Clinical profile of the functionally selective glucocorticoid receptor agonist BI 653048 in healthy male subjects

ABSTRACT

Background: An efficacious anti-inflammatory corticosteroid with reduced side effects has been long sought. We report the pooled results from three clinical proof-of-mechanism Phase I studies of BI 653048 in healthy subjects, a functionally selective, nonsteroidal glucocorticoid (GC).

Research design and methods: Three Phase I trials were conducted: a single rising-dose study and a multiple rising-dose study to evaluate the safety, tolerability, and pharmacokinetics of BI 653048, and a multiple parallel-arm-dose study with intravenous lipopolysaccharide challenge to assess in vivo pharmacodynamics. The pharmacodynamics, efficacy, and safety of BI 653048 and prednisolone were compared.

Results: Treatment with 200 mg BI 653048 was associated with a reduced expression of IL1R2, ITGB3, and SDPR versus 20 mg prednisolone; comparable levels of FKBP5, ZBTB16, and DDIT4 expression were observed. Changes in C-peptide, glucose, insulin, and cortisol were moderate compared with prednisolone. A greater reduction of osteocalcin was observed with 200 mg BI 653048 versus 20 mg prednisolone. Comparable anti-inflammatory efficacy was demonstrated for 200 mg BI 653048 and 20 mg prednisolone. BI 653048 was well tolerated in healthy subjects.

Conclusion: BI 653048 demonstrated the desired anti-inflammatory effects of the nonsteroidal GC; however, the undesirable side-effect profile associated with GC steroids could not be disassociated from BI 653048.

Trial registration: ClinicalTrials.gov identifier: NCT02217644.

Trial registration: ClinicalTrials.gov identifier: NCT02217631.

Trial registration: ClinicalTrials.gov identifier: NCT02224105.

KEYWORDS:

• Anti-inflammatory
• BI 653048
• corticosteroid
• glucocorticoid receptor
• prednisolone
• SEGRA

Acknowledgments

The authors wish to acknowledge Anthony Suffredini, NIH Clinical Center, for providing the LPS used in this study. Editorial assistance in the development of this manuscript was provided by Tina Borg and Leigh Church of OPEN Health Medical Communications (London, UK) and was funded by Boehringer Ingelheim. Trial registration numbers: NCT02217644, NCT02217631, NCT02224105.

Declaration of interest

C. Harcken, G. Nabozny, and D. Bianchi are employees of Boehringer Ingelheim. P. Scholl and D. Thomson were employees of Boehringer Ingelheim at the time this trial was performed. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

 Author contributions

Study conception and design: C. Harcken, P. Scholl, G. Nabozny, D. Thomson, D. Bianchi. Analysis and interpretation of data: C. Harcken, P. Scholl, G. Nabozny, D. Thomson, D. Bianchi. All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. C. Harcken had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This paper was funded by Boehringer Ingelheim.