A Boston Children’s Hospital trial of a repurposed experimental cancer drug has given parents, physicians, and scientists their first tantalizing evidence that it is possible to affect the course of a rare, fatal disease that causes children to age prematurely and die before reaching adulthood.
The disease, called progeria, affects only about 250 children in the world, but it is known to every medical student because of its heartbreaking trajectory and striking visual presentation, with children that almost seem to shrink into old age just as they are growing up. Children with the disease are far smaller than their peers, lose their hair, have small faces compared with their head size, and die of heart attacks or strokes in their teens.
The researchers brought more than two dozen children — three-quarters of the known cases worldwide when the study began in 2007 — to Boston to participate, and 25 ultimately completed the study.
The results announced Monday were modest. Nine children experienced more than a 50 percent increase in their rate of weight gain, and the scientists observed unanticipated improvements in a measure of cardiovascular health. They were unable to determine if the drug, called lonafarnib, will help the children live longer.
“There’s no question: We got up to bat and for sure made it on base, which is the first time in this disease anyone has done anything that in any way, shape, or form altered the natural history of this disease,” said Dr. Mark Kieran, a neuro-oncologist at the Dana-Farber/Children’s Hospital Cancer Center who headed the trial. “In order to stop them from dying of the disease, we haven’t tested it long enough to know if that’s possible. We hope that we will begin to do that.”
Scientists and physicians emphasized that the findings, published in the Proceedings of the National Academy of Sciences, are a first step and that although there are hopeful signs, they have no way of knowing whether the changes they measured will lead to the ultimate goal for patients and families: extending and improving the lives of the children.
Kieran acknowledged that it took some time to find a scientific journal that agreed to publish the results of the trial, in part because of tricky decisions the researchers had to make in designing a study for such a small group of patients, which deviated from typical clinical trials.
Dr. Francis S. Collins, whose lab in 2003 discovered the mutation — a single-letter mixup in the human genome — that causes the disease, said the results were an important step.
“While they did not generate the kind of weight gain that was originally put forward as the primary endpoint, the effects on the cardiovascular system — which is in many ways the most serious component of the disease — were gratifying,” said Collins, who is director of the National Institutes of Health.
Dr. Nicolas Levy, head of the Laboratory of Molecular Genetics of the Children’s Hospital La Timone in Marseille, France, was more reserved. Levy, who is preparing to publish the results of a clinical trial of a dozen children with progeria who were treated with two other drugs, said the cardiovascular effects were interesting. But he said he has reservations about the class of drugs used, called farnesyltransferase inhibitors, or FTIs, because of their side effects and disappointing preclinical laboratory research with the drugs.
Kieran said the process to seek approval from the US Food and Drug Administration has begun for lonafarnib, which was developed by Merck & Co. The children in the first trial have already been phased into a second trial that includes the same drug, plus two additional drugs.
Sandy and Steve Nighbor, parents of Megan, a 12-year-old from Dalton, Wisc., who took part in the trial, said that the opportunity to try something for their daughter was one they could not pass up. Megan initially suffered some side effects from the drug — nausea and diarrhea are commonly reported — but they said that she has been doing well and they have seen some improvements.
After being stuck at 30 pounds for a long time, Megan is up to 35 pounds, the Nighbors said. Her energy level is “through the roof.” Megan’s fingertips used to hurt and turn pure white when she went outside when it was cold. It was a symptom they never fully understood but assumed had something to do with her circulation. Now, they said, she tolerates the cold better — skateboarding, jumping on a trampoline, living the life of a normal kid. Perhaps, they said, that is because the drug has had some effect on her circulation.
“As parents, it can never go fast enough because it is such a time clock,” Sandy said.
The fact the trial occurred at all is a testament to the tenacity of a physician and scientist from Children’s Hospital who — faced with an unknown and fatal diagnosis for her own son over a decade ago — worked to bring together the resources and organization to catalyze research into the disease.
Dr. Leslie Gordon, a staff scientist at Children’s Hospital and the medical director of the nonprofit Progeria Research Foundation, said that she is grateful that she was in a position to do something about the disease when her son Sam was diagnosed, in 1998. The urgency for such research is real — Sam is 15 years old — and Gordon and others have worked to push the science forward at a rapid pace.
Finding the gene mutation that underlies the disease rapidly led scientists to understand how an errant protein, called progerin, begins to build up in cells. It happened that a drug already being developed to treat cancer targeted a mechanism that allows the progerin to stick to cells and accumulate.
“By keeping these children on lonafarnib and seeing how they do 5, 6, 10 years from now, that’s a long-term project,” Gordon said. “We know we have a treatment that does something, but we don’t know if those somethings are meaningful toward rate of heart attack, stroke, and longevity. We’re excited to find out.”