FMC-376 / Frontier Medicines - LARVOL DELTA

Frontier Medicines Announces FMC-220, the First Covalent p53 Y220C Activator Development Candidate, with Best-in-Class Potential (GlobeNewswire) - "Frontier’s pipeline of precision medicines continues to progress rapidly, with interim clinical data for FMC-376, an ON+OFF KRAS^G12C inhibitor currently in the Phase 1/2 PROSPER trial, expected 2H 2025."

P1/2 data • Solid Tumor

Phase 1/2 study of FMC-376 an oral KRAS G12C dual inhibitor in participants with locally advanced unresectable or metastatic solid tumors (PROSPER). (ASCO 2024) - P1/2 | "1. AACR 2023 Annual Meeting Discovery of FMC-376 a novel orally bioavailable inhibitor of activated KRAS G12C Kevin Webster, April 16, 2023."

Metastases • P1/2 data • CNS Disorders • Hematological Disorders • Infectious Disease • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

The clinical dual KRASG12C inhibitor FMC-376 has demonstrated potential as both a monotherapy and in combination for the treatment of patients with KRASG12C mutation positive NSCLC (AACR 2024) - "The potential for FMC-376 in the treatment of patients with KRASG12C mutant NSCLC has been assessed in a broad panel of NSCLC PDX models representing settings of sotorasib/adagrasib resistance, in a model of NSCLC CNS-metastasis and in combination with an immune checkpoint inhibitor. Furthermore, FMC-376 has demonstrated activity in combination with an anti-PD-1 mAb in a KRASG12C mutant mouse syngeneic tumor model. Together, these data demonstrate the potential of FMC-376, a next-generation clinical stage dual inhibitor of ON and OFF state KRASG12C, for the treatment of patients with KRASG12C mutant NSCLC as well as other KRASG12C positive tumors."

Clinical • IO biomarker • Monotherapy • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KEAP1 • KRAS

FMC-376 a dual inhibitor of ON and OFF states of KRASG12C is broadly active in PDX models of resistance (AACR 2024) - "This further translates into more durable tumor regressions in vivo in comparison to OFF state inhibitors like sotorasib. In vivo profiling of FMC-376 against a panel KRASG12C mutant patient derived xenograft (PDX) models of NSCLC, CRC and PDAC, has demonstrated that dual inhibition of both ON and OFF KRASG12C leads to complete suppression and regression of tumors carrying a broad spectrum of known genomic and non-genomic (adaptive) drivers of clinical resistance to OFF state KRASG12C inhibitors. FMC-376 a clinical stage dual inhibitor of ON and OFF state KRASG12C has the potential to overcome limitations of single acting and OFF state KRASG12C inhibitors."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDKN2A • HRAS • KEAP1 • KRAS • mTOR • NRAS • PI3K • PTEN • SMARCA4

Frontier Medicines Presents New Data for First-In-Class Dual ON+OFF KRAS G12C Inhibitor FMC-376 at the AACR Annual Meeting (GlobeNewswire) - "Frontier Medicines Corporation...presented new preclinical data on its KRASG12C inhibitor, FMC-376, at the American Association for Cancer Research (AACR) Annual Meeting 2024....Abstract #5948: In preclinical results, FMC-376 is shown to be highly active in models of G12C inhibitor resistance where ON state KRAS G12C is upregulated. FMC-376 is efficacious in KRASG12C mutant containing patient-derived xenograft (PDX) models derived from patients with colorectal cancer (CRC), non-small cell lung cancer (NSCLC) and pancreatic cancer, including tumors derived from heavily-treated patients."

Preclinical • Colorectal Cancer • Non Small Cell Lung Cancer • Pancreatic Cancer

Frontier Medicines Presents New Data for First-In-Class Dual ON+OFF KRAS G12C Inhibitor FMC-376 at the AACR Annual Meeting (GlobeNewswire) - "Frontier Medicines Corporation...presented new preclinical data on its KRASG12C inhibitor, FMC-376, at the American Association for Cancer Research (AACR) Annual Meeting 2024....Abstract #5949: These preclinical data demonstrate FMC-376 overcomes drivers of innate and acquired clinical resistance to OFF state inhibitors of KRASG12C, as demonstrated by robust anti-tumor activity across a broad panel of NSCLC PDX models. The combination of FMC-376 with an immune checkpoint inhibitor also leads to an increased response and survival in preclinical models."

Preclinical • Non Small Cell Lung Cancer

Frontier Medicines to Present Preclinical Data at the American Association for Cancer Research Annual Meeting 2024 (GlobeNewswire) - "Frontier Medicines Corporation...announced new preclinical data for FMC-376, a first-in-class direct dual inhibitor of ON+OFF KRASG12C currently being explored in a Phase 1/2 trial, will be shared at the upcoming American Association for Cancer Research (AACR) Annual Meeting 2024."

Preclinical • Oncology

Frontier Medicines Announces Oversubscribed $80 Million Series C Financing to Support Progress of Clinical-Stage Pipeline (GlobeNewswire) - "Frontier Medicines Corporation...announced the close of an oversubscribed $80 million Series C financing. The financing was co-led by Deerfield Management Company and Droia Ventures, with significant participation from Galapagos NV...as a strategic investor, and contributions from new and existing investors....This Series C financing brings the total capital raised since Frontier’s founding to $235.5 million....Financing proceeds will support the advancement of multiple wholly-owned pipeline programs into clinical studies, including FMC-376. Frontier today announced the first participant dosed in the Phase 1/2 PROSPER clinical trial (NCT 06244771) evaluating FMC-376 in patients with KRASG12C cancers."

Financing • Trial status • Solid Tumor

PROSPER: A Study Evaluating FMC-376 in Participants With KRAS G12C Mutated Solid Tumors (clinicaltrials.gov) - P1/2 | N=403 | Recruiting | Sponsor: Frontier Medicines Corporation | Not yet recruiting ➔ Recruiting

Enrollment open • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor

PROSPER: A Study Evaluating FMC-376 in Participants With KRAS G12C Mutated Solid Tumors (clinicaltrials.gov) - P1/2 | N=403 | Not yet recruiting | Sponsor: Frontier Medicines Corporation

New P1/2 trial • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Discovery of FMC-376 a novel orally bioavailable inhibitor of activated KRASG12C (AACR 2023) - "This results in potent inhibition of RAF1 and PI3Kα effector interactions (IC50 = 0.007 μM for both respectively at 2 h) in contrast to sotorasib or adagrasib (IC50 > 50 and ~ 5 μM respectively). Further evaluation of FMC-376 in vivo has demonstrated rapid and durable KRASG12C target occupancy (>90%) and pathway inhibition in tumors, resulting in regression of CDX/PDX tumor models. FMC-376, an inhibitor of both active and inactive forms of KRASG12C, provides a differentiated mechanism of action with the potential for broader and more durable response in the clinic."

Lung Cancer • Oncology • Solid Tumor • KRAS • PIK3CA

Frontier Medicines Presents New Preclinical Data on its Development Candidate, FMC-376, a Dual KRASG12C Inhibitor, at the 2023 AACR Annual Meeting (GlobeNewswire) - "Frontier Medicines Corporation, a precision medicine company seeking to unlock the proteome to advance breakthrough therapies against otherwise undruggable disease-causing targets, today unveiled new preclinical data on its KRASG12C inhibitor, FMC-376, demonstrating its uniquely differentiated mode of action. FMC-376 is the first product candidate discovered utilizing the Frontier™ Platform....FMC-376 has shown efficacy in vivo in multiple KRASG12C mutant CDX and PDX models, including in non-small cell lung, pancreatic and colorectal cancers. The company anticipates this will translate into substantial increases in objective response rate and duration of response. The Investigational New Drug (IND) filing for FMC-376 is planned for the second half of 2023."

IND • Preclinical • Oncology • Solid Tumor

Frontier Medicines to Spotlight Lead Candidate, Novel Dual KRASG12C Inhibitor FMC-376, and the Frontier Platform at the 2023 AACR Annual Meeting (GlobeNewswire) - "Frontier Medicines Corporation...announced upcoming presentations featuring preclinical data on its novel dual KRASG12C inhibitor FMC-376 and advances from the Frontier™ Platform. These data will be presented at the upcoming American Association for Cancer Research (AACR) Annual Meeting taking place April 14th-19th in Orlando, Florida. Preclinical data unveiling FMC-376’s discovery and unique mode of action will be featured in an oral mini-symposium on Small Molecule Therapeutic Agents on April 16th, followed by a presentation on the Frontier Platform in an April 18th poster session."

Preclinical • Oncology

Discovery of novel dual-acting KRASG12C inhibitors that target both the active and inactive forms of the protein (AACR 2022) - "Dual targeting of both GTP- and GDP-bound KRASG12C results in potent cellular activity in models that are both sensitive (NCI-H358 and MIA PaCa-2) and resistant (NCI-H2122) to adagrasib and sotorasib. Evaluation of dual-acting inhibitors of KRASG12C in vivo demonstrated rapid and > 90% KRASG12C target occupancy, resulting in regression of MIA PaCa-2 tumors. Dual-acting inhibitors of both the active and inactive states of KRASG12C may provide the potential for broader and more durable responses in the clinic."

Lung Cancer • Oncology • Solid Tumor • KRAS • PIK3CA