Fresh Data Add More Confusion to Eisai-Biogen Alzheimer’s Drug

Xconomy Boston — 

Three months after controversial data suggested an Alzheimer’s drug could slow the mental decline of the disease, the drug’s owners tried to bolster their argument today that the good news over the summer was not a statistical illusion.

The drug in question is dubbed BAN2401, and it’s being co-developed by Biogen (NASDAQ: BIIB) of Cambridge, MA, and Eisai, headquartered in Japan. In July, they presented results from a Phase 2 study (Study 201) that showed BAN2401 not only cleared the clumps, or plaques, of amyloid protein in patients’ brains, but surprisingly seemed to help patients function better. Critics immediately jumped on the data, however, to point out that the promising results might have stemmed from an imbalance across the study’s arms of people carrying a genetic mutation called ApoE4 that puts them at higher risk of the disease.

Eisai neuroscientist Chad Swanson, who is the director of Study 201, took to the stage Thursday at a medical conference in Barcelona to make the case that it was his company’s drug, and not a study flaw, that drove the reduction in cognitive decline the partners are reporting. “ApoE4 status isn’t a significant contributor to disease progression,” Swanson said.

The new data also showed that at the highest dose, the drug worked to slow cognitive decline much better in ApoE4-positive patients, with little effect in ApoE4-negative patients. (In the real world, about 10 to 15 percent of people are ApoE4 carriers; not all of them develop Alzheimer’s.) Eisai said that ApoE4 carriers had 63 percent more benefit than placebo based on a statistical analysis known as ADCOMS. In ApoE4-negative patients, the ADCOMS benefit was only 7 percent. Even the positive effect on ApoE4 carriers came with a big caveat: Only 10 ApoE4 patients lasted the full 18 months in the highest dose group. “There does appear to be a significant benefit, but there just aren’t enough data,” said David Morgan, an Alzheimer’s researcher at Michigan State University. (He has advised the drug’s developers in the past but has no active ties.)

Instead of clearing up questions that have been swirling around the program, this new twist only added more, as financial analysts noted immediately. “In our view, this data is confusing,” wrote Leerink analyst Geoffrey Porges in a note published after the presentation.

An example of how much Eisai and Biogen still need to prove came as soon as they ended their presentation. The conference floor opened for questions, and Reisa Sperling, a top Alzheimer’s researcher based in Boston, immediately asked whether the companies’ new analysis took into account “drop-outs,” that is, patients who had to leave the study because of side effects such as brain swelling. Swanson hesitated before answering, “We didn’t specifically look in the analysis at that kind of question.” (Sperling could not be immediately reached for further comment.)

Eisai and Biogen have been co-developing BAN2401 since 2014. In July, the companies said that patients on the highest dose of BAN2401 in Study 201 saw their cognitive decline slowed by 30 percent.

If BAN2401 can slow or even stop the disease, it could provide hope for millions of patients with no effective treatment options. It would also validate the popular “amyloid hypothesis” often used to explain the underlying cause of Alzheimer’s.

Every single drug meant to break up or prevent these amyloid plaques has failed, often after early promising signs that couldn’t be replicated in a large Phase 3 trial. Many in the field believe that the plaques are a symptom not a cause of the underlying disease, and preventing or destroying them is too little, too late to help blunt Alzheimer’s cruel effects. BAN2401—and Biogen’s encouraging early results with another experimental drug, aducanumab—have, for now, kept hopes alive that an amyloid approach could work.

The BAN2401 story is complicated, however. BAN2401 actually failed the main goal of its Phase 2 trial, which was to improve patients’ cognition after 12 months. The two companies continued the trial anyway and found that the 161 patients taking the highest, most frequent (biweekly) dose of BAN2401 saw their mental state improve after 18 months of treatment, compared to placebo patients.

Even those results had caveats. Eisai and Biogen used two different methodologies to measure cognition, making it harder to interpret the results. The drug also didn’t show a “dose response,” meaning higher doses didn’t necessarily lead to better results. And a tweak the companies had to make midstream created even more uncertainty: Patients carrying ApoE4 were excluded from group receiving high doses (10mg) and frequent infusions (biweekly) of BAN2401. As Wall Street analysts noted, some 30 percent of people on that dose were ApoE4 carriers compared with more than 70 percent in the placebo group. That imbalance could have “plausibly explained much or all of the apparent treatment benefit,” Leerink analyst Porges wrote in July. In other words, if ApoE4 carriers are likely to decline faster, having less of them in the treatment arm might make the drug look more effective.

Eisai countered that skepticism today, showing ApoE4 carriers and noncarriers alike progressed at similar rates in the placebo group. They also detailed how BAN2401 cleared amyloid from patients’ brains—the impact was “very impressive,” said Morgan—and reduced levels of proteins that mark the presence of the disease. And not just that: Eisai doubled down to say that the study might even be underestimating BAN2401’s treatment effect in the 10mg group.

Investors weren’t necessarily impressed. Biogen shares were down nearly 1 percent to $299.47 in midday trading. Eisai, traded publicly in Japan, was down nearly 6 percent on the Tokyo exchange.

Eisai and Biogen issued a statement Thursday that they are talking to regulators about the next steps for BAN2401. They also plan to put patients who have been in the Phase 2 trial in an open-label extension study to follow their progress over time.

With today’s fresh information, a much larger Phase 3 study seems to be the only way to answer the outstanding questions. Jeffrey Cummings, director emeritus of the Cleveland Clinic’s brain health center and a consultant to Eisai, said as much during today’s presentation: “These results need to be confirmed by additional studies, but they are moving in the direction we wanted.”

As analysts pointed out today, however, both Biogen and Eisai have other Alzheimer’s drugs in their shared pipeline. It’s not clear if BAN2401 will merit hundreds of millions more dollars of investment.

Ben Fidler contributed to this report.

Image courtesy of Dierk Schaefer via a Creative Commons 2.0 license.