New drug cites a 22% reduction in cognitive decline in early stage Alzheimer’s.

The FDA hasn’t approved a new drug for Alzheimer’s disease in more than 17 years. It looks like that is about to change. Aducanumab isn’t a cure by any means, but it’s the first drug to get this far in an approval process that actually modifies the underlying pathology of Alzheimer’s, and helps delay cognitive decline in early stage Alzheimer’s.

How does Aducanumab work?

Amyloid-beta is a protein that is normally present in the brain. In the Alzheimer’s brain the abnormal levels of the protein clump together to form amyloid plaques. Researchers think that these clumps lead to brain cell death.

Aducanumab is a monoclonal antibody that targets amyloid-beta.

Researchers developed it using Neurimmune’s proprietary Reverse Translational Medicine Platform. Neurimmune scientists discovered Aducanumab with a team of researchers at the University of Zurich. The human antibody targets the aggregated amyloid-beta. Through this interaction, Aducanumab could reduce the number of amyloid plaques present in the brain. This ultimately may slow neurodegeneration and disease progression.

Aducanumab in clinical trials

In 2007, Neurimmune licensed the exclusive rights to Biogen, which sponsored several clinical trials investigating Aducanumab in humans. Together, Neurimmune’s and Biogen’s scientists published a study in Nature 2016 that described how one year of monthly intravenous infusions of Aducanumab reduces brain beta amyloid in a dose- and time-dependent manner in patients with pre-dementia or mild Alzheimer’s disease. 1https://www.nature.com/articles/nature19323

The history of the clinical trials of Aducanumab is confusing. If you want to read the details about the trials continue reading. If you want the bottom line , scroll down and read from *But Biogen reversed course and decided to continue the trials.

On March 21, 2019, the manufacturer (Biogen) announced it had ended two Phase 3 clinical trials of Aducanumab for Alzheimer’s. The drug had failed a “futility analysis,” which means a clinical trial is stopped when the interim results suggest that it is unlikely to achieve statistical significance.1

But then just five months later, Biogen announced that they were applying for FDA marketing approval. They explained that data gathered in the three months between the start of the futility analysis and the decision to end the trial hadn’t been used in the original analysis. After adding the additional three months of data, they realized that a subset of patients who had been given higher doses saw significant benefits on measures of cognition and function, including memory, orientation and language. Those patients also saw benefits in daily living activities.2

The OptumRx Pipeline Surveillance team observed that despite the positive reported outcomes, Aducanumab has only demonstrated a statistically significant improvement in one of the two pivotal trials. Further, in the one positive trial, the reported improvements were small, and the true clinical relevance of the findings remain uncertain.

Researchers have completed three Phase 1 trials. These were assessing Aducanumab in healthy volunteers (NCT02782975) and in Alzheimer’s disease patients in the U.S. (NCT01397539) and Japan (NCT02434718).

A fourth, randomized, double-blind, and placebo-controlled Phase 1 trial (NCT01677572), PRIME, enrolled 192 pre-dementia and mild Alzheimer’s patients at 32 sites in the U.S. The goal was to assess the safety and effect of different aducanumab doses versus a placebo on amyloid plaques. Researchers measured this with positron emission tomography imaging.

Interim results from the first 165 patients showed that all doses of Aducanumab (given as monthly infusions into the bloodstream) significantly reduced amyloid plaques in the brain in a time- and dose-dependent manner. During the first year, 40 patients from both groups discontinued treatment. Little to no change was apparent in the placebo group after one year. The greatest reduction was present at higher doses. Aducanumab also appeared to slow the rate of cognitive decline. Researchers measured this as a change in the clinical dementia rating sum of boxes (CDR-SB) and the mini-mental state examination (MMSE).

They presented results from a long-term extension of the PRIME trial at the 2017 Clinical Trials on Alzheimer’s Disease meeting. In total, 143 patients from the initial trial opted to continue in the long-term extension study, where all patients received Aducanumab. This included data from patients who had been on Aducanumab for up to three years. During this time, patients who received Aducanumab continued to experience a time- and dose-dependent reduction in amyloid plaque levels.

Biogen also began two large-scale randomized, double-blind, and placebo-controlled Phase 3 clinical trials in people with early-stage Alzheimer’s disease. The first trial, called ENGAGE (NCT02477800), aimed to enroll 1,350 patients at 187 sites in North America, Australia, Europe, and Asia. The second trial, called EMERGE (NCT02484547), also sought to enroll the same number of patients at 194 sites in North America, Europe, and Asia.

The goal of both trials was to assess the efficacy of Aducanumab, given once a month at low and high doses by infusion into the bloodstream. Researchers measured the effectiveness of the treatment by changes from the start of the study in the CDR-SB, MMSE, Alzheimer’s disease assessment scale-cognitive subscale 13 items (ADAS-Cog 13), and Alzheimer’s disease cooperative study-activities of daily living inventory mild cognitive impairment version (ADCS-ADL-MCI) scores over a 78-week period. They had expected to complete the trials in 2022.

The company halted the trials because an independent data monitoring committee found that they were unlikely to meet their primary objective. This was based on initial data from the trials and not on safety concerns. Follow-up visits and closing-out activities for both trials are now complete.

The Phase 2 EVOLVE trial (NCT03639987) began in late 2018 to evaluate the safety of continued dosing of Aducanumab in participants with mild cognitive impairment due to Alzheimer’s disease or with mild Alzheimer’s disease dementia. This trial also was halted in March 2019 as a result of the committee’s findings.

*But Biogen reversed course and decided to continue the trials.

later analysis based on additional follow-up data, showed that EMERGE met its primary goal. Patients receiving the highest dose of Aducanumab experienced a significant reduction in the progression of cognitive and functional impairments. Although ENGAGE failed to meet its primary goal, Biogen stated that data from the sub-group of patients who had sufficient exposure to the medication also showed significant benefits. These and other supportive findings formed the basis of the company’s BLA (Biologics License Application) submitted to the FDA requesting the approval of Aducanumab for the treatment of Alzheimer’s disease.

In August 2020, Aducanumab was granted priority review by the FDA, meaning that the agency plans to expedite the review process to determine whether they will approve the medication. 

Are there any negative side effects from taking Aducanumab?

Researchers said a majority of the test subjects taking Aducanumab showed no negative side effects. In some cases, however, patients experienced swelling in the brain called “amyloid-related imaging abnormalities” (ARIA) and headache.

How is the drug administered?

Intravenous doses of Aducanumab are given about 4 weeks apart over approximately 52 weeks for a total of 14 doses. Qualifying patients can continue into the long-term extension at a dose approximately 4 weeks apart for up to an additional 112 doses.

When will Aducanumab become available?
The FDA process for reviewing applications for approval, called New Drug Applications or NDAs, usually takes around 10 months. Biogen has said the Aducanumab application has about 4,500 files with more than 2.5 million pages of data and information. Biogen believes a decision will be made by June 7, 2021. Though the FDA would continue to monitor the effects of the drug, to ensure no unexpected side effects from prolonged usage, after approval the drug can be made available widely. People with Alzheimer’s disease may have a new medication to take soon.

How much will it cost?

Aducanumab is expensive, with the annual cost projected to be around $50,000 for the recommended dosage, based on one infusion per month. Even if the drug is approved by the FDA, the Centers for Medicaid and Medicare Services can determine for themselves how much Medicaid and Medicare will cover Aducanumab if the cost is high. PET brain scans to detect amyloid beta plaques would probably be necessary to determine aducanumab coverage, and those are expensive as well.

Where can I buy it?

I ordered Memantine for my husband from Europe before it was available in the U.S. India manufacturers provide many of the drugs sold in the U.S. I found this website for an Indian Pharmaceutical company which sells Aducanumab throughout the world. https://indianpharmanetwork.co.in/buy-aducanumab.php

The problem, of course, with buying Aducanumab from an Indian pharmacy is that you’d have to find a doctor who is willing to administer it intravenously. Since it is expected to be approved this summer, it’s probably more prudent to wait until you can get it prescribed by your doctor. But keep in mind that you might be able to save money by ordering it from India even after it is approved by the FDA.

Although Aducanumab isn’t a cure for Alzheimer’s, it is the first drug that is showing some promise for providing more time to individuals with this insidious disease.

References

  1. The Lancet. A resurrection of aducanumab for Alzheimer’s disease. Published December 4, 2019. Accessed January 7, 2020.
  2. Bio Space. Biogen Alzheimer’s Plans Met with Hope, Some Skepticism. Published: December 6, 2019. Accessed January 7, 2020.

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