Star USC scientist faces scrutiny — retracted papers and a paused drug trial

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Corinne Purtill | Los Angeles Times (TNS)

LOS ANGELES — Late last year, a group of whistle-blowers submitted a report to the National Institutes of Health that questioned the integrity of a celebrated University of Southern California neuroscientist’s research and the safety of an experimental stroke treatment his company was developing.

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. Zlokovic, professor and chair of the department of physiology and neuroscience at the Keck School of Medicine of USC.

Three of Zlokovic’s research papers have been retracted by the journal that published them because of problems with their data or images. Journals have issued corrections for seven more papers in which Zlokovic is the only common author, with one receiving a second correction after the new supplied data were found to have problems as well.

For an 11th paper co-authored by Zlokovic the journal Nature Medicine issued an expression of concern, a note journals append to articles when they have reason to believe there may be a problem with the paper but have not conclusively proven so. Since Zlokovic and his co-authors no longer had the original data for one of the questioned figures, the editors wrote, “(r)eaders are therefore alerted to interpret these results with caution.”

“It’s quite unusual to see this volume of retractions, corrections and expressions of concern, especially in high-tier influential papers,” said Dr. Matthew Schrag, an assistant professor of neurology at Vanderbilt who co-authored the whistle-blower report independently of his work at the university.

Both Zlokovic and representatives for USC declined to comment, citing an ongoing review initiated in the wake of 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. “Consistent with federal regulations and USC policies, this review must be kept confidential.”

Zlokovic “remains committed to cooperating with and respecting that process, although it is unfortunately required due to allegations that are based on incorrect 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 post-publication process,” Jarrin wrote.

Authors of the whistle-blower report and academic integrity experts challenged that assertion.

“If these are honest errors, then the authors should be able to show the actual original data,” said Elisabeth Bik, a microbiologist and scientific integrity consultant who co-wrote the whistle-blower report. “It is totally human to make errors, but there are a lot of errors found in these papers. And some of the findings are suggestive of image manipulation.”

Given the staid pace of academic publishing, publishing this many corrections and retractions only a few months after the initial concerns were raised “is, bizarrely, pretty quick,” said Ivan Oransky, co-founder of Retraction Watch.

The whistle-blower report submitted to NIH identified allegedly doctored images and data in 35 research papers in which Zlokovic was the sole common author.

“There had been rumblings about things not being reproducible (in Zlokovic’s research) for quite some time,” Schrag said. “The real motivation to speak publicly is that some of his work reached a stage where it was being used to justify clinical trials. And I think that when you have data that may be unreliable as the foundation for that kind of an experiment, the stakes are just so much higher. You’re talking about patients who are often at the most vulnerable medical moment of their life.”

Over the years, Zlokovic has created several biotech companies aimed at commercializing his scientific work. In 2007, he co-founded ZZ Biotech, which has been working to gain 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 stroke treatment on 1,400 people.

In Phase II of the trial, which was published in 2018 and called Rhapsody, six of the 66 patients who received 3K3A-APC died in the first week after their stroke, compared to one person among the 44 patients who got a placebo. Patients who received the drug also tended to report more disability 90 days after their stroke than those who got the placebo. The differences between the two groups were not statistically significant and could have been because of chance, and the death rate for patients in both groups evened out one month after the initial stroke.

“The statements that there is a risk in this trial is 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.

One correction has been issued to the paper describing the Phase II results, fixing an extra line in a data table that shifted some numbers to the wrong columns. “This mistake is mine. It’s not anybody 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 represented any undue risk to patients.

“I believe it’s safe, especially when you consider that the purpose of Rhapsody was to find a dose — the maximum dose — that was tolerated by the patients without risk, and the Rhapsody trial succeeded in doing that. We did not find any dose that was too high to limit proceeding to Phase III. It’s time to proceed with Phase III.”

Schrag stressed that the whistle-blowers did not find evidence of manipulated data in the report from the Phase II trial. But given the errors and alleged data manipulation in Zlokovic’s earlier work, he said, it’s appropriate to scrutinize a clinical trial that would administer the product of his research to people in life-threatening situations.

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

None are “conclusive proof of harm,” he said. But “when you’re seeing a red flag or a trend in the clinical trial, I would tend to give that more weight in the setting of serious ethical concerns around the pre-clinical data.”

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

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

ZZ Biotech Chief Executive Kent Pryor, who in 2022 called the drug “a potential game-changer,” said he had no comment or information on the halted trial.

Zlokovic is a leading researcher on the blood-brain barrier, with particular interest in its role in stroke and dementia. He received his medical degree and doctorate in physiology at the University of Belgrade and joined the faculty at USC’s Keck School of Medicine after several fellowships in London. A polyglot and amateur opera singer, Zlokovic left USC and spent 11 years at the University of Rochester before returning in 2011. He was appointed director of USC’s Zilkha Neurogenetic Institute the following year.

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

©2024 Los Angeles Times. Visit latimes.com. Distributed by Tribune Content Agency, LLC.

As a key labor union pushes into the South, red states push back

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Kevin Hardy | Stateline.org (TNS)

Just days before workers at a Mercedes-Benz plant in Alabama began voting last week on whether to unionize, Republican Gov. Kay Ivey signed a new law that would claw back state incentives from companies that voluntarily recognize labor unions.

Alabama’s move follows similar efforts in Georgia and Tennessee, where GOP leaders also have passed laws pushing against a reinvigorated labor movement.

The laws require that unions be formed only by secret ballots rather than the so-called card check process, in which employers can voluntarily recognize a union without a protracted election process. And under the laws, companies that voluntarily recognize unions risk losing state incentives, which amount to billions of dollars invested by governments to bring automakers to the region.

These new laws speak to the growing push of labor unions into Southern states — and the fierce opposition of pro-business GOP leaders there. For decades, the region has attracted investments from foreign automakers with lucrative tax breaks, low-cost labor and a lack of labor unions. Labor leaders hope that is changing now that workers at Volkswagen’s plant in Chattanooga, Tennessee, overwhelmingly endorsed a union in April, becoming the first foreign auto plant in the South ever organized by the United Auto Workers.

Unions such as the UAW argue their involvement can help boost wages and improve the work environment at auto plants. But GOP forces in the South view unions as an existential threat to their manufacturing economies — of even more importance now that states are increasingly competing for electric vehicle and battery plants.

Mercedes-Benz workers outside of Tuscaloosa, Alabama, on Friday voted against joining a union at their plant, in a setback for the labor movement. But more organizing drives are underway in Alabama and South Carolina, as well as in California.

Many Southern states where unions have begun to focus already are less friendly to organizing. They are so-called right-to-work states, where each employee in a workplace can decide whether to join and pay union dues, though all workers are represented by the union.

Seeking to capitalize on major contract wins it secured for workers last year at the nation’s Big Three automakers (GM, Ford and Stellantis), the United Auto Workers union announced plans to spend $40 million through 2026 to help organize workers at auto and battery plants across the country, with a particular focus on the South. The union did not respond to multiple Stateline requests for comment.

A week before April’s monumental vote at the Tennessee Volkswagen plant, six Southern Republican governors warned that unionization would jeopardize the region’s auto jobs. In addition to Ivey in Alabama, the governors of Georgia, Mississippi, South Carolina, Tennessee and Texas also signed on.

And Ivey continued to rally against organized labor in auto plants last week, as she announced she had signed the state’s bill regarding secret ballots.

“Alabama is not Michigan,” Ivey said at a chamber of commerce event last week. “… We want to ensure that Alabama values, not Detroit values, continue to define the future of this great state.”

It’s unclear how much impact the new laws will have. The vote in Chattanooga was conducted by secret ballot with nearly three-quarters of all workers who voted in the election choosing to join the UAW. Tennessee awarded Volkswagen more than $500 million in incentives to build its plant there in 2008.

To Tennessee state Rep. Yusuf Hakeem, the 2023 law regarding union elections passed in his state was yet another GOP effort to “blockade” union power in the South.

“It’s typical, in my view, for Southern states to have that kind of a mindset: to have less of a voice for workers as opposed to having an exchange between workers and employer,” said Hakeem, a Democrat.

Hakeem said the UAW’s landslide win in his hometown of Chattanooga exposed a political miscalculation on the part of Republicans who view economic development prospects and union organizing as mutually exclusive.

“I thought it was huge,” he said. “They thought that scare tactics would be the winning thing for them … and the union workers demonstrated that they have a backbone.”

‘Right-to-work’ states

The American Legislative Exchange Council, a conservative group known as ALEC that works with lawmakers across the country, introduced model legislation similar to the laws already passed in Alabama, Georgia and Tennessee.

ALEC did not respond to a request for comment, but the organization’s involvement could further push the legislative concept across red states, particularly in the South.

That expansion is likely to happen, said Vincent Vernuccio, a senior fellow at the Mackinac Center for Public Policy, a conservative think tank that worked with Tennessee Republican lawmakers on their legislation.

“We’re seeing a snowball effect,” he said of the legislation. “It is getting noticed and I fully expect it to spread.”

Vernuccio said most Southern employers had been “protecting their employees” by calling for secret ballot elections rather than the signing of union cards in the open.

“There could be peer pressure, there can be coercion and intimidation,” he said, “and probably even more common is the union’s trying to make sure that employees … are not receiving both sides of the story on what would happen if a union organized them.”

Billy Dycus, president of the Tennessee AFL-CIO Labor Council, viewed fierce GOP opposition to Chattanooga’s union effort as a boon to the cause.

“I think that helped more than it hurt,” he said. “People say, ‘You know what, we’re kind of tired of the government telling us how we should run our lives.’ “

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Dycus, whose organization represents more than 60,000 union workers in the state, including teachers, steelworkers and nurses, said labor leaders have little incentive to mislead or pressure employees to join unions, especially in right-to-work states. Dycus said that because workers can choose whether to join unions, organizers must continually prove their worth to maintain membership and dues.

“They think that card check means we go in and twist arms and force people to sign cards. That doesn’t make any sense because you’re in a right-to-work state,” he said.

Opponents of the new union voting laws argue that pushing for elections through secret ballot run by the National Labor Relations Board — as opposed to card check — can subject workers to anti-union messaging from management. Such elections also might delay the inevitable, they argue, in cases where the union has identified a clear majority of support.

But pro-business Republicans portray the new laws as ways to protect the privacy of individual workers, who might feel peer pressure to sign union authorization cards in a card-check scenario.

“There’s absolutely nothing in this bill that would stop anybody from being able to unionize,” Georgia state Sen. Mike Hodges, a Republican who carried his state’s bill on the floor for Republican Gov. Brian Kemp, said in an interview.

Hodges said the new law aims to ensure a “level playing field” in union decisions. He noted that his father, a member of the International Brotherhood of Electrical Workers in Georgia, raised him and three siblings on union wages and benefits.

“We didn’t say we don’t want unions,” Hodges said. “Bless your heart, if you want to unionize, unionize.”

Alabama state Sen. Arthur Orr, a Republican who sponsored the legislation in his state, said the secret ballot process protects workers from both management and union leadership.

“Employees are caught in a tug of war, if you will,” Orr said. “Having the secret ballot provides the employees the ability to say what they want to, one side or the other. But when it comes to the ultimate voting, they can do it privately.”

Union expansion could hurt economic development prospects, Orr said, but workers always have the right to unionize.

“If companies are not taking care of their workers — and you can define that as you will, whether it’s pay or whether it’s time, job flexibility, safety, whatever — then that makes them vulnerable to an organization effort,” he said.

Legal challenges

While some labor advocates have argued the state bills could be preempted by federal labor law, Orr said he consulted with several attorneys on Alabama’s legislation. He noted that Tennessee’s law had not been challenged in court.

Still, it’s a “close question” as to whether these laws would hold up to a legal challenge since federal laws govern most labor issues in the private sector, said Benjamin Sachs, a professor of labor and industry at Harvard Law School. Some labor advocates expect courts could strike down the state laws, finding them preempted by federal labor law.

“What I can say for sure is that if it’s not preempted, then we are really opening up the landscape to dramatically more state and city intervention into labor relations and the rules of union organizing,” he said in an interview.

In his blog, OnLabor, Sachs warned anti-union forces to be careful what they wished for: If the Southern GOP laws stand, he wrote, it could open the door to blue states passing a litany of bills with opposite aims.

“If red states are entitled to tie economic incentives to a ban on card check, then blue states presumably are entitled to tie economic incentives on a requirement for card check,” he added in the interview.

While the recent labor win in Tennessee shows unions in the South can still succeed with a secret ballot process, Sachs said the legislation could have a “chilling effect” on companies that would otherwise prefer to voluntarily recognize unions.

“If it weren’t a big deal, they wouldn’t have enacted these laws,” he said.

Stateline is part of States Newsroom, a national nonprofit news organization focused on state policy.

©2024 States Newsroom. Visit at stateline.org. Distributed by Tribune Content Agency, LLC.

High price of popular diabetes drugs deprives low-income people of effective treatment

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By Renuka Rayasam, KFF Health News

For the past year and a half, Tandra Cooper Harris and her husband, Marcus, who both have diabetes, have struggled to fill their prescriptions for the medications they need to control their blood sugar.

Without Ozempic or a similar drug, Cooper Harris suffers blackouts, becomes too tired to watch her grandchildren, and struggles to earn extra money braiding hair. Marcus Harris, who works as a Waffle House cook, needs Trulicity to keep his legs and feet from swelling and bruising.

The couple’s doctor has tried prescribing similar drugs, which mimic a hormone that suppresses appetite and controls blood sugar by boosting insulin production. But those, too, are often out of stock. Other times, their insurance through the Affordable Care Act marketplace burdens the couple with a lengthy approval process or an out-of-pocket cost they can’t afford.

“It’s like, I’m having to jump through hoops to live,” said Cooper Harris, 46, a resident of Covington, Georgia, east of Atlanta.

Supply shortages and insurance hurdles for this powerful class of drugs, called GLP-1 agonists, have left many people who are suffering from diabetes and obesity without the medicines they need to stay healthy.

One root of the problem is the very high prices set by drugmakers. About 54% of adults who had taken a GLP-1 drug, including those with insurance, said the cost was “difficult” to afford, according to KFF poll results released this month. But it is patients with the lowest disposable incomes who are being hit the hardest. These are people with few resources who struggle to see doctors and buy healthy foods.

In the United States, Novo Nordisk charges about $1,000 for a month’s supply of Ozempic, and Eli Lilly charges a similar amount for Mounjaro. Prices for a month’s supply of different GLP-1 drugs range from $936 to $1,349 before insurance coverage, according to the Peterson-KFF Health System Tracker. Medicare spending for three popular diabetes and weight loss drugs — Ozempic, Rybelsus, and Mounjaro — reached $5.7 billion in 2022, up from $57 million in 2018, according to research by KFF.

The “outrageously high” price has “the potential to bankrupt Medicare, Medicaid, and our entire health care system,” Sen. Bernie Sanders (I-Vt.), who chairs the U.S. Senate Committee on Health, Education, Labor and Pensions, wrote in a letter to Novo Nordisk in April.

The high prices also mean that not everyone who needs the drugs can get them. “They’re kind of disadvantaged in multiple ways already and this is just one more way,” said Wedad Rahman, an endocrinologist with Piedmont Healthcare in Conyers, Georgia. Many of Rahman’s patients, including Cooper Harris, are underserved, have high-deductible health plans, or are on public assistance programs like Medicaid or Medicare.

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Many drugmakers have programs that help patients get started and stay on medicines for little or no cost. But those programs have not been reliable for medicines like Ozempic and Trulicity because of the supply shortages. And many insurers’ requirements that patients receive prior authorization or first try less expensive drugs add to delays in care.

By the time many of Rahman’s patients see her, their diabetes has gone unmanaged for years and they’re suffering from severe complications like foot wounds or blindness. “And that’s the end of the road,” Rahman said. “I have to pick something else that’s more affordable and isn’t as good for them.”

GLP-1 agonists — the category of drugs that includes Ozempic, Trulicity, and Mounjaro — were first approved to treat diabetes. In the last three years, the Food and Drug Administration has approved rebranded versions of Mounjaro and Ozempic for weight loss, leading demand to skyrocket. And demand is only growing as more of the drugs’ benefits become apparent.

In March, the FDA approved the weight loss drug Wegovy, a version of Ozempic, to treat heart problems, which will likely increase demand, and spending. Up to 30 million Americans, or 9% of the U.S. population, are expected to be on a GLP-1 agonist by 2030, the financial services company J.P. Morgan estimated.

As more patients try to get prescriptions for GLP-1 agonists, drugmakers struggle to make enough doses.

Eli Lilly is urging people to avoid using its drug Mounjaro for cosmetic weight loss to ensure enough supplies for people with medical conditions. But the drugs’ popularity continues to grow despite side effects such as nausea and constipation, driven by their effectiveness and celebrity endorsements. In March, Oprah Winfrey released an hourlong special on the medicines’ ability to help with weight loss.

It can seem like everyone in the world is taking this class of medication, said Jody Dushay, an assistant professor of medicine at Harvard Medical School and an endocrinologist at Beth Israel Deaconess Medical Center. “But it’s kind of not as many people as you think,” she said. “There just isn’t any.”

Even when the drugs are in stock, insurers are clamping down, leaving patients and health care providers to navigate a thicket of ever-changing coverage rules. State Medicaid plans vary in their coverage of the drugs for weight loss. Medicare won’t cover the drugs if they are prescribed for obesity. And commercial insurers are tightening access due to the drugs’ cost.

Health care providers are cobbling together care plans based on what’s available and what patients can afford. For example, Cooper Harris’ insurer covers Trulicity but not Ozempic, which she said she prefers because it has fewer side effects. When her pharmacy was out of Trulicity, she had to rely more on insulin instead of switching to Ozempic, Rahman said.

One day in March, Brandi Addison, an endocrinologist in Corpus Christi, Texas, had to adjust the prescriptions for all 18 of the patients she saw because of issues with drug availability and cost, she said. One patient, insured through a teacher retirement health plan with a high deductible, couldn’t afford to be on a GLP-1 agonist, Addison said.

“Until she reaches that deductible, that’s just not a medication she can use,” Addison said. Instead, she put her patient on insulin, whose price is capped at a fraction of the cost of Ozempic, but which doesn’t have the same benefits.

“Those patients who have a fixed income are going to be our more vulnerable patients,” Addison said.

This article was produced by KFF Health News and also ran on CBS News. Renuka Rayasam: rrayasam@kff.org@renurayasam

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs of KFF — the independent source for health policy research, polling and journalism.

Chris Finch explains his coaching decisions in Timberwolves’ Game 2 loss to Dallas

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Minnesota dropped Game 2 of the Western Conference Finals to Dallas by the narrowest of margins — one point — in a contest where Luka Doncic hit a triple with three seconds to play and Naz Reid’s potential game winner rimmed out at the horn.

Naturally, after such a tight bout, every minute detail and decision will be analyzed and debated.

Timberwolves coach Chris Finch isn’t immune to such discourse. Many of his decisions were questioned on social media during and after the game. Here’s what Finch had to say about his most pertinent calls:

On not calling a timeout when the Wolves gained possession of the ball up two with 32 seconds remaining to sub Mike Conley back into the game and call a play (the possession ended in Anthony Edwards throwing the ball out of bounds): “That’s on me in the sense that I should have called a timeout to get Mike back in the game on that second to last possession for us, or whatever. So I’ll take that one, it’s on me. But yeah, ball got static and turned it over. Same story as the other night, turnovers in the guts of the game, not gonna get it done.”

Finch was again asked about the decision to not take a timeout.

“I just said I shoulda called it,” Finch said. “But we thought the ball was in Ant’s hands, the differential on the clock wasn’t huge. But initially wanted to call it, but I didn’t.”

On the defensive plan on Dallas’ last offensive possession (the Wolves elected not to double team Doncic, instead switching a pick and roll that left Rudy Gobert on an island to guard Doncic): “The idea was switch up (and) press him inside the 3-point line.”

On leaving Karl-Anthony Towns on the bench for the final eight minutes of the contest in favor of Naz Reid (Towns went 4 for 16 from the field while Reid hit seven triples): “Naz was playing well, real well and gave us some switchable combinations out there and stuff like that.”

Finch said he didn’t converse with Towns about the decision during the game.

“No, I didn’t really have time to have that conversation,” he said.

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