Hugh and Chris Hempel, whose daughters Addi (left) and Cassi have Niemann-Pick type C-1 and receive cyclodextrin intravenously and via spinal injections.
Hugh and Chris Hempel

Why are people fighting over a promising treatment for a fatal childhood disease?

The National Institutes of Health's (NIH's) ambitious center devoted to speeding research from bench to bedside regularly touts an experimental drug for a rare metabolic disorder as one of its first big successes. But a bitter fight involving NIH, two companies, and opposing camps of researchers and parents of children with the fatal condition is marring the triumph. The flashpoints include how to administer the drug and whether the 5-year-old National Center for Advancing Translational Sciences (NCATS) in Bethesda, Maryland, has tilted the commercial playing field in favor of one company. A disgruntled, competing firm has even sent a letter to Francis Collins, the director of NIH, with copies to several members of Congress, complaining that the agency is "choosing winners and losers in the development programs of private enterprises."

The furor surrounds the use of cyclodextrins, a family of doughnut-shaped sugar molecules, to treat Niemann-Pick type C-1 (NPC), a lethal, inherited disease that prevents the body from metabolizing cholesterol and other lipids. The resulting accumulation of fats harms the brain, liver, and lungs. It is almost always the brain damage that kills, often by the time children reach their teens.

Over the past decade, researchers working with cat and mouse models of NPC have shown that cyclodextrins can alleviate symptoms and slow progression of the disease. Although their mechanism of action isn't fully understood, cyclodextrins readily bind cholesterol, depleting it from cells in culture. As word of the animal findings spread, a number of desperate parents obtained U.S. Food and Drug Administration approval for their physicians to administer the drug under "compassionate use" protocols. Their experiences produced anecdotal reports of improvements.

Meanwhile, to conduct lab studies of the compound and then formal human safety trials, NCATS was orchestrating a collaboration between several extramural investigators, six NIH institutes, and a handful of foundations launched by parents of children with NPC. In December 2014, the center entered a cooperative research and development agreement under which Vtesse, a Gaithersburg, Maryland, company, took over the therapy, speeding the drug into a pivotal, late-stage clinical trial in the space of 18 months. This is "a huge win for us, for patients: having gotten this compound through the so-called Valley of Death in this kind of collaborative team-based way in a remarkably short time and successfully handed it off to private industry," says NCATS Director Chris Austin.

If we could hold the neurological symptoms off some other way than giving my son a spinal tap every 2 weeks, believe me I would do it.

Philip Marella, parent who lost his daughter at 19 to the disease and whose 17-year-old son is receiving cyclodextrin intrathecally

But Vtesse has a rival, which is starting clinical trials of its own cyclodextrin. CTD Holdings, a small, Gainesville, Florida-based company that makes cyclodextrins for a broad variety of purposes, became aware of their potential as an NPC treatment after being contacted by Chris and Hugh Hempel, the parents of twin girls with the disease. Last month, it won regulatory approvals in the United States and the United Kingdom to launch trials studying the safety and pharmacological effects of Trappsol Cyclo, the cyclodextrin it has developed for NPC treatment. Whereas Vtesse's clinical trial delivers its drug, VTS-270, directly into the cerebrospinal fluid by lumbar puncture, CTD will test intravenous (IV) administration.

That difference is at the heart of the multifaceted dispute. To most effectively attack neurological symptoms, the drug must reach the brain, and cyclodextrin is a large molecule that does not cross the blood-brain barrier. That's why Vtesse, and before it the NCATS-convened team, chose the "intrathecal" route, into the cerebrospinal fluid. Vtesse says that unpublished results from an earlier trial when the drug was still being shepherded by NCATS showed that children with NPC who received the drug intrathecally had "significantly" less neurological progression after 12 and 18 months than a control group of untreated children. It is now running a late-stage, randomized, double blind, sham-controlled trial of its intrathecal cyclodextrin in children and teens with NPC in the United States and Europe, with additional trial sites awaiting approval in Australia.

How the drug could aid the brain if instead given intravenously is unclear, but some data suggest it can. In mouse models of the disease, cyclodextrin administered peripherally delayed disease onset, reduced brain accumulation of fat, and lengthened life significantly, several published studies have found. In presentations this summer, CTD representatives reported anecdotal cases of neurological improvements—such as in motor skills and speech—in children treated intravenously with the company's cyclodextrin on a compassionate use basis, including the Hempels' daughters. The company further notes that the IV delivery method may protect other organs affected by NPC.

Andrew and Dana Marella, in 2012. Dana died in 2013. Now 17, Andrew receives cyclodextrin by spinal injection in a clinical trial. An estimated 43 babies are born with Niemann-Pick type C-1 in the United States each year.
The Marella Family

The suggestion that the IV form of the drug can cause meaningful neurological improvements in children enraged some parents, however. At a June meeting in Tuscon, Arizona, of the Ara Parseghian Medical Research Foundation "all hell broke loose," recalls biochemist Elizabeth Neufeld of the University of California, Los Angeles, an expert in lysosomal storage diseases including NPC. "I have never seen anything like that at a meeting." The tensions continued at an August meeting of the National Niemann-Pick Disease Foundation in Danvers, Massachusetts.

Some parents and scientists charge that CTD is promising brain improvements its drug cannot deliver and siphoning rare patients who might otherwise enroll in the Vtesse clinical trial. "If you are going to try to start selling parents on 'You don't need to do intrathecal,' you are putting children at risk in my opinion. I got very upset," says Philip Marella, who lost his daughter at 19 to the disease and whose 17-year-old son is receiving cyclodextrin intrathecally as part of Vtesse's trial. "If we could hold the neurological symptoms off some other way than giving my son a spinal tap every 2 weeks, believe me I would do it."

Some NPC researchers not connected to Vtesse echo such concern. "This is a neurological disease and to have the best hope of helping the kids, the drug has to get into the brain," says biochemist Suzanne Pfeffer of Stanford University in Palo Alto, California.

Yet some parents of children with NPC are supportive of CTD's proposed trial and equally adamant that the IV route should be an option. "Not all NPC patients present with neurological complications. To generalize about a condition that is highly heterogeneous misses the point entirely," Chris Hempel says. "Intrathecal therapy alone is not enough for him," adds Shannon Reedy, whose 7-year-old son Chase has NPC. "I can tell you with certainty that after beginning just intravenous [cyclodextrin] my son began rapidly adding vocabulary and had improved swallow studies. His fine motor improved markedly as well."

A European NPC expert, who has no ties to either company and wishes to remain anonymous, says that a clear case can be made for testing IV-only cyclodextrin treatment of the disease—for instance, in families that may not want to expose their children to the more invasive intrathecal procedures, and in adults who develop a later-onset form of the disease that progresses more slowly. This researcher says that the CTD trial, which is enrolling adults in the United States and children in Europe, should resolve whether IV therapy has no neurological benefit, as critics contend.

We don't have any more control over what Vtesse is doing than I have over the Washington Nationals.

Chris Austin, Director, National Center for Advancing Translational Sciences

In a new twist, two Vtesse-affiliated, NIH-funded scientists are proposing their own trials of IV delivery. The development has infuriated CTD, which is criticizing NIH and several of its intramural and extramural investigators who study NPC. In a 19 August letter to Collins, attorneys representing CTD warned that NIH will undermine the company if it supports the two proposed trials, which would test IV delivery of Vtesse's cyclodextrin in babies and children, in hopes of protecting their livers and other organs that intrathecal delivery cannot reach.

One of the proposals lambasted by CTD comes from Forbes Porter of NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, who ran the NCATS-sponsored early human studies of the cyclodextrin that became VTS-270 and who now co-chairs Vtesse's Scientific Advisory Board. Porter would give the drug intravenously to affected children and monitor markers of chronic liver inflammation and liver lipid and cholesterol storage. In the other proposal, Daniel Ory, who studies NPC biomarkers at Washington University in St. Louis in Missouri and is a member of Vtesse's Preclinical Scientific Advisory Board, is seeking NIH funding to test VTS-270 intravenously in NPC newborns suffering from aggressive liver disease because of fat accumulation. The hope is that they might be spared liver transplants or downstream cancer or cirrhosis. In a second arm, Ory would add IV therapy to the regime of children receiving the drug intrathecally.

"Why would NIH launch an intravenous trial? That's a duplication of effort," charges developmental neuroscientist Sharon Hrynkow, CTD's senior vice president of medical affairs and former acting director of NIH's Fogarty International Center. "It's a waste of taxpayer dollars, because it is already being done by CTD."

CTD's complaints are "troubling" because the duplication of private sector work "is exactly what NCATS is not doing," Austin says. "We don't have any more control over what Vtesse is doing than I have over the Washington Nationals. … In fact, NCATS did exactly what the congressional legislation that established it said: to de-risk something just to the point where it can be licensed to the private sector."

N. Scott Fine, CTD's CEO, is not placated. "There is no line between Vtesse and NIH in this [VTS-270] development program. When NIH stands in public and speaks about cyclodextrin and Niemann-Pick type C, they speak from the mouth of Vtesse."

In the end, there is one thing that all sides agree on: that the conflict between parties who all share the goal of helping dying children is sad—and not what any of them would have chosen. Indeed, the whole controversy, says the European NPC expert, is muddying the water for parents challenged with deciding whether to enter a child in a clinical trial, and, if so, which one. "It makes it very difficult for them to make informed decisions about what they should do."