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Advocating for Cures
CHORI Clinical Scientist Wins FDA Approval for Experimental Treatment Protocol

"No one had a clear sense of what was going on. As soon as I saw them I feared it was a metabolic storage disease, and knew we had to go looking for the rare disorders."

CHORI clinical scientist Caroline Hastings, MD, first met two-year-old twins, Addi and Cassi Hempel, when it was clear that something was wrong but no one had yet diagnosed the problem. Bright and bubbly youngsters from birth, Addi and Cassi had begun to undergo a startling regression, from chattering away like any toddler to a complete loss of all vocabulary, as well as increasing problems with balance and other motor skills.

“They’d been seen by a number of specialists but no one had a clear sense of what was going on,” says Dr. Hastings. “They got sent to me because they had enlarged spleens, and as soon as I saw them I feared it was a metabolic storage disease, and knew we had to go looking for the rare disorders.”

Metabolic storage diseases are uncommon diseases that are caused by enzyme defects that keep that enzyme from functioning properly or that interfere with the movement of cell content. In Addi and Cassi's case, the disorder turned out to be Niemann Picks type C, or NPC.

"NPC is probably the rarest of the different types of the disorder, and it has no known treatment, in part b/c there isn't a completely clear understanding of what's happening," explains Dr. Hastings of the disease in which cholesterol can't be removed from the red blood cells. "Cholesterol is vital for life, but it's toxic if it isn't transported out of the cells."

The cholesterol build-up is particularly toxic to the nervous system in NPC, and the brain and central nervous system take the biggest hit. As children age, they start regressing instead of gaining.

"It's a devastating diagnosis because there are no proven treatments. Eventually children become so weak, they can't even swallow. They usually don't survive beyond age ten," says Dr. Hastings.

While the diagnosis for the Hempel family was horrific, it also meant that what was harming the twins now had a name.
"When the family got the news, they spent some time just investigating and then they came to me and said, 'we have to do something, if not for them, then for someone else.' Then they asked me if they found some potential treatments, would I try and get approval to use them."
And with that, Dr. Hastings went from a clinical member of the twins' treatment team to an advocate for the family to the Food and Drug Administration (FDA) that is responsible for approving any and every drug treatment protocol used in the United States.

The drug of greatest interest to the Hempel family was a sugar compound called cyclodextrin. While it's not completely clear how the sugar compound works, research studies have shown that it does help transport cholesterol out of the cell. Even better, the drug was already on market, used as a food additive and in intravenous medication, to make the primary medication more effective.

"That meant that it was readily available already, relatively cheap, and that there was a lot of information on people who have ingested it or received via intravenous fluids," says Dr. Hastings. "That made it much easier to take to the FDA, because it's not completely new - it's been felt to be a relatively harmless additive."

Still, the FDA required a specific treatment protocol, scientific markers to measure any potential benefit, and very strict safety guidelines. With a good deal of effort, Dr. Hastings was able to usher through an approval for cyclodextrin in May, and in spite of the very low dosing regimen dictated by the FDA, the girls seem to have made gains.
"The girls are much more alert and interactive, both are saying more words, and their steadiness has gotten much better," says Dr. Hastings. In addition, there have been no adverse effects, paving the way for a second protocol, just approved in July, for dosing the twins at clinically relevant levels.

"What was most interesting was that they seemed to get better a few days after infusion and then they'd lose some of it," says Dr. Hastings. "We feel like the drug must get utilized right away, and kind of like an insulin pump, and that they might need more frequent infusions. The new protocol will allow us to do two infusions a week. We're now starting the phase of treatment where if it's going to work we should really see something."

In the mean time, however, Dr. Hasting's work as an advocate to navigate the FDA isn't over. She's now working with other families and physicians in other cities, states and countries where people who have children with NPC and want to do the same treatment.

"Eventually, we hope to make it more of a phase one study where we can enroll patients around the world and collect data on all of them. If the treatment is as successful as we hope, I'm pretty confident we'll have a drug to treat NPC," says Dr. Hastings.

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Tuesday, May 17, 2011 8:19 AM

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