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Galecto Explores Anti-Cancer Potential of Inhibiting Fibrosis, Scarring Pathway


NEW YORK – Galecto is betting that inhibition of a pathway shown to be significant in the development of scar tissue and lung fibrosis will boost the number of cancer patients that can benefit from checkpoint inhibitor therapy.

Galecto was founded in 2011 in Copenhagen, Denmark, around research by professors Hakon Leffler and Ulf Nilsson of Lund University, Sweden. That research explored the role of a family of proteins called galectins in idiopathic pulmonary fibrosis. Galectins are proteins that bind cell surface glycoproteins. Each type of galectin recognizes specific glycoconjugates, and collectively they are involved in many biological functions including regulation of immune cells and recognition of microbes as part of the innate immune response.

Hans Schambye, former CEO of Recepticon and Gastrotech Pharma, and Tariq Sethi, an emeritus professor at King's College London, joined Leffler and Nilsson as founders of Galecto, which was initially focused on fibrosis, or the formation of scar tissue. Although galectins also had established significance in cancer, Galecto started its work in fibrosis because of investor interest.

"Galectin is as old as fungi," said Schambye, who is Galecto's CEO. "The way we understand it now is that its role is really acute protection." That means, according to Schambye, when there is an injury, galectin-3 helps to make scar tissue and prevent infection. Through the actions of galectin-3, fibroblasts are activated, a chain of events also involved in the disease process of fibrosis.

Galecto's fibrosis candidate, GB0139, is an inhaled inhibitor of galectin-3. In 2017, Galecto reported results from a Phase Ib/IIa clinical trial of GB0139 in 40 patients with idiopathic pulmonary fibrosis showing that it was safe and well tolerated. Through bronchoscopies before and after the treatment period, Galecto researchers observed reduced expression of galectin-3 on alveolar macrophages, and inhibition of galectin-3 expression in the lung was associated with reduction in plasma biomarkers of idiopathic pulmonary fibrosis.

"What we saw was clear target engagement," said Schambye. "We saw a number of fibrosis biomarkers being reduced by this in just two weeks, which was quite a positive surprise."

The results of that trial sparked more investor interest, and the company completed an $83 million financing round in 2018 co-led by Ysios Capital and OrbiMed. New investors from the US and Europe also participated in the financing, and the cash infusion helped Galecto advance a Phase II/III study of GB0139 and start clinical trials of its lead cancer agent, an oral galectin-3 inhibitor, dubbed GB1211. The company followed up with an equity financing and an initial public offering in 2020, adding an additional $150 million to its ledger.

Galecto has confidence in GB1211 in cancer since prior research has shown that patients with high levels of galectin-3 in their tumors have a poorer prognosis and don't respond as well to therapy, particularly checkpoint inhibitors, as patients without that marker. That suggests a role for galectin-3 inhibition in treating cancer, alone or in combination with checkpoint inhibitors.

In a preclinical study, mice with a knockout mutation of galectin-3 developed fewer tumors and metastases than wild-type mice, and those tumors were smaller. However, when the mice with the mutation received galectin-3-positive bone marrow transplants from wild-type mice, tumor growth was restored. And in mice with human and mouse lung adenocarcinoma, treatment with a small molecule galectin-3 inhibitor reduced tumor growth and blocked metastasis. The effect was enhanced with the use of a PD-L1 checkpoint inhibitor.

Galecto began the Phase IIa GALLANT-1 trial of GB1211 in combination with Roche's checkpoint inhibitor Tecentriq (atezolizumab) in June. The trial is evaluating the drug combination as first-line therapy for non-small cell lung cancer. In the first part of the trial, eight to 12 patients will receive 200 or 400 mg of GB1211 twice daily with the standard dose of Tecentriq. In the second part, researchers will evaluate safety and tumor shrinkage in as many as 75 patients randomized to receive GB1211/Tecentriq or placebo/Tecentriq. They will also analyze patients' tumor response rate based on RECIST criteria, clinical activity, and biomarkers including galectin-3 levels in both blood and tumor biopsies.

Support for the use of galectin-3 to predict response to immune checkpoint blockade comes from a recent publication in the Journal of Cancer Research and Clinical Oncology. In that study, 56 patients with NSCLC were separated into low and high expressers of galectin-3. Patients in the high-expresser group showed a non-statistically significant trend toward reduced progression-free survival and significantly shorter overall survival. Progression-free survival was 0.9 months in the high expressers compared to 3.7 months in the low expressers. Overall survival was 1.6 months for high expressers versus 12.3 months for low expressers. Roche is supplying Tecentriq for the trial under a collaboration agreement signed in 2021.

A unique advantage of GB1211, Schambye said, is that it seems to be very well tolerated. "We've given it to healthy volunteers without any safety events," said Schambye. "We're able to start directly in a double-blind placebo-controlled trial, which is very different from most cancer drugs, where you dose up slowly until you see toxicity."

Galecto expects to report results from this trial by mid-2023.

The relative safety of blocking galectin-3 seems paradoxical. Given its role in wound healing and scar formation, some side effects of slowed healing might be expected. In fact, adverse effects of blocking the pathway have not been evident in animal or human trials. Schambye speculated that there are likely redundant mechanisms that cover for the loss of galectin-3.

In Schambye's view, the connection between galectin-3's role in fibrosis and in cancer is more than coincidental. Out of the many mechanisms believed to contribute to cancer growth and metastasis, signaling by galectin-3, he suggested, may contribute to fibrosis or "stiffening" of the tumor microenvironment, leading to more aggressive cancer growth.

As Galecto advances the GB1211 program, it has few clinical stage competitors. Galectin Therapeutics is developing a product, called belapectin, that is currently undergoing a Phase Ib trial in combination with Bristol Myers Squibb's Yervoy (ipilimumab) in melanoma patients. However, Schambye pointed out that belapectin is different from GB1211 in that the former is a complex carbohydrate-based large molecule given by infusion, whereas the latter is an oral small molecule drug.

Galecto's experience expanding GB1211 from fibrosis to cancer may serve as a blueprint for other products in its portfolio. For example, the firm has another oncology candidate in its pipeline, GB2064, which targets LOXL2. Currently, the company is studying this drug in a Phase IIa trial for myelofibrosis. But, as with GB1211, Galecto plans to expand GB2064 into cancer indications in the future.