Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome

Abstract

Importance: Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare fatal premature aging disease. There is no approved treatment.

Objective: To evaluate the association of monotherapy using the protein farnesyltransferase inhibitor lonafarnib with mortality rate in children with HGPS.

Design, setting, and participants: Cohort 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.

Exposure: Treated patients received oral lonafarnib (150 mg/m2) twice daily. Untreated patients received no clinical trial medications.

Main outcomes and measures: The 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.

Results: Among 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 relevance: Among 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.

Figure 1.. Posttranslational Processing Pathways Producing Lamin A and Progerin, Including the Target Site for Lonafarnib

Panel A: A prelamin polypeptide chain with its C-terminal −CAAX box, representing cysteine (C), aliphatic amino acids (AA), and any amino acid (X). The α-helical rod domain is divided into segments to assist in displaying the progerin defect. Posttranslational processing consists of 4 steps: (1) A farnesyl group is attached to the cysteine residue of the −CAAX box by farnesyltransferase; (2) the last 3 residues are proteolytically cleaved by the zinc metalloprotease Zmpste24 or by Ras-converting enzyme (RCE1); (3) carboxymethylation by isoprenylcysteine carboxyl methyltransferase (ICMT); and (4) the terminal 15 C-terminal residues, including the farnesylated and carboxymethylated cysteine, are cleaved off by Zmpste24. Panel B: Representative progerin-expressing cell type (fibroblasts) demonstrating (left) lamin A associated with the inner nuclear membrane in a normal cell, (center) reduced lamin A and presence of farnesylated progerin in a Hutchinson-Gilford progeria syndrome (HGPS) cell, and (right) decreased progerin with appearance of nonfarnesylated preprogerin in a lonafarnib-treated HGPS cell. Progerin affects every level of cellular function; major progerin-associated cellular effects are listed in the box.

Figure 2.. Flow of Patients Through the Study

Two hundred fifty-eight patients were used to construct the untreated natural history analysis (panel A). Of these, 87 patients were both contemporaneous with the treatment trial patients and not included in a treatment trial at any time. To compare mortality rates among treated vs untreated patients, random matching was performed whereby (panel B) 27 patients from treatment trial 1, 63 patients from treatment trial 1 plus treatment trial 2, and 36 patients from treatment trial 2 were randomly matched on age, sex, and continent of residency in 3 separate analyses. ^aThese are the treated patients used in treatment trial 1–treated vs matched untreated comparison of mortality rates. ^bThese are the treated patients used in the treatment trial 2–treated vs matched untreated comparison of mortality rates.

Figure 3.. Kaplan-Meier Survival Curves for Untreated and Treated Hutchinson-Gilford Progeria Syndrome Cohorts

Number of patients at risk are presented below the x-axis. If any patient in a matched pair was censored, the corresponding match was censored at the same follow-up time and the number at risk decreased. Also shown are numbers of deaths that occurred before or at that time point and after the previous time point on the x-axis. For panel A, time 0 on the x-axis (ie, beginning of patient risk) is date of birth. For panels B-D, time 0 on the x-axis is defined for each matched pair as the age at treatment initiation for the treated patient in the matched pair. Panel A: The untreated cohort includes all patients never treated (median follow-up time, 11.8 [interquartile range {IQR}, 7.8-15.2] years); treated patients were also included but were censored at age of treatment initiation (median follow-up time, 6.0 [IQR, 3.5-8.9] years). There were 124 deaths among 258 patients. Mean and median survival times were 14.5 years and 14.6 years, respectively. Median follow-up time was 9.9 (IQR, 5.7-14.0) years. Panel B: For treatment trial 1, there was 1 death in 27 treated patients and there were 9 deaths in 27 matched untreated patients. P = .04 based on Cox proportional hazards regression conditioned on the matched pair. Median follow-up time was 2.2 (IQR, 1.9-2.2) years for treated and 2.1 (IQR, 1.0-2.2) years for untreated patients. Panel C: For treatment trial 1 + treatment trial 2, there were 4 deaths in 63 treated patients and 17 deaths in 63 matched untreated patients. P = .03 based on Cox proportional hazards regression conditioned on the matched pair. The median follow-up time was 2.2 (IQR, 1.4-2.3) years for treated and 1.7 (IQR, 0.6-2.2) years for untreated patients. Panel D: For treatment trial 2, there were 3 deaths in 36 treated patients and 8 deaths in 36 matched untreated patients. P = .18 based on Cox proportional hazards regression conditioned on the matched pair. The median follow-up time was 2.0 (IQR, 1.3-2.5) years for treated patients and 1.9 (IQR, 1.0-2.4) years for untreated patients.