One of the lead novel candidates in the Vernalis pipeline, V3381CC (Indantadol) is being developed as a potential treatment for chronic cough.

  • NMDA receptor antagonist
  • Monoamine oxidase inhibitor
  • Being evaluated for persistent cough

V3381CC exhibits a useful combined action, functioning both as a low affinity NMDA receptor antagonist, and as a reversible, non-selective monoamine oxidase A inhibitor.

Dual mechanism of action

Its dual mechanism of action gives V3381CC the potential to modulate diseases of the nervous system at both central and peripheral locations. We continue to evaluate whether other neuropathic pain conditions might be more favourably treated by V3381CC’s unique combination of actions. It is also being evaluated in a pilot study in patients with chronic cough for which there is no obvious underlying cause.

V3381CC (indantadol) was originally discovered and developed by the Italian pharmaceutical group Chiesi Farmaceutici SpA who licensed it to the Canadian company Cita Neuropharmaceuticals. It entered Vernalis’ portfolio when we acquired Cita in late 2005. Two patent families protect V3381CC, exclusively licensed to Vernalis.

 

NMDA receptors are widely distributed throughout the nervous system and are one of several target receptors for the excitatory amino acid neurotransmitter glutamate. NMDA receptors have been shown to play a role in diseases resulting from longer-term neural plasticity and blockade of NMDA receptors with specific antagonists has been shown to improve the control of neuropathic pain. Pain is also modulated at the level of the spinal cord by descending nerve fibres that use noradrenaline as the neurotransmitter. The activity of this pathway can, therefore, be enhanced by drugs such as monoamine oxidase inhibitors which inhibit the breakdown of amine neurotransmitters. Clearly, a drug with actions on both of these pain control pathways could have a beneficial effect on difficult to treat pain conditions.

A small number of patients develop a chronic cough that persists long after the original cause of the cough (such as a viral infection) has gone. Recent work has suggested that the similar neural plasticity changes to those that result in neuropathic pain may also be responsible for cough becoming chronic and persistent.

V3381 has been shown to be effective in a range of pre-clinical pain models.

  • Acute (hot plate) pain studies
  • Carageenan model of inflammatory pain
  • Formalin model of inflammatory pain
  • Capsaicin-induced hyperalgesia and allodynia model
  • Nerve ligation model of neuropathic pain
  • Chronic constriction injury model of neuropathic pain
  • Streptozotocin model of diabetic neuropathy

In each of these studies, V3381 was shown to have at least similar, and in several cases better, efficacy than the positive controls. These beneficial effects were not due to general CNS depression, as evidenced by the generally wide therapeutic window in comparison with the doses causing impairment of motor activity in rotorod studies.

Phase I clinical trials in healthy volunteers have found the tolerability profile of Indantadol in single doses up to 600mg, and twice-daily doses up to 400mg to be more favourable than comparable NMDA antagonists.

Two single dose healthy volunteer proof-of-concept studies have also been completed. Both studies showed that V3381CC was significantly better than placebo in reducing the area of secondary hyperalgesia induced by applying heat to skin made sensitive by the application of capsaicin. The second of these two studies included a single dose of gabapentin as a positive control, and the effects of V3381CC and gabapentin were shown to be very similar.

Another study, being carried out in collaboration with Professor Ashley Woodcock of the University Hospitals of South Manchester Foundation, seeks to evaluate the efficacy of Indantadol in patients suffering chronic cough, for which there is no obvious underlying cause.

Extensive series of pre-clinical safety and efficacy studies completed. Phase II clinical studies in patients with diabetic peripheral neuropathic pain complete. Disappointingly, it has not been possible to demonstrate a beneficial effect in this difficult to study indication. The pilot chronic cough study continues and a full evaluation of the potential benefits of V3381CC in other pain conditions is underway.