Biotech’s battle against skeletal dysplasia: Ray of hope for children with rare genetic disorder

Skeletal dysplasia, a group of genetic disorders that disrupts bone growth, affects one in 5000 babies. As treatments are intended to alleviate painful symptoms, two drugs are battling out in the clinic to prove their effectiveness. 

Bridge Bio’s infigratinib treatment outperforms FDA-approved Voxzogo for achondroplasia, a type of skeletal dysplasia

California-based BridgeBio’s late-stage drug infigratinib is currently being tested to treat achondroplasia, the most common form of dwarfism that affects around one in every 40,000 children, as well as hypochondroplasia – similar to, but milder than achondroplasia. Most cases of achondroplasia occur due to a sudden mutation in the FGFR3 gene, which is short for fibroblast growth factor receptor. This prevents bone growth and can lead to shortened arms and legs, poor muscle tone, and sometimes even a condition called kyphosis where a curved spine causes the upper back to appear rounded.

Infigratinib is an oral small molecule that is designed to target the root cause of the problem, which is FGFR3 gene signaling. The drug inhibits the overactive pathways associated with achondroplasia and hypochondroplasia to mitigate symptoms. 

The treatment helped boost the height of children in a phase 2 trial. It was found to be statistically significant and those in the dose escalation cohort had an increased annualized height velocity (AHV) – a measure for height growth – of more than 2.51cm/year after a year and over 2.5 cm/year at 18 months. Body proportionality improved from 2.02 at baseline to 1.88 after 18 months as well. For children of average stature, the ratio of upper to lower body segments tends to be 1.4 at birth, and can go down to one later in life.

There were no adverse effects and the drug was well-tolerated in the study.

“These data indicate that treatment with infigratinib is continuing to show increased growth velocity and improvements in body proportionality in children with achondroplasia. This is encouraging and suggests that infigratinib has the potential to enhance functionality for people living with achondroplasia in addition to increasing growth. We hope to see these improvements reflected in the ongoing PROPEL 3 pivotal study that will build toward providing a safe and effective oral therapy to those in the achondroplasia community who are seeking treatment,” said Ravi Savarirayan, the global lead investigator of the study, in a press release.

Infigratinib in phase 3 trial for skeletal dysplasia

Patients are currently being enrolled in a phase 3 study to test infigratinib for skeletal dysplasia. However, the drug, which was previously on the market to combat FGFR3-driven cancers since 2021, was withdrawn by the U.S. Food and Drug Administration (FDA) for the indication back in May. This setback came about as the drugmaker was unable to go through with a confirmatory clinical trial after it was granted accelerated approval, citing “difficulties in recruiting and enrolling study subjects.” 

Still, in skeletal dysplasias, Bridge Bio looks to take on multinational BioMarin Pharmaceuticals’ vosoritide, which is the first and only FDA-approved drug to help increase growth of children with achondroplasia. In fact, infigratinib already seems to have beat BioMarin’s drug in efficacy. 

Skeletal dysplasia treatments: Voxzogo vs infigratinib

BioMarin’s vosoritide, known under its brand name Voxzogo after grabbing FDA approval in October last year, the drug binds to a receptor natriuretic peptide receptor type B (NPR-B), which slows the activity of FGFR3. This way, it helps stimulate bone growth and alleviate painful symptoms. 

But up-and-coming rival infigratinib has overtaken Voxzogo, according to study data. BioMarin’s two-year results for its phase 3 extension study were 0.14 cms short of Voxzogo’s secondary endpoint for body proportionality.

Now, BioMarin has presented the results of a five-year follow-up of the therapy at the 2024 International Conference on Children’s Bone Health in Austria. The phase 2 study illustrates that children who were given Voxzogo experienced increases in bone length while maintaining bone strength. 

“In order for children with achondroplasia to experience meaningful changes in daily functioning following treatment to enable growth, it is critical that bone robustness is maintained to preserve strength,” said Cathleen Raggio, a pediatric orthopedic surgeon at the Hospital for Special Surgery in New York in a press release. “With this study, for the first time we have shown that treatment with Voxzogo enabled bones to remain strong as they lengthened, which is promising as we continue to better understand the impact of this therapeutic advancement.”

Meanwhile, BioMarin is also advancing the drug in the clinic to address hypochondroplasia and a growth disorder called idiopathic short stature in children, for both of which it is currently recruiting participants.

Can Ascendis’ Transcon CNP take on Voxzogo?

Aside from the infigratinib-Voxzogo race, there are a couple of other drugs that are on the radar. Transcon CNP is one of them. Danish biotech Ascendis Pharma has pushed its drug, Transcon CNP, into a global phase 2 trial for the treatment of achondroplasia. It is a prodrug of CNP, a protein that counteracts the growth-inhibiting effects of the FGFR3 mutation, and therefore, promotes bone growth. A prodrug is an inactive drug that becomes activated once it is taken up by the body.

Like Voxzogo, it is designed to elicit bone development with the help of CNP. However, it is unique in its delivery as it needs fewer doses and less amounts of CNP to do the job. The drug gets activated more slowly as it gets closer to the target, which helps turn down toxicities.

Recent phase 2 results suggest that it could be a worthy contender to Voxzogo. The drug was given to children aged two to 10 years old with achondroplasia and statistically significant improvements were observed. This was based on endpoints such as daily living functioning, emotional well-being, and the achondroplasia child experience measure-impact (ACEM) assessment, which measures the physical symptoms of the condition.

Another therapy in the making is California-based Tyra Biosciences’ TYRA-300, for which it plans to submit an Investigational New Drug (IND) application with the FDA later this year. Encouraging preclinical results for hypochondroplasia have shown that it increased bone size in FGFR3-mutated mice.

New gene mutation identified in Keutel syndrome 

Moreover, scientists have discovered another gene that could be linked to skeletal dysplasia. Earlier this year, a team at McGill University in Canada found that a defect in the MGP gene that is responsible for making the matrix Gla protein affects the structure of connective tissues that supports the body. The protein helps avoid the hardening of these connective tissues, and in its absence, leads to a rare disorder called Keutel syndrome, where parts of the body harden as they calcify. The findings highlight how future therapeutic interventions can eventually be carried out.

While more therapies mean more options for relief from symptoms, not everyone seems happy with these developments. These treatments have sparked controversy among some people with dwarfism, who fear that it will “eradicate dwarfism.” Plus, these medicines are only prescribed to children, so parents – most of whom do not have skeletal dysplasia – will have to consent on their child’s behalf, who may hold their own beliefs about dwarfism, according to a report by The Guardian.

Nevertheless, many view this as an issue of healthcare, and about improving the quality of life of patients with these disorders. And although they’re not a cure, these treatments could be the answer to allaying painful symptoms that children with skeletal dysplasia experience.

New treatments for skeletal dysplasia: