Eiger BioPharmaceuticals announced the U.S. Food and Drug Administration (FDA) has accepted the Investigational New Drug (IND) application for lonafarnib in the treatment of both Hutchinson-Gilford Progeria Syndrome (HGPS or progeria) and progeroid laminopathies. Eiger is collaborating with The Progeria Research Foundation and plans to submit a new drug application (NDA) to the FDA in 2019. There is no approved treatment for progeria or progeroid laminopathies. Lonafarnib is a first-in-class prenylation inhibitor in development for hepatitis delta virus (HDV) infection and also progeria and progeroid laminopathies.
"We had a positive pre-IND meeting with the Division of Gastroenterology and Inborn Errors Products at FDA in August and now plan to submit an NDA for lonafarnib in the treatment of progeria and progeroid laminopathies in 2019," said David Apelian, Chief Operating Officer and Executive Medical Officer of Eiger. "We are committed to bring the first approved therapy to market for patients suffering from these devastating disorders."
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Progeria, also known as Hutchinson-Gilford Progeria Syndrome (HGPS), is a rare and rapidly fatal genetic condition of accelerated aging in children caused by a point mutation in the lamin A gene yielding the farnesylated aberrant protein, progerin. Lamin A protein is the structural scaffolding that holds the nucleus together. Researchers now believe that defective lamin A protein makes the nucleus unstable, and that cellular instability leads to the process of premature aging in Progeria. Children with Progeria die of the same heart disease that affects millions of normally aging adults (arteriosclerosis), but at an average age of 14.5 years. Disease manifestations include severe failure to thrive, scleroderma-like skin, global lipodystrophy, alopecia, joint contractures, skeletal dysplasia, global accelerated atherosclerosis with cardiovascular decline, and debilitating strokes. It is estimated that 400 children worldwide have Progeria.
Progeroid laminopathies are genetic conditions of accelerated aging caused by a constellation of mutations in the lamin A and/or Zmpste24 genes yielding farnesylated proteins that are distinct from progerin. While non-progerin producing, these genetic mutations result in disease manifestations with phenotypes that have overlap with, but are distinct, from progeria. It is estimated that in addition to the 400 children with Progeria, an additional 400 children worldwide have progeroid laminopathies.
Lonafarnib is a well-characterized, late-stage, orally active inhibitor of farnesyltransferase, an enzyme involved in modification of proteins through a process called prenylation. Progerin is a farnesylated protein that cannot be cleaved, resulting in tight association with the nuclear envelope, which in turn results in changes in nuclear envelope morphology and subsequent cellular damage. Lonafarnib blocks the farnesylation of progerin and has been dosed in over 80 children with Progeria at Boston's Children Hospital in multiple Phase 1/2 and Phase 2 studies. Lonafarnib has been granted Orphan Drug Designation for Progeria by the FDA. Lonafarnib is not approved for any indication, and is licensed by Eiger from Merck Sharp & Dohme Corp.