This is an open label dose adjusted phase II trial of the oral farnesyltransferase inhibitor (FTI) lonafarnib (SCH66336) for patients with HGPS and progeroid laminopathies.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare "premature aging" disease in which all children die at an average age of thirteen years (range 8-20 years) of severe atherosclerosis leading to strokes and heart attacks. It is a multisystem disease with objective clinical markers for disease progression. These include abnormalities in growth and body composition, bone mineral density, joint function, endocrine function, alopecia, and vascular disease. There is no effective therapy for any of the progressive and deleterious aspects of this disorder.

The gene defect causing HGPS and most progeroid laminopathies has been identified as a mutation in the gene LMNA, coding for the nuclear protein lamin A. Lamin A is normally expressed by most differentiated cells, and requires posttranslational farnesylation to incorporate into the nuclear membrane. The lamin A C-terminal peptide, including the farnesyl group, is subsequently cleaved, and mature lamin A becomes a prominent component of the nuclear scaffold just internal to the nuclear membrane, affecting nuclear structure and function.

In most cases, HGPS is a sporadic autosomal dominant disease caused by a single base alteration (henceforth designated as G608G) in the LMNA gene, which creates a cryptic splice site giving rise to an altered lamin A protein product in which 50 amino acids are deleted. The defective protein product in HGPS (henceforth progerin) lacks the cleavage site for removal of the C-terminal farnesylated peptide, and likely produces disease via dominant negative effects on the nuclear structure and function of various cell types that express lamin A. Most other progeroid laminopathies are caused by various mutations in the LMNA gene, which also subsequently creates abnormally functioning lamin A.

Lonafarnib is a farnesyltransferase inhibitor that blocks the post-translational farnesylation of prelamin A and other proteins that are targets for farnesylation. Farnesylation is essential for the function of both mutant and non-mutant lamin A proteins, including progerin. Therefore, farnesyltransferase inhibitors are ideal candidates for treatment of HGPS, which is caused by a protein (progerin) that likely depends on carrying a farnesyl group to execute its aberrant functions.

Both cell culture and mouse model studies of HGPS demonstrate improved phenotype after exposure to FTI. In vitro, exposure of HGPS skin fibroblasts and progerin-transfected HeLa cells to FTIs, including lonafarnib, prevents preprogerin from intercalating into the nuclear membrane where it normally functions, and eliminates nuclear deformity. In vivo, three Progeria-like mouse models show no appreciable signs of toxicity after FTI administration. In all three of these models, disease is significantly reduced when compared to age-matched controls after oral administration of FTI.

We propose that clinical features of HGPS can be ameliorated or reversed by blocking posttranslational farnesylation via treating patients with lonafarnib. We hypothesize that reduction of the quantity of functional progerin or, in the case of other progeroid laminopathies, other abnormal lamin proteins, will improve disease signs, symptoms and outcome. We also hypothesize that the toxicity profile of FTI inhibition using lonafarnib will be similar to that observed in children with malignant brain tumors treated with the compound.

Inclusion Criteria:

• All patients must have confirmatory mutational analysis showing G608G mutation in the lamin A gene.
• Patients with progeroid laminopathies, showing clinical signs of Progeria but with other confirmed mutations in LMNA will be eligible for therapy. This population will be analyzed separately from those with the classical mutations.
• Patients must be willing and able to come to Boston for appropriate studies and examinations approximately once every 4 months.
• Patients must have a minimum of one year of weight data available, with five data points or more, each separated by one month or more over a one year period and approval by the study team.
• APC (ANC + bands + monocytes = APC) > 1,000/ml, Platelets > 75,000/ml (transfusion independent); Hemoglobin >9g/dl.
• creatinine less than or equal to 1.5 times normal for age or GFR > 70 ml/min/1.73m2.
• bilirubin less than or equal to 1.5 x upper limit of normal for age; SGPT (ALT) < and SGOT (AST) < 5 x normal range for age.
• PT/PTT < 120% upper limit of normal OR PI approval.
• No overt renal, hepatic, pulmonary disease or immune dysfunction.
• Patients taking growth hormone when entering the study must have pretreatment weight measures while on growth hormone which are specified above. In addition, patients must remain on growth hormone treatment for the duration of the present clinical trial. Patients entering the trial not on growth hormone must remain off of growth hormone for the duration of their participation.
• Signed informed consent according to institutional guidelines must be obtained and patient must begin therapy within twenty eight (28) days.

Exclusion Criteria:

• Patient must not be receiving any other experimental drug therapy.
• Patients must not be taking medications that significantly affect the metabolism of lonafarnib.
• Subjects who have known or suspected hypersensitivity to any of the excipients included in the formulation should not be treated.
• Patients must not be pregnant or breast-feeding. Female patients of childbearing potential must have negative serum or urine pregnancy test. Male and female patients of reproductive potential must agree to use a medically accepted form of birth control while on study and up to 10 weeks after treatment. It is permissible for female patients to take oral contraceptives or other hormonal methods while receiving treatment with lonafarnib.

The analysis population represents the 25 patients with classic HGPS who received the farnesyltransferase inhibitor lonafarnib for a minimum of 2 y. The analysis population does not include 1 patient (with prior history of strokes) who died of a stroke after 5 mo on study, or 2 additional patients who had nonclassic mutations.

Up to 2 years: Assessed at a minimum at weeks 16, 32, 52, 68, 84 and 104

This was an open label clinical trial on a very rare disease population. Patient numbers are small, though 26 participants represents a significant portion of the world's population of children with HGPS

Open Label