Revised clinical trial form for Alzheimer’s antibody warned of fatal brain bleeds | Science

Earlier this year, the developer of a promising antibody designed to slow Alzheimer’s disease strengthened a key warning given to participants in an ongoing trial of the experimental drug. Taking the antibody alongside blood clot medications, the Japanese biotech company Eisai cautioned, increases the risk of possibly fatal brain hemorrhages. That revision of its informed consent form, revealed in a 14 July version obtained by Science, appears to challenge the company’s contention that the antibody, known as lecanemab, played no role in the recently revealed deaths of two people who suffered dramatic brain bleeds while concurrently taking the drug and blood thinners.

The change to the form also raises questions about how effectively Eisai and its clinical trial partners communicated updated warnings to trial participants and how transparent the company has been about the risks of its product, which the U.S. Food and Drug Administration (FDA) has said it could approve for sale by 6 January 2023.

The revised consent form, distributed to investigators running the lecanemab trial, informs participants that they could die from combining the antibody with drugs that reduce blood clots. “While the overall risk of a major brain bleed is low with [lecanemab] treatment, the risk is higher in people who are also taking blood clot prevention medications. This risk is estimated to be more than 1 in 100 people, but less than 5 in 100 people,” the form from Eisai noted. “Bleeding in the brain, especially when you are taking medications that prevent blood clots, can be serious and can even lead to death. It is important to consider the risk of bleeding in your brain with the investigator before deciding whether or not to continue your participation in this study.”

Blood thinners and other drugs that affect coagulation are commonly prescribed for a range of ailments that afflict elderly people, including those with Alzheimer’s. And tPA—a powerful blood clot–busting agent—is a standard treatment for strokes, such as the one experienced by an Illinois woman in September who received lecanemab in Eisai’s trial, Science previously reported. After she was rushed to the hospital, her physicians checked a website containing information about the drug and, based on what they read there, decided an infusion of tPA posed a relatively small risk, according to her husband.

But his wife quickly began screaming, suffered seizures, was put on a ventilator, and died a few days later. An autopsy revealed a massive brain hemorrhage. (Science is withholding the names of the woman and her husband to protect the family’s privacy.)

Earlier this year, the Illinois woman had signed a consent form for the core lecanemab trial, in which she was randomized to getting the antibody or a placebo. It contained no direct warning about tPA use. The consent form’s language on anticoagulants was also less ominous than the revised version, written for an extension phase in which all trial participants could elect to receive lecanemab if they met certain inclusion criteria. In contrast to the stronger language in the revised form, the earlier version stated: “You may continue with these medications, but you and the investigator should discuss the risk of bleeding since medications which prevent clots and [lecanemab] are both associated with a slight risk of bleeding in the brain.”

It’s not clear whether, or how quickly, all the 247 sites in extension phase of the clinical trial passed along the updated blood clot medication warning to their participants. The Illinois woman’s husband could not locate an updated, signed consent form.

In October, STAT reported that a man in his late 80s, who was taking a blood thinner for a heart issue, also died after suffering a brain hemorrhage while receiving the antibody in the extension phase. But that occurred in June, before the date of the revised consent form Science has obtained.

In a third death of a person participating in the extension trial, which Science revealed earlier this month, a Florida woman on 25 July signed a version of the consent form that lacked the new anticoagulant warning. Then in September she received a minimal course of the blood thinner heparin after she experienced strokelike symptoms. (The form, and the woman’s medical records, were provided by the woman’s daughter, whose name has been withheld to protect the family’s privacy.)

Neurologists who reviewed the woman’s records for Science don’t think the heparin contributed significantly to her death, attributing it to the antibody alone. But some scientists say her case—together with the others—suggests U.S. regulators should make the potential risks associated with lecanemab clear to consumers, even if they approve the drug.

“Pending further evidence coming in, the highest level of warning [a “black box” caution on combined use of lecanemab and blood thinners] seems appropriate to me at this point,” says Eric Smith, a neurologist at the University of Calgary. Smith has consulted for Eisai partner Biogen and worked on a trial for an earlier antiamyloid antibody, called aducanumab (marketed as Aduhelm), developed by the two companies.

At a highly anticipated November scientific meeting where Eisai provided its most detailed results so far on the lecanemab trial, the company noted in a presentation slide that people in the extension phase were “allowed to continue on anticoagulation … with informed consent language regarding increased risk of cerebral hemorrhage with concomitant anticoagulant use.”

The company did not reply directly to questions from Science about the timing or reasons for its consent form changes, or how many extension trial participants received and signed off on the updated warning. An Eisai spokesperson said in a statement to Science that safety information from its trials is assessed by the company, independent experts, FDA, and other regulators. Eisai “promptly communicates important safety information,” including informed consent revisions—which must be approved by biosafety boards—to all of those parties, as well as trial investigators and patients, the statement noted. “Eisai is confident that the informed consents used in our studies accurately describe the known risks associated with lecanemab,” it added.

Smith declined to specifically comment on Eisai’s handling of the lecanemab trials consent forms. But he did say, “In general, the company is better served by being as open and transparent as possible about all potential risks.”

It should also invest, Smith adds, “in understanding the frequency and nature of these risks so that doctors and patients have all the information they need to make important decisions about the use of this treatment in the future, should it be approved by the FDA.” Smith was among several scientists who reviewed the medical records of the Florida case and who concluded lecanemab was clearly involved in the woman’s death.

Lecanemab, like many other experimental treatments for Alzheimer’s, targets beta amyloid, a protein found in clumps outside of brain cells in people with the condition. Although such protein deposits also occur in the brains of seemingly healthy individuals, many neuroscientists say a large body of evidence supports the theory that some forms of beta amyloid trigger a process that kills brain cells, causing debilitating dementia and death.

That’s why supporters of the so-called amyloid hypothesis were thrilled by the results of the recently completed phase 3 lecanemab trial, which included about 1800 people with early signs of Alzheimer’s. On average, those who received infusions of the antibody declined cognitively 27% more slowly than those on a placebo—the most beneficial response so far for an antiamyloid treatment.

But neurologists disagree about whether such a difference would be perceptible to patients. And three key trial subgroups—people under age 65, women, and people who carry two copies of APOE4, a gene variant that raises one’s risk of developing Alzheimer’s—did not show any statistically significant benefit.

Still, numerous scientists have said many Alzheimer’s patients would accept potentially serious health risks to try lecanemab, and the antibody appeared to cause less brain swelling and bleeding in its core trial than aducanumab and other amyloid-targeting drugs. The company also reported comparable death rates in treatment and placebo groups during the core trial. But it has not provided details on each death, frustrating some outside scientists.

The three media-reported clinical trial deaths during the open-label extension, tied by some neurologists to lecanemab, have sparked concerns among Alzheimer’s experts about the drug’s widely anticipated approval by FDA. Some worry the agency will not adequately scrutinize lecanemab, in part based on its controversial handling of Aduhelm. Critics say FDA approved the expensive treatment despite doubts about its efficacy. And yesterday a U.S. House of Representatives panel released a report that noted “FDA’s review and approval of Aduhelm consisted of atypical procedures and deviated from the agency’s own guidance.” Among its findings was that “FDA and Biogen inappropriately collaborated” on a briefing document for outside advisers that the agency had enlisted to review the antibody’s safety and efficacy.

Jason Karlawish, co-director of the Penn Memory Center at the University of Pennsylvania, calls the enthusiasm surrounding lecanemab justified. But many of his colleagues would not prescribe the antibody to anyone taking blood thinners, Karlawish says.

Sam Gandy, a neurologist and neuroscientist at the Icahn School of Medicine at Mount Sinai, also worries about people with cerebral amyloid angiopathy (CAA), a common condition among Alzheimer’s patients in which amyloid replaces blood vessel lining. Doctors in areas distant from major medical centers will face formidable challenges diagnosing CAA in potential lecanemab recipients, he notes. The condition makes brain swelling and bleeding more likely in combination with antiamyloid drugs such as lecanemab, contributing to risks of using blood thinners with the antibody.

Even if FDA approves lecanemab it could add conditions on its use. In addition to requiring a black box warning label, for example, the agency could require that lecanemab be enrolled in FDA’s Risk Evaluation and Mitigation Strategies (REMS) program for medications with “serious safety concerns.” REMS can require that physicians prescribing a new drug closely monitor side effects and report any to FDA, that the drug be administered in qualified health care settings, and that doctors get training about how to test patients for conditions—such as CAA in this case—that might increase the likelihood of dangerous side effects.

REMS could help ensure “that a drug that I think is widely accepted as risky, is used in a way that’s as safe as possible,” Karlawish says. He adds that “FDA needs to do its job” and form an expert advisory panel to weigh in on which features the REMS designation should include, including guidance on whether concurrent use of blood thinners with lecanemab should get a black box warning—usually denoting a risk of death.

Gandy agrees the agency should assess the need for a black box warning that could include every class of drug—such as anticoagulants, tPA, and antiplatelet treatments—that can cause or increase the risk of brain bleeding. He also favors genetic testing of potential lecanemab recipients to ensure they know their APOE4 status. In the completed core phase of the lecanemab trial, participants who carry at least one copy of the gene variant suffered a much higher rate of brain swelling and bleeding.

Eisai said it considers all serious adverse events in evaluating lecanemab’s safety. It did not reply to questions from Science about whether warnings should be included on its product label or whether the drug should be included in the REMS program, if approved by FDA.

This story was supported by the Science Fund for Investigative Reporting.

Earlier this year, the developer of a promising antibody designed to slow Alzheimer’s disease strengthened a key warning given to participants in an ongoing trial of the experimental drug. Taking the antibody alongside blood clot medications, the Japanese biotech company Eisai cautioned, increases the risk of possibly fatal brain hemorrhages. That revision of its informed consent form, revealed in a 14 July version obtained by Science, appears to challenge the company’s contention that the antibody, known as lecanemab, played no role in the recently revealed deaths of two people who suffered dramatic brain bleeds while concurrently taking the drug and blood thinners.

The change to the form also raises questions about how effectively Eisai and its clinical trial partners communicated updated warnings to trial participants and how transparent the company has been about the risks of its product, which the U.S. Food and Drug Administration (FDA) has said it could approve for sale by 6 January 2023.

The revised consent form, distributed to investigators running the lecanemab trial, informs participants that they could die from combining the antibody with drugs that reduce blood clots. “While the overall risk of a major brain bleed is low with [lecanemab] treatment, the risk is higher in people who are also taking blood clot prevention medications. This risk is estimated to be more than 1 in 100 people, but less than 5 in 100 people,” the form from Eisai noted. “Bleeding in the brain, especially when you are taking medications that prevent blood clots, can be serious and can even lead to death. It is important to consider the risk of bleeding in your brain with the investigator before deciding whether or not to continue your participation in this study.”

Blood thinners and other drugs that affect coagulation are commonly prescribed for a range of ailments that afflict elderly people, including those with Alzheimer’s. And tPA—a powerful blood clot–busting agent—is a standard treatment for strokes, such as the one experienced by an Illinois woman in September who received lecanemab in Eisai’s trial, Science previously reported. After she was rushed to the hospital, her physicians checked a website containing information about the drug and, based on what they read there, decided an infusion of tPA posed a relatively small risk, according to her husband.

But his wife quickly began screaming, suffered seizures, was put on a ventilator, and died a few days later. An autopsy revealed a massive brain hemorrhage. (Science is withholding the names of the woman and her husband to protect the family’s privacy.)

Earlier this year, the Illinois woman had signed a consent form for the core lecanemab trial, in which she was randomized to getting the antibody or a placebo. It contained no direct warning about tPA use. The consent form’s language on anticoagulants was also less ominous than the revised version, written for an extension phase in which all trial participants could elect to receive lecanemab if they met certain inclusion criteria. In contrast to the stronger language in the revised form, the earlier version stated: “You may continue with these medications, but you and the investigator should discuss the risk of bleeding since medications which prevent clots and [lecanemab] are both associated with a slight risk of bleeding in the brain.”

It’s not clear whether, or how quickly, all the 247 sites in extension phase of the clinical trial passed along the updated blood clot medication warning to their participants. The Illinois woman’s husband could not locate an updated, signed consent form.

In October, STAT reported that a man in his late 80s, who was taking a blood thinner for a heart issue, also died after suffering a brain hemorrhage while receiving the antibody in the extension phase. But that occurred in June, before the date of the revised consent form Science has obtained.

In a third death of a person participating in the extension trial, which Science revealed earlier this month, a Florida woman on 25 July signed a version of the consent form that lacked the new anticoagulant warning. Then in September she received a minimal course of the blood thinner heparin after she experienced strokelike symptoms. (The form, and the woman’s medical records, were provided by the woman’s daughter, whose name has been withheld to protect the family’s privacy.)

Neurologists who reviewed the woman’s records for Science don’t think the heparin contributed significantly to her death, attributing it to the antibody alone. But some scientists say her case—together with the others—suggests U.S. regulators should make the potential risks associated with lecanemab clear to consumers, even if they approve the drug.

“Pending further evidence coming in, the highest level of warning [a “black box” caution on combined use of lecanemab and blood thinners] seems appropriate to me at this point,” says Eric Smith, a neurologist at the University of Calgary. Smith has consulted for Eisai partner Biogen and worked on a trial for an earlier antiamyloid antibody, called aducanumab (marketed as Aduhelm), developed by the two companies.

At a highly anticipated November scientific meeting where Eisai provided its most detailed results so far on the lecanemab trial, the company noted in a presentation slide that people in the extension phase were “allowed to continue on anticoagulation … with informed consent language regarding increased risk of cerebral hemorrhage with concomitant anticoagulant use.”

The company did not reply directly to questions from Science about the timing or reasons for its consent form changes, or how many extension trial participants received and signed off on the updated warning. An Eisai spokesperson said in a statement to Science that safety information from its trials is assessed by the company, independent experts, FDA, and other regulators. Eisai “promptly communicates important safety information,” including informed consent revisions—which must be approved by biosafety boards—to all of those parties, as well as trial investigators and patients, the statement noted. “Eisai is confident that the informed consents used in our studies accurately describe the known risks associated with lecanemab,” it added.

Smith declined to specifically comment on Eisai’s handling of the lecanemab trials consent forms. But he did say, “In general, the company is better served by being as open and transparent as possible about all potential risks.”

It should also invest, Smith adds, “in understanding the frequency and nature of these risks so that doctors and patients have all the information they need to make important decisions about the use of this treatment in the future, should it be approved by the FDA.” Smith was among several scientists who reviewed the medical records of the Florida case and who concluded lecanemab was clearly involved in the woman’s death.

Lecanemab, like many other experimental treatments for Alzheimer’s, targets beta amyloid, a protein found in clumps outside of brain cells in people with the condition. Although such protein deposits also occur in the brains of seemingly healthy individuals, many neuroscientists say a large body of evidence supports the theory that some forms of beta amyloid trigger a process that kills brain cells, causing debilitating dementia and death.

That’s why supporters of the so-called amyloid hypothesis were thrilled by the results of the recently completed phase 3 lecanemab trial, which included about 1800 people with early signs of Alzheimer’s. On average, those who received infusions of the antibody declined cognitively 27% more slowly than those on a placebo—the most beneficial response so far for an antiamyloid treatment.

But neurologists disagree about whether such a difference would be perceptible to patients. And three key trial subgroups—people under age 65, women, and people who carry two copies of APOE4, a gene variant that raises one’s risk of developing Alzheimer’s—did not show any statistically significant benefit.

Still, numerous scientists have said many Alzheimer’s patients would accept potentially serious health risks to try lecanemab, and the antibody appeared to cause less brain swelling and bleeding in its core trial than aducanumab and other amyloid-targeting drugs. The company also reported comparable death rates in treatment and placebo groups during the core trial. But it has not provided details on each death, frustrating some outside scientists.

The three media-reported clinical trial deaths during the open-label extension, tied by some neurologists to lecanemab, have sparked concerns among Alzheimer’s experts about the drug’s widely anticipated approval by FDA. Some worry the agency will not adequately scrutinize lecanemab, in part based on its controversial handling of Aduhelm. Critics say FDA approved the expensive treatment despite doubts about its efficacy. And yesterday a U.S. House of Representatives panel released a report that noted “FDA’s review and approval of Aduhelm consisted of atypical procedures and deviated from the agency’s own guidance.” Among its findings was that “FDA and Biogen inappropriately collaborated” on a briefing document for outside advisers that the agency had enlisted to review the antibody’s safety and efficacy.

Jason Karlawish, co-director of the Penn Memory Center at the University of Pennsylvania, calls the enthusiasm surrounding lecanemab justified. But many of his colleagues would not prescribe the antibody to anyone taking blood thinners, Karlawish says.

Sam Gandy, a neurologist and neuroscientist at the Icahn School of Medicine at Mount Sinai, also worries about people with cerebral amyloid angiopathy (CAA), a common condition among Alzheimer’s patients in which amyloid replaces blood vessel lining. Doctors in areas distant from major medical centers will face formidable challenges diagnosing CAA in potential lecanemab recipients, he notes. The condition makes brain swelling and bleeding more likely in combination with antiamyloid drugs such as lecanemab, contributing to risks of using blood thinners with the antibody.

Even if FDA approves lecanemab it could add conditions on its use. In addition to requiring a black box warning label, for example, the agency could require that lecanemab be enrolled in FDA’s Risk Evaluation and Mitigation Strategies (REMS) program for medications with “serious safety concerns.” REMS can require that physicians prescribing a new drug closely monitor side effects and report any to FDA, that the drug be administered in qualified health care settings, and that doctors get training about how to test patients for conditions—such as CAA in this case—that might increase the likelihood of dangerous side effects.

REMS could help ensure “that a drug that I think is widely accepted as risky, is used in a way that’s as safe as possible,” Karlawish says. He adds that “FDA needs to do its job” and form an expert advisory panel to weigh in on which features the REMS designation should include, including guidance on whether concurrent use of blood thinners with lecanemab should get a black box warning—usually denoting a risk of death.

Gandy agrees the agency should assess the need for a black box warning that could include every class of drug—such as anticoagulants, tPA, and antiplatelet treatments—that can cause or increase the risk of brain bleeding. He also favors genetic testing of potential lecanemab recipients to ensure they know their APOE4 status. In the completed core phase of the lecanemab trial, participants who carry at least one copy of the gene variant suffered a much higher rate of brain swelling and bleeding.

Eisai said it considers all serious adverse events in evaluating lecanemab’s safety. It did not reply to questions from Science about whether warnings should be included on its product label or whether the drug should be included in the REMS program, if approved by FDA.

This story was supported by the Science Fund for Investigative Reporting.