Therapeutic focus - Expectations rising for FGF inhibitors

In signing FivePrime Therapeutics’ phase II fibroblast growth factor (FGF) inhibitor, Human Genome Sciences has locked up the most advanced unpartnered candidate in a promising field that seeks to block the action of proteins identified as potent contributors to tumour cell growth.

FGF inhibitors are being mooted largely for solid tumours, but a candidate from Exelixis has been tested for blood cancers, suggesting that hopes for the class are far-reaching. Given that phase III trials of the most advanced compound in the class, Bristol-Myers Squibb’s brivanib, are due to complete this year, some validation may be coming soon.


FGFs play a significant role in proliferation and differentiation of a wide number of human cells. Among their functions is the development of endothelial cells, and thus like vascular endothelial growth factors (VEGFs) play a role in development of blood vessels. It was this theory that Temusi was applying when it stimulated FGF to regrow blood vessels in patients with critical limb ischaemia (Gene therapy suffers another blow as Temusi crashes out, September 23, 2010).

Like VEGF inhibitors, it is hoped that FGFs will serve as an effective target to shut down the uncontrolled cell growth that results in tumour growth; some have suggested that FGFs may even play a role in resistance to VEGF therapy and chemotherapeutic options. If this theory were to be borne out, the potential of FGF inhibition in combination therapies would be clear.

While it is not a big pipeline, nor a particularly far advanced one, the appetite of big pharma and larger biotechs is clear: nearly every candidate in the clinic has an experienced development partner or has come from big pharma’s own laboratories (see table below).

Leader of the pack

Bristol-Myers Squibb has taken a lead in the space with brivanib, also known as BMS-582664. The New York company’s most advanced trial is in liver cancer, comparing the compound plus best supportive care against placebo and best supportive care in patients who have failed on Nexavar.

Final data collection is expected in December 2011 – which puts 2012 as a possibility for a launch, but more likely 2013.

Separately, the Canadian Cancer Society is also trialling brivanib in combination with Erbitux, against Erbitux alone in metastatic colorectal cancer to test the theory that epidermal growth factor receptor (EGFR) and FGF inhibitors together can be more effective than EGFR inhibitors alone. Investigators were scheduled to collect final data on that study in December 2010, but there has been no word on outcome.

That analysts have assigned value to a drug with a so-far unproven theory to support it – although one that is not dissimilar to marketed products - is a sign that there are some expectations of success. Brivanib is forecast to sell $308m in 2016 in the liver cancer indication, giving it a net present value of $1.07bn. Forecasts for 2014 have consistently been around $140m over the last 12 months, suggesting analysts await phase III data in liver cancer before changing their views on the product's potential.

Competitive runners

The only other product with a value attached to it is Novartis’ TKI258, which the Swiss company obtained with its acquisition of Chiron in 2006. The heavily risk-adjusted forecast, not surprising for a product in phase II, puts sales at $70m in 2016. Renal cell carcinoma trials are expected to report in mid-2012, although Novartis has also queued up a liver cancer trial against Nexavar.

FivePrime’s newly partnered FP-1039 – licensed by HGS for $50m and up to $445m in milestones – is in a phase II safety and pharmacokinetic trial in endometrial cancers with the FGF receptor 2 mutation. Final data collection is slated for mid-2012, so important validation of the compound is still a year away.


Exelixis is posing XL228 as a product available for partnering. The California firm reported safety data on the phase I candidate at ASCO in 2010, in multiple myeloma and solid tumours. Two trials are ongoing: one in advanced malignancies and one in chronic myeloid leukaemia or Philadelphia chromosome positive acute lymphocytic leukaemia.

Italy’s Ethical Oncology Sciences began dose ranging studies of E-3810, a VEGF and FGF inhibitor, in July 2010. Final data is expected to be collected in early 2012. Farther down the pipeline, UK firm Astex Technologies appears to be active in the space, with multiple FGF discovery partnerships with Johnson & Johnson.

The FGF pathway is one that has yet to be successfully trod and is looking increasingly attractive for oncology. A clearer view of its promise will be available soon, as several trials report in later this year and throughout 2012.

Fibroblast growth factor inhibitors in development Annual Sales WW ($m)
Product Pharmacological Class Company Originator Estimated launch 2012 2014 2016
Phase III BMS-582664 FGFR & VEGFr kinase inhibitor Bristol-Myers Squibb Bristol-Myers Squibb 2012  10  140  308
Phase II FP-1039 FGF antagonist Human Genome Sciences FivePrime Therapeutics  -  -  -
TKI258 VEGFr 1-3, FGFr 1-3, platelet-derived growth factor receptor (PDGFr) & angiogenesis RTK inhibitor Novartis Chiron 2014  -  20  70
Phase I XL228 FGF, IGF-1R, BCR-ABL & Src tyrosine kinase inhibitor Exelixis Exelixis  -  -  -
AZD4547 FGFR tyrosine kinase inhibitor AstraZeneca AstraZeneca  -  -  -
BGJ398 FGFR & VEGFr kinase inhibitor Novartis Novartis  -  -  -
E-3810 FGFR & VEGFr kinase inhibitor Ethical Oncology Science Advenchen Laboratories  -  -  -

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