Wednesday, April 26, 2023

Treating achondroplasia: eleven years online and a view of the future.

I have started this blog in March 2012, around the same time when pioneering initiatives to treat achondroplasia were just beginning to move from the lab desks to clinical development. Since then, the blog has received close to 500K visits!

However, reaching out to the point where we are now, with one treatment approved and being given to many children around the world, and many others in clinical trials, was not exactly easy. 

The cause of achondroplasia, a single point mutation in a key bone growth regulator gene, FGFR3, was identified in 1994 (1) but it was not until 2003 that the first attempts to control the activity of the protein fibroblast growth factor receptor 3 (FGFR3) were published (2). 

Almost 20 years after the discovery of FGFR3 as the cause of achondroplasia, the first potential treatment, vosoritide, was brought to the clinic in 2012, in a phase 1 study with healthy volunteers (NCT01590446) and then, in January 2014, to a phase 2 study which enrolled around 30 children with achondroplasia (NCT02055157) (3). 

That phase 2 study showed that vosoritide was able to partially restore bone growth velocity (3). In the subsequent larger phase 3 trial (4), after two years of treatment, the effects of vosoritide on bone growth in achondroplasia were considered consistent enough to grant its approval by the main drug development regulatory agencies around the world. Many children with achondroplasia are now being treated with vosoritide and there have been plenty of testimonies published in the social media about kids growing faster then they were before they started treatment.

The success of vosoritide attracted other drug developers: at this moment there are at least seven known other potential therapies in development for achondroplasia:

Table 1. List of therapies in development for achondroplasia (not exhaustive).

The above table is an updated version of the one I presented during the ALPE Congress back in October last year (there is another article in the blog about that meeting). Since then, the developers of infigratinib (see here) and TransCon-CNP (see here), have published promising results of their phase 2 studies, which will need to be confirmed in respective phase 3 trials. 

However, not all these initiatives have been successful. Recently, Pfizer, which was developing recifercept for achondroplasia, cancelled the program because the drug was not providing any increment on bone growth in children enrolled in their phase 2 study (see here). 

Meanwhile, Tyra, a small biotech from California, announced positive pre-clinical results of their TYRA-300 in an animal model of achondroplasia and their intention to take that asset to clinical development (see here). 

A search in the literature will also retrieve several other interesting studies evaluating different compounds that seem to have a positive impact on bone growth, directly or indirectly targeting FGFR3.

It's not only about height

I believe that all these work and accomplishments will certainly provide a wide range of benefits for children with achondroplasia. The impaired bone growth that is typical in achondroplasia does not cause only low final stature: there is plenty of evidence that impaired bone growth leads to a series of medical and psychological complications during the life span of affected individuals (5-7). Although it is too early to draw conclusions about any beneficial effects in other aspects linked to impaired bone growth in this skeletal dysplasia, one can estimate that, given these therapies have systemic effect, a decrease in the rate of typical orthopedic complications that affect both children and adults, such as arched legs, spinal stenosis and elbow mobility restrictions, among others, is predictable. 

Moreover, recently published studies have also evaluated quality-of-life (QoL) in children and adults with achondroplasia (5-7). In summary, they report that individuals with achondroplasia have lower QoL indexes compared to those of the general population. The impact on QoL has been linked to challenges with daily function, and also physical and mental health. (6,7). There is an expectation that, by improving the length of the long bones, some routine aspects of daily function such as self-hygiene may also improve. With better mobility and function, it is expected that other QoL indexes will improve as well.

It's not only about achondroplasia

One important concept to have in mind about bone growth is that it depends on an intricate system in which many agents work in concert either increasing or reducing the bone growth pace (you can read more about this in other articles of this blog). The fact is that, possibly influenced by all the progress we see for achondroplasia, there has been more research about the mechanism of action of those many bone growth agents in other skeletal dysplasias, too, including FGFR3.

For instance, we now know that in several skeletal dysplasias where FGFR3 is normal, the respective causative mutations seem to lead to FGFR3 axis over-activity, thus contributing to short stature. This has been already identified in RASopathies such as Noonan Syndrome (8), in Cartilage-Hair dysplasia (9), and in diastrophic dysplasia (10).

Furthermore, in skeletal dysplasias where the C-type natriuretic peptide (CNP) axis is not working, drugs that target FGFR3 directly may have an important role in rescuing bone growth. As you may know, CNP regulates FGFR3 activity in normal conditions; if the CNP axis is down, FGFR3 is free to work at will, thus causing severe bone growth impairment. This crosstalk between FGFR3 and CNP was the basis of the development of vosoritide.

Therefore, it is reasonable to think that there is space for the potential use of therapies directed to control FGFR3 activity in other skeletal dysplasias. In fact, there is already one ongoing study with vosoritide in children bearing other skeletal dysplasias (NCT04219007) such as hypochodroplasia (which is also caused by mutations in FGFR3), RASopathies, certain CNP-related dysplasias, SHOX-related dysplasias and ACAN-related dysplasias. Preliminary results from this study have already been released, too (see here).

The future at our door

As typical in the drug development field, there might be other failures ahead. However, drugs like the CNP analogs and those which directly target FGFR3, such as infigratinib, have been showing promising results in the ongoing studies. There will be more options in a few years ahead.

We are also starting to see research on the gene therapy field. These new generation approaches may, in the future, help to overcome mutations that would otherwise have huge impact on QoL of affected children with many genetic conditions. 

From genetic eye disorders or cystic fibrosis, or Duchenne muscular distrophy, to many other situations which have few to no treatment at all, one can imagine that, when the current technological challenges are resolved, how great it will be to have the possibility to provide a functional gene, for example, to a kid with diastrophic dysplasia. 

Based on the current available data, it is possible to envision a time, not far away from now, where children born with many of the genetic disorders such as skeletal dysplasias will be able to enjoy life as any average kid does.

The Treating Achondroplasia blog

Meanwhile, I will keep publishing news and reviews when relevant information about therapies for achondroplasia - and skeletal dysplasias - becomes available. Thank you for your continued interest in this blog!


1. Rousseau F, Bonaventure J, Legeai-Mallet L, Pelet A, Rozet JM, Maroteaux P, Le Merrer M, Munnich A. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 1994;371(6494):252-4.

2. Aviezer D, Golembo M, Yayon A. Fibroblast growth factor receptor-3 as a therapeutic target for achondroplasia--genetic short limbed dwarfism. Curr Drug Targets 2003;4(5):353-65.

3. Savarirayan R, Irving M, Bacino CA, Bostwick B, Charrow J, Cormier-Daire V, Le Quan Sang KH, Dickson P, Harmatz P, Phillips J, Owen N, Cherukuri A, Jayaram K, Jeha GS, Larimore K, Chan ML, Huntsman Labed A, Day J, Hoover-Fong J. C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia. N Engl J Med 2019;381(1):25-35.

4. Savarirayan R, Tofts L, Irving M, Wilcox W, Bacino CA, Hoover-Fong J, Ullot Font R, Harmatz P, Rutsch F, Bober MB, Polgreen LE, Ginebreda I, Mohnike K, Charrow J, Hoernschemeyer D, Ozono K, Alanay Y, Arundel P, Kagami S, Yasui N, White KK, Saal HM, Leiva-Gea A, Luna-González F, Mochizuki H, Basel D, Porco DM, Jayaram K, Fisheleva E, Huntsman-Labed A, Day J.  Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lancet. 2020;396(10252):684-92.

5. Savarirayan R, Ireland P, Irving M, Thompson D, Alves I, Baratela WAR, Betts J, Bober MB, Boero S, Briddell J, Campbell J, Campeau PM, Carl-Innig P, Cheung MS, Cobourne M, Cormier-Daire V, Deladure-Molla M, Del Pino M, Elphick H, Fano V, Fauroux B, Gibbins J, Groves ML, Hagenäs L, Hannon T, Hoover-Fong J, Kaisermann M, Leiva-Gea A, Llerena J, Mackenzie W, Martin K, Mazzoleni F, McDonnell S, Meazzini MC, Milerad J, Mohnike K, Mortier GR, Offiah A, Ozono K, Phillips JA 3rd, Powell S, Prasad Y, Raggio C, Rosselli P, Rossiter J, Selicorni A, Sessa M, Theroux M, Thomas M, Trespedi L, Tunkel D, Wallis C, Wright M, Yasui N, Fredwall SO. International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia.  Nat Rev Endocrinol 2022 Mar;18(3):173-89.

6. Constantinides C, Landis SH, Jarrett J, Quinn J, Ireland PJ. Quality of life, physical functioning, and psychosocial function among patients with achondroplasia : a targeted literature review. Disab Rehabil 2022;44(21):6166-78.

7. Yonko EA, Emanuel JS, Carter EM, Raggio CL. Quality of life in adults with achondroplasia in the United States. Am J Med Genet A 2021;185(3):695-701.

8. Ono K, Karolak MR, Ndong Jde L, Wang W, Yang X, Elefteriou F.The ras-GTPase activity of neurofibromin restrains ERK-dependent FGFR signaling during endochondral bone formation. Hum Mol Genet. 2013;22(15):3048-62.

9. Chabronova A, van den Akker GGH, Meekels-Steinbusch MMF, Friedrich F, Cremers A, Surtel DAM, Peffers MJ, van Rhijn LW, Lausch E, Zabel B, Caron MMJ, Welting TJM. Uncovering pathways regulating chondrogenic differentiation of CHH fibroblasts Non-coding RNA Res 2021;6(4):211-24. 

10. Zheng C. Lin X, Xu X, Wang C, Zhou J, Gao B, Fan J, Lu W, Hu Y, Jie Q, Luo Z, Yang L. Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias. EBioMedicine. 2019 Feb;40:695-709. 

Tuesday, November 15, 2022

Treating achondroplasia: Ascendis releases outcomes of the phase 2 study with TransCon-CNP

The ACcomplisH trial

 On November 13th, Ascendis Pharma released top line results of the ongoing phase 2 study with TransCon-CNP, an analog of c-type natriuretic peptide (CNP) wrapped in a transport molecule to allow slow-release and extend the half-life of the analog. 

Let's pause here for a moment as in this first sentence there is a lot of information already. 

In other words, TransCon-CNP is a competitor of vosoritide. The main difference between them is that the CNP analog from Ascendis uses a kind of taxi: its CNP analog is covered by a molecule that serves as a protection against the body clearance systems, so it has an extended time to exert its actions. The taxi allows the Ascendis CNP analog to be given just once a week as opposed to vosoritide, which needs to be administered daily.

As typical of phase 2 studies, the ACcomplisH trial was designed to evaluate several different doses to TransCon-CNP in order to define which one would have the best safety/efficacy profile.

In summary, these are the headlines directly from Ascendis press release

  • In the Phase 2 ACcomplisH Trial in children with achondroplasia aged 2-10, once-weekly TransCon CNP demonstrated the potential to meet patient and caregiver needs for a safe, effective, tolerable, and convenient treatment
  • The primary endpoint, annualized height velocity (AHV) at Week 52, demonstrated superiority of TransCon CNP at 100 μg/kg/week compared to placebo (p=0.0218)
  • TransCon CNP was generally well tolerated with low frequency of injection site reactions; all 57 randomized children continued, with the longest treatment duration beyond two years
  • Data showed robust and consistent results in prespecified analyses across age groups and dose levels, supporting continued development at the selected dose of 100 μg/kg/week


Three of the four doses tested lead to growth improvement but only the highest one was found to be significantly superior to placebo (Table 1).

It is important to learn that TransCon-CNP worked similarly in all age groups tested.

Table 1. Efficacy of TransCon-CNP weekly doses (from the AComplisH study presentation).



The press release informs us that TransCon-CNP was well tolerated. Most of the few adverse events reported were related to local injection site reactions.

Next steps

Based on the results of this study Ascendis informed that they are in conversations with regulators and also enrolling patients in their phase 2B study to further investigate the chosen dose for achondroplasia (100 µg/kg/week).


As we can see in Table 1, children  the highest dose of TransCon-CNP on average grew 1.07cm (24.6%) more than those in placebo. This is lower than what was obtained with vosoritide in its phase 3 study (1,2), which you can see below (transcript from the original publication;(2)):

  • In the placebo-controlled study, children randomized to treatment with vosoritide increased annualized growth velocity to 5.96 (1.51) cm/year at 26 weeks and 5.39 (1.87) cm/year at 52 weeks. In children randomized to placebo the annualized growth velocity was 4.08 (1.36) cm/year at 26 weeks and 3.81 (1.31) cm/year at 52 weeks.

Based on what we have already seen with vosoritide trials, one aspect to have in consideration is that there is a large variability of response to treatment (just look at the growth ranges among the treated groups in Table 1). This was also seen in vosoritide studies. 

The population treated in the phase 2 study with TransCon-CNP is considerably smaller than the one in the phase 3 vosoritide trial, but the results show the potential efficacy of the chosen dose that we would expect in the ongoing phase 2B study. It would be interesting to learn why the developer did not consider evaluating a higher dose of TransCon-CNP, as it is possible that its optimal dose (efficacy+safety) might not have been identified yet.

One relevant advantage of TransCon-CNP is its weekly dosing schedule, which would be likely considered more comfortable by parents and individuals than vosoritide's daily injection. 

Finally, if TransCon-CNP would be able to provide consistent growth in longer term (as we might see in the next step of its clinical development), and taking in account that it has been showing to work positively in younger kids, it might become a fair option to vosoritide in the future, even if the nominal growth increment was lower in the phase 2 study compared to the already approved treatment.


 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; Oct 10;396(10257):1070. Free access.

2.  Savarirayan R et al. Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study. Genet Med 2021 Dec;23(12):2443-47. Free access.