GLP-1 receptor agonists have garnered widespread attention due to their significant weight loss and diabetes treatment effects. However, despite the remarkable success of existing GLP-1 drugs, many pharmaceutical companies, including Novo Nordisk and Eli Lilly, already established leaders in the weight loss drug market, continue to seek breakthroughs with new drugs and develop convenient and effective treatment options.

After the successful Zepbound, which brought endless wealth, Eli Lilly has set its sights on the small molecule asset orforglipron as its next breakthrough, hoping to provide an oral alternative to treat obesity and diabetes.

All-round emergency

Although orforglipron showed promising results in early clinical trials, especially achieving 15% weight loss in the short term, this effect dropped significantly after entering late-stage trials, to only 11.2%.

In comparison, existing injectable GLP-1 drugs (such as Wegovy and Zepbound) demonstrate weight loss effects ranging from 15% to 21%, respectively. This significant disparity presents orforglipron with significant challenges in the market. In fact, orforglipron's clinical results have exposed the limitations of small molecule drugs in certain specific indications and targets, prompting in-depth comparison and reflection on the therapeutic efficacy and indications of small molecule drugs and peptide drugs.

Prior to orforglipron, Pfizer's two glipron small molecule weight loss drug pipeline assets had already failed before they even started. Lotiglipron and Danuglipron, both oral GLP-1 receptor agonists developed by Pfizer, failed to reach the forefront of the market and were ultimately terminated due to clinical challenges.

Danuglipron demonstrated significant weight loss and blood sugar reduction effects in early clinical trials, but subsequent clinical trials, particularly at higher doses, revealed liver toxicity. This safety concern forced Pfizer to halt development of the drug in 2025. Liver toxicity has become a major challenge for oral small-molecule GLP-1 drugs, impacting their market competitiveness.

Lotiglipron, another oral GLP-1 drug from Pfizer, demonstrated effective weight loss and blood sugar reduction in early clinical studies. However, its efficacy and side effects (such as gastrointestinal discomfort) fell short of expectations, leading to obstacles in its clinical development. While it offers the convenience of oral administration, its weight loss efficacy and long-term treatment tolerability lag behind existing injectable GLP-1 drugs, leading Pfizer to discontinue further development of the drug.

The termination of development of these two drugs reveals the dual challenges facing oral GLP-1 receptor agonists: limited efficacy on the one hand, and safety issues on the other, especially the management of side effects during long-term use. These issues make it difficult for them to compete with existing injectable GLP-1 drugs, especially in the market for treating diseases such as obesity and diabetes.

The clinical data directly impacted orforglipron's market competitiveness, particularly given the significant success of existing GLP-1 drugs. This result not only disappointed Eli Lilly but also prompted investors and clinicians to reconsider the potential of small molecule drugs in treating complex diseases such as obesity and diabetes.

In addition to its efficacy falling short of expectations, orforglipron's side effects also impact its clinical performance. According to clinical data, orforglipron caused significant gastrointestinal discomfort, such as nausea and vomiting, in patients in the high-dose group, and approximately 10% of patients discontinued treatment due to these side effects. This relatively common side effect poses certain challenges to the drug's actual clinical application, especially in patients who require long-term use, where poor tolerance may affect drug compliance.

Why the poor performance?

1. Limitations of target selectivity and affinity

Small molecule drugs typically have a smaller molecular structure, which makes them lack sufficient targeting and affinity compared to large molecule drugs (such as antibodies or peptide drugs). Small molecule drugs work by binding to target receptors, but due to their simple structure and low affinity, they often have difficulty forming strong and stable binding to target receptors, thus affecting their efficacy. Especially in the treatment of diseases that require highly targeted and precise effects, small molecule drugs often cannot achieve the same therapeutic effects as peptide drugs.

In contrast, peptide GLP-1 receptor agonists (such as Wegovy and Zepbound) mimic the natural GLP-1 hormone and bind to the GLP-1 receptor with high specificity, thereby exerting multiple mechanisms of action. These drugs can significantly promote insulin secretion, suppress appetite, and delay gastric emptying, achieving better blood sugar control and weight loss. In contrast, orforglipron, as a small molecule drug, has a low affinity for binding to the GLP-1 receptor, making it difficult to stimulate a sufficiently strong biological response, resulting in relatively weak efficacy.

2. Challenges of bioavailability and pharmacokinetics

Pharmacokinetics refers to the absorption, distribution, metabolism, and excretion of a drug in the body. Small molecule drugs typically need to be absorbed through the intestines and enter the bloodstream to be effective. Due to limitations in molecular structure and hydrophilicity, oral bioavailability can be low, making it difficult to maintain drug concentrations within the effective range. Although orforglipron can be administered orally, its therapeutic efficacy is not comparable to that of existing injectable GLP-1 drugs due to its low bioavailability.

In contrast, injectable GLP-1 drugs such as Wegovy and Zepbound, which enter the bloodstream directly, can quickly reach their targets and provide potent and long-lasting therapeutic effects. Small molecule drugs undergo multiple processes, including intestinal absorption and liver metabolism, and are metabolized more rapidly in the body, resulting in a shorter half-life. This makes their efficacy and duration inferior to those of injectable drugs.

3. Side effects and tolerance issues

Although small molecule drugs generally offer lower production costs and convenient administration, their side effects are often more complex and unpredictable than those of peptide drugs. Small molecule drugs may bind to multiple non-target molecules, leading to adverse reactions. For example, orforglipron caused significant gastrointestinal discomfort in the high-dose group, leading some patients to discontinue treatment.

In contrast, peptide drugs are generally able to avoid these nonspecific side effects due to their high targeting. Even though peptide drugs may cause some gastrointestinal side effects, because they act on specific receptors, the side effects are relatively few and patients are generally well tolerated.

Although small molecule drugs have advantages in cost and production, when therapeutic effect becomes the key, the high efficiency and high targeting of peptide drugs make them more competitive in the market.

Do you have a future?

Although small molecule drugs still have a place in many therapeutic areas, especially in terms of ease of administration, production costs and wide applicability, they often perform poorly in the treatment of some specific indications and targets, especially in areas that require highly targeted and precise treatment.

If small molecule drugs cannot compete with peptide drugs in terms of weight loss effects, their future development direction will need to focus on their unique advantages while looking for innovative paths to fill the existing gaps. The following are several potential development directions through which small molecule drugs can still occupy a place in the weight loss drug market:

1. Improving the efficacy of small molecule drugs: precise target selection, differentiation, and multi-target combination therapy

Small molecule drugs are generally less effective at reducing weight than peptide drugs, primarily due to their poor target selectivity and relatively single mechanism of action. Peptide drugs typically work through multiple pathways, including promoting insulin secretion, suppressing appetite, and delaying gastric emptying. Small molecule drugs, on the other hand, often rely on a single mechanism, limiting their effectiveness.

Small molecule drugs require precise target selection to improve their efficacy. In addition to traditional targets (such as the GLP-1 receptor and GIP receptor), multi-target combination therapy can be explored in the future. By acting on multiple key biological pathways simultaneously, small molecule drugs can more comprehensively regulate weight control mechanisms. For example, weight loss effects can be enhanced by combining multiple pathways such as appetite suppression, metabolic regulation, and lipolysis. With the advancement of drug screening technology and high-throughput screening platforms, target discovery for small molecule drugs will become more precise, and small molecule drugs with multiple targets can be designed. For example, regulating fat metabolism by targeting the lipolysis pathway in adipose tissue can enhance fat burning and conversion, thereby promoting weight loss.

2. Combined application with other treatment methods

Small molecule drugs lag behind peptide drugs in weight loss efficacy and may not provide the same potent therapeutic effects as injectable drugs when used alone. Combination therapy may become a key development direction for small molecule weight loss drugs. Combining small molecule drugs with other treatments (such as peptide drugs) can compensate for the lack of efficacy of a single drug. Small molecule drugs can be combined with injectable drugs or other new weight loss drugs to form a combination therapy, thereby improving patients' weight loss outcomes. For example, small molecule drugs can be used as adjuvant therapy in conjunction with drugs such as GLP-1 receptor agonists or SGLT-2 inhibitors to regulate different biological pathways and achieve synergistic effects.

A prime example of this is Madrigal's recent acquisition of SYH2086, a preclinical oral weight loss drug asset from Shijiazhuang Pharmaceutical Group, for up to $2 billion. SYH2086 is a small-molecule, oral GLP-1 receptor agonist independently developed by Shijiazhuang Pharmaceutical Group. Madrigal plans to combine it with its existing MASH (metabolic dysbiosis-associated steatohepatitis) drug, Rezdiffra, to create a novel mechanistic combination therapy, enhancing the efficacy and long-term management of weight loss drugs. Through this combination therapy, Madrigal aims to break through the current competitive landscape of homogenous GLP-1 drugs and develop a more comprehensive metabolic intervention system. The combination of SYH2086 and Rezdiffra creates a comprehensive therapeutic approach with the potential to improve both efficacy and patient compliance. This strategy stands in stark contrast to current single-agent GLP-1 therapy approaches. Madrigal's strategy, centered on MASH treatment, is to promote the co-development of small-molecule, oral GLP-1 agonists to form a multi-mechanism combination therapy.

3. Better side effect control and personalized treatment

Small molecule drugs have problems in controlling side effects, especially gastrointestinal discomfort (nausea, vomiting, etc.) and other systemic side effects, which lead to poor patient tolerance and low treatment compliance.

Developing small molecule drugs with fewer side effects, especially those related to gastrointestinal side effects, will be a key area of research. By optimizing molecular structure and adjusting the dosage-release mechanism, drug side effects can be reduced in the body. Sustained-release formulations and targeted delivery systems (such as nanoparticles and liposomes) can help reduce systemic side effects. Personalized treatment will also be a key area of research for the future development of small molecule drugs. Using data from genetic testing and individual metabolic responses, treatment plans can be customized for each patient, maximizing weight loss and minimizing side effects. For example, optimizing the delivery system can reduce the gastrointestinal burden of the drug and improve patient tolerance. Genomic data can also be used to identify patients who respond best to certain small molecule drugs and tailor personalized treatment plans.

4. Metabolic regulation and control of intestinal flora

The intestinal flora plays a key role in metabolism, appetite regulation, and fat storage, but research on small molecule drugs in regulating the intestinal flora is still in its infancy. Small molecule drugs can enhance weight loss effects by regulating the intestinal microbiome. Studies have shown that intestinal flora imbalance is closely related to the occurrence of metabolic diseases such as obesity and diabetes. Future small molecule weight loss drugs can further enhance weight loss effects by regulating the balance of intestinal flora and improving metabolic status. For example, intestinal microbiome regulators can use small molecule drugs to regulate beneficial intestinal flora and inhibit harmful flora, thereby improving metabolic disorders and obesity. Another example is that by regulating the intestinal inflammatory response, fat storage caused by chronic low-grade inflammation can be reduced, thereby contributing to weight loss.

5. Innovation in molecular design and drug delivery technology

The relatively simple structure and mechanism of action of small molecule drugs limit their effectiveness in treating complex diseases, particularly in weight loss. With the continuous advancement of drug delivery technology and innovations in molecular design, small molecule drugs are expected to achieve breakthroughs in weight loss treatment in the future. For example, targeted delivery systems (such as nanoparticles and liposome-based drug delivery systems) can precisely deliver drugs to adipose tissue or key metabolic targets, enhancing efficacy while minimizing side effects. Another example is long-acting small molecule drugs, which optimize their molecular structure to extend their half-life, thereby achieving long-lasting and sustained weight loss effects.

6. Better adapt to the needs of the global market

Although small molecule oral drugs offer the advantages of low production costs and convenient administration for the treatment of obesity, their efficacy still cannot compete with peptide drugs, which limits their share of the market for high-efficiency weight loss drugs. The potential of small molecule drugs in the global market is primarily reflected in their accessibility. Compared with peptide drugs, small molecule drugs have low production costs and flexible administration methods, making them easier to enter low- and middle-income countries and help alleviate obesity in these countries. Therefore, the low cost of production and wide applicability of small molecule oral drugs will make them an important supplement to the future weight loss drug market.

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