Elevating expectations
ABOUT LIRAFUGRATINIB
Lirafugratinib is a highly selective oral small molecule inhibitor of fibroblast growth factor receptor 2 (FGFR2) being developed for patients with FGFR2-altered cholangiocarcinoma (CCA) and other FGFR2-altered solid tumors1,2
FGFR2 alterations represent approximately 11k-35k patients in the United States per year across several tumor types. Additionally, FGFR2-activating fusions are particularly common in intrahepatic CCA.3-6
Currently, approved targeted therapies for FGFR2-altered solid tumors include pan-FGFR inhibitors that non-selectively inhibit multiple FGFR isoforms resulting in off-target side effects.6
Elevar Therapeutics holds exclusive global rights for lirafugratinib, including all further development and global commercialization activities.7
CLINICAL STUDIES
Lirafugratinib was granted breakthrough therapy designation*, orphan drug designation, and a pediatric study waiver by the FDA.7
- Lirafugratinib is being investigated in the global ReFocus trial in patients with FGFR2-altered tumors (NCT04526106). The patient enrollment was completed. A pivotal cohort of patients with FGFR2-fusion/rearrangement CCA was designed to support NDA submission via the Accelerated Approval Pathway. Interim data from this cohort were presented at the European Society for Medical Oncology (ESMO) Congress in 2022.7
- The study also includes cohorts in patients with other FGFR2-altered solid tumors, including gastric cancer, pancreatic cancer, and NSCLC. Interim data from these cohorts were presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in 2023 and 2024.7
In 2024, a meeting with the FDA was held to discuss data from the ReFocus trial and potential regulatory pathways. The FDA recommended that the company first file an NDA for FGFR2-driven CCA, followed by a supplemental NDA for other FGFR2-altered solid tumors with data from an expanded cohort of patients.7
MECHANISM OF ACTION (MOA) OF LIRAFUGRATINIB
Lirafugratinib is the first potent, highly selective, irreversible small molecule inhibitor of FGFR2. 6,8-10
In this schematic movie, apo FGFR1 (left panel) demonstrates rapid P-loop dynamics, while apo FGFR2 (right panel) displays less P-loop motion. Upon reversible binding of the inhibitor (0:20 seconds) to FGFR1, the P-loop motion is significantly slowed, resulting in an extended P-loop conformation that disfavors formation of a covalent bond between the inhibitor and the P-loop cysteine. In FGFR2, inhibitor binding does not significantly alter the P-loop dynamics, allowing lirafugratinib and P-loop cysteine to achieve sufficient proximity to form a covalent bond.8
Lirafugratinib demonstrated high selectivity for FGFR2 against 468 kinases screened compared with pan-FGFR inhibitors, with minimal off-target inhibition.3,8
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*Breakthrough therapy designation granted for cholangiocarcinoma.
References: 1. Borad MJ, et al. ASCO 2023. Oral (Abstract 4009). 2. Hollebecque A, et al. EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics 2024. Poster 58 PB04. 3. Data on file. Elevar Therapeutics; 2025. 4. Cleary JM, et al. Cancer Discov. 2021;11(10):2488-2505. 5. Krook MA, et al. Br J Cancer. 2021;124(5):880-892. 6. Schönherr H, et al. Proc Natl Acad Sci U S A. 2024;121(6):e2317756121. 7. Elevar Therapeutics. Press release. Accessed May 14, 2025. https://elevartx.com/2024/12/03/elevar-therapeutics-relay-therapeutics-licensing-agreement/. 8. Subbiah V, et al. Cancer Discov. 2023;13(9):2012-2031. 9. Liu PCC, et al. PLoS One. 2020;15(4):e0231877. 10. Sootome H, et al. Cancer Res. 2020;80(22):4986-4997
