Dear Readers,
Since the last review I posted here (2023) several studies with drugs in clinical development for achondroplasia have been published and new ones were announced. Let's see where we are now.
So, let's start with a panoramic view of the clinical research landscape in Table 1.
Table 1. Current status of approved and investigational therapies for achondroplasia.
Some of the drugs listed on Table 1 have treatment data already published, which you can see on Table 2. The others are still in early phase and their developers have not published any data yet.
Table 2. Annualized growth rate increase with treatments for achondroplasia compared to control arm.
How do we interpret Table 2?
Both vosoritide and navepegritide pertain to the same class, analogs of CNP, which implies that their effects on growth modulation could be similar. The key difference between these two molecules is that, while vosoritide is given as a daily shot, navepegritide is given in a weekly basis. Since they have similar effects on bone growth, and also have a similar safety profile, thinking on a 10- to 15-year treatment window, it seems that a weekly treatment has an additional advantage over one that needs to be given in a daily basis. Not surprisingly, the developer of vosoritide is now testing its own version of a long-acting CNP analog (BMN-333).
Infigratinib is the first oral treatment to reach clinical development for achondroplasia and, based on the phase 2 study report, it seems to be superior to CNP analogs. This probably has to do with its mechanism of action: CNP analogs modulate a cell signaling cascade (NPR-B) that naturally counteracts one of the cell cascades activated by FGFR3, whereas infigratinib acts directly on FGFR3 blocking all those cascades (Figure 1).
Figure 1. FGFR3 and CNP crosstalk.
When FGFR3 is activated by a FGF, it triggers a series of chemical cascades inside the chondrocyte, and two of them are responsible for the natural action of this receptor enzyme: MAPK and STAT1. CNP and its analogs, such as vosoritide, activate another receptor on the chondrocyte cell membrane, NPR-B. This receptor is a natural controller of FGFR3 activity: when NPR-B is turned on, it activates a cascade that works blocking the MAPK pathway, thus reducing the negative influence that FGFR3 exerts on bone growth.
Just one month ago, the developer of the combination of navepegritide and a long-acting GH analog presented the results of their phase 2 study in achondroplasia at the 2025 ASBMR Annual Meeting (7). At week 26, children either naive to any previous bone growth therapy or who were already treated with navepegritide had significant growth increase compared to pre-treatment baseline growth (Table 2) (Figure 2). This study brings new insight on the management of growth disorders, but also raises questions, such as whether the synergistic effect of GH therapy added to navepegritide will be maintained in long-term. In the past, at least one study with GH to treat achondroplasia showed improved growth only during the first year of treatment (10).
Figure 2. Annualized growth velocity at baseline and Week 26 in children with achondroplasia treated with a combination of navepegritide and long-acting GH.
Note: This figure is reproduced here for educational purposes only (7).
The research landscape
Several groups have published pre-clinical research on old and new molecules that may have a role in the treatment of achondroplasia and other skeletal dysplasias. I have added them on Table 3. This is not an exhaustive list, and perhaps some of them have already been abandoned.
Table 3. Other compounds with research on bone growth or potential to be evaluated in achondroplasia and other skeletal dysplasias
The future is bright
Vosoritide and some of the other drugs are now also being evaluated in children with other growth disorders, as predicted in past articles of this blog. This is a natural move as, even in skeletal dysplasias in which FGFR3 is not altered, there is mounting evidence that the FGFR3 pathway is overactive, therefore contributing to bone growth disruption. It will be a matter of time for children affected by many of the skeletal dysplasias to have therapies that will improve their general health and quality-of-life, and help them to live their lives as typically as any other non-affected children live.
References
1. Savarirayan R et al. Sustained growth-promoting effects of vosoritide in children with achondroplasia from an ongoing phase 3 extension study (doi.org/10.1016/j.medj.2024.11.019).
2. Savarirayan R et al. Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trial. (doi.org/10.1016/j.eclinm.2023.102258).
3. Savarirayan R et al. O13: Oral infigratinib for children with achondroplasia: Month 18 results from the PROPEL 2 study. (doi.org/10.1016/j.gimo.2025.102089).
4. Nakamura Y. Multiple Therapeutic Applications of RBM-007, an Anti-FGF2 Aptamer (doi.org/10.3390/cells10071617).
5. NCT06842355. A Study of TYRA-300 in Children With Achondroplasia: BEACH30.1
6. NCT06433557. A Phase 2 Clinical Trial to Evaluate Efficacy, Safety, and Tolerability of Navepegritide in Combination With Lonapegsomatropin in Children With Achondroplasia (COACH).
7. McDonnell C et al. 1126 Once-Weekly Lonapegsomatropin (TransCon hGH) Added to Once-Weekly Navepegritide (TransCon CNP) in Children with Achondroplasia: 26-Week Results from the Phase 2 COACH Trial.
8. jRCT2041230001. An exploratory clinical trial to Investigate the efficacy and safety of Meclizine hydrochloride in Achondroplasia patients (pediatrics). (MACH trial)
9. BMN-333. Biomarin press release; 04-Aug-2025.
10. Alatzoglou KS et al. Outcome of rhGH treatment in patients with achondroplasia and skeletal dysplasias. Endocrine Abstracts (2010) 24 P19.
11. PLX-138. Prolinx pipeline. 2025.
12. Shuhaibar LC et al. Phosphatase inhibition by LB-100 enhances BMN-111 stimulation of bone growth. JCI Insight 2021; May 10;6(9):e141426.
13. BDTX-4876. Black Diamond Therapeutics pipeline.
14. Martin L et al. Theobroma cacao improves bone growth by modulating defective ciliogenesis in a mouse model of achondroplasia. Bone Res 2022 Jan 25;10(1):8.
15. Lin Y-W et al. Cell-based screen identifies porphyrins as FGFR3 activity inhibitors with therapeutic potential for achondroplasia and cancer. JCI Insight 2023; Nov 22;8(22):e171257
16. Kawabe T et al. Phosphodiesterase 3 inhibitors boost bone outgrowth. Br J Pharmacol 2025 Sep;182(18):4327-42.
17. Vepugratinib. Lilly pipeline. 2025.
