The article quoted below makes the case, by example, that drugs that would be rejected based on early randomized double-blind clinical trials, can be revived by clever trial-and-error adjustments. Such improvisations saved the life of Magglio Boscarino, whose body began to develop antibodies that attacked the medicine that had been successfully treating his rare Pompe disease. Emil Freireich used trial-and-error adjustments to develop the chemo cocktail that cured many of childhood leukemia. He mentored Vincent DeVita who used trial-and-error adjustments to develop the chemo cocktails that cured many of Hodgkin’s lymphoma. Another approach, advocated by Dr. Ridker in a passage below, is to learn which patients will be able to take the drug with developing resistance to it–a form of personalized medicine that does not seem easily compatible with the oft-claimed “gold standard” of randomized double blind clinical trials.
(p. D1) 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.
. . .
In a paper published in March [2017] 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 re-(p. D6)sponding 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.
Pfizer was forced to stop the trial and pull the drug after investing billions of dollars.
. . .
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.
. . .
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.”
. . .
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.
For the full story see:
(Note: ellipses, and bracketed year, added.)
(Note: the online version of the story has the date May 15, 2017 [sic], and has the title “When the Immune System Thwarts Lifesaving Drugs.”)
The 2017 paper reporting the failed Pfizer clinical trial and mentioned above is: