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Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome.

ABSTRACT: 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.

SUBMITTER: Gordon LB

PROVIDER: S-EPMC4082404 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome.

Gordon Leslie B LB Massaro Joe J D'Agostino Ralph B RB Campbell Susan E SE Brazier Joan J Brown W Ted WT Kleinman Monica E ME Kieran Mark W MW

Circulation 20140502 1

<h4>Background</h4>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 na ...[more]

PMID: 24795390

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Project description:BackgroundHutchinson-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.MethodsThirty-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.ResultsNo 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.ConclusionsComparisons 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 registrationURL: http://www.clinicaltrials.gov. Unique identifiers: NCT00879034 and NCT00916747.

Project description:PURPOSE:Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on physical examination. The aim of this study was to describe the natural history and pathophysiology of these abnormal calcifications in HGPS, and to determine whether medications and/or supplements tested in clinical trials alter their development. METHODS:Children from two successive clinical trials administering 1) lonafarnib (n?=?26) and 2) lonafarnib?+?pravastatin?+?zoledronic acid (n?=?37) were studied at baseline (pre-therapy), one year on therapy, and at end-of-therapy (3.3-4.3?years after the baseline visit). Calcium supplementation (oral calcium carbonate) was administered during the first year of the second trial and was subsequently discontinued. Information on calcifications was obtained from physical examinations, radiographs, and serum and urinary biochemical measures. The mineral content of two skin-derived calcifications was determined by x-ray diffraction. RESULTS:Extraskeletal calcifications were detected radiographically in 12/39 (31%) patients at baseline. The odds of exhibiting calcifications increased with age (p?=?0.045). The odds were unaffected by receipt of lonafarnib, pravastatin, and zoledronate therapies. However, administration of calcium carbonate supplementation, in conjunction with all three therapeutic agents, significantly increased the odds of developing calcifications (p?=?0.009), with the odds plateauing after the supplement's discontinuation. Composition analysis of calcinosis cutis showed hydroxyapatite similar to bone. Although serum calcium, phosphorus, and parathyroid hormone (PTH) were within normal limits at baseline and on-therapy, PTH increased significantly after lonafarnib initiation (p?<?0.001). Both the urinary calcium/creatinine ratio and tubular reabsorption of phosphate (TRP) were elevated at baseline in 22/39 (56%) and 31/37 (84%) evaluable patients, respectively, with no significant changes while on-therapy. The mean calcium?×?phosphorus product (Ca?×?Pi) was within normal limits, but plasma magnesium decreased over both clinical trials. Fibroblast growth factor 23 (FGF23) was lower compared to age-matched controls (p?=?0.03). CONCLUSIONS:Extraskeletal calcifications increased with age in children with HGPS and were composed of hydroxyapatite. The urinary calcium/creatinine ratio and TRP were elevated for age while FGF23 was decreased. Magnesium decreased and PTH increased after lonafarnib therapy which may alter the ability to mobilize calcium. These findings demonstrate that children with HGPS with normal renal function and an unremarkable Ca?×?Pi develop extraskeletal calcifications by an unidentified mechanism that may involve decreased plasma magnesium and FGF23. Calcium carbonate accelerated their development and is, therefore, not recommended for routine supplementation in these children.

Project description:Importance:Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare disorder associated with premature death due to cardiovascular events during the second decade of life. However, because of its rarity (107 identified living patients), the natural history of cardiac disease remains uncharacterized. Therefore, meaningful cardiac end points for clinical trials have been difficult to establish. Objective:To examine the course of appearance of cardiac abnormalities in patients with HGPS to identify meaningful cardiac end points for use in future clinical trials. Design, Setting, and Participants:In this prospective, cross-sectional, observational study, 27 consecutive patients with clinically and genetically confirmed classic HGPS were evaluated at a single center for 1 visit from July 1, 2014, through February 29, 2016, before initiation of treatment. Exposure:Classic HGPS. Main Outcomes and Measures:Echocardiography was used to assess ventricular and valve function using standard techniques. Diastolic left ventricular (LV) function was assessed using tissue Doppler imaging. Previously published normative data were used to adjust findings to age and body size. Results:This study included 27 patients (median age, 5.6 years; age range, 2-17 years; 15 [56%] male). Among echocardiographic indicators, LV diastolic dysfunction, defined as a tissue Doppler septal or lateral early velocity z score less than -2, was the most prevalent abnormality, seen in 16 patients (59%). Diastolic dysfunction was seen in all age groups, and its prevalence increased with age, mirroring findings seen during normal aging. Indicators of LV diastolic function were more abnormal in older patients. The z scores for lateral and septal early velocities were lower (r = -0.77, P < .001; and r = -0.66, P < .001, respectively), whereas those for the ratio of early mitral inflow velocity to early diastolic tissue Doppler myocardial velocity were higher (r = 0.80, P < .001; and r = 0.72, P < .001, respectively) in older patients. Other echocardiographic findings, including LV hypertrophy, LV systolic dysfunction, and valve disease, were less prevalent in the first decade and were seen more frequently in the second decade. Conclusions and Relevance:In this largest-to-date cohort of patients with HGPS, LV diastolic dysfunction was the most prevalent echocardiographic abnormality and its prevalence increased with aging. Echocardiographic indicators of LV diastolic function may be useful end points in future clinical trials in this patient population.

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Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome.

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Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome.

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