Late last year, a group of whistleblowers filed a report with the National Institutes of Health questioning the integrity of a celebrated USC neuroscientist's research and the safety of an experimental stroke treatment his company was developing.
NIH has since halted clinical trials for 3K3A-APC, a stroke drug sponsored by ZZ Biotech, a Houston-based company co-founded by Berislav V. Zlokovicprofessor and chairman of the department of physiology and neuroscience at the Keck School of Medicine of USC.
Three of Zlokovic's research articles have been retracted by the journal that published them due to problems with the data or images. Journals have issued corrections for another seven articles in which Zlokovic is the only common author, one of which is a second correction after the newly supplied data also turned out to have problems.
For an eleventh article, co-authored by Zlokovic, the journal Nature Medicine published a expression of concern, a note that journals add to articles if they have reason to believe there may be a problem with the article, but this has not been conclusively proven. Because Zlokovic and his co-authors no longer had the original data for any of the figures surveyed, the editors wrote:[r]Readers are therefore cautioned to interpret these results with caution.”
“It is quite unusual to encounter this volume of retractions, corrections and expressions of concern, especially in high-level, influential articles,” said Dr. Matthew Schrag, assistant professor of neurology at Vanderbilt, who co-authored the whistleblower report , independently of his work. at University.
Both Zlokovic and USC representatives declined to comment, citing an ongoing investigation launched following the allegations. first reported in the journal Science.
“USC takes all allegations of academic integrity very seriously,” the university said in a statement. “In accordance with federal regulations and USC policy, this review must be kept confidential.”
Zlokovic “remains committed to cooperating with and respecting that process, although this is unfortunately necessary due to allegations based on inaccurate information and flawed premises,” his lawyer Alfredo X. Jarrin wrote in an email.
As for the articles, “corrections and retractions are a normal and necessary part of the scientific post-publication process,” Jarrin wrote.
Authors of the whistleblower report and experts in the field of scientific integrity disputed this statement.
“If these are honest mistakes, then the authors should be able to show the actual original data,” he said Elisabeth Bik, a microbiologist and scientific integrity advisor who co-wrote the whistleblower report. “It is perfectly human to make mistakes, but many errors are found in these papers. And some findings point to image manipulation.”
Given the steady pace of scientific publishing, publishing so many corrections and retractions just a few months after initial concerns were raised is “bizarrely quite fast,” says Ivan Oransky, co-founder of Withdrawal watch.
The whistleblower report submitted to the NIH allegedly identified doctored images and data in 35 research articles in which Zlokovic was the sole joint author.
“There were rumors that things wouldn't be reproducible [in Zlokovic’s research] for quite some time,” says Schrag. “The real motivation for speaking publicly is that some of his work reached a stage where it was used to justify clinical trials. And I think when you have data that might be unreliable as a basis for that kind of experiment, the stakes are much higher. You are talking about patients who are often at the most vulnerable medical moment of their lives.”
Over the years, Zlokovic has founded several biotech companies aimed at commercializing his scientific work. He was co-founder in 2007 ZZ Biotechthat has been working to obtain federal approval of 3K3A-APC.
The drug is intended to minimize the bleeding and subsequent brain damage that can occur after an ischemic stroke, in which a blood clot forms in an artery leading to the brain.
In 2022, USC's Keck School of Medicine received from NIH the first $4 million of a planned $30 million grant to conduct Phase III trials of the experimental treatment of stroke in 1,400 people.
In phase II of the trial, that was published in 2018 and called Rhapsody, six of 66 patients given 3K3A-APC died in the first week after their stroke, compared with one person among 44 patients given a placebo. Patients who received the drug also reported more disability 90 days after their stroke than those who received the placebo. The differences between the two groups were not statistically significant and could be due to chance, and the mortality rate for patients in both groups became similar one month after the first stroke.
“The claims that there is a risk in this trial are false,” said Patrick Lyden, a USC neurologist and stroke expert who was employed by Cedars-Sinai at the time of the trial. Zlokovic worked with Lyden as a co-researcher on the study.
A correction has been issued to the paper describing the Phase II results, fixing an extra line in a data table that caused some numbers to be moved to the wrong columns. “This mistake is mine. It doesn't belong to anyone else. I didn't notice it in multiple readings,” Lyden said, adding that he noticed the error and was already working on the correction when the magazine contacted him about it.
He disputed that the trial posed an excessive risk to patients.
“I believe it is safe, especially when you consider that the goal of Rhapsody was to find a dose – the maximum dose – that was tolerated by patients without risk, and the Rhapsody study succeeded in that. We did not find any dose that was too high to limit progression to Phase III. It is time to move on to Phase III.”
Schrag emphasized that the whistleblowers found no evidence of manipulated data in the Phase II study report. But given the errors and alleged data manipulation in Zlokovic's previous work, he said, it is appropriate to take a closer look at a clinical trial that would administer his research's product to people in life-threatening situations.
In the Phase II data, “there is a consistent pattern of this [patient] outcomes go in the wrong direction. There is a signal in the early mortality… there is a trend toward worse disability rates' for patients who received the drug instead of a placebo, he said.
None of these are “conclusive evidence of harm,” he said. But “if you see a red flag or a trend in the clinical trial, I would be inclined to give more weight to that if there are serious ethical concerns around the preclinical data.”
The NIH halted the clinical trial in November and it remains on hold, said Dr. Pooja Khatr, principal investigator of the NIH StrokeNet National Coordination Center. Khatr declined to comment on the pause or the future of the trial and referred further questions to USC and NIH.
The NIH Office of Extramural Research declined to discuss Rhapsody of Zlokovic, citing confidentiality regarding grant deliberations.
Kent Pryor, CEO of ZZ Biotech, who will be in 2022 called the medicine “a potential game-changer,” he said he had no comment or information about the halted trial.
Zlokovic is a leading researcher in the field of the blood-brain barrier, with a particular interest in its role in stroke and dementia. He received his medical degree and doctorate in physiology from the University of Belgrade and, after several fellowships in London, joined the faculty of USC's Keck School of Medicine. A polyglot and amateur opera singerZlokovic left USC and previously spent 11 years at the University of Rochester back in 2011. The following year he was appointed director of USC's Zilkha Neurogenetic Institute.
A USC spokesperson confirmed that Zlokovic has retained his titles as department chair and director of the Zilkha Institute.
