The daily injectable vosoritide (Voxzogo) appears promising for various genetic causes of short stature in children, new phase 2 trial data suggested.
Vosoritide is a C-type natriuretic peptide analog that binds its receptor on chondrocytes, promoting growth by inhibiting the extracellular signal-regulated protein kinases 1 and 2-mitogen-activated protein kinase pathways. It was approved in 2021 by the US Food and Drug Administration for the treatment of children aged 5 years and older with achondroplasia.
Now, preliminary data suggest that vosoritide produces growth increases > 3 cm a year in children with a variety of short stature conditions, including Noonan syndrome, aggrecan (ACAN) deficiency, heterozygous NPR2 mutations, and neurofibromatosis 1 (NF1). Phase 2 results published in April also showed vosoritide’s efficacy in treating hypochondroplasia.
“Previously, these patients would be diagnosed with ‘idiopathic short stature’, but now we know that some of them are due to these genetic defects,” the study’s lead author, Andrew Dauber, MD, chief of endocrinology at Children’s National Hospital in Washington, DC, told Medscape Medical News. “What unifies them is that they signal downstream through the same pathway.”
Growth hormone therapy can help accelerate growth in some of these conditions but not all. Vosoritide offers a potentially more effective alternative, he noted.
“We’ve had patients travel from literally all over the world to be a part of our trials because they’re so motivated and excited by this opportunity to have a therapy which can help their children grow. That’s been really gratifying and exciting to be a part of,” Dauber said.
Despoina Galetaki, MD, a postdoctoral fellow at Children’s National Hospital, presented the new data at the annual meeting of the Pediatric Endocrine Society in Chicago.
Cautioning Patience With Early Data
Asked to comment, session moderator Halley M. Wasserman, MD, associate professor of pediatric endocrinology at Cincinnati Children’s Hospital Medical Center, Cincinnati, told Medscape Medical News, “I thought it was a really interesting initial study of some beginning data, but it seems still quite early, with quite a lot left to learn.”
Of 24 patients enrolled in the study, 11 had completed 12 months of vosoritide treatment in the data Galetaki presented.
Wasserman pointed out, “In any kind of condition where growth is being treated, you might see an initial gain in that first year. Even with growth hormone, you get your best response in that first year, and then, it tapers off. And then of course, ultimately, the question is going to be how does this impact final adult height. Just because you increase their growth velocity doesn’t mean that it has a sustained effect on final adult height.”
Nonetheless, she said, “It looks promising.”
Growth Velocity Increased, Some Achieve Normal Height
The 24 study participants were all prepubertal children older than 3 years of age (mean, 7 years), with variants in one of six categories of genetic causes of short stature. None had growth hormone deficiency, and none had concurrent growth hormone treatment, although prior such treatment was allowed. Of the 11 who completed 1 year of vosoritide treatment, nine entered an extension study.
At baseline, the study participants had a mean height standard deviation of −3.09 (range, −8.99 to −2.16). Annualized growth velocity increased from 4.5 cm/y at baseline to 8.5 cm/y at 6 months, then leveled off at 8.1 cm/y at 1 year. These improvements were similar across the different genetic conditions (Noonan, NPR2, ACAN, and NF1).
“Some of the individual patients have now gone above standard deviation of −2, which is within the normal range. These are the patients who probably didn’t start from as low, but some have moved into the normal range and others are on their way there,” Dauber said.
Wasserman noted, “That’s more than we often get from growth hormone, so it’s encouraging to see. It’s just hard to know if that’s going to be sustained, but (the investigators) are looking at it.”
Scoliosis and Knock Knees: Due to the Condition or the Treatment?
Overall, the drug was well tolerated, and there were no discontinuations due to adverse events. Injection site reactions occurred in 33% of patients but all self-resolved.
There were no grade 4 or 5 adverse events. There were seven cases of grade 3 adverse events. These included two cases of genu valgum (aka, “knock knees”) in patients with Noonan and ACAN, which were potentially related to the treatment but could also have been due to the conditions themselves, Dauber said.
In addition, scoliosis was reported in seven patients, of which four cases were present prior to treatment.
“It’s unclear if genu valgum and scoliosis are related to the underlying growth disorder, the generalized increase in growth velocity, or specifically due to vosoritide treatment,” Galetaki said in her presentation.
Wasserman commented, “We have to continue to pay attention to this, not knowing if some of the skeletal deformities were just unmasked because of the growth or if there’s something related to the treatment.”
Scoliosis has also been observed with rapid growth from growth hormone use, she noted.
“I think that warrants further study as well, too, because you don’t want to just necessarily make these bones grow longer if they’re not growing straight as well.”
Dauber advised clinicians, “I think it’s really important for people to pay attention to a child who’s not growing well and to investigate further. And, if there are no signs of some other underlying illness, doing early genetic testing could be very helpful. I’m hopeful that in the future, we’ll have more precision medicine approaches for targeted treatment.”
The study was funded by an investigator-initiated grant from BioMarin Pharmaceutical to Dauber. Galetaki and Wasserman had no disclosures.
Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape Medical News, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X @MiriamETucker.