Development Programs

NASH Cirrhosis

NASH cirrhosis is the end stage of non-alcoholic steatohepatitis (NASH), where the scar tissue and regenerative nodules resulting from the inflammation and fibrosis of NASH has replaced healthy liver tissue, preventing the liver from functioning normally and potentially causing liver failure and death. NASH cirrhosis is fast becoming the leading cause of liver transplants in the U.S.

There is currently no cure for NASH cirrhosis apart from a liver transplantation.

The Significance of Esophageal Varices in NASH Cirrhosis

Development of esophageal varices is thought to be an early sign of more serious complications of NASH cirrhosis. Varices happen when scars in the liver block the flow of blood from the digestive system through the liver, causing internal blood vessels to dilate, similar to varicose veins in the legs. Bleeding varices are a cause of death in about one-third of cirrhotic patients. There is no approved therapy for preventing or treating varices in NASH cirrhosis patients. Galectin Therapeutics’ belapectin galectin-3 inhibitor may offer the first potential treatment to prevent such varices.

The Phase 2b NASH-CX trial of the use of belapectin in treating patients with NASH cirrhosis showed statistically significant and clinically meaningful results in reducing HVPG (hepatic venous pressure gradient) in comparison to placebo in NASH cirrhosis patients without esophageal varices, which represented 50% of the patients enrolled in the clinical trial.

The company believes this is the first large, randomized clinical trial of any drug to demonstrate a clinically meaningful improvement in portal hypertension or liver biopsy in patients with NASH cirrhosis without varices, a large and easily identifiable group of patients.

There is no current therapy for patients with NASH cirrhosis — and a therapy such as belapectin that could improve portal hypertension and potentially prevent the development of esophageal varices in NASH cirrhosis and subsequent complications — would be clinically valuable…

The NAVIGATE Phase 2b/3 Clinical Trial in NASH Cirrhosis

On June 30, 2020, the Company announced enrollment of its first patients in the NAVIGATE clinical trial. The NAVIGATE Study is an international, seamless, adaptively-designed Phase 2b/3 trial of the galectin-3 inhibitor belapectin (GR-MD-02), the company’s lead compound, in nonalcoholic steatohepatitis (NASH) cirrhosis patients who have clinical signs of portal hypertension and are at risk of developing esophageal varices. Belapectin had previously been shown to prevent the development of new varices in this patient population in the Phase 2b NASH-CX clinical trial (Gastroenterology 2020;158:1334–1345 or https://doi.org/10.1053/j.gastro.2019.11.296).

The NAVIGATE Study is expected to enroll approximately 315 NASH patients in the Phase 2b part of the trial at approximately 130 sites in 12 countries in North America, Europe, Asia and Australia. During the Phase 2b part of the trial, two belapectin doses, 2 mg/kg of lean body mass (LBM) and 4 mg/kg LBM, will be compared to placebo. Prior trials have demonstrated the good tolerance profile and apparent safety of belapectin with doses of up to 8 mg/kg LBM, notably for up to 52 weeks of treatment in patients with NASH cirrhosis (as done in the Phase 2b NASH-CX study).

The study design provides for a prespecified interim analysis (IA) of efficacy and safety data conducted after all planned subjects in the Phase 2b component have completed at least 78 weeks (18 months) of treatment and a gastro-esophageal endoscopic assessment. This adaptive design allows for patients to seamlessly transition from the Phase 2b component into the Phase 3 stage, as well as helps determine the optimal dose, bolsters the efficacy signal, and re-evaluates the sample size and statistical power for the Phase 3 stage of the trial. These adaptations are designed to increase the statistical power for detecting a successful outcome. The IA also provides for adjustment in the randomization ratio, refinement of inclusion/exclusion criteria and the potential termination of the study for overwhelming efficacy or for futility.

The unmet medical need for an effective treatment for patients with NASH cirrhosis remains a strong motivation to vigorously pursue therapy with belapectin. Moreover, if the results of the NAVIGATE trial are compelling, there could be the potential for accelerated FDA approval or partnership opportunities.

Focused on NASH Cirrhosis, a Major Unmet Medical Need

Once liver fibrosis has progressed to cirrhosis, NASH patients can no longer expect significant improvements from changes in their lifestyle. These patients are in dire need of new options, and this trial may prove pivotal in improving their condition. The NAVIGATE Study’s seamless and adaptive design is innovative, and the primary endpoint minimizes the inconvenience for patients while being relevant to real life medical practice.

Unlike most other clinical trials focused primarily on earlier stages of NASH, the NAVIGATE Study population will comprise patients with compensated liver cirrhosis. Based on the results of the NASH-CX trial, the NAVIGATE Study is focused on patients who have not yet developed esophageal varices but are at increased risk of developing these potentially life-threatening complications. Consequently, patient selection for both Phase 2b and Phase 3 will be based on clinical signs of portal hypertension such as a depressed platelet count (thrombocytopenia), an enlargement of the spleen (splenomegaly) and/or evidence of collateral vessels.

The primary endpoint of the trial is to assess the effect of belapectin on the incidence of new varices. A centralized review system of video recording of esophagogastroduodenoscopy (EGD) has been put in place, and the primary endpoint will be adjudicated by expert EGD readers. Key secondary endpoints will assess the type of varices (sizes and/or bleeding) and other clinical events, such as ascites, hepatic encephalopathy, listing for liver transplantation or death.

The NAVIGATE Study was designed in accordance with advice from the U.S. Food and Drug Administration (FDA) and with key contributions from the NAVIGATE co-primary study investigators, Dr. Naga Chalasani and Dr. Stephen Harrison, both widely recognized expert hepatologists for NASH, biostatistical experts and numerous other collaborators at Covance, the CRO for the study. The design of the NAVIGATE trial optimizes patient enrollment and retention and minimizes the need for invasive tests.

For more information on the NAVIGATE Study, visit the dedicated trial site, NAVIGATEnash.com, or www.clinicaltrials.gov (NCT04365868).

Cancer Immunotherapy

Based on studies in animal models, Galectin Therapeutics is exploring its galectin inhibitors in combination immunotherapy clinical trials. The initial cancer indication is advanced melanoma, the most deadly form of skin cancer. The American Cancer Society estimates that there were over 68,000 new diagnoses and 8,100 deaths from melanoma in the United States in 2011. Metastatic melanoma has a poor prognosis with less than 5% of patients surviving five years from the manifestation of visceral organ involvement.

Immunotherapy has been studied for decades to treat melanoma, but the only FDA-approved immunotherapeutic agent for metastatic melanoma was interleukin-2. There have been recent significant advances in the treatment of melanoma. In March, 2011, the FDA approved the use of ipilimumab, an anti-CTLA4 monoclonal antibody, for first or second-line treatment of metastatic melanoma. Since then additional immunotherapy agents have been approved. While these therapies are a major advance in melanoma therapy, there is still a need for improved therapy in patients with widespread melanoma.

Based on this basic research, the Providence Portland Medical Center filed an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) on December 27, 2013, to study belapectin (GR-MD-02) in combination with Yervoy® (ipilimumab) in a Phase 1B study of patients with metastatic melanoma. The application was prompted by findings from a preclinical study led by tumor immunology expert William L. Redmond, Ph.D., of the Providence Portland Medical Center’s Earle A. Chiles Research Institute (EACRI). The preclinical study found that GR-MD-02 increased tumor shrinkage and enhanced survival in immune competent mice with prostate and breast cancers when combined with one of the immune checkpoint inhibitors, anti-CTLA-4 or anti-PD-1. These findings suggest a role for GR-MD-02 in cancer immunotherapy.

Since then, the Providence Portland Medical Center has continued to fund and conduct investigator-initiated clinical trials on the use of belapectin in combination immunotherapy, particularly with KEYTRUDA® (pembrolizumab). Providence’s Phase 1 trial data showed a 50% objective response rate in advanced melanoma with belapectin (GR-MD-02) in combination with KEYTRUDA, and a significant decrease in the frequency of suppressive MDSCs following treatment in the responding patients (on day 85 post-treatment) was observed compared to non-responders. The published data on the use of KEYTRUDA by itself shows an objective response rate of 33% in this patient population.

Providence has also expanded the trial to head and neck cancer, in addition to metastatic melanoma.

Providence’s pre-clinical models also show synergy of GR-MD-02 with T-cell co-stimulatory agents, and further clinical translations of the basic science are planned.

Additional information about this clinical trial may be found at: www.clinicaltrials.gov/ct2/show/NCT02575404

Learn more about the science of cancer immunotherapy.

Psoriasis

Galectin Therapeutics conducted an exploratory Phase 2a clinical trial of GR-MD-02 in patients with moderate to severe plaque psoriasis based on the improvement of psoriasis seen in a patient in the GT-020 Phase 1 clinical trial. Psoriasis often occurs in patients with NASH cirrhosis. During the Phase 2 NASH-CX clinical trial, it was also observed that psoriasis was ameliorated in patients who had it. The results of this exploratory Phase I/II study were reported on March 14, 2017. The company is seeking to partner the use of the compound for treatment of psoriasis.

Atopic Dermatitis (Eczema)

Atopic dermatitis, commonly called eczema, is a chronic inflammatory condition of the skin caused by multiple factors that usually arises in early childhood, often in infancy. While it usually resolves by early teenage years, approximately 5-10% of patients have the disease extend into adulthood. Classic symptoms are itching and burning of the skin, resulting in thickening of the skin in response to the scratching. In some adults, it can be severe with debilitating itching, inability to sleep, and social stigmatization due to skin damage and thickening, often on the face.

Surveys suggest that up to 18% of the population have atopic dermatitis; up to 37% of those people seek medical care; and over 70% of those seeking care have mild disease that is handled by primary care physicians. Approximately 20% with mild and 2% with severe disease are referred to specialists. The national estimated cost of treatment is as high as $3.8 billion.

Galectin Therapeutics supported a small, open label, investigator-initiated study with GR-MD-02 in atopic dermatitis. There were no serious adverse events observed. All three patients showed clinical response as determined by reduction of the Eczema Area and Severity Index (EASI) score at week 12 having received 6 every other week doses, with two patients achieving a 64% and 74% reduction in EASI, respectively, at six weeks after receiving only 3 doses of GR-MD-02 (see graph below). These findings are believed to demonstrate a clinically significant effect of this novel investigational drug in this patient population.

The company is seeking to partner the use of the compound for treatment of atopic dermatitis (eczema)

Fibrosis

Our data show that belapectin (GR-MD-02) has a powerful therapeutic effect on fibrosis as shown in several relevant animal models. Therefore, we chose belapectin as the lead candidate in a development program targeted initially at fibrotic liver disease associated with fatty liver disease. Development programs in other liver diseases, lung fibrosis, kidney fibrosis, or cardiovascular fibrosis are potential programs that may be initiated in the future.

Because of promising phase 1 trial results, Galectin Therapeutics initiated an exploratory, single-site phase 2a randomized clinical trial involving a short course (four months) of therapy in patients with NASH fibrosis. While the study did not meet its primary or secondary endpoints, evidence of activity suggested that a longer course of treatment might show results. Belapectin (GR-MD-02) was found to be safe and well tolerated among the patient population with no serious adverse events.

Learn more about fibrosis.