From NYT: “When the Immune System Thwarts Lifesaving Drugs”

New York Times

The New York Times

MAY 15, 2017
GINA KOLATA

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Magglio Boscarino, who has the genetic disorder Pompe disease, with his mother Becka at home, above, and at school. Credit Max Whittaker for The New York Times

The miracle treatment that should have saved Becka Boscarino’s baby boy almost killed him.

Doctors diagnosed her newborn son, Magglio, with Pompe disease, a rare and deadly genetic disorder that leads to a buildup of glycogen in the body. Left untreated, the baby would probably die before his first birthday.

There is just one treatment: a series of infusions. But after the boy received his fifth dose, he turned blue, stopped breathing and slipped into anaphylactic shock.

The problem? Eventually doctors discovered that Magglio’s body was producing antibodies to the very drug saving his life.

It is a problem few patients and doctors have ever heard of; indeed, the phenomenon has not been systematically studied. But experts say what happened to Magglio has happened to many other patients taking many other drugs.

The body’s immune system produces antibodies, blood proteins, in order to attack molecules the body recognizes as alien, often carried on viruses and bacteria. But antibodies also are deployed against other foreign substances, and this may include drugs given to patients.

Antibodies directed against a particular drug can attach to the drug and completely neutralize its effects in the body. But there is no way to know in advance which patient is most likely to make them, or which drug is likely to trigger such a reaction in a large number of patients.

“Once a drug is approved and out in the market, it is pretty rare that a clinician would measure antibodies,” said Dr. Mary Crow, a rheumatologist and physician in chief at the Hospital for Special Surgery in New York City. “There is no commercially available test.”

In a paper published in March by The New England Journal of Medicine, Pfizer reported that in the final phase of testing a new drug to lower cholesterol, many of the 30,000 patients taking it had stopped responding to it.

Their cholesterol levels, which had plunged when they began taking the drug, were rising again. As it turned out, the subjects had begun making antibodies to the drug.

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Magglio needs a ventilator to breathe and plays on a baseball team for children with disabilities. His mother helps him bat. Credit Max Whittaker for The New York Times

Pfizer was forced to stop the trial and pull the drug after investing billions of dollars. (Similar drugs, made by Amgen and Sanofi Regeneron did not elicit such antibodies and are now being sold.)

The problem seems almost intractable.

Drugs containing proteins can provoke these immune system reactions. Steve Danehy, a Pfizer spokesman, said that up to 87 percent of patients taking drugs known as monoclonal antibodies, for instance, will develop antibodies of their own that block the drug. (Pifzer’s experimental drug was a monoclonal.)

Patients and their doctors often have no idea what has happened; patients notice only that a drug they take has stopped working. Doctors will switch them to a similar drug and hope for the best.

But that strategy only works when there are alternatives. For some diseases, there are none.

For the small subset of gout patients whose disease is extremely severe, for example, antibodies are “really a huge problem,” said Dr. Robert Terkeltaub, a gout specialist at the University of California, San Diego. There is only one drug that can help, and most patients develop antibodies that eventually block it.

Medicine Stops Working

For patients like Magglio Boscarino, finding a way to tamp down the immune system’s response to these drugs is a matter of life or death.

He had seemed fine at birth, but soon developed what looked like a bad cold and congestion. When he did not get better, his doctors X-rayed his chest and discovered a very large heart.

By the time Magglio was 6 months old, he was weak and lacked muscle tone. Then came the diagnosis of Pompe disease and the beginning of his treatments, infusions with an enzyme his body was failing to make.

At first, Magglio improved. Within a few months, he was learning to sit up and to use his arms. His enlarged heart was shrinking. But his fifth treatment was a disaster.

He fell into anaphylactic shock and stopped breathing. The doctors gave him oxygen and epinephrine, and eventually he recovered. They did not realize the drug was at fault, however, and two weeks later Magglio received another infusion — with the same result.

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Becka Boscarino, and her son, Magglio at home. Magglio has Pompe disease, which causes a buildup of glycogen in the body. Untreated, it usually kills within the first year. Credit Max Whittaker for The New York Times

Then doctors realized what the problem was. But because Magglio’s disease would worsen and kill him if he did not get the drug, his doctors kept hoping he might be able to tolerate repeated infusions.

For a year and a half, the treatments continued, and Magglio suffered severe reactions even as his disease was progressing. Soon he could not breathe on his own, and a tube was inserted in his trachea. He could not sit up. At 2 years old, he had heart failure.

“He was dying,” Ms. Boscarino said. “It was awful, so awful,”

Magglio was hardly alone: Most babies with Pompe disease who received the only available treatment soon produced antibodies that rendered it useless.

“We tried everything, but these babies did not make it,” said Dr. Priya Kishnani, a professor of pediatrics at Duke University.

Dr. Kishnani realized she had to find a way to trick the immune system so it would leave the infused protein alone. Her idea was to give the babies a chemotherapy drug, rituximab, that wipes out cells that develop into antibody producers.

Along with it, she tried giving the children methotrexate, which destroys many of the body’s white blood cells, and infusions of antibodies from pooled donors’ serum so the children would have a way to fight off infections.

And for babies like Magglio, who already were making antibodies that blocked the drug they need, she added another drug — bortezomib — to eliminate those antibody-producing cells.

As the children’s immune systems were brought under control, the treatments began to work again. “It was breathtaking,” Dr. Kishnani said. “We were able to rescue these babies.”

Broadening the Approach

The principles tried in children with this rare genetic condition may soon be applied to a wide range of patients. “I feel that Pompe opened up the field,” Dr. Kishnani said. “The more we talked about it, the more awareness there was of the role of antibodies.”

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“The good news is that he is still alive,” Ms. Boscarino said. “But he is a complete rag doll. He mouths words a lot. He does not have a voice so he uses his eyes to use a computer screen to talk for him.” Credit Max Whittaker for The New York Times

Already, scientists have begun clinical trials testing ways to help patients with very severe gout who make antibodies blocking their treatment. In one, investigators are altering the dose of the drug used to treat the disease and how often it is given.

In another trial, researchers at Selecta Biosciences are testing an antibody-suppressing drug packaged in a biodegradable nanoparticle to be taken along with the drug the patient needs.

At Brigham and Women’s Hospital in Boston, cardiologist Dr. Paul Ridker, who directed the Pfizer study, is taking a different tack.

He wants to do a large genetic study to see if he can predict which patients will develop antibodies to the Pfizer drug and perhaps to other drugs that the immune system might see as foreign.

“We probably have the best opportunity ever afforded to understand the cause of these antibodies,” Dr. Ridker said. “That would be very valuable for the development of future drugs if you could say, ‘This one patient out of 20 should not take this drug.’”

It would mean, too, that drugs that might have been abandoned could be developed for the patients who can tolerate them.

Magglio received the treatment to tamp down his immune system developed in Dr. Kishnani’s lab, and it seems to have worked. “The good news is that he is still alive,” his mother said.

“But he is a complete rag doll. He mouths words a lot. He does not have a voice so he uses his eyes to use a computer screen to talk for him.”

Magglio needs a ventilator to breathe, as he has since he was 9 months old. But he has his own sign language, using his tongue, his mother said.

Still, he goes to school — general education, 4th grade — and even plays on a baseball team for children with disabilities. His mother helps him bat.

“He’s a big Yankees fan,” Ms. Boscarino says.

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