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Abstract Background New therapies are urgently needed for Alzheimer’s disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide with a novel proposed mechanism of action. The first phase 3 clinical trial of GV-971 has been completed in China. Methods We conducted a phase 3, double-blind, placebo-controlled trial in participants with mild-to-moderate AD to assess GV-971 efficacy and safety. Participants were randomized to placebo or GV-971 (900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC+), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI). Safety and tolerability were monitored. Results A total of 818 participants were randomized: 408 to GV-971 and 410 to placebo. A significant drug-placebo difference on the ADAS-Cog12 favoring GV-971 was present at each measurement time point, measurable at the week 4 visit and continuing throughout the trial. The difference between the groups in change from baseline was − 2.15 points (95% confidence interval, − 3.07 to − 1.23; p

An immune response to recombinant human protein therapeutics, including type I interferons (IFNs), has the potential to have a serious negative impact on safety and efficacy. Monitoring of patients for neutralizing antibodies (NAbs) often is advisable. In the case of IFN-βtherapy for multiple sclerosis (MS), we obtained reproducible quantitative titers of NAbs using an improved and well-characterized assay based on a 10-fold reduction of a challenge dose of IFN-β. However, the observed titer was significantly affected by the preparation of IFN-βused as the assay challenge. NAb titers obtained using IFN-β1b averaged 3–5-fold lower than titers of the same sample assayed using either IFN-β1a or human fibroblast-derived IFN-β. This was the case whether neutralizing serum was obtained from patients on therapy with IFN-β1a or IFN-β1b. The reason for this apparent titer difference is not fully understood but appears to be related to protein folding or other structural properties that differentiate the IFN-β1b both from commercial IFN-β1a preparations and from human fibroblast-derived IFN-β. [ABSTRACT FROM AUTHOR]

Background: KHK6640 is a novel humanized anti-amyloid beta oligomer-specific antibody. Both KHK6640 and the mouse parent antibody E64 have demonstrated high potency and efficacy for cognitive improvement in several rodent Alzheimer's disease models, including an anti-amyloid beta injection mouse model and in age-matched double transgenic littermates. The favorable safety and pharmacokinetic profiles of KHK6640 reported in preclinical studies warrant clinical trials in Alzheimer's disease patients., Objectives: We evaluated the safety, pharmacokinetics, and efficacy of intravenous and subcutaneous oligomer-specific antibody KHK6640 in treating patients with prodromal Alzheimer's disease or mild to moderate Alzheimer's disease., Design: Phase I/2a, multicenter, randomized, double-blind, placebo-controlled trial., Setting: Nine sites in Europe participated in this clinical trial., Participants: 97 patients with prodromal Alzheimer's disease or mild to moderate Alzheimer's disease., Intervention: Single and multiple ascending intravenous and subcutaneous doses of KHK6640 in doses ranging from 0.1 mg/kg to 20 mg/kg or placebo was administered to patients monthly for six months., Measurements: Primary outcomes were safety including amyloid-related imaging abnormalities for edema and hemorrhage, assessed with magnetic resonance imaging. Plasma and cerebrospinal fluid samples were analyzed to investigate pharmacokinetics and KHK6640 effects on biomarkers. Cognition, brain glucose metabolism and amyloid load were exploratory outcomes., Results: No amyloid-related imaging abnormalities for edema were observed. Amyloid-related imaging abnormalities for hemorrhage were comparable to that of placebo and population background. KHK6640 exposure was approximately dose-equivalent, with a serum terminal elimination half-life of approximately 19 days. KHK6640 pharmacokinetics in serum and cerebrospinal fluid, including cerebrospinal fluid oligomers trapped by the antibody were dose related. Positive trends seen in the positron emission tomography brain glucose metabolism and amyloid load, cerebrospinal tau but cognition assessments were inconclusive, due to low numbers., Conclusions: KHK6640 was well-tolerated across all doses, without any amyloid-related imaging abnormalities for edema, and amyloid-related imaging abnormalities for hemorrhage was as population background. The demonstrated dose-response of specific target biomarkers provides dosing guidance on dose and administration method selection for further clinical development., Competing Interests: MC received consulting fees from Kyowa, CogRx, AlgRx, Acadia, Novartis, Jocasta and Schering. NDP consulting fees from Aribio, and Amylyx. He was a site PI on this KHK6640 trial sand co-PI of Fuji Film Toyama Chemical trial and received speaker fees from Biogen. NDP served on the DSMB of Abbvie’s M15-566 trial. NA He was a site PI on this KH6640 trial, and received consulting fees from Janssen, Lily, Eisai and Novaris.