The companies developing new weight-loss medicines have a problem: the balance of power has shifted, and patients are bailing out of their clinical trials.
People who don’t lose weight can quickly figure out that they were assigned to take a placebo instead of the real drug. And with highly effective obesity medications on the market — Eli Lilly & Co.’s Zepbound and Novo Nordisk A/S’s Wegovy shot and pill — that are getting cheaper, there’s little reason to stay in a study that doesn’t yield the intended benefits.
The new reality upends one fundamental assumption of clinical trials — that neither patient nor doctor can know who has been assigned the real medicine, a process known as blinding — creating a fresh set of difficulties for drugmakers.
“Right now, retention is challenging,” said Barbara McGowan, a consultant in diabetes and endocrinology in London and an investigator for several obesity-drug trials.
The shift is also a sign of how quickly the weight-loss field is moving, with 190 potential medicines in development. Patients can easily go purchase an approved obesity drug, whereas in the first generation of studies, they simply didn’t have other options — and at least they were getting help with diet and exercise.
“People learn pretty quickly whether they’re on placebo or not,” said Raymond Stevens, chief executive officer of Structure Therapeutics Inc., which is working on an experimental pill that’s shaping up to rival new oral treatments from Lilly and Novo. “It’s adding a challenge to conducting clinical trials.”
Tom, a New England patient who has struggled with his weight for years, said he has remained on a study for Lilly’s next-generation shot retatrutide because he didn’t think he met the criteria that would allow him to get Wegovy or Zepbound through his insurance. The 57-year-old, who suffered a heart attack more than a decade ago, asked that his last name not be used to protect his medical privacy.
When he first joined the trial and reduced his calorie intake, Tom lost about 45 pounds in less than a year. “I could tell the only reason I was dropping it was because I was being really vigilant about the diet,” he said. He couldn’t feel any impact from the drug, whose side effects can include nausea or vomiting. “My appetite was still 100% the same. Over time, my weight drifted back up again and it became pretty clear I was on the placebo.”
But now Tom’s insurance may cover Wegovy due to its benefit of protecting against heart disease and he plans to leave the retatrutide study if that works out.
Diet and Exercise
The experience of Tom, and others like him, are undermining the blinding process that has long been a key tenet of the most reliable clinical trials.
One of the risks, McGowan said, is that the patients left on the placebo arm are those who are losing weight from just diet and exercise, which don’t work for many patients with obesity. That could skew results by making the medicines look less effective.
Some patients in early weight-loss drug trials also dropped out because they knew they weren’t getting treatment. But with stronger drugs and more awareness, experts say the numbers are now growing.
“This is a change,” said Louis Aronne, an obesity doctor at Weill Cornell Medicine who has run clinical trials for Lilly and others. “It’s something we have to deal with.”
Patients on placebo are in some cases seeking out weight-loss drugs from other sources while still enrolled in the trials, Aronne said, in another development that could warp the findings.
That happened with Lilly’s highly anticipated pill orforglipron. In a large trial, 6.2% of patients in the placebo group dropped out because they weren’t satisfied with their weight loss, and 2.5% started looking for other ways to shed weight, which in some cases included different obesity medications, according to a Lilly spokesperson. While that technically wasn’t allowed, participants could stay in the trial if they stopped taking the study drug, the spokesperson said.
Reddit Effect
“These drugs can be rather, sort of, de-blinded,” Kenneth Custer, president of Lilly’s cardiometabolic health unit, said in an interview last year. “You’re sort of asking patients to sign up for a 72-week experience where they may very well be randomized to placebo. It’s a long time to go without efficacy.”
It doesn’t help that the medicines are hyped on social media, which has led to discussions about clinical trials in real time, something that’s unprecedented in the world of drug development.
“Go to the Reddit string on orforglipron,” said Stevens. “People aren’t supposed to be talking about these things, but it was on Reddit — during the trial.”
Roche Holding AG rethought how to run its large studies as a result. The Swiss drugmaker plans to offer patients the chance to stay in trials for a long-term extension period, which would give people who got the placebo the chance to take the experimental weight-loss drug. While the company is still working out the details, it said it believes this is a critical component to recruit and retain patients.
“We’re doing everything we can to keep people engaged and into the trials,” said Manu Chakravarthy, Roche’s head of cardiovascular, renal and metabolism product development.
Drop the Dummy
Another strategy could be designing trials that pit new compounds against existing weight-loss medicines, abandoning the dummy drug comparison. That’s standard practice for severe diseases like cancer. But for now, the US Food and Drug Administration and regulators in Europe still require comparing obesity treatments to a placebo. The FDA didn’t immediately respond to requests for comment. Neither did the European Medicines Agency.
“I think we’re going to see an evolution of how clinical trials are executed and that’s for good reasons,” Structure’s Stevens said.
Lilly would welcome such changes, according to Custer. Novo said it offers counseling and follow-up as part of its trials, helping some patients on placebo make lifestyle changes and lose weight as well.
Many overweight people have a long history of failing to cut pounds and obesity has only recently become recognized as a disease. “It almost feels like the definition of obesity and how we understand it as a disease has not made it into clinical-trial standards of care,” World Obesity Federation board member Amber Huett-Garcia said in an interview.
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