Debio-025 is an oral cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus activity in vitro. Its effect on viral load as well as its influence on intracellular Cyp levels was investigated in a randomized, double-blind, placebo-controlled study. Mean hepatitis C viral load decreased significantly by 3.6 log 10 after a 14-day oral treatment with 1200 mg twice daily (P < 0.0001) with an effect against the 3 genotypes (1, 3, and 4) represented in the study. In addition, the absence of viral rebound during treatment indicates that Debio-025 has a high barrier for the selection of resistance. In Debio-025-treated patients, cyclophilin B (CypB) levels in peripheral blood mononuclear cells decreased from 67 ؎ 6 (standard error) ng/mg protein (baseline) to 5 ؎ 1 ng/mg protein at day 15 (P < 0.01). Conclusion: Debio-025 induced a strong drop in CypB levels, coinciding with the decrease in hepatitis C viral load. These are the first preliminary human data supporting the hypothesis that CypB may play an important role in hepatitis C virus replication and that Cyp inhibition is a valid target for the development of anti-hepatitis C drugs. (HEPATOLOGY 2008; 47:817-826.)

The anti-hepatitis C virus (HCV) effect and safety of three different oral doses of the cyclophilin inhibitor Debio 025 in combination with pegylated interferon-␣2a (PEG IFN␣2a) were investigated in a multicenter, randomized, double-blind, placebo-controlled escalating dose-ranging phase II study in treatment-naïve patients with chronic hepatitis C. Doses of 200, 600, and 1,000 mg/day Debio 025 in combination with PEG IFN-␣2a 180 g/week for 4 weeks were compared with monotherapy with either 1,000 mg/day Debio 025 or 180 g/week PEG IFN-␣2a. In patients with genotypes 1 and 4, the 600-and 1,000-mg combination treatments induced a continuous decay in viral load that reached ؊4.61 ؎ 1.88 and ؊4.75 ؎ 2.19 log 10 IU/mL at week 4, respectively. In patients with genotypes 2 and 3, HCV RNA levels at week 4 were reduced by ؊5.91 ؎ 1.11 and ؊5.89 ؎ 0.43 log 10 IU/mL, respectively, with the same treatment regimens. Adverse events were comparable between treatment groups apart from a higher incidence of neutropenia associated with PEG IFN-␣2a and an increased incidence of isolated hyperbilirubinemia at the highest dose of Debio 025 (1,000 mg/day). Conclusion: These results confirm that Debio 025 has a potent activity and an additive effect on HCV RNA reduction in genotype 1 and 4 patients at 600 and 1,000 mg/day when combined with PEG IFN-␣2a.

( £ 1.735 nmol/L or £ 500 ng/L) during 9 months (253 days) of treatment. Secondary endpoints were luteinizing hormone levels, bone pain, prostate specific antigen levels, quality of life, testosterone pharmacodynamics, survival, and safety variables. RESULTSIn all, 284 men received either triptorelin (140) or leuprolide (144). The percentage of men with castrate levels of serum testosterone was lower at 29 days for triptorelin than for leuprolide (91.2% vs 99.3%; point estimate -8.0, 95% confidence interval -16.9% to -1.4%), but equivalent at 57 days (97.7% vs 97.1%). The mean (98.8% vs 97.3%) and cumulative (96.2% vs 91.2%) castration maintenance rates between 29 and 253 days were equivalent between the treatment groups. Secondary endpoints were equivalent between treatment groups except for the 9-month survival rate, which was significantly higher for triptorelin than for leuprolide (97.0% vs 90.5%; P = 0.033). Both treatments were well tolerated. CONCLUSIONTriptorelin reduced testosterone concentrations less rapidly, but maintained castration as effectively as leuprolide. There was no evidence that the slower onset of castration caused deleterious effects. KEYWORDSprostate cancer, LHRH agonist, triptorelin pamoate, leuprolide acetate, testosterone OBJECTIVETo compare the efficacy of monthly administrations of the luteinizing hormonereleasing hormone agonists triptorelin pamoate and leuprolide acetate to induce and maintain castrate levels of serum testosterone in men with advanced prostate cancer. PATIENTS AND METHODSMen with advanced prostate cancer were randomly assigned to receive triptorelin 3.75 mg or leuprolide 7.5 mg. The agent was injected intramuscularly every 28 days for nine injections. Primary endpoints were the percentages of men whose serum testosterone concentrations declined to and were maintained at or below castrate levels

The triptorelin 6-month formulation was well tolerated and was able to achieve and maintain castration for the treatment of locally advanced and metastatic prostate cancer. By reducing the frequency of required injections, this new formulation offers a more convenient treatment regimen. (Clinical Trial Registration,NCT00751790 at www.clinicaltrials.gov).

162 Background: Medical castration using gonadotropin-releasing hormone (GnRH) agonists is the mainstay of treatment for advanced prostate cancer. Achievement and maintenance of castrate serum testosterone (sT) levels <50 ng/dL (1.735 nmol/mL) has been the goal of therapy. However, patients are able to achieve and maintain sT levels <15 ng/dL after surgical castration (Oefelein M et al. J Urology 2000; 56: 1021-4). Some authors have suggested that 20 ng/dL should be the target threshold for medical castration(Perachino M et al. BJU Int 2010; 105: 648-51) but the clinical relevance of achieving such low sT levels (<20 ng/dL) remains unknown. Methods: The efficacy and safety of sustained-release triptorelin pamoate 22.5 mg 6-month formulation was recently evaluated in a 12-month (48-week), multicentre, open-label, phase III study in 120 patients with locally advanced or metastatic prostate cancer and/or increased prostate specific antigen (PSA) after failed local therapy. Initial results based on the standard castration level of 50 ng/dL were previously presented in comparison to triptorelin 1- and 3-month formulations (Lundström E et al. Clin Drug Investig 2009; 29: 757-65). We report the proportions of patients achieving sT levels of <20 ng/dL with the triptorelin pamoate 1-, 3- and 6-month formulations. Results: With the 6-month formulation, sT levels of <20 ng/dL were achieved in >90% of patients on Day 169 (6 months after first triptorelin injection) and on Day 337 (6 months after second injection; Table). Similar sT levels were achieved with triptorelin 1- and 3-month formulations in a phase III study over 9 months (Table). Conclusions: A high proportion of patients receiving the 6-month triptorelin formulation achieve sT levels <20 ng/dL. This compares favorably to the triptorelin 1- and 3-month formulations. [Table: see text] [Table: see text]