More Evidence Lowering Amyloid Is Clinically Beneficial in Early Alzheimer’s

 Is your competent? doctor ready with EXACT DEMANTIA PREVENTION PROTOCOLS?  

With your extra risk of dementia post stroke; DOES YOUR DOCTOR HAVE EXACT DEMENTIA PREVENTION PROTOCOLS? NO? So, your doctor is incompetent? 

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.`    

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

Alzheimer's Blood Test Cleared for Primary Care Use

Has your competent? doctor explained problems encountered with donanemab? No knowledge is grounds for firing!

donanemab (5 posts to January 2021)

The latest here:

More Evidence Lowering Amyloid Is Clinically Beneficial in Early Alzheimer’s

Reduced amyloid burden after treatment with the antiamyloid donanemab (Kisunla, Eli Lilly) correlated strongly with slower cognitive and functional decline in adults with early symptomatic Alzheimer’s disease (AD) in a secondary analysis of the phase 3 TRAILBLAZER-ALZ 2 trial.

The TRAILBLAZER-ALZ 2 study showed that donanemab effectively removed beta-amyloid plaques from the brain and demonstrated statistically significant slowing of cognitive and functional decline compared with placebo.

“This secondary analysis assessed the correlation between these two endpoints and showed that lower brain amyloid levels after treatment were directly associated with greater slowing of cognitive and functional decline,” Ming Lu, MD, associate vice president, Statistics, Eli Lilly and Company, and author on the secondary analysis, told Medscape Medical News. 

“These results support the growing body of knowledge that targeting beta-amyloid in the brain is a valid therapeutic approach and that patients may benefit from reducing beta-amyloid burden,” Lu said. 

The study was published online on October 13 in JAMA Neurology.

Lower Amyloid, Slower Decline

Results from the TRAILBLAZER-ALZ 2 trial showed treatment with donanemab significantly reduced amyloid plaque by 87 centiloids (CL) over 76 weeks and slowed clinical progression by 22% and 29% compared with placebo, as assessed by integrated AD Rating Scale (iADRS) and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) scores, respectively.

These results led to approval of donanemab for early symptomatic AD in July 2024.

Yet, the relationship between amyloid removal and clinical benefit has remained uncertain, with mixed results across studies of similar drugs such as aducanumab and lecanemab.

To investigate, Lu and colleagues analyzed 1582 participants (mean age, 73 years) from TRAILBLAZER-ALZ 2 with confirmed amyloid and tau pathology; 766 were treated with donanemab (every 4 weeks for up to 72 weeks, with outcomes assessed through 76 weeks), and 816 were given placebo.

They categorized participants into one of 10 groups (deciles) based on their lowest amyloid value observed after treatment. Cognitive decline was assessed using iADRS and CDR-SB scores over 76 weeks, and measured plasma biomarkers included phosphorylated tau (p-tau217 and p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL).

Correlations between median amyloid levels and biomarker or clinical changes were calculated using mixed models for repeated measures.

At baseline, mean amyloid values were 143.4 CL in the highest decile and 87.5 CL in the lowest decile compared with the overall trial mean of 102.9 CL. 

Across the trial population, lower posttreatment amyloid levels were correlated with slower clinical progression as measured by iADRS score (coefficient of determination [R²], 0.73) and CDR-SB score (R², 0.87) and with decreased p-tau217 (R², 0.86), p-tau181 (R², 0.88), and GFAP (R², 0.87) scores but not NfL scores (R², 0.03).

Notably, nearly all (99.6%) participants in the lowest three deciles of amyloid posttreatment received donanemab, and all (100%) donanemab-treated participants in the lowest three deciles achieved amyloid clearance (< 24.1 CL) by 76 weeks.

Participants in the lowest deciles of amyloid had the least cognitive decline, whereas those with higher posttreatment amyloid (mostly on placebo) worsened more rapidly. Patients who achieved amyloid clearance experienced the slowest disease progression.

‘Major’ Clinical Implications

“This is the first published analysis within one antiamyloid agent, as opposed to comparisons across drugs, that clearly shows that full clearance with treatment increases the likelihood of a clinical benefit,” study investigator David Knopman, MD, professor of neurology at the Mayo Clinic in Rochester, Minnesota, told Medscape Medical News. 

“This has major implications for understanding how the drugs work but also practically speaks to the value, or lack thereof, in continuing treatment beyond 18 months in a patient who failed to fully clear amyloid by 18 months,” Knopman said.

Commenting on the findings Rebecca M. Edelmayer, PhD, vice president of scientific engagement at the Alzheimer’s Association, said researchers have long known beta-amyloid buildup is key to Alzheimer’s progression. “This article reinforces that it also is an important, viable, and useful treatment target in people with early symptomatic Alzheimer’s,” she told Medscape Medical News, adding that major plaque reductions correlate with the best outcomes.

Edelmayer added that the analysis also “further reinforces the need for and benefits of early and accurate diagnosis and early intervention in order to get the greatest possible treatment effect.”

“In the real world, most people with dementia — regardless of diagnosis — have brain changes characteristic of more than one disease/dementia, including Alzheimer’s disease, vascular dementia, dementia with Lewy bodies, and others. This is known as mixed dementia. This reality reinforces the need to develop treatment strategies that address Alzheimer’s and other dementias in multiple ways, from multiple angles,” Edelmayer noted.

She added that the Alzheimer’s Association is committed to advancing all potential treatment avenues and exploring methods for combining diverse approaches into combination therapies. 

“For example, the Alzheimer’s Association’s Part the Cloud initiative has raised nearly $90 million and funded 72 clinical trials across the globe focusing on a wide range of new and innovative treatment targets,” Edelmayer added.

Funding for this research was provided by Eli Lilly and Company. Lu and eight co-authors declared having relationships with the company. Knopman and Edelmayer reported having no disclosures.

More Evidence Lowering Amyloid Is Clinically Beneficial in Early Alzheimer’s

 Has your competent? doctor explained problems encountered with donanemab? No knowledge is grounds for firing!

donanemab (5 posts to January 2021)

More Evidence Lowering Amyloid Is Clinically Beneficial in Early Alzheimer’s

Reduced amyloid burden after treatment with the antiamyloid donanemab (Kisunla, Eli Lilly) correlated strongly with slower cognitive and functional decline in adults with early symptomatic Alzheimer’s disease (AD) in a secondary analysis of the phase 3 TRAILBLAZER-ALZ 2 trial.

The TRAILBLAZER-ALZ 2 study showed that donanemab effectively removed beta-amyloid plaques from the brain and demonstrated statistically significant slowing of cognitive and functional decline compared with placebo.

“This secondary analysis assessed the correlation between these two endpoints and showed that lower brain amyloid levels after treatment were directly associated with greater slowing of cognitive and functional decline,” Ming Lu, MD, associate vice president, Statistics, Eli Lilly and Company, and author on the secondary analysis, told Medscape Medical News. 

“These results support the growing body of knowledge that targeting beta-amyloid in the brain is a valid therapeutic approach and that patients may benefit from reducing beta-amyloid burden,” Lu said. 

The study was published online on October 13 in JAMA Neurology.

Lower Amyloid, Slower Decline

Results from the TRAILBLAZER-ALZ 2 trial showed treatment with donanemab significantly reduced amyloid plaque by 87 centiloids (CL) over 76 weeks and slowed clinical progression by 22% and 29% compared with placebo, as assessed by integrated AD Rating Scale (iADRS) and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) scores, respectively.

These results led to approval of donanemab for early symptomatic AD in July 2024.

Yet, the relationship between amyloid removal and clinical benefit has remained uncertain, with mixed results across studies of similar drugs such as aducanumab and lecanemab.

To investigate, Lu and colleagues analyzed 1582 participants (mean age, 73 years) from TRAILBLAZER-ALZ 2 with confirmed amyloid and tau pathology; 766 were treated with donanemab (every 4 weeks for up to 72 weeks, with outcomes assessed through 76 weeks), and 816 were given placebo.

They categorized participants into one of 10 groups (deciles) based on their lowest amyloid value observed after treatment. Cognitive decline was assessed using iADRS and CDR-SB scores over 76 weeks, and measured plasma biomarkers included phosphorylated tau (p-tau217 and p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL).

Correlations between median amyloid levels and biomarker or clinical changes were calculated using mixed models for repeated measures.

At baseline, mean amyloid values were 143.4 CL in the highest decile and 87.5 CL in the lowest decile compared with the overall trial mean of 102.9 CL. 

Across the trial population, lower posttreatment amyloid levels were correlated with slower clinical progression as measured by iADRS score (coefficient of determination [R²], 0.73) and CDR-SB score (R², 0.87) and with decreased p-tau217 (R², 0.86), p-tau181 (R², 0.88), and GFAP (R², 0.87) scores but not NfL scores (R², 0.03).

Notably, nearly all (99.6%) participants in the lowest three deciles of amyloid posttreatment received donanemab, and all (100%) donanemab-treated participants in the lowest three deciles achieved amyloid clearance (< 24.1 CL) by 76 weeks.

Participants in the lowest deciles of amyloid had the least cognitive decline, whereas those with higher posttreatment amyloid (mostly on placebo) worsened more rapidly. Patients who achieved amyloid clearance experienced the slowest disease progression.

‘Major’ Clinical Implications

“This is the first published analysis within one antiamyloid agent, as opposed to comparisons across drugs, that clearly shows that full clearance with treatment increases the likelihood of a clinical benefit,” study investigator David Knopman, MD, professor of neurology at the Mayo Clinic in Rochester, Minnesota, told Medscape Medical News. 

Alzheimer’s Drug Faces Scrutiny Over Safety, Efficacy Concerns

FYI, Ask your competent? doctor for EXACT PROTOCOLS that will prevent your likely dementia. 

With your elevated chances of dementia post stroke,  your competent? doctor is responsible for preventing that! Have they taken on that responsibility? Or are they DOING NOTHING?

With your chances of getting dementia post stroke you need solutions. YOUR DOCTOR IS RESPONSIBLE FOR PREVENTING THIS!

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.`    

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

The latest here:

Alzheimer’s Drug Faces Scrutiny Over Safety, Efficacy Concerns

Summary: The FDA-approved Alzheimer’s drug donanemab is under scrutiny due to concerns about its effectiveness and safety, according to an investigation. The study highlights multiple patient deaths during trials, design flaws, and the financial ties of panelists who recommended the drug’s approval.

Critics question the data used to evaluate donanemab, pointing to a misleading portrayal of the drug’s impact on Alzheimer’s progression. Additionally, the report calls attention to undisclosed financial conflicts among the FDA-appointed advisers.

Key Facts:

• Donanemab has been linked to patient deaths and adverse side effects during trials.
• Financial conflicts were found among FDA advisers who reviewed the drug.
• Claims of effectiveness may have been exaggerated by using relative differences.

Source: BMJ

The safety and effectiveness of donanemab – an Alzheimer’s drug recently approved by the US Food & Drug Administration (FDA) – is called into question in an investigation published by The BMJ today.

Journalists Jeanne Lenzer and Shannon Brownlee explore concerns not only about its effectiveness and the number of deaths among patients taking the drug, but also about financial ties to drug makers among the “independent” advisory panellists who recommended approval.

Donanemab, developed by Eli Lilly, is the latest in a new class of anti-amyloid drugs that deliver antibodies to target beta amyloid, a protein believed to cause Alzheimer’s disease.

The investigation also reveals that seven of the eight doctors appointed by the FDA to review donanemab received direct payments from drug companies. Credit: Neuroscience News

In January 2023, the FDA denied approval of donanemab, citing a “high rate” of missing data and questioning the drug’s long term safety. The agency noted a higher rate of treatment discontinuation due to adverse events (frequently brain hemorrhage and swelling) among patients on donanemab compared with placebo, and an “imbalance” in overall deaths.

Lilly acknowledged three deaths in patients on donanemab, and an outside company it hired to obtain the missing data found two additional deaths among patients in the donanemab arm and five deaths in the placebo arm. 

But Steven Goodman, an expert in clinical trial design at Stanford University, says it is not possible to assess the reliability of the new data without more details of the outside company’s methods.

“There was also no information on health outcomes in those patients other than death, nor the causes of the deaths,” he says, adding that the “failure to formally follow patients who stopped treatment was a significant design flaw, particularly when that discontinuation was partly due to adverse drug effects.”

The investigation also reveals that seven of the eight doctors appointed by the FDA to review donanemab received direct payments from drug companies. 

Three had financial ties to Lilly, two had ties to Roche, Lilly’s development partner in creating a new blood test for Alzheimer’s disease, and two others have patents on amyloid antibodies, and the eighth doctor had research funding from Janssen for another Alzheimer’s drug. 

Using the public database OpenPayments, members’ CVs, disclosures in published articles, and the Google patent ownership database, The BMJ found that individual advisers received up to $62 000 (£47 000; €56 000) for consulting and speaking fees and up to $10.5m in research grants from 2017 through 2023.

Asked about the extensive financial conflicts among the physician advisors found by The BMJ, the agency stated, “The FDA does not comment on matters related to individual members of an advisory committee.”

Lenzer and Brownlee also describe how the main (primary) outcome of the donanemab trials was changed during the trial from the widely accepted “clinical dementia rating scale—sum of boxes” (CDR-SB) to Lilly’s own integrated Alzheimer’s disease rating scale (iADRS).

And despite results failing to show a clinically meaningful difference between patients on the drug and placebo, Lilly stated that donanemab slowed progression of Alzheimer’s by 22%. The company has also promoted donanemab as “slowing decline by 35%.”

“That is a misleading statement,” says Alberto J Espay, a neurologist and specialist in clinical epidemiology and healthcare research at the University of Cincinnati. “That’s a relative difference that transforms a very tiny absolute difference into a number that seems impressive.”

About this Alzheimer’s disease and Donanemab research news

Author: BMJ Group Media Relations
Source: BMJ
Contact: BMJ Group Media Relations – BMJ
Image: The image is credited to Neuroscience News

Original Research: The findings will appear in BMJ

Unanimous Thumbs-Up From FDA Advisors for Alzheimer's Drug

 

Do you have any proof your doctors follow and implement research? Because you will likely need this, better start shopping for doctors now before you need this. If we had any brains at all in stroke, trials would be done on stroke survivors to see if using this prevents getting dementia,

Your chances of getting dementia.

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.`    

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

The latest here:

Unanimous Thumbs-Up From FDA Advisors for Alzheimer's Drug

Advisory committee decision smooths the way for eventual FDA approval

by Judy George, Deputy Managing Editor, MedPage Today June 10, 2024

An FDA advisory committee on Monday unanimously supported the investigational drug donanemab for treating early Alzheimer's disease.

In an 11-0 vote, the Peripheral and Central Nervous System Drugs Advisory Committee said the benefits of donanemab outweighed its risks for the population of Alzheimer's disease patients with mild cognitive impairment and mild dementia enrolled in the donanemab clinical trials.

The committee also voted 11-0 that available data showed that donanemab was effective in treating Alzheimer's disease in that population. Though FDA staffers raised concerns last week that Alzheimer's patients with no or very low tau were excluded from the pivotal donanemab trial, the committee agreed overall that the drug should not be restricted to Alzheimer's patients with a specific tau burden.

"The evidence over the population studies in the trial is very strong and consistent across subgroups," said committee member and NIH biostatistician Dean Follmann, PhD.

"The biomarker data also were convincing of the effect," added committee member Kathleen Poston, MD, MS, of Stanford University in California. "The benefits outweigh the risks, as long as the risks are being monitored."

But, throughout the meeting, Poston and others voiced concerns about the lack of data on donanemab and other anti-amyloid drugs in African-American and Hispanic populations. "That will be important in the future to obtain to make sure that these encouraging findings can be extrapolated to everyone with Alzheimer's disease," she said.

While the risks, especially for amyloid-related imaging abnormalities (ARIA), were clear in the trial data, many of them could be mitigated, FDA advisors suggested. Safeguards to manage ARIA could be put in place and risks could be "safely clarified with a proposed MRI program and training," noted committee member Cynthia Carlsson, MD, MS, of the University of Wisconsin School of Medicine and Public Health in Madison.

Neurologist Marwan Sabbagh, MD, of the Barrow Neurological Institute in Phoenix, who wasn't involved with the donanemab trials, summed up the views of most Alzheimer's patients who spoke at the public hearing discussion during the meeting. Patients with Alzheimer's "have a 100% chance of getting worse and losing autonomy -- juxtaposed against a 6% chance of symptomatic ARIA," Sabbagh said.

Donanemab was tested in the phase III TRAILBLAZER-ALZ 2 trial of 1,736 early Alzheimer's patients. The drug met the trial's primary endpoint of change from baseline in the Integrated Alzheimer's Disease Rating Scale (iADRS), slowing decline relative to placebo (P<0.001). The drug also met a key secondary endpoint, showing less decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 76 weeks (P<0.001).

Like other anti-amyloid drugs, donanemab's safety issues centered around ARIA with edema or effusion (ARIA-E) and ARIA with microhemorrhages and hemosiderin deposits (ARIA-H). ARIA occurs more frequently in APOE4 homozygotes than in heterozygotes or noncarriers.

In TRAILBLAZER-ALZ 2, 24% of donanemab-treated participants had ARIA-E and 31.4% had ARIA-H. Two ARIA-related deaths were attributed to donanemab.

If approved, donanemab will be the third amyloid-targeted drug to come to market: the first being the controversial aducanumab (Aduhelm), which received accelerated approval but was subsequently abandoned, and the second being lecanemab (Leqembi), which received full FDA approval last year.

The FDA has not named a date for its final decision about donanemab. While the agency isn't required to follow its advisory committees' recommendations, it typically does.

• Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow

Donanemab slows disease progression, reduces amyloid in early symptomatic Alzheimer’s

Do you have any proof your doctors follow and implement research? Because you will likely need this, better start shopping for doctors now before you need this. If we had any brains at all in stroke, trials would be done on stroke survivors to see if using this prevents getting dementia,

Your chances of getting dementia.

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.`    

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

The latest here:

Donanemab slows disease progression, reduces amyloid in early symptomatic Alzheimer’s

Key takeaways:

• The randomized, double-blind study included 1,219 individuals with early symptomatic Alzheimer’s disease.
• Donanemab performed superior to placebo for both carriers and noncarriers of the APOE ε4 allele.

Compared with placebo, donanemab slowed disease progression and reduced amyloid presence at 76 weeks for carriers and noncarriers of the APOE ε4 allele in early symptomatic Alzheimer’s disease, according to data presented at CTAD.

“The APOE 4 allele increases the risk of developing Alzheimer’s disease, and is associated with amyloid accumulation, cerebral amyloid angiopathy risk and an earlier age of disease onset,” Cynthia D. Evans, PhD, a neuroscientist at Eli Lilly & Co., said in her presentation.

Results of a randomized, double-blind, placebo-controlled clinical trial found donanemab effective in slowing disease progression, reducing amyloid presence in early symptomatic Alzheimer’s. Image: Adobe Stock

Evans and colleagues sought to examine safety and efficacy of donanemab (Eli Lilly & Co.) by APOE ε4 carrier status for those with early symptomatic AD in the TRAILBLAZER-ALZ 2 clinical trial.

Their randomized, double-blind, placebo-controlled study included 1,729 individuals, 1,219 of whom were APOE ε4 carriers (mean age 72.6 years; 57.2% female) and 510 who were not (mean age 73.9 years; 58.0% female), with separate subsets of low-medium tau and high tau populations. Participants engaged in a screening period of up to 7 weeks, which included an MRI as well as amyloid and tau positron emission tomography scans. This was followed by a double-blind treatment period of 76 weeks during which IV donanemab was administered initially at three doses of 700 mg every 4 weeks for the first 12 weeks, then at 1400 mg every 4 weeks through week 76, or placebo administered every 4 weeks through week 76. Participants could enter a long-term extension of the study preceding a follow-up interval of up to 44 weeks.

Results showed that treatment with donanemab slowed clinical decline in both allele carriers and noncarriers at similar rates (36% vs. 35%) over 76 weeks, while clinical decline was faster for carriers and noncarriers given placebo.

In addition, efficacy rates for both allele carriers and noncarriers were similar in low-medium tau populations, but higher across all scales compared with the overall study population.

Data further showed that amyloid reduction for both carriers and noncarriers was significant at week 76 in the donanemab-treated population compared with placebo.

“Mean amyloid clearance was robust among all donanemab-treated participant groups,” Evans said. “Noncarriers decline faster than carriers on clinical scales in amyloid selected early symptomatic [Alzheimer’s disease] populations.”

Sources/Disclosures

Collapse

Source:

Evans CD, et al. Efficacy of donanemab by APOE ε4 carrier status in TRAILBLAZER ALZ 2, a phase 3 randomized clinical trial in early symptomatic Alzheimer’s disease. Presented at: CTAD; Oct. 24-27, 2023; Boston.

Disclosures: Evans is employed by Eli Lilly & Co., which sponsored the study and has a pending patent application on the blood test used in the research.

Donanemab in Early Symptomatic Alzheimer DiseaseThe TRAILBLAZER-ALZ 2 Randomized Clinical Trial

With your risk of dementia post stroke, what is your doctor's protocol to

objectively determine if  you have it? NOTHING LIKE USUAL?  Then you don't have a functioning stroke doctor.

RUN AWAY!

Your risk of dementia, has your doctor told you of this?  Your doctor is responsible for preventing this!

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.`    

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

The latest here:

 

Donanemab in Early Symptomatic Alzheimer DiseaseThe TRAILBLAZER-ALZ 2 Randomized Clinical Trial

John R. Sims, MD¹; Jennifer A. Zimmer, MD¹; Cynthia D. Evans, PhD¹; et al Ming Lu, MD, MS, MPH¹; Paul Ardayfio, PhD¹; JonDavid Sparks, PhD¹; Alette M. Wessels, PhD¹; Sergey Shcherbinin, PhD¹; Hong Wang, PhD¹; Emel Serap Monkul Nery, MD¹; Emily C. Collins, PhD¹; Paul Solomon, PhD²; Stephen Salloway, MD^3,4; Liana G. Apostolova, MD⁵; Oskar Hansson, MD, PhD⁶; Craig Ritchie, MD, PhD⁷; Dawn A. Brooks, PhD¹; Mark Mintun, MD¹; Daniel M. Skovronsky, MD, PhD¹; for the TRAILBLAZER-ALZ 2 Investigators

Author Affiliations Article Information

JAMA. Published online July 17, 2023. doi:10.1001/jama.2023.13239

visual abstract icon

Visual

Abstract

editorial comment icon

Editorial

Comment

• Editorial
  Donanemab for Alzheimer Disease—Who Benefits and Who Is Harmed?
  Jennifer J. Manly, PhD; Kacie D. Deters, PhD
• Editorial
  Amyloid-Targeting Monoclonal Antibodies for Alzheimer Disease
  Gil D. Rabinovici, MD; Renaud La Joie, PhD
• Editorial
  Novel Alzheimer Disease Treatments and Reconsideration of US Pharmaceutical Reimbursement Policy
  Meredith B. Rosenthal, PhD
• Editorial
  Ushering in a New Era of Alzheimer Disease Therapy
  Eric W. Widera, MD; Sharon A. Brangman, MD; Nathaniel A. Chin, MD

Key Points

Question  Does donanemab, a monoclonal antibody designed to clear brain amyloid plaque, provide clinical benefit in early symptomatic Alzheimer disease?

Findings  In this randomized clinical trial that included 1736 participants with early symptomatic Alzheimer disease and amyloid and tau pathology, the least-squares mean change in the integrated Alzheimer Disease Rating Scale score (range, 0-144; lower score indicates greater impairment) at 76 weeks was −6.02 in the donanemab group and −9.27 in the placebo group for the low/medium tau population and −10.19 in the donanemab group and −13.11 in the placebo group in the combined study population, both of which were significant differences.

Meaning  Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab treatment significantly slowed clinical progression at 76 weeks.

Abstract

Importance  There are limited efficacious treatments for Alzheimer disease.

Objective  To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque.

Design, Setting, and Participants  Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023).

Interventions  Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met.

Main Outcomes and Measures  The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes.

Results  Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was −6.02 (95% CI, −7.01 to −5.03) in the donanemab group and −9.27 (95% CI, −10.23 to −8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and −10.2 (95% CI, −11.22 to −9.16) with donanemab and −13.1 (95% CI, −14.10 to −12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, −0.67 [95% CI, −0.95 to −0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, −0.7 [95% CI, −0.95 to −0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related.

Conclusions and Relevance  Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population.

Trial Registration  ClinicalTrials.gov Identifier: NCT04437511

Scientists hail new drug that could treat Alzheimer's by slowing cognitive decline by one third

Do you have any proof your doctors follow and implement research? Because you will likely need this, better start shopping for doctors now before you need this. If we had any brains at all in stroke, trials would be done on stroke survivors to see if using this prevents getting dementia,

Your chances of getting dementia.

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.`    

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

The latest here:

Scientists hail new drug that could treat Alzheimer's by slowing cognitive decline by one third

Izzy Lyons

Tue, January 12, 2021, 4:40 PM EST

Alzheimer Disease, Mri - Universal Images Group Editorial

A new drug that could be used to treat Alzheimer's slows cognitive decline by one third, the initial stages of a clinical trial have found, as scientists hail the “potential therapy” for the disease.

The drug an investigational antibody therapy, is administered via an IV infusion and targets a protein found in the brains of those with Alzheimer's disease.

A trial involving 272 patients with early symptomatic Alzheimer’s found that donanemab contributed to a “significant slowing” of their cognitive decline compared to those who received placebo, renewing hope that researchers are closing in on therapies to fight the disease.

The two-year study, which has now concluded its second phase before entering a third and final phase, found patients’ decline was slowed by as much as 32 per cent over 18 months – a reduction researchers described as “statistically significant”.

Patients’ decline was measured with memory tests alongside assessments of how well they performed everyday activities like dressing themselves and preparing meals. 

Pharmaceutical giant Eli Lilly, which is leading the study, saw its share price soar by 14 per cent in light of the new discovery. 

Dr Daniel Skovronsky, the company’s chief scientific officer, praised the “positive results” of the trial which has provided “confidence” that donanemab could be a potential treatment for Alzheimer’s. 

The researchers have said that they are pursuing talks with global regulators about the next steps in rolling out the drug, should the final phases also prove successful. 

The full results of the study, named Trailblazer-Alz, will be presented at a future medical congress and submitted for publication in a peer-reviewed clinical journal.

“We are extremely pleased about these positive findings for donanemab as a potential therapy for people living with Alzheimer’s disease, the only leading cause of death without a treatment that slows disease progression,” said Mark Mintun, the vice president of pain and neurodegeneration at 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,” he added.

The trial also found that donanemab helped clear amaloid plaques, a hallmark of Alzheimer’s disease, in the brain.

Six to 12 months following the treatment, the amaloid plaques were gone and did not return, said Dr. Daniel Skovronsky.

More than 850,000 people suffer with dementia in the UK, which represents one in every 14 of the population aged 65 years and over. 

At the rate of current prevalence, the charity Alzheimer’s society predicts that there will be more than 1.5 million people with dementia in the UK by 2040. 

The news of Eli Lilly’s potential breakthrough in finding an Alzheimer’s treatment follows the 2019 “turning point” by pharmaceutical company Biogen and trials of the drug aducanumab. 

Despite initially failing trials, aducanumab proved to reduce symptoms in patients and their cognitive decline by 25 per cent after 18 months.

Biogen said that these patients who took aducanumab had better cognition, memory and language and were able to live independently for longer, including performing household chores and travelling on their own.

Michel Vounatsos, Biogen’s chief executive, said that it hoped to offer patients “the first therapy to reduce the clinical decline of Alzheimer’s disease”.