PET and MRI imaging helps companies to make go/no go decisions earlier
Attrition or failure of new drug programs is a major source of concern, with failure rates ranging from 75 percent in anti-infectives to 92 percent in CNS according to DiMasi’s 2010 study (Clin. Pharmacol. Ther. 87, 272-277).
Molecular imaging – both Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) can help improve these dismal statistics.
Given the immense costs involved in the later stages of development, the earlier that go/no go decisions can be taken the better. In practice, however, this is fraught with difficulties, as illustrated by a review by Morgain et al in 2012 (Drug Discovery Today 17, 419-424). The article revealed that in 43 percent of phase II decisions made in 44 Pfizer drug programs, it “was not possible to conclude whether the mechanism had been tested adequately.”
The same article three proposed three “Pillars of Survival”, describing the information required to take a go/no go decision with confidence. These were:
- Drug Exposure – at the target site of action for the desired length of time
- Target Engagement – drug binding to the right target
- Pharmacological Activity – proportional to the demonstrated target exposure and target binding
Molecular imaging can meet all of the above needs. PET can both provide a direct measurement the concentration of the drug candidate in question around the target site and also assay free concentration. PET can also calculate fraction occupancy of the drug at the target, which can then be used to confirm target engagement using PKPD modeling. And MRI provides accurate measurement of various pharmacodynamic effects, such as changes in blood flow/blood oxygenation.
Imanova is a proponent of the use of imaging in early stage trials. Too often we are called on to perform an “autopsy” of a failed trial; it would be far more valuable at the beginning of trials.
Even among the supporters of the potential of imaging there is a misplaced perception of high cost. It costs roughly $16,000 per patient to include imaging in Phase I studies; a worthwhile investment when you consider the costs of later stage failure.
A recent study on a new Parkinson’s compound illustrates this point. PET and MRI were used to distinguish whether the drug successfully entered the brain, the levels of receptor occupancy, and the relationship between the dose and receptor occupancy. Imanova implemented a new radiotracer for the receptor to enhance the research.
The use of specialist imaging techniques reduced cycle times and study costs, and demonstrated that full receptor blockade could be achieved with single doses. Execution phase of the study (including scanning, dosing and interim analysis for dose decision meetings) took just three months.
The use of imaging is no longer largely restricted to CNS. In fact, it is increasingly being applied in other areas, such as oncology and inflammatory diseases.
Kevin Cox, CEO, Imanova