Plaque-Fighting Drug Passes Early Clinical Test in Humans

Biogen Says it Will Proceed to Phase 3 Trial of Aducanumab

On March 20, from a conference in France, the Cambridge, Mass.-based biotech company, Biogen reported success in the PRIME trial, an early clinical trial of its Alzheimer’s drug, aducanumab. Results proved “better than expected,” the company said, from its phase 1 trial enrolling 166 subjects with prodromal-to-mild Alzheimer’s. Individuals treated with aducanumab had a significant reduction in amyloid and symptoms of cognitive impairment were slowed compared with untreated controls.

“Prodromal” Alzheimer’s is also referred to as mild cognitive impairment (MCI). On the continuum leading up to Alzheimer’s, it lies between preclinical Alzheimer’s, when it’s possible to detect biochemical changes associated with disease but no changes in cognition, and mild Alzheimer’s, where cognitive decline from Alzheimer’s begins to have an impact on mood and functioning. Not all people with MCI progress to Alzheimer’s.

These trial results, while promising, are among the earliest attempts to test aducanumab in humans,and have to be viewed with caution. Phase 1 trials are deliberately small and narrow in scope, designed to assess safety and establish safe dosing levels for promising agents as they head out of the starting gate. From a safety standpoint, aducanumab appears to be safe, although side effects were reported at higher dosing levels. These concerns will be analyzed further in data from this trial, and from phase 3 trials up ahead, which the company has announced it will pursue.

Phase 3 trials are considered the gold standard proof of clinical effectiveness, and are meant to test a drug’s effectiveness over time in the patient population it’s designed to treat. If successful, they typically lead to a drug’s approval by the U.S. Food and Drug Administration, at which point companies are free to market their product for specific conditions under a brand name.

New Hope—Could This Be the Dawn of Disease Modifying Therapies?

Aducanumab’s early success may signal a turn in the tide for anti-amyloid therapy. A New York Times story suggested as much, but also cataloged earlier, failed trials of similar agents. They included a joint effort by the pharmaceutical giants Johnson & Johnson and Pfizer to develop a plaque-fighting drug, which was abandoned at the clinical trial stage due to poor results. Disappointing early results also forced the Swiss pharmaceutical, Roche, to close a phase 3 trial of its anti-amyloid agent gantenerumab; however, development efforts are said to be ongoing.

Solanezumab, another anti-amyloid agent being developed by Lilly, also produced negative results in its first phase 3 clinical trials, which tested treatment for later stages of Alzheimer’s disease. However, results suggested the drug might be beneficial in subgroups who had very early Alzheimer’s. Now solanezumab is being retested at earlier disease stages in the large A4 trial, which is recruiting patients at dozens of sites in the United States and internationally (see our reports from September 2014 and June 2014). Reisa Sperling, MD, of Harvard, who received a 2010-14 BrightFocus grant for her amyloid imaging research, is helping to lead A4. (To learn more, watch this video.)

Despite fitful progress, anti-amyloid agents currently represent the nearest, best hope of taking Alzheimer’s treatment to a new level, where it’s possible to do more than achieve mild improvement in symptoms. These complexly designed biologically-active drugs have earned the title of potential “disease-modifying” agents because they’re believed capable of slowing down the disease and delaying onset of symptoms, including memory loss and cognitive decline.

All the evidence so far, including valuable knowledge gained from anti-amyloid trials that have failed, points to the likelihood that in order to stop Alzheimer’s, it has to be attacked very early in its 10- to 20-year course. That’s why disease-modifying agents are being targeted to the prodromal level and to very early, mild stages of Alzheimer’s disease.

Also, many experts now believe that Alzheimer’s disease doesn’t follow just one disease pattern, but make take several forms based on a patient’s genetic risk and other factors. That means anti-amyloid therapy may have to be customized to individual patients, and that more than one drug and/or approach may have to be used in combination. It will be important to have more than one plaque-fighting agent, as well as drugs attacking other aspects of the disease, at our disposal as clinical weapons.

BrightFocus remains cautiously optimistic about these latest results and about ongoing efforts in the field to develop anti-amyloid therapies. Stayed tuned for more news from AD/PD 2015, including BrightFocus-funded research presentations.