Eisai and Biogen announced Wednesday that patients with early Alzheimer's disease who received the highest dose of the experimental drug BAN2401 had a significant slowing of clinical decline of 30 percent compared to placebo at 18 months. In addition, in the mid-stage study, the anti-amyloid beta protofibril antibody demonstrated a dose-dependent reduction in amyloid plaques as measured by amyloid PET, which was significant at all doses.
Lynn Kramer, chief medical officer of Eisai's neurology business group, remarked "we think this result is really the first of its kind," and "robust enough to approach regulatory authorities to discuss next steps." However, shares in Biogen fell nearly 12 percent on the results, with investors potentially wary about the study design and unique endpoint used to measure efficacy (for related analysis, see KOL Views: Do Biogen, Eisai’s Phase II data for BAN2401 live up to the hype?).
Study 201 randomised 856 patients with mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's dementia with confirmed amyloid pathology in the brain to receive BAN2401 dosed at 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly or 10 mg/kg biweekly, or placebo. Last year, Eisai and Biogen said that an independent data monitoring committee determined that BAN2401 "did not meet the criteria for success" based on an analysis for the primary endpoint at 12 months, which uses Eisai's in-house developed Alzheimer's disease Composite Score (ADCOMS).
However, the companies announced earlier this month that a final analysis of the study showed that the highest dose of BAN2401 significantly slowed clinical decline versus placebo and reduced amyloid beta in the brain. More recently, Eisai and Biogen disclosed that they will move ahead with Phase III testing of BAN2401.
Detailed results presented Wednesday at the Alzheimer's Association International Conference (AAIC) indicated that 253 patients received BAN2401 dosed at 10 mg/kg monthly, with 161 subjects administered the drug dosed at 10 mg/kg biweekly, with a further 253 patients on placebo. Eisai and Biogen added that following a regulatory request in 2014, the allocation of APOE4 carriers to the 10 mg/kg biweekly treatment arm was restricted, resulting in fewer APOE4 carriers in this arm and more patients being allocated to the 10 mg/kg monthly treatment arm.
Data showed that for the 10 mg/kg biweekly dose, a significant slowing in cognitive decline from baseline on ADCOMS, which combines items from the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog), the Clinical Dementia Rating Sum of Boxes (CDR-SB) scale and the Mini-Mental State Examination (MMSE), was seen at six months, as well as at 12 months. Although patients dosed with BAN2401 at 10 mg/kg monthly also showed some slowing in cognitive decline, the result was not significant.
The drugmakers noted that the highest treatment dose of BAN2401 also demonstrated a significant 47-percent slowing of clinical decline as measured by ADAS-Cog compared to placebo at six months and 18 months, but not at 12 months. Eisai and Biogen added that at 18 months, slowing of clinical decline for the highest treatment dose of BAN2401 compared to placebo on CDR-SB was 26 percent, surpassing the pre-specified difference of 25 percent over the duration of the study.
Further results showed that in patients who received BAN2401 10 mg/kg biweekly, an analysis of amyloid accumulated in the brain using standardised PET as measured on the Centiloid scale demonstrated an observed mean at baseline of 74.5 and at 18 months of 5.5. Eisai and Biogen explained that the mean reduction in amyloid load was 70 units, which was significant, while in the highest dose group, 81 percent of patients converted from amyloid positive to negative at 18 months.
According to the drugmakers, BAN2401 showed "an acceptable tolerability profile" through 18 months, with the incidence rate of treatment-related adverse events being 26.5 percent for placebo, 53.4 percent for the 10 mg/kg monthly treatment arm and 47.2 percent for the 10 mg/kg biweekly group. The most common adverse events were amyloid related imaging abnormalities (ARIA), with an incidence of ARIA oedema of 9.9 percent at the highest treatment dose.
Jefferies analyst Michael Yee noted that the key results were in line with expectations, but that "some aspects were mixed, such as lower doses showing worse outcomes than a placebo."
Eisai licensed exclusive global rights to BAN2401 from BioArctic in 2007, and has been jointly developing the drug with Biogen under the terms of a 2014 agreement focused on treatments for Alzheimer's disease.
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