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Negative Antiamyloid Drug Trial: Lessons Learned

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A new study shows that the investigational anti-amyloid monoclonal antibody crenezumab (Genentech) is not superior to placebo in altering cognition, brain imaging, or biomarkers in individuals at genetically high risk for Alzheimer’s disease (AD).

Eric Reiman, MD

These results from the Alzheimer’s Prevention Initiative (API) Columbia Study of Autosomal Dominant Alzheimer’s Disease (ADAD), which included more than 250 participants, are “disappointing, actually heartbreaking; and we immediately think of families,” Eric Reiman, MD, Executive Director. , Banner from the Alzheimer’s Institute, Phoenix, Arizona, and one of the leaders of the trial, told Medscape Medical News.

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However, while group differences were not significant, mean annual changes in clinical and biomarker scores consistently favored active treatment over placebo, and as Reiman noted, important steps remain to be taken.

Also, while the results were negative, the study provides a template for future preventive trials, he said.

The main results of the study were published earlier this year. However, the researchers presented additional findings and perspectives at the International Conference of the Alzheimer’s Association in 2022.

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Neutralizing oligomers

Crenezumab was designed to neutralize neurotoxic oligomers, a form of beta-amyloid, and to minimize the inflammatory response of brain cells. So it should reduce amyloid-associated imaging abnormalities (ARIA), a common side effect with other antibodies, Reiman said.

The API ADAD study included 252 adults in Colombia between the ages of 30 and 60. About two-thirds of the participants were carriers of the PSEN1 E280A mutation, which virtually guarantees that carriers will develop mild cognitive impairment at an average age of 44, dementia at about 49, and death at about 59. At the time of registration, all participants had no cognitive impairment.

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The researchers note that Colombia has the largest population in the world with this early onset of autosomal dominant AD.

The analysis included 85 carriers receiving crenezumab and 84 carriers receiving placebo. The study also included 83 non-carriers who received a placebo “to avoid the need for people to know their genetic risk,” Reiman said.

Participants donated blood samples every year. For biomarker analysis of amyloid and tau, samples of cerebrospinal fluid (CSF) were obtained, PET and MRI were performed regularly.

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Reiman noted that about 94% of the participants completed the 5 to 8 year trial, which is “remarkable” especially because the study was conducted primarily in rural areas, amid the COVID-19 pandemic and civil unrest.

One of the associated endpoints was the rate of change in cognition as measured by the ADAD API Composite Cognitive Scale. The difference between drug and placebo groups in annual rate of change was 0.33 (95% CI, -0.48 to 1.13; P = 0.43).

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The other co-primary endpoint was episodic memory function as measured by the Free and Cued Selective Reminding Test (FCSRT) label index. The difference in the annual rate of change for this outcome was 0.008 (95% CI, -0.003 to 0.019; P = 0.16).

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As with comorbid outcomes, mean annual biomarker changes consistently outnumbered treatment versus placebo, but none of the differences were statistically significant.

The researchers note that the drug was safe and well tolerated. They add that no new crenezumab safety issues or ABCA symptoms have been identified.

At the end of the study, all carriers were switched to active treatment, while non-carriers continued to receive placebo.

Additional information

The results of the analysis of CSF amyloid oligomers to determine the interaction with targets, as well as pharmacokinetic / pharmacodynamic analyzes to measure the effect of the drug are still under development.

In addition, plasma biomarker results are yet to be obtained. Reiman said he is “most interested” in these results because they include measurements of phosphorylated tau (p-tau), which could shed important light on drug dosing effects.

By having p-tau in the samples provided by each person each year, “we can see how much he has moved at a lower dose compared to how much he has moved at a higher dose. We will see if the highest dose was really the difference maker,” Reiman said.

Although the dose of the drug was increased by more than seven times during the study, “unfortunately, participants took only the highest dose for an average of about 2 years,” he noted. “If the drug is going to work, we now think he probably needs the highest dose,” which is up to 60mg/kg intravenously per month.

Despite the negative test results, Reiman is not ready to abandon the amyloid hypothesis. “This study neither confirms nor refutes this hypothesis,” he said, adding that crenezumab does not reduce amyloid plaques, but targets soluble oligomers.

He noted that the results of the main trials of three other drugs that act on amyloids are expected in the near future. These agents include: lecanumab (Eisai), gantenerumab (Hoffmann-La Roche), and denanumab (Eli Lilly).

The “legacy” of the Colombian trial is that it lays the groundwork for the development of future prevention trials that will be “much more powerful,” Reiman said. For example, he presented a precedent-based agreement on data sharing that has been adapted by leaders in the field, he added.

“Not our best goal”

Commenting on the study for Medscape Medical News, Gregory S. Day, MD, assistant professor and senior associate consultant at the Mayo Clinic, Jacksonville, Florida, who has a special interest in dementia, said the results show that crenezumab “probably won’t be our the best target” for the prevention of Alzheimer’s disease.

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“They showed no clear reduction in the amount of amyloid plaques in the brain, at least as measured by amyloid PET. This suggests that this strategy is probably not the most effective,” said Day, who was not involved in the study.

However, this review contains “all the caveats presented by the team,” including that the study was underpowered for some results and that not enough people may have taken the maximum dose of the drug for long enough, he noted.

Day called the retention rate “incredible” and praised the study’s methodology. He also noted that the study had “excellent safety data.”

Also in a commentary for Medscape Medical News, Heather Snyder, Ph.D., vice president of medical and scientific relations at the Alzheimer’s Association, noted that crenezumab is a first-generation monoclonal antibody that targets amyloid, and that “this is really the first such trial in our stories”. space.”

In addition, the biomarker information that the study uncovered “answers some really important questions about the impact of this drug on biology,” she said.

Snyder noted that the “broader landscape” will include the results of other studies on amyloid-targeting monoclonal antibodies that are “based on new technologies or a better understanding of some biological processes.”

“Some of these trials have reported that when they lower beta-amyloid, they also lower tau or change the type of tau and also change some other markers,” she said.

The Colombia ADAD API Trial is a partnership between BAI, the Neuroscience Group of Antioquia at Antioquia University, Genentech and Roche, and the National Institute on Aging (NIA). It was funded by grants from NIA, Genentech, and Roche, as well as charitable donations to the Alzheimer’s Banner Foundation. Reiman is the Principal Investigator for several NIH, Foundation, and Arizona grants; inventor of a 2005 patent to accelerate the evaluation of Alzheimer’s prevention methods using biomarker endpoints; paid scientific consultant for Alzheon, Aural Analytics, Denali, Retromer Therapeutics and Vaxxinity; and co-founder and advisor to ALZPath. Day and Snyder did not disclose their respective financial relationships.

Alzheimer’s Association International Conference 2022 Submitted August 2, 2022

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