Neurodegenerative CNS Disorders: Translation fails again…

This week brought news of yet another ‘failure of translation’, with the announcement that a Phase 2a (‘Proof of Concept’) study of Lundbeck’s foliglurax showed no significant improvements in ‘Off’ time or dyskinesia in levodopa-treated patients with Parkinson’s disease (PD).  Development of the product is being discontinued.

After decades of focussing primarily on drugs targeting dopamine metabolism / effect within the CNS to improve PD symptoms, foliglurax (a novel selective positive allosteric modulator of the glutamate 4 receptor) was one of numerous recent attempts to improve clinical status through a more oblique approach – targeting other mechanisms and/or pathways that may have a beneficial effect on the neuronal deficits present in established PD.  The molecule had shown very promising results in non-clinical studies (including primates), yet its failure to reproduce these findings in humans is the latest in a long line of similar occurrences – what we might call ‘failures of translation’.

What questions do these events raise about the manner in which we evaluate candidates before making the decision to move into humans?  Are the non-clinical models we use valid or even relevant?  Are negative human studies appropriately designed, or conducted in the optimal population?  Do we really have the experience / knowledge available to guide such evaluations?

The industry has, of course, been well aware of these kinds of questions for many years now – but this failure (yet another huge disappointment for the PD community) must at least be used by drug developers as a reminder of the critical need for proactive analysis of what they intend to do as they transition from lab to bedside – it can never simply be a matter of ‘following the dots’ of previous development plans…

Reference: Lundbeck