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USC scientist faces scrutiny – retracted papers and suspended drug trial

Late last year, a group of whistleblowers submitted a report to the National Institutes of Health that questioned the integrity of a famous USC neuroscientist’s research and the safety of a treatment experimental against stroke that his company was developing.

The NIH has since suspended clinical trials of 3K3A-APC, a stroke drug sponsored by ZZ Biotech, a Houston-based company co-founded by Berislav V. Zlokovic, professor and chair of the department of physiology and neuroscience at the Keck School of Medicine of USC.

Three of Zlokovic’s research articles were retracted by the journal that published them due to problems with their data or images. The journals issued corrections for seven other articles in which Zlokovic is the only joint author, with one receiving a second correction after the new data provided also had problems.

For an 11th article co-authored by Zlokovic, the journal Nature Medicine published a expression of concern, a note that newspapers add to articles when they have reason to believe there may be a problem with the newspaper but have not conclusively proven it. Since Zlokovic and his co-authors no longer had the original data for any of the surveyed figures, the editors wrote, “readers are therefore alerted and should interpret these results with caution.”

“It’s quite unusual to see so many retractions, corrections and expressions of concern, especially in high-profile influential papers,” said Dr. Matthew Schrag, assistant professor of neurology at Vanderbilt and co-author of the paper. whistleblower’s report regardless of his work. at University.

Zlokovic and USC representatives declined to comment, citing an ongoing review launched following the allegations, which were first reported in the journal Science.

“USC takes any allegations of research integrity very seriously,” the university said in a statement. “In accordance with federal regulations and USC policies, this review must remain confidential.”

Zlokovic “remains committed to cooperating and respecting this process, even though it is unfortunately necessary due to allegations based on incorrect information and faulty premises,” his lawyer Alfredo X. Jarrin wrote in an email.

Regarding articles, “corrections and retractions are a normal and necessary part of the post-publication scientific process,” Jarrin wrote.

The authors of the whistleblower report and academic integrity experts have disputed this claim.

“If these are honest mistakes, then the authors should be able to show the actual original data,” said Elisabeth Bik, microbiologist and scientific integrity consultant who co-wrote the whistleblower report. “It is only human to make mistakes, but these documents contain many errors. And some findings suggest image manipulation.

Given the fast pace of academic publishing, publishing so many corrections and retractions just months after concerns were first raised “is, oddly, quite fast,” said Ivan Oransky, co-founder of Retraction Watch.

The whistleblower report submitted to the NIH identified allegedly falsified images and data in 35 research articles of which Zlokovic was the sole joint author.

“There were rumors that things were not reproducible (in Zlokovic’s research) for some time,” Schrag said. “The real motivation for speaking publicly is that some of his work reached a stage where it was being used to justify clinical trials. And I think when you have data that may be unreliable as a basis for this kind of experiment, the stakes are much higher. You’re talking about patients who are often at the most medically vulnerable time of their lives.

Over the years, Zlokovic created several biotechnology companies aimed at commercializing his scientific work. In 2007, he co-founded ZZ Biotech, which is working to obtain federal approval of 3K3A-APC.

The medication is intended to minimize 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, the Keck School of Medicine of USC received the first $4 million of a planned $30 million grant from the NIH to conduct Phase III trials of the investigational stroke treatment in 1,400 people .

During phase II of the trial, which was published in 2018 and called Rhapsody, six of the 66 patients who received 3K3A-APC died within the first week after their stroke, compared to one person among the 44 patients who received a placebo. Patients who received the drug also tended to report 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 of patients in both groups stabilized one month after the initial 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-investigator on the study.

A correction was issued to paper describing the results of Phase II, correcting an extra row in a data table that was moving some numbers to the wrong columns. “This mistake is mine. It’s not anyone else’s. I didn’t catch it in multiple readings,” Lyden said, adding that he noticed the error and was already working on the correction when the journal contacted him about it.

He disputed that the trial posed excessive risk to patients.

“I believe it is safe, especially considering that the goal of Rhapsody was to find a dose – the maximum dose – that was tolerated by patients without risk, and the Rhapsody trial was able to achieve that. We did not find any dose too high to limit the transition to phase III. It is time to move on to phase III.

Schrag emphasized that whistleblowers found no evidence of manipulated data in the Phase II trial report. But given the errors and alleged manipulation of data in Zlokovic’s previous work, he said, it is appropriate to take a close look at a clinical trial that would administer the product of his research to people in life-threatening situations.

In the Phase II data, “there is a consistent pattern of (patient) outcomes moving in the wrong direction. There is a signal of early mortality … there is a trend toward worse disability rates” for patients who received the drug instead of a placebo, he said.

None are “conclusive evidence of harm,” he said. But “when you see a red flag or a trend in the clinical trial, I would tend to give it more weight in the context of serious ethical concerns about preclinical data.” »

The NIH suspended the clinical trial in November and it remains suspended, said Dr. Pooja Khatr, principal investigator of the NIH StrokeNet National Coordinating Center. Khatr declined to comment on the pause or the future of the trial, referring further questions to USC and the NIH.

The NIH Office of Extramural Research declined to discuss Rhapsody or Zlokovic, citing confidentiality regarding grant deliberations.

Kent Pryor, CEO of ZZ Biotech, who in 2022 called the drug “this could be a game changer,” said he had no comment or information on the halted trial.

Zlokovic is a leading researcher on 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 joined the faculty of the Keck School of Medicine of USC after several fellowships in London. Polyglot and amateur opera singerZlokovic left USC and spent 11 years at the University of Rochester before back in 2011. He was named director of USC’s Zilkha Neurogenetic Institute the following year.

A USC spokesperson confirmed that Zlokovic retained his titles as department chair and director of the Zilkha Institute.

News Source : www.latimes.com
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