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A new indication for GR-MD-02
NORCROSS, Ga.—The GTCBio 9th Immunotherapeutics & Immunomonitoring Conference saw Galectin Therapeutics Inc. present data for GR-MD-02, its complex carbohydrate drug that targets the galectin-3 protein, from both preclinical models and first- in-human data from two investigator-initiated Phase 1 combination trials.
“Galectin-3 is a protein which is expressed predominantly in immune cells and at the highest levels in macrophages, which are part of the innate immune response. Galectin-3 expression is upregulated in inflammation, wound repair and fibrogenesis in lots of different situations. It is a protein that is secreted from cells and it binds to various cell surface receptors as well as the interstitial material, so it promotes cell-cell interactions and it modifies cell signaling proteins. So it’s a fairly ancient protein that’s part of the innate immune system, and it’s upregulated in inflammation,” explains Dr. Peter Traber, president, CEO and chief medical officer of Galectin.
He adds that galectin-3 is upregulated in a majority of cancers.
“Galectin-3 is one of those proteins that helps promote the tumorgenicity of the cancers. It inhibits cell death, it promotes invasion because of its cell-cell interaction quality, it promotes metastasis because it makes the tumor cells more sticky when they are released into the bloodstream, and the thing that is of most interest to us is that it inhibits the patient’s immune system from being able to recognize and kill tumor cells,” Traber tells DDNews. “So in the microenvironment of the cancer, where galectin-3 is expressed, it binds to immune cells like cytotoxic T cells and other cell types, and prevents them from killing the tumor. So it turns out it’s very important in helping the tumor promote itself, which makes it an interesting target as an anticancer agent.”
Galectin-3 overexpression also plays a role in inflammatory states and is critical in organ scarring due to chronic inflammation, leading to issues like liver, kidney and lung fibrosis, he adds.
Traber is positive about the preclinical data in animal models, noting that “We have really quite robust and broad effects in animal models. The thing that is most exciting to me is that our primary collaborators at the Providence Cancer Center in Portland, Oregon, have shown that by combining GR-MD-02 with multiple different immunotherapies, they were able to markedly enhance the tumor killing, survival of the animals, reduction in metastasis, etc.”
The Providence team has looked at GR-MD-02 together with pembrolizumab (Keytruda), ipilimumab (Yervoy) and anti-OX40, and Traber says they saw a notably increased response in all cases in animal models, in tumor types such as “skin, sarcoma, breast cancer, prostate cancer.” The results were the impetus for the Phase 1 trials, he notes, saying that the Providence team was “so excited about these preclinical results that they started two Phase 1b open-label trials with combination therapy.”
In one of those trials, patients with advanced melanoma received GR-MD-02 combined with pembrolizumab, and the study was expanded to patients with oral/head and neck cancer and non-small cell lung cancer. Six patients with advanced melanoma have been enrolled in the lowest dose cohort, 2 mg/kg, with no safety concerns related to GR-MD-02. So far, one partial response and one mixed response were observed, with the partial response patient seeing a noticeable reduction in tumor size at week 12 following three doses of the combination therapy. That patient had previously failed to respond to two other intensive courses of treatment.
In a separate study, GR-MD- 02 was combined with ipilimumab in advanced melanoma patients, and seven subjects were treated with the two lowest dose cohorts of GR-MD-02—1 and 2 mg/kg—and completed with no safety signals attributed to GR-MD-02.
Traber tells DDNews that further development of the galectin-3 program in cancer will be based on the response rate of the ongoing trials, something echoed by Dr. Brendan D. Curti, director of the Providence Biotherapy Program at Providence Cancer Center.
“We are encouraged by these early safety results and look forward to further data on the safety and efficacy of GR-MD- 02 used in combination with pembrolizumab in patients with metastatic melanoma, OHN or NSCLC,” Curti noted in a press release. “While we cannot conclude from the one partial response in the pembrolizumab study that the response was related to GR-MD-02, it provides us with a clinically relevant signal to follow as GR-MD-02 doses are escalated. We hope to report additional data in early 2018, when we anticipate a decision on progressing to Phase 2. This decision will be based on the response rate of the combination of pembrolizumab with GR-MD-02 as compared to historical response rates to pembrolizumab alone.”