8-K: Galectin Therapeutics Presents Positive NAVIGATE Trial Results

Galectin Therapeutics announced positive biomarker and clinical outcome analyses from its NAVIGATE trial for belapectin in MASH cirrhosis with portal hypertension at the AASLD 2025 Annual Meeting.

Summary

• NAVIGATE trial results for belapectin 2 mg/kg demonstrated consistent antifibrotic effects through new biomarker analyses.
• A lower proportion of patients treated with belapectin 2 mg/kg experienced 30% or 5 kPa increases in liver stiffness (LSM) by FibroScan compared to placebo, indicating slowing of fibrosis progression and stabilization of liver function.
• Belapectin 2 mg/kg showed a lower incidence of new varices across all ELF fibrosis risk categories compared to placebo, with the largest benefit in patients with ELF > 11.3 (22.7% vs 42.9%).
• Pro-C3 biomarker analysis demonstrated a >50% reduction from baseline at 18 months with belapectin 2 mg/kg versus placebo (mean 6.4 ng/mL reduction vs 4.5 ng/mL for placebo).
• Analysis of YKL-40, a biomarker associated with Galectin-3 upregulation, showed a 20% reduction in a higher proportion of patients treated with belapectin 2 mg/kg compared to placebo (33.8% vs 23.1%).
• Analysis of PRO-C4, a key biomarker of liver injury and fibrogenesis, showed a 20% increase in a higher proportion of placebo-treated patients compared with those receiving belapectin 2 mg/kg (13% vs 3%).
• For available patients who completed 36 months of therapy, belapectin maintained the sustained reduction in new variceal development seen at 18 months (cumulative incidence at 36 months: 23.4% for placebo, 12.4% for 2 mg/kg, and 16.7% for 4 mg/kg cohorts).
• The safety profile of belapectin remains highly encouraging, with incidence of adverse events and serious adverse events comparable across the three cohorts, and no drug-related SAEs reported.
• The primary endpoint composite strategy (new varices and/or intercurrent events or drop out) in the Intent-to-Treat (ITT) population was not statistically significant (p=0.139 for 2mg/kg vs placebo).
• In the per-protocol population (completers), belapectin 2 mg/kg showed a significantly lower incidence of new varices (p=0.04).

Sentiment

Score: 7

Explanation: The filing presents strong positive clinical and biomarker data for belapectin 2 mg/kg in MASH cirrhosis, particularly in the per-protocol population and long-term follow-up. The safety profile is excellent. While the primary ITT endpoint did not achieve statistical significance, the detailed explanations and other positive outcomes suggest a promising path forward, albeit with acknowledged risks related to funding and regulatory approval.

Positives

• Consistent antifibrotic effects of belapectin 2 mg/kg demonstrated by new biomarker analyses (Pro-C3, YKL-40, PRO-C4).
• Lower proportion of patients on belapectin 2 mg/kg experienced clinically meaningful worsening in liver stiffness (LSM) compared to placebo.
• Significant reduction in the incidence of new varices with belapectin 2 mg/kg, especially in high-risk patients (ELF > 11.3: 22.7% vs 42.9% for placebo).
• Over 50% reduction in Pro-C3 biomarker from baseline at 18 months with belapectin 2 mg/kg versus placebo, supporting disease-modifying potential.
• Sustained reduction in new variceal development through 36 months of therapy.
• Highly encouraging safety profile, comparable to placebo, with no drug-related serious adverse events.
• Belapectin 2 mg/kg reduced varices incidence by 43.2% compared to placebo in the ITT population and 48.9% in the per-protocol population.
• U.S. enrolled patient results suggest synergistic benefit with GLP-1 therapy, highlighting belapectin's potential as both monotherapy and in combination regimens.
• Belapectin has Fast Track designation by the U.S. Food and Drug Administration for MASH cirrhosis.
• Encouraging clinical response in difficult-to-treat cancers in combination with checkpoint inhibitor, with an IND filed and approval to proceed received from FDA for Head & Neck cancer.

Negatives

• The primary endpoint composite strategy (new varices and/or intercurrent events or drop out) in the Intent-to-Treat (ITT) population was not statistically significant (p=0.139 for 2mg/kg vs placebo).
• Fewer recorded varices than expected in the trial, impacting statistical power.
• Mid-study sample size re-estimation was based on a composite endpoint, not solely on varices, which may have diluted the varices outcome.
• Shorter treatment duration for primary analysis (18 months instead of 36 months) may have impacted the statistical significance of the primary endpoint.
• Higher dropout rate (18.3% observed vs. 10% expected), mostly during COVID and the first 4 months, affected the ITT population analysis.
• Lack of dose response at higher doses (4 mg/kg) of belapectin, suggesting a target-mediated drug disposition where higher concentrations may not enhance efficacy.

Risks

• Full analysis of the NAVIGATE trial data may not produce positive data.
• Galectin may not be successful in developing effective treatments and/or obtaining the requisite approvals for the use of belapectin or any of its other drugs in development.
• The Company may not be successful in scaling up manufacturing and meeting requirements related to chemistry, manufacturing and control matters.
• The Company's current clinical trial and any future clinical studies may not produce positive results in a timely fashion, if at all, and could require larger and longer trials, which would be time consuming and costly.
• Plans regarding development, approval and marketing of any of Galectin's drugs are subject to change at any time based on the changing needs of the Company as determined by management and regulatory agencies.
• Regardless of the results of any of its development programs, Galectin may be unsuccessful in developing partnerships with other companies or raising additional capital that would allow it to further develop and/or fund any studies or trials.
• Galectin has incurred operating losses since inception, and its ability to successfully develop and market drugs may be impacted by its ability to manage costs and finance continuing operations.

Future Outlook

The company is focused on advancing regulatory discussions and exploring strategic partnerships to accelerate the next phase of development for belapectin in MASH cirrhosis. They also aim to leverage extensive scientific and development expertise as well as established relationships with external sources to achieve cost-effective and efficient development. FDA feedback on NAVIGATE results is planned by year-end. Advancement of additional clinical programs in cancer immunotherapy is largely dependent on finding a suitable partner.

Management Comments

• Raj Vuppalanchi, M.D., Professor of Medicine and Director of Hepatology at Indiana University School of Medicine, stated: "The long-term NAVIGATE data presented at AASLD provide important insights into the potential of Galectin-3 inhibition in advanced fibrosis. The sustained improvements in liver stiffness and multiple serum biomarkers, including ELF, PRO-C3, and YKL-40, are particularly noteworthy, as they collectively suggest a consistent antifibrotic effect and stabilization of disease. These results are encouraging for patients with MASH cirrhosis and portal hypertension, a population with few effective therapeutic options."
• Dr. Khurram Jamil, Chief Medical Officer at Galectin Therapeutics, stated: "The consistency we observed across both clinical and biomarker endpoints reinforces belapectin's potential as a disease-modifying therapy for patients with compensated MASH cirrhosis and portal hypertension. The 2 mg/kg dose demonstrated a clear and clinically meaningful reduction in the incidence of new varices across all ELF risk categories, with the strongest effect seen in patients at highest risk for liver complications. In addition, the more than 50% greater reduction in Pro-C3 levels versus placebo further supports belapectin's antifibrotic activity and alignment between biomarker and clinical outcomes."
• Joel Lewis, Chief Executive Officer at Galectin Therapeutics, added: "We are very encouraged to see the robust effects of belapectin maintained over 36 months of therapy. These results represent an important milestone for the belapectin program and for patients living with MASH cirrhosis, a population with no approved therapeutic options today. With a solid foundation of clinical and biomarker evidence, we are focused on advancing regulatory discussions and exploring strategic partnerships to accelerate the next phase of development. We are deeply encouraged by the potential of belapectin to make a meaningful difference for patients and families affected by this serious disease."

Industry Context

MASH cirrhosis represents a significant market opportunity in the U.S. with no FDA-approved treatment, affecting an estimated 5 million Americans who progress to this stage. It is expected to become the most frequent reason for liver transplants, with approximately 30% of those listed for liver transplant dying while waiting. Belapectin, as a proprietary galectin-3 inhibitor, targets a key protein involved in multiple inflammatory and fibrotic diseases, positioning it as a novel therapy in an area of high unmet medical need.

Comparison to Industry Standards

• MASH cirrhosis is a population with few effective therapeutic options and no approved therapeutic options today.
• The NAVIGATE trial enrolled the most advanced patients of recent MASH trials, requiring both MASH cirrhosis and portal hypertension, indicating a focus on a high-need patient group.
• Belapectin's unique mechanism of Galectin-3 inhibition positions it as a differentiated and complementary candidate for MASH cirrhosis therapy.
• Galectin Therapeutics is the only company to exclusively focus on treatment for MASH cirrhosis and portal hypertension.

Stakeholder Impact

• Patients with MASH cirrhosis and portal hypertension: Potential for a new, effective therapeutic option where few currently exist, offering disease modification and reduction in severe complications like varices.
• Shareholders: Positive clinical data could increase the company's valuation and attract partnerships, but the lack of statistical significance on the ITT primary endpoint and ongoing need for capital raise present risks.
• Investment professionals: Provides detailed clinical and biomarker data for evaluating the drug's potential and the company's strategic direction.
• Regulatory authorities: The data will inform ongoing discussions with the FDA regarding belapectin's approval pathway.

Next Steps

• Advancing regulatory discussions for belapectin in MASH cirrhosis.
• Exploring strategic partnerships to accelerate the next phase of development for belapectin.
• Seeking FDA feedback on NAVIGATE results by year-end.
• Further development of oncology programs (belapectin + Keytruda for head and neck cancer) is largely dependent on finding a suitable partner.
• Continuing discovery programs to identify subcutaneous forms of carbohydrates and oral small molecules (oral galectin-3 inhibitors).

Key Dates

Recommendation

The NAVIGATE trial results for belapectin 2 mg/kg show promising clinical and biomarker data, particularly in the per-protocol population and sustained effects over 36 months, addressing a high unmet medical need in MASH cirrhosis. The safety profile is also excellent. However, the primary endpoint in the ITT population did not achieve statistical significance, which introduces uncertainty regarding regulatory approval pathways and timelines. The company's reliance on partnerships and potential capital raises for future development also adds a layer of financial risk. Given the mixed but generally positive clinical signals and the significant market opportunity, a 'hold' recommendation is appropriate, awaiting further clarity on regulatory discussions and partnership developments.

Keywords

MASH cirrhosis, portal hypertension, belapectin, NAVIGATE trial, galectin-3 inhibitor, liver fibrosis, esophageal varices, biomarkers, Pro-C3, YKL-40, PRO-C4, AASLD, clinical trial results, hepatology, drug development, Galectin Therapeutics, GALT, oncology, cancer immunotherapy