Russian Pharmaceutical Technologies LLC is a research and development company focused on transforming innovative scientific discoveries into novel therapeutic agents.
Brief company description
City and country: Saint-Petersburg, Russian Federation
Date of foundation: 12 April 2012
Residence status: Skolkovo Foundation Resident, Moscow
Team: Russian and World experts in oncology and drug development
Brief product description
Product: Alofanib, allosteric inhibitor of fibroblast growth factor receptor 2
Indication: FGFR2-expressing tumors
Stage of development: application for Phase 1 approval /Ministry of Health/
Expected date of Phase 1 clinical study: April 2017
RPT835 is first allosteric FGFR2 inhibitor in oncology
Allosteric inhibitors decrease activity of receptor by binding an allosteric site at the receptor (that is, a site other than the receptor's active site). There are no approved allosteric targeted agents in oncology.
Alofanib (RPT835) is a low-molecular weight allosteric inhibitor of FGFR2.
Principle benefits of allosteric inhibitors:
High specificity | Low toxicity | Cells with mutations sensitive to treatment |
Different isoforms of receptor could be targeted |
Alofanib binds to allosteric site of extracellular part of FGFR2 and changes the conformation of receptor
Characterisation and comparison of RPT835
The preclinical data obtained with RPT835 are consistent with potent inhibition of FGF signaling, angiogenesis, and cancer growth. Results were presented at the different international meetings
Fibroblast Growth Factor Receptor 2 as a target for RPT835
The recent identification of fibroblast growth factor receptor 2 (FGFR2) overexpression or mutations in different cancer types has generated an opportunity for a novel target-based therapy.
ESMO Asia 2016: First-in-class inhibitor of FGFR2 shows promising results in preclinical studies
SINGAPORE – A novel allosteric fibroblast growth factor receptor 2 (FGFR2) inhibitor, alofanib, has potent anti-tumour and antiangiogenic activity, according to the results of preclinical studies.
The results were presented at the ESMO Asia 2016 Congress in Singapore on December 16-19, 2016 (Abstract 151O). The data provided a strong rationale for the evaluation of the compound in patients with FGFR2-expressing cancers.
“Alofanib is a novel first-in-class allosteric small-molecular inhibitor of FGFR2. The compound binds to the extracellular domain of FGFR2 and has an inhibitory effect on FGF2-induced phoshphorylation,” said lead author Ilya Tsimafeyeu, MD, PhD, director of the Kidney Cancer Research Bureau and scientific adviser of Ruspharmtech LLC (Russia).
“The in vivo data are consistent with alofanib being a predominantly FGFR-selective inhibitor. In preclinical xenograft models, alofanib significantly inhibited aggressive growth of FGFR2 high-expressing triple-negative breast cancer and had moderate activity in the FGFR2 low-expressing triple-negative breast cancer. Treatment with alofanib did not result in FGFR2-negative lung cancer growth. Accordingly, we believe that alofanib is capable of clinically testing an FGFR tumour-driven hypothesis, aiming to select patients based on deregulated tumour FGFR2 expression,” said Tsimafeyeu.
“There is compelling evidence for deregulated FGF/FGFR2 signalling in the pathogenesis of many cancers that originate from different tissue types, for example, gastric and endometrial cancers. This study provides the first pharmacologic profile of the allosteric inhibitor alofanib with potential as a targeted antitumour therapy,” said Olivier Rixe, MD, PhD, professor of the division of hematology/oncology and associate director for clinical research, The Dana Wood endowed chair in cancer therapeutics and early phase clinical research, University of New Mexico Comprehensive Cancer Center (U.S.)
In the present study, authors showed that alofanib inhibited phosphorylation of FRS2α with IC50 values of 7 and 9 nmol/L in cancer cells expressing different FGFR2 isoforms (IIIc and IIIb). In a panel of cell lines representing several tumour types (triple negative breast cancer, melanoma, ovarian cancer), alofanib inhibited FGF-mediated proliferation.
Alofanib dose dependently inhibited the proliferation and migration of human and mouse endothelial cells (GI50 11-58 nmol/L) compared with brivanib and bevacizumab. Treatment with alofanib ablated experimental FGF-induced angiogenesis in vivo.
In a FGFR-driven human tumour xenograft model, oral administration of alofanib was well tolerated and resulted in potent anti-tumour activity. Importantly, alofanib was effective in FGFR2-expressing models. For example, alofanib significantly inhibited aggressive growth of triple-negative breast cancer tumour xenograft (SUM 52PE).
The tumour growth curve shows a nearly exponential increase in the median tumour volume up to day 31 in the vehicle group and a high rate of slow-growing tumours up to day 40 in the alofanib group.
Early data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased anti-tumour activity. FGFR2 amplification and high-level polysomy may be a promising molecular target for serous ovarian cancer. FGFR2 amplification was found in 17.1 percent of patients with advanced serous ovarian cancer. Thus, the aim of the presented xenograft studies was to increase the efficacy of chemotherapy by adding the alofanib FGFR2 inhibitor.
As expected, intravenous alofanib significantly potentiated the efficiency of the combination of paclitaxel and carboplatin. A daily intravenous regimen resulted in a three-fold tumour growth delay in comparison with the vehicle, and an inhibition rate of 80 percent was achieved.
The proliferative index Ki-67 was significantly reduced in mice treated with alofanib. In this study, antiangiogenic activity in an ovarian carcinoma model using a combination of alofanib and chemotherapy was observed. Alofanib decreased the number of vessels by 49 percent and initiated vascular changes in the tumours.
“In acute and chronic toxicity studies, alofanib was well-tolerated,” said Dr. Tsimafeyeu.
“There was no treatment-related mortality, severe toxicity or significant changes to the organs in the six-month study. Body weight remained stable and it was comparable to vehicle groups. We found new side effects such as the suppression of spermatogenesis. Spermatocytes express FGFR2, and theoretically alofanib could inhibit the proliferation of these cells,” he said.
“A phase Ib clinical study protocol has been selected for the ECCO-AACR-EORTC-ESMO Workshop on Methods in Clinical Cancer Research, better known as the ‘Flims’ Workshop, and a clinical study will be initiated at the beginning of 2017,” said Dr. Tsimafeyeu.
The studies were supported by a grant from the Skolkovo Foundation.