New Alzheimer’s Drug Slowed Cognitive Decline in Trial, Drugmaker Announces
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Pharmaceutical giant Eli Lilly and Company (Lilly) has announced encouraging data from its Phase 3 study of Alzheimer’s drug donanemab, a monoclonal antibody that Lilly claims slowed trial participants’ cognitive decline by 35%.
The search for Alzheimer’s disease treatments
Alzheimer’s disease (AD) is an incurable neurodegenerative disease. It is characterized by the formation of abnormal proteins in the brain, known as tau tangles and amyloid plaques. These occur alongside neurological symptoms such as problems with memory, language and reasoning.
Current estimates suggest that 6.7 million Americans over the age of 65 are currently living with AD, though this is forecast to rise to 12.7 million by 2050 – importantly, efforts to develop treatments are ongoing. Lilly has been developing one such drug, an investigational monoclonal antibody, donanemab, which targets amyloid plaques thought to be involved in the progression of the disease.
Its Phase 3 study, TRAILBLAZER-ALZ 2, was designed to measure the safety and efficacy of donanemab in people with early symptomatic AD, including those with the precursor condition mild cognitive impairment and the mild dementia stage of AD, with confirmed presence of AD neuropathology such as tau and amyloid.
In a recent press release, Lilly announced “positive results” from the trial data so far, which is yet to be peer-reviewed. "These Phase 3 data confirm the benefit observed in our TRAILBLAZER-ALZ study and show that donanemab, if approved, may represent a significant step forward for people with early symptomatic Alzheimer's disease, and allow them to continue to participate in activities that are meaningful to them," said Anne White, executive vice president of Lilly and president of Lilly Neuroscience.
Promising Phase 3 trial results
The randomized, double-blind and placebo-controlled study recruited a primary analysis population of 1,182 participants with “intermediate” tau levels and clinical symptoms of AD. Participants were considered to have completed their treatment course with donanemab once clearance of amyloid plaques reached a prespecified level.
According to the announcement by Lilly, donanemab was able to slow cognitive decline by 35% in this population compared to placebo. At 18 months, the treatment also led to a 40% reduced decline in the ability to perform daily living tasks such as managing finances, hobbies and navigating outside the home, measured by the Alzheimer's Disease Cooperative Study – instrumental Activities of Daily Living Inventory (ADCS-iADL).
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Additionally, 47% of participants receiving donanemab had no progression of their disease after 1 year of the trial, compared to 29% in the placebo group. This was defined as no decline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale, which quantifies the severity of dementia symptoms.
Patients taking donanemab also had a 39% lower risk of progressing to the next stage of the disease compared to the placebo group.
Positron emission tomography (PET) scans showed that donanemab also significantly reduced levels of amyloid plaques in the brain from as early as 6 months after commencing treatment. Many patients’ amyloid levels were reduced to such an extent that they were considered negative for pathology – 34% of participants with “intermediate” tau levels achieved amyloid clearance at 6 months, and 71% achieved clearance at 12 months.
“Although we only have a press release, this announcement is consistent with earlier Phase 2 results – and confirms that we are in a new era of disease modification for Alzheimer’s disease,” said Prof. Nick Fox, professor of clinical neurology and group leader at the UK Dementia Research Institute. “Dramatic and rapid amyloid removal was accompanied by slowing of cognitive decline.”
Risks of significant side effects
Nonetheless, the announcement also reported considerable side effects of the treatment, such as amyloid-related imaging abnormalities (ARIA), which have also been observed with other amyloid plaque-clearing antibody therapies.
24% of donanemab-treated participants experienced temporary swelling of the brain, known as ARIA-E. This resulted in 6.1% experiencing ARIA-E symptoms, which typically include headache, confusion and vomiting. Furthermore, 31.4% of the donanemab group and 13.6% of the placebo group experienced small brain hemorrhages known as ARIA-H.
Lilly announced that most ARIA cases were mild to moderate and were “resolved or stabilized with appropriate management”. However, there was a 1.6% incidence of serious ARIA, in which two participants’ deaths were attributed to ARIA and another death occurred after a serious ARIA incident.
“It is important to note that there were rare serious side effects of the treatment with brain swelling and small strokes that seem to have contributed to the death of three of the participants in the trial. Regulators will have to decide whether the benefits of treatment outweigh these risks,” said Prof. Tara Spires-Jones, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh and president of the British Neuroscience Association.
Prospects of regulatory approval
Using these data, Lilly now aims to submit donanemab to the U.S. Food and Drug Administration (FDA) this year.
"We are encouraged by the potential clinical benefits that donanemab may provide, although like many effective treatments for debilitating and fatal diseases, there are associated risks that may be serious and life-threatening," said Dr. Mark Mintun, group vice president neuroscience research and development at Lilly, and president of Avid Radiopharmaceuticals. "We note that these results suggest that people in the early pathological stage of the disease could be the most responsive to therapeutics targeting amyloid. We thank the participants in the clinical trial and their loved ones for their time and commitment to finding solutions for this disease."
However, publication of the full, peer-reviewed study is required to examine the rigor of this trial and the efficacy of donanemab in more detail.
“This press release from Eli Lilly and Company sounds very promising,” said Spires-Jones. “While the full data have not been shared with the scientific community, meaning we can’t yet judge how robust they are, the company reports that their drug donanemab slowed decline in people with early AD.”
This article is a rework of a press release issued by Eli Lilly and Company. Material has been edited for length and content.