NIH Clinical Center

The National Institutes of Health Clinical Center.

National Institutes of Health

Clinical trial setback ignored in paper on success story of NIH bench-to-bedside center

When Francis Collins, the director of the National Institutes of Health (NIH), proposed a new translational medicine center at NIH 5 years ago, he met with plenty of skepticism. Former Merck & Co. CEO Roy Vagelos told a congressional committee that the idea that the $600 million NIH effort could surmount drug development problems that industry has failed to solve was like believing “in fairies.”

So Chris Austin, the Collins protégé who has run the National Center for Advancing Translational Sciences (NCATS) in Bethesda, Maryland, since soon after its launch, has been under plenty of pressure to produce success stories. And NCATS has had some, such as the discovery that an existing antihistamine, chlorcyclizine, blocks the ability of the hepatitis C virus to infect cells. Through a brute-force chemical screen in the midst of the 2014 Ebola epidemic, NCATS researchers also identified 53 compounds that block that virus from entering cells.

But none has made quite as good a story as that of VTS-270, a potential treatment for the rare, incurable, inherited disease Niemann-Pick type C-1 (NPC). It was shepherded through early development by an NCATS-orchestrated collaboration and then handed off to the small Gaithersburg, Maryland, company, Vtesse. Now, however, an early chapter in that story is getting a rewrite that raises questions about whether participants in the collaboration downplayed a key setback.

Vtesse is currently running a late-stage clinical trial of the drug, a large sugar molecule known as a cyclodextrin, in which it is injected by lumbar puncture into the spinal fluid of children with the disease (see “Why are people fighting over a promising treatment for a fatal childhood disease”). However, there was a big bump along the road to the current trial, when the NCATS-convened team, in a first attempt, injected the drug directly into the brain ventricles—the cisterns that hold cerebrospinal fluid—using an implanted reservoir normally deployed to inject brain cancer chemotherapy. The reservoirs of two of three children quickly became infected and the trial was put on clinical hold on 30 April 2013.

That study—called an ICV trial for “intracerebroventricular” drug administration—is back in the limelight because a mother of two children afflicted with NPC recently asked for a correction in an article that appeared in the journal Current Topics in Medicinal Chemistry. Written by 25 authors, it described the collaboration between government, academic researchers, and disease advocacy groups that led to the ICV trial as a model of the teamwork that can speed drugs through early development, boosting their chances of being commercialized. The paper was submitted to the journal 9 days after the trial was put on clinical hold, was revised 2 months later, and was not published until 2014. However, it nowhere mentions the failure of the trial and the abandonment of the direct brain route of administration. 

Chris Hempel, the mother of 12-year-old twin girls with NPC and a prominent figure among advocates for development of NPC therapies, last week pointed out the omission to the journal’s editor, Allen Reitz in Doylestown, Pennsylvania. (One of Hempel’s daughters suffered a stroke after ICV administration of cyclodextrin, although not as part of the NIH trial; it was being administered separately under a compassionate use protocol approved by the Food and Drug Administration.)

 Reitz now says he is preparing to run a correction. It will read:

“It has come to our attention that at the time of submission of this manuscript and during peer review that the Phase I Clinical Trial as described involving ICV administration using an Ommaya reservoir was in fact already on clinical hold. Dr. [Elizabeth] Ottinger, senior author on this paper, has updated the clinical status of this program to say that the trial was subsequently resumed using the intrathecal (IT) route of administration.”  

In an email to Science, Reitz added: “Even though the focus of the paper was on the collaboration, which is a good thing, and the paper was well-written, the authors had a responsibility to accurately represent the state of the collaboration at that point in time.” Reitz emphasizes, however, that the physicians running the trial did quickly make the information public. In a 45-minute conference call convened by the National Niemann-Pick Disease Foundation 3 days after the trial was put on hold, they updated NPC parents about the setback and the hold.

Austin and the other authors believe the correction is unnecessary. He wrote to Science: “The theme of the particular issue of the journal in which the article was published was collaborative science, and therefore the article was focused on the process and collaborative environment contributing to the development of the drug. The information regarding the clinical trial is currently being written for submission to a research journal. The senior authors did not agree with the published corrigendum, and albeit to no avail, explicitly had asked the editor for the opportunity of a discussion before he published it.”