Innovations In Clinical Neuroscience

ISCTM Supplement 2015

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

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Innovations in CLINICAL NEUROSCIENCE [ 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 ] 20S to clinical outcome). The probabilistic reward task assesses the capacity to learn based on reward. We also employed a clinical outcome scale that h as been demonstrated to be sensitive to treatments—the Snaith-Hamilton Pleasure Scale (SHAPS). Exploratory investigations will include 1) additional circuit measures (i.e., OEEG measure of cingulate activity), 2) additional behavioral measure (i.e., effort expenditure for reward tasks) assesses the degree to which one is motivated by reward as demonstrated by effort, 3) additional self-report scale (i.e., Temporal Experience of Pleasure Scale [TEPS]). We also included the HAM-A and HAM-D to allow linking this study to prior DSM-based work. We considered using the Snaith- Hamilton scale for pleasure as the primary outcome measure. However, it seemed likely that this would result in our study being significantly underpowered and risky. Instead, a circuit outcome was used as primary outcome and as a basis for go/no-go decisions. If the circuitry is not engaged, it would not make sense to move forward in development with our compound, even if there is a therapeutic effect on a clinical or self- report endpoint. This would likely be a setup for a failed Phase III trial. Choice of subject population. One novel aspect of our study design is to employ the Snaith-Hamilton Pleasure scale as a screening tool to identify subjects with anhedonia. We would have liked to use our measure of ventral strial circuitry activity level for this purpose; however, the work completed to date provided an insufficient basis for doing so. It is important to note that we are also requiring people to have a DSM-based diagnosis of a mood or anxiety disorder in addition to meeting anhedonia entry criteria. This ensures that we will be studying subjects with reward-related difficulty who have a mood and anxiety spectrum disorder. However, because anhedonia is a diagnostic symptom of depression, we felt it important to take steps to ensure that our study has cross-diagnostic relevance in keeping with the RDoC approach. Based on input from our consultants, it was concluded that our options were to demonstrate that treatment improves anhedonia but N OT a depression scale (HAM- D/MADRS) or that treatment improves anhedonia across DSM diagnoses in a population where some individuals do not meet criteria for major depression. We took that latter approach and decided to include a subset of subjects who met DSM criteria for an anxiety disorder and did not meet criteria for major depression. General limitations/risk of fast- fail we faced. There are challenges in determining number of subjects for FAST-MAS studies. We decided to carry out a study that is powered to detect an effect size of 0.5 in our primary outcome measure: ventral striatal activation during the monetary incentive delay task based on fMRI With this stated, the capacity to estimate effect size on the primary outcome measure was limited by there being very few treatment studies having been carried out with monetary incentive delay task fMRI. Our experience has illustrated that carrying out studies using the FAST- MAS approach will require further developing means of establishing target engagement and establishing POC. We currently lack the means to do this for many RDoC constructs and potential targets. Further, the FAST- MAS strategy cannot prevent Phase III failures due to relatively uncommon unanticipated adverse effects due to studying a small number of people, but should be a more efficient and more cost savings approach. Lessons learned 1. Target selection. Choosing the appropriate target requires a great deal of time and consideration. Lessons learned 2. Outcome Measures. There is a great need to develop a means to establish target engagement and to assess whether engaging a target has the hypothesized effect on brain/behavior. Lessons learned 3. Logistics. Coordinating different aspects of this initiative required partnerships between government, academic, and industry. CASE 4: THE PHARMACOLOGICAL CHARACTERISTICS OF A THERAPEUTICALLY ACTIVE DOSE OF TWO FIRST-IN-CLASS-DRUGS: AMOREXANT (ORX1/2 ANTAGONIST) AND RIMONABANT (CB1-ANTAGONIST) Preface. By definition, first in class drugs lack registered congeners that can be used to benchmark the activity profiles, in such cases, dose selection for clinical trials is usually based on an assessment of preclinical safety and efficacy data, and on pharmacokinetics and tolerability in healthy subjects. Unfortunately, this frequently leads to disappointing clinical trial outcomes, and few truly innovative CNS-active drugs have made it to the clinic in the past decade. Moreover, a large proportion of drugs that are registered become subject to reductions of recommended doses after launch, or are withdrawn from the market. Even though validated pharmacological endpoints are often lacking for new drugs, it can still be useful to characterize the pharmacologic effects of first in class drugs in healthy individuals. This can provide important information about the various dose- or concentration-effect relationships for potentially desirable or detrimental effects of the new compound. This offers the possibility to rationally select a dose with specific pharmacologic activity, and to cautiously escalate the dose along the concentration effect curve during testing. An approach such as this may prevent unexpected clinical outcomes, which otherwise may occur if the pharmacologic activity of a traditionally selected dose becomes outside of the optimal therapeutic-safety window. Pharmacologically guided dose selection can also increase confidence that the drug is not overdosed. Two examples of this approach are provided. For the first dual orexin antagonist, pharmacologically guided dose selection was successfully used to identify a minimal sleep-promoting dose and to avoid potential narcolepsy-

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