PRO4 EFFICACY AND SAFETY OF LONAFARNIB FOR THE TREATMENT OF PROGERIA: A QUALITATIVE SYSTEMATIC REVIEW OF LITERATURE

Abstract

Progeria is a rare, genetic, premature aging disease with no approved treatments currently. As lonafarnib is being investigated in Phase 2 clinical trials for treatment of progeria, we systematically reviewed the literature to identify the studies evaluating lonafarnib for the treatment of progeria. PubMed, Cochrane, and Clinicaltrials.gov databases were searched on 18 October 2018 using keywords such as “progeria,” “Hutchinson-Gilford Syndrome,” “HGPS,” and “premature aging syndrome”. Efficacy and safety data were extracted from studies selected after abstract and full-text screening. Quality assessment of included studies was performed using Downs and Black checklist. Eight publications were included, which reported data from three, Phase 2, single-arm trials of lonafarnib. Lonafarnib was administered as monotherapy in NCT00916747 and NCT00425607 and as triple-drug therapy with zoledronic acid and pravastatin in NCT00879034. In lonafarnib monotherapy trials, 36% of patients achieved successful rate of weight gain. Cardiovascular parameters improved in children treated with lonafarnib monotherapy. Although no additional cardiovascular benefit was observed with triple-drug therapy, significant improvements in absolute and height-adjusted areal bone mineral density (BMD) (p<0.001) and radial volumetric BMD at all sites (p<0.001–0.006) were observed. A successful rate of weight gain or decreased echodensity with triple-drug therapy was observed in 71% of patients. When compared with matched untreated cohort, survival analyses showed no significant difference in patients on triple-drug therapy; however, lonafarnib monotherapy (hazard ratio: 0.12; 95% confidence interval: 0.010.93; p=0.04) was associated with significantly decreased mortality. None of the patients withdrew from monotherapy or triple-drug therapy trial due to treatment-related toxicities. Adverse events (AEs) were consistent with previously reported AEs for lonafarnib. Lonafarnib was safe and well tolerated in the monotherapy and triple-drug therapy studies. Lonafarnib monotherapy improved cardiovascular parameters and survival of progeria patients. However, triple-drug therapy showed no additional cardiovascular benefit over monotherapy or survival benefit over matched untreated patients.