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Abstract
Background/aims Cortisol is involved in the regulation of intraocular pressure (IOP). This study aimed to assess the effect of 11β-hydroxysteroid-dehydrogenase type 1 (11βHSD1) inhibition by oral administration of RO5093151 on IOP.
Methods The exposure of key ocular compartments following oral administration was assessed in rabbits. An adaptive, randomised, placebo-controlled study gated by a Bayesian decision criterion was performed in 35 patients with primary open angle glaucoma (POAG) or ocular hypertension (OHT). Following a 7-day placebo-controlled run-in period, 200 mg twice daily RO5093151 or placebo (4:1) were administered for 7 days. The extent of 11βHSD1 inhibition was assessed by the ratio of urinary tetrahydrocortisol (5α and 5β)/tetrahydrocortisone (THF/THE). Time-matched IOP assessments were performed.
Results A high distribution of RO5093151 into the rabbit eye was observed. In humans, a high and sustained inhibition of 11βHSD1 was shown by the decrease of THF/THE from 0.9 at baseline to 0.18 on day 7. There was no statistically significant difference in change of IOP from baseline. In the ‘worse eye’, the adjusted least square mean change from baseline was −2.7 mm Hg (95% CI −4.2 to –1.2) and −2.9(95% CI −5.9 to 0.1) in the RO5093151 and placebo group, respectively.
Conclusions Despite high inhibition of 11βHSD1 and expected moderate to high tissue distribution in ocular tissues, a 7-day treatment with a high oral dose of RO5093151 did not result in a clinically meaningful effect on IOP in patients with POAG or OHT.
- IOP
- 11β-HSD
- clinical trial
- glaucoma
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Footnotes
Acknowledgements The authors would like to thank Dr Svetlana Spassova, Senior Medical Director at PPD, Sofia, Bulgaria, for scientific advice regarding the definition of ocular inclusion and exclusion criteria and the principal investigators Mária Ferencz (Fövárosi Önkormányzat Szent Imre Kórház, OSZMSZ Szemészeti Profil, Budapest, Hungary), Jara Hornova (Fakultni Nemocnice Kralovske Vinohrady, Oftalmologicka Klinika, Praha, Czech Republic) and Jana Kadlecová (Oční klinika FN, Hradec Králové, Czech Republic) for participating to the trial.
Contributors DS, PJ, SF-R and WCS designed the clinical study.
DH designed, analysed and provided contribution to the preclinical study.
CS, AP, SF-R were involved in the design and analysis of the data.
MET and HD were responsible for data acquisition and research execution. A
ll authors were involved in revising and final approval of the manuscript.
Competing interests DS, CS, AP, SF-R, DH and PJ were employees of F. Hoffmann La Roche Ltd. The study was funded by Roche Pharmaceutical Research and Early Development.
Patient consent Patient.
Ethics approval Health authority approval in the USA, Bulgaria, Hungary and Czech Republic, corresponding ethics approval by Quorum Review IRB, Ethics Committee for Multi-centre Trials, Egeszsegugyi Tudomanyos Tanacs, Eticka komise Fakultni nemocnice, respectively.
Provenance and peer review Not commissioned; externally peer reviewed.