Latest research explained
In Alzheimer’s disease, clumps of of proteins collect in brain regions associated with memory. These clumps make it difficult for neurons to communicate with each other. BAN2401 is an antibody against one of those proteins, called amyloid beta. Antibody therapies use a passive immune response to break down harmful substances, like amyloid beta. BAN4201 binds to soluble clumps (protofibrils) of amyloid beta and reduces levels of amyloid beta in the brain. This drug has at least a 1,000 fold higher selectivity for a special type of amyloid beta clumps (protofibrils) that are likely more toxic to neurons, compared to smaller pieces (monomers). Researchers were encouraged by the idea that this drug could target more toxic forms of amyloid beta and hopefully help prevent or reverse memory decline in humans.
In this clinical trial, BAN2401 reduced amyloid plaques visible on PET scans. Participants on the highest dose of BAN2401 showed a slowing of cognitive decline as measured by a neuropsychological test (Alzheimer’s Disease Composite Score [ADCOMS]). However, at the 12 month mark it did not quite meet the criteria that researchers had set for success. Using a specialized statistical analysis of the ADCOMS data, researchers concluded that BAN2401 did not provide enough of an improvement in neuropsychological test scores to say it provided a protective effect. It also did not meet futility criteria (criteria to show it had no effect), so the trial continued for 6 more months.
At 18 months, researchers analyzed the data at all previous timepoints. They found a statistically significant reduction in cognitive decline at six, twelve, and eighteen months for patients receiving the 10mg/kg dose of BAN2401. These patients also had a significant reduction of amyloid beta in their brains, as measured by amyloid PET scans.
However, there were concerns about randomization of the trial. As it went on, the trial used an algorithm to assign participants to dosages of the drug that were most likely to be effective. Certain trials choose to use this type of algorithm to maximize the number of people who will see improvement during the trial.
The change in randomization was based on their APOE genes, which affects a person’s risk for Alzheimer’s disease. The risk of developing Alzheimer’s disease is 2-3 times greater in people with one APOE4 allele and about 12 times higher in those with two APOE4 alleles. The European Medicines Agency (EMA) asked that participants with the APOE4 variant not be put on the highest dose of BAN2401 due to medical concerns. They also requested that APOE4 carriers who had been on the drug for less than 6 months to be changed to a lower dosage. Why did the EMA make this change? A condition called ARIA-E, where an abnormal buildup of fluid is visible in a brain MRI scan, has been found to be more common in APOE4 carriers.
As a result, there were very few APOE4 carriers in the trial receiving the highest dose of the drug, even though the highest dose (10 mg/kg monthly) was best at preventing cognitive decline[7,8]. Questions have arisen about whether having a higher proportion of high-risk participants (with the APOE4 allele) in certain dosage groups could skew results. To address this issue, a subgroup analysis was performed, looking at rate of cognitive decline for each APOE variant for participants receiving the highest dosage of the drug. Researchers found that APOE4 carriers actually benefited more from BAN2401 treatment than noncarriers, suggesting that the apparent success is not due to a lack of randomization in the treatment groups.
BAN2401 is the first late-stage drug showing slowing of cognitive decline and a decrease in levels of amyloid beta. As of February 4th, 2019, it was announced that Eisai is initiating a Phase 3 confirmatory study of BAN2401 in early Alzheimer’s patients in the first quarter of 2019.
AlzForum. Therapeutics: BAN2401. Retrieved from https://www.alzforum.org/therapeutics/ban2401 on 10 Jan 2019.
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Biogen. (2018, July 28). News Releases: Esai and Biogen announce detailed results of Phase II clinical study of BAN2401 in early Alzheimer’s disease at Alzheimer’s Association International Conference (AAIC) 2018. Retrieved from on 10 Jan 2019.
Biotech Innovations. (2018, September 11). Promising Results in 18-Month Analysis of Alzheimer Drug Candidate. Retrieved from on 10 Jan 2019.
Gupta, S. (2012). Use of Bayesian statistics in drug development: Advantages and challenges. Int J Appl Basic Med Res, 2(1): 3-6.
Michaelson, D. (2014). APOE ε4: The most prevalent yet understudied risk factor for Alzheimer's disease. Alzheimer’s & Dementia, 10(6): 861-8.
Sperling, Jack, Black, et al. (2011). Amyloid related imaging abnormalities (ARIA) in Amyloid Modifying Therapeutic trials: recommendations from the Alzheimer's Associationg Research Roundtable Workgroup. Alzheimer's Dement., 7(4): 367-385.
AlzForum. (2018, November 2). Second Look at BAN2401 Data Still Positive, Despite Snafu. Retrieved from on 10 Jan 2019.