Achondroplasia, which affects around one in 20,000 babies, has just one approved treatment: BioMarin’s Voxzogo. However, new investigational treatments are vying to compete in the area.
Achondroplasia is a genetic bone disorder that causes short limbs and dwarfism. Although this growth disorder affects around one in 20,000 babies, it currently has just one FDA-approved treatment. In July 2024, Sanofi announced that its achondroplasia investigational agent, SAR442501, will not be advancing further than its current Phase II trial.
The sole approved treatment for achondroplasia, BioMarin’s Voxzogo (vosoritide), is a C-type natriuretic peptide dosed by weight and administered as a once-daily subcutaneous injection. Voxzogo works by activating natriuretic peptide receptor B, thus restoring cartilage development and boosting skeletal growth.
When initially approved in 2021, Voxzogo was only indicated for children ages 5 and older with achondroplasia whose growth plates remained open. The drug was then granted a label expansion in October 2023 for all children with achondroplasia and open epiphyses.
Voxzogo sales brought in $190 million for BioMarin in Q3 2024 alone. It is currently in clinical trials for five other skeletal conditions in addition to achondroplasia.
Despite Voxzogo’s approval, additional achondroplasia treatments could increase the availability and accessibility of interventions. Early intervention is particularly important because left untreated, the skeletal disease leads to complications such as obesity and posture problems.
Meanwhile, other companies are researching investigational treatments to promote bone growth in children suffering from achondroplasia via other mechanisms.
BridgeBio, for example, is running Phase III trials examining the use of infigratinib for achondroplasia.
Unlike the infigratinib capsule formulation that was withdrawn from the market in May 2024 for cholangiocarcinoma due to commercial reasons, the infigratinib used in the trial is formulated as an oral minitablet. It is a fibroblast growth factor receptor (FGFR) 1-3-selective tyrosine kinase inhibitor that improves skeletal growth.
In June 2024, BridgeBio reported positive results from its Phase II achondroplasia trial, PROPEL 2. In the trial, patients were split into five cohorts, with each cohort receiving different doses of infigratinib. BridgeBio reported that the highest infigratinib dose increased the annualized height velocity and height-for-age z score and decreased upper-to-lower body segment ratio at 18 months of treatment.
Another company in this space, Ascendis Pharma, recently completed Phase II trials with TransCon CNP, an investigational prodrug of C-type natriuretic peptide (CNP) administered once weekly via subcutaneous injection.
Because TransCon CNP is an investigational prodrug that requires activation within the body to take effect, the sustained release formulation allows it to be safer and efficacious despite being administered at lower doses than Voxzogo, according to Ascendis. In its June 2024 data readout, Ascendis released positive Phase II results from its ACcomplisH trial. In terms of trial design, unlike PROPEL 2, ACcomplisH had placebo, experimental and open-label extension cohorts.
In addition to stimulating linear growth when comparing various doses to placebo, TransCon CNP also demonstrated lower injection site reaction and symptomatic hypotension rates than has been observed in Voxzogo trials.
Finally, Ribomic is developing RBM-007, an investigational anti-FGF2 aptamer designed to restore defective bone growth.
In November 2024, Ribomic released positive interim Phase IIa data demonstrating an increase in annualized growth rate of up to +3.3 cm/year in children 5 years of age and older in the low dose cohort compared to before the administration of the test drug (although three of the five children in the cohort experienced no increase in growth).
Low-dose (0.3 mg/kg) subcutaneous injections were administered once every two weeks for eight weeks (a total of four times), and if safety and tolerability were confirmed, the administration interval was changed to once a week for the next 26 weeks.
Ribomic intends to release more data on the second cohort in September 2025. RBM-007 is also under active development for other disease states such as age-related macular degeneration, cancer pain and lung cancer.
Given what is known about current Phase III treatments, while patient preference for orally-administered treatments may favor infigratinib, the lack of a placebo arm makes the PROPEL 2 safety data assessment premature at best.
And while TransCon CNP may offer a safer and longer-acting alternative to Voxzogo, there is no conclusive answer yet as to whether the treatment will be able to increase final adult height in children with achondroplasia.
Although RBM-007 and TransCon CNP could make once-daily injections a thing of the past, RBM-007 is at an earlier stage of development than its potential competitors.
Regardless, given that both infigratinib and TransCon CNP are currently in early Phase III, a Voxzogo competitor approval for achondroplasia will likely not arrive until 2029 or 2030 at the earliest. It is safe to say that BioMarin’s Voxzogo could dominate the achondroplasia market for the next 4–5 years.
Correction (Jan. 27): This article has been updated from its original version to correct that BridgeBio’s Phase III trials of infigratinib are fully enrolled and that infigratinib was pulled from the market in cholangiocarcinoma for commercial reasons, not due to data. BioSpace regrets the errors.
