It’s been 7 years since dozens of children with progeria—a devastating disease that causes symptoms resembling premature aging—first began receiving an experimental drug called lonafarnib. That’s an eternity for them and their parents given that most afflicted with the extremely rare condition die by their teenage years. There’s now a hint that this medical gamble has paid off, at least to a small extent. The Progeria Research Foundation (PRF), which funded the initial trial of the drug and an ongoing follow-up involving it and two other drugs, announced this week that the interventions have likely added, on average, about 19 months to the children’s lifespans.
This is “an important first step,” says Leslie Gordon, a physician who, along with her husband, founded PRF after their son was diagnosed with progeria. “Though these medications are not curative, we show for the first time that lifespan may be influenced in children with progeria.” But that conclusion, detailed in a study published online on 2 May in Circulation, has many scientists questioning whether the results are meaningful, because the trials lacked an untreated control group—as is sometimes the case for extremely rare disease treatments.
Only about one in 4 million to 8 million newborns have the mutation in a gene called LMNA that causes what is formally known as Hutchinson-Gilford progeria syndrome. LMNA normally produces a protein that helps provide a scaffold for a cell’s nucleus. The mutation leads to the buildup of an abnormal version of the protein, which causes misshapen nuclei and other changes within cells. The ultimate result is a collection of symptoms that resembles premature aging of certain tissues: hair and weight loss, thin skin, joint stiffness, and atherosclerosis. The latter leads to heart attacks that cause the majority of deaths from the disease.
In 2005, a study led by researchers at the University of California, Los Angeles, showed that a class of drugs called farnesyltransferase inhibitors (FTIs), which block the attachment of a molecule to the faulty protein that allows it to accumulate around the nucleus, restored normal shape to cells from kids with progeria. Several groups working with mice having the same mutation next established that the drug also reduced signs of premature aging in those rodents. Because FTIs had already been tested in children with cancer, with no significant side effects, PRF quickly pushed to start a trial of the FTI lonafarnib in 2007. Gordon, working with a team led by oncologist Mark Kieran of the Dana-Farber Cancer Institute in Boston, initially followed 25 children as they received the drug for at least 2 years. The trial results, published in 2012, showed that many of the patients had small weight gains and reductions in the stiffness of their blood vessels, though some scientists found the results inconclusive and hard to interpret.
In the new analysis, Gordon and her colleagues wanted to see whether children treated so far—including those in the first lonafarnib trial and those in an ongoing trial that adds two other drugs to the treatment—survived longer than untreated kids. But because there are so few children with progeria, and the disease is invariably fatal, PRF and the study designers had agreed not to create a group receiving a placebo; all who participated in the study received the drug, including Gordon’s son. For a comparison group, Gordon and her colleagues instead collected data about untreated children from historical records in the foundation’s international registry, previously published case reports, and public databases.
That’s what makes some question whether the apparent lifespan extension is real. Studies with historical controls are “notoriously unreliable,” says Donald Berry, a biostatistician at the University of Texas MD Anderson Cancer Center in Houston. Because various studies and databases may have different criteria for including a patient, factors outside the efficacy of the drug could contribute to differences in lifespan. Gordon and her colleagues, however, tried to address this issue by matching children in the treatment group with untreated kids of the same age and gender, born on or after the treated subjects. The comparison found that in the 6 years after starting treatment, those receiving the drug survived, on average, 1.6 years longer than their untreated counterparts. Over that period, 21 of 43 children with progeria who hadn’t enrolled in the study died, compared with 5 of the 43 who had received a treatment.
The finding “is very gratifying and encouraging,” says physician-geneticist Francis Collins, who is director of the National Institutes of Health in Bethesda, Maryland, and whose research team has studied the mechanisms of and potential treatments for progeria. Collins acknowledges that the lack of a direct control group enrolled in the trial is “not ideal,” but he notes “there really wasn’t much of an alternative to what was done—namely, to do an open-label trial where all of the kids were given the chance to have access to the drug.”
But others, including Berry, have trouble drawing a positive conclusion from the study in light of that limitation. He notes that a more dramatic improvement in lifespan might have overcome his doubts: “Had the patients lived a normal life span then the results would have been compelling. But even an improvement of ‘only’ 10 years (and possibly even 5 years) would have been enough to establish the principle that the treatment was effective.”
Beyond the age and gender issues Gordon’s team addressed, there are untold differences between trial participants and the untreated group, notes Howard Worman, a cell biologist and physician at Columbia University, who was the first to characterize the LMNA gene. The children and their parents who enroll in a clinical trial may be more aware of their disease and more proactive with their health than nonparticipants, for example. “Until there’s a matched, concurrent, ideally placebo-controlled group, it’s hard to say if there really is a survival advantage,” he says.
Gordon and her colleagues continue to track the children in the study, who are still taking the FTI and the two other medications—more time may make any survival advantage more obvious. Her son, recently the subject of an award-winning documentary, died in January.