Selected Colloquium
Session Room 216
Session Room 216
Wednesday, June 18, 12:15 PM – 01:15 PM
Selected Colloquium 10: Promises and Pitfalls of Clinical Trial Design: How can we better evaluate novel target antipsychotics?
Clinical trials are an essential means to evaluate clinical efficacy of new medications. However, many agents that appeared to be highly effective in preclinical studies and early stage evaluations failed in the multi-center trials. This could be due to several factors, including the lack of efficacy across a broad population, or a trial design that is ineffective at identifying novel target compounds. These limitations could prevent the entry of more effective medications that may be highly beneficial to the patient populations. For example, it may be that some medications are only effective in subgroups of patients. The other issue is the trial design, in that clinical trials for antipsychotic drugs have relied on the principle that once a drug is washed out of the system over a 1-2 week period, a new medication can be introduced. While this has been effective in identifying “me-too” D2 antagonist antipsychotic drugs, there is the likelihood that the original drug has altered the system in such a way that only another drug of the same class can be effective. Indeed, in preclinical studies it has been shown that the D2 supersensitivity induced by 3 weeks of treatment with the D2 antagonist haloperidol interfered with the efficacy of a novel GABAergic drug that was found to be highly effective in non-pre-exposed animal models. In this panel, we will discuss the potential limitations of current clinical trial design, and how these shortcomings may be circumvented. Dr. Kim Q. Do will present data showing that the antioxidant N-acetyl cysteine is only effective in patients in the early phase psychosis showing high oxidative status and mitochondrial impairments. In a randomized double blind clinical trial with supplementation of NAC, patients’ subgroup with high baseline plasma exosomal levels of microRNA-137, the key regulator of mitochondrial oxidative stress, showed significant improvements of cognitive and functional outcomes. The latter was associated with a reduction in exosomal microRNA-137 levels. Dr. Patrick McGorry will discuss the benefits of clinical trials networks as platforms for delivering rapid, high quality trials of novel treatments, with a particular focus on the Australian early psychosis network. This will explore the therapeutic potential of pomaglumetad; a compound that failed in pharma run clinical trials but may have been prematurely dismissed due to a focus on the wrong stage of illness and lack of a theoretical mechanism for targeting its use. Dr. Anthony Grace will present preclinical data showing that drugs such as pomaglumetad, which failed in large multicenter trials, was highly effective in reversing the pathophysiology in a developmental disruption model of schizophrenia. A reason for this discrepancy is suggested by his studies showing that prior exposure to D2 antagonist antipsychotic drugs interfere with potential therapeutic actions of a novel target compound, a GABA A alpha 5 PAM. He will also present a unique approach for investigating novel target antipsychotic drugs without extended withdrawal periods. Dr. Pat McGorry will then provide an integration and describe how trial designs may be modified to more effectively test novel compounds for efficacy.