Berberine Ursodeoxycholate (HTD1801) Consistently Demonstrates Comprehensive Benefits for Patients with Type 2 Diabetes Mellitus, Approaching NDA

HighTide Therapeutics Announces HTD1801 Meets the Primary Endpoints in Two Phase 3 Clinical Trials in Patients with Type 2 Diabetes Mellitus

HighTide Therapeutics, Inc. (2511.HK), a clinical-stage biopharmaceutical company specializing in the development of multifunctional, multi-targeted therapies for chronic liver and metabolic diseases, today announced that two Phase 3 trials (SYMPHONY 1 and SYMPHONY 2) of berberine ursodeoxycholate (HTD1801) in Chinese patients with type 2 diabetes mellitus (T2DM) met their primary endpoints and gated secondary endpoints.

The results of these two Phase 3 clinical trials provide robust evidence that HTD1801 delivers comprehensive benefits for patients with T2DM. Based on these highly positive read-outs, HighTide plans to submit a new drug application (NDA) for HTD1801 as a treatment for T2DM to the Center for Drug Evaluation (CDE) of China's National Medical Products Administration (NMPA) later this year.

SYMPHONY 1 (NCT06350890) and SYMPHONY 2 (NCT06353347) are randomized, double-blind, placebo-controlled, Phase 3 clinical trials designed to evaluate the efficacy and safety of HTD1801 in adults with T2DM and inadequate glycemic control despite using diet and exercise (SYMPHONY 1; N=407) or Metformin (SYMPHONY 2; N=549). The primary endpoint in both studies was the change in HbA1c from baseline with HTD1801 compared to placebo after 24 weeks of treatment. Gated secondary endpoints included the percentage of subjects achieving HbA1c <7.0%, change in fasting plasma glucose (FPG), low-density lipoprotein cholesterol (LDL-C), glutamyl transpeptidase (GGT), and high-sensitivity C-reactive protein (hs-CRP).

The primary endpoint was achieved in both trials, showing a clinically meaningful, consistent glucose-lowering effect of HTD1801

SYMPHONY 1 (HTD1801 as monotherapy): At week 24, the reduction from baseline in HbA1c with HTD1801 (-1.3%) was superior to placebo. Further, those with more severe disease had a greater decrease with HTD1801: reduction in HbA1c was -1.5% for those with a baseline HbA1c ≥8.5%.

SYMPHONY 2 (HTD1801 as an add-on therapy to Metformin): At week 24, the reduction from baseline in HbA1c with HTD1801 (-1.2%) was superior to placebo. Further, those with more severe disease had a more significant decrease with HTD1801: reduction in HbA1c was -1.6% for those with a baseline HbA1c ≥8.5%.

In both Phase 3 trials, the efficacy on HbA1c reduction in patients treated with HTD1801 was sustained through week 24.

In both trials, gated secondary endpoints were achieved, suggesting multiple advantages of HTD1801 beyond glucose-lowering including improvement in cardiometabolic risk indicators

At week 24, in both studies, the proportion of patients who achieved HbA1c <7.0% was significantly higher in the HTD1801 treatment groups compared to placebo. Improvements in HbA1c with HTD1801 were parallelled with significant improvements in postprandial and fasting plasma glucose compared with placebo. In addition, HTD1801 demonstrated lipid-lowering effects, including significant reductions in low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C). Moreover, HTD1801 treatment led to reductions in key inflammatory biomarkers - glutamyl transpeptidase (GGT) and high-sensitivity C-reactive protein (hs-CRP) - both of which are associated with cardiovascular risk in patients with T2DM.

Favorable safety and tolerability profile 

Overall, safety and tolerability were favorable and consistent with previous clinical trials of HTD1801. The most commonly reported adverse events were gastrointestinal. In both studies <2% of patients discontinued early due to an adverse event. The incidence of hypoglycemia was low, with no severe hypoglycemia events reported.

“The encouraging results from these studies suggest that HTD1801 may offer a novel and improved therapeutic option for patients with T2DM,” said Dr. Linong Ji, the leading principal investigator for the two Phase 3 clinical trials and former Vice President of the International Diabetes Federation (IDF), Director of the Peking University Diabetes Center and Director of the Department of Endocrinology and Metabolism, Peking University People’s Hospital. “As an innovative drug candidate, HTD1801 exhibits a unique dual mechanism of action - AMP kinase activation and NLRP3 inflammasome inhibition - that is distinct from any existing T2DM drugs on the market. It is an oral therapy designed to deliver comprehensive clinical benefits - not only lowering blood glucose but also improving lipid metabolism and exerting anti-inflammatory effects - thereby potentially reducing diabetes-related complications and addressing significant unmet clinical needs. With continued clinical exploration, HTD1801 is expected to further expand its application to benefit patients globally. In today’s pharmaceutical landscape, investment has become heavily concentrated on GLP-1-based drug development. While GLP-1 therapies hold significant clinical value, they do not adequately address the full spectrum of pathophysiological mechanisms underlying T2DM. To truly meet the multifaceted needs of T2DM management, continued innovation across a diverse range of therapeutic targets remains essential.”

“We extend our deepest gratitude to the patients who participated in these pivotal trials,” said Dr. Liping Liu, HighTide’s founder and CEO. “HTD1801’s innovative dual-action approach – targeting both metabolic regulation and inhibiting inflammation – represents a potential breakthrough in diabetes treatment. We look forward to sharing data from the 28-week open-label extension of these studies and a Phase 3 head-to-head comparison with the dapagliflozin; we will continue to explore the clinical potential of HTD1801 to provide patients with chronic metabolic diseases a comprehensive treatment solution.”

About Type 2 Diabetes Mellitus (T2DM)

According to the International Diabetes Federation (IDF), 537 million adults (ages 20-79) were living with diabetes in 2021, and this number is projected to grow to 783 million (representing 1 in 8 adults) by 2045, of these, around 90% are T2DM cases. China has the largest population of diabetes patients worldwide, estimated to be 141 million in 2021, and projected to grow to 174 million in 2045. Diabetes is a global societal burden leading to over 6 million deaths per year. To address this urgent challenge, there is a critical need for innovative therapies that can deliver comprehensive clinical benefits for patients worldwide.

About Berberine Ursodeoxycholate (HTD1801)

Berberine ursodeoxycholate (HTD1801) is an orally delivered, gut-liver anti-inflammatory metabolic modulator being developed for the treatment of metabolic and digestive diseases. HTD1801, an ionic salt of berberine and ursodeoxycholate, is a new molecular entity with a unique dual mechanism of action: AMP kinase activation and NLRP3 inflammasome inhibition. These two key mechanistic pathways have been associated with improvements in insulin resistance, glucose metabolism, lipid metabolism, and hepatic inflammation, potentially providing a comprehensive treatment platform for the multifaceted nature of complex metabolic diseases.

HTD1801 is being developed for multiple indications. In addition to T2DM, its efficacy in treating metabolic dysfunction-associated steatohepatitis (MASH) has been demonstrated in a Phase 2a clinical trial and a global multicenter Phase 2b trial assessing the histologic benefit of HTD1801 is currently ongoing, with topline results expected in 2025.

About HighTide Therapeutics

HighTide Therapeutics, Inc. (Stock Code: 2511.HK) is a globally integrated biopharmaceutical company focusing on the discovery and development of first-in-class multifunctional, multi-targeted therapies with poly-indication potential across chronic liver and metabolic diseases with significant unmet medical needs. HighTide is currently developing several clinical assets and associated global intellectual property rights, and advancing multiple mid-to-late-stage clinical trials including therapies for metabolic dysfunction-associated steatohepatitis (MASH), type 2 diabetes mellitus (T2DM), severe hypertriglyceridemia (SHTG) and primary sclerosing cholangitis (PSC). Berberine ursodeoxycholate (HTD1801), HighTide’s lead drug candidate, received Fast Track designation from the United States Food and Drug Administration for both MASH and PSC and Orphan Drug designation for PSC. HTD1801 has been included in the National Major New Drug Innovation Program under the 13th Five-Year Plan for Major Technology Project in China.