Revised clinical trial form for Alzheimer’s antibody warns against fatal brain haemorrhages | Science

Earlier this year, the developer of a promising antibody designed to slow Alzheimer’s disease reinforced an important warning given to participants in an ongoing trial of the experimental drug. Japanese biotech company Eisai has warned that taking the antibody along with blood clot drugs increases the risk of possibly fatal cerebral hemorrhage. This revision of the informed consent form appeared in the July 14 version received by Scienceappears to challenge the company’s claim that the antibody, known as lecanemab, played no role in the recent deaths of two people who suffered dramatic cerebral hemorrhages while taking the drug and blood thinners at the same time.

The change in form also raises questions about how effectively Eisai and his clinical trial partners communicated up-to-date warnings to trial participants and how transparent the company is about the risks of its product, as the U.S. Food and Drug Administration (FDA) says. It can approve the sale by January 6, 2023.

The revised consent form distributed to the researchers conducting 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 cerebral hemorrhage is low, [lecanemab] The risk is higher in people who are taking anticoagulant medications at the same time as the treatment. In the form from Eisai, this risk is estimated to be more than 1 in 100 people, but less than 5 in 100 people. “Bleeding in the brain can be serious and even lead to death, especially when taking medications that prevent blood clotting. It is important that you and the researcher consider the risk of bleeding in your brain before deciding whether to continue your participation in this study.”

Blood thinners and other drugs that affect clotting are often prescribed for a number of diseases that affect older people, including Alzheimer’s patients. And tPA, a potent blood-clotting agent, is standard treatment for strokes, as experienced by an Illinois woman who took lecanemab in Eisai’s trial in September. Science previously reported. After she was hospitalized, her doctors checked a website with information about the drug and, based on what they had read there, concluded that the tPA infusion posed a relatively small risk, according to her husband.

However, his wife quickly started screaming, had seizures, was put on a ventilator, and died a few days later. An autopsy revealed that he had a severe cerebral hemorrhage. (Science to protect the privacy of the family, he withholds the names of the woman and her husband.)

Earlier this year, the Illinois woman signed a consent form for the core lecanemab trial, in which she was randomized to receive either antibodies or a placebo. It did not contain a direct warning about the use of tPA. The language of the consent form regarding anticoagulants was also less of a concern than the revised version, which was written for an extension phase in which all trial participants could choose to receive lecanemab if they met certain inclusion criteria. Contrary to the stronger language in the revised form, the previous version said: “You can continue with these drugs, but you and the researcher should discuss the risk of bleeding because anticoagulant drugs and [lecanemab] both are associated with a slight risk of bleeding in the brain.”

It is unclear whether all 247 sites in the extension phase of the clinical trial delivered the updated blood clot drug warning to their participants, or how quickly they passed. The Illinois woman’s husband was unable to find an updated, signed consent form.

In October, STAT reported that a man in his late 80’s who was on blood thinners for a heart problem also died after suffering a cerebral hemorrhage while taking the antibody in an extension phase. However, this happened in June, before the date of the revised consent form. Science achieved.

In the third death of a person participating in the extension case, Science Earlier this month, it was revealed that a Florida woman signed a version of her consent form without the new anticoagulant warning on July 25. She then took the minimal blood thinner heparin after experiencing stroke-like symptoms in September. (The form and the woman’s medical records were provided by the woman’s daughter, whose name is withheld to protect the family’s privacy.)

Neuroscientists examining the woman’s records Science Do not think that heparin significantly contributes to its death by simply binding it to the antibody. But some scientists say his case, along with others, suggests that US regulators need to clarify the potential risks associated with lecanemab for consumers, even if they do approve the drug.

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

At the much anticipated November scientific meeting where Eisai presented his most detailed results ever on the lecanemab trial, the company noted in a presentation slide that people in the extension phase were “permitted to continue anticoagulation … with the language of informed consent of the increased risk.” Cerebral hemorrhage with concomitant use of anticoagulants.

The company did not directly respond to their questions. Science about the timing or reasons for changes to the consent form, or how many extension attempt participants have received and signed the updated notice. An Eisai spokesperson said in a statement: Science Evaluation of safety information from trials by the company, independent experts, the FDA, and other regulators. The statement said Eisai promptly communicated “important safety information” to all these parties, as well as trial investigators and patients, including informed consent revisions that must be approved by biosafety boards. “Eisai is confident that the informed consents used in our studies accurately describe the known risks associated with lecanemab,” he added.

Smith declined to comment privately on Eisai’s handling of lecanemab trials consent forms. However, “Overall, it serves the company better to be as open and transparent as possible about all potential risks,” he said.

Smith also “must invest 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 Florida case’s medical records and concluded that lecanemab was clearly related to the woman’s death.

Lecanemab, like many other experimental treatments for Alzheimer’s, targets beta amyloid, a protein found in clumps outside brain cells in people with the condition. While such protein deposits also occur in the brains of apparently healthy individuals, many neuroscientists say there is ample evidence to support the theory that certain types of beta amyloid trigger a process that kills brain cells, causing debilitating dementia and death.

Therefore, supporters of the so-called amyloid hypothesis were excited by the results of the recently completed phase 3 study of lecanemab, which included approximately 1800 people with early symptoms of Alzheimer’s. On average, those who received the antibody infusion had a 27% slower cognitive decline than those who received the placebo; this was the most beneficial response ever for an antiamyloid therapy.

But neurologists disagree on whether such a difference would be perceived by patients. And three key subsets of trials—people under 65, women, and people with duplicates. APOE4a gene variant that increases a person’s risk of developing Alzheimer’s – did not show a statistically significant benefit.

Still, multiple scientists said many Alzheimer’s patients would accept the potentially serious health risks of trying lecanemab, and the antibody caused less brain swelling and bleeding in the core trial than aducanumab and other amyloid-targeted drugs. The company also reported comparable death rates in the treatment and placebo groups during the baseline trial. However, it did not provide details on each death, angering some outside scientists.

Three clinical trial deaths reported in the media during the open-label extension attributed to lecanemab by some neurologists have raised concerns among Alzheimer’s specialists about the drug’s widely anticipated approval by the FDA. Some worry that the agency won’t be able to adequately review lecanemab, partly based on the controversial Aduhelm administration. Critics say the FDA has approved the expensive treatment despite doubts about its effectiveness. And yesterday, a US House of Representatives panel released a report stating that “the FDA’s review and approval of Aduhelm consisted of atypical procedures and deviated from the agency’s own guidance.” Among their findings was that “the FDA and Biogen improperly collaborated on a briefing paper for external consultants that the agency commissioned to review the antibody’s safety and efficacy.”

Jason Karlawish, co-director of the Penn Memory Center at the University of Pennsylvania, justifies the enthusiasm surrounding lecanemab. But Karlawish says most of her colleagues won’t prescribe antibodies to people on blood thinners.

Sam Gandy, a neurologist and neuroscientist at the Icahn School of Medicine at Mount Sinai, is also concerned for people with cerebral amyloid angiopathy (CAA), a condition common in Alzheimer’s patients, in which amyloid replaces the blood vessel lining. He notes that doctors in areas far from major medical centers will face difficult challenges in diagnosing CAA in potential lecanemab recipients. This makes brain swelling and bleeding more likely in combination with antiamyloid drugs such as lecanemab, adding to the risks of using blood thinners with the antibody.

Even if the FDA approves lecanemab, it may add conditions to its use. For example, in addition to requiring a black box warning label, the agency may require lecanemab to be registered in the FDA’s Risk Assessment and Reduction Strategies (REMS) program for drugs with “serious safety concerns.” REMS may require physicians prescribing a new drug to closely monitor and report side effects to the FDA, if any, to administer the drug in qualified healthcare settings, and to train physicians in how to test patients for conditions (such as CAA in this case). This can increase the likelihood of dangerous side effects.

Karlawish says REMS can help ensure that “a drug that I consider broadly considered risky is used as safely as possible.” He adds that “the FDA needs to do its job,” and set up an expert advisory panel to weigh what features the REMS designation should include, including guidance on whether concomitant use of blood thinners with lecanemab should get a black box warning — often a risk of death.

Gandy agrees that the agency should consider the need for a black box warning that could include any class of drugs (such as anticoagulants, tPA, and antiplatelet therapies) that could cause or increase the risk of brain hemorrhage. He also favors genetic testing to make sure potential lecanemab recipients know their condition. APOE4 situation. In the completed core phase of the lecanemab trial, participants carrying at least one copy of the gene variant experienced a much higher rate of brain swelling and bleeding.

Eisai said he considered all serious side effects when evaluating the safety of lecanemab. did not answer questions Science whether to include warnings on the product label or to include in the REMS program if the drug is approved by the FDA.

Supported by this story Science Investigative Reporting Fund.

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