CR4056 is a first-in-class imidazoline-2 (I2) receptor ligand endowed with potent analgesic activity in different animal models of inflammatory, neurogenic, neuropathic, postoperative, fibromyalgia-like, and osteoarthritis pain. In these experimental paradigms, CR4056 emerged as one of the most effective non-opioid analgesics ever described.
Accumulating evidence on the function(s) of I2 receptors shows that:
- I2 ligands modulate the enzymatic activity of monoamine oxidases (MAO), thus facilitating the noradrenergic inhibitory (descending) pain pathways with an innovative molecular mechanism. Importantly, the pattern of analgesic effects of CR4056 in experimental models is different, broader and much more potent than that of conventional MAO inhibitors
- I2 receptors interact with the opioid system at different levels, but no opioid-like side effects have been shown in humans. This interaction may favour CR4056 opioid-sparing activity in severe pain and prove useful for the management of opioid tolerance (as shown experimentally).
Four Phase I clinical studies, which investigated the safety, tolerability, and pharmacokinetics of single and repeated ascending oral doses of CR4056 in healthy subjects, have been completed so far and included the exploration of the drug-drug interaction profile of the compound.
Given Rottapharm Biotech’s expertise and interest to develop a Rheumatology Platform, the first Phase IIa trial consisted of a randomized, placebo-controlled trial in moderate to severe knee osteoarthritis pain, with extensive phenotyping of participating patients. Clinical development plans include a large Phase IIb dose-response trial in osteoarthritis and Phase IIa proof-of-concept studies in models of postoperative pain and opiate combination.