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UB-311, a novel UBITh® amyloid ? peptide vaccine for mild Alzheimer's disease.

ABSTRACT: INTRODUCTION:A novel amyloid ? (A?) synthetic peptide vaccine (UB-311) has been evaluated in a first-in-human trial with patients of mild-to-moderate Alzheimer's disease. We describe translational research covering vaccine design, preclinical characterization, and phase-I clinical trial with supportive outcome that advances UB-311 into an ongoing phase-II trial. METHODS:UB-311 is constructed with two synthetic A?1-14-targeting peptides (B-cell epitope), each linked to different helper T-cell peptide epitopes (UBITh®) and formulated in a Th2-biased delivery system. The hAPP751 transgenic mouse model was used to perform the proof-of-concept study. Baboons and macaques were used for preclinical safety, tolerability, and immunogenicity evaluation. Patients with mild-to-moderate Alzheimer's disease (AD) were immunized by intramuscular route with 3 doses of UB-311 at weeks 0, 4, and 12, and monitored until week 48. Safety and immunogenicity were assessed per protocol, and preliminary efficacy was analyzed by Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Mini-Mental State Examination (MMSE), and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). RESULTS:UB-311 covers a diverse genetic background and facilitates strong immune response with high responder rate. UB-311 reduced the levels of A?1-42 oligomers, protofibrils, and plaque load in hAPP751 transgenic mice. Safe and well-tolerated UB-311 generated considerable site-specific (A?1-10) antibodies across all animal species examined. In AD patients, UB-311 induced a 100% responder rate; injection site swelling and agitation were the most common adverse events (4/19 each). A slower rate of increase in ADAS-Cog from baseline to week 48 was observed in the subgroup of mild AD patients (MMSE ? 20) compared with the moderate AD subgroup, suggesting that UB-311 may have a potential of cognition improvement in patients with early stage of Alzheimer's dementia. DISCUSSION:The UBITh® platform can generate a high-precision molecular vaccine with high responder rate, strong on-target immunogenicity, and a potential of cognition improvement, which support UB-311 for active immunotherapy in early-to-mild AD patients currently enrolled in a phase-II trial (NCT02551809).

SUBMITTER: Wang CY

PROVIDER: S-EPMC5651432 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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UB-311, a novel UBITh<sup>®</sup> amyloid β peptide vaccine for mild Alzheimer's disease.

Wang Chang Yi CY Wang Pei-Ning PN Chiu Ming-Jang MJ Finstad Connie L CL Lin Feng F Lynn Shugene S Tai Yuan-Hung YH De Fang Xin X Zhao Kesheng K Hung Chung-Ho CH Tseng Yiting Y Peng Wen-Jiun WJ Wang Jason J Yu Chih-Chieh CC Kuo Be-Sheng BS Frohna Paul A PA

Alzheimer's & dementia (New York, N. Y.) 20170414 2

<h4>Introduction</h4>A novel amyloid β (Aβ) synthetic peptide vaccine (UB-311) has been evaluated in a first-in-human trial with patients of mild-to-moderate Alzheimer's disease. We describe translational research covering vaccine design, preclinical characterization, and phase-I clinical trial with supportive outcome that advances UB-311 into an ongoing phase-II trial.<h4>Methods</h4>UB-311 is constructed with two synthetic Aβ<sub>1-14</sub>-targeting peptides (B-cell epitope), each linked to d ...[more]

PMID: 29067332

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Project description:Backgroundα-Synuclein (αSyn) is believed to play a central role in Parkinson's disease (PD) neuropathology and is considered a target for disease modification. UB-312 is a synthetic αSyn peptide conjugated to a T helper peptide and is expected to induce antibodies specifically against oligomeric and fibrillar αSyn, making UB-312 a potential immunotherapeutic for synucleopathies.ObjectiveTo investigate the safety, tolerability, and immunogenicity of UB-312 vaccination in healthy participants and to determine a safe and immunologically optimal dose for the first-in-patient study.MethodsFifty eligible healthy participants were enrolled in a 44-week, randomized, placebo-controlled, double-blind study. Participants in seven cohorts were randomized to three intramuscular UB-312 or placebo injections at weeks 1, 5, and 13 (doses ranging between 40 and 2000 μg). Safety and tolerability were assessed by adverse events, clinical laboratory, vital signs, electrocardiograms, and neurological and physical examinations. Immunogenicity was assessed by measuring serum and cerebrospinal fluid (CSF) anti-αSyn antibody concentrations.ResultsTwenty-three participants received all three vaccinations of UB-312. Most adverse events were mild, transient, and self-resolving. Common treatment-emergent adverse events included headache, nasopharyngitis, vaccination-site pain, lumbar puncture-site pain, and fatigue. UB-312 induced dose- and time-dependent antibody production. Antibodies were detectable in serum and CSF of all participants receiving the 300/300/300 μg UB-312 dose regimen. The average CSF/serum ratio was 0.2%.ConclusionsUB-312 was generally safe, well tolerated, and induced anti-αSyn antibodies in serum and CSF of healthy participants. The 100 and 300 μg doses are selected for further evaluation in participants with PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Project description:BACKGROUND:Optimized scales and composite outcomes have been proposed as a way to more accurately measure Alzheimer's disease related decline. AFFITOPE® AD02, is an amyloid-beta (A?)-targeting vaccine to elicit anti-A? antibodies. IMM-AD04, commonly known as Alum, originally designated as a control agent, appeared to have disease-modifying activity in a multicenter, parallel group phase II study in early AD patients. OBJECTIVES:To develop adapted outcomes for cognition, function and a composite scale with improved sensitivity to decline and treatment effects in early AD (mild plus prodromal AD) based on historical data and to assess these adapted outcomes in this phase II study. DESIGN:Data from public datasets was analyzed using a partial least squares model in order to identify an optimally weighted cognitive outcome, Adapted ADAS-cog, and an optimally weighted ADL outcome, Adapted ADCS-ADL which were prospectively defined as co-primary endpoints for the study and were also combined into a composite scale. Data from 162 patients in the placebo groups of ADCS studies and 156 mild patients in the ADNI I study were pooled for this analysis. The Adapted ADAS-cog scale considered 13 ADAS-cog items as well as several Neuropsychological test items and CogState items, the Adapted ADCS-ADL considered all ADCS-ADL items. After the pre-specified analyses were complete, additional adapted and composite scales were investigated in a post-hoc manner. Evaluation of the adapted and composite scales was performed on Phase II trial data for AFFITOPE® AD02 (AFF006, Clinical Trial Identifier: NCT01117818) and historic data in early AD. Least square means, standard deviations, and least squares mean to standard deviation ratios were compared among adapted and composite scales and traditional scales for the 5 treatment groups in the phase II study and overall for the historic data. Treatment effect sizes and p-values were also compared for the phase II study. RESULTS:Cognitive items that were selected for the adapted cognitive scale (aADAS-cog) and had the highest weights were Word Recall, Word Recognition, and Orientation. Delayed Word Recall and Digit Cancellation were among the items excluded due to lack of improved sensitivity to decline. Highly weighted ADL items included in the adapted functional scale (aADCS-ADL) were using the telephone, traveling, preparing a meal/snack, selecting clothing, shopping and using appliances. Excluded items were primarily basic ADLs such as eating, walking, toileting and bathing. Comparisons between traditional scales and primary outcome adapted scales show improved sensitivity to group differences with the adapted scales in the phase II trial. Most of the improvement in the sensitivity of the aADAS-cog and the aADCS-ADL is due to a larger treatment difference observed rather than the improved sensitivity to decline in the comparison groups. CONCLUSION:To our knowledge, this is the first study to prospectively use optimized scales as primary endpoints and to demonstrate the superior power of optimized scales and composites in early disease. Although it is possible that the treatment difference between randomized groups is due to a factor other than the treatment itself, for instance baseline imbalance, the improved power to detect these differences still argues in favor of the adapted scales. The issue of oversensitivity to detect treatment effects is controlled by selection of the alpha level for significance, and in our case will happen less than 5% of the time. Clinical relevance of the treatment difference should be assessed separately from statistical significance, and in this phase II study, is supported by significant or similar sizes of effect on function, behaviour and quality of life outcomes, which are important to patients and caregivers.

Dataset Information

UB-311, a novel UBITh® amyloid ? peptide vaccine for mild Alzheimer's disease.

Publications

UB-311, a novel UBITh<sup>®</sup> amyloid β peptide vaccine for mild Alzheimer's disease.

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