Ficlatuzumab (anti-HGF IgG1 mAb)

Ficlatuzumab (also known by its research code AV-299) is a potent humanized IgG1 monoclonal antibody that targets hepatocyte growth factor, or HGF. The HGF/cMET pathway is implicated as an escape mechanism for epidermal growth factor receptor, or EGFR, blockade. By binding to the HGF ligand with affinity and specificity, ficlatuzumab has demonstrated differentiated inhibition of HGF/cMET downstream signaling and demonstrated a strong additive anti-tumor effect in preclinical studies and early clinical trials.

Ficlatuzumab in HNSCC

Ficlatuzumab has been granted Fast Track designation by the FDA for the evaluation of ficlatuzumab in combination with cetuximab for the treatment of patients with human papillomavirus, or HPV, negative recurrent or metastatic, or R/M, head and neck squamous cell carcinoma, or HNSCC, patients.

Results from a randomized confirmatory Phase 2 study of ficlatuzumab as a single agent or in combination with cetuximab (ERBITUX®), an EGFR-targeted antibody, in patients who relapsed or were refractory to prior immunotherapy, chemotherapy, and cetuximab (pan-refractory) with R/M HNSCC demonstrated that the ficlatuzumab and cetuximab combination arm met the study’s primary endpoint of median progression free survival (PFS), with the 32 evaluable patients in the arm demonstrating a median PFS of 3.6 months. Patients with HPV negative disease, which is associated with poorer outcomes compared to HPV positive disease, who received the combination demonstrated prolonged PFS (4.1 months) and a response rate of 38%, which included 18% complete responses. See study results

Assuming the timely manufacturing of ficlatuzumab, the availability of financial resources or a strategic partner with adequate funding, and the ability to finalize the trial design with the FDA under the Fast Track designation, AVEO expects to initiate a potential registrational clinical trial of ficlatuzumab in combination with cetuximab in patients with HPV negative HNSCC in the first half of 2023.

Ficlatuzumab in other indications

Ficlatuzumab has also been studied in combination with chemotherapy in pancreatic cancer and acute myeloid leukemia in early stage clinical trials. Both studies demonstrated promising efficacy activity and an acceptable tolerability profile. AVEO continues to evaluate additional opportunities for further clinical development of ficlatuzumab in these therapeutic areas.

HGF/cMET as a Therapeutic Target

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HGF is the sole ligand for the c-MET receptor and this pathway is frequently dysregulated in a broad range of human cancers. HGF binding with c-MET can activate multiple intracellular signaling pathways and lead to both tumor growth and metastatic progression of cancer cells. HGF-induced MET activation is also an escape mechanism for EGFR inhibition, leading to resistance. Ficlatuzumab has demonstrated differentiated inhibition of HGF.

  • High affinity (pM) and slow off-rate for HGF
  • High potency (nM) inhibiting all biological activities of HGF, including autocrine/paracrine activation loops

Ficlatuzumab is an investigational drug and has not yet been approved by the FDA.