Vernalis identified FAAH as a target that might be amenable to our research techniques back in 2007. V158866 was the lead molecule to emerge from this research programme, demonstrating our ability to generate promising candidates that go on to full pipeline development.
The FAAH enzyme metabolises endocannabinoids (ECs), which are neurotransmitters acting on a range of different receptors. Inhibition of FAAH leads to elevated EC levels in the nervous system. Amongst the receptors which the ECs act upon are CB1, CB2 and TRPV1, stimulation of which has been shown to relieve pain. ECs also act on the PPARα receptor, which is known to reduce inflammation.
Since ECs are only produced on demand, it may be that FAAH inhibitors, such as V158866, can selectively increase the local levels of neurotransmitter in tissues. This could deliver a powerful analgesic and anti-inflammatory response, without the side effects that more widespread cannabinoid receptor activation can generate. Additional possible indications for the class include the treatment of anxiety and depression.
V158866 has been shown to be a potent and selective slowly reversible inhibitor of human FAAH1 (IC50 24nM). It has been evaluated in a series of pre-clinical pain models and has been shown to have efficacy in:
- Carageenan-induced thermal hyperalgesia
- Carageenan-induced inflammation
- Mono-iodoacetate model of osteoarthritis
- Chronic constriction injury model of neuropathic pain
It has no significant effect on locomotor function in pre-clinical models, even at high doses.
A range of pre-clinical safety and pharmacokinetic studies were conducted on V158866.
Positive results were announced in September 2011 for V158866 in a Phase I SAD and MAD study. The double-blind, placebo controlled study investigating single and multiple ascending doses was conducted in healthy male volunteers. The objective of the study, to identify doses of V158866 that are both safe and well tolerated and to measure the compound’s effect on FAAH activity and endocannabinoid levels, was achieved. The study has confirmed V158866 is a potent inhibitor of human FAAH and has identified once daily doses to be tested in future studies in pain or other indications.
In August 2015, the Company announced results from a Phase II POC study in which the programme was being investigated in patients with neuropathic pain as a result of spinal cord injury. Although the dosing of V158866 resulted in elevated endocannabinoid levels, on an intent-to-treat basis, the study failed to meet its pain reduction primary endpoint. Treatment did show a trend towards efficacy on a per protocol basis and was generally well tolerated.
Neuritek Therapeutics plans to develop V158866 for post-traumatic stress disorder and other CNS diseases. Under the terms of the agreement, Ligand will receive an upfront license fee and is eligible to receive a financing-related milestone, development and commercialisation milestones and tiered royalties on net sales in the mid-to-high single digits.