RG-4929

We assessed safety and efficacy of two selective 11β‐HSD1 inhibitors (RO5093151/RO‐151 and RO5027383/RO‐838) in this randomized, controlled study in metformin‐treated patients with type 2 diabetes.

Patients either received placebo (N = 21), RO‐151 BID 5 mg (N = 24) or 200 mg (N = 20) or RO‐838 QD 50 mg (N = 21) or 200 mg (N = 24) for 28 days. Metabolic assessments comprising of nine‐point plasma glucose profiles, oral glucose tolerance tests and determination of metabolic biomarkers including insulin, C‐peptide, glucagon, HbA1c and lipids were done at baseline and end of treatment.

Despite the short treatment duration, both RO‐151 and RO‐838 showed trends for improved HbA1c and consistent reductions in body weight (–0.86 to –1.67 kg) exceeding those observed with placebo (–0.28 kg, p = 0.019 for 200 mg RO‐151 vs. placebo). Insulin sensitivity parameters (e.g. HOMA‐IR and Matsuda‐Index) improved non‐significantly with 200 mg RO‐151. Lipid parameters did not consistently improve with either compound, but RO‐838 led to non‐significant increases in triglycerides and VLDL‐cholesterol versus placebo. Both compounds were well tolerated and showed inhibitory effects on 11β‐HSD1 activity based on urinary corticosteroid excretion. As reported for other 11β‐HSD1‐inhibitors increased concentrations of ACTH and adrenal androgen precursors were found with RO‐151, but not with RO‐838.

Slight metabolic improvements were seen, in particular with RO‐151 high dose, however, the observed changes often did not reach statistical significance and were not clearly dose dependent. Studies of longer duration are needed to further investigate potential benefits and risks of these compounds.

The prevalence of non-alcoholic fatty liver disease is increasing worldwide and an effective and safe pharmacological treatment is needed. We investigated whether inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, also known as HSD11B1) by RO5093151 could safely and effectively decrease liver-fat content in patients with this disorder.

We did this phase 1b trial at four centres in Germany and Austria. Participants with non-alcoholic fatty liver disease (defined as (1)H magnetic resonance spectroscopy liver-fat content >5·56%), insulin resistance (homoeostatic model assessment of insulin resistance [HOMA-IR] of at least 2·0 mmol/L·mU/L), BMI greater than 27 kg/m(2), and aged 35-65 years were randomly assigned by interactive voice response system in a 1:1 ratio, stratified for triglyceride concentration (<1·7 mmol/L or ≥1·7 mmol/L), to oral RO5093151 (200 mg twice daily) or matching placebo for 12 weeks. The main exclusion criteria were other liver diseases, aspartate aminotransferase or alanine aminotransferase concentrations of more than two and a half times the upper limit of normal, history of diabetes or bariatric surgery, and use of weight lowering drugs. Participants and investigators were masked to assignment throughout the study. The primary endpoint was change in liver-fat content from baseline to week 12. Efficacy analysis was by modified intention to treat, including all patients who received at least one dose of study drug and had a baseline and follow-up measurement of liver-fat content. Safety analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01277094.

We did this trial between Jan 13, 2011, and March 28, 2012. 41 patients were randomly assigned to RO5093151 and 41 to placebo. 35 patients in the RO5093151 group and 39 in the placebo group were included in the efficacy analysis. Mean liver-fat content decreased in the RO5093151 group (from 16·75% [SD 8·67] to 14·28% [8·89]), but not in the placebo group (from 18·53% [10·00] to 18·46% [10·78], p=0·02 for between group difference). 26 participants (65%) in the RO5093151 group had adverse events, compared with 21 (53%) in the placebo group. The most common adverse events were gastrointestinal disorders (12 patients [30%] in the RO5093151 group vs seven [18%] in the placebo group), and infections and infestations (eight [20%] vs nine [23%]). Nervous system disorders occurred in significantly more patients in the RO5093151 group than in the placebo group (nine [23%] vs two [5%]; p=0·02); all other differences in adverse events were non-significant. One participant (3%) in the placebo group and three participants (8%) in the RO5093151 group had serious adverse events. All serious adverse events were deemed unrelated to study treatment.

Inhibition of 11β-HSD1 by RO5093151 was effective and safe in reducing liver-fat content, suggesting that targeting of 11β-HSD1 might be a promising approach for the treatment of non-alcoholic fatty liver disease.

F Hoffmann-La Roche.