The oral biologics revolution: How macrocyclic peptides could reshape drug delivery

As the global pharmaceutical industry advances toward greater patient accessibility and convenience, macrocyclic peptides are emerging as a breakthrough solution. These structurally engineered molecules offer the therapeutic precision of biologics while enabling oral administration—an innovation that could disrupt how biologic drugs are delivered across inflammation, cardiometabolic, and rare disease markets. With Merck & Co., Inc. (NYSE: MRK) leading the charge through enlicitide, and biotech firms like Protagonist Therapeutics and Orbis Medicines accelerating macrocyclic platforms, oral biologics are no longer speculative—they are becoming commercially viable.

What are macrocyclic peptides and why are they important in drug delivery?

Macrocyclic peptides are tightly folded cyclic molecules composed of amino acid chains. Their unique three-dimensional structure allows them to mimic the binding strength of antibodies while maintaining the chemical stability needed to survive the digestive tract. Traditionally, biologics—large, complex proteins like monoclonal antibodies—have required injection due to their poor oral bioavailability. Macrocyclic peptides bridge this gap, offering a class of drugs capable of modulating intracellular protein–protein interactions through oral delivery.

Advances in peptide stabilization, prodrug strategies, and absorption enhancers have brought macrocyclic peptides into late-stage pipelines. The resulting oral therapies promise to improve adherence, reduce clinic visits, and expand treatment access. This shift represents more than a formulation change—it reflects a broader industry push toward decentralizing drug delivery.

How Merck’s enlicitide is leading the oral PCSK9 race

Merck & Co., Inc. has placed itself at the forefront of this transition with enlicitide (MK-0616), a once-daily oral macrocyclic peptide that inhibits PCSK9, a key regulator of LDL cholesterol. In June 2025, Merck announced positive topline results from two Phase 3 trials—CORALreef HeFH and CORALreef AddOn. The trials demonstrated 50–60% LDL-C reductions, matching the efficacy of injectable PCSK9 inhibitors like evolocumab and alirocumab.

Enlicitide’s format addresses a critical unmet need: patient reluctance toward injectables. By enabling a high-efficacy oral cholesterol-lowering agent, Merck may unlock a broader adherence profile across primary and secondary prevention cohorts. Institutional analysts have flagged the drug as a strategic asset. Morgan Stanley and Jefferies projected peak global revenues of $4–6 billion and noted that enlicitide could become “a pipeline-defining molecule.” Regulatory filings are expected in early 2026.

Merck’s macrocyclic ambitions extend beyond enlicitide. In April 2025, the American pharmaceutical company entered into a collaboration with Austria-based Cyprumed, investing up to $493 million to expand its oral peptide platform across cardiometabolic and immunology assets. This platform strategy signals Merck’s commitment to transforming oral biologics from niche to mainstream.

Which biotech companies are advancing oral biologics platforms?

Protagonist Therapeutics (NASDAQ: PTGX) is another leader in the macrocyclic space. Its oral peptide icotrokinra, which targets IL-23, is in late-stage development for plaque psoriasis and partnered with Johnson & Johnson. Recent Phase 3 readouts have been promising, and the drug is expected to be submitted to the U.S. Food and Drug Administration by the end of 2025. Protagonist also has early-stage candidates in inflammatory bowel disease and rare hematologic conditions, including oral hepcidin mimetics.

The American biotech company has received significant strategic backing. Johnson & Johnson and Takeda have both partnered on Protagonist programs, and institutional analysts view the firm as a mid-cap innovator capable of scaling macrocyclic drug delivery into multiple therapeutic areas.

Meanwhile, Orbis Medicines, based in Denmark, is developing a preclinical pipeline of oral macrocycles targeting historically “undruggable” intracellular targets. In 2024, Orbis secured €90 million in Series A funding led by New Enterprise Associates and joined by Bristol Myers Squibb. While still pre-revenue, Orbis represents the next generation of platform biotech players pursuing macrocyclic peptide drugs beyond cardiometabolic indications.

AstraZeneca has also entered the field through a licensing deal with Syneron Biologics, reportedly valued at over $3 billion in milestones. The British–Swedish pharmaceutical company aims to develop oral peptide-based inhibitors for oncology and autoimmune diseases, applying macrocyclic technology to previously antibody-dominated domains.

Can oral biologics improve adherence and reduce healthcare costs?

The clinical and economic burden of nonadherence is well-documented across chronic diseases like hyperlipidemia, hypertension, and diabetes. Injectable biologics, while effective, face barriers related to fear of needles, inconvenience, and administration costs. Oral macrocyclic peptides directly address these issues.

Studies of oral semaglutide, Novo Nordisk’s GLP-1 receptor agonist, showed higher treatment persistence compared to injectables. Analysts expect similar patterns to follow in the PCSK9 and inflammation segments once oral peptide candidates are launched. From a payer perspective, fewer clinic visits and streamlined pharmacy distribution could reduce total cost of care, especially in vertically integrated systems.

However, the full commercial benefit will depend on pricing, formulary inclusion, and real-world outcomes. Value-based contracts could accelerate uptake if macrocyclic peptides demonstrate similar or superior outcomes to injectables in broader populations.

What is the market outlook for macrocyclic peptide drugs?

Industry estimates suggest the global macrocyclic peptide therapeutics market could reach $10 billion in annual sales by 2030, spanning cardiometabolic, inflammatory, rare, and oncology indications. Currently, enlicitide and icotrokinra are the most advanced candidates, both targeting approval between late 2025 and early 2026. A second wave of clinical entries is expected between 2026 and 2028, including next-gen IL-17 and GLP-1R modulators, as well as oncology-targeted macrocycles.

The financing environment remains strong. Deal sizes for macrocyclic platforms have ranged from $200 million in upfronts (Merck–Cyprumed) to over $3 billion in potential milestones (AstraZeneca–Syneron). Venture funding is also robust, with at least five startups raising over $50 million in Series A or B rounds since 2023.

Market analysts at Evaluate Pharma and GlobalData expect that macrocyclic peptide drugs will secure regulatory designations for accelerated review in high-priority areas like cardiovascular prevention, immuno-inflammatory control, and metabolic disorders.

Which oral biologic developers could deliver investor upside?

Merck & Co., Inc. holds a clear first-mover advantage in the cholesterol space with enlicitide, a once-daily oral macrocyclic peptide PCSK9 inhibitor that has demonstrated LDL-C reductions on par with leading injectables. Following positive Phase 3 data from the CORALreef HeFH and AddOn trials, Merck has positioned itself at the forefront of this emerging class. The American pharmaceutical company’s strategic collaboration with Austria-based Cyprumed, valued at up to $493 million in milestones, further underscores its long-term commitment to macrocyclic peptide delivery platforms. Through this alliance, Merck is not only securing formulation innovation but also building out a modular peptide architecture intended for use across cardiometabolic, inflammatory, and immunologic programs. Analysts believe enlicitide could become a multibillion-dollar franchise, serving as both a market disruptor and a pipeline-enabling model for future peptide-based assets.

Protagonist Therapeutics is another critical player in the macrocyclic peptide space, with its lead asset icotrokinra (oral IL-23 receptor antagonist) advancing rapidly through late-stage development in plaque psoriasis. In partnership with Johnson & Johnson, Protagonist has also announced trials in ulcerative colitis and Crohn’s disease, potentially expanding icotrokinra’s utility across both dermatology and gastrointestinal immunology. Analysts from SVB Securities and Raymond James have emphasized the biotech firm’s dual revenue potential—first from royalties tied to Johnson & Johnson’s commercial launches, and second from its retained rights in select geographies and pipeline indications. The American biotech company is further exploring oral hepcidin mimetics and IL-17 inhibitors, which could expand its macrocyclic portfolio into hematology and inflammation. With multiple assets in or approaching pivotal trials, Protagonist is emerging as one of the most mature and diversified macrocyclic peptide developers in the public biotech universe.

Orbis Medicines and Syneron Biologics, while earlier in development, represent high-risk, high-reward investment opportunities in next-generation oral peptide therapeutics. Orbis, headquartered in Denmark, raised €90 million in a 2024 Series A round backed by New Enterprise Associates, Forbion, and Bristol Myers Squibb. The biotech company is developing a proprietary macrocycle engine that applies synthetic biology and AI-assisted design to generate highly stable oral peptide candidates targeting protein–protein interactions. Although preclinical, Orbis has disclosed several oncology and fibrosis programs it expects to advance into clinical trials by late 2026. Meanwhile, Syneron Biologics has secured over $3 billion in milestone-based licensing agreements with AstraZeneca to co-develop oral peptides targeting autoimmune and oncologic pathways, further validating the platform’s long-term scalability. These startups are particularly attractive to venture investors seeking differentiated modality exposure with big pharma exit optionality.

For institutional investors, macrocyclic peptides represent a convergence of scientific novelty and commercial pragmatism. Unlike cell and gene therapies, which require bespoke manufacturing and cold-chain logistics, oral macrocyclic peptides are compatible with existing pharmaceutical supply chains and retail pharmacy channels. This scalability offers both margin expansion and faster market penetration upon approval. Moreover, macrocyclic peptides dramatically improve the patient experience by eliminating injections, which can be a major barrier in chronic disease management. As adherence becomes a key performance metric in payer-driven models, therapies that combine clinical efficacy with ease of administration will likely see greater formulary inclusion and patient uptake.

With 2026 expected to be a pivotal year for the first macrocyclic peptide approvals, institutional interest is rising steadily. Hedge funds with healthcare mandates and long-only biotech-focused asset managers are increasingly rotating capital into companies like Merck and Protagonist, as well as allocating to earlier-stage platforms through crossover rounds. Sell-side analysts have flagged the macrocyclic peptide category as a top trend to watch, placing it alongside AI in drug discovery and antibody-drug conjugates in oncology in terms of potential impact. As more real-world data emerges, particularly for enlicitide and icotrokinra, investor focus will likely shift from platform speculation to commercial validation, unlocking further upside for early adopters in this innovative therapeutic class.