paluratide (LUNA18) / Roche, Chugai Pharmaceutical - LARVOL DELTA

First-in-human study of paluratide (LUNA18), a novel, orally available cyclic peptide acting via pan-RAS-GDP inhibition, in patients with RAS-mutant advanced solid tumors (ESMO 2026) - No abstract available

Clinical • First-in-human • Metastases • P1 data • Oncology • Solid Tumor

Chemical optimization of N–Alkylated macrocyclic peptides enables oral bioavailability and KRAS–selective RAS inhibition (ACS-Fall 2026) - "Notably, AUBE00 exhibited absorption properties comparable to those of LUNA18, with 24–65% oral BA in animal models without the use of specialized formulations, while demonstrating a 10–14-fold preference for KRAS over other RAS isoforms. Together, these results demonstrate the feasibility of achieving oral BA and precise isoform selectivity in macrocyclic peptides and provide important guidance for the future optimization of drug-like peptides."

HRAS • KRAS • NRAS

Industrializing N-Alkyl-rich cyclic peptides: Kilogram-scale GMP production of the KRAS inhibitor LUNA18 | Poster Board #1498 (ACS-Fall 2026) - "Through a convergent synthetic approach with rigorous impurity control, consisting of 24 telescoped chemical transformation steps followed by a single final crystallization step, LUNA18 was successfully synthesized with >98.5% purity (HPLC-UV) and >30% overall yield. This LPPS process enabled the rapid supply of high purity LUNA18 API at the kilogram scale under GMP conditions."

KRAS

Rational design of cyclic peptides through backbone stabilization using φ/ψ plots of amino acids (ACS-Fall 2026) - "We found that main chain stabilization was achieved by substituting amino acids that exhibited lower conformational entropy and reduced φ/ψ free energy at the target conformation. This rational guidance led to the clinical compound LUNA18 through Leu → Pro substitution at position 8 and MePhe → Aib substitution at position 9, demonstrating the platform's practical applicability for developing orally bioavailable cyclic peptides at a practical computational cost."

KRAS

Anti-tumor activity of orally available cyclic peptide LUNA18 through direct pan-RAS inhibition across diverse RAS genetic alterations. (PubMed, Mol Cancer Ther) - "In xenograft models where the efficacy of KRASG12C-i was limited, combination with LUNA18 achieved more durable anti-tumor effects compared with the monotherapies. These findings suggest that LUNA18 could be a promising new therapeutic option for RAS-driven cancers."

Journal • Oncology • KRAS

Structure-Activity Relationship Analysis of Macrocyclic Peptide RAS Inhibitors: Spotlight on the Solvent-Exposed Region. (PubMed, ACS Med Chem Lett) - "We present the structure-activity relationship (SAR) analysis of LUNA18 (paluratide, an 11-mer macrocyclic peptide RAS inhibitor) focusing on the amino acid side chains at position 5 in the solvent-exposed region...Structural analysis identified two structural features: peptides forming a ″cavity″, which possess the hydrophobic interaction network among positions 1, 8, and 9, exhibited minimal changes upon position 5 modification, whereas those forming a ″groove″, lacking this interaction network, showed significant differences. These findings provide practical guidelines for optimizing macrocyclic peptides: evaluate the contributions of solvent-exposed side chain at key points and interpret SARs in the context of spatially proximal side chains."

Journal

HighRes_Builder: improved access and modeling of noncanonical residues for protein structure prediction. (PubMed, Brief Bioinform) - "Furthermore, by integrating HighRes_Builder with structure prediction systems, AlphaFold3 for linear peptides and HighFold3 for cyclic peptides, we successfully model the conformation of the linear peptide drug Relamorelin and the cyclic therapeutic peptides LUNA18 and JNJ-77242113 in complex with their target proteins, elucidating structural determinants of their mechanism of action. This work establishes a scalable and accurate framework for structure prediction of diverse nonstandard peptides, highlighting its potential to accelerate rational design of peptide-based therapeutics."

Journal

Chemical optimization of an orally bioavailable macrocyclic peptide KRAS inhibitors that achieve KRAS selectivity by recognizing a single amino acid difference (AACR 2026) - "Using this technology, we previously reported LUNA18 (Paluratide), a mid-sized cyclic peptide that binds reversibly to GDP-bound RAS isoforms (KRAS, NRAS, HRAS), inhibiting their signaling (J. In mouse xenograft models, oral administration of AUBE00 resulted in robust antitumor efficacy. A Phase 1 clinical trial in patients with advanced solid tumors is currently ongoing."

Oncology • Solid Tumor • HRAS • KRAS • NRAS

Combination of LUNA18, a novel RAS inhibitor, with KRAS G12C inhibitors augments anti-tumor activity via inhibition of MAPK pathway reactivation (AACR 2024) - "We orally administered LUNA18 and the KRAS G12C inhibitor to a xenograft model, which showed temporal response and then acquired resistance to the KRAS G12C inhibitor, and found that LUNA18 significantly suppressed emergence of resistance to the KRAS G12C inhibitor. These results suggest that LUNA18 could be a promising candidate for combination therapy with KRAS G12C inhibitors."

Oncology • HRAS • KRAS • NRAS

Anti-tumor activity of orally-available cyclic peptide LUNA18 through direct RAS inhibition in RAS-altered tumors (AACR 2024) - "We orally administered LUNA18 and a KRAS G12C inhibitor to a xenograft model, which showed temporal response and then acquired resistance to a KRAS G12C inhibitor, and found that LUNA18 significantly suppressed emergence of resistance to a KRAS G12C inhibitor. These results supported that the combination of the KRAS G12C inhibitor with LUNA18 could be a promising option to patients with KRAS G12C mutation by suppressing resistance to a KRAS G12C inhibitor through the suppression of rebound of the MAPK pathway."

Oncology • BRAF • HRAS • KRAS • NRAS

Progress made in R&D activities during the period from January 1, 2025 to December 31, 2025 was as follows. (Chugai Press Release) - "We made a management decision to discontinue the in-house development of a RAS inhibitor LUNA18, considering obtained data up to date and the portfolio status. We made a management decision to discontinue the in-house development of an anti-CD137 agonistic switch antibody STA551, considering obtained data up to date and the portfolio status. We made a management decision to discontinue the in-house development of an anti-latent TGF-β1 monoclonal antibody SOF10, considering obtained data up to date and the portfolio status. We made a management decision to discontinue the in-house development of an anti-CLDN6/CD3/CD137 trispecific antibody SAIL66, considering obtained data up to date and the portfolio status."

Discontinued • Gastric Cancer • Non Small Cell Lung Cancer • Ovarian Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Thoracic Cancer

Rational Activity Improvement of Cyclic Peptides through Stabilization and Rigidification of Main Chain Using φ/ψ Plots of Amino Acids. (PubMed, ACS Omega) - "We validated this approach for the derivatization of AP0343 to the clinical KRAS inhibitor LUNA18 and confirmed its utility in an actual drug discovery project. This method is effective for optimizing main chain structures and advancing orally available medium-sized cyclic peptides."

Journal • KRAS

A Dose-escalation Study of LUNA18 in Patients With Locally Advanced or Metastatic Solid Tumors (With Expansion). (clinicaltrials.gov) - P1 | N=128 | Terminated | Sponsor: Chugai Pharmaceutical | N=195 ➔ 128 | Trial completion date: Aug 2026 ➔ Nov 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: May 2026 ➔ Nov 2025; Sponsor decided to discontinue this study upon having LPLV.

Enrollment change • Monotherapy • Trial completion date • Trial primary completion date • Trial termination • Solid Tumor

Overcoming Challenges in the Metabolism of Peptide Therapeutics: Strategies and Case Studies for Clinical Success. (PubMed, J Med Chem) - "Low permeability and bioavailability of peptides are also briefly covered. Case studies, including semaglutide, MK-0616, LUNA18, sulanemadlin, and oxytocin analogs, illustrate successful applications of these strategies, highlighting how rational design and optimization have advanced peptide candidates from discovery to clinical stage."

Journal • Review • Cardiovascular • Diabetes • Metabolic Disorders • Oncology

Impact of the Mucin Barrier on the In Vitro Membrane Permeability of Cyclic Peptides. (PubMed, Eur J Pharm Sci) - "The permeability of paracellular markers (FD4 and LY) and digoxin (a low molecular weight compound) remained unaffected by mucin presence when using biosimilar mucin. Conversely, cyclosporin A, a commercially available cyclic peptide drug, showed reduced permeability...Similarly, the permeability of LUNA18, a cyclic peptide under development, was reduced by 54.1 and 26.0 % in both Caco2/HT29 co-cultured and HT29 cells...These findings suggest that current permeability evaluation methods, which do not account for the mucin layer, may overestimate the permeability of highly lipophilic cyclic peptides. The mucin layer may serve as a rate-limiting factor in cyclic peptide membrane permeability, highlighting the importance of including mucin layer permeability in cyclic peptide evaluation protocols."

Journal • Preclinical

Structural optimization of mid-sized cyclic peptide: From hit to clinical compound (ACS-Fall 2025) - "Through structural optimization, we created Paluratide/LUNA18, a unique mid-sized cyclic peptide...(2) Effective use of phi/psi plots (Ramachandran plots) for semi-quantitative understanding of peptide structure to interpret SAR caused by subtle changes in the peptide main chain. Our findings provide valuable insights into the structural optimization of mid-sized peptides binding to protein-protein interaction interfaces, contributing to the continuous drug discovery of orally available mid-sized cyclic peptides."

Clinical • KRAS

A Dose-escalation Study of LUNA18 in Patients With Locally Advanced or Metastatic Solid Tumors (With Expansion). (clinicaltrials.gov) - P1 | N=195 | Active, not recruiting | Sponsor: Chugai Pharmaceutical | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • Solid Tumor

Peptide inhibitors: Breaking cancer code. (PubMed, Eur J Med Chem) - "Key examples include RAS-targeting peptides such as KRpep-2D, cyclo-CRVLIR, L5UR, RAS-binding peptide (RBP), the mutant KRAS peptide vaccine combined with Nivolumab and Ipilimumab, cyclorasin B4-27, and LUNA18, as well as mTOR-targeting peptides like P1_WT, PDHK1-241aa, TRIM1-269aa, and the micropeptide human small regulatory polypeptide of amino acid response (hSPAR). Among these, the mutant KRAS peptide vaccine (with Nivolumab and Ipilimumab) and LUNA18 demonstrate promising clinical potential and are currently undergoing trials."

Journal • Review • Oncology • Sarcoma • Solid Tumor • KRAS • MID2

A Dose-escalation Study of LUNA18 in Patients With Locally Advanced or Metastatic Solid Tumors (With Expansion). (clinicaltrials.gov) - P1 | N=195 | Recruiting | Sponsor: Chugai Pharmaceutical | Trial primary completion date: Mar 2025 ➔ May 2026

Monotherapy • Trial primary completion date • Solid Tumor

A Dose-escalation Study of LUNA18 in Patients With Locally Advanced or Metastatic Solid Tumors (With Expansion). (clinicaltrials.gov) - P1 | N=195 | Recruiting | Sponsor: Chugai Pharmaceutical | Trial completion date: May 2026 ➔ Aug 2026

Monotherapy • Trial completion date • Oncology • Solid Tumor

A Dose-escalation Study of LUNA18 in Patients With Locally Advanced or Metastatic Solid Tumors (With Expansion). (clinicaltrials.gov) - P1 | N=195 | Recruiting | Sponsor: Chugai Pharmaceutical | Trial completion date: Mar 2025 ➔ May 2026

Trial completion date • Oncology • Solid Tumor

Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display. (PubMed, Bioorg Med Chem) - "LUNA18, a clinical KRAS inhibitor, was transformed-without scaffold hopping-from the initial hit by using an mRNA display library that met our criteria for drug-likeness...Since there are four positions where side chain modification is permissible in terms of activity, it is possible to flexibly adjust the pharmacokinetic profile by structurally optimizing the side chain. The side chain transformation findings demonstrated here may be generally applicable to hits obtained from mRNA display libraries."

Journal • KRAS

Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets. (PubMed, J Am Chem Soc) - "In this study, we validated a new methodology to create oral drugs beyond the rule of 5 for intracellular tough targets by elucidating structural features and physicochemical properties for drug-like cyclic peptides and developing library technologies to afford highly N-alkylated cyclic peptide hits. We discovered a KRAS inhibitory clinical compound (LUNA18) as the first example of our platform technology."

Journal • KRAS

Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor. (PubMed, J Am Chem Soc) - "Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS...This study demonstrates how the chemical optimization of bio-active peptides can be achieved without scaffold hopping, much like the processes for small molecule drug discovery that are guided by Lipinski's rule of five. Our approach provides a versatile new strategy for generating peptide drugs starting from drug-like hits."

Journal • KRAS

Broadly Applicable and Comprehensive Synthetic Method for N-Alkyl-Rich Drug-like Cyclic Peptides. (PubMed, J Med Chem) - "Using this newly established method, we successfully synthesized thousands of cyclic peptides to explore the scope of this modality in drug discovery. We here demonstrate the syntheses of a hundred representative examples, including our first clinical N-alkyl-rich cyclic peptide (LUNA18) that inhibits an intracellular tough target (RAS), in 31% total yield and 97% purity on average after 23 or 24 reaction steps."

Journal