• Leslie B Gordon, Heather Shappell, Joe Massaro, Ralph B D'Agostino, Joan Brazier, Susan E Campbell, Monica E Kleinman, and Mark W Kieran.
• Department of Pediatrics, Division of Genetics, Hasbro Children's Hospital, Providence, Rhode Island.
• JAMA. 2018 Apr 24; 319 (16): 1687-1695.

ImportanceHutchinson-Gilford progeria syndrome (HGPS) is an extremely rare fatal premature aging disease. There is no approved treatment.ObjectiveTo evaluate the association of monotherapy using the protein farnesyltransferase inhibitor lonafarnib with mortality rate in children with HGPS.Design, Setting, And ParticipantsCohort study comparing contemporaneous (birth date ≥1991) untreated patients with HGPS matched with treated patients by age, sex, and continent of residency using conditional Cox proportional hazards regression. Treatment cohorts included patients from 2 single-group, single-site clinical trials (ProLon1 [n = 27; completed] and ProLon2 [n = 36; ongoing]). Untreated patients originated from a separate natural history study (n = 103). The cutoff date for patient follow-up was January 1, 2018.ExposureTreated patients received oral lonafarnib (150 mg/m2) twice daily. Untreated patients received no clinical trial medications.Main Outcomes And MeasuresThe primary outcome was mortality. The primary analysis compared treated patients from the first lonafarnib trial with matched untreated patients. A secondary analysis compared the combined cohorts from both lonafarnib trials with matched untreated patients.ResultsAmong untreated and treated patients (n = 258) from 6 continents, 123 (47.7%) were female; 141 (54.7%) had a known genotype, of which 125 (88.7%) were classic (c.1824C>T in LMNA). When identified (n = 73), the primary cause of death was heart failure (79.4%). The median treatment duration was 2.2 years. Median age at start of follow-up was 8.4 (interquartile range [IQR], 4.8-9.5) years in the first trial cohort and 6.5 (IQR, 3.7-9.0) years in the combined cohort. There was 1 death (3.7%) among 27 patients in the first trial group and there were 9 deaths (33.3%) among 27 patients in the matched untreated group. Treatment was associated with a lower mortality rate (hazard ratio, 0.12; 95% CI, 0.01-0.93; P = .04). In the combined cohort, there were 4 deaths (6.3%) among 63 patients in the treated group and 17 deaths (27.0%) among 63 patients in the matched untreated group (hazard ratio, 0.23; 95% CI, 0.06-0.90; P = .04).Conclusions And RelevanceAmong patients with HGPS, lonafarnib monotherapy, compared with no treatment, was associated with a lower mortality rate after 2.2 years of follow-up. Study interpretation is limited by its observational design.

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