3:23 PM
Apr 06, 2017
 |  BC Innovations  |  Targets & Mechanisms

Competing for growth

Therachon and BioClin hope FGFR3 blockers can outlast BioMarin’s vosoritide

Editor's Note: This article was updated on Apr 07, 2017 at 12:32 PM PDT

With little in the clinical pipeline for achondroplasia beyond BioMarin Pharmaceutical Inc.’s late-stage vosoritide, startups Therachon AG and BioClin Therapeutics Inc. are rethinking how to tackle the disease. By targeting FGFR3 directly, the two companies think they can block a signal vosoritide misses, and produce compounds that have better efficacy and require less frequent dosing.

The field appears poised for an uptick of activity, triggered by BioMarin’s positive Phase II data and recent publications that validate the FGFR3 biology underlying the disorder.

Achondroplasia is the most common form of short-limb dwarfism, and is caused by a single point mutation in FGFR3 that constitutively activates the receptor and inhibits bone growth. The treatment landscape involves either painful limb-lengthening surgery or, typically, a one-year course of human growth hormone, which has limited benefit.

BioMarin’s approach is to block a downstream mediator in the FGFR3 pathway that is responsible for chondrocyte growth. Its candidate, vosoritide, is a stable analog of the peptide agonist CNP that acts via the cell surface receptor NPR2 to inhibit a ras-driven cascade downstream of FGFR3. In December, BioMarin initiated a Phase III trial of vosoritide in patients aged 5-14.

Ascendis Pharma A/S is taking a similar approach with its TransCon CNP, a sustained-release prodrug of CNP. The company plans to submit an IND this year.

By contrast, Therachon and BioClin are targeting FGFR3 activity directly, which allows them to block chondrocyte proliferation as well as growth (see “A Fork in the Road”).

Figure: A fork in the road

Achondroplasia, a monogenic disease characterized by short stature and a variety of skeletal growth-related co-morbidities, is caused a by a single point mutation in FGFR3 that causes constitutive receptor activation leading to decreased bone growth.

In the bone growth plate, chondrocyte proliferation, growth & maturation and matrix production occur progressively. FGFR3 is a transmembrane receptor tyrosine kinase (RTK) with three extracellular immunoglobulin domains, a transmembrane domain and two intracellular RTK regions, and is only expressed on the surface of proliferating and maturing chondrocytes. After binding its FGF8 and FGF19 ligands (green circles), which are secreted by the pericardium, FGFR3 signals through a branched cascade to inhibit chondrocyte proliferation and growth.

One signaling pathway activates an intracellular kinase cascade involving Ras, CRAF, MEK and MAPK, which activate the transcription factor SOX9 that suppresses chondrocyte growth.

Other signals are transduced by cytoplasmic STAT1, PP2A and RBL1, which ultimately activates nuclear STAT1 to inhibit chondrocyte proliferation.

BioMarin Pharmaceutical Inc. (NASDAQ:BMRN)'s Phase III candidate vosoritide...

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