SAN DIEGO – Following up on its October announcement that it would file for FDA approval of beta-amyloid-targeting aducanumab, Biogen Inc. presented the final dataset for the phase III Emerge and Engage studies at the 12th Clinical Trials on Alzheimer’s Disease Meeting.
Both Alzheimer’s disease studies were terminated earlier this year after a pooled futility analysis found that the studies were unlikely to meet their primary endpoints.
But when the company looked at the full final dataset of Emerge, the high dose produced an improvement of -0.39 points over placebo (-22%) in Clinical Dementia Rating-Sum of Boxes (CDR-SB), the primary endpoint of the study (p=0.0120). The high dose also produced improvements in Mini-Mental State Examination (18% vs. placebo, p=0.0493), the AD Assessment Scale-Cognitive Subscale 13 Items (27% vs. placebo, p=0.097) and the AD Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version (40% vs. placebo, p=0.0006).
The larger dataset included patients who had been treated at higher doses for longer, which Cambridge, Mass.-based Biogen believes explains the differences between the interim and final results. In March 2017, the company amended the clinical trial protocol to allow patients with the Apolipoprotein E 4 (APOE4) allele to be titrated to 10 mg/kg, the same dose used by APOE4-negative patients. The APOE4 carriers had previously been limited to 6 mg/kg due to the potential for developing amyloid-related imaging abnormalities (ARIA), but a safety study found that titration could limit the side effect. The cutoff for the population of patients included in the interim analysis was just a few months later in June 2017.
Patients treated before and during the protocol amendment had a cumulative exposure of 116 mg/kg at week 78, compared to 153 mg/kg for patients enrolled after the protocol amendment.
Data from Engage, the second study designed with the same protocol, weren’t positive, with the high dose actually producing a 0.03-point (2%) worse effect in CDR-SB compared to placebo. The secondary endpoints also didn’t show an effect.
The different results for Engage and Emerge may be explained by the timing of enrollment. At the time of the protocol amendment, the enrollment for Emerge was 200 patients behind that of Engage, which resulted in more patients in the successful Emerge study being exposed to the higher dose for longer. In fact, 29% of patients in the Emerge study received the full possible 14 doses of 10-mg/kg doses, compared to 22% of patients in the Engage study.
A post-hoc analysis of patients enrolled after the dosing protocol amendment, which included 51% of patients in Emerge and 47% of patients in Engage receiving the full possible 14 doses of 10 mg/kg, showed an improvement of -0.53 (-30%) and -0.48 (-27%) in CDR-SB for the Emerge and Engage studies, respectively.
"From my perspective, it’s interesting and it’s positive, but it’s not definitive," Laurie Ryan, chief of the dementias of aging branch of the division of neuroscience at the National Institute on Aging, told BioWorld. "We’ve seen other post-hoc data that goes one direction, but then another trial is done and you don’t always see the same finding."
Many analysts agreed with Ryan’s interpretation of the mixed data.
"For starters, this represents a highly selected patients population that may not be representative of a real world. And even when we look at this Engage population (n=282), the confidence interval crosses zero on CDR-SB (-1.02, 0.06), meaning that the truth of the data may very well lie where drug does not improve vs. placebo if the study were to be run again," Mizuho Securities analyst Salim Syed wrote of the post-hoc subset analysis.
J.P. Morgan analyst Cory Kasimov was equally unimpressed, noting that the presentation "did little to boost our confidence in a regulatory approval and answered very few of our key questions (namely, why results for the two studies were so different) … Based on what we have seen here today, we remain skeptical around approvability."
Guggenheim Securities analyst Yatin Suneja was a more bullish, noting that he believes the "potential approval will come down to the FDA’s willingness to approve a drug on relatively weak data for a disease that impacts millions and has few current treatment options."
Despite the rather muted response to the data by analysts, shares of Biogen (NASDAQ:BIIB) closed up $9.87, or 3.4%, to $299.39 on Thursday. Syed explained that the stock reaction was mostly based on investors’ low expectations, "The setup going into the dataset today was risk/reward skewed to the downside. Lots of investors thought today would be a day of noise with incremental analysis presented. The fact that Biogen didn't put out earth-shattering additional negative data that begs further question is a relative positive."