A treatment for Niemann-Pick type C (NPC), an extremely rare and ultimately fatal neurodegenerative disease, performed no differently than placebo in a pivotal trial in 56 children and youths, its corporate sponsor announced on Tuesday. Perplexingly, though, the disease did not progress in either the treatment or placebo groups during the 1-year study, the company said. Normally, the condition, a result of impaired cholesterol metabolism, inexorably worsens, causing loss of balance, difficulty swallowing, seizures, and cognitive disabilities.
The drug, VTS-270, a doughnut-shaped sugar molecule called a cyclodextrin, “did not show a statistically significant separation from placebo,” Steven Romano, Mallinckrodt Pharmaceuticals’s executive vice present and chief scientific officer told investors on a conference call on Tuesday. “But importantly, neither did [patients in the active or placebo arms of the trial] show disease progression as would have been anticipated in the neurodegenerative condition over 52 weeks of observation.” The drug was given by spinal injection into the cerebrospinal fluid, which circulates to the brain.
The news—and the way Mallinckrodt, which has its U.S. headquarters in St. Louis, Missouri, delivered it—came as a shock to families in the NPC community, who learned of it when investors began to tweet about it. (The company did email a letter to NPC disease groups on Tuesday. Mallinckrodt, whose stock is publicly traded, added in a statement emailed to Science that securities laws prevented the company from notifying patients sooner.)
Will Evans, a family practitioner in Leeds, U.K., is chair of the charity Niemann-Pick UK. His 11-year-old son, Sam, was in both an earlier trial to determine a safe dose of the drug and in the most recent trial. “Many families, ours included, have invested several precious years in this trial—taking our children fortnightly to trial sites to undergo invasive procedures—and across the community, so much hope has been hung on the outcomes of this trial,” Evans says. “For these families to receive this news via the reporting of a financial call on Twitter is incredibly disappointing and hurtful. It has caused enormous upset for many families.”
“It’s devastating news,” adds Chris Hempel of Reno, Nevada, whose twin daughters, Addi and Cassi, 14, have received spinal injections of cyclodextrin for 8 years on a compassionate-use basis approved by the U.S. Food and Drug Administration (FDA). She says the treatment helped her daughters recover hearing and stabilized their swallowing, although other symptoms have gotten worse. “As we know from our own experience and that of others in the patient community, there are children who respond to cyclodextrin treatment. Obviously, the latest results are confusing and create a lot of questions around how the clinical trial was designed.”
Some researchers who study extremely rare diseases like NPC say the trial’s results suggest using traditional double-blind, randomized controlled trials may simply be inappropriate for such conditions, leading to hard-to-interpret outcomes like the current one. The difficulty of enrolling patients, they say, may prevent traditional trials from having enough statistical power to achieve predefined statistical significance, even when the experimental agent is actually effective.
Marc Patterson, a child neurologist at the Mayo Clinic in Rochester, Minnesota, who has conducted NPC research and cared for NPC children for 30 years, says: “This is a disappointing result but a very important one. The question I have is: Is it truly the case that this agent is not effective, or is the result the consequence of a trial design that in retrospect might have been better?”
Patterson argues that the drug, which showed positive results in mouse and cat models of the disease, might work in some children but not others, and that factors like the length of the current trial—1 year in the course of a disease that can be slowly progressive—might have masked such successes. He also argues that FDA should consider setting a different “bar” when assessing therapies for extremely rare, individually variable diseases like NPC, such as allowing effectiveness in a given child to be defined by comparing disease progression during the study to the same child’s rate of progression prior to beginning the drug.
Romano told investors that the company had expected both the children who received spinal injections of the active drug every 2 weeks for a year and those who received sham, placebo injections—one-third of those in the 56-patient study—would worsen during the trial, but that the children receiving the drug would worsen more slowly. The company is studying “the totality of data available to us,” he added, to try to understand whether and how the drug might still produce results that would win FDA approval. For instance, the company will look at data from what Romano called “a large number” of individual patients who have been treated through FDA compassionate use programs. And it will consider data from an ongoing, “open-label” stage of the trial, in which all patients who participated and who wish to are continuing to receive drug injections.
“We’ll need to look at those open-label treatment patients and see if there’s any difference that gradually accrues over the course of that additional treatment period,” Romano said.
VTS-270 has been one of the most promising drugs shepherded by the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH) in Bethesda, Maryland. NCATS collaborated with Vtesse, a biotechnology company in Gaithersburg, Maryland, which funded it to bring the drug through a first clinical trial at the NIH Clinical Center. When, less than 2 years later, Vtesse had moved the drug into the new, pivotal trial, the bench-to-bedside center pointed to the drug’s quick progress as a “huge win” for patients—an example of how the U.S. biomedical agency can develop drugs in their earliest stages to the point where industry takes them over.
Then in March 2017, privately held Vtesse was acquired for $200 million by the global biopharmaceutical company Sucampo Pharmaceuticals. Eight months later, last December, Sucampo was acquired by Mallinckrodt for $1.2 billion in cash. Mallinckrodt’s press release that day declared that the acquisition, among other things, “bolsters our pipeline in rare diseases with VTS-270.”