper in the journal Nature (#1 scientific journal in the world) mentions GALT GR-MD-02 (belapectin) as a promising approach for cancer immunotherapy. Chiles Research Institute previously found that GR-MD-02 reduces MDSCs in the clinical trial.

Inflammation and tumor progression: signaling pathways and targeted intervention

"The CXCR1 and CXCR2 chemokine receptors are known to recruit immune suppressive cells, such as MDSCs into the TME. Blocking the CXCR2 chemokine signaling using anti-CXCR2 mAb was reported to disrupt the CXCR2-mediated tumor trafficking of MDSCs, and improved the therapeutic efficacy of anti-PD1 therapy.674 Other approaches inhibiting the infiltration of MDSCs in patients include the inhibition of galectin-3 by GR-MD-02 and the inhibition of CCR2 by CCX872.675,676 In general, targeting cytokine or chemokines related to the expansion and infiltration of MDSCs has been shown to significantly improve the efficacy of anti-tumor immunotherapy."

https://www.nature.com/articles/s41392-021-00658-5

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"Immunosuppressive Roles of Galectin-1 in the Tumor Microenvironment"

Galectin Therapeutics Inc. has developed two such polysaccharides, GM-CT-01 (Davanat; Figure 2C) and GR-MD-02 (Belapectin; Figure 2D), which have been tested in clinical trials. In addition to binding to Gal-1, both GM-CT-01 and GR-MD-02 bind to Gal-3 [79]. GM-CT-01 has been tested alone and in combination with the chemotherapy drug 5-Fluorouracil (5#$%$ in pre-clinical trials in Phase I and Phase II of clinical studies for metastatic colorectal cancer (ClinicalTrials.gov: NCT00110721 and NCT00054977) [80]. The clinical results show that: (a) GM-CT-01 was non-toxic, and a dose-limiting toxicity was not reached; (b) 70% of the patients were stabilized at the highest GM-CT-01 dose level (280 mg/m2/day) level; (c) a 46% increase in longevity of the patients (based on the Median Overall Survival) was achieved compared with the best standard of care; and (d) a 41% reduction in serious adverse effects was achieved compared to the best standard of care. In Phase II clinical studies, GR-MD-02 showed significant and clinically meaningful effects in nonalcoholic steatohepatitis (NASH) cirrhosis patients without esophageal varices (ClinicalTrials.gov: NCT02462967) [81]. There is an ongoing Phase I clinical study designed for a dose escalation of GR-MD-02, with the standard therapeutic dose of anti-PD1 (pembrolizumab) in patients with advanced melanoma, non-small-cell lung cancer, and head and neck squamous cell cancer (ClinicalTrials.gov: NCT02575404)."

https://www.mdpi.com/2218-273X/11/10/1398/htm

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How does the branched structure of GALT belapectin work to inhibit galectin-3? This recent paper from Germany (14 April 2021) explains the binding properties of carbohydrate inhibitors for cancer therapy.

According to the GALT description, "Currently in development, belapectin, a new chemical entity, is a proprietary galactoarabino-rhamnogalacturonan polysaccharide polymer comprising galacturonic acid, galactose, arabinose, rhamnose and smaller amounts of other sugars. Structural studies have shown that belapectin binds to galectin-1 and galectin-3, though it has greater binding affinity to galectin-3 than to galectin-1. Belapectin targets extracellular galectins."

The new German study looks at galactans that are mainly composed of galactose and arabinose. It is well documented that rhamnose is a galectin inhibitor. This new study reinforces the evidence how galactose and arabinose also act to inhibit galectin-3.

Thus, we have belapectin which has 3 galectin inhibitor molecules: galactose, arabinose, rhamnose in a potent combination.

Degraded Arabinogalactans and Their Binding Properties to Cancer-Associated Human Galectins

https://www.mdpi.com/1422-0067/22/8/4058/htm

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“What we found was really astonishing for us. After we inhibited the galectin1 protein, the brain tumors simply didn't grow for several months," says Arezu Jahani-Asl, an Associate Professor of Medicine at McGill University. "To improve patient response to therapy, we must exploit these newly identified vulnerabilities in cancer stem cells."

Fighting brain cancer at its root

https://medicalxpress.com/news/2021-08-brain-cancer-root.amp

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This should make big pharma curious:


"Alzheimer's disease: Is there a role for galectins?"

New in the 15 Oct 2021 publication.

This can only serve to increase the curiosity of big pharma.

Lots of interesting details reviewing various studies, followed by the conclusion,

"counteracting the inflammatory process and protein sedimentation have been proposed as a potential therapeutic strategy to alleviate the progression of neurodegenerative diseases. Thus it could be worthwhile to evaluate gal-3 in the context of AD-modifying drugs for future therapeutic strategies."

"Despite significant progress that has already been achieved in terms of understanding AD, the disease is presently without any effective/selective mode of treatment. Newer agents must be evaluated for the development of more effective treatment strategies. In this respect, a broad systematic analysis of the molecular pathogenesis of AD must be conducted with a special focus on galectins. In the near future, this may help devise more advanced therapeutic approaches for an early diagnosis and management of Alzheimer’s."

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https://www.sciencedirect.com/science/article/pii/S0014299921005902

Here's what big pharma, and the experts saying about GALT belapectin potential for cancer.

Copied and pasted from a Bristol Myers Squibb patent from last year, the last sentence with reference to the GALT trial:

Gal-3 is localized in many cellular locations such as the
cytoplasm, nucleus, and cell surface. Gal-3 is also secreted by
various cell types, mainly macrophages and monocytes, into the
bloodstream. Gal-3 is involved in the development of the fibrotic
process in multiple organs such as lung and kidney. Gal-3 has
also been identified as a biomarker for heart failure. Modulation
of Gal-3 can be used in the treatment of cancer. Recently, Gal-3
inhibitors have proven to have positive effects when used in
combination immunotherapy.

Statement from Chiles Research Institute, the same world renowned cancer research center that helped with the 2018 Nobel Prize for the development of cancer immunotherapy:

“Immunotherapy is a significant breakthrough in the treatment of many cancers, but tumor-induced immune suppression contributes to treatment resistance. Galectin-3 is an important driver of this tumor-induced immunosuppression, and this clinical study constitutes proof-of-concept that the addition of belapectin, a galectin-3 inhibitor, to a PD-1 inhibitor can benefit cancer patients,” said Dr. Brendan Curti, M.D., Earle A. Chiles Research Institute, a division of Providence, and the first author of the paper.

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Harvard study

Increased Circulating Levels of Galectin Proteins in Patients with Breast, Colon, and Lung Cancer

https://www.mdpi.com/2072-6694/13/19/4819/htm

Abstract
Galectins are proteins with high-affinity ß-galactoside-binding sites that function in a variety of signaling pathways through interactions with glycoproteins. The known contributions of galectins-1, -3, -7, -8, and -9 to angiogenesis, metastasis, cell division, and evasion of immune destruction led us to investigate the circulating levels of these galectins in cancer patients. This study compares galectin concentrations by enzyme-linked immunosorbent assay (ELISA) from each stage of breast, lung, and colon cancer. Galectins-1 and -7, which share a prototype structure, were found to have statistically significant increases in breast and lung cancer. Of the tandem-repeat galectins, galectin-8 showed no statistically significant change in these cancer types, but galectin-9 was increased in colon and lung cancer. Galectin-3 is the only chimera-type galectin and was increased in all stages of breast, colon, and lung cancer. In conclusion, there were significant differences in the galectin levels in patients with these cancers compared with healthy controls, and galectin levels did not significantly change from stage to stage. These findings suggest that further research on the roles of galectins early in disease pathogenesis may lead to novel indications for galectin inhibitors.

Currently, work is underway to use galectins as biomarkers and as targets for clinical therapy. Galectins have been investigated as markers for heart failure, atrial fibrillation, endometriosis, and various cancers [19,22,23,24,25,26,27,28,29,30,31,32]. Research and clinical trials are also considering galectins as potential therapeutic targets, where galectin-1 and -3 inhibitors are specifically being investigated [33,34,35]. Additionally, the galectin profiles of the patients generated from this study will improve the characterization of their disease state and allow for potential identification of patients who would benefit from participation in clinical trials of galectin inhibitors.