- - Thursday, February 14, 2019

President Trump recently called on all Americans to “get behind: the fight against childhood cancer” while acknowledging all the tremendous progress made in treating life-threatening diseases. Last year, the U.S. Food and Drug Administration (FDA) approved 59 new drugs, compared with an annual average of 37 in the preceding three years. Nearly one-third of last year’s new drugs treat cancer; others provide advanced therapy for heart disease, HIV, mental illness and other serious conditions.

Having served on the health subcommittee in Congress for many years, it’s clear to me change is happening swiftly — perhaps too swiftly. Let’s consider gene therapy, which the National Institutes of Health (NIH) defines as an “experimental technique that uses genes to treat or prevent a disease.” Gene therapy generally works by replacing a mutated, disease-causing gene with a healthy copy of the gene from another source.

While the description is simple, the process is highly complex and fraught with dangers. An editorial in the journal Nature described the dire consequences of an experiment with a gene-therapy treatment for a condition called ornithine transcarbamylase deficiency (OTC). People with OTC lack an enzyme to break down ammonia, so the chemical accumulates in the blood, causing disease.

At age 18, Jesse Gelsinger, had his OTC under control with diet and medication, but researchers proposed introducing a weakened cold virus carrying a normal gene for the enzyme into his body. The result was disastrous. Gelsinger, according to The New York Times, “suffered a chain reaction that the testing had not predicted — jaundice, a blood-clotting disorder, kidney failure, lung failure and brain death.”

The Gelsinger failure led to the revelation that there were 691 “serious adverse events” — that is, serious deterioration or death in U.S. human gene-therapy experiments in the preceding seven years.

No wonder the journal Nature concluded in its editorial that researchers “must proceed with caution” with gene therapy. As NIH warns on its website: “Although gene therapy is a promising treatment option for a number of diseases, the technique remains risky and is still under study to make sure that it will be safe and effective.”

But despite these warnings, regulators and researchers appear to be letting down their guard.

In 1995, Judith Melki and her team at Inserm (France’s equivalent to NIH) identified a mutuation in the survival motor neuron 1 (SMN1) gene as the cause of the disease Spinal Muscular Atrophy, or SMA. The mutation affects nerve cells in the spinal cord and can cause infant death. Some 21 years later, the FDA approved Spinraza as the first treatment for SMA.

Cure SMA, a patient organization, announced at the time, “Thanks to the dedication of our community and the ingenuity of our researchers, we now have the first-ever approved treatment that that targets the underlying genetics of SMA.”

Then in October, a company called AveXis, which had been acquired by the Swiss pharmaceutical company Novartis, filed for FDA approval of a new way to treat SMA, this time with gene therapy. The treatment is called Zolgensma, and it is expected to cost $4 million to $5 million per patient. Zolgensma delivers a healthy SMN1 gene encased in the shell of a genetically engineered virus.

But cost aside, a big potential problem with gene therapy is that no one can tell its long-term consequences. Replacing a gene in a patient’s body with a gene from outside could affect more than the replaced gene, as the Gelsinger experience showed so tragically.

The trials for Zolgensma have involved very small groups over short periods. The Phase 1 trial for the AveXis drug involved only 15 infants; the Phase 3 trial involved 20.

The FDA has approved a few other genetic therapies in the past 18 months, but those were for more desperate cases. For example, Kymriah for childhood leukemia and Yescarta for lymphoma were approved for patients who did not respond to other drugs, and Luxturna treats a kind of rare childhood blindness that had no effective alternative treatment.

Zolgensma is on a fast track for an approval decision by May. But does that make sense? Has it been tested enough for assurance that the therapy won’t go awry — especially considering that a treatment for SMA already exists? There is a lot at stake here, including the risk that a Gelsinger-style failure could set back progress for another decade or two.

When it comes to gene therapy, our political leaders and regulators need to put the interests of patients first.

• Bill Richardson is a former governor of New Mexico, member of the U.S. House of Representatives where he served on the health subcommittee, and the U.S. ambassador to the United Nations.

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