Biogen presents data on controversial Alzheimer’s drug, but doesn’t sway analysts

Shares of the biotech company were up following the presentation on the drug, aducanumab, but investment bank analysts continued to raise questions about its future, particularly its prospects of FDA approval.

Biogen faced renewed skepticism from analysts following its presentation of data for a controversial Alzheimer’s disease drug at a medical conference.

The Cambridge, Massachusetts-based biotech company presented updated data from its Phase III EMERGE and ENGAGE trials of aducanumab at the Clinical Trials on Alzheimer’s Disease conference in San Diego. But despite the upbeat mood of presenters – who included company executives and physicians who participated in the trials – the data did little to change the opinions of investment bank analysts.

Shares of the company were nevertheless up about 1.5% on the Nasdaq as of Friday afternoon. A Biogen spokesperson declined to comment on analysts’ remarks.

The presentation included numbers from a larger data set that the company presented in October, when it announced aducanumab’s revival, as well as a final data set. Data from the larger data set of EMERGE showed that among 547 patients receiving the higher dose of aducanumab, there was a statistically significant 23% decrease in their score on the Clinical Dementia Rating Sum of Boxes (CDR-SB), with the final data set showing a 22% decline, meaning that the study met its primary endpoint. ENGAGE, whose design was identical to EMERGE, did not meet its primary endpoint. The final data set also showed statistically significant improvements on the secondary endpoints using the Mini-Mental State Exam (MMSE), the 13-item Alzheimer’s Disease Assessment Scale-Cognitive Plus (ADAS-Cog 13) and the Alzheimer’s Disease Cooperative Study-Activities of Daily Life-Mild Cognitive Impairment (ADCS-ADL-MCI) tests.

Still, the company’s plans to file for Food and Drug Administration approval continued to raise eyebrows. On an after-hours conference call following the CTAD presentation, an analyst inquired about what was driving the company’s confidence, given that the FDA has not generally approved drugs based on post-hoc analyses. “We don’t file willy-nilly,” Biogen CEO Al Sandrock said in response, pointing to the amount of work that goes into a filing. “We only go to filing when there is a benefit-risk argument based on science, based on data. If you look at our history, we haven’t done filings right and left without good reason.”

But in a note to investors ahead of the call, Baird analyst Brian Skorney wrote that the presentation “turned out to be largely a non-event.” He also expressed concern about aducanumab’s “worse than expected” safety profile, citing what he called clear, dose-related increases in brain edema, microhemorrhage and symptomatic amyloid-related imaging abnormalities, or ARIA, a side effect associated with amyloid-targeting drugs like aducanumab. However, EMERGE and ENGAGE experienced low patient discontinuation rates due to adverse side effects.

Cowen analyst Phil Nadeau wrote that while the physicians assembled were in favor of the drug having a biologic effect, the data were unlikely to change the debate much, and the bigger question would be the FDA’s willingness to be flexible. Overall, he gave the drug a 30-50% chance of winning approval.

During the course of the two studies, the company amended their protocols so that patients harboring the gene ApoE4 could increase dosage to 10mg/kg, thereby increasing their median cumulative dose and also increasing the percentage of patients receiving 10mg/kg from 20% to 50%. Consequently, the percentage of patients receiving the full possible 14 doses at 10mg/kg went from 21% in EMERGE and 15% in ENGAGE to 51% and 47%, respectively.

In a note, Oppenheimer analyst Jay Olson noted that a post-hoc subset analysis of those post-PV4 patients showed an effect and dose response in EMERGE and ENGAGE on the CDR-SB endpoint and other measures. “We view the analysis as complicated but reasonable considering trials must answer whether drug exposure led to benefit,” he wrote.

Still, Olson wrote that a key question remains the difference in outcomes between EMERGE and ENGAGE. The post-hoc subset analysis showed an effect on the CDR-SB endpoint in both trials. Nevertheless, EMERGE was successful, while ENGAGE was not.

On Friday, Skorney wrote that the post-PV4 subset analysis had actually emerged as a major concern. “We said there wasn’t much new amongst the efficacy data presented yesterday, but the more we look at it the more we think there is one big red flag,” he wrote. “Recall, that Biogen highlighted a subgroup analysis consisting of patients who received 10 or more doses of 10mg/kg of aducanumab as explaining the differences between ENGAGE and EMERGE and indicating an exposure relationship to clinical effect, albeit extremely modest. Of course this analysis is problematic because they are comparing compliant treated patients to all placebo patients, which in a normal situation is a big no-no, but in the case where one is very likely to be selecting out of ApoE4+ carriers, it is even more problematic.”

GlobalData senior pharma analyst Alessio Brunello was likewise skeptical, pointing to the inconsistency of results between the two clinical trials. “The data from the EMERGE study were positive with convincing clinical efficacy with the high-dose arm, however, the ENGAGE study did not show the same pattern of target engagement or clinical efficacy,” he said in a statement by the data and analytics company.

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