These are not the best of times for the Big Pharma players betting the house on Alzheimer’s drugs. Dismal demand, controversial trial methods, and alleged ethical breaches have largely dissipated whatever enthusiasm these companies had generated among dementia sufferers — not to mention Wall Street investors. And the trend has some researchers looking beyond pharmaceuticals in their search for a cure.
The rise and fall of Aduhelm, which Biogen pulled from the market earlier this year, has been well documented, but the symptoms leading to its demise seem to be contagious. Leqembi, a collaboration between Biogen and Eisai, entered the Alzheimer’s sweepstakes last year only to confront similar marketplace obstacles: Only a small portion of dementia patients qualify for the treatment, the out-of-pocket expense (as much as $6,600 annually) is prohibitive, and the regimen (biweekly infusions, frequent MRI scans) can be daunting. All this for the vague possibility that the drug may slow the advance of the disease by about five months.
Then there are the side effects. The drugs have been shown in clinical trials to cause brain swelling and bleeding — particularly among participants most genetically susceptible to Alzheimer’s. Indeed, As The New York Times reported recently, more than one in three patients carrying two copies of the APOE4 gene experienced brain bleeding or swelling during the Leqembi trial.
And both Eisai and Eli Lilly have come under fire by medical ethicists for their clinical trial practices. Although they test participants to determine whether they carry the APOE4 gene prior to the trial, they don’t tell them the results because, researchers argue, it may affect how they rate their progress. Dozens of volunteers have subsequently suffered “severe” brain bleeding after infusions; a handful have died.
“Researchers unfortunately have an inherent conflict of interest,” Robert Klitzman, MD, director of the Masters of Bioethics Program at Columbia University, tells the Times. “They want people to be in their study, and there are researchers who feel, if I tell people the full facts and risks, they may not want to be in the study.”
Meanwhile, the Securities and Exchange Commission (SEC) in September brought charges against Cassava Sciences for allegedly publishing misleading research results of its simufilam drug trials. A federal grand jury indicted the company’s lead researcher, Hoau-Yan Wang, PhD, for falsifying study data, much of his published research has been retracted, and he was placed on administrative leave from the City University of New York. Cassava’s CEO and his wife, a lead scientist, have resigned.
The company and the SEC eventually agreed to a $40 million settlement, but simufilam remains, implausibly, poised for government approval.
Phase 3 clinical trials, involving some 1,900 patients, are reportedly ongoing, and officials at the Food and Drug Administration tell the Times they “may take appropriate action” if a detailed review reveals any false data.
It’s the prevalence of such chaos that seems to be nudging an increasing number of scientists toward a new approach to fighting the disease. Big Pharma’s obsession with amyloid-lowering drugs — when it’s been shown that the plaque doesn’t always appear in Alzheimer’s patients — is muddying the research waters, notes Matthew Schrag, MD, PhD, a Vanderbilt University neurologist. “While beta amyloid may play a role in Alzheimer’s disease,” he says, “it’s not the central disease driver, and we need a more nuanced understanding of this disease if we’re going to be successful in really moving the ball.”
That might mean more focus on such mundane issues as sleep quality, regular exercise, and eating habits. Or, as Tarek Rajji, MD, argues, it might mean exploring a combo of cognitive therapy and transcranial direct current stimulation (tDCS), a type of noninvasive brain stimulation.
Rajji, a psychiatry professor at the University of Texas Southwestern Medical Center, and his team of researchers recruited 375 older adults and divided them into two groups; one group received a combination of cognitive therapeutic treatment (puzzles and logic problems) along with tDCS, while the control group was given a “sham” intervention. The five-days-a-week sessions lasted for eight weeks and included five-day “booster” sessions every six months over the course of four years. Researchers then tracked the volunteers’ cognitive performance for another three years.
The results, published last week in JAMA Psychiatry, may offer some hope in the midst of Big Pharma chaos. “We are very pleased to show, after seven years of close monitoring, that this combination of therapies is effective in slowing down cognitive decline for some of our most vulnerable populations,” Rajji said in a statement. “This study shows promise that the multiprong, nonpharmacological approaches for people with a high risk of developing dementia could help them live a more independent life for a longer time.”
I suspect such findings aren’t going to nudge Eisai, Biogen, Lilly, Cassava, and their Big Pharma brethren from the Alzheimer’s battlefield anytime soon. Despite the current setbacks, these researchers simply don’t know any other way to address the disease. It’s just the way they think. Perhaps they should undergo a little brain stimulation.
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