Clinical development of onercept, a tumor necrosis factor binding protein, in psoriasis.
BACKGROUND
Tumor necrosis factor (TNF)-α plays a critical role in psoriasis pathogenesis, and several anti-TNF agents have been developed as therapeutic drugs in this indication.


METHODS
To present the preclinical rationale and clinical data for onercept, a novel anti-TNF agent developed for the treatment of moderate-to-severe psoriasis, and to critically evaluate the onercept clinical development program.


RESULTS
Onercept was shown in preclinical studies to inhibit TNF-α and suppress clinical signs in several inflammatory conditions. In phase II studies onercept demonstrated a therapeutic benefit in psoriasis and psoriatic arthritis and no safety issues were identified. Based on these results, a phase III program comprising three multicenter, randomized, double-blind, placebo-controlled studies examining onercept in moderate-to-severe plaque psoriasis was initiated. Following the occurrence of two cases of systemic inflammatory response syndrome (SIRS) and lower than expected efficacy results, an independent Data Safety Monitoring Board (DSMB) determined that the risk-benefit ratio was not sufficiently favorable to justify continued development, and all clinical studies were promptly terminated. Although not initially diagnosed as such by the investigators, two further SIRS events were reported, one after study discontinuation. Although an increased incidence of infection and sepsis-like events has been associated with other anti-TNF therapies, an increased risk of infection was not observed with onercept treatment. Moreover, no infectious etiology was determined in the SIRS cases. The data suggest that the SIRS reactions were due to a systemic inflammatory response.


CONCLUSIONS
Despite promising early clinical results, onercept showed many of the expected risks associated with other anti-TNF agents and proved not to have an exceptional efficacy and safety profile. The clinical development of onercept highlights the critical importance of DSMBs and closely monitoring patient safety and evaluating risk-benefit profiles in large clinical programs.
Papp
Kim
K
Probity Medical Research Inc., Waterloo, Ontario, Canada. kapapp@probitymedical.com
D000818:Animals; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D055808:Drug Discovery; D006727:Hormone Antagonists / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D011485:Protein Binding; D011565:Psoriasis / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced / Q000453:epidemiology; D016896:Treatment Outcome; D053319:Tumor Necrosis Factor Decoy Receptors / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D006727:Hormone Antagonists; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1