Spotlight – Seeking target selectivity in achondroplasia

As Bridgebio appears to validate FGFR3 as a target in achondroplasia, who else might follow suit?

If infigratinib’s use in achondroplasia has given Bridgebio a new lease of life, a similar claim could be made about Tyra Biosciences, a little-known biotech whose TYRA-300 has a related mechanism of action. As luck would have it, just seven days ago Tyra vowed to put TYRA-300 into the clinic in achondroplasia, and its stock has risen 24% since Friday.

Still, a trial will not start for well over a year, and in the meantime companies that also have assets targeting FGFR might take a second look at their projects’ selectivity for the FGFR3 isoform, whose mutation is said to cause achondroplasia. Among these Lilly’s LOXO-435 could be promising, though Sanofi and a few others also have anti-FGFR3 assets.

The relevance of this mechanism in achondroplasia involves a mutation known as G380R, which causes activation of FGFR3. Because FGFR3 is thought to inhibit chondrocyte proliferation its excessive activity results in the short stature evident in people with achondroplasia.

The industry pipeline is full of molecules with broad activity against FGFR1-4, the vast majority in development for cancer. This includes Bridgebio’s own infigratinib, which as Truseltiq was approved for cholangiocarcinoma, though it is no longer being sold. Incyte’s Pemazyre and Otsuka’s Lytgobi carry the same indication, while Johnson & Johnson’s Balversa is approved in bladder cancer.

The importance of selectivity

However, broad FGFR1-4 activity carries serious toxicities, including hyperphosphataemia and liver enzyme elevations. One mystery about the win in the Propel2 trial on Monday is how Bridgebio managed to dose infigratinib low enough to avoid the toxicity due to its broad FGFR targeting, yet still saw sufficient activity on FGFR3 to result in an effect on achondroplasia.

It could be argued that a project with far greater FGFR3 selectivity could have a wider therapeutic window, and by being dosed higher could show an even better effect on achondroplasia than infigratinib. This is where Tyra’s TYRA-300 and Lilly’s LOXO-435 come in: these are said to have up to 63 and 361-fold respective selectivity for FGFR3 versus other FGFR isoforms, according to preclinical data.

However, both are being studied in FGFR3-mutant cancers, and Lilly has not suggested achondroplasia as a target for LOXO-435. Tyra came up with a plan for the short stature indication this month, but while playing up TYRA-300’s FGFR3 selectivity it said it would not get around to submitting an IND filing for a phase 2 achondroplasia trial until 2024.

Clinical projects with purported FGFR3 selectivity…
Project Company Mechanism Status
Recifercept Pfizer (ex Theracon) Soluble FGFR3 (decoy) Failed ph2 in achondroplasia
TYRA-300 Tyra Biosciences Anti-FGFR3 TKI Ph1/2 in FGFR3-mutant cancers
FPI-1966 Fusion Pharmaceuticals Anti-FGFR3 MAb alpha emitter (vofatamab-Ac-225) Ph1/2 in FGFR3-mutant cancers
Vofatamab Fusion (ex Rainier Therapeutics) Anti-FGFR3 MAb Ph1/2 cancer trials terminated
LOXO-435 Lilly (ex Loxo) Anti-FGFR3 TKI Ph1 in FGFR3-mutant cancers
SAR442501 Sanofi Anti-FGFR3 MAb Ph1 for achondroplasia (no entry)
Note: TKI=tyrosine kinase inhibitor. Source: Evaluate Pharma &

It is worth mentioning a few other FGFR3-specific industry assets. In achondroplasia Pfizer had been developing recifercept, a soluble FGFR3 acting as a “decoy” receptor to sequester FGFR3 ligands. However, this failed an interim phase 2 analysis, and Pfizer discontinued it in January.

Two anti-FGFR3 MAbs, Sanofi’s SAR442501 and Rainier’s vofatamab, have apparently been studied. Sanofi reportedly took the former into phase 1 for achondroplasia in 2020, but this has not appeared in clinical trial registries. The latter has been discontinued in cancer and acquired by Fusion Pharmaceuticals, which has souped it up with actinium-225 and is studying it as a radiopharmaceutical in oncology.

Still, even if an antibody approach were to succeed in the clinic its commercial chances would be seriously hampered by injectable dosing; achondroplasia already has an approved treatment, Biomarin’s SC Voxzogo, and a key potential advantage of infigratinib is oral dosing.

Of course, another possibility is that companies with assets across FGFR isoforms start looking at some of these in achondroplasia. After all, infigratinib is not selective for FGFR3, so if Bridgebio can find a therapeutic window perhaps others can too.

…and some TKIs with pan-EGFR activity
Project Company Target Status
Balversa (erdafitinib) J&J FGFR1-4 Approved for 2nd-line, FGFR2/3-altered bladder cancer
Lytgobi (futibatinib) Taiho (Otsuka) FGFR1-4 Approved for 2nd-line, FGFR2-mut cholangiocarcinoma
Pemazyre (pemigatinib) Incyte FGFR1-3 Approved for 2nd-line, FGFR2-mut cholangiocarcinoma
Truseltiq (infigratinib) Bridgebio FGFR1-3 Approved for 2nd-line, FGFR2-mut cholangiocarcinoma (promotion discontinued)
E7090 Eisai FGFR1-3 Ph2 in FGFR2-mut cholangiocarcinoma
HMPL-453 Hutchmed FGFR1-3 Ph2 in FGFR2-mut cholangiocarcinoma & mesothelioma
3D-185 3D Medicines FGFR1-3 Ph2 in cholangiocarcinoma
Gunagratinib (ICP-192) Innocare FGFR1-4 Ph2 in FGFR-mut solid tumours
Derazantinib Merck & Co (ex Arqule) FGFR1-3 Ph2 in cancer (discontinued by Basilea)
ABSK091/ AZD4547 Abbisko (ex Astrazeneca) FGFR1-3 Ph1/2 in FGFR2/3-mutant bladder cancer
KIN-3248 Kinnate Biopharma FGFR1-4 Ph1 in FGFR2/3-mutant bladder cancer & cholangiocarcinoma
CPL304110 Celon Pharma FGFR1-3 Ph1 in solid tumours
ABSK121 Abbisko Therapeutics FGFR2-3 Ph1 in solid tumours
Note: excludes projects with broad TKI activity beyond FGFR. Source: Evaluate Pharma &

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