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 more.

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 conditions 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!

 References

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. 

 

 

 

 

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
  

 Efficacy

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).

 

Safety

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).

Context

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.

References

 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.

Treating Achondroplasia: ten years online. A review of the current achondroplasia therapy landscape

Ten years in a row

The blog Treating achondroplasia is celebrating 10 years online. I have not been posting as often as some years ago but I keep my eyes open to all new relevant information that comes to the field and share them with the interested reader here. 

Ten years ago, I started this blog with the main objective of translating the hard jargon that is typical in scientifc publications into a more relatable language that could be accessible to all. The blog has received more than 430K visits since its launch and I hope it has been a helpful source of information for you.

So, to start this new year (I know, it's already February) I want to share with you an updated review about therapies for achondroplasia that I prepared for Fundación Alpe (Gijón, Spain). Alpe is one of the world's strongest advocacy groups for acondroplasia and skeletal dysplasias and you can find the original article translated to Spanish here. This review provides you with high level information about all drugs that are known to be (or could be) in clinical development for the treatment of achondroplasia. You can find more details about them here in the blog: you just need to search for them in the index page.

Nevertheless, the research for therapies does not stop with the drugs listed in Table 1 below. New therapeutic approaches are being explored that we will be reviewing in the next blog's article.

Thank you for your interest in the Treating Achondroplasia blog!

An update of the therapies for achondroplasia

Note: this review has been prepared originally for Fundación Alpe.

Achondroplasia is the most common form of short-limbed dwarfism. This skeletal dysplasia is caused by a single point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, which in turn encodes the protein FGFR3, which is located across the cell membrane of the chondrocytes (1). Upon binding of its ligands (the FGFs), it is activated and drives several important cell functions (Figure 1).

FGFR3 has a key role in bone development by regulating the growth plate cartilage function. FGFR3 helps regulating bone growth by, like a brake in a car reducing its speed, counteracting the effect of many other agents which, as the car accelerator, promote bone growth (1). Without FGFR3, bones would elongate without control causing several medical complications (2). In achondroplasia, however, because of the mutation, FGFR3 is working a little too much thereby impairing bone growth (1). More potent mutations in FGFR3 lead to significantly more severe, sometimes lethal forms of skeletal dysplasia.

The consequences of the FGFR3 mutation are well known and go beyond the short stature typical of achondroplasia. Sudden death and neurological problems in early infancy, sleep apnea, recurrent ear infections and multiple orthopedic complications among others throughout life, not to mention significant impact on the quality-of-life, have been already extensively documented in many studies (3,4).

Since the mutation was discovered much has been learned about how it causes achondroplasia. Scientists started thinking and investigating how to control or reduce the activity of FGFR3 to help restoring bone growth. For instance, one of the first objective attempts to target FGFR3 for the treatment of achondroplasia was explored by the group led by Dr. Avner Yayon, who developed an antibody that could block FGFR3 and its activation (5). Unfortunately, FGFR3 works, as we saw above, in the growth plate cartilage, a very special tissue located within the very ends of each of our bones. The growth plate cartilage is a dense tissue that does not receive direct blood supply and these singular features prevent large molecules to transit inside it. As antibodies are very large molecules, in contrast to their vast use in treating many other diseases and in particular cancer, they couldn’t reach their target (FGFR3) in the growth plate, making them inappropriate for the treatment of achondroplasia.

Nevertheless, as scientists were mapping the chemical reactions driven by or affecting FGFR3 (Figure 1), they learned about many other bone growth-promoting agents, too. For instance, they learned that the C-type natriuretic peptide (CNP) pathway plays a key role in bone growth and that it also antagonizes FGFR3 in growth plate chondrocytes. Increasing CNP levels in the growth plate restores, at least partially, bone growth (6,7). With this knowledge in hands, vosoritide has been developed (8), followed by TransCon-CNP (9).

Figure 1. Pharmacological strategies targeting the FGFR3 pathway in the chondrocytes.

 

Modified from Matsushita M et al. 2013 (10). Reproduced here for educational purposes only.

As FGFR3 may play important roles in some types of cancer, scientists have tried to block it with molecules called tyrosine kinase inhibitors (TKIs) which have the ability to “turn it off” or deactivate it. It was natural to think that a TKI could be explored in achondroplasia. Actually, two of them are in development for achondroplasia (see below) and others might follow the clinical development path (Figure 1).

Scientists also paid attention in how FGFR3 is activated and if it was possible to prevent it. This resulted in the design of molecules like recifercept, a modified FGFR3 molecule that can circulate free, capturing the activators (FGFs) before they reach out to the genuine FGFR3. Using the same strategy, another molecule called aptamer was designed to do the same job, blocking one of the key FGFs before they turn on FGFR3 (Figure 1).

You can find a list of the pharmacological agents being explored for the treatment of achondroplasia on Table 1 and more details about them below.


Table 1. List of current and potential therapies for achondroplasia.

Name	Type	Developer	RoA	Frequency	Status
Vosoritide	CNP analog	Biomarin	SC	daily	Approved
TransCon-CNP	CNP analog	Ascendis	SC	weekly	Phase 2
Infigratinib	TKI	QED	oral	daily	Phase 2
Recifercept	Ligand trap	Pfizer	SC	daily	Phase 2
Meclizine	Anti-histaminic	Nagoya University	oral	daily	Phase 1
RBM-007	FGF2 Aptamer	Ribomic	SC	NA	Phase 1
SAR442501	Antibody	Sanofi	IV(?)	NA	Phase 1
ASP-5878	TKI	Astellas	NA	NA	Pre-clinical
ASB-20123	CNP analog	Daichii-Sankio	NA	NA	Pre-clinical

CNP: C-type natriuretic peptide. RoA: route of administration. SC: subcutaneous. TKI: 

Vosoritide

After long years of clinical development culminating with a successful phase 3 study (11), vosoritide, branded as Voxzogo, has been approved for the treatment of achondroplasia in 2021. In Europe (EMA countries) and Brazil, vosoritide has been approved for children two years of age and older while, in the US, the Food and Drug Administration (FDA) authorized the treatment for children from five years old onward. Other countries will soon follow suit.

Beyond the phase 2 and 3 studies in older children, Biomarin is also testing vosoritide in other three clinical trials, one in infants (NCT03583697), one in children with achondroplasia at higher risk of clinical complications (NCT04554940) and also in a study with other selected forms of genetic growth disorders (NCT04219007). 

TransCon-CNP

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 analog in contrast with vosoritide's daily dosing. In pre-clinical studies they showed that their CNP analog was superior to vosoritide (9).

Ascendis Pharma is conducting the phase 2 study ACcomplisH with TransCon-CNP. During the JPMorgan 2022 Healthcare Conference in early January (Figure 2), they reported that TransCon-CNP has been well tolerated during the study, with already 65 weeks of drug exposure. They plan to release the data from the phase 2 study in the end of 2022.

Figure 2. ACcomplisH study design (from Ascendis’ JPMorgan 2022 Healthcare Conference presentation).








Infigratinib

Infigratinib is an oral molecule 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 (Figure 1). 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 rescued bone growth in a mouse model of achondroplasia, in doses much lower than those used in the first studies in cancer (12,13).

QED, a BridgeBio arm, has been conducting the phase 2 trial called PROPEL and, according to their presentation during the JPMorgan 2022 Healthcare Conference, infigratinib has been showing a safe profile. They estimate to have results from the study by the end of the second quarter this year (Figure 3). Depending on the results they plan to open the phase 3 study right in 2023.

Figure 3. Phase 2 study PROPEL design (from the BridgeBio’s JPMorgan 2022 Healthcare Conference presentation).








Recifercept

Recifercept is a modified, free form of FGFR3 that works as a "ligand trap", capturing FGFR activators (ligands: the FGFs) before they can bind and activate these receptors, including FGFR3. Without the activators FGFR3 would not be as active as expected and this would help restoring bone growth (14,15).

Pfizer has started a phase 2 study with recifercept in the end of 2020 but there have been no significant updates since then. 

Meclizine

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 (10,16). They have subsequently conducted a phase 1 study in children with achondroplasia (17). The study showed that meclizine could be suitable for a single daily dose (but that it would need to be further explored in subsequent studies). More recently, they conducted another study to evaluate multiple doses of meclizine for a period of two weeks, but no results have been published yet.



RBM-007

Ribomic has been developing RBM-007, an anti-FGF2 aptamer designed to treat conditions where FGF2 has a relevant role in the mechanism of disease (18). 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.

Ribomic published their pre-clinical studies with RBM-007, which indeed rescued bone growth in a model of achondroplasia (19). They have already started a phase 1 clinical trial to evaluate this aptamer for achondroplasia and are planning to start a phase 2 study in children with achondroplasia during 2022 (Figure 4).

Figure 4. Clinical development plan of RBM-007 for achondroplasia (from Ribomic’s JPMorgan 2022 Healthcare Conference presentation).







SAR442501

Last year, Sanofi announced that SAR442501, an anti-FGFR3 antibody, was transitioned to Phase 1 clinical development. However, no study information could be found on the European Clinical Trial Register, on ClinicalTrials.gov, or the Australian Clinical Trial Register. Apart from being listed in the Sanofi’s pipeline website and in their Feb 2021 financial report (and other reports in their website), no further information about the development of SAR442501 could be found there. Neither pre-clinical data could be found in the Pubmed portal nor through a Google search as of 31-Jan-2022.

Although the antibody strategy is attractive due to its high specificity, the ability of a specific antibody to target FGFR3 in the growth plate in a model of achondroplasia needs to be confirmed in an appropriate model. As mentioned above, the growth plate is a unique body tissue because it lacks direct blood supply. Nutrients and oxygen must traffic through a dense matrix which involves the chondrocytes. In this setting, large molecules such as antibodies might not be able to reach out to chondrocytes to exert their effects (20).

SAR442501 is not the first antibody against FGFR3 to be developed (6). Until recently, B-701 (R3Mab) (21), also known as votafamab, was being developed for cancer and potentially for achondroplasia, but it seems that the research for this indication has been abandoned as there have been no reports about this antibody for this indication for a long time. 

ASP-5878

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 (22). They found that the drug was able to improve bone growth, however it was less effective compared to a positive control, a CNP analog bearing the same structure of vosoritide. 

ASB-20123

Asubio, a Japanese biotech that was recently incorporated by Daichii-Sankio (DS), was developing another CNP analog based on the fusion of the active fragment of CNP and a backbone fragment of the hormone ghrelin to help extending the known short CNP’s half-life. They have published some studies showing that their molecule was able to improve bone growth in pre-clinical models (23) but there has been no news about this compound in the DS website or in the literature lately.


A new era started

With the approval of vosoritide, a new era started. Treating achondroplasia goes far beyond simply improving the final individual height, which nevertheless is an important objective. Although long term data about the effects of vosoritide (and of course the others, too) is not available yet, based on current evidence, there is a fair chance that these therapies may mitigate or prevent several clinical challenges children with achondroplasia face in their daily routine, as mentioned in the beginning of this review.

These children now may have access to a therapy that might help them develop better and have the same opportunities and challenges an average child has while they grow into adulthood. Neither more nor less. I think this is a good perspective. 

References

1. Horton WA et al. Achondroplasia. Lancet 2007; 370: 162–72.

2. Toydemir RM et al. A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome. Am J Hum Genet 2006;79(5):935-41. Open access.

3. Savarirayan R et al. International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia. Nat Rev Endocrinol 2021 Nov 26. Open access.

4. Hoover-Fong J et al. Lifetime impact of achondroplasia: Current evidence and perspectives on the natural history. Bone. 2021 May;146:115872. Open access.

5. Aviezer D et al. Fibroblast growth factor receptor-3 as a therapeutic target for Achondroplasia--genetic short limbed dwarfism. Curr Drug Targets 2003 Jul;4(5):353-65.

6. Golembo M and Yayon A. Method and composition for treatment of skeletal dysplasias. US patent 20040138134. September 2003. Open access.

7. Yasoda A, Nakao K. Translational research of C-type natriuretic peptide (CNP) into skeletal dysplasias. Endocr J 2010;57(8):659-66. Open access.

8. Lorget F et al. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet 2012 Dec 7;91(6):1108-14. Open access.

9. 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.

10. Matsushita M et al. Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia. PLoS One 2013 Dec 4;8(12): e81569. doi: 10.1371/journal.pone.0081569. Open access.

11. 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.

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