Triple-Receptor Agonist DR10624 Shows Promise in Phase II Trial for Severe Hypertriglyceridemia
Key Insights
DR10624, a novel triple-receptor agonist targeting FGF21 (search), glucagon, and GLP-1 receptors, demonstrated significant triglyceride reductions of 66-75% across all dose levels in a 12-week Phase II trial.
The investigational drug achieved triglyceride levels below 500 mg/dL in 89.5% of treated patients compared to only 25% of placebo recipients, addressing a challenging clinical condition.
Beyond lipid improvements, DR10624 reduced liver fat content by up to 67%, offering potential benefits for patients with metabolic dysfunction-associated steatotic liver disease (search).
DR10624, an investigational triple-receptor agonist, demonstrated substantial efficacy in reducing triglyceride levels among patients with severe hypertriglyceridemia (search) in a Phase II clinical trial presented at the American Heart Association 2025 Scientific Sessions in New Orleans. The weekly subcutaneous injection targets three key metabolic receptors—fibroblast growth factor 21 (FGF21 (search)), glucagon, and glucagon-like peptide-1 (GLP-1)—representing the first medication of its kind to simultaneously activate all three pathways.
Significant Triglyceride Reductions Across All Doses
The double-blind, placebo-controlled study enrolled 79 patients with severe hypertriglyceridemia (search) (triglyceride levels between 500-2,000 mg/dL) at 35 centers across China. Participants had a mean age of 46 years, with 88.6% being male and a median body mass index of 27.9 kg/m². Approximately 25.3% had type 2 diabetes (search), and the median baseline triglyceride level was 832.5 mg/dL.
After 12 weeks of treatment, all three DR10624 dose groups achieved substantial triglyceride reductions compared to placebo. The 12.5 mg dose produced a median 74.5% reduction, the 25 mg dose achieved 66.2% reduction, and the 50 mg titration dose resulted in 68.9% reduction. In contrast, the placebo group experienced only an 8.0% reduction.
"DR10624 was safe, tolerable, and efficacious in patients with severe hypertriglyceridemia (search)," said lead investigator Jianping Li, MD, PhD, from Peking University First Hospital in Beijing. He emphasized that severe hypertriglyceridemia "is a risk factor for acute pancreatitis (search), cardiovascular disease (search), and liver disease (search)."
Clinically Meaningful Target Achievement
The study's most striking finding was that 89.5% of patients receiving DR10624 achieved triglyceride levels below 500 mg/dL, compared to only 25% of placebo recipients. Additionally, 78.5% of DR10624-treated patients experienced greater than 50% triglyceride reduction from baseline, versus just 5% in the placebo group.
Karol Watson, MD, PhD, from UCLA Health (search), who was not involved in the study, highlighted the clinical significance during the media briefing: "As someone who runs a lipid clinic, I can tell you hypertriglyceridemia is becoming our most vexing problem."
Additional Metabolic Benefits
Beyond triglyceride reduction, DR10624 demonstrated significant effects on liver fat content, with median relative reductions of 63.2% with the 12.5 mg dose, 53.7% with 25 mg, and 67.0% with the 50 mg dose, compared to only 8.4% reduction with placebo. This finding is particularly relevant given that many patients with severe hypertriglyceridemia (search) also develop metabolic dysfunction-associated steatotic liver disease (search) (MASLD).
The medication also improved other lipid parameters, including total cholesterol, HDL cholesterol, non-HDL cholesterol, and triglyceride-rich lipoprotein cholesterol. Notably, LDL cholesterol levels increased while apolipoprotein B remained stable, suggesting conversion of very low-density lipoprotein cholesterol to LDL.
Safety Profile and Mechanism of Action
The most common adverse events were gastrointestinal symptoms, consistent with other GLP-1 receptor (search)-targeting medications. These side effects were generally mild, though researchers noted that gradual dose escalation in future studies might help minimize such symptoms.
Regarding the mechanism of action, Li suggested that FGF21 (search) receptor activation likely contributes most significantly to the triglyceride-lowering effects, though he acknowledged that determining the relative contributions of fatty acid oxidation, decreased lipogenesis, or lipolysis requires further investigation.
Clinical Context and Future Directions
Current treatment options for severe hypertriglyceridemia (search) include fibrates (search), prescription omega-3 fatty acids, and statins (search), but these therapies often provide insufficient triglyceride reduction and limited effects on liver fat. DR10624 represents a novel approach by simultaneously targeting multiple metabolic pathways involved in lipid and glucose metabolism.
"DR10624 could become a game-changer for patients with severe hypertriglyceridemia (search) by reducing long-term risks of pancreatitis, as well as conditions like MASLD and cardiovascular disease (search)," Li stated. He noted that severe hypertriglyceridemia is often difficult to manage with existing treatments, making additional therapeutic options crucial for improving patient outcomes.
The researchers acknowledged several study limitations, including the small sample size, short 12-week duration, and conduct only in China. Li emphasized that "additional clinical studies are needed, which should include more participants from diverse parts of the world and last for a longer period in order to confirm the findings in this phase II trial."
Future research directions include longer-term efficacy and safety studies, head-to-head comparisons with existing triglyceride-lowering therapies, and potential combination approaches with other metabolic medications such as SGLT2 inhibitors (search) or DPP-4 inhibitors (search) for patients with comorbid conditions like type 2 diabetes (search) or cardiovascular disease (search).