Reports of amyloid beta’s death have been greatly exaggerated. Or at least, that’s the news from Biogen, which drew attention Tuesday when it announced it would submit for Food and Drug Administration approval a drug whose Phase III clinical trials were previously discontinued when an analysis indicated they would fail.
The Cambridge, Massachusetts-based biotechnology company said Tuesday it was planning a regulatory filing with the FDA for the drug aducanumab in Alzheimer’s disease in early 2020. The decision, based on consultation with the agency, followed an analysis of a larger data set from the company’s Phase III studies of the drug.
In a conference call with investment bank analysts, Biogen CEO Michel Vounatsos said that the results of the futility analysis had been “incorrect.”
“Based on what we know now, it was clear that the prespecified futility criteria did not adequately anticipate the effect of all the variables in these trials,” Vounatsos said.
The news coincided with an announcement of the company’s third-quarter 2019 earnings, wherein the company reported sales of $3.6 billion, a 5 percent increase over third quarter 2018. Shares of Biogen were up more than 35 percent on the Nasdaq Tuesday morning.
The rise in the company’s share price might be in part because the last time aducanumab was in the news, it was in March, when the company and development partner Eisai announced they were discontinuing its Phase III ENGAGE and EMERGE trials of the drug due to a futility analysis that indicated they would fail to meet their primary endpoints. The March 21 announcement came as a huge letdown to the market, and the company’s shares fell by nearly 30 percent.
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
But the March announcement also raised questions about the scientific premise on which aducanumab’s development was based, namely the amyloid beta hypothesis. The idea is that by targeting the plaques of amyloid beta, or Abeta, that build up in the brains of Alzheimer’s patients, one can treat the disease. Other drugs designed to target amyloid beta have failed, but aducanumab was seen as the one that could potentially succeed because it targeted the protein in a highly potent manner.
However, the company said Tuesday that it had since gained additional data from a sample of 3,285 patients, including 2,066 who had the opportunity to complete the full 18 months of treatment.
Whereas the futility analysis had shown the trials would not succeed, the analysis of the larger data set showed that EMERGE reached statistical significance on its primary endpoint of change from baseline in patients’ Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. In the EMERGE analysis, patients treated with a high dose of aducanumab showed a significant reduction in clinical decline in their CDR-SB scores after 78 weeks, at 23 percent compared with placebo. Reductions in clinical declines on secondary endpoints also occurred, including the AD Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version (40 percent versus placebo), the AD Assessment Scale-Cognitive Subscale 13 Items (27 percent versus placebo) and the Mini-Mental State Examination (15 percent versus placebo), though the MMSE measure missed statistical significance.
Meanwhile, although ENGAGE did not meet its primary endpoint, the company believes a subset of patients – particularly those who received enough exposure to aducanumab – supports the EMERGE findings.
Indiana University School of Medicine professor of Alzheimer’s disease research Dr. Liana Apostolova described her view as “cautiously and subduedly optimistic.”
“We are clearly in desperate need of any drug that could alter the course of Alzheimer’s disease,” she wrote in an email. “However, as encouraging as this news is, one has to keep in mind that the data presented earlier today by Biogen reflect post-hoc analyses. Post-hoc analyses tend to make a great deal of assumptions that might in reality not be true.”
On the one hand, both EMERGE and ENGAGE show that aducanumab removes amyloid from the brain, as well as a reduction in cerebrospinal fluid phosphorylated tau protein. But the results diverge beyond those biomarker findings, she wrote. While EMERGE shows improvements in the aforementioned primary and secondary endpoints, ENGAGE showed the opposite for CDR-SB and MMSE in addition to its lack of statistical significance. Meanwhile, the sample of patients who received sufficient drug exposure – 10 or more doses of 10 mg/kg without interruption – represented only 127 patients from EMERGE and 97 from ENGAGE, she noted.
Still, she wrote that Biogen’s decision to pursue approval was encouraging.
In a note to investors Tuesday, Cowen analyst Phil Nadeau wrote that the submission presents a high reward, but comes at a high risk. While the rationale makes sense, he wrote, it is unclear if the totality of the data support FDA approval. That uncertainty comes from the failures of the futility analysis and ENGAGE itself, as well as the lack of clarity as to whether some biases were introduced within subsets either due to discontinuations or the simple fact of their being subset analyses, he wrote.
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