Hoth Therapeutics, Inc. (NASDAQ: HOTH), a clinical-stage biopharmaceutical company, announced positive data from its HT-VA study, conducted under its Cooperative Research and Development Agreement (CRADA) with the U.S. Department of Veterans Affairs and Emory University, demonstrating that parenteral GDNF (Glial Cell-Derived Neurotrophic Factor) directly reprograms liver fat metabolism at the genetic level in a preclinical model of metabolic-associated fatty liver disease (MAFLD).

The data highlights statistically significant improvements in key genes responsible for fat production and fat metabolism, positioning GDNF as a potentially differentiated therapeutic approach targeting the root cause of fatty liver disease and metabolic dysfunction.

• Statistically significant reduction in Srebf1, a key gene driving fat production in the liver
• Increased expression of Pparα, a central regulator of fat metabolism and fat burning
• GDNF outperformed semaglutide in key gene expression markers tied to liver fat regulation
• Demonstrated broad metabolic impact at the genetic level, not just weight reduction

Unlike existing therapies that primarily focus on weight loss, GDNF directly targets the biological mechanisms responsible for fat accumulation in the liver.

• Srebf1 reduction → less fat being created
• Pparα activation → more fat being burned
• Net effect → reprogramming of liver metabolism

This dual mechanism suggests GDNF may offer a disease-modifying approach for MAFLD, obesity, and related metabolic disorders.

"HT-VA represents a major milestone for Hoth as we expand into high-value metabolic indications," said Robb Knie, Chief Executive Officer of Hoth Therapeutics.

"These results demonstrate that GDNF is not simply reducing fat, but fundamentally reprogramming how the body produces and metabolizes fat at the genetic level. The ability to shut down fat creation while activating fat metabolism differentiates GDNF from existing therapies, including GLP-1 agonists."

SCIENTIFIC SUMMARY (HT-VA STUDY)

The HT-VA study evaluated the effects of parenteral GDNF in a diet-induced obesity and MAFLD model.

Key observations include:

• Western diet significantly increased liver fat accumulation and metabolic dysfunction
• GDNF treatment significantly improved liver gene expression linked to fat metabolism
• Reduced lipogenesis signaling (Srebf1) and enhanced metabolic regulation pathways (Pparα)
• Gene expression changes support improved hepatic lipid handling and metabolic efficiency

STRATEGIC IMPLICATIONS

• Entry into MAFLD/NASH and obesity markets 
• Differentiation vs. GLP-1 therapies through gene-level mechanism
• Potential for first-in-class metabolic reprogramming therapy
• Expansion beyond Hoth's core dermatology and oncology pipeline

NEXT STEPS

Hoth plans to:

• Advance HT-VA findings into additional preclinical validation studies
• Evaluate clinical development pathways for metabolic and liver diseases
• Explore strategic partnerships and collaborations to accelerate development