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 ] 14S data set of all the placebo controlled pomaglumetad trials, patients early in their disease (10–15% of study patients ≤3 years of illness) were i dentified and found to show a therapeutic response on PANSS-Total scores when treated with pomaglumetad 40mg, orally twice daily. In contrast, patients late in their illness (≥10 years) did not receive any benefit to pomaglumetad, suggesting that a possible hyperglutamatergic illness state may be the necessary target for a pomaglumated response. 10 It is also hypothesized that previous exposure to atypical antipsychotics could have led to down-regulation of mGlu2R with a resulting sub- therapeutic response to pomaglumetad, as has been reported to occur in animal models. 11 A post-hoc analysis, once again utilizing the HBBM data set as well as an integrated data set of all the placebo controlled pomaglumetad trials, was thus carried out which dichotomized between patients that were exposed to a subset of typical antipsychotics (identified as predominant dopamine D 2 receptor antagonists) or a subset of atypical antipsychotics (identified as prominent 5-HT 2A receptor antagonists) in the two years prior to screening visit for any of the pomaglumetad trials in the analysis. This post-hoc analysis did demonstrate that subjects previously exposed to prominent 5-HT 2A receptor antagonists (including atypical antipsychotic drugs and other CNS drugs) failed to have significant antipsychotic response to pomaglumetad whereas those patients whose prior antipsychotic exposure was to predominant dopamine D 2 antagonists (essentially either haloperidol or fluphenazine) did show a therapeutic response to pomaglumetad. 10 Lastly, a post-hoc analysis of HBBM demonstrated that non-Hispanic white subjects homozygous for the minor allele of the 5-HT 2A receptor snp reported above (T/T allele) once again confirmed PANSS response to pomaglumetad 40mg, when given orally twice a day, as compared to other study cohorts. 12 Although caution should be taken when testing alternative hypotheses through post- hoc evaluations, these results may further our understanding of how a g lutamatergic-based therapeutic may require a carefully identified target population rather than the general illness population to show drug efficacy in new drug development clinical trial investigations. Conclusion. This overview of those specific decision points that led to the progression of pomaglumetad development as well as the ultimate termination of the program may provide lessons learned to help guide alternative decision paths for drug development, certainly for glutamatergic-based compounds with antipsychotic aspirations. Animal models of psychosis may identify valid drug targets but not necessarily identify the appropriate clinical population of the target. Early Phase II clinical trials should be designed to better understand genotypic and phenotypic distinctions between responders and non-responders. Late Phase II trials should be able to conclude on the best targeted approach and optimal drug dose. Phase III trials should be powered appropriately and designed to be confirmatory of prior best possible assumptions. Negative Phase III programs may ultimately provide a useful platform for new hypothesis generation/testing during post hoc examinations. Speculation on the possible reasons(s) for negative efficacy outcomes can be evaluated with the datasets generated from Phase I to III clinical trials. The post- hoc exploratory data analysis of the unique disease-state or disease trait factors that may influence response to pomaglumetad suggest targeted therapeutic strategies that may aid in future clinical trial design. Lessons learned 1. Spectrum of illness. Only neuroleptic responsive patients in HBBM were included and this could have been a limitation. Early onset patients with schizophrenia may have been more appropriate as a potential hyperglutamatergic mediated disease state may have yielded a greater response to pomaglumetad. Lessons learned 2. Prior medication effects. Chronic use of n euroleptics may have led to subsensitivity of mGlu2R and prior exposure to 5-HT 2 receptor blockade could produce less sensitivity to mGlu2R agonists and lack of treatment response. Lessons learned 3. Picking the right patient. Individuals with schizophrenia that have the minor allele of the 5-HT 2A receptor may be more apt to respond to pomaglumetad. CASE 2: DELAYING THE ONSET OF MILD COGNITIVE IMPAIRMENT: EPIDEMIOLOGIC TRIAL DESIGN INCORPORATING GENETIC AND DRUG TREATMENT METHODOLOGY Preface. Over the last several years, the dementia field has moved toward earlier treatment of Alzheimer's disease (AD), particularly by incorporating treatments that may have the ability to delay the onset of disease symptoms. This case study will examine the ability of a novel therapeutic strategy to delay the onset of mild cognitive impairment (MCI) due to AD in cognitively normal subjects. In order to conduct a clinical trial of this nature a number of challenges needed to be addressed. First, a potential mechanism to enrich the study population with participants at elevated risk for developing MCI due to AD in the timeframe of the trial (which is five years for this trial) is discussed. Essentially, the use of genetic biomarkers to dictate this enrichment was employed. Second, as subjects entering into the trial will all be cognitively normal, and as expected during the trial some of the subjects will progress to having first indications of abnormal cognition (MCI), use of a battery of tools with sufficient sensitivity to ascertain whether cognition is impaired at the early stages of decline into AD were needed. Third, the therapy that will be administered to delay onset of MCI must have a well-established tolerability profile given the length of this study. As pioglitazone has been

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