While advocacy groups and families of people with Down syndrome are lobbying for their inclusion in drug trials for Alzheimer’s – the most common cause of death for people with Down’s – and treatment with these drugs, neurological experts are resisting, citing safety risks.
Former biotech executive Hampus Hillerstrom is leading an effort to gain parity with neurotypical adults for his son, Oskar (9) and others with Down syndrome.
The boy’s aunt also had Down syndrome, and died at 60 of Alzheimer's.
Their objective is to get them promising new drugs like Eisai and Biogen’s recently approved Leqembi, and Eli Lilly’s experimental donanemab, as well as inclusion of people with Down’s in clinical trials of treatments for Alzheimer’s.
“The goal is to make sure we get access,” Hillerstrom said. “Ideally, we needed to be part of these trials from the beginning.”
Reuters interviewed five top neurologists who recommend against immediate use because the drugs are untested in this population, whose unique predisposition to Alzheimer’s could pose extra safety risks.
This puts Hillerstrom, chief executive of the Down syndrome research organisation LuMind IDSC, and other advocacy groups in the unusual position of being at odds with prominent experts in the field.
Additionally, advocacy groups have taken their message directly to the US Government Medicare health programme, seeking changes to written policies they believe could disqualify people with Down syndrome from reimbursement for the treatments.
Down syndrome affects 400 000 people in America and more than 6m globally. People with the condition inherit a third copy of chromosome 21, giving them an extra helping of a gene that causes them to overproduce the protein called beta amyloid.
By 30, most people with Down syndrome have abnormal clumps of amyloid in their brain, and many show signs of dementia in their 40s and 50s.
Clinical trials of Leqembi and donanemab, which is expected to win US approval later this year, have shown that removing beta amyloid can slow cognitive decline in people with early-stage Alzheimer’s.
Patient advocates and three neurologists interviewed by Reuters believe the same may be true of people with Down syndrome.
However, the drugs can cause brain swelling and bleeding, a risk that is especially high among people with a condition called cerebral amyloid angiopathy (CAA), which affects nearly half of Alzheimer’s patients.
In an extended portion of Eisai’s main Leqembi trial, CAA was associated with one death.
People with Down syndrome, who were not included in either Eisai or Lilly’s late-stage trials, have higher-than-average rates of CAA, and neurologists are concerned that removing amyloid with a drug like Leqembi could weaken artery walls, leading to bleeding in the brain.
Dignity of risk
Hillerstrom said the groups are strongly lobbying Eisai and Lilly to conduct the safety trials in Down syndrome, and he’s been meeting with the companies to push them to design such trials.
Because of the unique risks, LuMind and others advise families to wait for the data.
With such trials only in planning stages, however, it could be three or four years before they yield answers, so advocates and others on the front lines also want barriers to FDA-approved drugs removed.
Emily Largent, a bioethicist and health policy expert at the University of Pennsylvania Perelman School of Medicine, said when faced with a fatal disease, people with Down syndrome should be allowed to weigh the risks and benefits of treatment, which she referred to as “the dignity of risk”.
Part of that entails convincing Medicare to change language in its national coverage policy, advocates including Hillerstrom say. That would involve including validated cognitive assessment scales to detect memory changes in people with Down syndrome, three expert sources told Reuters.
LuMind and a coalition of six other advocacy groups made their case in a July meeting with Medicare, stressing that all other treatments approved by the US Food and Drug Administration are available to people with Down syndrome, even when they had not been tested in candidates with the condition, they said.
Already, doctors are fielding requests for the drug. Dr Beau Ances, a neurologist at Washington University, said he would not offer the treatment until it was shown to be safe, and was following published guidance from leading neurologists.
But he is frustrated by the wait. “I’ve lost a number of patients this year alone,” he said. “I’m tired of giving hugs. I really want to give a therapy.”
Instead, Ances asks patients to join a clinical trial sponsored by the National Institute on Ageing that has been screening potential patients using cognitive tests designed to measure changes in memory, language and attention, specifically in people with Down syndrome.
They also undergo genetic testing, brain scans and other tests necessary to take part in a treatment trial, and provide informed consent themselves or through a legally authorised representative.
So far, 19 specialty clinics, including Washington University, have enrolled 180 volunteers.
Dr Michael Rafii, a University of Southern California neurologist who is leading the trial, is negotiating with drugmakers about testing one or more anti-amyloid treatments in a placebo-controlled safety and efficacy trial next year.
Lilly declined to comment on whether it is considering either a safety trial or taking part in that study.
An Eisai spokeswoman said the company “has no immediate plans” to conduct clinical trials of Leqembi in people with Down syndrome.
Living longer
Alzheimer’s is a relatively recent worry for people with Down syndrome.
Advances in care have resulted in a more than doubling of life expectancy, from an average age of 25 in 1983 to 60 currently. But that longer lifespan has brought with it the near-certainty of developing Alzheimer’s.
Dr William Mobley, a neurologist at UC San Diego School of Medicine, said people with Down syndrome have come far since the 1950s, when standard medical advice was to send infants to an institution.
“They’re living longer, but almost all of them are dying of Alzheimer’s disease when they get beyond 60,” he said.
Mobley and many other neurologists and patient advocates agree on the importance of safety trials, and the inclusion of people with Down syndrome in trial designs for future drugs, rather than waiting years until they are approved.
Dawn Brooks, Lilly’s global development leader for donanemab, said the company did not explicitly exclude people with Down syndrome.
Because Alzheimer’s typically occurs in people with Down syndrome by their mid-50s, it was challenging to find people who could take part in the main donanemab study, which enrolled people starting at 60.
The company is collaborating with LuMind in a study, gathering data on how Alzheimer’s manifests in people with Down syndrome.
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