Debate over whether amyloid beta represents the most worthy target in the casualty-fraught Alzheimer's disease (AD) space hasn't stopped big pharma with biotech partners from hoping that work with beta-secretase cleaving enzyme (BACE) inhibitors might yield a modifying therapy, and Eisai Inc. – paired with Biogen Inc. on the effort – is the latest to wade into phase III waters with E2609, kicking off a trial called MISSIONAD, the first of two in the program.

"We feel pretty strongly about BACE," Beyhan Zaim, Eisai's global AD lead and vice president of commercial development, told BioWorld Today, citing "a bunch of animal data, pharmacologic and genetic, that when you knock out BACE in the 40, 50, 60 percent range," benefit accrues. The BACE strategy may help block amyloid buildup; Eisai also has a phase II monoclonal antibody that may help clear it, and might be used in combination with the BACE compound. The double-pronged approach "puts Eisai in a pretty unique position," she said. "We think we're in a good spot."

Jefferies analyst Brian Abrahams noted that Eisai, of Woodcliff Lake, N.J., has talked up the favorable characteristics of the drug, including amyloid-beta suppression with quick absorption, plus a half-life and enzyme inhibition profile suitable for once-daily dosing, along with "favorable brain penetration, suggesting this could have positive characteristics in this promising class." But phase II data are limited, and researchers "will need to ensure concordance of beta-amyloid declines to actual clinical improvement," he said. What's more "identifying prodromal/early AD patients is a known challenge," he wrote in a research report. Cambridge, Mass.-based Biogen is forking over a $50 million milestone payment as part of the deal when the first patient is dosed and "with screening likely taking about two months to complete, according to Eisai, before dosing starts, whether this would be reflected in Biogen's research and development [R&D] in the fourth quarter of this year or the first quarter of next is still an unknown." (See BioWorld Today, March 6, 2014.)

Discovered by Eisai and being developed with Biogen, E2609 will be the subject of a global, multicenter, placebo-controlled, double-blind, parallel-group experiment in 1,330 patients with biomarkers confirmed for early AD. The treatment group will get 50 mg of drug daily for 24 months, and the primary endpoint to measure improvement will be the score on the Clinical Dementia Rating Sum of Boxes.

Biogen also has in phase III trials the antibody aducanumab, which binds to and may reduce amyloid plaques in the brain. During the company's earnings call about a week ago, analyst Ying Huang of Bank of America/Merrill Lynch, pointed out that Wall Street is "anxiously waiting for the top line from the solanezumab phase III [trial] in December," referring to the candidate from Indianapolis-based Eli Lilly and Co. She wanted to know what might be the implications of solanezumab's outcomes for aducanumab. Michael Ehlers, Biogen's vice president of R&D, declined to speculate but said "there are scenarios that one can envision that we are certainly taking into consideration. We very much look forward to seeing their data. A couple things I would point out on this is, although both are amyloid-beta antibodies, these are actually fundamentally quite different mechanisms of action. We think if there were positive results out of the solanezumab trial, this would give great credence to the amyloid hypothesis of AD, and I think [they would] bode well for the potential results of aducanumab." Some scientists have implicated tau proteins more than amyloid plaques in AD. "It is far more difficult to interpret a negative result" if the Lilly drug fails, Ehlers added, as it has in late-stage work before. Biogen's chief medical officer Al Sandrock noted that "the population is a little different. In solanezumab, they are studying the mild patients, which makes sense, because that is where they saw some evidence of efficacy" in previous experiments, "whereas in the case of aducanumab, we're study prodromal in the early mild patients." Eisai's Zaim pointed out that "there are different species of amyloid," and BAN2401, Eisai's anti-amyloid antibody in Phase 2, targets protofibrils, whereas the Lilly's compound "is more toward the soluble a-beta." She added that "it's not either/or" with regard to tau vs. BACE, and her firm has "some very early preclinical programs" in the former. (See BioWorld Today, Aug. 27, 2012.)

FLEXIN' OREXIN IN PHASE II

Separately, Eisai also said its phase II adaptive study with the amyloid beta antibody BAN2401 has reached its full enrollment of 800 patients. In the view of Jefferies' Abrahams, "the longer study continues, the likelier it is that activity is being observed though the magnitude may be more modest as compared to aducanumab. As there is less attention on this asset – with aducanumab titration data appearing qualitatively supportive, and all eyes on the forthcoming solanezumab data – the BAN2401 program could provide an interesting additional potential shot on goal for the Biogen/Eisai collaboration. Interestingly, Eisai noted the potential of combining BAN2401 with their BACE inhibitor in an arm of a future phase III program." Leerink analyst Geoffrey Porges noted in a report that, "at this stage, Biogen's management seems engaged and interested in E2609, but fairly disinterested in its partner's amyloid antibody."

In any case, it was the BACE mechanism that occupied center stage because of Eisai's trial start with E2609. This summer, Astrazeneca plc, of London, and Lilly won fast-track status for their BACE inhibitor AZD3293, which began a phase II/III trial in late 2014. Kenilworth, N.J.-based Merck & Co. Inc. also has a phase II/III BACE inhibitor, MK-8931. Not all BACE candidates advance as far. In the early part of last year, Ingelheim, Germany- based Boehringer Ingelheim GmbH (BI) put a voluntary clinical hold on BI 1181181 at the phase Ib stage for AD because of skin reactions, a move that put a dent in shares of partner Vitae Pharmaceuticals Inc., of Ft. Washington, Pa., and BI backed out of the deal the following July. With BACE, clinical answers will not be fast to come. Trials "are all going to be reading out around a similar time frame – 2019, 2020, 2021," Zaim said. (See BioWorld Today, March 2, 2015.)

Eisai and partner Purdue Pharma L.P., of Stamford, Conn., also said the phase II study has begun with Eisai's internally discovered oral dual orexin receptor antagonist lemborexant (E2006) in patients with mild to moderate AD who suffer from irregular sleep-wake rhythm disorder (ISWRD). Often seen in AD, ISWRD causes sleeping and waking to happen at irregular, inconsistent times during the day and night. The trial will evaluate the efficacy and safety of lemborexant in 125 patients ages 65-90 with ISWRD and mild to moderate AD. Patients will be randomized to receive 2.5, 5, 10 or 15 mg of lemborexant or placebo orally once daily for four weeks.

Over the four weeks of treatment with lemborexant compared to placebo, the primary endpoint will be the dose response of the change from baseline in sleep efficiency and wake efficiency during the last seven nights of treatment. Those changes will be measured using actigraphy, a non-invasive device worn on the wrist that is used to assess sleep-wake patterns continuously for many days.