During the Alzheimer’s anti-amyloid drug trials for Leqembi and Kisunla, drugmakers were accused of knowing which volunteers might be at higher risk of brain bleeds. Experts weigh in on why the companies didn't disclose that risk — and whether they did the right thing.
Would you still participate in an Alzheimer’s clinical trial if you found out that because of your genetics, you were more vulnerable to serious side effects?
When drugmakers Eisai and Eli Lilly ran their Phase 3 trials for their anti-amyloid monoclonal antibody drugs Leqembi and Kisunla, they gave prospective participants a genetic test to see if they carried the ApoE4 gene.
Homozygotes for the ApoE4 gene (people who carry two copies of it, one from each parent) have a significantly higher risk of developing Alzheimer’s disease — and, it turns out, they have a significantly higher risk of brain swelling and bleeding (ARIA) during treatment from this new class of Alzheimer’s drugs.
According to reports, neither company disclosed this risk to study participants — about one in six volunteer participants in the drug trial were ApoE4 homozygotes. Participants would only learn their genetic status at the end of the study.
Today, it is standard practice to inform participants about their ApoE4 risk. But at the time of these trials, the drug companies didn’t tell participants their genetic status, which some experts believe undermined “informed consent.” Meanwhile, other experts argue the decision was justified because the link between ApoE4 and ARIA wasn’t so clear at the time.
So, what’s informed consent — and why does it matter in clinical trials?
Informed consent is a big deal in clinical trials. When people sign up, researchers are supposed to tell participants about the treatment’s potential risks, uncertainty, and potential benefits — including, for example, known genetic risks related to the treatment at hand. Some people might decide not to participate if they think the side effects might be too risky. And if they do opt to stay in the trial, they’ll be fully informed when they give their consent.
Would informing people they were at higher risk of side effects affect trial recruitment?
A study presented at the 2024 Clinical Trials on Alzheimer’s Disease conference last month suggests that people might be dissuaded from anti-amyloid treatments because of the side effects. The researchers surveyed 404 people who themselves were in the early stages of Alzheimer’s or were care partners for a loved one. Almost half said they were unsure about or not planning to seek treatment with anti-amyloid drugs citing side effects as a major concern. While the study didn’t explicitly ask about clinical trials or APOE genotyping, it suggests that people might be less willing to take these drugs because of the side effects.
The study was conducted by the biotechnology company Prothena, which itself is in the early stages of developing anti-amyloid and anti-tau monoclonal antibodies.
Though trial recruitment may be affected, it is now standard practice for anti-amyloid trials to ask participants whether they want to learn they carry ApoE4 to understand how it might affect their risk during the trial.
Alzheimer’s Drugs and ARIA: Leqembi ‘Brain Bleeds’ Side Effect, Explained
Putting Leqembi and Kisnula trials into context
In response to a New York Times report, Eisai declined to speak to the issue; Eli Lilly issued a statement saying that it gave participants the option to learn their genetic profiles, but only after the trial ended: “Our advice is for participants to assume they have the higher risk” at the outset of the trial, Lilly neurologist Dr. John Sims, who oversaw the trial, told Times.
An Eisai spokesperson defended the practice, telling Being Patient that, alarmingly: “Not informing study participants regarding the results of their ApoE4 genetic tests was consistent with other Alzheimer’s disease clinical trials being conducted.”
Reporting in the NYT brought up that the decision to withhold ApoE4 status from participants during the trial was approved by the ethics review board run by Advarra, a for-profit review company involved with Leqembi. In 2023, the U.S. Government Accountability Office raised concerns about for-profit institutional review boards like Advarra, and flagged the need for more government oversight over such companies, especially as private firms play an increasing role in ethics approvals.
“Not informing study participants regarding the
results of their ApoE4 genetic tests was consistent
with other Alzheimer’s disease
clinical trials being conducted.”
However, A 2019 survey of the 30 Alzheimer’s Disease Research Centers found that none of the centers routinely disclosed this information to participants and only two had ever disclosed results. According to the Clinical Trials database, Eisai initiated the Phase 3 trial of Leqembi that year while Eli Lilly began their trial in 2020. At the time, it wasn’t standard practice to tell participants whether they had the ApoE4 gene.
“We take very seriously our responsibility to inform clinical research participants of reasonably foreseeable risks,” a Lilly spokesperson told Being Patient.
Explaining why this information wasn’t disclosed beforehand, the spokesperson said that it could introduce bias when measuring the safety and effectiveness of the drug.
Dr. George Perry, the editor of the Journal of Alzheimer’s Disease and a professor at the University of Texas at San Antonio, told the Times that the decision not to disclose genetic status is “ethically fraught” and that not disclosing genetic risk status raises significant ethical concerns in patient autonomy and informed consent. Other experts echoed this disdain: University of Minnesota bioethicist Carl Elliot studies ethics in clinical trials and pharmaceutical marketing. He told Being Patient that hiding genetic information from the participants is “deceptive, disgraceful, and wrong — but also unsurprising.”
In 2008, the University of Minnesota professor brought attention to ethical issues and malpractice in a clinical trial run at his university that resulted in the death of a trial participant. “The research protection system in this country is deeply flawed,” Elliot said. “What do you expect when you turn ethics approval over to a for-profit company owned by a private equity firm?”
Trials do, of course, carry risks — as do the vast majority of drugs on the market, prescription and otherwise. Other experts posited dramatically different viewpoints from Elliot’s to consider.
Dr. Robert C. Green, a geneticist and professor at Harvard Medical School, spearheaded the REVEAL study which sought to understand the impact of disclosing genetic risk factors, like ApoE4 to understand the risks.
Given how long it takes to plan drug trials, Green suspects “that this notion of ‘not disclosing,’ kind of, is a carryover from that time when people felt that disclosing ApoE to people would cause “serious psychological distress.”
“When I started the work,” Green explained,” it was considered extremely dangerous to disclose ApoE4 [status] to people.” But in his research, Green and his colleagues discovered that, in fact, telling someone they had this Alzheimer’s risk gene did not cause “serious psychological distress.”
That said, not disclosing the genetic status of participants is “not a scandal” he said. “There was enough question about what ApoE4 knowledge would do [psychologically] that the drug company was probably within their rights” to decide not to disclose the genetic status to participants, he added.
Scott Roberts, a professor at the University of Michigan who was also involved in the REVEAL study, told Being Patient that at the time the trials were first being run, the link between APOE4 and ARIA was less established. “I think it’s a little bit more of a gray area at the time,” Roberts said.
Between 2013 and 2020, only 85 research papers had been published about ARIA, with researchers noting a link between APOE4 status and ARIA risk in previous unsuccessful anti-amyloid drugs. (Since then, some 200 scientific papers have been published discussing ARIA with the link between APOE4 and ARIA risk becoming more clear.)
Dr. David Weisman, a neurologist at Abington Neurological Associates, said this understanding came, in part, from these very trials. “The precise genetic risk was measured only by completing the clinical trials,” Weisman wrote to the Times in response to their report. The previous Phase 2 trials, he added, did not have enough participants to know for sure that people with two copies of ApoE4 were at a higher risk.
Dr. Jason Karlawish, a professor of medicine at the University of Pennsylvania, put the burden of responsibility back on the individual participating in the clinical trial to consider the possibility of risk — and to understand that some of the risks may not yet be knowable.
“A person deciding whether to enroll in research should have the information a reasonable person needs to make an informed decision,” Karlawish told Being Patient. The studies should ask potential participants if they want to learn about their genetic risk. “With this knowledge the person can decide whether the risks are worth the potential benefits.”
“A person deciding whether to enroll in
research should have the information a
reasonable person needs to
make an informed decision.”
Although drug companies may have been justified in not revealing the genetic status to participants, Roberts said he’d err on the side of caution. Now, it’s standard practice for clinical trials to disclose ApoE status to potential participants.
“I’m glad it seems like the field has moved towards this model of disclosure up front,” Roberts said.
“Now, it’s standard practice for clinical trials to disclose ApoE status to potential participants.” Are you sure? As recently as 2023 I was refused that information and ended up with brain edema, brain bleeding, a TIA, and seizures among a myriad of lesser ills. While caution about disclosing genetic information may ring true, the paper the author cites debunking this myth is from 2008. It was common knowledge well before mAbs were being tested. Money is the reason for the lack of disclosure and seniors are the vulnerable population being preyed upon. No matter how they try to justify it, the withholding of critical personal risk information was/is unethical.
Hi Kristine — thank you so much for reading, and more, for sharing your experience here. The idea that this is standard practice to disclose came to our reporter via a few different channels: one of the experts he interviewed, University of Michigan professor who studies the impact of ApoE4 disclosure, Scott Roberts, told us that this is the way the field has moved. We paired that with the knowledge that several researchers have published guidelines recommending the disclosure of ApoE4 status in trials, and that large trials testing monoclonal anti-amyloid drugs — i.e. AHEAD-3-4,5 — currently do ask participants whether they want to learn their genetic status, according to Alzheimer’s researcher Joshua Grill (in a post on the UC Irvine Institute for Memory Impairments and Neurological Disorders blog). All this said, your insight is valuable here, and might indicate there’s more to the story. Because of your comment, we’re looking into a new piece on this question. It might be helpful for Being Patient reporter Simon Spichak to hear more about your experience. Would you be at all interested in emailing him directly? He can be reached at simon@beingpatient.com.
I chose to take Leqembi knowing I was APOE4 because there was nothing else that could confront my Alzheimer’s
My journey just to get a diagnosis was difficult enough
Multiple Doctors & Hospitals
Hi Michael, thank you for sharing your journey with us. We’re glad you found a path with Leqembi after navigating the challenges of getting a diagnosis. As part of our Journey to Diagnosis campaign, we’re sharing stories of people living with a diagnosis—feel free to explore it here: https://www.beingpatient.com/journey-to-diagnosis/?utm_source=organic&utm_medium=elilillysocial . Wishing you strength and support as you continue this journey.