Laura M. Gault

Tau: From research to clinical development

Alzheimers Association Research Roundtable Fall 2015—Tau: From research to clinical development. Tau pathology is recognized as the key driver of disease progression in Alzheimers and other neurodegenerative diseases. Although this makes tau an attractive target for the development of novel diagnostic and therapeutic strategies, the mechanisms underlying the onset and progression of tau‐related neurotoxicity remain elusive. Recent strides in the development of sophisticated preclinical models and the emergence of tau PET imaging and fluid biomarkers provide new opportunities to increase our understanding of tau biology, overcome translational challenges, and accelerate the advancement of tau therapeutics from bench to bedside. With this in mind, the Alzheimers Association convened a Research Roundtable in October 2015, bringing together experts from academia, industry, and regulatory agencies to discuss the latest understanding of tau pathogenic pathways and review the evolution of tau therapeutics and biomarkers currently in development. The meeting provided a forum to share experience and expertise with the common goal of advancing the discovery and development of new treatment strategies and expediting the design and implementation of efficient clinical trials.

Safety and Efficacy of ABT-089 in Pediatric Attention-Deficit/Hyperactivity Disorder: Results from Two Randomized Placebo-Controlled Clinical Trials.

OBJECTIVE To assess the safety and efficacy of ABT-089, a novel α(4)β(2) neuronal nicotinic receptor partial agonist, vs. placebo in children with attention-deficit/hyperactivity disorder (ADHD). METHOD Two multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of children 6 through 12 years of age were conducted. Study 1 (n = 274) assessed six treatment groups over 8 weeks: 4 once-daily (QD) ABT-089 doses (0.085-0.700 mg/kg), QD atomoxetine, and placebo. Study 2 (n = 119) assessed three treatment groups over 6 weeks: 2 QD ABT-089 doses (0.7 mg/kg, 1.4 mg/kg) and placebo. The primary efficacy variable was the investigator-administered Attention-Deficit/Hyperactivity Disorder Rating Scale-IV: Home Version (ADHD-RS-IV [HV]) Total Score. Safety was assessed by adverse event (AE) monitoring, laboratory tests, vital signs, physical examinations, and electrocardiogram measures. RESULTS There was no statistically significant difference between ABT-089 and placebo in mean change from baseline to final evaluation of ADHD-RS-IV (HV) Total Score or other outcome measures at any dose in either study. In Study 1, atomoxetine showed statistically significant improvement for the primary and most secondary endpoints. ABT-089 was generally safe and well tolerated, with no statistically significant difference between any ABT-089 dose and placebo in the overall incidence of any specific AE, and no clinically significant changes in other safety measures. CONCLUSIONS ABT-089 did not show efficacy on the primary efficacy variable, the ADHD-RS-IV (HV) Total Score, or other measures of ADHD symptomatology in children with ADHD, and had a safety profile similar to placebo. These results contrast with published reports of efficacy of nicotinic modulators in adults with ADHD.

A randomized study of H3 antagonist ABT-288 in mild-to-moderate Alzheimer's dementia.

BACKGROUND ABT-288, a highly selective histamine-3 receptor antagonist, demonstrated efficacy across several preclinical cognitive domains, and safety in healthy subjects and elderly volunteers. OBJECTIVE Evaluate the efficacy and safety of ABT-288 in subjects with mild-to-moderate Alzheimers dementia. METHODS The study used a randomized, double-blind, placebo- and active-controlled, parallel group design with pre-defined futility criteria to permit early study termination. A total of 242 subjects were randomized in an equal ratio to ABT-288 1 mg or 3 mg, donepezil 10 mg, or placebo once daily for 12 weeks. The primary efficacy endpoint was the change from baseline to final evaluation on the 13-item Alzheimers Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score. RESULTS The study was prematurely terminated because futility criteria were met. Point estimates on the ADAS-Cog scores for both ABT-288 dose groups were numerically inferior to placebo but no statistical differences were detected. Donepezil demonstrated statistically significant improvement. Adverse events were generally mild and self-limiting. CONCLUSION ABT-288 did not demonstrate efficacy in the symptomatic treatment of Alzheimers dementia.

A phase 2 randomized, controlled trial of the α7 agonist ABT-126 in mild-to-moderate Alzheimer's dementia

The safety and efficacy of the novel α7 nicotinic acetylcholine receptor agonist ABT‐126 were investigated in subjects with mild‐to‐moderate Alzheimers dementia (AD).

Efficacy and Safety of ABT-126 in Subjects with Mild-to-Moderate Alzheimer's Disease on Stable Doses of Acetylcholinesterase Inhibitors: A Randomized, Double-Blind, Placebo-Controlled Study.

BACKGROUND ABT-126 is a potent, selective α7 nicotinic acetylcholine receptor agonist with putative procognitive effects as a monotherapy in treating Alzheimers disease (AD). OBJECTIVE This randomized, double-blind, placebo-controlled multicenter study (NCT01549834) investigated the efficacy and safety of ABT-126 in subjects with mild-to-moderate AD who were taking stable doses of acetylcholinesterase inhibitors (AChEIs). METHODS Subjects received 25 mg ABT-126 (n = 143), 75 mg ABT-126 (n = 145), or placebo (n = 146) once daily for 24 weeks. Subjects who completed the 24-week double-blind study were eligible to enroll in a 28-week open-label extension study (NCT01690195) and received 75 mg ABT-126 daily. The primary efficacy endpoint was the change from baseline to week 24 in the 11-item total score of the Alzheimers Disease Assessment Scale- Cognitive Subscale (ADAS-Cog). RESULTS Neither dose of ABT-126 demonstrated significant improvement compared with placebo in the primary efficacy endpoint. However, 25 mg ABT-126 demonstrated significant improvement compared with placebo in ADAS-Cog scores at week 4 (least squares mean difference, -1.21; standard error, 0.51; p <  0.010, one-sided); 75 mg ABT-126 did not demonstrate significant improvements in ADAS-Cog scores compared with placebo at any time point. A treatment effect was not observed for any secondary efficacy measures of cognition, function, or global improvement. ABT-126 was generally well tolerated; the most common adverse events were agitation, constipation, diarrhea, fall, and headache. CONCLUSIONS Overall, the efficacy profile of ABT-126 did not warrant further development as add-on therapy to AChEIs to treat mild-to-moderate AD.

ABT-126 monotherapy in mild-to-moderate Alzheimer’s dementia: randomized double-blind, placebo and active controlled adaptive trial and open-label extension

BackgroundResults from a phase 2a study indicated that treatment with the novel α7 nicotinic acetylcholine receptor agonist ABT-126 25 mg once daily (QD) was associated with a trend for improvement in cognition in subjects with mild-to-moderate Alzheimer’s dementia (AD). A phase 2b program was designed to evaluate a broader dose range of ABT-126 as monotherapy in subjects with mild-to-moderate AD. The program consisted of a double-blind, placebo and active controlled study of ABT-126 (dose range 25–75 mg) and an open-label extension study (75 mg).MethodsThe randomized double-blind study enrolled 438 subjects (Mini-Mental Status Examination score of 10–24, inclusive) not currently taking acetylcholinesterase inhibitors or memantine. Subjects received 24 weeks of ABT-126 25 mg QD (n = 77), ABT-126 50 mg QD (n = 108), ABT-126 75 mg QD (n = 73), donepezil 10 mg QD (n = 76), or placebo (n = 104). The primary endpoint was the change from baseline to week 24 in the 11-item Alzheimers Disease Assessment Scale—Cognitive subscale (ADAS-Cog) total score. Subjects completing the double-blind study could enroll in the 28-week open-label extension study. Adverse events (AEs) and other safety parameters were monitored in both studies.ResultsA total of 367 patients (83.8 %) completed the double-blind study and 349 (79.7 %) entered the open-label study. Compared with placebo, donepezil significantly improved ADAS-Cog 11-item total scores from baseline to week 24 (−2.29 ± 0.95; one-sided P = 0.008). No ABT-126 dose demonstrated a statistically significant improvement vs placebo at week 24 in the ADAS-Cog total score: ABT-126 25 mg, −0.47 ± 0.94 (P = 0.309); ABT-126 50 mg, −0.87 ± 0.85 (P = 0.153); and ABT-126 75 mg, −1.08 ± 0.94 (P = 0.127). Rates of serious AEs and discontinuations due to AEs were similar across treatment groups. The most frequently reported AEs in both studies were constipation, fall, and headache. No clinically meaningful changes were observed in other parameters.ConclusionsIn the double-blind trial, donepezil significantly improved ADAS-Cog scores but no statistically significant improvement was seen with any ABT-126 dose. ABT-126 had an acceptable safety profile in subjects with mild-to-moderate AD in both studies.Trial registrationClinicalTrials.gov NCT01527916, Registered 3 February 2012 (randomized trial). ClinicalTrials.gov NCT01676935. Registered 29 August 2012 (open-label extension study).

APOE-ɛ4 Carrier Status and Donepezil Response in Patients with Alzheimer’s Disease

Abstract Background: Previous studies have investigated associations between apolipoprotein E (APOE)-ɛ4 allele status and acetylcholinesterase inhibitor treatment response in patients with Alzheimer’s disease. The ability to draw definitive conclusions regarding the effect of APOE-ɛ4 genotype on treatment response has been hindered by inconsistent results among studies and methodological limitations that restrict interpretation of study findings. Objective: To determine whether APOE-ɛ4 carrier status influences the magnitude of change in 13-item Alzheimer’s Disease Assessment Scale−Cognitive Subscale (ADAS-cog) score associated with acetylcholinesterase inhibitor treatment (i.e., donepezil). Methods: Analyses were performed using pooled data from the donepezil and placebo treatment arms of three consecutive, similarly designed, 12-week, multi-national, randomized clinical studies that enrolled patients with mild-to-moderate Alzheimer’s disease. Correlations between APOE-ɛ4 carrier status and ADAS-cog scores were evaluated using analysis of covariance. Results: No appreciable interaction between donepezil response and APOE-ɛ4 carrier status or copy number was detected. Both carriers and non-carriers of APOE-ɛ4 who received donepezil experienced significant improvements from baseline in ADAS-cog score versus placebo (p <  0.05). Change from baseline to final observation in the donepezil treatment group was – 2.95 for APOE-ɛ4 carriers and – 4.09 for non-carriers (p = 0.23). In contrast, non-carriers of APOE-ɛ4 in the placebo treatment group exhibited a greater improvement from baseline versus carriers (–2.38 versus – 0.60, p = 0.05). Conclusion: Within this population, APOE genotype had no statistically significant effect on cognitive response to donepezil treatment; however, APOE-ɛ4 allele status was associated with a difference in the magnitude of the change in ADAS-cog of placebo-treated patients.

Challenges and Opportunities in Bringing New Medications to Market for Pediatric Patients

The discovery and development of new chemical entities (NCEs) is a risky and costly proposition that proceeds in a highly regulated global environment. Only one or two of every 10,000 compounds generated will display safety and efficacy profiles to enable approval. Because of the large number of preclinical and clinical studies required for registration of an NCE, the average time from synthesis to market exceeds 10 years, and average cost per drug is approaching

RESULTS OF A PHASE 1, SINGLE ASCENDING DOSE, PLACEBO-CONTROLLED STUDY OF ABBV-8E12 IN PATIENTS WITH PROGRESSIVE SUPRANUCLEAR PALSY AND PHASE 2 STUDY DESIGN IN EARLY ALZHEIMER’S DISEASE

1 billion (Fig. 1). In addition, the period that a drug is on the market before similar medication becomes available has been reduced from 10 years to approximately 1.2 years. Bringing a new drug to market often involves thousands of people with different areas of expertise who synthesize the NCE, investigate its putative mechanisms of action and toxicology, evaluate its pharmacokinetics and clinical pharmacology, develop formulations and manufacturing processes, and finally, demonstrate its efficacy and safety in humans (Fig. 1). Each of the steps in this process is complex and requires extensive documentation. Of equal importance to a demonstration of efficacy is the focus on the safety of the compound. In fact, the effort devoted to acquisition and analysis of safety data by the sponsors (the pharmaceutical companies) is usually greater than the effort devoted to demonstrate efficacy.

Preclinical abuse liability assessment of ABT-126, an agonist at the α7 nicotinic acetylcholine receptor (nAChR)

computerized tests and traditional neuropsychological tests to predict amyloid status will be presented along with cognitive results for additional participants. Conclusions:Our findings demonstrate the validity of the ReVeRe cognitive test battery, including the first successful automation and validation in clinic and at home of a test of verbal memory using speech recognition software. Such tests will enable widespread testing in home, primary care, and clinical trial settings and improve identification of patients in the earliest stages of AD.