Robert Alexander

AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate Kinetics

A growing body of pathological, biomarker, genetic, and mechanistic data suggests that amyloid accumulation, as a result of changes in production, processing, and/or clearance of brain amyloid-β peptide (Aβ) concentrations, plays a key role in the pathogenesis of Alzheimer’s disease (AD). Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid-β protein precursor (AβPP) to Aβ peptides, with the soluble N terminal fragment of AβPP (sAβPPβ) as a direct product, and BACE1 inhibition is an attractive target for therapeutic intervention to reduce the production of Aβ. Here, we report the in vitro and in vivo pharmacological profile of AZD3293, a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. The in vitro potency of AZD3293 was demonstrated in several cellular models, including primary cortical neurons. In vivo in mice, guinea pigs, and dogs, AZD3293 displayed significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aβ40, Aβ42, and sAβPPβ. The in vitro potency of AZD3293 in mouse and guinea pig primary cortical neuronal cells was correlated to the in vivo potency expressed as free AZD3293 concentrations in mouse and guinea pig brains. In mice and dogs, the slow off-rate from BACE1 may have translated into a prolongation of the observed effect beyond the turnover rate of Aβ. The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293.

Glutamate-based depression GBD.

We describe a new term: glutamate-based depression (GBD). GBD is defined as a chronic depressive illness associated with environmental stress and diseases associated with altered glutamate neurotransmission. We hypothesize that glutamate-induced over-activation of extrasynaptic NMDA receptors in the subgenual cingulate area called Brodmanns 25 plays an important role in the etiology of depression and may be responsible for the high incidence of co-morbid depression associated in diseases with glutamate etiology. While depression is a syndrome with multiple possible etiologies, we propose that a disruption in glutamatergic neurotransmission may underline a substantial proportion of clinically observed depression. The high rates of depressive symptoms associated with various disorders in which altered glutamatergic functions have been identified, may suggest a common pathophysiological mechanism is underlying the diverse clinical presentations.

MONITORING THE SOLUBLE AMYLOID PRECURSOR PROTEIN ALPHA (SAPPA) AND BETA (SAPPB) FRAGMENTS IN PLASMA AND CSF FROM HEALTHY INDIVIDUALS TREATED WITH BACE INHIBITOR AZD3293 IN A MULTIPLE ASCENDING DOSE STUDY: PHARMACOKINETIC AND PHARMACODYNAMIC CORRELATE

Subjects Completing Month 12, n (%) 28(77.8) 27(73) 30(83.3) 29(78.4) Male, n (%) 13(36.1) 18(48.6) 19(52.8) 12(32.4) Mean Age (SD) 73.3(8.79) 73.5(8.34) 74.1(9.26) 70.5(8.68) ApoE *e4 Carriers, n (%) 22(61.1) 22(59.5) 22(61.1) 22(59.5) Symptomatic AD Treatment 29(80.6) 30(81.1) 34(94.4) 30(81.1) Mean Florbetapir PET GCA SUVR (SD) 1.74(0.294) 1.75(0.313) 1.87(0.299) 1.85(0.316) Mean MMSE Total Score (SD) 22.3(2.84) 22.3(2.78) 21.5(2.47) 21.9(2.99) Mean ADAS-Cog/11 Total Score (SD) 18.3(6.70) 19.6(9.47) 20.9(7.66) 18.4(8.34) Mean DAD Total Score (SD) 86.5(15.31) 81.7(17.41) 86.1(12.92) 85.2(13.25) Florbetapir PET GCA SUVR Change From Baseline at Month 12 Within-treatment LS Mean 0.000 -0.014 -0.066 -0.021 (95% CI) (-0.062, .063) (-0.078, .050) (-0.129, -0.004) (-0.084, 0.004) p-value 0.991 0.661 0.038 0.492 Florbetapir PET GCA SUVR Change From Baseline at Month 12 Between-treatment Difference of LS Means -0.015 -0.067 -0.022 (95% CI) (-0.103, 0.074) (-0.155, 0.022) (-0.109, 0.066) p-value 0.747 0.138 0.627 Poster Presentations: P1 P447

Prerequisites to launch neuroprotective trials in Parkinson's disease: an industry perspective.

Realizing that 60% to 80% of dopaminergic nigrostriatal neurons are nonfunctional at the time of clinical diagnosis, there is an emerging consensus that disease‐modifying treatments should be initiated in the earliest stages of Parkinsons disease (PD). To date, clinical trial designs and metrics in PD have been focused on motor symptoms as the core feature of the clinical disease. To identify earlier or “pre‐motor” populations in PD, new markers have been proposed. We address the prerequisites needed to use these pre‐motor markers in clinical trials for the selection of subjects, definition of populations, and monitoring of disease progression. This may require the development of new diagnostic criteria potentially based on non‐motor clinical signs, imaging techniques, or biological features, all requiring discussion in a regulatory framework. Questions addressed include: Which steps must be taken to gain a broad consensus in the field from academic opinion leaders, patient advocacy groups, regulatory bodies, and industry? How do we prevent the selection of subgroups, which may not be representative of the full disease spectrum? Is there a way forward in personalized medicine? How do we balance risk and benefit in an at‐risk population? While many tools are available, a concerted effort is required to develop integrated data sets, as well as to achieve the necessary standardization for multicenter clinical trials. To this end, public‐private consortia (including academic centers, patient advocacy groups, and industry) will be of crucial importance to prospectively investigate and define the best tools and treatment paradigms.

Prediction and Modeling of Effects on the QTc Interval for Clinical Safety Margin Assessment, Based on Single-Ascending-Dose Study Data with AZD3839

Corrected QT interval (QTc) prolongation in humans is usually predictable based on results from preclinical findings. This study confirms the signal from preclinical cardiac repolarization models (human ether-a-go-go-related gene, guinea pig monophasic action potential, and dog telemetry) on the clinical effects on the QTc interval. A thorough QT/QTc study is generally required for bioavailable pharmaceutical compounds to determine whether or not a drug shows a QTc effect above a threshold of regulatory interest. However, as demonstrated in this AZD3839 [(S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate] single-ascending-dose (SAD) study, high-resolution digital electrocardiogram data, in combination with adequate efficacy biomarker and pharmacokinetic data and nonlinear mixed effects modeling, can provide the basis to safely explore the margins to allow for robust modeling of clinical effect versus the electrophysiological risk marker. We also conclude that a carefully conducted SAD study may provide reliable data for effective early strategic decision making ahead of the thorough QT/QTc study.

Population pharmacokinetic and pharmacodynamic analysis of plasma Aβ40 and Aβ42 following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers

Modulating deposition of Aβ‐containing plaques in the brain may be beneficial in treating Alzheimers disease. β‐site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors have been shown to reduce Aβ in plasma and CSF in healthy volunteers. In this study safety, pharmacokinetics and pharmacodynamics that is reduction of the plasma biomarkers Aβ40 and Aβ42, of the BACE1 inhibitor AZD3839 were evaluated.

BACE1 Inhibitor Lanabecestat (AZD3293) in a Phase 1 Study of Healthy Japanese Subjects: Pharmacokinetics and Effects on Plasma and Cerebrospinal Fluid Aβ Peptides

Lanabecestat (AZD3293; LY3314814) is an orally active potent inhibitor of human β‐secretase 1 in clinical development for the treatment of Alzheimer disease. In this first Japanese clinical study for an Alzheimer disease intervention to include cerebrospinal fluid (CSF) sampling in Japanese elderly healthy subjects, we report the pharmacokinetics and effects on plasma and CSF amyloid‐β (Aβ) peptides of lanabecestat in a phase 1 study involving 40 healthy Japanese subjects (NCT02005211). No safety and tolerability concerns were identified in healthy Japanese subjects exposed to lanabecestat up to the highest doses given, which is consistent with observations in a US phase 1 study of lanabecestat. Exposure to lanabecestat was similar for young and elderly subjects and increased in a dose‐dependent manner. For elderly subjects, plasma lanabecestat half‐life after multiple dosing was 12 to 17 hours (on days 10 and 14). Robust plasma and CSF Aβ peptide reductions were also seen at all doses, with CSF Aβ42 concentrations reduced by 63% and 79% in the 15‐ and 50‐mg lanabecestat groups, respectively. CSF soluble amyloid‐β precursor protein β also decreased following lanabecestat treatment. Suppression of CSF Aβ peptides was similar in elderly healthy Japanese subjects and US patients with mild to moderate Alzheimer disease. Lanabecestat is a promising potentially disease‐modifying treatment in phase 3 development for patients with early Alzheimer disease.

Clinical pharmacology in the development of new antidepressants: the challenges.

Given the lack of fundamental knowledge about the causes and pathophysiology of depression, it is a challenge for Phase I in antidepressant development to efficiently and thoroughly test new drugs. Initiation of Phase I should always be preceded by a careful consideration of what is known about the target and the molecule. While some early indicators of efficacy, such as the Emotional Test Battery, EEG markers, and fMRI correlates of anhedonia are available, further work is needed for their full incorporation in Phase I. Phase I studies of antidepressants should incorporate new measures and methods to the extent possible, and have the freedom to explore new hypotheses and move beyond the predetermined and inflexible study designs of traditional Phase I studies.

AZD3293, a potent and selective orally active, brain-permeable BACE1 inhibitor

Samantha Budd Haeberlein, Gvido Cebers, Kina H€oglund, Hugh Salter, Susanna Eketj€all, Anna Bogstedt, Tina Olsson, Robert Alexander, Michael Poole, AstraZeneca R&D, Cambridge, Massachusetts, United States; Translational Science Centre, Solna, Sweden. Contact e-mail: samantha.budd@azneuro.com Background: A growing body of pathological, biomarker, genetic and mechanistic data suggests that amyloid accumulation as a result of changes in production, processing and/or clearance of brain Ab levels plays a key role in the pathogenesis of Alzheimer’s disease (AD). G enetic mutations in APP have been linked causally to earlyonset AD, and two mutations in APP (K670N/M671L the Swedish mutation, and the A673T variant) have been associated with changes in Beta-site amyloid precursor protein cleaving enzyme1 (BACE1) activity and confer early onset AD and reduced risk for AD respectively. BACE1 is the first step in the processing of APP to Ab peptides, and its inhibition is an attractive target for therapeutic intervention to stop the production of A b.Methods:We report here the pharmacological profile of a potent and selective, orally active, brain permeable BACE1 inhibitor AZD3293. Results: The potency of AZD3293 in cellular models on secretion of Ab40 has been studied in SHSY5Y/APP cells (human neuronal cells over expressing human APPwt), N2A cells (mouse neuronal cells), primary mouse neurons and primary guinea pig neurons, using ELISA technology. Mice treated with AZD3293 as a single administration, or repeated administrations twice daily during 7 days, demonstrated a statistically significant doseand time-dependent reduction of the levels of Ab40, Ab42 and sAPPb in plasma and brain. Guinea pigs treatedwithAZD3293 as a single administration demonstrated a statistically significant doseand time-dependent reduction of the levels of Ab40, Ab42 and sAPPb in plasma, CSF and brain. In vitro potency inmouse and guinea pig primary cortical neuronal cells was strongly correlated to potency in mouse mouse and guinea pig in vivo potency.Conclusions: In conclusion, AZD3293 is a potent and selective, orally active, brain permeable BACE1 inhibitor with a promising preclinical profile for treatment of AD.

ADJUDICATING MILD COGNITIVE IMPAIRMENT DUE TO ALZHEIMER’S DISEASE AS A NOVEL ENDPOINT EVENT IN THE TOMMORROW STUDY: A DELAY-OF-ONSET PHASE 3 CLINICAL TRIAL

Carl Chiang, PhD1, Robert Alexander, MD2, Kathleen A. Welsh-Bohmer, PhD3,4, Brenda L. Plassman, PhD3,4, Heather Romero, PhD3, Kathleen M. Hayden, PhD3,4, Richard S.E. Keefe, PhD4, 5, Alexandra S. Atkins, PhD5, Patrick Harrigan, BChE6*, Janet O’Neil, MBA6, Meredith Culp, BS6, Ryan Walter, BS7, Jingtao Wu, PhD6, LaDonna Randle, BA7, Stephen Haneline, MS1, Deborah Yarbrough, MS, MBA6, Daniel K. Burns, PhD1, Ann M. Saunders, PhD1, for the TOMMORROW Study Investigators 1Zinfandel Pharmaceuticals, Inc., Durham, NC, USA; 2Takeda Development Center Americas, Inc., Cambridge, MA, USA; 3Duke University Bryan ADRC, Durham, NC, USA; 4Department of Psychiatry, Duke University Medical Center, Durham, NC, USA; 5NeuroCog Trials, Durham, NC, USA; 6Takeda Development Center Americas, Inc., Deerfield, IL, USA; 7PRA Health Science, Deerfield, IL, USA