Clinical development of onercept, a tumor necrosis factor binding protein, in psoriasis

Abstract

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.

Scope:

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.

Findings:

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.

Key words:

• Anti-TNF
• Clinical trials
• Onercept
• Psoriasis
• Safety monitoring

Transparency

Declaration of funding

The studies described were funded by Merck Serono S.A. - Geneva, Switzerland (an affiliate of Merck KGaA, Darmstadt, Germany), the manufacturer of onercept. In collaboration with the principal investigators, Merck Serono S.A. - Geneva designed the studies, analyzed and interpreted the data, and edited the report. Data were recorded at participating clinical centers and maintained by Merck Serono S.A. - Geneva. All investigators had full access to the data. The authors had final responsibility for the decision to submit for publication.

Declaration of financial/other relationships

K.P. has acted as a consultant for Merck Serono S.A. - Geneva, Switzerland (an affiliate of Merck KGaA, Darmstadt, Germany) and has received research grants from Merck Serono S.A. - Geneva that are directly relevant to the content of this article. Peer reviewers may receive honoraria from CMRO for their review work. Peer Reviewer 1 has disclosed that he/she has no relevant financial relationships. Peer Reviewer 2 has disclosed that he/she has acted as a consultant to Abbott, Amgen, Astellas, Cambridge Pharma, Can-Fite Biopharma, Centocor, DermaGenoma, DermiPsor, GlaxoSmithKline, Leo, Novartis and Ranbaxy.

Acknowledgments

The authors are grateful to and would like to thank Alberto Gimona, MD (previously employed by Merck Serono S.A. - Geneva, Switzerland [an affiliate of Merck KGaA, Darmstadt, Germany]) for overall management of the onercept clinical development program. Editorial assistance was provided by Medi Cine International and was supported by Merck Serono S.A. - Geneva.