Reworked drug helps kids get medicine down
Pill for rare disease eliminates the terrible side effects
Before the drug Cystagon, the parents of babies diagnosed with the rare disease cystinosis were told to take their children home and love them as best they could before they died, usually before age 10.
The drug was a literal lifesaver. Except Cystagon was also a nightmare.
To be effective, it must be taken around the clock, at six-hour intervals. It tastes terrible, and it very often causes severe stomach problems — vomiting, nausea, gutwrenching cramps. Some parents had to pin down their children to force them to take the medicine. Many older children flat-out refused to take it.
So when a Bay Area pharmaceutical company reworked that drug — just tweaked it, really — and made it more tolerable, families lined up to volunteer for clinical trials. Last week, the Food and Drug Administration approved the new drug, called Procysbi, and it should be widely available sometime this year.
“I’m so thrilled with the approval. The quality of life for the kids and for
our family is amazing,” said Teresa Partington of Sacramento, whose 8year-old twins, Jenna and Patrick, both have cystinosis. The twins have been taking Procysbi for two years as part of the clinical trials to get FDA approval.
“They still have symptoms of cystinosis. They have lethargy, they get overheated, and they do have a diagnosis of kidney disease. They still take about 10 different medications every day,” Partington said. “But right now, they’re doing really well.”
Rare genetic disease
Cystinosis is what’s known as an orphan disease because it’s so rare — there are about 500 children with it in the United States. Cystinosis is genetic, and children can only get it if they have two parents who carry the gene for it.
These children lack the ability to clear the amino acid cystine from parts of their cells. In healthy people, cystine molecules typically will link together to form proteins, which are then metabolized or broken down within parts of the cell called lysosomes. The leftover pieces are then transported out of the lysosomes to be reused. The entire process is an essential part of sustaining the body’s metabolism.
But in children with cystinosis, that last step — transporting cystine out of the lysosomes — doesn’t work, and the cystine builds up and forms crystals. Those crystals increasingly effect cellular function and eventually cause cellular death.
The kidneys almost always are affected first. The earliest symptoms of cystinosis in infants and small children are excessive thirst and urination, dehydration and failure to thrive. If untreated, children will usually die before age 10.
Children with cystinosis will almost always need a kidney transplant at some point. The disease also affects their vision, and eventually it causes muscle wasting and disease in the liver and other organs.
The first new drug
Since Cystagon was introduced in the mid-1980s, first as an experimental drug and later as an FDA-approved therapy, it’s dramatically improved the health of patients. Children who take it every six hours as instructed can make it into their 20s without a kidney transplant and still in fairly good health. They can live into their 40s.
“When Cystagon was discovered, doctors finally had a drug they could use. It was transforming to the cystinosis population,” said Chris Starr, chief executive of Raptor Pharmaceuticals, the Novato company that developed Procysbi. “Usually that would be the end of the story, but in this case, doctors found that most patients couldn’t take the drug.”
The problem is that many children can’t get as much of the drug as they need. Studies suggest only 20 percent of children are able to tolerate the drug well enough to get the full benefit of it.
“Cystagon is a medication that hurts. Many children and teenagers hate taking it because it makes them feel miserable,” said Dr. Paul Grimm, a pediatric nephrologist at Lucile Packard Children’s Hospital at Stanford, who is one of a handful of cystinosis experts in the United States.
“The patients that do the well on (Cystagon), they are very lucky. A huge percentage aren’t so lucky,” Grimm said. “I’ve seen a lot of patients who are only getting it two or three times a day, and once they’re teenagers they just stop taking it. That leads to a lot of complications in their 20s and 30s.”
The drug’s downside
Cystagon comes in a capsule. For kids too young to swallow the capsule, parents will break it open and poor the contents over their food or mix it with water. The drug smells of rotten eggs and tastes metallic, and many children feel worse after taking it than they did before.
Children who have bad reactions to the drug — vomiting and severe nausea and stomach cramps — might kick and scream and refuse to take it. Many children will miss middle-of-the-night doses when their parents are too exhausted to get up with them. Older children, especially teenagers responsible for taking the capsules themselves, are especially prone to missing doses.
Doctors believe that even a single missed dose a day can cause levels of cystine crystals to increase. Over time, that could mean those children need kidney transplants at an earlier age, or suffer the later effects of cystinosis like muscle wasting.
“The need to have consistent drug levels in your system is really critical,” Starr said. “When (cystine) forms crystals in the cells, they never get smaller, they only get bigger. So every time you miss a dose, the crystals just get a little bigger.
“What we’ve found is that if you don’t take the middle-of-the-night dose, kidney function deteriorates,” Starr said.
More tolerable drug
The new drug, Procysbi, utilizes a deceptively simple technique to make Cystagon more tolerable. Scientists added an enteric coating to the granules inside the capsule, and that coating prevents the drug from being absorbed by the stomach. Instead, the coating causes gradual, extendedrelease absorption in the small intestine.
The result is that side effects are less severe, if not entirely absent, and patients are able to take the drug in two doses 12 hours apart. The downside: Procysbi will be far more expensive than its predecessor. Cystagon costs about $10,000 a year — Procysbi could cost about $250,000 a year.
In the first round of clinical trials, in 60 patients who already were doing well with Cystagon, the new formulation proved just as beneficial as the old one. Raptor has started a second trial to see if children who aren’t tolerating Cystagon do better with Procysbi.
Grimm, who has seen patients in both the first and second clinical trials, believes that simply by being able to take the drug as often as they need to, children will see better results with Procysbi.
“I have a number of patients currently in the study who could not take Cystagon, or could only take tiny amounts without feeling totally miserable,” Grimm said. “These people, if they are actually able to take a reasonable dose of the new medication, that is a huge difference for them.”
Other options
In addition to the recent approval of Procysbi, last year the FDA gave the go-ahead for an eye drop called Cystaran to reduce the buildup of cystine crystals in the corneas. Meanwhile, researchers at UCLA are studying a technique that uses a patient’s own stem cells to repair the genetic malfunction that causes cystinosis.
Both Cystagon and Procysbi are not close to a cure for cystinosis, Grimm said. The stem cell therapy may cure patients someday, but that research will take many years.
But families and doctors alike said it’s thrilling how far treatment for cystinosis has come in just the past 25 years, especially considering how rare the disease is and how difficult it can be to find scientists interested in studying it, and the money to fund their research.
When Valerie Hotz’s nephew, Joshua, was diagnosed with cystinosis in 1982, his parents were told there was no treatment for him and he could expect to die very young. He ended up getting an experimental therapy of Cystagon three years later, but Hotz recalls that taking the drug was an ordeal for the whole family — he hated it and fought and cried.
Still, he survived. And his family created the Cystinosis Foundation to help raise money and awareness for the disease.
“My nephew is experiencing muscle wasting to various degrees now, and he must use a wheelchair because he can’t walk long distances. It’s serious and painful for him,” said Hotz, who lives in Moraga. “But with treatment he’s been able to have, he’s lived a full life.”