Innovations In Clinical Neuroscience

ISCTM Supplement 2015

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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[ V O L U M E 1 2 , N U M B E R 3 – 4 , S U P P L E M E N T A , M A R C H – A P R I L 2 0 1 5 ] Innovations in CLINICAL NEUROSCIENCE 9S tolerated, with a half-life of 14 hours. Some insomnia effects were observed at higher doses, while PET studies showed 80- to 90-percent o ccupancy at 10mg. High occupancy was targeted but it is unclear what the optimal occupancy might be for the indications evaluated in Phase II. Electroencephalography studies in animals and humans demonstrated dose-response effects at higher frequencies, including gamma power, suggesting that an H 3 antagonist may improve attention and other aspects of cognition. Another Phase I study examined the efficacy of MK-0249 on excessive daytime somnolence comparing its effects with modafinil (an approved treatment). While MK- 0249 was shown to be superior to placebo, it was not as effective as modafinil. And another Phase I study examined whether MK-0249 would reverse scopolamine-induced deficits in healthy subjects using the Cog- State Battery. Scopolamine impaired reaction-time, choice reaction-time, executive functioning, as well as episodic and short-term memory. MK-0249 improved some scopolamine-induced deficits and had an additive effect with the Alzheimer's disease treatment donepezil for some cognitive domains, although notably not episodic memory. 11 These positive results from phase I indicated clinically relevant target engagement and pharmacodynamics efficacy relevant and suggested that MK-0249 could improve symptoms in disorders of wakefulness and cognition. Unfortunately, in several Phase II trials in a variety of indications, MK- 0249 did not demonstrate sufficient efficacy to warrant further development. In a study of subjects with daytime somnolence due to sleep apnea, MK-0249 did not provide beneficial effects compared to placebo. 12 In contrast, the active modafinil was superior to placebo, demonstrating the conduct of the trial was sufficient to detect efficacy. In a second Phase II trial of adult ADHD, MK-0249 improved exploratory measures of attention and executive function, but not the primary outcome measure, the ADHD Investigator Symptom Rating Scale (J. Herring et al., unpublished). I n a third Phase II trial, MK-0249 treatment did not improve cognition in patients with schizophrenia on a summary score of cognitive tests or individual cognitive domains. Some subjects in this trial were receiving antipsychotic medications, which had H 1 antagonist effects, which could have reduced the trial's power to detect a therapeutic effect. 13 Finally, MK-0249 was tested in patients with mild to moderate Alzheimer's disease. No effect was observed on any cognitive scores using a computerized test batter. A trend for a positive effect on a secondary measure, the ADAS-Cog, was seen at two but not four weeks. 14 Despite substantial evidence from preclinical studies as well as robust evidence of target engagement and pharmacodynamics efficacy in Phase I, no clinically significant therapeutic effects were seen in four Phase II trials in different disorders. It is clear that multiple POC studies using one compound and overlapping biomarker sets was an efficient use of resources providing information on multiple indications. The current studies also demonstrate, however, that evidence of target validation was insufficient. In the future, successful drug development in neuropsychiatry may depend on stronger support for a drug target. It seems likely that animal models are poorly predictive of efficacy in humans, although efficacy in animal models may be necessary but not sufficient. In terms of biomarkers, CNS drug development programs should ideally include both measures of target engagement as well as pharmacodynamic efficacy. Future studies should focus on targets with substantial evidence, particularly genetic evidence, that the target is implicated in the critical disease process. In Alzheimer's disease, for example, the beta secretase enzyme is a good target with CSF A-beta serving as a potential pharmacodynamics biomarker. OPTIMIZING PHASE II STUDIES TO SET THE STAGE FOR SUCCESS IN PHASE III TRIALS Optimizing each stage in the drug discovery process would not necessarily optimize drug development equally, but optimizing Phase II likely has the greatest impact. Minimizing the placebo response is also important for trial optimization. Three pillars have been identified as important for enhancing treatment development: 1) exposure at the target, 2) pharmacological activity commensurate with target exposure, and 3) binding to the target. 2 When these three pillars are all met, the likelihood of clinical development success is enhanced. The framework for choosing a plan have been previously explored and known as the axes of development. Efficient Phase IIa POC studies followed by a Phase IIb study can focus on the quick termination of a target. With high optimization and effect sizes, registration of the compound could be fast-tracked. This strategy also provides a dose- response curve of the treatment being developed. Using positive controls can be beneficial but the conditions for such a control need to be understood. The power for the positive control must be high so that a failure of the treatment to separate from placebo is not by chance. Positive controls can reduce the sensitivity of the analyses with changes from control perhaps due to less effective placebos or unequal distribution to groups. When conducting studies with multiple dose levels, interim analyses can enable dosing decisions throughout the study (e.g., identifying the "best dose" or eliminating doses altogether). Moreover, model-based analyses can be more efficient than straight- forward pairwise comparisons. The power gained from these small dose- finding Phase II studies can be used

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