Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin. This multisystem disorder causes failure to thrive and accelerated atherosclerosis leading to early death. Farnesyltransferase inhibitors have ameliorated disease phenotypes in preclinical studies. Twenty-five patients with HGPS received the farnesyltransferase inhibitor lonafarnib for a minimum of 2 y. Primary outcome success was predefined as a 50% increase over pretherapy in estimated annual rate of weight gain, or change from pretherapy weight loss to statistically significant on-study weight gain. Nine patients experienced a ≥50% increase, six experienced a ≥50% decrease, and 10 remained stable with respect to rate of weight gain. Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes. Results from this clinical treatment trial for children with HGPS provide preliminary evidence that lonafarnib may improve vascular stiffness, bone structure, and audiological status.

Conflict of interest statement

Conflict of interest statement: W.R.B. and P.S. are employees of Merck Pharmaceutical, the company that supplied the experimental agent for this clinical trial. L.B.G. is the mother of a child with progeria who participated in this study.

Figures

Fig. 1.

Effect of lonafarnib on body weight. Pretherapy rate of weight change (x axis) vs. on-therapy rate of weight change (y axis) in 25 trial participants. Blue circles, 50% increase in rate of weight gain (success) (n = 9). Red triangles, <50% increase in rate of weight gain (lack of success) (n = 16).

Fig. 2.

PWV improvements with lonafarnib therapy. PWVcf in m/s (y axis) for each trial participant at pretherapy (circles) and end of therapy (squares); connecting lines show change in PWV for each child (n = 18). Published normal range (4.8–6.6 m/s) (23) is plotted as a solid horizontal blue bar for comparison. All participants except one (dashed line) showed improvement in PWV.

Fig. 3.

Lonafarnib normalized skeletal rigidity in HGPS. Box plots of (A) cross-sectional axial (EA), (B) bending (EI), and (C) torsional (GJ) rigidities measured using pQCT at the fourth percentile radial site in control (C), HGPS pretherapy [HG(P)], and HGPS end-of-therapy [HG(E)] groups. We published this control group’s data previously (15) and include it here for statistical comparison with the HGPS groups. Top and bottom box edges represent the 75th and 25th interquartile (IQR) ranges, respectively. Horizontal lines within boxes represent medians. Lower and upper whiskers represent Q1 − 1.5 × IQR and Q3 + 1.5 × IQR. *P < 0.01; **P < 0.001; NS, P > 0.05.