PRN1371 / Sanofi - LARVOL DELTA

PRN1371, an irreversible, covalent inhibitor of FGFR1-4 exhibits sustained pathway inhibition in cancer cell lines (AACR 2017) - P1; "PRN1371 is a potent, highly selective irreversible inhibitor exhibiting sustained inhibition of FGFR signaling across cancer cell lines harboring different FGFR alterations. The duration of inhibition of the downstream signaling was comparable across cancer cell lines harboring different FGFR alterations, including mutations, fusions and amplification of FGFR and was prolonged when compared to a non-covalent inhibitor. A Phase 1 clinical trial of PRN1371 for the treatment of solid tumors harboring FGFR alterations is ongoing (NCT02608125)."

Biosimilar • Oncology • Renal Disease

Structural insights into the potency and selectivity of covalent pan-FGFR inhibitors. (PubMed, Commun Chem) - "In addition, the co-crystal structures of SRC/FIIN-2, SRC/TAS-120 and FGFR4/PRN1371 complexes reveal structural basis for kinase targeting and gatekeeper mutations. Taken together, our study not only provides insight into the potency and selectivity of covalent pan-FGFR inhibitors, but also sheds light on the development of next-generation FGFR covalent inhibitors with high potency, high selectivity, and stronger ability to overcome gatekeeper mutations."

Journal • FGFR4

A phase 1, multicenter, dose-escalation study of PRN1371, an irreversible covalent FGFR1-4 kinase inhibitor, in patients with advanced solid tumors, followed by expansion cohorts in patients with FGFR genetic alterations. (ASCO 2017) - P1; "Circulating tumor DNA from patients at baseline and during follow up is analyzed for FGFR genetic alterations. Pre and on-treatment tumor biopsies in Part B will be tested for a panel of pharmacodynamic biomarkers of FGFR inhibition."

Biomarker • Biosimilar • Oncology

A Dose Escalation Study in Solid Tumors and a Dose Expansion Study of PRN1371 in Adult Patients With Metastatic Urothelial Carcinoma (clinicaltrials.gov) - P1; N=45; Terminated; Sponsor: Principia Biopharma Inc.; Trial completion date: Feb 2021 ➔ Jun 2020; Active, not recruiting ➔ Terminated; Trial primary completion date: Dec 2020 ➔ Jun 2020; focus portfolio on immune-mediated diseases

Trial completion date • Trial primary completion date • Trial termination • Oncology • Solid Tumor • Urothelial Cancer • FGF23 • FGFR

Discovery of the Irreversible Covalent FGFR Inhibitor 8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido2,3-dpyrimidin-7(8H)-one (PRN1371) for the Treatment of Solid Tumors. (PubMed, J Med Chem) - "An irreversible covalent binding mechanism imparts many desirable pharmacological benefits including high potency, selectivity, and prolonged target inhibition. Herein we report, the structure-based design, medicinal chemistry optimization and unique ADME assays of our irreversible covalent drug discovery program which culminated in the discovery of compound 34 (PRN1371), a highly selective and potent FGFR1-4 inhibitor."

Journal • Biosimilar • Bladder Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

A Dose Escalation Study in Solid Tumors and a Dose Expansion Study of PRN1371 in Adult Patients With Metastatic Urothelial Carcinoma (clinicaltrials.gov) - P1; N=9; Active, not recruiting; Sponsor: Principia Biopharma Inc.; Recruiting ➔ Active, not recruiting; N=50 ➔ 9

Clinical • Enrollment change • Enrollment closed • FGF23

Principia announces expansion of its BTK franchise with PRN473 topical (GlobeNewswire) - "The company also announced suspension of PRN1371, an FGFR inhibitor for bladder cancer to focus the portfolio on immune-mediated diseases."

Pipeline update

The role of fibroblast growth factor receptor (FGFR) protein-tyrosine kinase inhibitors in the treatment of cancers including those of the urinary bladder. (PubMed, Pharmacol Res) - "Similarly, dovitinib, AZD4547, CH5183284, infigratinib, lenvatinib, LY2874455, and lucitanib are type I½ inhibitors...Ponatinib binds to FGFR4 in a DFG-D conformation and is classified as a type II inhibitor. Futibatinib, roblitinib, H3B-6527, fisogatinib, and PRN1371 bind covalently to their FGFR target and are classified as type VI inhibitors. Nintedanib, pazopanib, pemigatinib, rogaratinib, and PRN1371 are FGFR inhibitors lacking drug-enzyme crystal structures...The development of FGFR inhibitors has lagged behind those of other receptor protein-tyrosine kinases. However, the FDA approval of erdafitinib for the treatment of urinary bladder cancers may stimulate additional work targeting the many other FGFR-driven neoplasms."

Journal • Review • CSF1R • FGF23 • FGFR1 • FGFR4 • FLT1 • FLT3

Principia Presents Phase 1 Data of PRN1371 in Patients with Metastatic Bladder Cancer (GlobeNewswire, Principia Biopharma Inc.) - P1, N=36; NCT02608125; Sponsor: Principia Biopharma; "FGFR inhibitor PRN1371 well tolerated in 36 patients in dose-escalation phase; dose expansion in metastatic urothelial carcinoma patients ongoing --. (Nasdaq: PRNB), a late-stage biopharmaceutical company dedicated to bringing transformative oral therapies to patients with significant unmet medical needs in immunology and oncology, today announced data from its Phase 1, multicenter, dose-escalation clinical trial of PRN1371, an irreversible covalent FGFR1-4 kinase inhibitor, in patients with advanced solid tumors."

Clinical • Clinical data

Principia Biopharma reports fourth quarter and full year 2018 financial results (Nasdaq) - "PRN1371 for the treatment of bladder cancer: (i) Completed Phase 1 dose escalation; (ii) Initiated Phase 1 expansion cohort in patients with metastatic urothelial carcinoma; Potential PRN1371 milestone: Phase 1 dose escalation data: first half of 2019."

P1 data • Trial status

A Dose Escalation Study in Solid Tumors and a Dose Expansion Study of PRN1371 in Adult Patients With Metastatic Urothelial Carcinoma (clinicaltrials.gov) - P1; N=50; Recruiting; Sponsor: Principia Biopharma Inc.; Active, not recruiting ➔ Recruiting; Trial completion date: Dec 2019 ➔ Feb 2021; Trial primary completion date: Dec 2019 ➔ Dec 2020

Clinical • Enrollment open • Trial completion date • Trial primary completion date