12.04.2024

Why are makers of Alzheimer’s ‘wonder drug’ so silent over its side effects?

It was while taking part in a medical trial for a new dementia ‘wonder drug’ that Genevieve Lane, 79, suffered a fatal brain seizure. Her death, reported by The Mail on Sunday last week, came amid great hope for lecanemab, which experts had hailed as ‘the beginning of the end’ for Alzheimer’s – the degenerative disease that blights the lives of a million Britons.

But it also emerged that Genevieve, from Florida, was just one of three people who have died from problems which may potentially be linked to lecanemab, and has led to some experts calling for a pause to its rollout.

The drug is currently being assessed by the NHS spending watchdog, the National Institute for Health and Care Excellence (NICE), which will soon decide if it will be offered to tens of thousands of Britons.

Now concerns about lecanemab are growing deeper. Today we can reveal further startling revelations that cast additional doubt on the integrity of the data used to prove the drug’s safety.

Genevieve  Lane, a retired car hire manager was first diagnosed with dementia two years earlier in 2020, after she noticed small lapses in her memory

Ms Lane, pictured with her daughters, died in September 2022 after her third dose of Alzheimer's wonder drug lecanemab

Ms Lane, pictured with her daughters, died in September 2022 after her third dose of Alzheimer’s wonder drug lecanemab

And experts are now telling The Mail on Sunday they believe rolling out lecanemab in the UK could put lives at risk.

The issues raised include:

lThat the severity of possible dangerous side effects, such as brain shrinkage, may have been underestimated;

lAlzheimer’s doctors have accused the drug manufacturer, Eisai, of withholding crucial information, including details of three patients who died after taking the medicine;

lClinicians have called for the full safety data to be available before US regulators meet next month to decide whether to approve lecanemab, although Eisai is under no legal obligation to do this;

lInsiders have raised concerns that Eisai failed to properly investigate Genevieve’s death, meaning the full extent of any side effect are not known;

lThe firm reportedly waited two months before informing US health authorities of the death – typically, trial deaths must be reported within a week.

Such is the worry over lecanemab that some experts are calling for an ‘urgent re-evaluation’ of the data collected by Eisai which was used to prove its safety.

Ms Lane suffered a massive bleed on the brain, shown here on this scan

Ms Lane suffered a massive bleed on the brain, shown here on this scan

Research has shown that one in six patients treated with the ‘wonder drug’ suffer from brain bleeds while at least three of the people involved in the clinical trial died

The drug first attracted public attention in September when Eisai published the results of a major trial involving 1,800 participants and carried out over 18 months at 240 sites across the world, including the US, UK and Australia. It was found to slow cognitive decline by a third and was the first treatment proven to delay progression of the disease

The drug first attracted public attention in September when Eisai published the results of a major trial involving 1,800 participants and carried out over 18 months at 240 sites across the world, including the US, UK and Australia. It was found to slow cognitive decline by a third and was the first treatment proven to delay progression of the disease

‘The drug company has said lecanemab is safe, but these deaths could suggest otherwise,’ says Robert Howard, professor of old age psychiatry at University College London’s Institute of Mental Health.

‘There is a credible risk that, if rolled out on the NHS, more lives could be put in danger. Which is why there is a moral imperative to release the full data.’

Other brain experts agree. ‘The handling of the deaths raises doubts as to whether serious lecanemab side effects are being spotted and properly reported,’ says Dr Matthew Schrag, a neurologist at Vanderbilt University in Nashville, Tennessee, who carried out Genevieve’s autopsy.

‘There are question marks over whether the published safety data is representative of the facts. It is crucial that Alzheimer’s doctors see this information before this drug is approved.’

The drug first attracted public attention in September when Eisai published the results of a major trial involving 1,800 participants and carried out over 18 months at 240 sites across the world, including the US, UK and Australia. It was found to slow cognitive decline by a third and was the first treatment proven to delay progression of the disease.

Elusive route to Alzheimer’s cure

Lecanemab is the latest in a series of Alzheimer’s drugs that work in a similar way.

Many believe the disease is triggered by amyloid – a toxic protein. Normally these circulate in the blood, but for reasons not fully understood they can clump together in the brain and form plaques, which disrupt cell function and cause brain damage.

Anti-amyloid drugs such as lecanemab work by using the immune system to attack the plaques. The theory is that, in doing so, deterioration may be slowed or even halted. And a number of these drugs have been shown to be effective at removing amyloid plaque from the brain. However, until lecanemab, there was no evidence that this slows down the progress of the disease.

Lecanemab is the latest in a series of Alzheimer¿s drugs that work in a similar way

Lecanemab is the latest in a series of Alzheimer’s drugs that work in a similar way

Some experts say this is because treatment is being given too late, meaning the Alzheimer’s has progressed too far to be stopped.

But others believe the theory that amyloid plaque triggers Alzheimer’s is incorrect. They argue that the build-up of amyloid is a by-product of the disease, rather than the cause, meaning that removing amyloid is unlikely to have an impact on slowing the disease.

An alternative idea is that faulty genes cause Alzheimer’s by triggering a mass die-off of brain cells.

Earlier this month, scientists said they had identified 92 genes that increase the risk of Alzheimer’s developing.

Professor Julie Williams, director at the UK Dementia Research Institute at Cardiff University, said that this could lead to a gene therapy capable of treating the disease by 2040.

Professor John Hardy, a dementia researcher at University College London, declared the findings the ‘beginning of the end’ for Alzheimer’s and said he hoped it would be available on the NHS within a year.

Lecanemab, given every two weeks as a drip via a vein in the arm until it stops working, clears a protein known as amyloid which builds up in the brains of Alzheimer’s patients. Amyloid clumps are thought to cause the progressive brain damage seen in dementia.

But initial trials revealed that in some cases lecanemab can cause unwanted problems in the brain – including swelling, bleeding and inflammation, a condition known medically as amyloid-related imaging abnormalities, or ARIA. About one in ten participants in the trial developed brain swelling and one in six suffered brain bleeds, according to Eisai data.

Trial participants were monitored with MRI brain scans every three months, and those who developed ARIA were taken off the drug. The majority had no symptoms.

Eisai said lecanemab was not related to an increased risk of death as the fatality rate was similar to that of the group in the trial who were given a placebo.

‘No deaths were considered by the investigators to be related to lecanemab or occurred with ARIA’, said the study’s authors, from Yale University.

But autopsy investigators and an investigator on the trial have now identified three cases, including that of Genevieve Lane, where lecanemab patients died of unexpected symptoms likely connected to the drug. One case happened during the trial, the other two after it had been completed.

In two cases, the deaths were said to be related to an interaction between lecanemab and blood thinners – medicines which reduce the risk of strokes and heart attacks but can increase bleeding risk.

Genevieve was not on blood thinners and was relatively healthy. But shortly after her third dose, she suffered a massive seizure. Five days later, she died. An autopsy found lecanemab was the most likely cause of death. In all three cases, Eisai has either denied the death was linked to the drug or declined to comment.

Speaking to the MoS, Genevieve’s family claim the trial doctors – who worked for an independent clinical trial company employed by Eisai – missed vital warning signs, including worrying symptoms, that would have prevented her death.

‘We believe Mum told her doctor about headaches when she returned for her second dose. But he still proceeded to give her the treatment and did not suggest carrying out any scans,’ says Genevieve’s younger daughter, Charlotte Lane, 56. ‘It’s shocking to think that, on the trial of an experimental drug, it seems like no one was looking out for worrying symptoms.’

The family believe that the trial doctors failed to properly investigate their mother’s death.

When her children wanted to know more about what had led to her death, ‘we were surprised the trial company didn’t show any interest in carrying out an autopsy,’ says Charlotte. ‘It didn’t seem like they wanted to investigate anything more.’

Genevieve’s daughters eventually contacted researchers at Vanderbilt University, who agreed to carry out an autopsy.

Eisai said it could not comment on individual participants. ‘The wellbeing of patients enrolled in our studies is always Eisai’s top priority,’ said a spokesman. ‘Eisai has established rigorous safety monitoring process. This includes an independent data safety monitoring committee of external experts. Eisai promptly communicated important safety information to regulatory agencies, sites, investigators and subjects.’

But some experts have questioned this. One neurologist familiar with Genevieve’s case raised concerns her death may not have been reported to the US medicines watchdog, the Food and Drug Administration (FDA), until December 2022 – nearly two months after Eisai announced lecanemab was safe and effective.

The other people who died during the trial were taking blood thinners – medicines that help reduce the risk of strokes and heart attacks but can increase the risk of bleeding. Until now, experts have believed it was the combination of lecanemab and blood thinners that raised the risk of life-threatening side effects

Eisai declined to comment. An FDA spokesman also declined to say when the information was received, citing ‘patient privacy’.

Researchers often closely monitor patients after studies end, to keep note of potential long-term side effects, known as an extension trial. Eisai will collect data on their lecanemab trial participants until 2027.

Did it cause these three deaths?

So far, three deaths related to lecanemab have been identified by medical reports.

The first two deaths are thought to be a deadly interaction between lecanemab and blood thinners – medicines given to about 700,000 Britons that reduce the risk of strokes and heart attacks, but can cause bleeding.

The first was a man in his 80s from the US. He suffered a major brain haemorrhage while participating in the early phase of the trial in June 2022, according to medical magazine Stat News.

An investigator reportedly concluded the death was related to the drug. But its maker, Eisai, has denied this and did not count the patient as a death in its trial results.

Next, in August, after the trial had finished, a 65-year-old woman from Chicago died after suffering several brain haemorrhages. She had previously suffered an unrelated stroke, according to the autopsy report – parts of which were published in medical magazine Science.

Lecanemab was said to have inflamed and weakened the blood vessels in her brain, and several of them burst when she was given blood-thinning drugs as treatment. The report concluded she would likely still be alive if she had not been taking lecanemab. Eisai declined to comment.

In September 2022, 79-year-old Genevieve Lane became the third person to die of suspected lecanemab side effects following a massive brain bleed. Genevieve’s family told the MoS she suffered problems almost immediately after taking the drug.

‘She was moving slowly, needed to spend a lot of time in bed and complained of headaches,’ says 59-year-old daughter Julie.

Two weeks after her third dose, she died.

Seven months on from the release of the initial trial results, Eisai has thus far declined calls to publish any follow-up data, which would include two of the deaths.

Speaking at a major neurology conference last week in Boston, US, lead investigator of the lecanemab trial, Professor Christopher van Dyck, would not answer questions or provide information about its extension trial results. Eisai also declined the MoS’s request to see the data.

Experts say it is crucial this information is made public as soon as possible.

Meanwhile, recent evidence has sparked further concerns about lecanemab. Last month, Australian researchers published a study showing patients taking anti-amyloid drugs, including lecanemab, experienced accelerated brain shrinkage. This is often an indicator that cognitive decline is worsening. Patients taking the drugs saw their brains shrink 40 per cent faster than those who didn’t have any treatment.

‘We currently don’t know which patients are most at risk of these sorts of side effects because we haven’t seen information that tells us about characteristics that might have made them more vulnerable,’ says Professor Scott Ayton, dementia expert at the Florey Institute of Neuroscience and Mental Health in Melbourne, Australia.

But one group, who carry a gene called APOE4 which has long been linked to dementia, could be six times more likely to see brain swelling after taking lecanemab and three times as likely to experience brain bleeds, according to a study in the medical journal Jama Neurology last month.

Researchers analysed available Eisai data, which showed genetic traits of patients who suffered severe side effects.

Importantly, studies estimate up to 65 per cent of Alzheimer’s patients carry the APOE4 gene and may be at risk.

‘We need to know whether patients with these genes who suffered bad side effects also had underlying conditions, so we know exactly who should not be taking lecanemab,’ says Dr Madhav Thambisetty, a neurologist at the US National Institute of Aging. ‘Researchers have asked for this information time and time again – and Eisai has refused.’

Genevieve’s family share these frustrations. They are yet to receive her full medical records from Eisai, even though they were requested in January. Last month the firm finally agreed to send the documents, but they haven’t yet arrived.

‘We felt ignored for months after Mum died,’ says Charlotte. ‘It’s only now we’ve started talking publicly about her death that they’ve agreed to anything.

‘We deserve to know what happened. There are missing pieces of the puzzle. We want someone to take responsibility.’

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