Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) and Biogen Inc. (Nasdaq: BIIB) (Headquarters: Cambridge, Massachusetts, United States, CEO: Michel Vounatsos, “Biogen”) announced detailed results from the Phase II study (Study 201) with BAN2401, an anti-amyloid beta (A\u03b2) protofibril antibody, in 856 patients with early Alzheimer\u2018s disease as part of Session DT-01 “Recent Developments in Therapeutics (Presentation number: DT-01-07) at the Alzheimer\u2019s Association International Conference (AAIC) 2018 being held in Chicago, Illinois, United States on July 25. This abstract was accepted for Late Breaking oral presentation at AAIC.<\/p>\n
Study 201 (ClinicalTrials.gov identifier NCT01767311) is a placebo-controlled, double-blind, parallel-group, randomized Phase II clinical study in 856 patients with mild cognitive impairment (MCI) due to Alzheimer\u2019s disease or mild Alzheimer\u2018s dementia (collectively known as early Alzheimer\u2018s disease) with confirmed amyloid pathology in the brain. Patients were randomized to five dose regimens, 2.5 mg\/kg biweekly, 5 mg\/kg monthly, 5 mg\/kg biweekly, 10 mg\/kg monthly and 10 mg\/kg biweekly, or placebo. This study used a Bayesian Adaptive Randomization Design to automatically allocate newly enrolled patients into the study to treatment arms showing higher probability of efficacy based on the results of interim analyses.<\/p>\n
The study assessed changes from baseline to 18 months in biomarkers measuring the underlying disease pathophysiology, including changes in amyloid accumulated in the brain as measured by amyloid PET (positron emission tomography). The clinical endpoints of Alzheimer\u2019s Disease Composite Score (ADCOMS), Alzheimer\u2018s Disease Assessment Scale-cognitive subscale (ADAS-Cog) and Clinical Dementia Rating Sum of Boxes (CDR-SB) \u00a0were also assessed from baseline to 18 months of treatment.<\/p>\n
Through Bayesian interim analyses, the highest doses of 10 mg\/kg monthly and 10 mg\/kg biweekly were determined to be the treatment dosages with higher efficacy early in the trial, and as a result, the proportion of patients allocated to these treatment arms was greater (placebo: 247 patients, 2.5 mg\/kg biweekly: 52 patients, 5 mg\/kg monthly: 51 patients, 5 mg\/kg biweekly: 92 patients, 10 mg\/kg monthly: 253 patients, 10 mg\/kg biweekly: 161 patients). Following a regulatory request (outside of the United States) in July 2014, the allocation of APOE4 carriers to the 10 mg\/kg biweekly treatment arm was restricted, resulting in fewer APOE4 carriers\u00a0 in this arm and more patients being allocated to the 10 mg\/kg monthly treatment arm.<\/p>\n
BAN2401 demonstrated a dose-dependent reduction in amyloid plaques as measured by amyloid PET, and this reduction was statistically significant at all doses. At the highest dose of BAN2401 (10 mg\/kg biweekly), an analysis of amyloid accumulated in the brain using standardized PET as measured on the Centiloid scale showed an observed mean at baseline of 74.5 and at 18 months of 5.5. Using a Mixed-effects Model with Repeated Measures (MMRM), the mean reduction in amyloid load was 70 units, which was statistically significant (p<0.0001). In amyloid PET image visual read, BAN2401 demonstrated a dose dependent conversion from amyloid positive to negative, and at the highest dose, 81% of patients converted from amyloid positive to negative at 18 months (p<0.0001).<\/p>\n
Conventional statistical methods on predefined clinical endpoints at the 18 month final efficacy time point confirmed a dose-dependent slowing in cognitive decline from baseline on ADCOMS. The highest treatment dose of 10 mg\/kg biweekly demonstrated a statistically significant slowing of clinical decline of 30% compared to placebo at 18 months (p=0.034). A statistically significant slowing of decline on ADCOMS was observed as early as 6 months (p<0.05) as well as at 12 months (p<0.05). Dose-dependent slowing in cognitive decline from baseline on ADAS-Cog was also observed for BAN2401, with the highest treatment dose of BAN2401 demonstrating a significant slowing of clinical decline compared to placebo at 18 months (47% slower decline, p=0.017). Furthermore, dose-dependent slowing in cognitive decline from baseline on CDR-SB was observed, surpassing the pre-specified difference of 25% over the duration of the study. At 18 months, slowing of clinical decline for the highest treatment dose of BAN2401 compared to placebo on CDR-SB was 26%. The rate of clinical decline for the placebo group was consistent with the results of research by the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI) in the United States.<\/p>\n
In a Bayesian analysis of ADCOMS at 12 months, the estimated probability that the highest dose of BAN2401 slows clinical decline more than placebo was 98%. While the criteria for early success at 12 months was pre-specified as an 80% or higher estimated probability of demonstrating a clinically significant difference (a 25% or greater slowing in clinical decline) from baseline compared to placebo, the actual probability for this criteria was 64% according to Bayesian analysis.<\/p>\n
A dose-dependent increase in A\u03b2 levels in cerebrospinal fluid (CSF) in patients on BAN2401 (highest dose at 18 months: p<0.0001) was observed. Combined analysis of patients receiving BAN2401 at 10 mg\/kg (either monthly or biweekly) demonstrated a statistically significant reduction in total tau over time compared to placebo (p<0.05).<\/p>\n
BAN2401 demonstrated an acceptable tolerability profile through 18 months of study drug administration. \u00a0The incidence rate of treatment-related adverse events was 26.5% for the placebo arm, 53.4% for the 10 mg\/kg monthly treatment arm and 47.2% for the 10 mg\/kg biweekly treatment arm. The most common treatment emergent adverse events were Amyloid Related Imaging Abnormalities (ARIA) and infusion-related reactions. Incidence of ARIA-E (edema) was 9.9% at the highest treatment dose, and not more than 10% in any of the treatment arms. Incidence of ARIA-E in APOE4 carriers was 14.6% at the highest dose. Per protocol, all patients presenting with ARIA-E on MRI were discontinued in the study. The incidence rate of serious adverse events was 17.6% for the placebo arm, 12.3% for the 10 mg\/kg monthly treatment arm and 15.5% for the 10 mg\/kg biweekly arm.<\/p>\n
This release discusses investigational uses of an agent in development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that any investigational uses of such product will successfully complete clinical development or gain health authority approval.<\/p>\n
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Biogen Safe Harbor Statement<\/strong><\/p>\n This press release contains forward-looking statements, including statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 about results from the Phase II study of BAN2401; the potential clinical effects of BAN2401; the potential benefits, safety, and efficacy of BAN2401 and therapies for other neurological diseases; the clinical development program for BAN2401; risks and uncertainties associated with drug development and commercialization; the timing and status of current and future regulatory filings; Biogen\u2018s strategy and plans; the anticipated benefits and potential of Biogen\u2019s collaboration arrangements with Eisai; and the potential of Biogen\u2018s commercial business and pipeline programs, including BAN2401, elenbecestat, and aducanumab. These forward-looking statements may be accompanied by words such as “aim,” “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,” “intend,” “may,” “plan,” “potential,” “possible,” “will,” and other words and terms of similar meaning. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. Results in early stage clinical trials may not be indicative of full results or results from later stage or larger scale clinical trials and do not ensure regulatory approval. You should not place undue reliance on these statements or scientific data presented.<\/p>\n These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including without limitation, unexpected concerns that may arise from additional data, analysis, or results obtained during clinical trials; regulatory authorities may require additional information or further studies, or may fail or refuse to approve or may delay approval of Biogen\u2019s drug candidates, including BAN2401, elenbecestat, and\/or aducanumab; the occurrence of adverse safety events; risks of unexpected costs or delays; the risks of other unexpected hurdles; uncertainty of success in the development and potential commercialization of BAN2401, elenbecestat, and\/or aducanumab, which may be impacted by, among other things, unexpected concerns that may arise from additional data or analysis, the occurrence of adverse safety events, failure to obtain regulatory approvals in certain jurisdictions, failure to protect and enforce Biogen\u2018s data, intellectual property, and other proprietary rights and uncertainties relating to intellectual property claims and challenges; uncertainty as to whether the anticipated benefits and potential of Biogen\u2019s collaboration arrangement with Eisai can be achieved; product liability claims; and third party collaboration risks. \u00a0The foregoing sets forth many, but not all, of the factors that could cause actual results to differ from Biogen\u2018s expectations in any forward-looking statement. Investors should consider this cautionary statement, as well as the risk factors identified in Biogen\u2018s most recent annual or quarterly report and in other reports Biogen has filed with the U.S. Securities and Exchange Commission. These statements are based on Biogen\u2019s current beliefs and expectations and speak only as of the date of this press release. \u00a0Biogen does not undertake any obligation to publicly update any forward-looking statements, whether as a result of new information, future developments or otherwise.<\/p>\n Media Inquiries<\/strong><\/b><\/p>\n