Biogen and Eisai revealed data from an 800-patient trial showing their amyloid-fighting antibody significantly slowed cognitive decline and amyloid buildup in the brain. The findings are a first in a field rife with prospects that show early promise but fail to deliver in phase 3.
An early readout for the candidate, reported back in December, showed it failed to meet its primary endpoint. But the duo kept at it, playing the trial out to its prespecified 18-month endpoint. The phase 2 trial tested five different dose regimens of BAN2401, an anti-amyloid beta protofibril antibody, in 856 patients with early Alzheimer's disease. After 18 months of treatment, the highest dose of 10 mg/kg biweekly slowed clinical decline by 30% and 47%, as measured by ADCOMS and ADAS-Cog respectively.
Only the highest dose, 10 mg/kg, showed significant benefit. It was only tested in 161 patients. and two doses—2.5 mg/kg and 5 mg/kg—actually did worse numerically than placebo.
The data were presented at the Alzheimer's Association International Conference.
"This is the second Alzheimer’s clinical trial that has demonstrated both clearance of amyloid from the brain and cognitive benefits—again, the studies were not large enough to definitely demonstrate cognitive efficacy and the BAN2401 study did not meet its primary endpoint. That said, these two studies indicate that amyloid remains an important therapeutic target to pursue in Alzheimer’s disease," the Alzheimer's Association said in a statement.
“This is the first late-stage anti-amyloid antibody study to successfully achieve statistically significant results at 18 months, further validating the amyloid hypothesis,” said Lynn Kramer, chief clinical officer and chief medical officer of Eisai’s neurology unit, when the companies announced topline data from the trial. “We will discuss these very encouraging results with regulatory authorities to determine the best path forward.”
Biogen's shares spiked Tuesday in anticipation of the news and was still riding high upon the reveal, but then fell sharply down by more than 11% after hours as investors digested the data. Given how much is riding on this for Biogen and that Alzheimer's is such a risky proposition to place these kind of big bets on, this is hardly surprising.
Investors also seem to have not liked what they saw when they dug a little deeper into the data. Analyst Geoffrey Porges said in a note to clients: "The disparity between the 30% rate of APOe4 carriers in the highest 10mg/kg Q2 week arm, and the 71% rate in the placebo arm, and the 73-91% rate of APOe4 carriers in the other active arms, provides a putative explanation for the difference in cognition decline seen in the highest dose arm compared to placebo and other active arms. If Eisai’s sub group analysis suggests that this difference in decline persists even in the patients in all the arms who are not APOe4 carriers, this program may have a future, but if not, it could easily turn out to be an interesting artefact in the ongoing beta amyloid Alzheimer’s disease saga."
BAN2401 is based on the amyloid hypothesis, which asserts that the buildup of amyloid beta proteins in the brain triggers processes that eventually lead to cognitive decline and the destruction of brain cells. The field has relied on amyloid plaques and tau tangles as targets, but has not seen a new treatment approved in more than 15 years. Every drug targeting amyloid has failed to modify the disease in late-phase trials. Researchers are pursuing alternative hypotheses, including one linking the amount of herpes virus in a person's brain to the presence of Alzheimer's markers.
The latest Alzheimer's hopefuls to fall from grace include a pair of BACE inhibitors, one from Biogen and Eisai and the other from Janssen. Janssen dropped its atabacestat program in May after clinical trials turned up liver safety issues. The “the benefit-risk ratio is no longer favorable to continue development of atabecestat for people who have late-onset preclinical stage Alzheimer’s disease," the company said at the time. As for Biogen/Eisai's elenbecestat, the med failed to slow the decline of clinical symptoms more than placebo in exploratory endpoints.
Analysts at Jefferies waded into the debate over the data last night, saying: “Overall we think Debate number 1 (carrier vs non carrier imbalance) is not too big of an issue and Debate number 2 (why is 5mg/kg mid-dose not very good and 10mg/kg monthly is OK but not super convincing) is more perplexing and head-scratcher.....net-net stock will eventually recover but we need to get to the "next analysis" data update on the subgroups to answer these two debates which is probably at CTAD conference Oct 24-27 (Spain).”