Metabolic disease drug development landscape evolves

Triple to quadruple receptor agonists emerge in the market

Multi-Target Therapies Advance to target not only GLP-1, GIP, Glucagon but FGF21, PYY

Targets various metabolic diseases including MASH, not just obesity

Innovative efforts in the development of new drugs for metabolic disorders such as obesity and diabetes are steadily gaining traction in Korea and abroad.

 

The success of standalone GLP-1 therapies has driven the evolution toward multi-hormonal agents, and recently, major global pharmaceutical companies and biotech firms are accelerating new drug development by targeting not only GLP-1, GIP, and glucagon combinations but also new metabolic hormones such as FGF21 and IGF-1.

 

In essence, a multi-target approach that goes beyond simple weight loss to regulate energy metabolism, insulin sensitivity, and liver fat improvement is becoming a reality.

 

Development of multi-agonists starts with Mounjaro...

 

Biomed announces Phase II trial

According to industry sources on the 30th, the US pharmaceutical and biotech company Biomed Industries recently announced the results of its Phase II clinical trial for NA-931, an oral quadruple receptor agonist candidate for obesity and metabolic disorders.

 

The results were presented at the American Diabetes Association's annual diabetic conference (ADA 2025) that was held in Chicago from the 21st to the 24th.

 

NA-931 is a small-molecule drug that acts on four receptors: glucagon-like peptide (GLP-1), gastric inhibitory peptide (GIP), glucagon (GCG), and insulin-like growth hormone type 1 (IGF-1).

 

Recently, research has also been conducted on quadruple receptor agonists that utilize additional metabolic-related hormones such as IGF-1, FGF21, and PYY, in addition to GLP-1, GIP, and GCG.

 

FGF21 is a hormone produced in the liver that is involved in fat oxidation, insulin sensitivity, and temperature regulation.

 

It is gaining attention as a next-generation target due to its ability to induce metabolic improvements similar to those observed with intermittent fasting.

 

PYY is an appetite-suppressing hormone derived from the gut that can contribute to enhancing satiety by interacting with GLP-1.

 

The Phase II clinical trial presented at the conference was a 13-week, randomized, double-blind, placebo-controlled, parallel-group study involving 125 adults with obesity (BMI ≥ 30 kg/m²) or overweight (BMI ≥ 27 kg/m²).

 

The primary endpoints were the safety, tolerability, and weight loss efficacy of the investigational drug NA-931.

 

Results showed that the group administered NA-931 at a dose of 150 mg once daily experienced an average weight reduction of 13.8% compared to baseline, with a statistically significant reduction of 12.4 percentage points compared to the placebo group.

 

The incidence of treatment-emergent adverse events was also favorable.

 

Gastrointestinal (GI) adverse events were mostly mild, with nausea and vomiting observed in 7.3% of participants and diarrhea in 6.3%.

 

No muscle mass reduction was reported, and there was no clinically significant difference in the incidence of GI-related adverse events among subjects treated with NA-931 compared with placebo.

 

The researchers explained, “NA-931 appears to induce weight loss while preserving muscle mass and has a lower incidence of side effects than existing drugs.

 

It can be regarded as a viable alternative that can improve the shortcomings of existing GLP-1 class treatments.” Development of quadruple receptor agonists continue… to treat MASH in addition to obesity

Clinical studies of quadruple receptor agonists targeting indications other than obesity are also actively underway.

 

Among domestic companies, Wonjin Biotechnology has entered the clinical trial phase for a quadruple receptor agonist.

 

Wonjin Biotechnology received approval in the US last year for the Investigational New Drug (IND) application for its candidate compound ‘OGB21502’ for the treatment of metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis.

 

OGB21502 is an innovative drug candidate that combines GLP-1, glucagon, FGF21, and an IL-1 receptor agonist (IL-1RA), an immune modulator, to simultaneously regulate metabolic disorders and chronic inflammation.

 

OGB21502 induces appetite suppression and energy metabolism activation through GLP-1 and glucagon receptors while promoting lipid metabolism via FGF21 action.

 

Additionally, by blocking IL-1 signaling involved in inflammation, the company expects it to demonstrate a multi-layered therapeutic effect by preventing inflammatory exacerbation of metabolic diseases.

 

According to Wonjin Biotechnology, there is growing evidence that therapies blocking IL-1 signaling are effective in alleviating liver fibrosis.

 

In fact, anakinra, a recombinant IL-1 receptor antagonist, has been shown in multiple studies to inhibit NLRP3 activation and reduce hepatic stellate cell (HSC) activity and blood-based fibrosis markers.

 

In preclinical studies, OGB21502 demonstrated a reduction in lipid markers, including cholesterol and triglycerides, as well as the expression of fibrosis-related markers, compared to semaglutide and FGF21 analogs in obese mouse models.

 

In a mouse model of non-alcoholic fatty liver disease (NAFLD), liver tissue staining analysis revealed that OGB21502 significantly reduced the non-alcoholic fatty liver disease activity score (NAS) and improved steatosis and lobular inflammation.