LUNA18 / Roche - LARVOL DELTA

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