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: unveiling the mechanism of action of statins on bone growth

Introduction

The text below could look very technical, but you can read more about the basics in other articles of this blog. You just need to go to the index page in your preferred language (English, Spanish or Portuguese; see the bar on top of this page) to find out more information about everything discussed here, such as the growth plate and statins. I have also added several links to those articles throughout the text. 

What's the role of FGFR3 in bone growth?

Bone growth is a tightly controlled process that takes place within thin layers of cartilage located in the extremities of children's long bones, the growth plates. The cells responsible for the bone growth in the growth plates are called chondrocytes (Figure 1) (1).


Figure 1. Cartilage growth plate structure.

 
As we know, fibroblast growth factor receptor 3 (FGFR3) helps modulating the chondrocyte cell cycle within the growth plate through two main chemical pathways, one managed by a group of enzymes called MAPK and the other defined by its main enzyme STAT1. While STAT1 controls the cell's multiplication (proliferation) pace, the MAPK pathway is a key controller of the chondrocyte differentiation (hypertrophy) pace (Figure 2) (1). FGFR3, working through these pathways, inhibits bone growth.

Figure 2. FGFR3 pathways.

Signaling pathways activated by FGF/FGFR. FGFs induce dimerization, kinase activation and transphosphorylation of tyrosine residues of FGFRs, leading to activation of downstream signaling pathways. Multiple pathways are stimulated by FGF/FGFR signaling such as Ras-MAP kinase, PI-3 kinase/AKT and PLC-γ pathways. Furthermore, FGF signaling can also stimulate STAT1/p21 pathway. FGF/FGFR signaling also phosphorylates the Shc and Src protein. FGF/FGFR play crucial roles in the regulation of proliferation, differentiation and apoptosis of chondrocytes via downstream signaling pathways. From Su N et al., Bone Res. 2014 (2). Reproduced here for educational purposes only.

Don't worry about the complexity here, visit the blog's glossary for a brief description of the growth plate and its layers. Other articles of the blog also contain more detailed descriptions of the growth plate (you could try this one).

Statins for achondroplasia?  

Statins have been under the spotlight since 2014, when a Japanese group published an elegant study exploring the use of statins for achondroplasia: they found out that statins were able to rescue bone growth in a model of achondroplasia (you can read more here) (3). However, they could not elucidate how those drugs were working (their mechanism of action). Later on, the Czech group lead by Dr. Pavel Krejci published a study in which they ruled out any direct effect of statins on FGFR3 (4), keeping the question of how statins could have rescued bone growth in that original study without an appropriate answer. 

Thinking about therapeutic solutions for achondroplasia statins could turn to be a handy solution: they are inexpensive, have a known safety profile and have been largely used for several clinical indications, including in children and pregnant women. Read more about statins here. 

If statins don't block FGFR3, how do they rescue bone growth?

• Statins restore chondrocyte proliferation

A very recent study published by another Japanese group seems to have finally unveiled the mechanism of action of these drugs, explaining how statins could induce bone growth in achondroplasia.

Ishikawa et al. (5) found out that fluvastatin, one of the statins, was able to increase the expression of one of the key regulators of bone growth, a protein called Indian Hedgehog (IHH). IHH, in turn, induces the release of a local growth plate peptide called Peptide related to Parathyroid Hormone (PTHrP). When PTHrP is released in the growth plate, it stimulates chondrocytes to stay in a proliferative state (1), delaying their transition to the hypertrophic state. This article of the blog has more information about the IHH-PTHrP activities in the growth plate.

Therefore, both IHH and PTHrP are bone growth promoters, in contrast with FGFR3, which works naturally as a growth brake in the growth plate.

Is there any correlation between FGFR3 and IHH ? 

Back in 2001, Chen et al. (6) demonstrated that FGFR3 had a direct inhibitory effect in the IHH-PTHrP axis in the growth plate (Figure 3). The exact mechanism by which FGFR3 inhibits IHH and PTHrP remains elusive although it seems that one of the chemical pathways activated through FGFR3 (the STAT1 pathway - Figure 2) induces cell cycle inhibitors (agents that block cell multiplication) leading to inhibition of IHH (which is, as said above, a cell proliferation promoter).

Figure 3. Crosstalk between FGFR3 and IHH in the growth plate.

Model of the relations between FGF-FGFR3 and IHH-PTHrP–PTHrP-R signaling in endochondral bone formation. FGF-FGFR3 and IHH-PTHrP–PTHrP-R signals are transmitted by two integrated parallel pathways that mediate both overlapping and distinct functions during the growth of long bones. Both FGFR3 and IHH affect chondrocyte proliferation. However, FGFR3 is a negative regulator of bone growth, whereas IHH positively regulates bone growth. Evidence suggests that FGF-FGFR3 signaling induces activation of STAT proteins, upregulation of the expression of cell cycle inhibitors and downregulation of IHH expression. Both FGF-FGFR3 and PTHrP–PTHrP-R signals inhibit chondrocyte differentiation, and both signals appear to act in a dominant and independent manner. From Chen L et al. Hum Mol Gen 2001;10(5):457-65 (6). Reproduced here for educational purposes only.

So, in summary Ishikawa et al. found out that statins seem to restore the IHH-PTHrP axis in chondrocytes affected by FGFR3 signaling, improving these cells' ability to proliferate.

Why is this finding important?

 
As we saw above, FGFR3 inhibits bone growth by reducing both the chondrocyte proliferation rate and its ability to differentiate and enlarge (to become mature, a process called hypertrophy). These two chondrocyte's stages represent the core of the bone growth process.

To put this information in context and help readers to understand its relevance it is important to know that the current most advanced potential therapy for achondroplasia, vosoritide, which is a C-type natriuretic peptide (CNP) analogue, works specifically over the MAPK pathway, so it rescues only one of the key processes regulated by FGFR3 (7).

In this context, it is possible that strategies that aim to inhibit the activity of FGFR3 directly might provide better outcomes in terms of bone growth rescue because they would be affecting both main pathways triggered by this receptor (Figure 2). This is the case of recifercept (TA-46) and infigratinib (BGJ-398) (check out the articles in the blog reviewing these molecules).

In conclusion, the data provided by Ishikawa et al. may provide grounds for investigators to explore the combination of therapies targeting the MAPK pathway - all CNP-based therapies, anti-MAPK kinase inhibitors and meclizine - with statins, taking advantage of their unique mechanisms of action. These combinations might work in sinergy to rescue bone growth in achondroplasia and in other skeletal dysplasias in which FGFR3's excessive activity plays a relevant role.

References

1. Long F, Ornitz DM. Development of the endochondral skeleton. Cold Spring Harb Perspect Biol 2013;5(1):a008334. Free access.

2. Su N et al. Role of FGF/FGFR signaling in skeletal development and homeostasis: learning from mouse models. Bone Res. 2014;2:14003. Free access.

3. Yamashita A et al. Statin treatment rescues FGFR3 skeletal dysplasia phenotypes. Nature 2014 ;513(7519):507-11.

4. Fafilek B et al. Statins do not inhibit the FGFR signaling in chondrocytes. Osteoarthritis Cartilage. 2017 Sep;25(9):1522-1530. Free access.

5. Ishikawa M et al. The effects of fluvastatin on indian hedgehog pathway in endochondral ossification. Cartilage. 2019 Jul 22:1947603519862318.

6. Chen L et al. A Ser(365)-->Cys mutation of fibroblast growth factor receptor 3 in mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia. Hum Mol Genet 2001; 10(5):457-65. Free access.

7. 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 ;91(6):1108-14. Free access.

Treating achondroplasia: CNP under the spotlight

Extra, Extra!   

I can tell you. There are so many news recently published about C-type natriuretic peptide (CNP) for achondroplasia and other skeletal conditions that it is hard for me to choose where to start from. 

But, wait a minute...

I know, I know, all we want to talk is about CNP. But be patient as I believe that a bit of background information can make it easier to understand CNP, fibroblast growth factor receptor 3 (FGFR3) and achondroplasia and how to put all the new information in context. So, let's start with a brief review of how bones grow.

How bones grow

As the seventeen readers of this blog know, bone growth is a long, structured and very complex process that occurs during the development of a child through adulthood. Influenced by dozens of local and systemic agents, the bone growth process could be seen as a Mozart's symphony, where many different instruments play together in perfect harmony to create wonderful art. If you stop to think about it, what is on stake and how it is achieved, you would conclude that it is a piece of natural miracle. Every single player in the growth process works in fine tuning to achieve what is planned in our DNA.

Our long bones grow from thin cartilage layers located in their extremities called growth plates. Within the growth plates, chondrocytes, the master cells of bone growth, will "wake up" from a dormant state, start a proliferating frenzy, become very enlarged and, in the end of their life cycle, will give place to osteoblasts, the bone builder cells (Figure 1) (1). As said above, this process is regulated by many local and systemic agents. When they are not in balance, the normal process is compromised either leading to stunted or to excessive bone growth.

Figure 1. Growth plate.

What happens in achondroplasia

In achondroplasia, FGFR3, one of the local agents that regulate how chondrocytes wake up, proliferate and enlarge, is working too much due to a mutation in its structure (2,3). Since the normal action of FGFR3 is to reduce chondrocyte proliferation and hypertrophy (enlargement) pace, when it is working excessively chondrocytes just stop their normal functions and bone growth is severely compromised.

FGFR3 is what is called a receptor enzyme. It is placed across the chondrocyte cell membrane, just like an antenna on top of the house roof (Figure 2). While a TV antenna will capture TV signals to deliver them to our TVs inside home, FGFR3 transmits chemical messages delivered by FGFs from outside the cell to the cell nucleus. 

Basically, when a FGF binds to the part of FGFR3 that is outside the cell, it activates (turns on) FGFR3 starting a series of chemical reactions consisting of an enzyme activating the next one and further like in a domino chain, until the last one enters the cell nucleus (Figure 3). Inside the cell nucleus, this last enzyme will turn on local agents that will trigger (or stop) the production of proteins from the DNA, each of them with distinct functions. In chondrocytes, the signals coming from FGFR3 "tell" the cell nucleus to stop cell multiplying activities. If chondrocytes stop multiplying, bone growth is compromised (2,3).

Figure 2. FGFR3 is like a roof antenna, picking up signals from outside the cell and delivering them to the cell nucleus.

Figure 3. FGFR3 signaling pathways.

From Su N et al. Bone Res 2014; 2: 14003. Reproduced here for educational purposes only.

As you see in Figure 3, FGFR3 activation turns on several enzymatic cascades. The MAPK (for Mitogen-Activated Protein Kinase) cascade is the important one for us in the context of CNP. The MAPK cascade consists of the enzymes RAS, RAF, MEK and ERK (at the right in Figure 3) (3). ERK is the one which goes to the nucleus.

Several studies established that under FGFR3 activation MAPK is specially responsible for regulating the enlargement of chondrocytes (hypertrophy, see Figure 1) (2,3). The hypertrophic zone seems to be the most important layer in the growth plate in regards to bone growth. Under FGFR3 overactivation in achondroplasia, there are fewer chondrocytes proliferating and enlarging and it is here where CNP has a role. Let's see how it works. 

CNP and FGFR3

CNP is produced within the cartilage growth plate and works as a bone growth promoter, so it has the opposite effect of FGFR3. When released, this small peptide binds its receptor on the chondrocyte cell membrane (just like FGFR3) and activates (turns on) a chemical pathway inside the chondrocyte that inhibit MAPK at the level of RAF (Figure 4) (2). Do you get the point? CNP works naturally reducing the activity of the FGFR3 pathway.

Figure 4. FGFR3 and CNP crosstalk.

From Klag KA and Horton WA. Hum Mol Gen 2016; 25:R2-R8. Reproduced here for educational purposes only.

CNP and bone growth 

Loss-of-function mutations in the CNP gene or in the CNP receptor (called NPRB) that impair their normal function cause a very rare genetic bone dysplasia called acromesomelic dysplasia Maroteaux type, which has some features resembling achondroplasia (4,5). On the contrary, mutations leading to gain-in-function lead to bone overgrowth (6,7). The role of CNP in bone growth was further described in achondroplasia and CNP-null mouse models (8).

Turning CNP into a viable therapy for achondroplasia

Life is not easy for peptides. The growth plate processes are tightly regulated, as we have already learned, but in fact this is true for all organic processes running in our body. Circulating active proteins and peptides like CNP can initiate, increase, decrease or stop many chemical reactions so the body has several systems to clear these agents off the circulation to avoid them to cause undesirable effects. One of these systems is comprised by blood enzymes that target peptides like CNP (they are called endopeptidases or endoproteases). This is so true that once released in the blood stream, CNP will last for about only two minutes (what is called half-life) (9).

Around ten years ago, scientists had proved that CNP has a positive role in bone growth and that it could counteract the inhibitory effect of FGFR3 in achondroplasia (8), but with that short half-life of just 2 min, how would they manage giving CNP to restore bone growth? They were able to show that continuous infusion of CNP had a positive effect on bone growth (8), but having an infusion pump connected to the body did not seem to be a reasonable option when thinking about long term therapies at that time.

Therefore, there might be other solutions out there. CNP is part of a family of three closely related molecules called natriuretic peptides. One of them, the brain natriuretic peptide (BNP) was shown to be naturally more resistant to endoproteases due to a prolonged "tail" that CNP does not have (Figure 5). With this knowledge in hand, researchers developed a form of CNP which bears a prolonged tail similar to BNP (10).

Figure 5. Natriuretic peptides.

Developing vosoritide

The modified CNP (called analogue), which we know by the name of vosoritide (BMN-111), not only retains the biological functions of the original peptide but also is more resistant to neutralization by the clearance enzymes, with a prolonged half-life of 20 minutes. Being able to circulate longer in the blood stream gave enough time to vosoritide to reach the growth plates to exert its expected function (10).

In fact, both pre-clinical studies in mice and monkeys resulted in additional growth and the recently published results of the phase 2 study in children with achondroplasia (10-12) demonstrated that once-daily subcutaneous (SC) injection of vosoritide resulted in increased bone growth velocity and additional growth compared to what would be expected without the treatment. Vosoritide is now being tested in more than 100 children in a phase 3 study (NCT03197766), with results to be available by the end of this year and, if successful, the drug could be on the market next year.

Now, let's take a look on the results of the phase 2 study, just published in the New England Journal of Medicine (NEJM) last week (12). Actually, the main results reported in this paper had already been released during the R&D Day event held by Biomarin in June 2018 and repeated during the JP Morgan conference on last January. Unfortunately, the links to those presentations are no longer available at the Biomarin's site but you can see a snapshot of the R&D Day presentation from June 2018 in Figure 6.

Figure 6. Effect of vosoritide in average growth velocity after 42 months in the 3rd cohort of the phase 2 trial (15mcg/kg).

Snapshot from Biomarin's R&D Day presentation (Jun 2018).

The phase 2 study paper contents are protected by copyright but the NEJM released a picture in their Twitter account showing one of the main results of the trial (Figure 7).

Figure 7. Increase of bone growth velocity after six months of starting treatment with vosoritide.

From Savararayan R et al. NEJM 2019; image (corresponding to Figure 1A in the original article) obtained from NEJM's Twitter open access account and reproduced here for educational purposes only.

In summary, vosoritide (15mcg/kg) was able to restore bone growth velocity in exposed children with achondroplasia closer to the average bone growth velocity seen in non-affected children (Figure 6). The effect was sustained after 42 months of exposure. I cannot display it here but in one of the pictures (Figure 1B in the original text) one could interpret that there is what it seems to be a slight trend to a reduction on the effect on bone growth over the 42 months (12). 

Nevertheless, the study showed progressive improvement on the z-score for height with 15mcg/kg/day which, in real world language, means that the difference of the exposed children growth pattern compared to the standard growth curves decreased overtime (12). 

One question that was raised in the beginning of the clinical development of vosoritide years ago was whether the drug would cause worsening of the body disproportion. Results from this study show that this was not the case, but by the other side, there was no significant improvement on this aspect of the dysplasia (12). Bear in mind that most of the disproportion is set in the first two years of life, and that the children in this study were at least six years-old on enrollment, possibly too late to see relevant effects in this aspect of achondroplasia.

On the safety side, it seems that vosoritide has a fair safety profile, with the majority of adverse events linked to injection site reactions, which were mostly mild in intensity. Exposure to biologicals may trigger an immune response by the body, which may produce antibodies against that drug. This is common in the treatment with monoclonal antibodies against cancer and other inflammatory conditions, so it is not surprising that anti-drug antibodies (ADA) were found in this study (12). However, it seems that the presence of ADAs would not have had an impact in the drug efficacy (13).

A question waiting answer: given that results from the 42 months of exposure were already available one year ago, why were results from beyond that cutoff not included in this study, which has just been published?

Is there space for improvement?

Well, vosoritide has been consistently showing results that, if confirmed in the ongoing phase 3 study (NCT03197766), may pave the way to be approved for the treatment of achondroplasia in the next year or so. These are wonderful news, as this therapy may help improving the quality of life of many children in the future. However, it seems that there is space for even better bone growth effects with CNP.

Ascendis Pharma is developing another CNP analogue (they call CNP-38 meaning a CNP molecule with 38 aminoacids) but using proprietary technology to improve how long their CNP circulates to exert its effects in the bones. They have created a carrier system (we can call it a transport or "taxi") for delicate molecules like CNP (Figure 8). Protected by Ascendis taxi, TransCon, their CNP was shown to have a much longer half-life compared to vosoritide. In fact, they have just published the complete results of their pre-clinical studies made with TransCon CNP, which included tests comparing their CNP with vosoritide (14). As a matter of information, in their study they have reproduced the molecule corresponding to vosoritide, which is a CNP with 39 aminoacids (thus CNP-39) to compare with their CNP-38. Let's take a look on their study.

Figure 8. TransCon carrier system.

From Ascendis Pharma. You can learn more here.

In brief, due to the characteristics of their taxi and their CNP structure, they found that their TransCon system provided stable exposure of their CNP for a week, without the plasma peak observed with vosoritide, so with minimal if any effect on blood pressure. The effect in bone growth was at least as good as with CNP-39 (Figure 9) (14).

Figure 9. Effect of TransCon CNP (40 and 100 mcg/kg) vs. placebo and CNP-39 on body length and bones.

From Breinholt VA et al. J Pharmacol Exp Ther June 24, 2019, jpet.119.258251. (Open access article). Reproduced here for educational purposes only. 

Ascendis has already conducted a phase 1 study with TransCon CNP in healthy volunteers, and they confirmed the long half-life of their analogue, which will allow a weekly dose, in contrast with the daily dose of vosoritide. There were no cardiac safety concerns. Ascendis should be starting their phase 2 study in children soon.

Is this the end of the story?

No, not at all as Daiichi Sankio, a Japanese pharma industry, is developing ASB20123, a new analogue of CNP. In this case, the compound is a fusion molecule where the active part of CNP is combined with a fragment of the peptide hormone ghrelin (Figure 10). This engineering makes CNP resistant to endopeptidases giving more time for it to exert its functions (15,16). Basically, it is the same principle used for Biomarin's and Ascendis' analogues.

Figure 10. Structure of ASB20123, a new CNP analogue.

From Morozumi N et al. PlosOne 2019, reproduced here for educational purposes only.

 ASB20123 demonstrated clear positive effects in bone growth as seen in their experiments in their mouse model (Figure 11). Note that it is possible that under the highest dose tested it might have occurred overgrowth. Unfortunately, there are no radiographs in this study allowing to check bone densities or shapes but, in fact, the researchers mention that overgrowth likely occurred when the animals were given higher doses (16).

Figure 11. ASB20123 effects in growth in a mouse model.

Growth curves of female juvenile ICR mice treated with ASB20123 sc during the 8 weeks of the dosing period and the 4 weeks of the washout period. Body weight (A), body length (B) and tail length (C) data are shown in the upper panels, and the photographs in the lower panel represent the gross appearance of mice at Day 56 (D). Each value represents the mean ± SD of 10 (for the dosing period) or 5 mice (for the washout period). NS: not significant (p > 0.05), *: significant difference (p < 0.05) compared to the control group using Dunnett’s test. From Morozumi N et al. PlosOne 2019 (open access), reproduced here for educational purposes only.

The researchers also tested ASB20123 given through a SC pump, again providing sustained release of their analogue, with improved growth results. The argument is that the use of a SC pump may allow stable but lower concentrations of their analogue to promote bone growth without cardiac adverse events (especially hypotension) (16). Newer SC pumps seem to be more comfortable than older models and would spare children to have daily or weekly shots. I don't feel exactly comfortable about this approach yet but I think it is too early to draw conclusions about it.

Bright horizon

The achondroplasia therapy landscape is becoming crowded. Now, there are two CNP analogues in clinical development, one of them, vosoritide, closer to marketing approval, pending results from their phase 3 study in the end of this year. The other, TransCon CNP, heading to phase 2. Therachon is developing TA-46, a molecule based on FGFR3 and designed to compete against the mutated receptor for the FGFs (17). A Japanese group has been working with meclizine, an old antiemetic drug that showed positive effects on bone growth (18). QED Therapeutics, a small biotech, started working with infigratinib, a molecule designed to block FGFR activation (19). The Japanese group from Daiichi Sankio has just introduced their CNP analogue (16). Osteocrin, a natural peptide, has shown to improve bone growth by blocking NPRC (a trap receptor for natriuretic peptides) rendering more time to CNP to exert its effects in bone growth (20). Investigators have also found that a family of drugs used to lower cholesterol, the statins, may also be used to improve bone growth in achondroplasia (21). Furthermore, there is already initial research exploring gene editing to treat achondroplasia (to be reviewed in a future article).

However, this is still not the end

With the mounting knowledge about the chemical pathways altered in achondroplasia and the research to put them in balance again, researchers have also started to explore the use of therapies initially designed for achondroplasia in other skeletal dysplasias where the FGFR pathways may have a relevant role. The most natural example is hypochondroplasia, which is also caused by mutations in FGFR3. But there are other initiatives.

For instance, a study showed that BMN111 (vosoritide) had positive effects in a model of Crouzon Syndrome, a craniosynostosis linked to a FGFR2 mutation (22). The MAPK pathway, key in achondroplasia, is also fundamental in the family of genetic disorders called RASopathies, in which enzymes of the MAPK pathway or their regulators have mutations impairing their normal functions, which causes a plethora of clinical complications. The RASopathies include Neurofibromatosis and Noonan Syndrome among several other disorders. A recent work with statins in Noonan Syndrome showed that they were able to rescue growth in that RASopathy (23). The same group working with ASB20123 tested CNP in a mouse model of cardio-facio-cutaneous syndrome, another RASopathy, with positive results (24).

Things are getting better. A few months ago, Chinese investigators published a study where they found that FGFR3 has an important role in the mechanism of genetic disorders linked to mutations in the gene SLC26A2, which include diastrophic dysplasia. They showed that inhibiting FGFR3 with infigratinib (the FGFR blocker in development by QED) improved bone formation and the phenotypes of two lethal forms of SLC26A2 disorders: achondrogenesis type IB and atelosteogenesis type II (25). If they were able to ammeliorate the phenotypes in those devastating forms of genetic disorders linked to sulphate transport, what would be the results in milder forms such as diastrophic dysplasia? 

The big question is not anymore if there is, or will be, any treatment available. The question now is: in which other skeletal dysplasias therapies for achondroplasia could also provide benefit?

Division

The interested community has been divided lately with diverging opinions about what  these new potential therapies' purposes "really" are. Some claim that they would be just cosmetic, a threat to human diversity. A flow of accusations and harsh judgement over parents taking decisions about their children without their "consent" is being published in the social media, as decisions are not what parents always take, every single day, from the most banal to the most fundamental issue (whatever they are). 

Embracing the change 

Not long ago, there was nothing to be done after a diagnosis of a genetic disorder, but to resign, as there were no perspectives ahead. 

Now, the time for resignation is over. Therapies for genetic bone growth disorders are on their way and they have nothing to do with reducing human diversity as some have been declaring lately. They have to do with providing a better life for affected children, future adults.

By restoring bone growth, many clinical complications seen in skeletal dysplasias may finally be prevented or minimized. This will result in better functioning and better quality of life for our beloved children as they grow up to become adults. Can you imagine your kid not having to undergo major surgeries at young age, or having to deal with life-long orthopedic and neurological complications? (26, 27) Wouldn't that be good enough?

And finally, if restoring bone growth in achondroplasia and other bone disorders will make treated individuals taller, even better, for they will be able to better face the many existent challenges in the world outside. If you are still not there yet, you should start thinking in embracing the change. It is coming.

 
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