Proof-Of-Principle For New Drug Development Tool
Miicro, Inc., which specializes in imaging techniques as CNS drug development tools, has presented results of its Phase I SBIR grant on metabolic neuroimaging for dose evaluation in clinical trials. The presentation occurred September 3 at the conference of the Society of Nuclear Imaging in Drug Development. Miicro's study demonstrated the quantitative regional effects on cerebral glucose metabolism of two different acute doses of Prozac (fluoxetine), Eli Lilly's antidepressant drug. The study also showed that Prozac's effects on brain metabolism persisted one week after subjects received the drug, supporting the belief that Prozac continues to affect the brain long after it has left the blood stream. The study utilized Miicro's patented technique of acquiring and analyzing metabolic brain "maps" with positron emission tomography (PET). This study confirmed the proof of principle for Miicro's Optimum Dose Evaluation (ODE) service, which the company sells to pharmaceutical manufacturers to help limit risk and save time and money in bringing effective new drugs to market.
Development of CNS drugs is one of the most expensive, time consuming, and risky areas of pharmaceutical research. CNS drug development is inherently difficult due to a lack of reliable animal models, high placebo effects among patients, difficulties in studying brain effects in humans, and the heterogeneity of patient populations. These challenges lead to increased risks of failure, extended development times, and significantly higher development costs than for non-CNS drugs. Determining the appropriate dose range for evaluation in patients is the most significant problem faced by pharmaceutical manufacturers, and is believed to be the leading factor in the failure of most CNS clinical trials. Miicro's PET technique measures downstream changes in regional cerebral glucose metabolism to show how drugs alter the brain's activity, specifically, the end-effect of the drug-receptor interaction and sequentially induced post-synaptic responses.
Miicro claims to be the first company to offer a service based on the quantitative dose response and dose duration relationship of a CNS drug using metabolic PET imaging. Their PET service provides data critical to evaluating the regional dose effects of CNS compounds, which can be used to help design clinical trials.
Though this study was performed with healthy volunteers, the service can be easily conducted in target patient groups with either acute or chronic treatment. Miicro plans to submit the findings of its Phase I study in an application for a $750,000 Phase II SBIR grant. The Phase II award will be used to extend the application of this service into patient populations with additional CNS drugs and to develop proprietary software for dose-related image analysis and display. Data from the Phase II work will be added to Miicro's growing database of the central effects of CNS drugs.
Statistical map of a single transaxial slice of the human brain acquired with Miicro's PET method after subjects had received fluoxetine (Prozac) and placebo
Ciaran Cooper, president and CEO of Miicro, commented, "The use of non-invasive neuroimaging to demonstrate the dose-related effects of CNS drugs is a significant breakthrough for the pharmaceutical and biotech industries. Our clients can use these data to make strategic decisions and design follow-on clinical trials from a rational basis, resulting in time and money savings and less risk of failure due to inappropriate dose selection. This work represents a new model process for evaluating potential CNS drugs. We are very excited."
PET Imaging in CNS Drug Development
Several neuroimaging techniques have been utilized in CNS drug development with varying degrees of success. PET scans in drug development have typically involved cerebral blood flow and radioligand binding occupancy as surrogate markers of central drug effects and dose response. However, recent adaptations of PET methods using 18F-fluorodeoxyglucose FDG responses to pharmacological challenges provide in-vivo dose dependent measurements that appear capable of determining effective therapeutic dose ranges and determining drug dosing intervals from tissue half-time responses.
The method measures the downstream changes in regional glucose metabolism that are the net end-effect of the drug-receptor interaction and sequentially induced post-synaptic responses. PET has significant advantages for confirmation of central effect, identification of direct tissue dose response, and intra-class drug comparisons. Its advantages include the ability to characterize atypical compounds with varying affinities and mixed receptor agonist and antagonist profiles.
PET is a quantitatively robust measure that can be used reliably in small test groups to provide an objective basis for the decision making required in late Phase I/early Phase II clinical trials. The application of quantitative neuroimaging in the early phases of clinical development could provide early recognition of both viable and non-viable drugs, and could have significant beneficial effects on the time and cost of CNS drug development.
For more information: Ciaran Cooper, CEO, Miicro, Inc., 1021 West Adams St., Suite 107, Chicago IL. Tel: 312-455-0934. Fax: 312 455-0964.