Treating achondroplasia: news about the clinical development of vosoritide

Yesterday, during the R&D Day meeting held in New York, Biomarin presented an update about the ongoing phase 2 study with vosoritide (BMN-111) for achondroplasia.

In summary, they showed that:

1. Among the participants enrolled in the third cohort (15 mcg/kg) the effects on growth velocity were sustained after one year of exposure to the CNP analogue. The average annual gain in growth velocity with this dose is 50% compared to the average growth velocity before starting the drug;

2. After all participants of the first and second cohorts (lower doses) were moved to the higher dose (15 mcg/kg), the average annualized growth velocity rate increased and matched that of the group in the third cohort, which shows that the effects seen with vosoritide are dose-dependent (Tables 1 and 2 from Biomarin's press release); 

Table 1: Subject Disposition and Demographics

*Subjects increased dose to 15 µg/kg/day after at least 6 months at 2.5 and/or 7.5 µg/kg/day;  4 of original 16 subjects in Cohorts 1 and 2 did not initiate dosing at 15 µg/kg/day due to subject decision to withdraw from the study (2), declining  extension study (1),  and growth plate closure (1).

Table 2: Vosoritide Summary of Efficacy Results from Phase 2 Study in Children with Achondroplasia.

* Nominal p-value, not adjusted for multiplicity.

** Mean Annualized Growth Velocity change from baseline increases to 2.0 cm/year (50% increase) if one patient who missed majority of doses between 6 and 12 months is excluded

3. The safety profile of both 15 mcg/kg and 30 mcg/kg are similar. No serious adverse event has been reported so far. Most participants reported local reactions at the site of injection, which usually resolved within one hour after dosing. There was also a couple of transient events related to hypotension (decrease in blood pressure);

4. A slight trend towards a decrease in disproportionality has been seen but Biomarin thinks it will be necessary more time or a controlled study to assess if vosoritide would be effectively able to address this clinical feature of achondroplasia (Figure 1, from Biomarin's presentation).

Figure 1. Effect of vosoritide in body proportionality.

5. The developer plans to wait for more data from the fourth cohort before deciding for the dose to be used in the phase 3 study;

6. The phase 3 study is planned to start by the end of 2016;

7. There are plans also to start a phase 2 study in younger kids;

What has not been said

Most of the information provided in the yesterday meeting was already available from previous public hearings. Good news are that vosoritide keeps showing a favorable safety profile and that its effect is sustainable in longer term (no drug tolerance effect observed so far).

It is also good to hear that there might be a positive effect in body disproportionality, even if it still needs to be confirmed, for an improvement in this clinical feature of achondroplasia could bring relevant positive impact for affected individuals in daily life.

However, some aspects of the phase 2 study were not disclosed during the presentation. For instance, no interim data about the efficacy of 30 mcg/kg dose has been released. This could be related to some of the participants not having completed the 6 first months of therapy so the data would be incomplete. Nevertheless, during the same presentation, Biomarin released very early and interim data coming from another project in development for hemophilia, so it's not easy to understand why no information about the current status of the efficacy endpoint in the fourth cohort of vosoritide was disclosed.

Additionally, it would be informative to learn more about the plans for starting a higher dose in the phase 2 trial (up to 60 mcg/kg according to the clinicaltrials.gov registry) once the current dose in test, 30 mcg/kg, has been showing to be safe. This could be because again there is still no data on the efficacy of this dose, but by the other side, the study is open label and data would be available immediately.

I think that for a so important and exciting program the more information is provided the better expectations are managed. This has even more relevance now with the recent publication of a study with a tyrosine kinase inhibitor in development by Novartis that seems to block fibroblast growth factor receptor 3 (FGFR3) in quite a specific fashion, and that showed to be more effective than BMN-111 in the same mouse model used in the pre-clinical tests with this CNP analogue (1).

Here are the relevant links for the Biomarin R&D meeting:

• Biomarin's press release

• Biomarin's presentation

• Biomarin's webcast

Here, the links for the clinicaltrials.gov registries related to vosoritide:

• A Multicenter, Multinational Clinical Assessment Study for Pediatric Patients With Achondroplasia

• A Phase 2 Study of BMN 111 to Evaluate Safety, Tolerability, and Efficacy in Children With Achondroplasia (ACH)

• A Study to Evaluate Long-Term Safety, Tolerability, & Efficacy of BMN 111 in Children With Achondroplasia (ACH)

 Reference

1. Komla-Ebri D et al. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model. J Clin Invest. 2016 Apr 11. pii: 83926. doi: 10.1172/JCI8392.