paluratide (LUNA18) / Roche - LARVOL DELTA

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

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

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

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