In recent years, several strategies that selectively inhibit pro-inflammatory
cytokines, have yielded effective
protein-based
therapies for inflammatory disorders, validating the therapeutic hypothesis that intervention in
cytokine signalling can provide clinical benefit. However, these
protein-based products must be administered by injection, a constraint associated with inconvenience, adverse effects and expense for patients, caregivers and insurers. Besides interfering with the effects of
cytokines such as
TNF-alpha or IL-1beta that have already been produced, inhibition of pro-inflammatory
cytokine production or signalling with low-molecular weight orally-active drugs would combine the convenience of conventional
pharmaceuticals with the focused efficacy of the
protein therapies. Reducing IL-1beta and
IL-18 production by inhibition of IL-1beta converting
enzyme (ICE, caspase-1) is one promising strategy because of the key roles of these
cytokines in many inflammatory diseases.
Pralnacasan, the first orally available, potent and selective
ICE inhibitor to enter clinical trials, is currently under investigation in
rheumatoid arthritis.