For most of her life, Allison Corona lived in a world dimmed by bad genetic luck. A disease called Leber’s congenital amaurosis left her legally blind at age 4. She could not navigate the short distance from her driveway to her front door after dusk.
Three years ago, Corona, now 23, received an experimental medical treatment aimed at fixing the faulty genes in her eyes. Researchers at the Children’s Hospital of Philadelphia injected viruses carrying a good copy of her errant gene into her right eye and, nine days later, her left eye.
The world around her, once dark and austere, soon grew brighter. Her vision is still far from perfect, but for the first time, she sees that paper towels have texture. She marvels at the velvet floral wallpaper that covers her bedroom wall. She takes a college class that gets out at 10:30 p.m. and no longer fears getting stranded in the night.
“Things became much more beautiful for me,” Corona said.
First tested in patients a quarter-century ago, gene therapy — a risky approach aimed at fixing the malfunctioning genes at the root of some diseases — is finally emerging from its own darkness after weathering high-profile tragedies, including the death of a teenage patient.
As it evolves from experimental to applied medicine, gene therapy might soon find itself steeped in a new controversy: soaring drug prices. No therapy is approved yet in the United States, so discussions about price — as well as crucial questions about how much patients will pay directly — are hypothetical. But industry leaders are already talking about ways to get ahead of potentially massive one-time price tags that could make insurers and patients balk.
A gene therapy approved in Europe in 2012 costs close to $1 million, and prices are expected to follow suit in the United States. The therapies in the pipeline are mostly for rare genetic diseases: sickle cell, hemophilia or immune deficiency. Their likely high prices stem from the expected value; unlike drugs that a person takes regularly, gene therapies are designed to be given once and have lasting effects.
But everyone involved anticipates the potential backlash against a seven-figure price tag, which is leading to radical proposals. Instead of paying for a treatment all at once, insurers and patients could make installment payments as long as the therapy works, similar to a mortgage on a house. Some researchers are adding up the cost of the traditional treatments that a patient will be able to avoid each year to determine a price that, although high, could lead to savings for the health-care system.
To Corona, the gift of vision is something approaching a miracle. But how much is that miracle worth in dollars?
In the 1980s, a daring idea seized the imagination of scientists and physicians. What if they could design a drug that wouldn’t just treat the symptoms of a disease caused by a mutant gene, but could instead replace the gene with one that worked normally?
Gene therapy was technically difficult but conceptually simple. Scientists would modify a virus so that when it infected a cell, it would ferry in the correct version of a broken gene.
If the process worked, doctors would have a powerful weapon against rare but devastating maladies such as cystic fibrosis and “bubble boy” disease, which leaves children without immune defenses.
As basic research moved forward, excitement about gene therapy soared. But, as with many new biomedical technologies, that initial exuberance would die down as the powerful idea of replacing broken genes collided with the inherent complexity of human biology. For gene therapy, the blip wouldn’t be just a scientific setback fought out on the pages of scientific and medical journals, but an international scandal in which patients were harmed and public faith was shaken.
In 1999, an Arizona teenager named Jesse Gelsinger died after he experienced an unexpected, severe immune reaction while participating in a clinical trial of gene therapy led by researcher James M. Wilson at the University of Pennsylvania.
“Everybody sort of stepped back and said, ‘Okay, we really have to consider, now that gene therapy has lost its innocence, what are we doing here? And what are the ways in which, if we’re going to do additional experiments, we don’t let this happen again?’ ” Francis Collins, director of the National Institutes of Health, said recently. “It was big; it was very big. I would not be surprised if some young scientists who were thinking of going down this path decided to do something else.”
Wilson became the subject of legal action and scathing media coverage. The government restricted his work on human subjects. Lawmakers on Capitol Hill held hearings to probe the lack of oversight and the ethical lapses that had marked some gene-therapy trials. Gelsinger’s father, Paul, told one Senate panel in 2000, “The concern should not be on getting to the finish line first but on making sure no unnecessary risks are taken, no lives filled with potential and promise are lost forever, no more fathers lose their sons.”
Also in the early 2000s, a few patients in a French gene-therapy trial developed leukemia. Along with the Gelsinger case, it proved a tipping point. Private investment in the field rapidly dried up, and it entered what Cowen & Co. Managing Director Phil Nadeau calls a “nuclear winter.” Regulators halted dozens of trials. To many, gene therapy seemed close to dead; a field of science that had been on a fast track appeared to have been relegated to little more than an interesting academic pursuit for a small cadre of researchers.
With less money, less hype, and much more humility and caution, Wilson and other researchers searched for ways to improve the safety of the viruses used to insert genes.
“It was a realization that the technology we had, which was on the shelf when we began the field, was inadequate for this field to move forward in any substantive way,” Wilson recalled. “It was really to go back to the drawing board, for me. That was a complete reorganization of what I was doing, how I was doing it, the kind of people who worked for me. It was a complete reboot.”
Gene therapy’s comeback started with a trickle. In 2008, researchers reported that a small number of patients with an inherited form of blindness gained modest improvements in vision with gene therapy. Not long after, gene therapy restored immune function in eight of 10 children with typically lethal “bubble boy” disease.
Katherine High, a researcher at the Children’s Hospital of Philadelphia who worked on one of the early blindness trials, started getting cold calls from investors and from pharmaceutical companies, asking if they could partner with her. Then the team of experts she had assembled in Philadelphia began to get job offers.
“I remember very clearly, around 2011, I began to think to myself, ‘If we don’t form a company so we can all stay together, I’m going to lose these people,’ ” High said. She co-founded Spark Therapeutics, which went public this year and is sponsoring the trial in which Corona participated. The company is expected to put its blindness therapy before U.S. regulators, likely next year.
It’s one of many companies with treatments in the pipeline. UniQure’s drug, Glybera, in 2012 became the first gene therapy approved in Europe, for a rare metabolic disease. Bluebird Bio, a biotechnology company that went public in 2013, is developing a variety of gene therapies, including a treatment for a genetic blood disease. Regenxbio, where Wilson serves as chief scientific adviser, went public in September.
“This is only the beginning of what’s going to be a remarkable era in medicine,” Wilson said. “But if it’s the beginning, that suggests there’s significant room for improvement. That means there will be failures and there will be successes.”
On the precipice of having a treatment finally make it onto the market, gene therapy faces yet another controversy: price.
Although much of the current outrage has been spurred by companies that take old drugs and jack up their prices, the potential sticker shock from a million-dollar drug — even if it’s for a previously incurable disease — is sure to raise some of the same questions from politicians and the public.
Nadeau, of Cowen & Co., said his firm has estimated that Spark Therapeutics’ gene therapy will cost $500,000 per eye. A study published last year in the journal Nature Biotechnology examined current health-care spending on hemophilia B and found that a gene therapy could conceivably be priced as a one-time payment of $4 million to $6 million. The authors argued that paying $150,000 a year as long as the drug works could potentially save the health-care system money.
Spark Therapeutics chief executive Jeffrey Marrazzo is reluctant to talk about a dollar figure, but he does think it’s time to consider changes in the way the health-care system pays for treatments.
The options being discussed include a down-payment model, with annual payments. University of Washington economist Anirban Basu has proposed an alternate health currency, HealthCoin, that insurers pay for when buying a cure and then sell to another insurance plan at a depreciated price if a patient switches insurers or becomes eligible for Medicare.
The feasibility of these plans remains uncertain. But gene-therapy executives are arguing that, even at unprecedented prices, their drugs will save the health-care system money — and carry other benefits.
“How do we recognize that there’s truly something that’s important and valuable to people, not only to have certain aspects of their vision restored, but . . . to have it done once and then have the ability to go on with their lives?” Marrazzo said.
Corona, who excitedly woke up her family in the middle of the night when she read about the possibility of gene therapy years ago, didn’t have to pay for her treatment, because she was part of a clinical trial.
But she said her family would have found a way to get her the therapy if it had already been on the market, even if it meant battling an insurance company or taking out a loan. After all, she said, it’s not only about seeing better. She now feels like a happier, more confident person. That part feels priceless.