P1vital, a contract research organisation (CRO) based at Oxford University’s Department of Psychiatry in Warneford Hospital and specialising in experimental medicine for central nervous system (CNS) disorders and, has formed a ‘pre-competitive’ consortium with four pharmaceutical companies in the UK.

The consortium agreement, which involves investment of £4 million (€5.29 million) split among the partners, is aimed at establishing and validating CNS experimental models in healthy volunteers, an area in which P1vital has already made considerable headway. The pharmaceutical companies involved are AstraZeneca, GlaxoSmithKline, Lundbeck (Organon/Schering-Plough) and Wyeth.

The consortium members will fund a series of studies over a three-year period to establish the sensitivity of healthy volunteer CNS experimental medicine models and validate their ability to detect the efficacy of novel compounds. P1vital will carry out the studies in collaboration with internationally recognised academic clinical psychopharmacology groups at the Universities of Oxford, Bristol, Cardiff and Manchester as well as London’s Institute of Psychiatry.

The objective is to validate existing healthy volunteer models and develop novel models in the fields of anxiety, cognitive disorders, depression and schizophrenia.

P1vital’s existing range of CNS experimental medicine models includes, for example, a facial-expression recognition test that has been used to gauge emotional processing in volunteers given the SSRI antidepressant citalopram; a customised Universal Eating Monitor (UEM) programme to measure food intake and subjective ratings of food palatability, hunger and fullness in response to anti-obesity interventions (in collaboration with Liverpool University); and a CO2 challenge model for panic disorder validated with the benzodiazepine lorazepam.

The consortium’s initial studies will validate new surrogate biomarkers for positive, negative and cognitive deficits in schizophrenia. In depression, the partners will validate an at-risk group (dysphoric volunteers) using a recently established emotional test battery as a surrogate population for depressed patients. Studies in cognitive disorders will focus on two recently developed virtual reality models and will assess their utility for the early detection of cognitive deficits in mild cognitive impairment and schizophrenia. Further studies will investigate the potential efficacy of antidepressants in treating anxiety disorders using an experimental model of anxiety.

Poor translation
Compound failure is a particular problem in the development of CNS medicines, where there is a lower than average chance of success due to poor translation from preclinical models to clinical efficacy, P1vital points out. “Almost all of the medicines we think of as new, atypical antipsychotics, for example, were conceived as refinements of previous treatments,” it comments.

Placebo-controlled trials are difficult to conduct in patients with the type and degree of depression that most requires pharmacologic intervention, the CRO adds. That leaves study populations in which placebo response rates are high, confounding the detection of positive treatment effects. Consequently, there is “a growing gap for many pharma companies between their preclinical portfolio and willingness to invest” in ever more expensive, large-scale clinical studies.

One way of bridging this gap is to introduce experimental and translational medicine models at the interface between Phase I and II clinical trials, P1vital notes. However, this strategy is still in its infancy, while progress for any individual pharmaceutical company trying to validate experimental medicine models as effective decision-making tools for CNS drug development is likely to be “slow and very expensive”. Since expertise in experimental medicine resides largely in clinical academic centres of excellence with access to suitable volunteers and patients, a consortium effort straddling academia and industry offers a cost-efficient and mutually beneficial solution, P1vital argues.

Co-founded by chief executive officer Dr Colin Dourish and chief scientific officer (CSO) Dr Gerry Dawson, P1vital was incorporated in October 2004. Both of the founders have extensive pharmaceutical industry experience: Dr Dourish as senior vice president, research and CSO of Vernalis Group, research director and co-founder of Cerebrus, director of neuropharmacology at Wyeth Research and section head at Merck Sharp & Dohme Research Laboratories; Dr Dawson as senior director and head of in-vivo neuroscience at Merck’s Neuroscience Research Centre.