Addison and Cassidy Hempel are seven-year-old identical twins who are among only about 500 people in the world with an extremely rare but fatal neurological disease that gradually destroys the young mind and body. The US Food and Drug Administration (FDA) has not approved any therapies for this rare disease, known as Niemann-Pick disease type C1 (NPC). So under normal circumstances, Addi and Cassi would not live through adolescence. But that fate is not yet sealed because in 2010 they became the first children in the world to start receiving injections of an experimental drug called cyclodextrin.
In an effort to bring this treatment to other children with NPC, the US National Institutes of Health (NIH) announced on 23 January that scientists at its National Center for Advancing Translational Science (NCATS) will begin a phase 1 clinical trial to evaluate the safety and effectiveness of cyclodextrin in nine other NPC patients. Both NCATS and its clinical trial partner, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), are based in Bethesda, Maryland.
Charles Vite, a veterinary neurologist at the University of Pennsylvania in Philadelphia who has tested cyclodextrin in a feline model of NPC, says the the drug “shows clear improvements in the animal model” above and beyond other compounds scientists have tried. “It’s very exciting because this drug has the potential to be successful in children.”
In NPC, a genetic defect in the molecular machinery that clears cholesterol out of cells leads to accumulation of cholesterol inside the liver, brain and other organs, causing progressive damage to the nervous system, and resulting in problems such as slurred speech, difficulty swallowing, dementia and seizures.
Symptoms develop around age ten and most patients die within five to ten years of diagnosis. As such, scientists have had difficulty knowing straight away whether a therapy is helping. “One of the problems is that NPC is a slow-progressing disease and requires a mixture of biomarkers to confirm that the drug is working,” says John McKew, director of NCATS Division of Pre-Clinical Innovation. “The purpose of this trial is to look at a broad base of outcomes, including specific NPC biomarkers in the blood.”
The road to attaining NPC treatments has been difficult in the US. In January 2009, the EU approved a drug called Zavesca (miglustat), designed by the Swiss company Actelion, to block the action of an enzyme that produces cholesterol, as the first-ever NPC treatment. However, in March 2010 the FDA rejected Zavesca in the US, requesting additional preclinical and clinical information from the manufacturer, despite the drug’s approval in not only the EU but places such as South Korea, Brazil, Russia, Australia and Canada.
Zavesca is associated with severe gastrointestinal side-effects and a prolonged use of the drug was linked to inflammatory lesions of the large intestine in mice. Even so, the FDA’s decision was a major setback for the families of about 200 US patients. “Without FDA approval, medical insurance will not cover the drug and we have to buy it off-label and [pay] over $100,000 out of pocket,” says Cindy Parseghian, the founder of the non-profit Ara Parseghian Medical Research Foundation that provides medical research funding for the treatment of NPC, and a mother of several children affected by NPC. “We would love to see the FDA approve the drug.”
Researchers have been using cyclodextrin for years to bind and deliver insoluble drugs into the blood stream. Research in mice lacking the NPC gene recently showed that the drug can restart cell’s cholesterol metabolism to empty cells of accumulated cholesterol and increase the lifespan of the mice from 85 to 115 days.
“We are optimistic that we will determine a safe and effective dose and lay the groundwork for a larger phase 2 trial to focus on clinical outcomes,” says Forbes Porter, NICHD clinical director and one of the investigators to conduct the trial. “The FDA understands what’s at stake and has been extremely helpful in working with us in meeting the challenges of a rare disease model.”
An additional unknown about the trial in children is whether cyclodextrin can cure the cognitive abnormalities associated with NPC. “We are not going to regenerate new neurons but we will stop the decline,” McKew hopes. The research team is already collaborating with the NIH’s Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) to plan an expanded multicenter phase 2 trial.
For more about Addi and Cassi’s story, here is an interview they did with Good Morning America: