One of the key drivers of a shift in CNS drugs hinges on the success or failure of Biogen’s aducanumab for Alzheimer’s disease.
A team of analysts with Canaccord Genuity Capital Markers recently issued an in-depth report on central nervous system (CNS) therapeutics titled, “Biotechnology Monthly: The neuro paradigms, they are a’changin’ in 2021?”
One of the key drivers of a shift in CNS drugs hinges on the success or failure of Biogen’s aducanumab for Alzheimer’s disease.
Earlier this year, the U.S. Food and Drug Administration (FDA) extended the review period for Biogen and Eisai Co.’s Biologic License Application (BLA) for aducanumab for Alzheimer’s disease. The drug has been fraught with controversy—and unexpected hopes. The decision by the FDA on the drug application was expected on March 7 but is now delayed until June 7, 2021.
In March 2019, Biogen and Tokyo-based Eisai announced they were discontinuing the global Phase III clinical trials, ENGAGE and EMERGE, of aducanumab in patients with mild cognitive impairment for Alzheimer’s and mild Alzheimer’s dementia.
They were also discontinuing the EVOLVE Phase II trial and the long-term extension PRIME Phase Ib trial. An independent data monitoring committee indicated they were unlikely to hit their primary endpoint.
It appeared to be the final nail in the amyloid theory of Alzheimer’s disease. Aducanumab is an antibody targeting beta-amyloid, one of the proteins that accumulates in the brains of Alzheimer’s patients.
But in October 2019, the two companies announced plans to pursue regulatory approval for the drug. It turned out, the Phase III EMERGE trial met its primary endpoint, showing a significant decrease in clinical decline.
Biogen presented the findings of the final data analysis in a December conference, and although there was still some skepticism about the overall data, it did appear to be enough to file for a BLA and the company planned to do so in the second quarter of 2020.
What they presented was that the Phase III EMERGE trial met its primary endpoint, showing a significant decrease in clinical decline. Biogen said the data from a subset of patients that received a high enough dose of the drug had significant benefits on measures of cognition and function, including memory, orientation, and language, as well as benefits on activities of daily living.
Although many had issues with some of the data, which was very complex, the companies felt they had a strong enough case to submit it to the FDA and were expected to do so this spring.
Then, in April 2020, they announced that although the company had begun to submit parts of the BLA, they did not expect to complete it until the third quarter of this year.
The submission was completed in August 2020 with ongoing collaboration with the FDA and include data from the Phase III EMERGE and ENGAGE trials, as well as the Phase Ib PRIME study. Biogen has also requested Priority Review.
In November 2020, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee slammed the drug submission, voting 1 yes, 8 no and 2 uncertain on the question, “Does Study 302 (EMERGE), viewed independently and without regard for Study 301 (ENGAGE), provide strong evidence that supports the effectiveness of aducanumab for the treatment of Alzheimer’s disease?”
It also voted 0 yes, 7 no and 4 uncertain on whether Study 103 (PRIME) supported the effectiveness of the drug. Again and again, the committee voted against the drug.
Apparently the newest delay is related to the FDA requesting additional analyses and clinical data. Biogen complied, and the FDA considered it a Major Amendment to the application, thus requiring additional review time.
The authors of the Canaccord Genuity study wrote, “We view the pending aducanumab biologics license application (BLA) as the most important non-COVID-19-related biopharma decision on the FDA’s plate currently. Recall, Biogen’s adu could become the first product to be approved in the U.S. that slows the progression of Alzheimer’s disease.”
But Biogen and aducanumab are not the only products the industry is watching in the CNS space. These include Acadia Pharmaceuticals’ Nuplazid (pimavanserin) for dementia-related psychosis (DRP) which has a target action date of April 3, and Intra-Cellular Therapies’ Caplyta (lumateperone) for bipolar depression, which has a target action date in the second half of 2021.
Nuplazid was approved in April 2016 for Parkinson’s disease psychosis. The supplemental New Drug Application (sNDA) for dementia-related psychosis was based on the HARMONY study, where the drug met its primary endpoint and was halted at the pre-planned interim analysis for positive efficacy. It reduced the risk of relapse of psychosis by 2.8-fold compared to placebo.
In the case of Caplyta, Intra-Cellular Therapies submitted sNDAs to the FDA for two indications: as a monotherapy, and as adjustive therapy with lithium or valproate for depressive episodes associated with bipolar I or II disorder in adults. If approved, it would be the first therapy for those indications.
The report also looked at Sage Therapeutics’ zuranolone, which in October 2020 reported interim, topline results from a July data cut of its ongoing Phase III SHORELINE trial. The drug is being advanced for major depressive disorder (MDD). The announcement from the company was complex, focusing mostly on the primary endpoint of safety and tolerability. The drug was well-tolerated at the 30-mg dose and among the first patients treated with a 50-mg dose. They expect to report comprehensive data from the 30-mg dose in the first half of 2021 with additional subsets of data within the primary and secondary endpoints.
The Canaccord Genuity analysts wrote, “We are cautiously optimistic on Sage’s zuranolone as we head into the WATERFALL Phase III data for major depressive disorder (MDD) in 1H/mid-21. In fact, we view Sage’s zuranolone as Biogen’s most important pipeline product after the collaboration deal.”
That deal was announced on November 30, 2020. Biogen paid Sage $1.52 billion upfront to jointly develop and commercialize zuranolone for MDD, postpartum depression (PPD) and other psychiatric disorders, as well as SAGE-324 for essential tremor and other neurological disorders.
The report also discussed Compass Pathways’ “magic mushroom” drug, psilocybin for depression, as well as Neurocrine Biosciences luvadaxistat for schizophrenia. Psilocybin is the active, psychedelic compound in so-called “magic mushrooms.”
On March 2, 2021, Neurocrine announced topline data from the Phase II INTERACT trial in adults with negative symptoms of schizophrenia. The drug met secondary endpoints of cognitive assessment, which, the company stated, “merit further clinical evaluation.” It did not, however, meet the primary endpoint of change from baseline on the PANSS NSFS at Day 84.
The authors of the Canaccord report wrote, “We see 2021 as a very important year as there are several upcoming events for stocks within our neuro-focused coverage. These range from key regulatory decisions—the highest profile of which is the FDA’s pending decision on Biogen’s aducanumab (early Alzheimer’s disease)—to important clinical data, to even how some indications may be targeted from a commercial standpoint. Needless to say, we believe these upcoming catalysts are likely to influence broader sentiment in the neuro space from both an industry and investor perspective.”
