Treatments for progeria are limited but lonafarnib and FTIs as a class have given renewed hope for children with the condition
Despite an unpromising start for development of farnesyltransferase inhibitors (FTIs) in cancer indications, lonafarnib is now providing new hope for children with the rare and life-threatening genetic disease, progeria. Results from the first-ever clinical trial in children with progeria have recently been published, with every child showing an improvement in her symptoms (weight gain, bone structure, hearing and/or vascular stiffness).
Affecting one in eight million live births, progeria (also known as Hutchinson-Gilford Progeria Syndrome or HGPS), is a rare and fatal disease characterised by symptoms of premature ageing in children.
Children with the disorder appear healthy at birth, but then fail to thrive. By the age of 18–24 months, symptoms such as limited growth, whole-body alopecia and distinctive facial features, become apparent. As the children age, signs and symptoms get progressively worse, with kidney failure, loss of eyesight and cardiovascular problems commonly reported.
Similarly to elderly people, affected children develop musculoskeletal degeneration with a loss of body fat and muscle, stiff joints, osteoporosis and often dislocation of the hips. The average lifespan of children with progeria is 13 (range 8–20) years, with death usually a consequence of heart attack or stroke caused by atherosclerosis.
Rarely inherited, progeria is caused by a sporadic, single-base mutation at position 1824 in the LMNA gene, resulting in substitution of thymine instead of cytosine. Normally, the LMNA gene produces the lamin A protein, which is the structural scaffolding that holds the cell nucleus together. Specifically, this occurs when a farnesyl functional group is attached to prelamin A, allowing temporary attachment to the nuclear rim and subsequent removal of the farnesyl group to produce lamin A.
The mutated lamin A protein that causes progeria is called progerin. Permanent farnesylation in progerin results in irreversible attachment to the nuclear membrane, causing inadequate structural support and interference with mitosis and other such processes.
Treatments for progeria are limited and, to date, have focused mostly on reducing cardiovascular symptoms and growth abnormalities. Low-dose aspirin is often used for prevention of heart attacks and children have received heart bypass surgery. Treatment with growth hormones has also been attempted. FTIs have been proposed as potential new therapies for progeria, since they block farnesyltransferase, the enzyme that attaches the farnesyl group to progerin – ultimately inactivating progerin and leading to improvement in progeria symptoms.
FTIs: unrealised potential
Since farnesyltransferase is also known to prevent proper functioning of Ras, a family of proteins often abnormally activated in cancer, FTIs were first developed as potential anticancer agents. A number of FTIs underwent preclinical testing but were found to have major side effects, while others entered clinical development in a variety of cancers, only to be discontinued at phase I due to a lack of efficacy.
This lack of efficacy is thought to be due to alternative K- and N-Ras activation pathways (through geranylgeranyltransferase modification), which allow tumour cells to survive. Lonafarnib and tipifarnib are the most successful of the FTIs, currently in Phase II development for breast cancer, and acute myeloid leukaemia and glioma, respectively.
FTIs are also being tested in other clinical indications. They inhibit farnesylation in parasites, such as Trypanosoma brucei (African sleeping sickness) and Plasmodium falciparum (malaria). Their success in this indication is because (due to a lack of geranylgeranyltransferase I) some protozoan parasites are more sensitive than humans to farnesyltransferase inhibition.
FTIs are also in very early development in Alzheimer's disease and neurodegenerative disorders: AstraZeneca has a preclinical research programme in neurodegenerative disease therapeutics and OSI 754 is in phase I development in this indication.
Ground-breaking results for lonafarnib
Lonafarnib (Sarasar) is an orally active FTI under clinical development with Schering-Plough (now Merck & Co) in capsule formulation for the treatment of progeria and various types of cancer (including breast cancer, glioblastoma and glioma).
A randomised, double-blind, phase II trial (NCT00081510) evaluating anastrozole with or without lonafarnib in 124 postmenopausal women with hormone receptor-positive locally advanced or metastatic breast cancer was completed in October 2009, but results have not yet been published.
Results from an open-label phase I trial (NCT00612651) investigating lonafarnib plus temozolomide in 36 patients with grade 3 or 4 malignant glioma (gliosarcoma, glioblastoma or anaplastic astrocytoma) showed the combination to be an attractive therapeutic strategy. Development in other oncological indications (chronic myeloid leukaemia, myelodysplastic syndrome, non-small cell lung cancer, pancreatic cancer and head and neck cancer) has been discontinued.
Clinical development of lonafarnib in progeria began in May 2007 with the initiation of an open-label phase II study (NCT00425607) conducted by Boston Children's Hospital in collaboration with Schering-Plough and the Progeria Research Foundation (PRF). Approximately 29 children with HGPS and progeroid laminopathies received lonafarnib monotherapy twice daily at dosages between 115 and 150 mg/m2 for up to 24 months. The study was completed in October 2009.
Also, a phase II pilot study in children with progeria was initiated in March 2009 to investigate the feasibility of administering lonafarnib in combination with oral pravastatin and intravenous zoledronic acid (NCT00879034) for up to six months. The open-label study was also led by Boston Children's Hospital in collaboration with Schering-Plough, the Dana-Farber Cancer Institute and Brigham and Women's Hospital.
Pravastatin is a HMG-coA reductase inhibitor used to reduce cholesterol levels in patients with dyslipidaemia and to prevent cardiovascular disease. Zoledronic acid is a bisphosphonate used to treat osteoporosis and to prevent skeletal fractures in patients with some types of cancer (eg, multiple myeloma and prostate cancer). Pravastatin and zoledronic acid target farnesylation pathways, but at varying points, and it is hoped that these drugs will work synergistically with lonafarnib to produce a greater effect on progerin than using any one of the drugs alone.
Preclinical studies have shown that the combination of pravastatin and zoledronic acid reversed abnormalities of the nucleus in transgenic mice expressing progerin, as well as in cultured cells from human patients with progeria. Although pravastatin and zoledronic acid are both approved by the US FDA, they are not specifically sold as a treatment for progeria. Side effects from the triple combination were found to be acceptable, so in September 2009, the Boston Children's Hospital initiated a larger phase II trial in collaboration with Schering-Plough and the PRF (NCT00916747; also called the Progeria Efficacy trial).
Final results of this two-year, open-label study were recently published in Proceedings of the Natural Academy of Sciences, demonstrating statistically significant improvements in bodyweight gain, the primary outcome of the study, bone structure and the cardiovascular system.
A total of 26 children with genetically confirmed classic progeria (approximately 75 per cent of the known total number of cases of progeria worldwide) were enrolled from 16 countries. The children received twice-daily lonafarnib at dosages of 115–150 mg/m2 as a capsule or liquid suspension for up to 29 months and underwent extensive medical testing on a four- to six-monthly basis at Boston Children's Hospital.
Since children with progeria fail to thrive and have extremely slow bodyweight gain over time, the primary endpoint was defined as a 50 per cent increase in bodyweight from baseline or a change from pretherapy weight loss to a statistically significant on-study weight gain.
Nutritional, cardiovascular (arterial stiffness), skeletal (dual X-ray absorptiometry of the lumbar spine, total hip and whole body) and audiological testing (sensorineural and conductive hearing status) were also performed.
Noteworthy improvements in the study population included a greater than 50 per cent increase in the annual rate of bodyweight gain, or a switch from weight loss to weight gain, in one in three children due to significant increases in muscle and bone mass; improvement of bone rigidity to normal levels; a median 35 per cent decrease in arterial stiffness; and improvement in blood vessel wall density following FTI treatment.
Treatment was generally well tolerated with no patients withdrawing from the study due to toxicity. Adverse effects were consistent with the known tolerability profile of lonafarnib, with treatment-related toxicities such as mild diarrhoea, fatigue, nausea, vomiting, anorexia and reduced serum haemoglobin reported. Adverse effects improved over time in the majority of patients.
Dr Mark Kieran, clinical trial chair and Director of Paediatric Medical Neuro-Oncology at the Dana-Farber and Children's Hospital Cancer Center, confirmed that further trials are planned with other drugs that, like FTIs, have shown exciting results in progeria cells and animal models.
Future prospects for progeria
Another FTI with potential promise in progeria is FTI 277. Originally being developed by researchers at the University of Pittsburgh, Pennsylvania, US, FTI 277 was undergoing preclinical investigation in France and the US as a potential treatment for Ras-dependent tumours; however, no recent developments have been reported in this indication.
Preclinical studies in transfected HeLa cells expressing progerin have shown that FTI 277 is able to restore nucleolar antigen localisation completely.
The pathway to discovering an effective therapy for children with progeria has been unprecedented. After the gene that causes progeria was first discovered in 2003, the potential value of FTIs for this rare disease was realised and the first child was treated with lonafarnib just four years later in June 2007.
Lonafarnib and FTIs as a class have given renewed hope for children with progeria. Continued study of this disease is hoped to further understanding into human ageing in general. Lamin A defects are also associated with normal ageing, and research has shown that low levels of progerin are produced in all humans and accumulate with age.
It is hoped that through continuing research into the effects of FTIs, valuable biological insights into cardiovascular will be gained, along with new ways to slow down normal ageing processes.