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 ] 12S therapeutics for complex central nervous system (CNS) disorders, a number of subjective variables are monitored and considerable variance i n patient populations occur, in part due to diagnostic impression, which may lead to diluted treatment effects and diminished potential for delivery on their promised mechanism. Even prior to the stage of human clinical trials, preclinical investigations can offer great insights into the potential mechanism of action and efficacy of compounds in treatment of CNS disorders. However, given the complexity of neuropsychiatric illnesses with translational efforts having inherent imprecision their applicability is sometimes questioned. This article focuses on evaluating the scientific process once a compound meets the current rigors of preclinical evaluation and is ready to undergo testing in humans. Creating methodologically intact clinical trials to test a known medication target in humans, or even a proof of principle agent (i.e., hypotheses driven), carries forward important considerations that at times are specific to the field of neuropsychiatry and deserves much needed attention. This article includes case presentations of past drug development programs' efforts and novel methodological approaches that highlight caveats and potential insights to the future of CNS drug development. This article is based on proceedings from the "Designing the Right Series of Experiments" session, which was held during the International Society for Clinical Trials Meeting (ISCTM) in Philadelphia, Pennsylvania, September 30 to October 2, 2013. CASE 1: WHAT WE WOULD CONSIDER DOING DIFFERENTLY: LESSONS FROM THE mGLuR2/3 AGONIST SCHIZOPHRENIA PROGRAM Preface. Pomaglumetad methionil (pomaglumetad) is a potent and highly selective agonist at the metabotropic glutamate 2 and 3 receptors (mGlu2/3R). Here we review the key pivotal steps of the Phase I through III clinical development program at Eli Lilly and Company to assess the efficacy and safety of pomaglumetad in improving the psychopathology of s chizophrenia, either as monotherapy in patients with an acute psychotic exacerbation or as an add-on therapy in patients with prominent negative symptoms. Although this program yielded negative primary outcomes, lessons were learned from this significant undertaking that may influence the design and anticipated outcome of future efforts to develop innovative and hopefully more effective drug therapies for schizophrenia. Preclinical studies. Schizophrenia is believed to be a disorder, in part, due to pathophysiologic dysregulation of glutamatergic neurons, and possibly more so during prodromal and early periods of this disease. Stimulation of mGlu2/3R decreases glutamate release from pyramidal neurons and is hypothesized to equilibrate glutamatergic signaling. Pomaglumetad methionil is the methionine prodrug of the mGlu2/3R agonist LY404039. The prodrug enhances oral bioavailability of the active compound LY404039, which has limited gastrointestinal absorption. Preclinical studies with pomaglumetad suggest this agent to be a potential novel first in class antipsychotic that is devoid of affinity for dopamine (DA) and 5-HT 2 receptors. For instance, pomaglumetad dose-dependently reverses the hyperglutamatergic effects of ketamine in key regions of the brain. 1 Ketamine, a NMDA receptor antagonist, produces behavioral hyperactivity in animals that may serve as a model for psychosis in humans. Phencyclidine (PCP or "angel dust"), also a NMDA antagonist and a substance of abuse, produces a psychotic state in humans. Pomaglumetad blocks the effects of PCP in animal models of psychosis as does raclopride, an antagonist at the dopamine D 2 receptor, the major biochemical receptor target of traditional antipsychotic agents. 1 Furthermore, the combination of pomaglumetad with risperidone (an atypical antipsychotic with greater 5- HT 2 :D 2 receptor affinity) produces a synergistic inhibition of the conditioned avoidance responses, an animal model of antipsychotic drug a ctivity, greater than either agent alone. 2 These diverse preclinical data led to early indications that pomaglumetad may be effective as 1) a monotherapy for schizophrenia, and 2) an add on to standard of care antipsychotic treatment for enhanced efficacy (e.g., the adjunctive treatment of persistent prominent negative symptoms). Based upon CSF studies in humans, it was concluded that pomaglumetad 40mg, twice a day, in humans would provide an exposure in the CNS equivalent to that in rat brain which blocks the PCP response. Numerous lines of evidence were thus in favor of pomaglumetad having potential to ameliorate the pathophysiologic aspects of schizophrenia as derived from animal models. The Phase 2 proof of concept study H8Y-MC-HBBD (HBBD) was carried- out in acutely ill patients with schizophrenia using pomaglumetad 40mg given orally twice a day as monotherapy. This multicenter study (10 sites, single country) demonstrated that pomaglumetad decreased the Positive and Negative Syndrome Scale (PANSS; a rating scale used in schizophrenia) Total Score to similar levels as that of olanzapine in patients with schizophrenia (both treatments were statistically significantly different from placebo). 3 In HBBD, pomaglumetad was well tolerated by patients with a low association to weight gain, extrapyramidal symptoms, hyperprolactinemia, or serious safety or efficacy concern. These positive encouraging results led to a Phase IIb dose-ranging study H8Y-MC-HBBI (HBBI) to assess four doses of pomaglumetad (5mg, 20mg, 40mg, 80mg) to be given orally twice a day in 669 patients from nine countries. However, none of the four doses of pomaglumetad or the olanzapine comparator group in HBBI were subsequently found to separate from placebo resulting in a failed trial that

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