Therapies from industry leaders BioMarin and Ascendis Pharma supply a key hormone that promotes bone growth. In order to move the field forward, challengers are looking to address the underlying cause of the rare, genetic disease.
In November 2021, the FDA approved BioMarin’s Voxzogo for children 5 years and older with achondroplasia, giving hope to more than 10,000 patients and their families across the U.S.
Voxzogo marked the industry’s first-ever therapy for the rare, genetic disorder characterized by short stature in children. Despite qualifying as a rare disease—it affects one in 15,000 to one in 40,000 newborns—achondroplasia is the most common cause of dwarfism.
Now, nearly four years later, the achondroplasia community is once again awaiting regulatory action that could open up a new treatment option for the disease. On November 30, the FDA is set to make a decision on Ascendis Pharma’s TransCon CNP, which the biotech is proposing as a weekly treatment for children with achondroplasia.
“When Ascendis Pharma announced TransCon CNP results, BioMarin’s stock fell 17%,” Sadaf Javed, manager of Forecasting and Analytics at DelveInsight, told BioSpace in an email.
Javed said that despite the drawbacks of cross-trial comparisons, TransCon CNP’s profile seems to be “competitive” in terms of efficacy, safety and convenience. In particular, its once-weekly schedule is a “strong differentiator,” she added, compared to Voxzogo, which is given via daily subcutaneous injections.
The market for TransCon CNP and Voxzogo is ample. There are around 24,000 clinically eligible patients from birth to 18 years of age globally, according to Jefferies analyst Andrew Tsai. With Voxzogo so far achieving around 17% market penetration, or 4,000 patients. “This therefore implies a global market opportunity in [achondroplasia] of just north of $5B assuming full penetration,” Tsai told BioSpace in an email.
Even as BioMarin and Ascendis jockey for leadership in the achondroplasia arena, many other players are gunning for a share of this sizeable market, looking to stand out through better efficacy and safety, novel mechanisms or convenience.
Spurring Growth
Both Voxzogo and TransCon CNP work by mimicking the function of a naturally occurring hormone called the C-type natriuretic peptide (CNP), a signaling molecule involved in a key achondroplasia pathway.
Achondroplasia, Javed explained, is caused by a gain-of-function mutation in the FGFR3 gene, which leads to the over-activation of the FGFR3 receptor. This, in turn, suppresses the activity of cells that are crucial for bone development, “effectively stalling bone growth at the growth plate,” she continued.
These molecular underpinnings explain the key symptoms of achondroplasia: short limbs, hydrocephalus, curved spine and bowed legs. Patients with achondroplasia also suffer from physical developmental delays and, when left unchecked, back pain, breathing problems, obesity and recurrent infections.
CNP enters the picture partway through the FGFR3 cascade. The hormone “naturally counteracts FGFR3 activity,” to promote bone growth, Javed said, opening up a promising treatment mechanism for achondroplasia. With Voxzogo’s approval in 2021, BioMarin verified the clinical and regulatory value of the CNP pathway and “set the bar on an approvable endpoint” for achondroplasia, Tsai added.
Indeed, Phase III data submitted by the biotech to the regulator to support the approval showed that Voxzogo treatment improved annual growth velocity by 1.57 cm per year at 52 weeks, compared with placebo. Over the years, BioMarin has only strengthened Voxzogo’s profile, drawing from “more than 6,000 patient-years of data” across the drug’s clinical development and real-world use, Chief Commercial Officer Cristin Hubbard told BioSpace in an email.
This continued effort led to another victory in October 2023, when the FDA approved the drug’s expansion into children under 5 years of age.
“Voxzogo is the first and only approved medicine for achondroplasia starting at birth,” Hubbard said. Current consensus guidelines, published just this year in Nature Reviews Endocrinology and arranged by a global consortium of experts and patient advocates, highlight the value of timely treatment.
“Treatment should be initiated as early as possible,” the consensus statement read, pointing to new data suggesting that starting intervention within the first months of life could lead to better growth improvements.
Despite Voxzogo’s strong clinical profile, the achondroplasia market is hardly open-and-shut. Hubbard herself concedes that there remains unmet need with thousands of children worldwide still in need of treatment.
If approved this fall, Ascendis’ longer-acting CNP analog could help fill this need.
In the Phase II ACcomplisH study, TransCon CNP led to an annualized growth velocity of 5.42 cm per year, as opposed to 4.35 cm per year in placebo comparators. The difference was statistically significant in favor of Ascendis’ drug, according to a November 2023 publication in The Lancet, which also demonstrated a favorable overall safety profile.
“Ascendis’ likely approval of TransCon CNP for achondroplasia poses a major threat to BioMarin’s top-selling drug,” Javed said, however noting that BioMarin continues to hold not only a geographical advantage—with a commercial footprint of around 50 countries—but also a stronger label.
“[The] majority of children in the United States are actually diagnosed prenatally and often, the decision to treat is made prenatally,” she added. “BioMarin is the only one that is indicated in infants.”
Ascendis declined to comment for this article, citing the ongoing regulatory review for its drug application.
Striking at the Root
Despite being the preferred pathway of the two market leaders, the CNP cascade has some drawbacks, keeping the field open for alternative approaches.
For one, the CNP hormone is a vasodilator—a compound that widens the blood vessels—and therapeutic analogs come with concerns of low blood pressure, Javed explained. The molecule’s composition also poses a practical problem. CNP is a peptide hormone with a relatively short half-life, necessitating daily or weekly injections to maintain its therapeutic benefits. This, according to Javed, “can be burdensome” for patients.
Looking beyond CNP, some drugmakers, including California-based BridgeBio, are striking at the root of achondroplasia.
BridgeBio is developing infigratinib, a small-molecule drug that works by blocking the mutant FGFR3 receptor, in turn hitting achondroplasia “directly at its genetic source,” Justin To, CEO of Skeletal Dysplasias at the company, told BioSpace by email.
In November last year, the company published data from the Phase II PROPEL 2 study, touting a 2.5 cm per year increase in annualized growth velocity at 18 months of follow-up. Of note, infigratinib also demonstrated a significant improvement in body proportionality, defined as the ratio between the patients’ upper and lower body segments.
“Notably, Voxzogo and TransCon CNP weren’t effective on proportionality, which is of key importance to the patient/doc community,” Jefferies’ Tsai said, “so I think there is a real opportunity here for [infigratinib] to differentiate with broad and meaningful benefit.”
Aside from the proportionality edge, BridgeBio also hopes to compete on convenience. “We have heard from both families of children with achondroplasia and clinicians that there is a significant need for an oral treatment option,” To said. “If approved, [infigratinib] would be the first oral treatment option for children with achondroplasia.”
BridgeBio is currently running the fully-enrolled Phase III PROPEL 3 study of infigratinib in achondroplasia, with topline data expected early next year.
Aside from BridgeBio, Tsai also pointed to Tyra Biosciences’ FGFR3 blocker TYRA-300 as another promising upcoming achondroplasia treatment. The drug, also called dabogratinib, “is being positioned as a more selective FGFR3 inhibitor,” he continued, potentially even “more selective than infigratinib.” While primarily studying dabogratinib for bladder cancer, Tyra is also trialing the drug in mid-stage studies for achondroplasia.
Therapies that target the molecular root of achondroplasia, such as dabogratinib and infigratinib, “could translate to superior efficacy vs. existing CNP analogs,” Tsai said.
Of course, BioMarin, currently the undisputed achondroplasia leader, isn’t just sitting back and letting its challengers speed on ahead.
Tsai, in particular, has his eye on BMN-333, a long-acting CNP formulation, which is currently in early-stage testing. BMN-333, he said, “has been designed to sustain elevated CNP levels” and improve upon Voxzogo’s once-daily dosing regimen. BioMarin’s Hubbard noted that the company is set to start a pivotal Phase II/III study for BMN-333 in the first half of 2026.
But the biotech will continue to work on Voxzogo, even looking to position the drug as a treatment for other skeletal growth conditions. For instance, BioMarin has a late-stage program for hypochondroplasia, a genetic disorder that also results in dwarfism. Voxzogo is also being tested for two other genetic disorders, Noonan syndrome and Turner syndrome, that, aside from physical abnormalities, result in developmental defects. The Noonan and Turner programs are in Phase II.
“It’s the everyday milestones that families share that drive us,” Hubbard said. “Reaching a car door, riding a roller coaster, turning on a light switch, putting up his or her own hair. These moments, and the clear unmet need, are why we remain deeply committed to leading innovation in rare conditions.”
