Immunotherapy Offers Hope Against Neurodegeneration

The new wave of treatment for Alzheimer’s disease includes antibodies that can remove the buildup of proteins from the brain. A new drug from Eli Lilly appears to remove these harmful plaques, while improving brain function. It’s a step in the right direction.

While there are FDA-approved drugs that can ease symptoms of Alzheimer’s disease and improve quality of life, they do not target the hallmarks of the disease—beta-amyloid plaques and tau pathology. Amyloid-β (Aβ) and tau proteins currently represent the two most promising targets to treat Alzheimer’s disease. The most extensively developed method to treat the pathologic forms of these proteins is through the administration of exogenous antibodies, or passive immunotherapy. 

Donanemab is a monoclonal antibody therapy developed to reduce the amount of amyloid plaque in the brain. The drug is an active immunotherapy designed to stimulate the patient’s immune system to attack and destroy beta amyloid plaques that are believed to form in the brain and spur the memory-wasting disease. During this clinical trial, donanemab slowed mental decline by 32 percent relative to placebo. It was however done in a trial with fewer than 300 patients.

The rationale behind donanemab is that targeting deposited plaque itself is necessary to clear existing amyloid burden from the brain, rather than merely prevent deposition of new plaques or growth of existing plaques. Biogen’s experimental Alzheimer’s treatment, aducanumab, also targets amyloid plaque in the brain, but it is facing regulatory scrutiny that is delaying progress.

Eli Lilly says its Alzheimer’s drug and target are different than similar studies in the past.

Its antibody goes after a modified form of beta amyloid called N3pG, and targeting this showed in its mid-stage results a significant slowing of decline in a composite measure of cognition and daily function in patients with early symptomatic Alzheimer’s disease compared to placebo. The treatment also should also ease symptoms of Parkinson’s disease, which has similar pathology to Alzheimer’s disease. The primary difference between Alzheimer’s and Parkinson’s is that each disease targets a different region of the brain, which explains the differing symptoms (memory versus motion).

From May 2013 to August 2016, Lilly ran a Phase 1 study in 100 people with mild cognitive impairment due to Alzheimer’s disease, or mild Alzheimer’s disease, in the United States and Japan. Participants had to have a positive amyloid PET scan. In December 2015, Lilly started a second Phase 1 study in 150 people with prodromal to moderate Alzheimer’s disease, again in the United States and Japan. 

In October 2020, Lilly began recruiting for TRAILBLAZER-ALZ 2, a Phase 2 safety and efficacy trial in 500 people with early onset Alzheimer’s disease. This month, Eli Lilly announced that TRAILBLAZER-ALZ met its primary endpoint, with donanemab slowing decline on the Integrated Alzheimer’s Disease Rating Scale (iADRS) by 32 percent compared to placebo. The company claimed improvement on all secondary endpoints of cognition and function, although not all were statistically significant. Treatment resulted in an average reduction in amyloid plaque by 84 centiloids, from 108 at baseline.

“We are extremely pleased about these positive findings for donanemab as a potential therapy for people living with Alzheimer’s disease. We are committed to reproducing and extending these important findings in our second ongoing donanemab trial, TRAILBLAZER-ALZ 2,” said Mark Mintun, M.D., vice president of pain and neurodegeneration, Eli Lilly and Company. “With more than 30 years of dedication to finding solutions for this devastating disease, we are proud of our progress moving the field forward and advancing the science. These positive results give us hope for patients and their families.”

By targeting N3pG beta amyloid, donanemab treatment has been shown to rapidly result in high levels of amyloid plaque clearance, as measured by amyloid imaging.

In TRAILBLAZER-ALZ, donanemab-treated patients, on average, showed an 84 centiloid reduction of amyloid plaque at 76 weeks compared to a baseline of 108 centiloids (less than 25 centiloids is typical of a negative amyloid scan). In this study, patients stopped receiving donanemab and switched to placebo once their plaque level was below 25 centiloids for two consecutive measures or below 11 centiloids at any one measure.

“This unique mechanism and antibody for clearing plaques, discovered at Lilly, has the potential to provide high levels of durable amyloid plaque clearance after limited duration dosing,” said Daniel Skovronsky, M.D., Ph.D., Lilly’s chief scientific officer and president of Lilly Research Laboratories. “In conjunction with our expertise in amyloid and tau imaging, this allowed us to conduct a trial to test if reducing amyloid plaques in Alzheimer’s patients to levels seen in scans of healthy individuals could result in clinically meaningful slowing of cognitive decline. The positive results we have obtained today give us confidence in donanemab and support its rapid and deep plaque clearance for the potential treatment of Alzheimer’s disease.”

The full results of the TRAILBLAZER-ALZ study will be presented at a future medical congress and submitted for publication in a peer-reviewed clinical journal. Lilly plans to discuss these results with regulators to assess next steps for donanemab. In addition, TRAILBLAZER-EXT is an ongoing trial for those who participated in TRAILBLAZER-ALZ.

“It’s a big moment for Alzheimer’s disease patients. There’s hope again,” said Daniel Skovronsky, Lilly’s chief scientific officer.

Almost 10 million new cases of dementia are diagnosed each year worldwide—one new case every three seconds. Millions of additional cases go undiagnosed. The annual societal and economic cost of dementia is estimated at $1 trillion, an amount that is expected to double by 2030. There is no cure for Alzheimer’s disease.

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Gary Chandler is a prion expert. He is the CEO of Crossbow Communications, author of several books and producer of documentaries about health and environmental issues around the world. Chandler is connecting the dots to the global surge in neurodegenerative disease, including Alzheimer’s disease, Parkinson’s disease, Creutzfeldt-Jakob disease, chronic wasting disease and other forms of prion disease. The scientific name for prion disease is transmissible spongiform encephalopathy. The operative word is “transmissible.” Even the global surge in autism appears to be related.