Leap Therapeutics has announced promising preclinical data for FL-501, its novel monoclonal antibody targeting growth differentiation factor 15 (GDF-15), showing significant potential in treating cancer cachexia. The data will be presented at the American Association for Cancer Research (AACR) Annual Meeting taking place April 25-30, 2025, in Chicago.
Cancer cachexia, a devastating condition characterized by severe weight loss, muscle wasting, and reduced quality of life, affects many cancer patients and contributes significantly to cancer-related mortality. Currently, there are no effective treatment options available.
"Cancer cachexia is a devasting and potentially life-threatening condition characterized by significant weight loss, muscle wasting, fatigue, and severely reduced quality of life. It is a major contributor to cancer-related mortality, and unfortunately there are no effective treatment options available to patients," said Jason Baum, PhD, Chief Scientific Officer of Leap Therapeutics.
Superior Pharmacokinetic Profile
The preclinical data revealed that FL-501 demonstrated a 2-3-fold longer half-life and 50% reduced clearance compared to its wild-type precursor and ponsegromab, a competing GDF-15 targeting antibody. This improved pharmacokinetic profile suggests potential for less frequent dosing and better patient compliance in future clinical applications.
Efficacy in Multiple Cachexia Models
In mouse cachexia models using GDF-15-overexpressing colorectal cancer cells, FL-501 fully restored body composition, performing comparably or better than clinical-stage antibodies visugromab and ponsegromab. This restoration of body composition is a critical endpoint for cachexia treatment, as it directly correlates with improved quality of life and potentially survival outcomes.
Additionally, in a non-small cell lung cancer patient-derived xenograft model, FL-501 effectively countered cisplatin-induced weight loss, restoring body weight, composition, and condition scores. This finding is particularly significant as chemotherapy-induced cachexia represents a major clinical challenge in cancer treatment.
"These data not only demonstrate that FL-501 is a novel and potential best-in-class anti-GDF-15 antibody, but also capable of fully restoring body composition in preclinical models that is comparable or better than other, clinical-stage antibodies," Baum added. "We look forward to progressing the development of FL-501 and bringing the asset into the clinic in 2026."
Mechanism of Action and Broader Potential
FL-501 targets GDF-15, a cytokine produced at elevated levels in response to various stresses, including chronic inflammation, obesity, cardiovascular diseases, cancers, and chemotherapy treatment. High GDF-15 expression is associated with cancer cachexia symptoms including loss of appetite, nausea, and weight loss.
The antibody was engineered for higher affinity to GDF-15 and longer plasma half-life compared to competing therapies. Beyond cachexia, FL-501 may have potential to reverse immunosuppression in cancers where elevated GDF-15 correlates with poor survival, as well as treat other GDF-15-related diseases.
Clinical Development Timeline
Leap Therapeutics plans to advance FL-501 into clinical trials by 2026. The company is developing the antibody through a collaboration agreement with Adimab, leveraging their expertise in antibody discovery and optimization.
Market Context and Unmet Need
Cancer cachexia affects approximately 50-80% of cancer patients, depending on the cancer type, and is directly responsible for at least 20% of cancer deaths. The condition not only reduces quality of life but can also limit patients' ability to tolerate cancer treatments, further compromising survival outcomes.
The global cancer cachexia market is projected to grow significantly in the coming years due to increasing cancer prevalence and aging populations. Currently, treatment approaches are limited to nutritional support and symptom management, with no approved therapies directly targeting the underlying mechanisms of cachexia.
About Leap Therapeutics
Leap Therapeutics (Nasdaq: LPTX) focuses on developing targeted and immuno-oncology therapeutics. The company's most advanced clinical candidate, sirexatamab (DKN-01), is a humanized monoclonal antibody targeting the Dickkopf-1 (DKK1) protein currently being studied in patients with colorectal cancer.
The poster presentation, titled "FL-501 is a potential best in class GDF-15 inhibitor with extended half-life and potent anti-cachexia activity in preclinical models," will be presented by Roma Kaul, PhD, from Leap Therapeutics on Tuesday, April 29, 2025, from 9:00 a.m. to 12:00 p.m. CT at the AACR Annual Meeting.
