HighTide Therapeutics announced positive results from its Phase 3 SYMPHONY 2 trial evaluating HTD1801 in patients with type 2 diabetes mellitus inadequately controlled with metformin. The data was presented at the 61st Annual Meeting of the European Association for the Study of Diabetes (EASD) in Vienna, marking the second successful Phase 3 study for this first-in-class anti-inflammatory metabolic modulator.
Trial Design and Primary Results
The randomized, double-blind, placebo-controlled study enrolled 549 patients who were randomized 2:1 to receive HTD1801 1000 mg twice daily (N=365) or placebo (N=184). The trial met its primary endpoint at Week 24, with HTD1801-treated patients achieving an LS mean change in HbA1c of -1.21% compared to -0.68% with placebo (LS mean difference: -0.53, p<0.0001).
Notably, 33% of HTD1801-treated patients achieved HbA1c levels below 7% at Week 24 versus only 11% with placebo (p<0.0001). The improvements in HbA1c were accompanied by significant improvements in both postprandial and fasting glucose levels at Week 24.
Dual Mechanism of Action
HTD1801 operates through a unique dual mechanism of action, simultaneously activating AMPK and inhibiting the NLRP3 inflammasome. These pathways converge at the nexus of metabolic dysregulation beyond glucose control and chronic inflammation, positioning the drug as a potential comprehensive cardiovascular-kidney-metabolic therapy.
"HTD1801 is an innovative small-molecule drug with a novel dual mechanism of action, simultaneously activating AMPK and inhibiting the NLRP3 inflammasome," said Professor Linong Ji, the leading principal investigator and former Vice President of the International Diabetes Federation. "In completed Phase 3 clinical trials, it demonstrated consistent and clinically meaningful glucose-lowering effects with a favorable safety profile."
Cardiovascular and Renal Benefits
Secondary endpoints explored effects on cardiovascular, metabolic, and renal comorbidities. In patients with mild renal impairment, HTD1801 improved estimated glomerular filtration rate (eGFR), suggesting reno-protective potential. The drug also demonstrated significant reductions in lipids and inflammatory markers.
Professor Ji emphasized the broader therapeutic potential: "Beyond glycemic control, HTD1801 has also shown multiple additional benefits, including lipid reduction, attenuation of inflammation, and improvements in renal function. As an orally administered antidiabetic agent, HTD1801 uniquely provides both cardiometabolic risk factor modification and renal protection."
Safety Profile
Safety and tolerability were favorable and consistent with previous clinical trials of HTD1801. Serious adverse events occurred in 4% of HTD1801-treated patients versus 6% of placebo patients. Importantly, no patient experienced severe hypoglycemia during the study. An open-label extension is ongoing to confirm the durability of HTD1801's benefits.
Regulatory Path Forward
"The SYMPHONY 2 trial is our second Phase 3 study in type 2 diabetes to achieve its primary endpoint, underscoring the consistency and robustness of HTD1801's clinical profile," said Liping Liu, Founder, Chairwoman and CEO of HighTide Therapeutics. The company is well-positioned to submit its New Drug Application in China later this year.
HTD1801 has already received regulatory recognition, including two Fast Track designations and one Orphan Drug designation from the US Food and Drug Administration. The drug has also been included twice in the National Major Science and Technology Project for Significant New Drug Development in China.
Clinical Significance
HTD1801 represents a first-in-class new molecular entity addressing the residual risks of cardiovascular-kidney-metabolic diseases. Multiple global clinical trial results have demonstrated comprehensive benefits including improved insulin resistance, glycemic control, lipid lowering, renal benefit, weight loss, hepatic benefits, and anti-inflammatory effects, positioning it as a potential foundational therapy for cardiovascular-kidney-metabolic conditions.
