American pharma giant Biogen has announced that its therapeutic compound for Alzheimer’s disease (AD), aducanumab, is to be taken to the FDA for approval. Despite being seemingly killed off after a study in March produced disappointing results, new analysis suggests that aducanumab met its target endpoints. If confirmed, this would make aducanumab the first therapy able to slow cognitive decline in AD.
An unexpected reversal
After a series of high-profile failures, aducanumab was considered the last roll of the dice for pharmacological interventions targeting the pathological protein beta-amyloid, which is thought to have a central role in AD pathology.
In a Biogen press release, study lead Dr. Anton Porsteinsson said, “This large dataset represents the first time a Phase 3 study has demonstrated that clearance of aggregated amyloid beta can reduce the clinical decline of Alzheimer’s disease, providing new hope for the medical community, the patients, and their families.”
More measured praise was also forthcoming from leaders in the field not associated with the study: Professor Bart De Strooper, Director of the UK Dementia Research Institute, University College London, commented, “It is fantastic to hear of these new positive results emerging from the aducanumab trials. We currently have no effective treatments to slow or halt the progression of Alzheimer’s disease and I hope this signifies a turning point.”
Bigger dose, better results?
Aducanamab, a monoclonal antibody, targets both soluble and insoluble forms of beta-amyloid, clearing it from the brain. Biogen said that the study results published in March, which had raised fears around side effects such as brain swelling, had been based upon an “incorrect” futility analysis.
According to Biogen, the new analysis suggests that the now-positive result (it is incredibly rare for clinical trial results to be reversed in this way) was due to increased exposure to a higher dose of aducanumab.
Delving into the datasets released by Biogen will take some time, although some in-depth analysis can be found here. In summary, the drug was tested in two trials, one of which (named EMERGE) has proved to have statistically positive results in the new, larger analysis, whilst the other (ENGAGE) trended towards significance in a subset of patients who received the higher dose (but was still insignificant). Patients were assessed on both their amyloid burden, and their performance on a battery of standardized cognitive tests. On one test, the CDR-SB, a higher dose group showed a decline in their performance that was 23% slower than patients on a placebo. But the performance of participants in other tests was not significantly different, and any significance was only found in the EMERGE group. Why patients would perform worse in these different tests is currently unclear.
Contradictions need to be cleared
The data released by Biogen also contained some strange results, such as a worse performance in some tests by patients on a higher dose of aducanumab in ENGAGE, the exact opposite of the results from EMERGE. Whilst these concerns would normally move the FDA to order another trial using the conditions that proved positive in EMERGE, one might expect immense pressure to be put on the regulator to approve the drug, given the complete lack of other effective treatments.
A “shot in the arm” for AD research
One might desperately hope that an unusually cold winter signals a reversal of rising global temperatures, even if the great majority of data suggests otherwise. In the same way, researchers across the field will desperately hope that Biogen have got things right second time around, but they will be waiting with bated breath.
At the Society for Neuroscience’s 2019 conference, Alzheimer’s researcher Li-Huei Tsai told Technology Networks, “The news today this morning that Biogen put out is exciting. For Alzheimer's disease, in the last 15 years, there has not been a successful trial. So, if they succeed this time, I will say it's a very strong shot in the arm. I think we need some positive results.”
Tsai went on to temper her praise with some words of caution, “But with aducanumab, when they halted the trial, they said there was no hope that this drug would ever succeed. I think right now this new information, even though it's exciting, I think when they designed the trial, they didn't really know what patient population to go into. It seems that it's not that everybody responded, only a very small population of people responded. I think there is still a need for something that can be beneficial to the many, many people who suffer from memory loss and dementia.”