Lonafarnib

Lonafarnib is a small-molecule drug that acts as a farnesyltransferase inhibitor (FTI). It binds to the active site of farnesyltransferase, an enzyme that attaches a farnesyl lipid group to proteins with a CAAX motif, including lamins and several signaling proteins. In Hutchinson-Gilford progeria syndrome (HGPS), a mutant lamin A protein called progerin remains permanently farnesylated, contributing to abnormal cell structure and function. By inhibiting farnesylation, lonafarnib aims to reduce progerin-associated cellular abnormalities and slow disease progression. The drug is taken orally.

Indications and use: In the United States, lonafarnib is approved for the treatment of Hutchinson-Gilford progeria syndrome and processing-defective disorders related to farnesyltransferase inhibition. It has been studied in clinical trials for other cancers, but no additional approved cancer indications have emerged.

Clinical evidence: Trials in children with HGPS have reported improvements in growth and weight and stabilization of certain cardiovascular disease markers. Some analyses have suggested a potential survival benefit compared with historical data, though lonafarnib is not curative and responses can vary among patients. Ongoing monitoring and supportive care remain important components of management.

Safety and administration: Lonafarnib is administered by mouth, with dosing individualized to the patient under medical supervision. Common adverse effects include gastrointestinal symptoms (nausea, diarrhea, decreased appetite), fatigue, and infections. Clinicians assess liver function and potential drug interactions, particularly with other medications metabolized by cytochrome P450 enzymes.