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The "ups and downs" of Alzheimer's R&D

By The Editor - 12 November 2020

Will aducanumab become one day the first medication approved for Alzheimer? What happened last week confirms if needed that the story has not been written yet and that the cycle failure is not over.

November 4, Biogen's and Eisai's shares both soared more than 40 % on Wednesday after internal FDA staff documents suggested the companies had "provided substantial evidence of effectiveness to support approval" of aducanumab as a potential treatment for Alzheimer's disease. According to two trials Emerge and Engage, the effect of aducanumab was seen as "robust and exceptionally persuasive on several of the instruments used to evaluate efficacy." However, the different results seen between the two trials have prompted some experts to recommend that a third Phase III trial be conducted to clarify aducanumab's benefit in Alzheimer's disease patients.

Two days later, on November 6, a FDA advisory committee panel voted against approval of the same Biogen and Eisai's medication. The independent panel said evidence from a single positive study was not enough to demonstrate the drug's efficacy. The panel voted 8-1 that the positive Emerge trial could not be viewed as providing strong evidence supporting the effectiveness of aducanumab, without taking into account the conflicting Engage data. Two other panelists were undecided on that question.

Aducanumab has followed a complicated road until this year. In 2016, the drug excited markets when early results from its first human studies showed that the treatment could improve cognition among people with early signs of Alzheimer's. Further studies confirmed that the drug reduced the amount of amyloid plaques in the brain.

But in May 2019, Biogen suddenly stopped two large, ongoing late-phase studies of the drug after a planned analysis of the data showed futility. It reversed course in October 2019 and revived plans to seek US approval, claiming that positive results from a new analysis of the trials backed the effectiveness of high-dose aducanumab when administered to patients over an extended period. Furthermore, in March 2020, Biogen started a new Phase IIIb open-label, multicenter safety study of aducanumab named Embark, which was halted due to the Covid-19 pandemic.

In July 2020, the companies submitted a "biologics license application" (BLA) to the FDA. After last week opposite decisions, the FDA is expected to make a final decision on Biogen and Eisai's drug by March 7 next year. According to analysts, the organisation could still approve the candidate.

No drug has been approved in the past 17 years to treat Alzheimer's disease although the global social burden of the disease is expected to grow as the population ages. Almost 99 % of the 190 research programs on drugs developed have failed clinical trials in the last ten years. There are currently only four approved drugs which treat the symptoms of the disease affecting nearly 19 millions of people in the OECD (and 5 millions Americans among them). A figure that is likely to double by 2030...

But most analysts remain skeptical on the "clinical data package" of aducanumab. J.P. Morgan estimates the possibility of success of the whole regulatory process at 55 %, while others consider the therapy to have only a 33 % probability of success.

The treatment under review is based on the approach on BACE inhibitors, aimed to prevent a protein from producing the amyloid that builds up in the brains of Alzheimer's patients and form deposits, called plaques. Biogen's product works to clear amyloid plaques in the brain.

If approved, aducanumab could become "the first therapy to reduce the clinical decline of Alzheimer's disease and would also be the first therapy to demonstrate that removing amyloid beta resulted in better clinical outcomes", outlined the companies.

In the end, will an Alzheimer's drug, that slows the progress of the brain disorder instead of treating the symptoms, ever come to market? Several announcements of failed Alzheimer's treatments over the past months disappointed both markets and investors.

The latest setback was in February 2020 when Roche and Eli Lilly announced that results from the Phase II/III DIAN-TU-001 study showed that the experimental anti-amyloid drugs gantenerumab and solanezumab did not significantly slow the rate of cognitive decline in patients who have an early-onset, inherited form of Alzheimer's disease, compared with placebo.

Previously, in January 2019, Roche and partner AC Immune stopped two Phase 3 studies (known as Cread 1 and Cread 2) of their drug crenezumab in Alzheimer's early, after an interim analysis by a committee of investigators showed those trials were likely to fail. The drug had already shown disappointing Phase 2 results in 2014.

In June 2018, AstraZeneca and Eli Lilly announced they scrapped two late-stage trials of their experimental Alzheimer's drug, lanabecestat, they have co-developed since 2014.

In 2016, solanezumab from Eli Lilly, already failed a study called Expedition 3 in patients with early Alzheimer's, after two failed trials in 2012 (Expedition 1 and Expedition 2) in later-stage patients.

Others companies also stopped their trials, like Pfizer in January 2018, Axovant Sciences Ltd or Merck and Co, with verubecestat, that failed in 2017 on a clinical trial of patients with mild to moderate Alzheimer's. Boehringer Ingelheim also decided to axe its BACE inhibitor drug, too, following another trial failure.

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