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2021-03-14| R&DTrials & Approvals

Lilly’s Positive Data for Alzheimer’s Drug Bodes Well for Candidates Rooted in Amyloid Hypothesis

by Rajaneesh K. Gopinath
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Alzheimer’s disease (AD) is an age-related neurodegenerative disorder that accounts for 60%-80% of all dementia cases. The disease is characterized by two major neuropathological hallmarks — amyloid plaques composed of amyloid beta (Aβ) proteins and Tau protein-containing neurofibrillary tangles. AD patients experience a slow cognitive decline, wherein the progressive loss of brain cells affects memory, reasoning, and thinking abilities eventually requiring full-time care.

Aβ is produced through the proteolytic cleavage of a larger amyloid precursor protein (APP) by β- and γ-secretase enzymes and are cleared from the brain in healthy individuals. However, in AD patients’ brains, the misfolded amyloid-beta protein intermediates aggregate into insoluble clumps to form extracellular amyloid plaques in between nerve cells. This observation in addition to the discovery of dominantly inherited mutations in genes that encode for APP and γ-secretase enzymes in familial forms of the disease gave rise to the amyloid beta hypothesis. The hypothesis purports that the accumulation of Aβ proteins is the primary cause of AD and is a potential therapeutic target.

 

The Downward Curve

However, after dominating the Alzheimer’s disease field for over the past 25 years, the frenzy surrounding the amyloid-beta hypothesis has started to wane. Several drugs that aimed to clear the plaques and improve cognitive decline in patients have failed at different stages of their respective clinical trials, causing skepticism in even some of the staunchest proponents and look for alternative targets like Tau.

The latest high-profile candidate in that list is aducanumab, an Aβ targeting monoclonal antibody developed by Neurimmune and licensed by Biogen. In 2019, following a futility analysis, Biogen decided to discontinue the trials, only to make a U-turn after a few months, when new analyses demonstrated that aducanumab did slow the cognitive and functional decline in patients with mild AD. Yet, that excitement was short-lived as the FDA’s advisory committee rejected the application claiming that the EMERGE trial does not provide strong evidence supporting aducanumab’s effectiveness for Alzheimer’s Disease treatment.

 

Donanemab – A Promising Entrant

While Biogen looks to bounce back with better evidence, the positive results attained by Eli Lilly’s investigational Alzheimer drug, donanemab, will offer more hope. At the JPMorgan Healthcare Conference in January, Lilly presented primary results saying donanemab demonstrated rapidly high levels of amyloid plaque clearance in patients. After obtaining the full data, Lilly has now announced that donanemab has met its primary endpoint and showed significant slowing of cognitive and functional decline. As measured by the integrated Alzheimer’s Disease Rating Scale (iADRS), at 76 weeks compared to baseline, donanemab slowed decline by 32 percent versus the placebo.

“We are confident in the results of the TRAILBLAZER-ALZ study,” said Daniel Skovronsky, M.D., Ph.D., Lilly’s Chief Scientific Officer and President of Lilly Research Laboratories. “This is the first late-stage study in Alzheimer’s disease to meet its primary endpoint at the primary analysis.”

The data was presented at the 15th International Conference on Alzheimer’s & Parkinson’s Diseases™ 2021 and simultaneously published in the New England Journal of Medicine journal.

 

Modest Returns in Secondary Outcomes

Lilly also claimed that data from the Phase 2 study showed that donanemab outperformed the placebo in achieving secondary endpoints. In all the four tests that measured a patient’s memory and function, donanemab consistently slowed the cognitive and functional decline, with ranges between 20-40 percent. However, those were achieved with only a “nominal statistical significance” at certain time points. This wouldn’t impress many as aducanumab managed to register significant benefits in those measures but still came short in the FDA review.

However, the encouraging takeaways from the trial were that donanemab achieved amyloid plaque clearance in 40% of participants in six months, which increased to 68% when measured at 18 months. Besides, it also curbed Tau accumulation across key brain regions in patients. The study, therefore, equates the slowing of cognitive decline to the actual clearance of both the disease hallmarks.

“Donanemab has the potential to become a very important treatment for Alzheimer’s disease. We were pleased to see not only slowing of cognitive and functional decline but also very substantial clearance of amyloid plaques and slowing of spread of Tau pathology. The constellation of clinical and biomarker results indicates the potential for long-term disease modification. We are grateful to the patients, caregivers, and investigators who participated in this landmark study”, Dr. Skovronsky added.

 

Affirmation from Alzheimer’s Community

These results would hugely support the amyloid beta hypothesis and once again provide a lifeline to those who subscribe to it. Lilly’s announcement was met with great enthusiasm by the Alzheimer’s Drug Discovery Foundation.

“The combination of changes in Alzheimer’s biomarkers and the slowing of clinical symptoms of the disease seen in this study is promising,” said Howard Fillit, M.D., Founding Executive Director and Chief Science Officer of the Alzheimer’s Drug Discovery Foundation (ADDF).

“We are encouraged by today’s news, and if these results are confirmed in the larger study now in progress, donanemab could offer the potential for a disease-modifying therapy that can help patients maintain cognitive abilities and their independence longer. We eagerly await results from future trials.”

If aducanumab manages to bag FDA approval, it will not only become the first to mark a milestone in AD treatment in nearly 20 years but will also open regulatory doors to donanemab and similar such candidates.

Related Article: Lilly’s Donanemab Aces Phase 2 Trial, Slows Clinical Decline in Alzheimer’s Patients

 

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