127 was originally developed for the treatment of cancer. In 2012, researchers reported that children with HGPS receiving lonafarnib showed modest improvement in weight gain and a large reduction in vascular stiffness. 8 Although survival was extended by lonafarnib, 9 lonafarnib was not a cure, so additional efforts to find a more effective therapy or combination of therapies were needed. An evidence-based rationale for a tripletherapy approach—adding a statin and a bisphosphonate to lonafarnib—was suggested by molecular pathway considerations and preclinical testing, including life-extending results of statin-bisphosphonate combination treatment in a Zmpste24 mouse model of HGPS. 10 A trial of a statin (pravastatin) and a bisphosphonate (zoledronic acid) was initiated in patients with HGPS in France in 2008, and a trial combining an FTI, pravastatin, and zoledronic acid was begun in 2009 in Boston.

Although the triple-combination therapy used in the Boston trial was well tolerated by children with HGPS, it demonstrated little benefit beyond that seen with lonafarnib alone. The small, additive benefit was increased bone mineral density, most likely attributable to the bisphosphonate. However, osteoporosis is not a primary contributor to premature mortality in HGPS, so it is not clear that this represents a clinically relevant advance. Furthermore, troubling evidence, presumably also secondary to bisphosphonates, was found of increased plaque formation in the carotid and femoral arteries, as well as apparent acceleration of the extraskeletal calcifications that are a feature of HGPS. It will be very interesting to learn the results of the French trial to see whether any of these same complications arose. The results reported here leave unresolved the question of whether an FTI plus a statin (without the bisphosphonate) might have provided benefit.