Key result
Triple combination therapy improves weight gain or carotid echodensity in ~71% of patients.
Why the study?
Hutchinson-Gilford progeria syndrome causes fatal premature aging due to progerin, and prior lonafarnib monotherapy showed some cardiovascular and bone benefits but further improvement was sought by additional inhibition of progerin prenylation.
Does the addition of pravastatin and zoledronic acid to lonafarnib improve weight gain or carotid artery echodensity in children with Hutchinson-Gilford progeria syndrome?
Does the addition of pravastatin and zoledronic acid to lonafarnib improve weight gain or carotid artery echodensity in children with Hutchinson-Gilford progeria syndrome?
p-value: p=<0.0001
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“They indicate that even though the three-drug regimen improves bone size and mineral density, no additional benefits over the one-drug treatment is observed in cardiovascular structure and function.”
“enthusiasm is tempered by recognizing that lonafarnib is not a cure for HGPS because several aspects of the phenotype, including alopecia, joint contractures, insulin resistance, and conductive hearing loss, do not improve with treatment.”
“A poignant example of the pressing need for effective treatments is one of the rarest of rare diseases: Hutchinson-Gilford progeria syndrome (HGPS), and this issue of Circulation reports the results of a triple-combination therapy trial for HGPS.”
The addition of pravastatin and zoledronic acid to lonafarnib in children with Hutchinson-Gilford progeria syndrome provides additional bone mineral density benefits but likely no added cardiovascular benefit compared to lonafarnib monotherapy.
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 Hutchinson-Gilford progeria syndrome 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 because of side effects. Primary outcome success was predefined 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 predefined. Secondary improvements included increased areal (P=0.001) and volumetric (P<0.001-0.006) bone mineral density and 1.5- to 1.8-fold increases in radial bone structure (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 the addition of pravastatin and zoledronic acid. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00879034 and NCT00916747.
No takes yet. Share an insight, caveat, or question.
Gordon et al. (2016) studied Hutchinson-Gilford progeria syndrome (n=37). pravastatin, zoledronic acid, and lonafarnib vs. prior lonafarnib monotherapy trial was evaluated on improved per-patient rate of weight gain or carotid artery echodensity (p=<0.0001). Combination therapy with pravastatin, zoledronic acid, and lonafarnib achieved primary outcome success (improved weight gain or carotid echodensity) in 71.0% of participants (P<0.0001).
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: