Friday, January 1, 2021

Treating achondroplasia: 2020 in review

A tough year

This 2020 was tough, challenging year for all of us. The new coronavirus pandemic has been causing so much disruption in our world and nobody can say when our lives will be back (or close to) normal again.

In a previous article, I mentioned that I didn't want to just keep repeating the same information over and over again here and that was the explanation for not posting more frequently in the blog. I have also mentioned that I keep a Facebook group called Achondroplasia, where followers can stay on top of the newest information about therapies for achondroplasia as they are released to the public. In this sense, the blog Treating Achondroplasia keeps being active, providing more in depth information to all interested people.

Notwithstanding, there have been so many new research developments in the achondroplasia field in 2020 that I thought it would be good to go through them in a short review here. 

Let's start checking out each of the main potential treatments and introducing the new ones announced during the year. In Table 1 you can see their current development status as publicly available. All of them but the tyrosine kinase inhibitor (TKI) ASP-5878 have already been reviewed in the blog. To get more detailed information about these drugs just visit the index page to find those articles.

Table 1. List of potential therapies for achondroplasia.

CNP: C-type natriuretic peptide. RoA: route of administration. SC: subcutaneous. MA: market authorization. TKI: tyrosine kinase inhibitor. NA: not available.


 The main news about vosoritide is that Biomarin has submitted market authorization applications both to the European and American regulatory agencies (EMA and FDA) back in August, with a potential approval estimated to be released in US by August 2021.

Back in September, the developer has published the full results from the phase 3 study (1), which demonstrated a significant improvement in growth velocity with vosoritide compared to placebo after one year. More recently they announced that the improvement in growth velocity has been shown to be sustained after two years of therapy with vosoritide, similar to what has been seen in the long term extension study with the participant of the phase 2 study. Furthermore, the phase 2 study with infants and toddlers (<5 years old) is currently ongoing.

Also recently, they have started a study with vosoritide in other causes of short stature.


The main difference between TransCon-CNP and vosoritide is that TransCon-CNP is delivered through a slow release system allowing a weekly dose with sustained exposure to their analogue in contrast with vosoritide's daily dosing. In pre-clinical studies they showed that their CNP analogue was superior to vosoritide (2).

Ascendis Pharma has started the phase 2 study ACcomplisH with TransCon-CNP and, according with the site they are still accepting candidates.


The original TA-46 molecule has been initially developed by Therachon as a weekly subcutaneous injection (3). Back in September, during the Achondroplasia Research Conference organized by the Chandler Crews Project, we learned that the developer is now working with a daily dosing schedule. In the end of December Pfizer has published the pre-clinical tests performed with recifercept, showing that this molecule is, in fact, the result of modifications made in the original molecule TA-46 developed by Therachon (4). Recifercept is a modified, free form of the fibroblast growth factor receptor 3 (FGFR3) that works as a "ligand trap", capturing FGFR activators before they can bind and activate these receptors, including FGFR3. Without the activators (ligands) FGFR3 would not be as active as expected and this would help restoring bone growth. Two weeks ago, Pfizer announced the start of their phase 2 study.


Infigratinib is an oral TKI initially developed to treat several types of cancer where FGFRs play an important role for the progression of the disease. It works by blocking the FGFRs' signaling cascades inside the cell. Given that an abnormal, overactive FGFR3 is the cause of achondroplasia, investigators sought to find whether infigratinib could be used to treat this skeletal dysplasia. Preclinical studies demonstrated that it indeed rescues bone growth in a mouse model of achondroplasia, in doses much lower than those used in the first studies in cancer (5). They recently presented a poster in the ENDO 2020 meeting with pre-clinical tests performed with infigratinib showing significant improvement of bone growth and no effect on phosphorus metabolism with low doses similar to those intended for clinical trials (6). This is important from the safety standpoint. In those studies they also found that infigratinib was superior to vosoritide. QED has recently started their phase 2 study with infigratinib.



Drug repurposing is a strategy where investigators try to find new therapeutic indications for old drugs. The concept is that its development for the new purpose should be much less expensive and the final drug cost, if approved, would be surely more affordable than the cost of newly created compounds. Meclizine is an old drug that has been used to treat motion sickness for decades. In an effort to find potential treatments for achondroplasia the Japanese group from University of Nagoya leaded by Dr. Kitoh has found that meclizine was able to inhibit the FGFR3 function and to partially rescue bone growth in their animal model (7). They have subsequently conducted a phase 1 study in children with achondroplasia (8). The study showed that meclizine could be suitable for a single daily dose (but this needs to be further explored in subsequent studies). They were planning to start a phase 2 study during 2020, but I couldn't find any updates on the status of this program lately.



 Ribomic has been developing RBM-007, an anti-FGF2 aptamer developed to treat conditions where FGF2 has a relevant role in the mechanism of disease (9). Since FGF2 is considered a key activator (ligand) of FGFR3 and that in achondroplasia FGFR3 is overactive, then if it was less activated by FGF2 perhaps bone growth could be restored. In their website, Ribomic mentions that in preclinical studies RBM-007 indeed rescued bone growth (but I could not find any published article showing their results in a model of achondroplasia). They have already started a phase 1 clinical trial to evaluate this aptamer for achondroplasia.



Astellas Pharma has recently published a study where they explored the use of ASP-5878, a TKI similar to infigratinib, in pre-clinical models to treat achondroplasia (10). They found that the drug was able to improve bone growth, however it was less effective compared to a positive control, a CNP analogue bearing the same structure of vosoritide.



Asubio, a Japanese biotech that was recently incorporated by Daichii-Sankio (DK), was developing another CNP analogue based in the fusion of the active fragment of CNP and a backbone fragment of the hormone ghrelin to help improving the known short half-life of CNP. They have published some studies showing that their molecule was able to improve bone growth in pre-clinical models (11) but I couldn't find any news about this compound in the DK website or in the literature.



1. Savarirayan R et al.
Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lancet 2020; 396 (10257):1070.

2. Breinholt VM et al. TransCon CNP, a Sustained-Release C-Type Natriuretic Peptide Prodrug, a Potentially Safe and Efficacious New Therapeutic Modality for the Treatment of Comorbidities Associated with Fibroblast Growth Factor Receptor 3-Related Skeletal Dysplasias.  J Pharmacol Exp Ther 2019; 370(3): 459-71. Open access.

3. Garcia S et al. Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. Sci Transl Med 2013; 5 (203):203ra124. Open access after registration.

4. Gonçalves D et al. In vitro and in vivo characterization of Recifercept, a soluble fibroblast growth factor receptor 3, as treatment for achondroplasia. PLoS ONE 2020; 15(12): e0244368. Open access.

5. Komla-Ebri D et al. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model. J Clin Invest 2016; 126(5):1871-84. Open access.

6. Demuynck B et al. Support for a new therapeutic approach of using a low-dose FGFR tyrosine kinase inhibitor (infigratinib) for achondroplasia. Approved by but not presented at ENDO 2020 due to COVID-19 pandemics. Acessed on 01-Jan-2021. Open access.

7. Matsushita M et al. Meclozine promotes longitudinal skeletal growth in transgenic mice with achondroplasia carrying a gain-of-function mutation in the FGFR3 gene.  Endocrinology 2015; 156(2):548-54. Open access.

8. Kitoh H et al. Pharmacokinetics and safety after once and twice a day doses of meclizine hydrochloride administered to children with achondroplasia. PLoS ONE 2020;15(4):e0229639. Open access.

9. Ling Jin et al. Dual Therapeutic Action of a Neutralizing Anti-FGF2 Aptamer in Bone Disease and Bone Cancer Pain.  Mol Ther 2016; 24 (11): 1974-1986. Open access.

10. Ozaki T et al. Evaluation of FGFR inhibitor ASP5878 as a drug candidate for achondroplasia. Sci Rep 2020; 10: 20915. Open access.

11. Morozumi N et al. ASB20123: A novel C-type natriuretic peptide derivative for treatment of growth failure and dwarfism. PLoSONE 2019;14(2):e0212680. Open access.

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