Albert Einstein is often attributed as saying: “The definition of insanity is doing the same thing over and over again, but expecting different results.” He likely didn’t actually say this, but regardless of its origins, this witticism comes sharply into focus when you read Eisai’s press release about starting new trials for BAN2401.
Just yesterday, the Japanese pharma and its U.S. Big Biotech partner Biogen announced they were canning several late-stage trials of their key Alzheimer’s disease (AD) drug aducanumab, and other earlier stage tests, after a group of independent experts said it was going to flop.
This sent shares of the companies plummeting into the red, with Biogen having around $18 billion wiped from its market cap; both the Nasdaq Biotech Index and the S&P Biotech were also hit hard, given Biogen’s weight across biotech shares.
You’d be forgiven for thinking that Eisai would take a breather and reflect: Full data have not yet been published, and a proper postmortem will need to be made. But just 24 hours later, it is looking to push on with another attempt at AD with a separate drug, BAN2401, although its target as an anti-amyloid, now surely one of the most failed targets in biopharma, isn’t that different from aducanumab.
This new phase 3 trial, which has just started, will look at 1,566 patients with mild cognitive impairment, or mild Alzheimer’s disease dementia, with amyloid accumulation, pitting it against placebo.
This comes after the mixed bag of data coming out from the drug last year, specifically at the CTAD meeting in Barcelona, which tried to use subgroup analyses and biomarker data to build the argument that the anti-amyloid drug was showing a significant effect on the progression of Alzheimer’s disease.
There was a lot of excitement when the two companies reported 18-month data from the phase 2 trial at AAIC earlier in the year, when it found a significant effect on cognitive decline in mild AD patients that hadn’t been shown at 12 months, the study’s primary endpoint. The study also revealed a startling effect on amyloid plaque build-up in the brain, eliminating signs of this on PET scans in more than 80% of patients.
There was one problem with the dataset, however, and that was a big imbalance in the proportion of patients who were carriers of APOE4, a mutation that increases the risk of developing AD, in the high dose group (10 mg/kg biweekly) that seemed to be getting the most benefit from the drug.
The imbalance was caused by regulatory demands to stop recruiting APOE4 carriers into the study because of a fear of side effects, which led to suggestions that the benefit of the drug may have been overestimated.
At CTAD, Biogen and Eisai tried to answer those suggestions with a series of analyses that they claimed show the APO4 carrier imbalance didn’t amplify BAN2401’s effects, and according to Eisai scientist Chad Swanson, Ph.D., senior director of clinical research for neurology, may in fact have underestimated its benefit as patients with the mutation actually did better on the drug than those without.
He said at the time that there was a “statistically meaningful effect of 30% less decline in disease progression seen for 10 mg/kg bi-weekly dose versus placebo at 18 months on ADCOMS [that] was driven by BAN2401 treatment effect and not an imbalance in subject allocation by APOE4 status.”
But the continuing skepticism about BAN2401 seems to stem from the small number of APOE4 carriers in the high-dose group relative to placebo and a pooled analysis of 10 mg/kg bi-weekly and monthly groups. The latter showed 21% less decline overall versus placebo on the ADCOMS score at 18 months, but that was skewed to the carrier group who had a 25% benefit compared to 6% for noncarriers.
Analysts at Jefferies said the data has some good elements but "seems a bit all over the place." In particular, they said it was encouraging that disease progression of carriers and noncarriers is generally consistent "and suggests that the placebo arm and carrier imbalance did not help drive the drug."
Eisai, and partner for this test BioArctic, still hope this confirmatory trial will prove to be a winner and help set up regulatory filings. But the history of AD drug development casts a long shadow, as we saw just yesterday.
Gunilla Osswald, Ph.D., CEO at BioArctic, remained upbeat, saying: “We are very pleased to see that the confirmatory phase 3 study with BAN2401 in early Alzheimer's disease is now initiated. There is a plan for fast recruitment and Eisai is targeting a final readout already in 2022.
“The phase 3 study is designed to confirm the previously observed positive phase 2b results in early Alzheimer's disease patients. The intention with BAN2401 is to slow down the progression of the disease and improve the quality of life for Alzheimer's patients.”