Impact of Farnesylation Inhibitors on Survival in Hutchinson-Gilford Progeria Syndrome

• Published in: Circulation (New York, N.Y.) Vol. 130; no. 1; pp. 27 - 34
• Main Authors: Gordon, Leslie B., Massaro, Joe, D’Agostino, Ralph B., Campbell, Susan E., Brazier, Joan, Brown, W. Ted, Kleinman, Monica E., Kieran, Mark W.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.07.2014
• Subjects: Adolescent; Adult; Alkyl and Aryl Transferases - antagonists & inhibitors; Atherosclerosis (general aspects, experimental research); Atherosclerosis - etiology; Atherosclerosis - genetics; Atherosclerosis - prevention & control; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cause of Death; Child; Child, Preschool; Clinical Trials as Topic - statistics & numerical data; Cohort Studies; Dimethylallyltranstransferase - antagonists & inhibitors; Diphosphonates - administration & dosage; Diphosphonates - pharmacology; Diphosphonates - therapeutic use; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Drug Therapy, Combination; Female; Genes, Dominant; Genotype; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Imidazoles - administration & dosage; Imidazoles - pharmacology; Imidazoles - therapeutic use; Kaplan-Meier Estimate; Lamin Type A; Male; Medical sciences; Multicenter Studies as Topic - statistics & numerical data; Nuclear Proteins - deficiency; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Piperidines - administration & dosage; Piperidines - pharmacology; Piperidines - therapeutic use; Pravastatin - administration & dosage; Pravastatin - pharmacology; Pravastatin - therapeutic use; Progeria - complications; Progeria - drug therapy; Progeria - mortality; Proportional Hazards Models; Protein Precursors - deficiency; Protein Precursors - genetics; Protein Precursors - metabolism; Protein Prenylation - drug effects; Pyridines - administration & dosage; Pyridines - pharmacology; Pyridines - therapeutic use; Treatment Outcome; Young Adult; Zoledronic Acid; Antineoplastic agent; Skin disease; Senescence; Prognosis; lamins; Estimation; Ageing; Cardiovascular disease; Survival; Syndrome; Kaplan-Meier method; Dwarfism; Vascular disease; Lonafarnib; Progeria; Atherosclerosis; prenylation; Inhibitor; Circulatory system; aging; Cardiology; Kaplan-Meier estimate; atherosclerosis; progeria; lonafarnib
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.113.008285

Hutchinson-Gilford progeria syndrome is an ultrarare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single-arm clinical trials administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications. We generated Kaplan-Meier survival analyses for the largest untreated Hutchinson-Gilford progeria syndrome cohort to date. Mean survival was 14.6 years. Comparing survival for treated versus age- and sex-matched untreated cohorts, hazard ratio was 0.13 (95% confidence interval, 0.04-0.37; P<0.001) with median follow-up of 5.3 years from time of treatment initiation. There were 21 of 43 deaths in untreated versus 5 of 43 deaths among treated subjects. Treatment increased mean survival by 1.6 years. This study provides a robust untreated disease survival profile that can be used for comparisons now and in the future to assess changes in survival with treatments for Hutchinson-Gilford progeria syndrome. The current comparisons estimating increased survival with protein farnesylation inhibitors provide the first evidence of treatments influencing survival for this fatal disease. http://www.clinicaltrials.gov. Unique Indentifiers: NCT00425607, NCT00879034, and NCT00916747.