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An Open Label Dose Adjusted Phase II Trial of the Oral Farnesyltransferase Inhibitor (FTI) Lonafarnib (SCH66336) for Patients With Hutchinson-Gilford Progeria Syndrome (HGPS) and Progeroid Laminopathies

Phase 2
1 Year
Open (Enrolling)
Progeria, Hutchinson-Gilford Syndrome

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Trial Information

An Open Label Dose Adjusted Phase II Trial of the Oral Farnesyltransferase Inhibitor (FTI) Lonafarnib (SCH66336) for Patients With Hutchinson-Gilford Progeria Syndrome (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

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

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

- 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.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To evaluate the therapeutic effect of oral lonafarnib in patients with HGPS. Activity will be assessed by determining the change in rate of weight gain over baseline determined pre-therapy for each patient.

Outcome Time Frame:

Duration of the study

Safety Issue:


Principal Investigator

Mark W Kieran, MD, PhD

Investigator Role:

Study Chair

Investigator Affiliation:

Dana-Farber Cancer Institute, Children's Hospital Boston


United States: Food and Drug Administration

Study ID:




Start Date:

May 2007

Completion Date:

October 2009

Related Keywords:

  • Progeria
  • Hutchinson-Gilford Syndrome
  • Hutchinson-Gilford Progeria Syndrome
  • HGPS
  • Progeria
  • FTI
  • Farnesyltransferase Inhibitor
  • Lonafarnib
  • Progeria



Children's Hospital Boston Boston, Massachusetts  02115