LOS ANGELES — Late last yr, a gaggle of whistleblowers filed a report with the National Institutes of Health stating: questioned the integrity of the research of a celebrated neuroscientist on the University of Southern California and the security of an experimental stroke treatment his company was developing.
The NIH has since paused clinical trials for 3K3A-APC, a stroke drug sponsored by ZZ Biotech, a Houston-based company co-founded by Berislav V. ZlokovicProfessor and Chair of the Department of Physiology and Neuroscience on the Keck School of Medicine of USC.
Three of Zlokovic's research papers were retracted by the journal that published them due to problems with the information or images. Journals have issued corrections for seven other papers where Zlokovic is the only real joint creator, with one a second correction after it was discovered that the newly provided data also had problems.
For an eleventh paper co-authored by Zlokovic, the journal Nature Medicine published a Expression of concerna note that journals append to articles after they have reason to imagine there could also be an error within the article but haven’t proven it conclusively. Because Zlokovic and his co-authors now not had the unique data for certainly one of the figures in query, the editors wrote, “readers are therefore urged to interpret these results with caution.”
“It's quite unusual to see this level of retractions, corrections and expressions of concern, especially for high-level, high-impact work,” said Dr. Matthew Schrag, an assistant professor of neurology at Vanderbilt University who co-authored the whistleblower report independently of his work on the university.
Both Zlokovic and USC representatives declined to comment, citing an ongoing investigation that was launched in response to the allegations. first reported within the journal Science.
“USC takes all allegations regarding research integrity very seriously,” the university said in a press release. “In accordance with federal regulations and USC policies, this review must be kept confidential.”
Zlokovic “remains committed to cooperating and respecting this process, although unfortunately this is required due to allegations based on false information and faulty premises,” his attorney Alfredo X. Jarrin wrote in an email.
Regarding the articles, “corrections and retractions are a normal and necessary part of the scientific process after publication,” Jarrin wrote.
The authors of the whistleblower report and academic integrity experts questioned this claim.
“If these are honest errors, then the authors should be able to present the actual original data,” said Elisabeth Bika microbiologist and scientific integrity consultant who co-authored the whistleblower report. “It's completely human to make mistakes, but many errors were found in these papers. And some of the results suggest image manipulation.”
Given the slow pace of educational publishing, the publication of so many corrections and retractions just months after the primary concerns arose is “oddly quite rapid,” said Ivan Oransky, co-founder of Retreat clock.
The whistleblower report submitted to the NIH identified allegedly manipulated images and data in 35 research papers by which Zlokovic was the only real co-author.
“There have been rumors for some time that things (in Zlokovic's research) are not reproducible,” Schrag said. “The real reason to talk about it publicly is that some of his work has reached a stage where it has been used to justify clinical trials. And I think when you have data that may be unreliable as the basis for an experiment like this, the stakes are just much higher. We're talking about patients who are often at the most medically vulnerable moment of their lives.”
Over the years, Zlokovic founded several biotech corporations that desired to commercialize his scientific work. In 2007, he co-founded ZZ Biotechwhich advocates for federal approval of 3K3A-APC.
The drug is meant to attenuate the bleeding and subsequent brain damage that may occur after an ischemic stroke, by which a blood clot forms in an artery resulting in the brain.
In 2022, the Keck School of Medicine of USC received the primary $4 million of a planned $30 million grant from the NIH to conduct Phase III trials of the experimental stroke treatment in 1,400 people.
In Phase II of the study, the published in 2018 and called Rhapsody, six of the 66 patients who received 3K3A-APC died in the primary week after their stroke, compared with one person among the many 44 patients who received a placebo. Patients who received the drug also tended to report greater disability 90 days after their stroke than those that received the placebo. The differences between the 2 groups weren’t statistically significant and can have been because of probability, and the death rate of patients in each groups evened out one month after the primary stroke.
“The claims that there is a risk in this study are false,” said Patrick Lyden, a USC neurologist and stroke expert who was employed at Cedars-Sinai on the time of the study. Zlokovic worked with Lyden as a co-investigator on the study.
One correction was issued to the Paper Describing the Phase II results, correcting an additional row in a knowledge table that had moved some numbers to the mistaken columns. “This error is mine. No one else has encountered it. I didn't notice it after reading it several times,” Lyden said, adding that he noticed the error and was already working on correcting it when the journal contacted him about it.
He denied that the study posed an unreasonable risk to patients.
“I believe it is safe, especially considering that the purpose of Rhapsody was to find a dose – the highest dose – that patients could tolerate without risk, and the Rhapsody trial did that. We did not find a dose that was too high to limit progression to Phase III. It is time to move on to Phase III.”
Schrag stressed that the whistleblowers found no evidence of manipulated data within the Phase II trial report. However, given the errors and alleged data manipulation in Zlokovic's previous work, it could be appropriate to review a clinical trial by which the outcomes of his research could be administered to people in life-threatening situations.
In the Phase II data, “there is a consistent pattern of (patient) outcomes trending in the wrong direction. There is a signal in early mortality … there is a trend toward worse disability numbers” in patients who received the drug as an alternative of a placebo, he said.
None of those are “conclusive evidence of harm,” he said. But “if you see a warning sign or a trend in the clinical trial, I would tend to give that more weight in the face of serious ethical concerns about the preclinical data.”
The NIH Office of Extramural Research declined to debate Rhapsody or Zlokovic, citing confidentiality regarding grant consideration.
ZZ Biotech CEO Kent Pryor, who will called the drug “a potential turning point,” said he had no comment or information on the interrupted process.
Zlokovic is a number one researcher in the sector of the blood-brain barrier, with a specific 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, became a lecturer on the Keck School of Medicine at USC. A polyglot and Amateur opera singerZlokovic left USC and spent 11 years on the University of Rochester before Return in 2011The following yr, he was appointed director of the Zilkha Neurogenetic Institute at USC.
A USC spokesman confirmed that Zlokovic retained his titles as department head and director of the Zilkha Institute.
image credit : www.mercurynews.com