Clinical Trial of Protein Farnesylation Inhibitors Lonafarnib, Pravastatin and Zoledronic Acid in Children with Hutchinson-Gilford Progeria Syndrome
Background—Hutchinson-Gilford progeria syndrome is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA yielding the farnesylated aberrant protein, progerin. Without progerin-specific treatment, death occurs at an average age of 14.6 years from an accelerated atherosclerosis. A previous single-arm clinical trial demonstrated that the protein farnesyltransferase inhibitor, lonafarnib, ameliorates some aspects of cardiovascular and bone disease. This present trial sought to further improve disease by additionally inhibiting progerin prenylation.
Methods—Thirty-seven participants with HGPS received pravastatin, zoledronic acid and lonafarnib. This combination therapy was evaluated, in addition to descriptive comparisons with the prior lonafarnib monotherapy trial
Results—No participants withdrew due to side effects. Primary outcome success was pre-defined by improved per patient rate of weight gain or carotid artery echodensity; 71.0% of participants succeeded (P<0.0001). Key cardiovascular and skeletal secondary variables were pre-defined. Secondary improvements included increased areal (P=0.001) and volumetric (P<0.001-0.006) bone mineral density, and 1.5-1.8-fold radial bone structure increases (P<0.001). Median carotid artery wall echodensity and carotid-femoral pulse wave velocity demonstrated no significant changes. Percentages of participants with carotid (5% to 50%; P=0.001) and femoral (0 to 12%; P=0.13) artery plaques and extraskeletal calcifications (34.4% to 65.6%; P=0.006) increased. Other than increased bone mineral density, no improvement rates exceeded those of the prior lonafarnib monotherapy treatment trial.
Conclusions—Comparisons with lonafarnib monotherapy treatment reveal additional bone mineral density benefit, but likely no added cardiovascular benefit with addition of pravastatin and zoledronic acid.
- Received February 26, 2016.
- Revision received May 17, 2016.
- Accepted May 30, 2016.