Advertisement

FDA approval summary for lonafarnib (Zokinvy) for the treatment of Hutchinson-Gilford progeria syndrome and processing-deficient progeroid laminopathies

Published:December 12, 2022DOI:https://doi.org/10.1016/j.gim.2022.11.003

      Abstract

      The U.S. Food and Drug Administration recently approved lonafarnib as the first treatment for Hutchinson-Gilford progeria syndrome (HGPS) and processing-deficient progeroid laminopathies. This approval was primarily based on a comparison of patients with HGPS treated with lonafarnib in 2 open-label trials with an untreated patient cohort. With up to 11 years of follow-up, it was found that the lonafarnib treated patients with HGPS had a survival benefit of 2.5 years compared with the untreated patients with HGPS. This large treatment effect on the objective endpoint of mortality using a well-matched comparator group mitigated potential sources of bias and together with other evidence, established compelling evidence of a drug effect with benefits that outweighed the risks. This approval is an example of U.S. Food and Drug Administration’s regulatory flexibility for a rare disease while ensuring that standards for drug approval are met.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      ACMG Member Login

      Are you an ACMG Member? Sign in for online access.

      Subscribe:

      Subscribe to Genetics in Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Gordon L.B.
        • Shappell H.
        • Massaro J.
        • et al.
        Association of lonafarnib treatment vs no treatment with mortality rate in patients with Hutchinson-Gilford progeria syndrome.
        JAMA. 2018; 319: 1687-1695https://doi.org/10.1001/jama.2018.3264
        • Gordon L.B.
        • Massaro J.
        • D’Agostino Sr., R.B.
        • et al.
        Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome.
        Circulation. 2014; 130: 27-34https://doi.org/10.1161/CIRCULATIONAHA.113.008285
        • Kieran M.W.
        • Gordon L.
        • Kleinman M.
        New approaches to progeria.
        Pediatrics. 2007; 120 (Published correction appears in Pediatrics. 2007;120(6):1405.): 834-841
        • Toth J.I.
        • Yang S.H.
        • Qiao X.
        • et al.
        Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes.
        Proc Natl Acad Sci U S A. 2005; 102: 12873-12878https://doi.org/10.1073/pnas.0505767102
        • Fong L.G.
        • Frost D.
        • Meta M.
        • et al.
        A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria.
        Science. 2006; 311: 1621-1623https://doi.org/10.1126/science.1124875
        • Gordon L.B.
        • Kleinman M.E.
        • Miller D.T.
        • et al.
        Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome.
        Proc Natl Acad Sci U S A. 2012; 109: 16666-16671https://doi.org/10.1073/pnas.1202529109
      1. Howard Worman EB. Progeroid laminopathies white paper; 2020.

        • Shackleton S.
        • Smallwood D.T.
        • Clayton P.
        • et al.
        Compound heterozygous ZMPSTE24 mutations reduce prelamin A processing and result in a severe progeroid phenotype.
        J Med Genet. 2005; 42: e36https://doi.org/10.1136/jmg.2004.029751
        • Moscicki R.A.
        • Tandon P.K.
        Challenges for small biopharmaceutical companies.
        N Engl J Med. 2017; 376: 1698https://doi.org/10.1056/NEJMc1702644
        • Kieran M.W.
        • Packer R.J.
        • Onar A.
        • et al.
        Phase I and pharmacokinetic study of the oral farnesyltransferase inhibitor lonafarnib administered twice daily to pediatric patients with advanced central nervous system tumors using a modified continuous reassessment method: a Pediatric Brain Tumor Consortium study.
        J Clin Oncol. 2007; 25: 3137-3143https://doi.org/10.1200/JCO.2006.09.4243
      2. US Food and Drug Administration. Drug approval package: ZOKINVY. FDA Drug Approvals and Databases. Published December 18, 2020. Accessed November 16, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213969Orig1s000TOC.cfm

        • Kearns G.L.
        • Abdel-Rahman S.M.
        • Alander S.W.
        • Blowey D.L.
        • Leeder J.S.
        • Kauffman R.E.
        Developmental pharmacology—drug disposition, action, and therapy in infants and children.
        N Engl J Med. 2003; 349: 1157-1167https://doi.org/10.1056/NEJMra035092
        • Upreti V.V.
        • Wahlstrom J.L.
        Meta-analysis of hepatic cytochrome P450 ontogeny to underwrite the prediction of pediatric pharmacokinetics using physiologically based pharmacokinetic modeling.
        J Clin Pharmacol. 2016; 56: 266-283https://doi.org/10.1002/jcph.585