According to a recent article in BioSpace, Biogen and Eisai have launched a new preclinical Phase III trial of BAN2401 to treat pre-clinical Alzheimer’s disease. The new study follows the discontinuance in March 2019 of their global Phase III trials (ENGAGE and EMERGE) investigating aducanumab.
The companies also discontinued their EVOLVE Phase II trial and PRIME Phase 1b of aducanumab. A safety review of aducanumab showed that the ratio of risk to benefit was unfavorable. This brought about a recommendation to end the trials.
About the New Trial
The new trial named AHEAD 3-45 is investigating BAN2401, an anti-amyloid beta (Aβ) protofibril (a type of fiber) antibody.
A total of 1400 people will be enrolled and receive BAN2401 therapy for 216 weeks. The subjects, who are evaluated as clinically normal, will be separated into the A3 or the A45 trial according to the level of amyloid in their brain.
The trial is being conducted in the U.S., Canada, Japan, Singapore, Europe, and Australia.
Then and Now
The discontinuance of the EMERGE and ENGAGE trials might signal the end of an era for researchers in the “amyloid-beta” field. Researchers have focused on preventing the accumulation of amyloid-beta in Alzheimer’s patients’ brains for decades.
After years of failure, researchers are beginning to rethink their theories as being either completely wrong or just not complete. They are now focusing on using other approaches while not entirely turning away from amyloid-beta. They still believe that tau and beta-amyloid are part of the process.
One new theory is that there is a specific energy malfunction possibly related to the brain’s immune cells. Another potential theory suggests that neuro-inflammation may play a larger role in Alzheimer’s than amyloid.
Getting Closer to the Missing Link
Temple University researchers discovered a form of energy malfunction called mitochondrial calcium transport remodeling. It is believed to be associated with Alzheimer’s progression.
Although generally helpful, this mechanism, which involves a cell’s production of energy, may begin to malfunction. When that occurs it causes a drop in mitochondrial function, cognition, and memory.
John Elrod, associate professor at Temple University, says that this theory is not new.
For some time now, metabolic dysfunction and calcium regulation have been discussed in connection with Alzheimer’s development. But until recently, he stated, it has not been investigated. He believes this study identifies the missing link in the progression of Alzheimer’s disease.
A New Therapeutic Angle Using Mouse Models
Professor Elrod stated that a protein called NCLX is the most important regulator of mitochondrial calcium transport. NCLX is vital for the outflow of mitochondrial calcium in neurons.
The team studied a mouse model of mitochondrial calcium uptake by neurons found in Alzheimer’s disease. The mouse had three gene mutations that showed Alzheimer’s progression comparable to that of humans.
Mitochondrial calcium uptake became limited in tandem with the steady decline in protein expression as the mouse aged. The result was calcium overload that caused damage to the cells. The loss of NCLX caused an increase in oxidant production also damaging cells.
With and Without NCLX
First, the researchers eliminated NCLX expression in the brain of Alzheimer’s disease mice. The result was severe cognitive and memory impairment which led researchers back to tau and beta-amyloid.
The team then restored NCLX causing a decrease in tau and beta-amyloid clumps. It reestablished neuronal mitochondrial calcium levels as well as putting a halt to cognitive decline.
A Similar Viewpoint
A BioSpace interview with Professor Rudy Tanzi of Harvard University quoted the professor as saying that he thinks that tangles and amyloid trigger Alzheimer’s but do not directly cause dementia.
Professor Tanzi believes that amyloid can appear fifteen years prior to symptoms. He noted that all genetics point to Alzheimer’s beginning with amyloid. Yet he does not believe the death of some neurons by amyloid is sufficient to create dementia.
He does believe, however, that there eventually is a tipping point. At that point, the brain’s immune system reaches severe levels of neuro-inflammation, causing cell death and dementia symptoms..
In conclusion, the Chief Clinical Officer of Eisai said that their new study is representative of the next level in the development of treatment for Alzheimer’s Disease.