Treating achondroplasia: BMN-111 and the catch up growth phenomenon

Growing bones

In the last four public meetings, when speaking about the BMN-111 program for achondroplasia, Biomarin frequently mentioned two topics: growth velocity and the catch up growth phenomenon. For the phase 2 study, change in growth velocity has been considered the main efficacy outcome, although they are also looking at several other parameters, such as changes in disproportionality. Biomarin refers that the average growth velocity in pre-pubertal children is ~6 cm/year and that in children with achondroplasia this average is 4cm/year. Their expectation is that as an effect of the therapy with BMN-111, the growth velocity in the children participating in the study would reach the "normal" average or, in other words, that the growth velocity would increase in about 50%. Growth rate higher than these 50% would be considered catch up growth because it would surpass the normal growth velocity rate.

Theoretically, catch up growth may occur as a response of the natural growth program when the reason for growth restriction is solved (1,2).

The most common cause of growth restriction is malnutrition and catch up growth occurs in malnourished children and animals receiving appropriate nutrition (Figure 1) (1). It is translated in a phase of accelerated growth till the child reaches the individual threshold dictated by his/her genetic growth program and age. Then the growth pace returns to normal.

Figure 1. The catch up growth phenomenon in rats

Effect of food restriction and re-feeding on the height of the EGP. Twenty-four-day-old male SD rats were allowed to eat ad libitum (AL), subjected to 40% food restriction for 11 days (RES) or subjected to 10 days of food restriction followed by one day of re-feeding ad libitum (CU). The arrows indicate the height of the EGP. Magnification, 40×. EGP = epiphyseal growth plate. Ref 1. Copyright © 2015 by the authors; licensee MDPI, Basel, Switzerland. Reproduced here for educational purposes only. 

How would catch up growth be explained in achondroplasia? 

The cause of achondroplasia is a mutation in an enzyme called fibroblast growth factor receptor 3 (FGFR3) that makes it more active than normal. FGFR3 plays a very important role in the natural growth program, acting as a brake for the chondrocytes within the growth plate. Because of the mutation the brake works excessively, impairing normal bone growth. FGFR3 exerts its actions through several chemical chain reactions produced by other client enzymes inside the chondrocyte and one of them, called MAPK, is thought to be the main of these chains working too much in achondroplasia. 

BMN-111 is an analogue of a natural human peptide called c-type natriuretic peptide (CNP). CNP has its own cell chemical pathway and works reducing the activity of MAPK (Figure 2) in chondrocytes. Studies have showed that BMN-111 works in the same way (see this article in the blog) (3). It is fair to say that FGFR3 and CNP have antagonistic roles in the growth plate chondrocyte.

So, how would be this catch up growth after all?

In this exercise, let's give normal FGFR3 a grade for its level of activity. Let's say that in normal conditions, FGFR3 would have a level 5 of activity and that in achondroplasia its activity level is 7 (remember, it is working more than expected). In this scenario, if CNP or its analogue was capable to push FGFR3 back to level 5, then we could be normalizing the growth velocity. Since the mutated FGFR3 is the only reason for growth impairment in achondroplasia, the normalization of its activity could provide the conditions for the growth rescue.

BMN-111 was studied in two different animal models of FGFR3-related mutations. The first one was a mild model, in which the use of BMN-111 rescued bone growth virtually to normal (3). The second model was much more severe, resembling the human FGFR3 mutation that causes tanatophoric dysplasia (TD)(4). In this TD-like model the therapy with BMN-111 produced significant improvement in bone growth, but couldn't rescue the defect completely. In an analogy, we could say that the activity level of FGFR3 was 7 in the first study and 9 in the second one. With BMN-111 the first model could have FGFR3 brought to a normal activity level and in the second model there would be still FGFR3 over activity in spite of the therapy.

Figure 2. CNP and FGFR3 crosstalk.

Based on the above scenario, one could speculate that catch up growth could take place in the phase 2 participants if BMN-111 was working in an intensity enough to downgrade MAPK over-activity, restoring it to normal levels. 

FGFR3 influences a number of other agents that are active in the bone growth program and several of them through the action of MAPK. However, the defect in achondroplasia is a single one: no other agent has problems. Reinforcing what I have just mentioned above, my opinion is that in achondroplasia the growth program (which encompasses dozens of those agents) is working normally and FGFR3 would be the sole reason for growth restriction. Well, if FGFR3 activity was under control, then the program could resume its natural pace. This could include a rescuing phase of catch up growth.

Biomarin has been announcing that the results of the phase 2 study will be released in June. Just a few more days and we will see...

Suggestions

In this article I have just briefly written about the biology of achondroplasia and it might seem complex to first time readers to understand part of the text. There are other articles of the blog where the science is explained in more detail.  For instace, to learn more about CNP and BMN-111 you could visit one of the index pages (choose your language) on the top of this page. You will find several other articles reviewing CNP and its analogue. There are also valuable references in the Reference page.

Finally, just yesterday (May 27th), the Japanese group leaded by Kazua Nakao has published a new compelling study dissecting the relevance of CNP for bone growth. The article is open access (5).

References

1. Gat-Yablonski G and Phillip M. Nutritionally-Induced Catch-Up rowth. Nutrients 2015; 7(1):517-51; doi:10.3390/nu7010517. Free access.

2. Lui JC et al. Growth plate senescence and catch-up growth. in Cartilage and bone development and its disorders. Camacho- Hübner C, Nilsson O, Sävendahl L (eds):
Endocr Dev. Basel, Karger, 2011, vol 21, pp 23–29. Free access.

3. 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.

4.  Lorget F et al. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse modelrecapitulating achondroplasia. Am J Hum Genet 2012;91(6):1108-14. Free access.

5. Nakao K et al. The local CNP/GC-B system in growth plate is responsible for physiological endochondral bone growth. Sci Rep 2015 May 27;5:10554. doi: 10.1038/srep10554. Free access.