The child in the picture has spinal muscular atrophy (SMA). She made the news in Mumbai when her parents tried to one of the new and extraordinarily expensive treatments for her.
This week's news was about two children who died from liver failure caused by a gene-therapy used to treat spinal muscular atrophy (SMA). We don’t yet know the details of these cases, so it is too soon to judge whether their therapy-induced complications were treated appropriately.
Such deaths were inevitable. The gene therapy was delivered by a viral vector. Viral vectors induce immune responses that can lead to liver damage or liver failure. There is a boxed warning in the drug's labeling about liver damage. Usually, the damage can be controlled with steroids.
What are the implications of the two deaths? How should we weigh the risk of treatment against the risk and burden of disease?
SMA is a heartbreaking disease. Babies are born with intact cognition but no muscle strength. They cannot breathe. They cannot swallow. Their bodies are like cages in which their minds are entrapped. Before treatments were available, parents and professionals faced the agonizing choice of either letting the babies die or sustaining them with ventilators and feeding tubes for the rest of their lives.
t The new treatments seemed miraculous. Babies and children gained strength before our eyes. Older children were able to walk for the first time.
It was hard to imagine a fair price for such miracles. But drug companies did. The price tag for nusinersen, the first approved drug, was nearly a million dollars for the first year and half a million for every year after that. It had to be given for the patient’s whole lifetime. The next approved drug, onasemnogen abeparvovec, only had to be given once. Its price: $2.1M.
These drugs were hailed not just as breakthroughs in the treatment of SMA but also as a proof of the concept that gene therapy could be successful in treating rare genetic diseases.
That proof of concept was crucial because gene therapy had been under a cloud since the death of Jesse Gelsinger in 1999 from an experimental gene therapy. Gelsinger died of liver failure caused by the therapy. His death led to serious questions about whether the risks of such treatments outweighed the benefits and whether researchers’ conflicts of interest clouded their judgments and their scientific integrity. Those questions will now surface again.
There are two ways to respond to these deaths. One is with suspicion. Many people who are involved in the evaluation of the drugs have financial conflicts interest. Past scandals give us reason to think that these deaths could be the tip of the iceberg and that the company knows more about bad side effects than it has revealed.
Another response would be to shrug these deaths off. After all, most new therapies are dangerous. The first heart and kidney transplant patients had terrible outcomes. But we learned, and now such transplants have much better outcomes and have become almost routine.
Both responses would be wrong. First, we need to know what really happened. Were these patients treated according to current best-practice protocols? If so, then the protocols might need to be revised. If they were not, that would be reassuring about the safety of the drug using best practices.
Second, we need to recognize that gene therapy is not the magic bullet that some had hoped it would be. Children who receive these drugs improve but they are not cured. Many continue to require mechanical ventilation and tube feeding, though the daily duration of each decreased.
Gene therapy will turns out to be a half-way technology. That termed, coined by Rene Dubos, describes treatments that keep patients alive but don’t cure them. We hoped that gene therapy would cure SMA. Instead, it is helping us appreciate just how complex the interactions are between viral vectors and the human immune system.
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