Progeria triple-therapy findings ‘disappointing’
medwireNews: Pravastatin and zoledronic acid provide no additional clinically relevant benefit to lonafarnib monotherapy for patients with Hutchinson-Gilford progeria syndrome (HGPS), study findings indicate.
Although the triple-therapy regimen resulted in improved bone density that was not seen in a previous trial of lonafarnib monotherapy, there were also increases in carotid and femoral artery plaques and extraskeletal calcifications, Leslie Gordon (Hasbro Children’s Hospital, Providence, Rhode Island, USA) and colleagues report in Circulation.
“Since increased bone fracture is not a disease feature, the addition of the combination of statin and bisphosphonate to lonafarnib therapy is not recommended for clinical treatment of HGPS”, they say.
The researchers treated 37 patients with the extremely rare, premature ageing syndrome with pravastatin, zoledronic acid and lonafarnib for 40 to 52 months.
They hoped that additionally inhibiting progerin prenylation would enhance the cardiovascular improvements seen with the protein farnesyltransferase inhibitor lonafarnib in a previous trial.
Overall, therapy was well tolerated, with no withdrawals due to treatment-related toxicity.
Among the 31 participants included in the full efficacy analysis, 22 (71.0%) had a successful response, defined as either weight gain (10% annualised increase in rate of weight gain vs pre-study or conversion from decreasing to increasing annualised change) or improved internal carotid artery adventitia echodensity (reduction to ≤90% of the value at study entry).
Individually, 15 (48.4%) of 31 participants achieved weight gain success, while echodensity success was achieved in 11 (31.4%) of 35 participants assessed.
Only six (12.9%) of the 35 participants succeeded for both outcome measures. This suggests that “it is unlikely that rate of weight gain is a surrogate for cardiovascular health”, Gordon and co-authors remark.
The team also observed significantly increased areal and volumetric bone mineral density and 1.5–1.8-fold increases in radial bone structure.
However, the proportion of patients with carotid artery plaques increased from 5% to 50% during the course of the study, while femoral artery plaques increased from 0% to 12% and extraskeletal calcifications went from 34% to 66%.
These increases could not be accounted for by increasing participant age alone and were not detected in the prior lonafarnib monotherapy trial, the researchers note.
Editorialist Francis Collins (National Institutes of Health, Bethesda, Maryland, USA) says that this finding is “troubling” and presumably “secondary to bisphosphonates”.
He concludes: “Though the results […] are disappointing, additional therapeutic options are emerging, and there is more momentum than ever in the basic and clinical research communities” to find a cure for HGPS.
By Laura Cowen
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