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Oral Macrocyclic Peptides Are Gaining Quiet Momentum
01、Oral macrocyclic peptides are hitting the spotlight "The rapid warming up of the oral macrocyclic peptide track has a fairly clear underlying driver," Dr. Liu Dan, Managing Partner at Pivotal Bioventure Capital, pointed out to the author. "What has recently drawn market attention is oral cyclic peptides. Their core value lies in the potential to resolve the classic 'molecular dilemma'. Traditional small molecules are orally available yet often lack sufficient affinity and specificity. Macromolecular antibodies boast high targeting precision but can only be administered via injection. Oral macrocyclic peptides aim to combine the strengths of both, breaking through the physical barrier of oral delivery." In addition, macrocyclic peptides are not merely drug molecules; they can also serve as delivery carriers. Such scalability greatly broadens their application scenarios and opens up broader imagination for investors. Macrocyclic peptides are not a new concept. Cyclic peptide antibiotics such as Vancomycin and Daptomycin have long been widely used in clinical practice. Since the 21st century, more macrocyclic peptide drugs have gained regulatory approval. For instance, C5-blocking macrocyclic peptides including Zilucoplan have emerged as a new generation of therapies for autoimmune diseases. However, it should be noted that all previously approved macrocyclic peptide drugs are formulated for injection. The development of oral macrocyclic peptide drugs has long been recognized as a formidable challenge. With a relatively large molecular weight and structural rigidity arising from their cyclic architecture, macrocyclic peptides adopt highly complex three-dimensional conformations that far exceed the computational and simulation capabilities of conventional drug design approaches. "For a macrocyclic peptide small molecule, its size and complexity are four to five times those of a typical small molecule, making scale-up production a bold endeavor," said David Thaisrivongs, Chief Chemistry Director at Merck. However, several recent cases have demonstrated the feasibility of oral macrocyclic peptides. Recently, at the Annual Scientific Session of the American College of Cardiology (ACC), Merck unveiled the latest Phase III clinical data for enlicitide (MK-0616), an oral macrocyclic peptide PCSK9 inhibitor. The results showed that among patients already on statin therapy, enlicitide reduced levels of LDL-C, the so-called "bad cholesterol", by more than 64%, a far greater reduction than that achieved by existing oral lipid-lowering medications. This marks the third successful Phase III trial of enlicitide. Previously, it achieved an LDL-C reduction of 58.2% in patients with heterozygous familial hypercholesterolemia and a 57.1% reduction in the broader high-risk cardiovascular population. On March 18, 2026, Johnson & Johnson announced that the FDA has approved Icotyde (icotrokinra) for the treatment of moderate to severe plaque psoriasis in adults and pediatric patients aged 12 years and older weighing at least 40 kilograms who are candidates for systemic therapy or phototherapy. This is an oral IL-23R cyclic peptide antagonist. In the prior Phase III ICONIC-LEAD trial, 74% of patients achieved almost complete skin lesion clearance (IGA 0/1) at week 24, while nearly half, or 46%, attained complete skin lesion clearance (IGA 0). Although preclinical studies have shown that the oral bioavailability of Icotyde is only 0.1%–0.3%, it still delivers definite pharmacological activity without the use of absorption enhancers. The compound exhibits high stability in plasma, gastrointestinal contents and hepatocytes, with a relatively low protein binding rate of approximately 50%. It can be widely distributed to target tissues such as the skin and joints. No serious adverse events were observed in the first-in-human trial. These two cases prove that oral macrocyclic peptides are now commercially viable, undoubtedly boosting confidence across the entire industry track. 02、Oral bioavailability remains a major challenge. Strictly speaking, the core challenge of oral macrocyclic peptides has not yet been truly overcome. Many investors hold the view that the market is currently still paying a premium for the concept alone. Liu Dan stated: "There have indeed been some positive signs recently, but the problem is far from being solved." He believes oral bioavailability is the most critical metric in this track. "Whoever can stably lift the oral bioavailability of cyclic peptides above 5% will truly secure the admission ticket to this field." Oral macrocyclic peptides need to avoid degradation by gastric acid and intestinal enzymes, while also penetrating intestinal epithelial cells to enter the bloodstream—a highly challenging process. In addition, oral macrocyclic peptides exhibit low and non-linear absorption rates, making it difficult to maintain stable plasma drug concentrations. Excessively low bioavailability gives rise to multiple issues. For one thing, most of the drug is wasted, placing substantial pressure on production costs. For another, raising the dosage to compensate for low absorption rates may trigger more severe gastrointestinal side effects. Moreover, extremely low bioavailability is often accompanied by high pharmacokinetic variability. Drug absorption varies greatly among individuals and under different feeding states, making therapeutic efficacy difficult to control. Over the past few years, GLP-1 drugs have dominated the industry’s attention. With the launch of Novo Nordisk’s oral Wegovy and Eli Lilly’s small-molecule GLP-1 receptor agonist Orforglipron, the competition in weight-loss medications has officially entered the oral era. Data shows that there are currently 84 novel oral small-molecule GLP-1 drugs under global research and development, among which 52 have entered clinical stages. Amid such fierce competition, the requirement for oral bioavailability of peptides has also been driven to a higher standard, laying valuable experience for the development of oral macrocyclic peptides. According to data from Novo Nordisk, the bioavailability of oral semaglutide tablets is only 0.4%–1%. As a non-peptide molecule, Orforglipron boasts a much higher bioavailability of approximately 30%–40%. In November 2025, Ascletis Pharma announced that ASC37 oral tablets, developed leveraging its Peptide Oral Transport Enhancement Technology (POTENT), achieved an average absolute oral bioavailability of 4.2% in head-to-head non-human primate (NHP) studies. Overall, oral bioavailability remains an unsolved challenge for cyclic peptides with no mature solutions available. Most candidates with promising preclinical data are still confined to animal trial stages. Liu Dan also stated that he has not yet seen any platform technology capable of systematically solving this problem. "For example, even if a company manages to raise the oral bioavailability of a single pipeline candidate above 5%, such capability cannot be directly transferred to another pipeline to guarantee the same outcome. At present, most companies’ data remain limited to the optimization of individual molecular candidates, still far from forming a versatile, scalable platform. Even so, every player in the field is working hard toward this goal." 03、AI Becomes the Core Betting Focus Although bioavailability stands as the core metric, given that no player has yet delivered a comprehensive solution, it is still impossible to screen investment targets based on tangible outcomes from an investment perspective. "No one can achieve this in a stable and mature manner. If we screen candidates by the benchmark of stably achieving an oral bioavailability above 5%, not a single company can meet the requirement," an investor commented. Since what investors truly want to see remains unattainable, they have no choice but to adopt a different line of reasoning. "Investors have to settle for the next best thing: looking into whether a team has prior experience in cyclic peptide development, built up expertise in peptide drug research, or established solid analytical capabilities and data reserves via AI design in this field," the aforementioned investor said. Liu Dan shares this view. He points out that current investment decisions rely heavily on tools and experience for judgment. "Since the outcomes everyone hopes to see — especially clinical data — have not yet materialized, investors can only evaluate which companies possess capable technical tools and which teams have long-standing experience deeply rooted in this field. Most investors are currently making judgments based on this logic." In the past, the screening and optimization of macrocyclic peptides mainly relied on high-throughput experiments, which suffered from long cycles, high costs, and a high failure rate. The emergence of AI has opened up new possibilities for the industry: AI can be used to design peptide chain combinations and spatial conformations, as well as predict their oral absorption properties. Consequently, AI-aided design and development have become a major focal point in the oral macrocyclic peptide track. For example, as mentioned earlier, YuanSi Peptide's Synova platform integrates AI, data science and high-throughput screening, aiming to discover macrocyclic peptide drugs that combine the specificity of biological drugs with the druggability characteristics of small molecules. In March 2025, AstraZeneca entered into a strategic cooperation with YuanSi Peptide to jointly develop first-in-class macrocyclic peptide drugs for chronic diseases, granting AstraZeneca access to the Synova technology platform. Under the terms of the agreement, AstraZeneca will pay a $75 million upfront payment plus near-term milestone payments, as well as research, development and commercialization milestone payments of up to $3.4 billion in total, together with tiered royalties based on global sales. In addition, AstraZeneca will make an equity investment in YuanSi Peptide. The company also plans to expand its R&D center in Beijing through this collaboration. UNP has also garnered favor from multiple multinational pharmaceutical companies. In 2024, UNP sealed a $220 million collaboration with Merck. This February, Novartis obtained access to its AI-driven macrocyclic peptide discovery platform with a $100 million upfront payment and total deal value exceeding $1.7 billion, to jointly develop therapeutics for cardiovascular diseases. UNP’s integrated discovery engine combines AI-guided molecular design, massively parallel synthesis and direct biological screening, enabling the rapid generation of potent and highly selective macrocyclic compounds suitable for both oral and injectable administration routes. According to UNP, the platform integrates digital and wet-lab technologies through continuous macrocycle optimization cycles. Each cycle rapidly iterates toward more drug-like macrocyclic peptide molecules. Liu Dan believes that although no company has yet truly leveraged AI to specifically tackle the core challenge of oral bioavailability, having an additional tool is always worth a try. "Many VC investors are willing to bet on this tool. In drug R&D, any new method that can boost efficiency and cut trial-and-error costs will attract institutional investment. I also hold positive expectations for this direction." 04、Conclusion The maturation of every new drug modality has always followed a long journey from widespread skepticism to preliminary validation, and eventually to broad industry acceptance. This holds true for monoclonal antibodies, bispecific antibodies, and ADCs alike. Today, oral macrocyclic peptides stand at precisely the same inflection point. Multinational pharmaceutical companies have locked in technology platform licensing with substantial capital, and clinical data have initially validated the underlying concept. Nevertheless, there is still a long way to go before genuine technological maturity is achieved. Is the current boom in oral macrocyclic peptides merely a bubble, or a genuine starting point? Only time and data will tell. Disclaimer： Reposted from: https://news.yaozh.com/ All images and texts are copyrighted by their original authors. This repost is for the purpose of disseminating more information and does not represent the views of this platform. If you have any issues concerning content, copyright, or other related matters, please leave a message on this platform, and we will remove the relevant content promptly.
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