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Vosoritide as a targeted therapy for FGFR3-related thanatophoric dysplasia

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:

FGFR3-related thanatophoric dysplasia (TD) is a severe skeletal dysplasia that is classically considered perinatal lethal. Thoracic narrowing leads to pulmonary hypoplasia and oxygenation concerns. Advanced neonatal resuscitation methods have improved outcomes for some, and a growing body of evidence demonstrates that a subset of patients with TD can survive past the perinatal period and even into adulthood. For those that survive, skeletal manifestations drive medical concerns, including the narrow thorax and foramen magnum.


Vosoritide is an FDA-approved therapy for infants with achondroplasia, the more common and less severe form of FGFR3-related skeletal dysplasia. Missense gain-of-function variants in FGFR3 underlie both achondroplasia and TD, with the strength of FGFR3 constitutive activation directly correlating with the severity of symptoms. Vosoritide’s mechanism of action reduces the activity of FGFR3, is approved for infants with achondroplasia, and is well tolerated with limited side effects. We hypothesized that vosoritide treatment is safe and effective for infants with TD. 




Methods:

Three infants with molecularly confirmed FGFR3-related TD were cared for in our Level IV neonatal intensive care unit. Informed consent was obtained for reporting of clinical information. Per the Duke University Health System IRB policy, the review of medical records for publication of 3 or fewer cases is not considered to be research involving human subjects and is considered exempt. Vosoritide was provided by BioMarin via unsolicited request.




Results:
Patient 1 is an 11-week-old female treated with vosoritide beginning at 14 days of life. Shortened long bones were observed on late first trimester ultrasound. Single-gene cell-free fetal DNA screening returned at 19 weeks gestation with a known TD-related pathogenic variant in FGFR3 (c.1118A>G (p.Y373C)). Repeat anatomy ultrasound was notable for a thoracic to abdominal circumference ratio of 0.6, suggestive of lethality. The patient was born via C-section at 37 weeks gestation with Apgar scores of 1, 3, 3, and 6 and admitted in critical condition. Medical Genetics was consulted at 20 hours of life and vosoritide use was considered. With the family’s goal of survival to discharge, compassionate use of vosoritide was approved in the first week of life. Prior to the first dose, the patient developed seizures, which were controlled with phenobarbital. Treatment started on day 14 of life and has continued daily with no serious adverse events. Hypotension has been reported with vosoritide, and our patient experienced a slight reduction in systolic pressure for 10 minutes with her first dose, which resolved without intervention. The patient has since transitioned to a conventional ventilator and received a tracheostomy. She continues to make progress towards discharge.


Patient 2 is a 4-week-old male with a previously reported TD variant (FGFR3 c.742C>T (p.R248C)). Vosoritide and supportive care were offered to the family, however, given the severity of disease, the family elected to pursue comfort care.


Patient 3 is a 20-month-old male with TD who had an initial 10 month stay in our NICU. Prior to discharge, he had a foramen magnum decompression surgery, a tracheostomy, and G-tube surgery. He receives high-level care at home and continues to make developmental progress. He is now babbling and starting to roll from back to front. Vosoritide treatment initiation is actively being arranged.



Conclusion:

Vosoritide can be used as a targeted therapy for thanatophoric dysplasia. Treatment with vosoritide, as early as days 14 of life, is well tolerated without adverse effects. Earlier treatment is likely to have the most benefit for surival by enhancing rib cage and linear growth. Further work is needed to assess drug safey in larger cohots and to develop outcome measures and biomarkers for future clinical trials. Patients with TD should be considered candidates for future FGFR3-targeted therapies.




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