Wednesday, March 14, 2018

Treating Achondroplasia: frequent questions about treatment


I have no employment relationship or receive any compensation or incentive from any company researching medications or treatments for achondroplasia. What I write is based on the knowledge acquired from the scientific literature and the information published by the respective companies.


I have been receiving many questions about how the research for achondroplasia treatments is going and more specifically about vosoritide. As the treatment is a relevant theme to many, I thought it would be useful to share my knowledge with everyone in the form of questions and answers.

All product information in this text is in public domain and referenced. Where there is no bibliographical reference the text reflects my personal opinion.

Visit the index page to learn more about the topics covered here. The blog contains many reviews on achondroplasia and on basically all potential treatments already published in the scientific literature so far. 

  • What is vosoritide?
Vosoritide, also known as BMN-111, is an improved copy of a substance produced naturally by the human body, called the C-type natriuretic peptide (CNP) (1). CNP is one of the substances that positively regulate the growth of the bones, Vosoritide does exactly what CNP does: it stimulates the growth of the bones. 

  • What is the reason for using CNP or vosoritide in achondroplasia?
Research has shown that CNP reduces the activity of FGFR3, the mutated protein in achondroplasia. FGFR3 is a bone growth regulator, but works naturally as a brake. However, due to the mutation, FGFR3 becomes so active that it prevents normal bone growth. The natural function of CNP (and by similarity, of vosoritide) is to reduce the action of FGFR3, that is, it releases the brake. Another important aspect of the action of the mutant FGFR3 is that it also reduces the amount of CNP present in the cartilage growth plate. Therefore, providing CNP or CNP analogs helps bone growth in achondroplasia (2-6).

  • What is the risk of using CNP or vosoritide in children with achondroplasia?
In animal studies, CNP and vosoritide showed a good safety profile (3). CNP belongs to a family of substances that interferes with blood pressure. It is expected that the CNP application will have a negative effect on blood pressure. In fact, all studies or reports in humans published on vosoritide so far indicate that there is a slight drop in blood pressure after its application. This reduction is considered to be mild and transitory and rarely accompanied by any symptoms. To date, there is no other relevant adverse effect published on vosoritide (7).

  • What is the risk of using vosoritide in the long term?
CNP, and therefore its copies, have a very short action time and do not accumulate in the body. These substances are quickly eliminated by the body. Thus, in addition to not producing short-term problems, they are not expected to produce long-term toxic effects. However, only time can confirm if there are in fact no undesirable consequences with the use of the medication in the long term. 

  • What to expect from treatment with vosoritide?
If vosoritide works as expected, it will promote more growth of the body's bones. In addition to a likely higher final stature, with longer limb bones, it is estimated that treatment could reduce the large number of orthopedic and neurological complications associated with achondroplasia. We will only be able to know about this in the future as the children in treatment reach adulthood. 

  • Does vosoritide really work?
According to test results published so far, vosoritide was able to increase bone growth rate by about 40-50% on average in treated children (8). This approximates the growth speed of treated children to that of children not affected by the mutation. Only over time we will know if it will maintain this rhythm in the long run. 

  • Who will benefit from the use of vosoritide (or any treatment for achondroplasia)?
Only individuals who still have "open" bone growth plates can benefit from growth-promoting drugs. Growth plates are small specialized structures present at the ends of long bones. They are responsible for stretching the bones. It is exactly in the growth plates that FGFR3 and CNP work.

Growth plates close at the end of puberty, representing the end of the growth period of the body. Unfortunately, CNP, vosoritide or any other treatment aimed at blocking the action of FGFR3 will cease to be useful when the individual reaches adulthood because there will be no more growth activity then.

  • When to start treatment with vosoritide for the treatment of achondroplasia (or any other medication that is approved to treat it)?
Since the effects of the FGFR3 mutation begins already durign pregnancy, it seems essential that treatment should be started as soon as possible, probably soon after birth. Growth is a natural phenomenon with expiration date, as we have seen above. It is likely that the longer the treatment the better the final outcome will be when the individual reaches adulthood. 

  • As for vosoritide, when will it become available?
Vosoritide is still in clinical trials to confirm its effectiveness and safety. These tests are mandatory and controlled by the agencies that regulate medicines (in US, the agency is the FDA).

Vosoritide is being tested in a Phase 3 study, and the results of this study will allow the laboratory developing it to obtain the license to market it provided it is successful in the tests. The current prediction by the developer is that the results of the phase 3 study will be available in the second half of 2019 to be submitted to the FDA (9). Based on this prediction, if approved, it may be available in the United States at the beginning of 2020. Availability in other countries will depend on the
strategy of the developer of vosoritide and the speed of the drug approval process of the regulatory agencies in those other countries. 

  • Are there other medications being tested?
There are several other initiatives to identify and test potential treatments for achondroplasia. A list of all these initiatives can be found here. Some of these initiatives may reach the clinical development stage in the near future.

For example, the developer of the molecule known as TA-46 announced in February 2018 that it wants to start the Phase 1 study soon (10). Another company that is developing a new form of CNP known as TransCon-CNP also intends to request authorization to start clinical studies soon (11). As a consequence of a study in an animal model of achondroplasia in which it showed promising results, a company was created to continue the development of the molecule NVP-BGJ398 (12,13).

These are just a few examples, there are other initiatives underway, but I believe these are the most promising at the moment. All these initiatives are still far from the pharmacy, but some of them, if successful, could be available in about 4-5 years .

I hope this little review helps to clarify some doubts. The blog Treating Achondroplasia is active. New articles will be published whenever there is any theme that may interest readers.


1. Wendt DJ et al. Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism. J Pharmacol Exp Ther 2015; 353(1):132-49. Free access.

2. Krejci P et al. Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix homeostasis. J Cell Sci 2006; 118: 5089-00.

3. 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.

4. Nakao K et al. Impact of local CNP/GC-B system in growth plates on endochondral bone growth. Pharmacol Toxicol 2013; 14 (Suppl 1):48.

5.Yasoda A et al. Systemic Administration of C-Type Natriuretic Peptide as a Novel Therapeutic Strategy for Skeletal Dysplasias. Endocrinology 2009;150: 3138–44.

6.Yasoda A and Nakao K. Translational research of C-type natriuretic peptide (CNP) into skeletal dysplasias. Endocrine J 2010; 57 (8): 659- 66.

7. Hoover-Fong J et al. Vosoritide in children with achondroplasia: Updated results from an ongoing Phase 2, open-label, sequential cohort, dose-escalation study. Abstract presented at the American Society of Human Genetics Meeting 2016, Vancouver. Meeting Abstract book p. 1301. Free access.

8. Biomarin R&D Day 2017 presentation.

9. Biomarin press release. BioMarin Announces Fourth Quarter and Full Year 2017 Financial Results.

10. Therachon Feb 14, 2018.Therachon Announces Dosing of First Subject in Phase 1 Clinical Trial Evaluating TA-46, a Novel Investigational Therapy for the Potential Treatment of Achondroplasia.

11. Ascendis Pharma. TransCon-CNP.

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

13. FiercePharma Jan 30, 2018. BridgeBio’s QED Therapeutics picks up discarded Novartis cancer drug.

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