Wednesday, April 24

Opinion | Gene therapies could transform rare diseases. Are we holding them back?

On January 8, 2020, while I was parking my car, I received a long-awaited phone call from one of my son’s doctors. He informed me that our 7-month-old son, Eliot, had Duchenne muscular dystrophy, a fatal neuromuscular disease.

I still remember the way the Los Angeles winter sunlight hit the dashboard. I can see my neighbor carrying her groceries upstairs, a leaf falling, oblivious to the devastation below. “Life changes in an instant,” wrote Joan Didion. “The ordinary moment.” Our son had a fatal illness. He would die before us.

DMD prevents the production of dystrophin, a protein necessary to protect and repair muscle cells. It is caused by a genetic mutation on the X chromosome, so the disease almost exclusively affects children (one in 3,300). Over time, children with DMD lose muscle mass and therefore the ability to do basic things like run and walk. Over time, they lose the ability to breathe and experience heart failure. There is no known cure. While existing treatments have helped prolong the lives of sufferers, they primarily focus on controlling symptoms.

In my search for answers about how to save my son, I contacted Dr. Jerry Mendell, a neurologist now retired from Nationwide Children’s Hospital in Columbus, Ohio, who was conducting clinical trials for an experimental gene therapy he developed to enable the production of dystrophin in children with DMD The treatment, now known as Elevidys, offered the prospect of not only controlling symptoms, but also slowing the progression of the disease or even stopping it in its tracks, and potentially, for the first time in the history of this terrible disease, allow children with DMD a chance to thrive.

Since I had that first conversation with Dr. Mendell (also a senior advisor to Sarepta, the maker of Elevidys), clinical trials for gene therapy have had their ups and downs and some adverse effects have been reported. But in June 2023, based on a two-part clinical trial, the Food and Drug Administration granted accelerated approval for the treatment for 4- and 5-year-olds who have no other disqualifying conditions. FDA approval was contingent on continuing trials showing evidence of improved motor function, something that had not yet been established.

Before Eliot received his treatment, he had difficulty climbing stairs. He complained of being tired after walking just a block or two, even on Halloween, when candy should have motivated him. Jumping on one foot, a milestone for a 4-year-old, was impossible.

On August 29 he finally received the single infusion. Three weeks later, she was already climbing the stairs and could jump again and again. After four weeks, she could hop on one foot. Six weeks after treatment, Eliot’s neurologist decided to readminister the North Star Ambulatory Assessment, used to evaluate children with DMD on skills such as balance, jumping, and getting up from the ground without assistance. In June, Eliot’s score was 22 out of 34. By the second week of October, she was a perfect 34: that of a healthy, typically developing 4-year-old. With my head in my hands, I cried with joy. This was science at its finest, almost a miracle.

But the goal of offering this possible future to more DMD patients is in jeopardy. Sarepta is seeking FDA approval to treat children over 5 years old. Disagreements over the results of the latest clinical trial threaten to derail that outcome.

Additionally, what the FDA decides to do next with Elevidys could set the tone for how it handles other emerging gene therapies for rare diseases. We can already see obstacles preventing more families from gaining access to these new treatments, from high costs and insurance challenges to disagreement over how flexible regulators should be when interpreting clinical trial results and taking improvements into account. qualitative. What’s at stake in the debate around Elevidys is more than just the opportunity to give other children with DMD a more normal life. The challenges we are witnessing with Elevidys are a harbinger of the struggles we may see with gene therapies developed for other rare diseases.

There is an opportunity to reduce those barriers now, while these treatments are still in their early phases. Every child suffering from a life-threatening illness deserves the opportunity that Eliot has been given.

The biggest obstacle to receiving these treatments is cost. Gene therapies cost, on average, between 1 and 2 million dollars. Priced at $3.2 million per patient, Elevidys is the second most expensive drug in the world. Insurance companies would probably prefer not to foot the bill, and without full FDA approval, insurance companies may refuse to cover these treatments on the grounds that they are medically unnecessary or experimental. Before Eliot’s treatment began, my insurance company initially said it would cover the cost, but then began delaying coverage and questioning the urgency of Eliot’s treatment. I was able to call Dana Goldman, dean of the Sol Price School of Public Policy at the University of Southern California, where she works, to help me navigate the process. She was in the rare position of marshalling resources and assistance to pressure my insurance company to cover Elevidys. Across the country, doctors are fighting denials and seeking appeals for their young patients.

Dr. Goldman has argued that one way to incentivize insurance companies to cover the high costs of treatments such as gene therapies is to amortize how much the companies pay over time if the effectiveness of such treatments does not last (analogous to a system of pay for performance). model). Another option is for pharmaceutical companies to offer a guarantee that provides a prorated refund to the insurance company if a patient needs to return to prophylaxis treatment within a certain number of years. Costs are an especially frustrating issue for rare diseases like DMD, for which the extremely small patient population deters companies from investing money and resources into developing new treatments. Some experts believe the federal government should do more to directly supplement funding for rare disease research, as it has done through the Orphan Drug Act for more than four decades. The government could also defray the cost to consumers by offering subsidies directly to patients.

There is another important role that the government can play in accelerating gene therapies, in addition to intervening in costs, and that is to make the regulatory approval mechanisms for these drugs less onerous. Flexibility does not have to come at the expense of security. The FDA acted quickly to approve an antiretroviral drug for HIV in the 1980s and Covid vaccines in December 2020, saving millions of lives without putting people in harm’s way.

But Elevidys is a case study in how the FDA can get in its own way. DMD patients ages 4 and 5 received access to the drug through accelerated approval, the first time a drug was approved under this new framework. But this was reportedly only because Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, disagreed with his own staff’s rejection. The current concern about the approval of Elevidys for children over 5 years of age focuses on the results of the most recent clinical trials, which showed that older children, whose muscle impairment is more advanced, did not improve their motor function as measured by the North Star Outpatient Evaluation after treatment. However, as Sarepta has pointed out, they still saw improvements in their ability to get up off the ground and walk 10 meters, indicating a possible slowing of the disease that could significantly improve and prolong their lives.

Critics suggest that this improvement is not enough to meet approval requirements. This is a common problem in rare disease trials because they often consist of very few participants. In such cases, a narrow focus on numbers ignores the real quality-of-life benefits that doctors, patients, and their families gain from these treatments. During the Elevidys advisory committee meeting in May 2023, I heard FDA analysts express skepticism about the drug after watching videos of children treated with Elevidys swimming and cycling. These experts, who had been given the ultimate responsibility of evaluating treatments on behalf of the lives of others, seemed unable to see the forest for the trees as they focused on statistics versus real-life examples.

The FDA can take a more flexible view of treatment effectiveness without losing focus on safety. As with any drug, whether for migraine or asthma, there will be a spectrum of effectiveness. The same will be true for all gene therapies, and the FDA should reconsider the metrics it uses to greenlight these treatments now, before it potentially leaves thousands of patients in the lurch, without access to something that will save their lives.

Gene therapy is the future of medicine. But our bureaucracy and our insurance companies should not prevent patients from receiving pioneering treatments that could transform their lives. As parents, we don’t ask for the moon. We just want our children to live.

Elizabeth Currid-Halkett is a Guggenheim Fellow and professor of public policy at the University of Southern California.

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