The field of diabetes drugs is undoubtedly dominated by peptide molecules, but recently an oral small molecule diabetes pipeline drug inspired by traditional Chinese medicine has shown great promise in a head-to-head trial against MNC's blockbuster drug dapagliflozin.

01
Head-to-head 3-round success

Recently, Junshengtai Pharmaceutical 's Phase 3 diabetes pipeline asset, HTD1801, has yielded remarkable results in three Phase 3 clinical trials. The latest published result is from the HARMONY trial, a randomized, double-blind, actively controlled Phase 3 study conducted in China. It enrolled 369 adult patients with type 2 diabetes whose condition was not adequately controlled by metformin, comparing HTD1801 with AstraZeneca's SGLT2 inhibitor dapagliflozin in terms of HbA1c changes at 24 weeks, with a non-inferiority margin set at 0.4%.

The results showed that, while maintaining a stable metformin dose, the mean least squares HbA1c level at week 24 decreased by 1.12% from baseline in the HTD1801 group and by 0.93% in the dapagliflozin group, with a difference of 0.2 percentage points (95% confidence interval: -0.37 to -0.03, p < 0.001), meeting both non-inferiority and statistical significance. Meanwhile, HTD1801 also performed better on key "gated" secondary endpoints, including greater reductions in low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) than dapagliflozin, and a lower proportion requiring intensive statin therapy. In terms of safety, the incidence of serious adverse events was 3.8% in the HTD1801 group and 4.4% in the dapagliflozin group ; the most common adverse events were mild to moderate gastrointestinal reactions, and no serious hypoglycemic events were observed in either group.

HARMONY marks the third time HTD1801 has demonstrated excellent metabolic improvement capabilities in a large-scale Phase 3 trial. Prior to this, HighTide had completed two placebo-controlled Phase 3 studies in China: SYMPHONY-1 and SYMPHONY-2. Both trials were randomized, double-blind, placebo-controlled, with a total sample size approaching 1,000. SYMPHONY-1 evaluated the efficacy of HTD1801 as monotherapy for type 2 diabetes mellitus (T2DM), while SYMPHONY-2 evaluated its effect as an adjunct to metformin.

The published results showed that at week 24, in SYMPHONY-1, HTD1801 monotherapy reduced HbA1c by an average of 1.3% from baseline, significantly better than placebo ; while in SYMPHONY-2, the addition of HTD1801 to metformin resulted in an average HbA1c reduction of 1.2%, also significantly better than placebo. Both trials included an open-label extension period, and at week 52, the HbA1c reduction in the original HTD1801 group remained at approximately 1.1%–1.2%, and patients switching from placebo to HTD1801 also achieved a similar reduction as in the double-blind period, suggesting that the efficacy has a certain degree of durability.

In the subgroup with higher baseline HbA1c (≥8.5%), the HbA1c reduction induced by HTD1801 in SYMPHONY-1 and SYMPHONY-2 reached 1.5%–1.6%. Both trials also observed improvements in several cardiometabolic and liver-related indicators, including fasting blood glucose, target achievement rate (HbA1c <7%), LDL-C, gamma-glutamyl transferase, and high-sensitivity C-reactive protein, providing preliminary support for their positioning as "comprehensive metabolic regulation".

It is precisely because of the placebo-controlled trials of SYMPHONY-1 and SYMPHONY-2, coupled with the numerical advantage achieved in the head-to-head HARMONY trial compared to dapagliflozin, that HTD1801 has transformed from a "promising natural product derivative" into a small molecule new drug case that has truly completed multiple Phase 3 validations in the 2025 metabolic disease drug landscape.

An oral drug derived from berberine and ursodeoxycholic acid ion salt can form a relatively complete data loop in terms of HbA1c reduction, blood lipid improvement, and safety. This will naturally prompt the industry to rethink whether new molecules obtained from natural products through modern chemical reconstruction are moving towards a more mainstream stage than before.

02
"Re-creation" in the modern sense

HTD1801 is not a natural drug in the traditional sense. It is not a simple compound of Chinese herbal extracts, nor is it a modern dosage form of traditional herbs. Instead, it is a reconstruction of two chemical components with clear origins and well-defined mechanisms through ion pairing: berberine and ursodeoxycholic acid. Both molecules have a history of use in traditional medicine, but their traditional methods of administration, indications, and efficacy logic are not equivalent to modern pharmaceutical science. Therefore, they are incorporated into HTD1801 as structural modules, rather than being simply adopted verbatim.

Berberine is mainly derived from bitter medicinal herbs such as Coptis chinensis, Phellodendron chinense, Gynostemma pentaphyllum, and Phellodendron amurense. These herbs are mostly bitter and cold in nature, and their main functions include clearing heat and drying dampness, purging fire and detoxifying . In classic medical texts such as *Shennong Bencao Jing*, *Shanghan Lun*, and *Jinkui Yaolue*, herbs rich in berberine, such as Coptis chinensis and Phellodendron chinense, are frequently recorded, often used for symptoms such as diarrhea, abdominal distension, bitter taste in the mouth, and irritability caused by damp-heat. In *Huanglian Jiedu Tang*, Coptis chinensis is the principal herb, mainly responsible for clearing heart fire, purging fire and detoxifying, and also has the effect of clearing heat and drying dampness; it is the core drug in the entire formula for relieving intense heat toxicity. In *Banxia Xiexin Tang*, Coptis chinensis, Scutellaria baicalensis, and dried ginger together form a "pungent-opening and bitter-descending" stomach-regulating system, used to relieve symptoms such as "abdominal distension" and "disharmony of stomach qi." From the perspective of modern pharmacology, although these traditional descriptions cannot be directly equated with modern diseases, the symptoms they point to can correspond to modern research: berberine can indeed regulate the intestinal flora, inhibit intestinal glucose absorption, intervene in bile acid metabolism, and improve energy homeostasis through AMPK signaling . There is a certain physiological overlap between these mechanisms and its traditional experience in treating symptoms such as damp-heat, diarrhea, and abdominal distension.

However, berberine itself suffers from several unavoidable pharmacokinetic defects. Its oral bioavailability is less than 1%, and it is easily excreted or metabolized in the gastrointestinal tract, making it difficult to achieve adequate absorption. Furthermore, higher doses can cause significant gastrointestinal irritation, making it almost impossible to achieve stable, quantifiable, and reproducible therapeutic effects using traditional dosage forms. Therefore, despite its broad pharmacological potential, berberine is unlikely to become a controllable metabolic drug in the modern sense.

Ursodeoxycholic acid (UDCA) can be traced back to bear bile powder, an animal-derived medicine. Records of bear bile powder can be found in classic Chinese medical texts such as the *Compendium of Materia Medica*, *Classified Materia Medica*, and *Golden Mirror of Medicine*. It is bitter and cold in nature, and its main functions are clearing the liver and gallbladder, detoxifying and reducing jaundice, and relieving hypochondriac pain. It is often used for symptoms such as jaundice, bitter taste in the mouth, and hypochondriac pain caused by damp-heat in the liver and gallbladder. Modern scientific research shows that UDCA is the most important and pharmaceutically significant bile acid component among the active substances in bear bile powder . It can reduce the cytotoxicity caused by hydrophobic bile acids, relieve hepatocyte stress, and promote bile flow. Therefore, it has been included in modern international guidelines (AASLD/EASL) for the treatment of primary biliary cholangitis (PBC). However, UDCA also has significant limitations: its effects on glucose metabolism and insulin sensitivity are limited, and its regulation of lipid metabolism is weak. Therefore, it is difficult to develop a truly comprehensive metabolic regulator drug based solely on UDCA.

Junshengtai Pharmaceuticals' breakthrough lies in its departure from the traditional concept of compound formulations. Instead, it employs an ionic salt reconstruction approach, stably pairing the positively charged quaternary ammonium structure of berberine with the negatively charged carboxylate group of UDCA to form a single, controllable, and structurally defined new chemical entity. This reconstruction alters the fate of both components in vivo, resulting in pharmacokinetic and pharmacodynamic properties far exceeding those of their individual uses: the lipophilicity of UDCA enhances the membrane-penetrating efficiency of berberine, improving its absorption and exposure; the AMPK activation of berberine complements the homeostatic regulation of UDCA in the enterohepatic circulation, generating structural synergy in the cross-pathways of energy metabolism and chronic inflammation. More importantly, the ionic salt form makes this synergy a predictable, repeatable, and clinically verifiable drug, no longer relying on the uncertainty of the component ratios in traditional medicinal materials.

The medicinal value of HTD1801 does not come from the direct inheritance of traditional medicines, but from the modern re-creation of traditional active molecules. The traditional Chinese medicine system provides inspiration, not finished products; what truly makes it a drug is the complete system constituted by modern chemistry, modern pharmacokinetics, and modern clinical validation.

03
Inspiration from Traditional Chinese Medicine for Modern Drug Design

The successful Phase 3 study of HTD1801 once again serves as a prime example of how traditional Chinese medicine (TCM) components can be successfully integrated into modern drug design. Can TCM truly become a viable pathway for modern drug discovery? Historically, the answer is clearly yes.

The discovery of artemisinin opened up new avenues for antimalarial research using natural products as clues; paclitaxel revolutionized cancer drug development; atorvastatin's parent structure is derived from fungal metabolites; and even some successful immunotherapies have indirect connections to traditional biological components. Natural products provide a wealth of structural templates for modern medicinal chemistry. These structures often possess characteristics such as high molecular complexity, strong stereoselectivity, and high target affinity, making them difficult to generate directly through artificial design.

Many chemical components in traditional Chinese medicine (TCM) belong to the family of natural products, but historically, their complexity has often prevented them from entering the mainstream global drug development system. Over the past few decades, many attempts at "modernizing TCM" have remained at a macro level, such as preserving complete formulation systems or attempting to maintain efficacy using traditional processing methods. These approaches are difficult to quantify and clearly define in a modern sense, and therefore often fail to enter the international standard review system.

HTD1801, however, took a completely different path. It is a drug derived from traditional ingredients but rationally modified. From this perspective, drug design inspired by traditional Chinese medicine is not a return to tradition, but a redefinition of traditional materials based on modern tools, modern mechanism theories, and modern manufacturing capabilities. This model requires adapting to the rigor of clinical trials, the transparency of regulatory systems, and the reproducibility of drug production, and the success of HTD1801 demonstrates that this is entirely possible.

HTD1801 is neither a simple return to tradition nor a mere supplement to the modern system, but rather a fusion. Drugs inspired by traditional Chinese medicine are not meant to replicate traditional medicine, but rather to deconstruct traditional materials using modern chemistry and medicine, giving them new clinical value within the current scientific framework. It is not an isolated case, but rather a demonstration. If this model can ultimately be validated in more disease areas, then natural product-inspired drug design will occupy an increasingly solid place in the future innovative drug system.

04
HTD1801 has a promising future.

The three Phase 3 trials of HTD1801 not only demonstrated its ability as an oral small molecule to improve multiple metabolic pathways beyond the GLP-1 era, but also prompted the industry to seriously assess its position in actual market competition. The traditional reference drug in the field of metabolic diseases is undoubtedly SGLT2 inhibitors, with AstraZeneca's dapagliflozin (Farxiga) being the most representative.

According to publicly available financial reports, Farxiga's global sales reached $2.14 billion in the third quarter of 2025, with annual sales approaching $10 billion, making it a super-selling drug spanning three major indications: diabetes, chronic kidney disease, and heart failure. This scale means that any new drug seeking to enter the same market must face a competitor with extensive clinical experience, established guidelines, and strong commercial penetration.

Against this backdrop, the numerical advantage achieved by HTD1801 in the HARMONY head-to-head trial is no longer limited to the level of "non-inferiority" but begins to provide a basis for discussing its "substitutability." Especially in the diabetes treatment system, SGLT2 inhibitors are not primarily valued for their HbA1c reduction, but rather for their value in establishing cardiovascular and renal outcomes. In contrast, the pharmacological structure of HTD1801 indicates a greater focus on comprehensive metabolic regulation, providing both approximately 1%–1.3% HbA1c reduction and sustained improvement in LDL-C, non-HDL-C, inflammatory markers, and liver-related indicators. Although it has not yet entered the cardiovascular and renal outcome trial phase, its metabolic-inflammatory cross-mechanism and stability in phase 3 trials suggest the potential for future expansion into a broader metabolic spectrum.

If we extrapolate the potential of HTD1801 from a market landscape perspective, the most noteworthy aspect is not whether it can replace Farxiga, but whether it can find a clear clinical positioning in an already highly crowded market . In the current stratification of diabetes treatment, GLP-1 and SGLT2 have become the two strongest main lines, while HTD1801's advantage lies in its completely different target logic and oral administration, giving it the opportunity to enter the "non-GLP-1 era" population level: including those with poor GLP-1 tolerance, gastrointestinal sensitivity, unwillingness to accept injection regimens, or borderline cardiac and renal function.

Furthermore, the improvements in liver and inflammatory markers demonstrated by HTD1801 in two placebo-controlled phase 3 trials suggest further potential for its future expansion into fatty liver disease, early-stage MASH, or metabolic syndrome. This parallels Farxiga's successful multi-indication expansion to some extent, but their pharmacological mechanisms are entirely different. Therefore, they are more likely to complement each other rather than directly replace each other in the future.

The three successful Phase 3 trials of HTD1801 have, for the first time, made it possible for this model to directly compete with blockbuster drugs from multi-company drug manufacturers (MNCs). In the future, if HTD1801 can enter the international market, complete validation in more populations, and gradually explore broader metabolic indications, it not only has the opportunity to gain a foothold in diabetes treatment but may also prompt the entire industry to re-examine the strategic value of natural product structures in modern drug design.