Progress in Macrocyclic Peptide Drug Development

The cyclic structure of macrocyclic peptides not only confers high binding affinity and molecular stability but also overcomes key challenges faced by traditional peptides, such as enzymatic degradation and low oral bioavailability. By 2025, with multiple pivotal clinical breakthroughs and technological innovations, macrocyclic peptide drug development has entered the oral therapeutics era, showcasing strong potential to reshape the paradigm of modern drug discovery. This article provides an overview of the current progress in macrocyclic peptide drug research and development.

Structural Features and Pharmacological Advantages

Macrocyclic peptides are a class of peptide molecules characterized by a ring-like structure, typically composed of 5-17 amino acid residues with a molecular weight ranging from 500 to 2000 Da. Positioned between small-molecule compounds and large biological therapeutics, they combine the structural and functional advantages of both, making them a promising direction in peptide drug discovery. The cyclic architecture endows these peptides with exceptional target-binding affinity and biological stability, enabling them to effectively modulate protein-protein interactions (PPIs) and intrinsically disordered proteins (IDPs)—targets traditionally considered “undruggable.” These features highlight their vast potential in the development of orally available peptide drugs.

Enhanced Bioactivity, Stability, and Selectivity

Compared with linear peptides, macrocyclic peptides demonstrate higher target specificity and biological activity, allowing for potent therapeutic effects at lower doses while minimizing off-target interactions and systemic toxicity. Their rigid cyclic structure improves resistance to gastric acid and proteolytic enzymes, prolonging in vivo half-life and enhancing pharmacodynamic persistence. Moreover, macrocyclic peptides exhibit remarkable structural diversity and design flexibility, allowing chemical modifications to meet diverse therapeutic needs. With low immunogenicity, strong target selectivity, and minimal impact on normal cells, they are emerging as safe and effective candidates for next-generation precision therapeutics. Continuous advancements in delivery technologies further enhance their clinical feasibility.

With their superior pharmacological profiles and evolving synthetic technologies, macrocyclic peptides have become one of the hottest frontiers in peptide drug research. They hold the promise of achieving precise target engagement, improved safety profiles, and optimized efficacy, positioning themselves as a cornerstone in the future of innovative therapeutic strategies.

Clinical Pipeline of Macrocyclic Peptide Drugs

The number of macrocyclic peptide drugs entering clinical development has been steadily increasing (Table 1), with orally administered macrocyclic peptides emerging as a major focus area. Since the approval of Cyclosporine A by the FDA in 1983, macrocyclic peptide therapeutics have made remarkable advances across multiple therapeutic fields. However, orally bioavailable macrocyclic peptides remain relatively rare. With the rapid emergence of new technologies, the development of oral peptide therapeutics is expected to achieve significant breakthroughs in the coming years. Several oral macrocyclic peptide candidates have now advanced into clinical trials, with representative examples including the following:

01. MK-0616 (Merck & Co.)

MK-0616 is an oral PCSK9 inhibitor currently in Phase III clinical trials. Designed as a macrocyclic peptide capable of binding to PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9), MK-0616 aims to reduce low-density lipoprotein cholesterol (LDL-C) levels. In contrast to current PCSK9-targeting antibody therapies that require subcutaneous injection, MK-0616’s oral formulation is expected to greatly improve patient adherence and reduce treatment costs. Although the peptide itself has limited permeability, the inclusion of an absorption enhancer allows an oral bioavailability of approximately 2%. On June 9, 2025, Merck announced that both pivotal Phase III trials—CORALreef HeFH and CORALreef AddOn—achieved their primary endpoints in patients with hypercholesterolemia, marking a major milestone for oral peptide drug development.

02. JNJ-2113 (Johnson & Johnson)

JNJ-2113 is an oral IL-23 receptor antagonist currently in Phase III clinical development. The program originated from a collaboration between Protagonist Therapeutics and Johnson & Johnson, established in 2017, with J&J leading subsequent development and commercialization. In November 2024, JNJ-2113 achieved positive topline results in its pivotal ICONIC-LEAD Phase III trial, demonstrating robust efficacy and oral potential in patients with moderate-to-severe plaque psoriasis (PsO), including adolescents aged 12 years and older. If successfully approved, JNJ-2113 is poised to become the first oral peptide drug targeting the IL-23 receptor, representing a transformative step in the treatment of chronic inflammatory diseases.

03. LUNA18 (Chugai Pharmaceutical)

LUNA18 is a KRAS inhibitor currently in Phase I clinical trials in Japan and the United States. In preclinical studies, LUNA18 demonstrated oral bioavailability ranging from 21% to 47% across multiple species (mice, rats, monkeys, and dogs), without the need for permeability enhancers—indicating excellent membrane penetration and drug-like properties. Moreover, dose-dependent antitumor activity was observed in animal models, underscoring its strong therapeutic potential as a next-generation macrocyclic peptide-based KRAS inhibitor.

Drug Name	Highest Clinical Phase	Source Type	Clinical Trial ID	Route of Administration
AP301	Phase III	Natural product derivative	NCT04551300	Oral
BMS-986229	Phase III	mRNA display	NCT04161781	Injectable
JNJ-2113	Phase III	Phage display	NCT05364554	Oral
MK-0616	Phase III	mRNA display	NCT05952896	Oral
ORMD-0801	Phase III	Natural product derivative	NCT04817215	Oral
PL9643	Phase III	Natural product derivative	NCT05201170	Ophthalmic
Plitidepsin	Phase III	Natural product source	NCT01102426	Injectable
Balixafortide	Phase III	Natural product derivative	NCT03786094	Injectable
Rusfertide	Phase III	Natural product derivative	NCT04202965	Injectable
BT8009	Phase II/III	Phage display	NCT04561362	Injectable
VT1021	Phase II/III	Natural product derivative	NCT03970447	Injectable
ALRN-6924	Phase II	Stapled peptide design	NCT02264613	Injectable
AMY-101	Phase II	Phage display	NCT03694444	Injectable
AZP-3813	Phase II	mRNA display		Injectable
Certepediol	Phase II	Phage display	NCT03517116	Injectable
Dolcamatide	Phase II	Natural product derivative	NCT01983306	Oral
PL8177	Phase II	Natural product derivative	NCT05466890	Oral
THR-149	Phase II	Phage display	NCT04527107	Injectable
TE-232	Phase II	Natural product derivative	NCT00422786	Injectable
BHV-1100	Phase I/II	mRNA display	NCT04634435	Injectable
BT1718	Phase I/II	Phage display	NCT03486730	Injectable
FOG-001	Phase I/II	Phage display	NCT05919264	Injectable
Lonodelestat	Phase I/II		NCT03748199	Inhalation
BT5528	Phase I/II	Phage display	NCT04180371	Injectable
BT7480	Phase I/II	Phage display	NCT05163041	Injectable
LUNA18	Phase I	mRNA display	NCT05012618	Oral

Cyclic Peptides at Creative Peptides

CAT#	Product Name	M.W	Molecular Formula
10-101-103	Vancomycin	1449.25	C66H75Cl2N9O24
10-101-104	Teicoplanin	1879.66	C88H95Cl2N9O33
10-101-112	Bremelanotide	1025.18	C50H68N14O10
10-101-169	Pasireotide	1047.20624	C58H66N10O9
10-101-186	Romidepsin	540.69584	C24H36N4O6S2
10-101-325	Semaglutide	4113.57	C187H291N45O59
10-101-62	Ziconotide	2639.13	C102H172N36O32S7
10-101-78	Dalbavancin	1816.69	C88H100Cl2N10O28
AF083	Polymyxin B
MFP-041	Rezafungin	1226.4	C63H85N8O17
R04030	Cyclo(-Arg-Gly-Asp-D-Phe-Val)	574.64
R1574	Octreotide	1019.24	C₄₉H₆₆N₁₀O₁₀S₂
R1812	Lanreotide	1096.33	C54H69N11O10S2
R1824	Cyclo(RGDyK)		C31H43F6N9O12
R2018	Capreomycin
R2029	Enviomycin	685.69	C26H43N11O11
R2052	Zilucoplan		(C2H4O)nC126H186N24O32
R2238	Telavancin	1755.6	C80H106Cl2N11O27P
R2239	Oritavancin	1793.1	C86H97Cl3N10O26
R2240	Bacitracin	1422.69	C66H103N17O16S