“Tremendous breakthrough drug shows promise in treating children with a rare and fatal disease,” the Daily Mail has reported. The story is based on a small trial of a drug for children with progeria, an extremely rare and currently untreatable genetic condition characterised by children appearing to age prematurely and failing to thrive, leading to early death.
Due to its age-related symptoms, the condition has been inappropriately labelled in some parts of the media as “Benjamin Button” disease, in reference to the F. Scott Fitzgerald novella (and film) The Curious Case of Benjamin Button , about a man who is born old and becomes younger as his life progresses.
Progeria is a condition diagnosed in children whose bodies are not able to produce a properly functioning version of a protein called “lamin A”, which is involved in important functions such as DNA repair. Instead, their bodies make a defective version of the protein, known as progerin, which triggers a range of adverse effects at the cellular level. This causes major damage to multiple parts of the body, mimicking advanced ageing.
This study involved an experimental drug called lonafarnib, which researchers felt could block some of the harmful effects of the progerin protein. The trial tested the effects of the drug in 25 affected children – an impressive sample size given the rarity of the condition.
The researchers found that all of the children treated experienced at least one or more improvements in outcomes, such as weight gain, bone strength and blood vessel health.
The results of this case series are promising and suggest that lonafarnib may in future be helpful in the treatment of this devastating disease.
Where did the story come from?
The study was carried out by researchers from several US institutions including Boston Children’s Hospital and Harvard Medical School.
It was funded by the Progeria Research Foundation, the Dana-Farber Cancer Institute and several other charitable organisations.
The study was published in the peer-reviewed journal Proceedings of the National Academy of Sciences.
The Mail’s claim that this is a “tremendous breakthrough” is perhaps premature as it is still unclear what effect this drug could have on a patient’s life expectancy. But as this drug is the first effective treatment to emerge since the condition was identified in 1886, the study is certainly newsworthy.
What kind of research was this?
This was a phase II patient (clinical) trial of a drug called lonafarnib in children with Hutchinson-Gilford progeria syndrome (HGPS). While there are different forms of progeria, HGPS is the classic type.
It is an extremely rare (one in 4 million live births), premature ageing disease in which children fail to thrive and develop symptoms and conditions normally only seen in the elderly, such as:
- hardening of the arteries (atherosclerosis)
- weight loss
- hair loss
- aged-looking skin
- heart disease
- weakening of the bones (osteoporosis)
HGPS is caused by a mutation in a gene which produces lamin A, a protein referred to as the structural “scaffolding” that holds the nucleus of a cell together. Researchers believe that the abnormal protein produced, progerin, makes the nuclei of cells unstable, leading to the process of premature aging.
Lonafarnib comes from a class of drugs that have shown promise for HGPS in earlier pre-clinical studies.
The trial was a single-arm trial or case series. This means there was no control group of children with HGPS (who would not have been given the drug) to compare outcomes with.
What did the research involve?
The researchers originally enrolled 26 children aged three years old or younger with confirmed HGPS from 16 countries, representing an impressive three-quarters of the children worldwide diagnosed with the disease. As many cases in the developing world may go unreported, the researchers estimated that this figure accounted for 15% of all cases across the world.
The children all had their pre-trial weights measured at regular intervals of at least one month in the year before the study so that their individual annual rate of weight change could be estimated.
All the children were given the drug orally for a minimum of two years, with dosage set according to their weight. The children were monitored for adverse effects on the liver and kidneys and their dosage reduced where necessary. Adverse events and side effects were monitored throughout the study.
One of the children died of a stroke after five months of the study.
All weight measurements and other outcomes were monitored by the children’s doctors and other health professionals. The weight outcome was particularly important, in particular the rate at which children gained or lost weight while in the study. The researchers said that children with HGPS have individual rates of progressive weight gain or loss that remain consistent over time, which means that weight loss without treatment is predictable.
The success of the treatment was measured as a 50% increase over the estimated annual rate of weight gain or as a change from pre-treatment weight loss to a statistically significant weight gain.
According to the researchers, this method allowed each patient to act as their own control, with their rate of changes in weight before treatment compared with the rate while on treatment.
The trial design, based on 25 patients, required that at least three or more patients achieve improvements in the rate of weight gain (defined as at least a 50% increase over the annual rate of weight gain) to show that the drug had a statistically significant positive effect.
Before and during the trial the researchers also measured:
- the children’s daily calorie intake
- their blood vessel stiffness
- bone density (hip and spine)
What were the basic results?
Overall, the researchers said the drug was well tolerated and no child had to be withdrawn from the study due to adverse effects. Side effects included mild diarrhoea, fatigue and nausea.
For the main outcome measure of weight:
- Nine of the 25 children had a 50% or more increase over their estimated annual weight gain before treatment.
- Ten had the same rate of weight gain as before treatment.
- Six had a 50% lower rate of weight gain.
They reported that all patients improved in one or more of the other outcomes:
- measurements of blood vessel stiffness
- measurements of bone density
- measurements of sensorineural hearing (a type of hearing loss that is often related to ageing)
How did the researchers interpret the results?
The researchers said that the results provide preliminary evidence that lonafarnib may improve blood vessel stiffness, bone structure and hearing in children with HGPS. The improvements in cardiovascular status is a potentially important finding because children with HGPS usually die from heart disease.
This trial of a drug for this rare and fatal condition had some promising results. However, as the authors noted it also has several limitations, some due to the rare nature of this disorder:
- Only 26 children were in the study and only 25 completed it without a control group, but this is understandable as the condition is so rare.
- A number of children could not adequately perform various tests because of their age and fragility.
- Because the disease is so rare, there is little long-term data available, which made the choice of which outcomes to measure difficult.
- The trial only looked at clinical markers of possible improvements for symptoms like arterial stiffness and bone strength. It was not able to assess the effect of the drug on cardiovascular health directly for example, or on survival rates.
A longer study, ideally with a control group and longer follow-up, will be needed to evaluate the safety and effectiveness of this drug further.
The expected cost of the drug is not mentioned by the researchers.