Veronika Logovinsky

Can we prevent Alzheimer's disease? Secondary “prevention” trials in Alzheimer's disease

Current research including the basic biology of Alzheimers disease (AD) provides a foundation to explore whether our current state of knowledge is sufficient to initiate prevention studies and allow us to believe prevention of AD is possible. Current research and recently revised criteria for the diagnosis of AD by the National Institutes on Aging and the Alzheimers Association suggest a continuum of disease from preclinical asymptomatic to symptomatic Alzheimers dementia. In light of these revised criteria, the possibility of secondary prevention and even primary prevention is under discussion. The Alzheimers Association Research Roundtable convened a meeting to discuss the rationale and feasibility of conducting secondary prevention trials in AD.

Perspectives on future Alzheimer therapies: amyloid-β protofibrils - a new target for immunotherapy with BAN2401 in Alzheimer's disease

The symptomatic drugs currently on the market for Alzheimer’s disease (AD) have no effect on disease progression, and this creates a large unmet medical need. The type of drug that has developed most rapidly in the last decade is immunotherapy: vaccines and, especially, passive vaccination with monoclonal antibodies. Antibodies are attractive drugs as they can be made highly specific for their target and often with few side effects. Data from recent clinical AD trials indicate that a treatment effect by immunotherapy is possible, providing hope for a new generation of drugs. The first anti-amyloid-beta (anti-Aβ) vaccine developed by Elan, AN1792, was halted in phase 2 because of aseptic meningoencephalitis. However, in a follow-up study, patients with antibody response to the vaccine demonstrated reduced cognitive decline, supporting the hypothesis that Aβ immunotherapy may have clinically relevant effects. Bapineuzumab (Elan/Pfizer Inc./Johnson & Johnson), a monoclonal antibody targeting fibrillar Aβ, was stopped because the desired clinical effect was not seen. Solanezumab (Eli Lilly and Company) was developed to target soluble, monomeric Aβ. In two phase 3 studies, Solanezumab did not meet primary endpoints. When data from the two studies were pooled, a positive pattern emerged, revealing a significant slowing of cognitive decline in the subgroup of mild AD. The Arctic mutation has been shown to specifically increase the formation of soluble Aβ protofibrils, an Aβ species shown to be toxic to neurons and likely to be present in all cases of AD. A monoclonal antibody, mAb158, was developed to target Aβ protofibrils with high selectivity. It has at least a 1,000-fold higher selectivity for protofibrils as compared with monomers of Aβ, thus targeting the toxic species of the peptide. A humanized version of mAb158, BAN2401, has now entered a clinical phase 2b trial in a collaboration between BioArctic Neuroscience and Eisai without the safety concerns seen in previous phase 1 and 2a trials. Experiences from the field indicate the importance of initiating treatment early in the course of the disease and of enriching the trial population by improving the diagnostic accuracy. BAN2401 is a promising candidate for Aβ immunotherapy in early AD. Other encouraging efforts in immunotherapy as well as in the small-molecule field offer hope for new innovative therapies for AD in the future.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel γ‐secretase modulator, E2212, in healthy human subjects

E2212, a novel γ‐secretase modulator, is under development for the treatment of Alzheimers disease. The safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending oral doses (10–250 mg, double‐blind, placebo‐controlled, randomized) of E2212 were evaluated. In this phase I clinical trial, E2212 was found to be well tolerated in single doses. Maximum tolerated dose was not achieved up to 250 mg. Most AEs were mild to moderate in severity with no identifiable dose related pattern. There were no clinically significant findings on physical and ophthalmologic examinations as well as vital signs, laboratory, ECG and C‐SSRS assessments. E2212 was rapidly absorbed, with median tmax values ranging from 0.5 to 1.0 h. E2212 exhibited biphasic disposition with the terminal t1/2 of 12.5–19.0 h. Renal excretion was the minor pathway for E2212 elimination. Increased PD response (reduction in plasma concentrations of Aβ(x–42)) was observed with increasing doses. The maximum PD response was observed in the highest dose 250 mg cohort, with ΔAUAC(0–24 h) of 44.1% and Amax of 53.6%. These results support further clinical development of E2212.

E2012, a novel gamma-secretase modulator, decreases plasma amyloid-beta (Aβ) levels in humans

Results: E2012 reduced plasma Aβ40 and Aβ42 in healthy subjects in a dose-related manner. Aβ42 decreased to a greater extent than Aβ40 (maximum reductions at 400 mg ~ 50% and ~30%, respectively) at 4-6 hrs post-dose, without a rebound effect. AUC0-inf increased proportionally up to 400 mg. Cmax increased proportionally up to 200 mg and less than proportionally thereafter. Results from rat studies with E2012 were predictive of the results obtained in humans for plasma Aβ effect over 24 hr. Effects on rat CSF and brain Aβ followed similar trends, supporting the use of CSF as a surrogate matrix for effects on brain Aβ in humans.

ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials.

Background Development of new therapies for Alzheimers disease (AD) is increasingly focused on more mildly affected populations, and requires new assessment and outcome strategies. Patients in early stages of AD have mild cognitive decline and no, or limited, functional impairment. To respond to these assessment challenges, we developed a measurement approach based on established scale items that exhibited change in previous amnestic Mild Cognitive Impairment (aMCI) trials. Methods Partial least squares regression with a longitudinal clinical decline model identified items from commonly used clinical scales with the highest combined sensitivity to change over time in aMCI and weighted these items according to their relative contribution to detecting clinical progression in patients’ early stages of AD. The resultant AD Composite Score (ADCOMS) was assessed for its ability to detect treatment effect in aMCI/prodromal AD (pAD) clinical trial populations. Results ADCOMS consists of 4 Alzheimers Disease Assessment Scale–cognitive subscale items, 2 Mini-Mental State Examination items, and all 6 Clinical Dementia Rating—Sum of Boxes items. ADCOMS demonstrated improved sensitivity to clinical decline over individual scales in pAD, aMCI and in mild AD dementia. ADCOMS also detected treatment effects associated with the use of cholinesterase inhibitors in these populations. Improved sensitivity predicts smaller sample size requirements when ADCOMS is used in early AD trials. Conclusions ADCOMS is proposed as new standard outcome for pAD and mild AD dementia trials, and is progressing in a CAMD-sponsored qualification process for use in registration trials of pAD.

Coalition Against Major Diseases Precompetitive Collaborations and Regulatory Paths to Accelerating Drug Development for Neurodegenerative Diseases

Precompetitive collaborations have been successful in several disease areas and industries. Such collaborations are critical to address the gaps and challenges in therapeutic development for chronic neurodegenerative diseases. On November 5, 2012, members of the scientific community, advocates, regulators, industry, and government officials met at the US Food and Drug Administration to develop tools to expedite drug development and maximize the potential for success in future drug trials for Alzheimer disease and Parkinson disease. The meeting established that multiple collaborative approaches are essential for accelerating drug development. Such approaches include precompetitive data sharing, regulatory qualification of biomarkers and clinical outcome assessments, implementation of data standards, and development of quantitative drug disease trial models. While challenges to collaboration among industry partners are formidable, they are not insurmountable. The Coalition Against Major Diseases (CAMD) has several positive examples to highlight. This review represents proceedings from CAMD’s annual conference and discusses the key themes that are being advanced by the Critical Path Institute.

Design of a Bayesian adaptive phase 2 proof-of-concept trial for BAN2401, a putative disease-modifying monoclonal antibody for the treatment of Alzheimer's disease

Recent failures in phase 3 clinical trials in Alzheimers disease (AD) suggest that novel approaches to drug development are urgently needed. Phase 3 risk can be mitigated by ensuring that clinical efficacy is established before initiating confirmatory trials, but traditional phase 2 trials in AD can be lengthy and costly.

A first-in-human study of BAN2401, a novel monoclonal antibody against beta-amyloid protofibrils

a similar pattern to that described in Finland[4] . Possible environmental aetiological factors include a rural-urban effect [1], proximity to mining, selenium[5], or another factor, yet to be identified. 1. Russ et al. (2012) Int J Epidemiol 41:1012-32.2. Starr et al. (1997) Pyschiat Genet 7:147-52.3. Gat z et al. (2005) Neurobiol Aging 26:439-47.4. Sulkava et al. (1988) Regional differences in the prevalence of Alzheimer’s disease. In: Proceedings of the International Symposium on Alzheimer’s Disease, University of Kuopio, Finland.5. Parkman & Hultberg (2002) Occurrence and effects of selenium in the environment a literature review.

A multimodal imaging study of mAb158, a murine monoclonal antibody with high selectivity for amyloid protofibrils, in Tg2576 mice

P4-282 A MULTIMODAL IMAGING STUDY OF MAB158, A MURINE MONOCLONAL ANTIBODY WITH HIGH SELECTIVITY FOR AMYLOID PROTOFIBRILS, IN TG2576 MICE Bradford Navia, Carlos Perdomo, Stephen Krause, June M. Kaplow, Akihiko Koyama, Tyler Teceno, Ben Gershman, Veronika Logovinsky, Chad Swanson, Robert Lai, Christer M€oller, Lars Lannfelt, Andrew Satlin, Paul McCracken, Eisai Inc., Woodcliff Lake, New Jersey, United States; Eisai Inc., Andover, Massachusetts, United States; InviCRO, LLC, Boston, Massachusetts, United States; Eisai Ltd., Hatfield, United Kingdom; BioArctic Neuroscience AB, Stockholm, Sweden; Uppsala University, Uppsala, Sweden. Contact e-mail: paul_mccracken@ eisai.com

Composite measures in Alzheimer’s disease clinical trials: How an in-study data quality program ensures immediate and ongoing quality of the sum of their parts

Hospital, Second Military Medical University, Shanghai, China; Department of Neurology, The 10th People’s Hospital, Tongji University, Shanghai, China; Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China; Department of Geriatric Neurology, Chinese PLA General Hospital, Beijing, China; Department of Neurology, The First Hospital of Jilin University, Shanghai, China; Mental Health Center of Hebei Province, Baoding, China; Department of Neurology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Beijing Hui-Long-Guan Hospital, Peking University, Beijing, China; Department of Geratology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; First Affiliated Hospital of Kunming Medicine University, Kunming, China; Guangzhou Psychiatric Hospital, Guangzhou, China; Department of Neurology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; Affiliated Hospital of GuilinMedical School, Guilin, China; Department of Neurology, The First Affiliated Hospital of Xiamen University, Xiamen, China; Neurological Department, The Third Xiangya Hospital of Central South University, Hunan, China; Department of Health Statistics, Second Military Medical University, Shanghai, China. Contact e-mail: wtshhwy@ 163.com