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 log10 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‐α2a (PEG IFN‐α2a) 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‐α2a 180 μg/week for 4 weeks were compared with monotherapy with either 1,000 mg/day Debio 025 or 180 μg/week PEG IFN‐α2a. 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 log10 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 log10 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‐α2a 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‐α2a. (HEPATOLOGY 2009.)
In vitro data suggest that alisporivir is a substrate and inhibitor of CYP3A4 and P-gp. Hence, the potential for drug-drug interactions when alisporivir is co-administered with CYP3A4 and/or P-gp ...inhibitors such as ketoconazole, azithromycin and CYP3A4 inducers such as rifampin were evaluated in three separate clinical studies. Co-administration with ketoconazole (a strong CYP3A4 inhibitor) increased the Cmax , AUC and terminal elimination half-life of alisporivir by approximately two-, eight- ,and threefold, respectively. Co-administration with azithromycin (a putative weak CYP3A4 inhibitor and substrate) had no impact on the Cmax and AUC of alisporivir. Rifampin (a CYP3A4 inducer) caused an approximate 90% reduction in alisporivir Cmax and AUC and a fourfold reduction in alisporivir terminal elimination half-life. Alisporivir as an inhibitor of CYP3A4 caused a 39% increase in azithromycin exposure. The results from these studies establish alisporivir as a sensitive CYP3A4 substrate in vivo. Consequently, co-administered potent CYP3A4 inhibitors and inducers are likely to cause clinically significant changes in the exposure to alisporivir.
Afabicin (formerly Debio 1450, AFN-1720) is a prodrug of afabicin desphosphono (Debio 1452, AFN-1252), a novel antibiotic in development which targets the staphylococcal enoyl-acyl carrier protein ...reductase (FabI) and exhibits selective potent antibacterial activity against staphylococcal species, including methicillin-resistant
As part of clinical development in bone and joint infections, a distribution study in bone was performed in 17 patients who underwent elective hip replacement surgery. Patients received 3 doses of 240 mg afabicin orally (every 12 h) at various time points before surgery. Afabicin desphosphono concentrations were measured by liquid chromatography-tandem mass spectrometry in plasma, cortical bone, cancellous bone, bone marrow, soft tissue, and synovial fluid collected during surgery at 2, 4, 6, or 12 h after the third afabicin dose. The study showed good penetration of afabicin desphosphono into bone tissues, with mean area under the curve ratios for cortical bone-, cancellous bone-, bone marrow-, soft tissue-, and synovial fluid-to-total plasma concentrations of 0.21, 0.40, 0.32, 0.35, and 0.61, respectively. When accounting for the free fraction in plasma (2%) and synovial fluid (9.4%), the mean ratio was 2.88, which is indicative of excellent penetration and which showed that the afabicin desphosphono concentration was beyond the MIC
of
over the complete dosing interval. These findings, along with preclinical efficacy data, clinical efficacy data for skin and soft tissue staphylococcal infection, the availability of both intravenous and oral formulations, and potential advantages over broad-spectrum antibiotics for the treatment of staphylococcal bone or joint infections, support the clinical development of afabicin for bone and joint infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02726438.).
Debio 025 is a cyclophilin (Cyp) inhibitor without calcineurin-binding properties. The drug inhibits viral replication of genotype 1b and 2a replicons in nanomolar concentrations and shows an ...additive to synergistic antiviral effect with interferon, ribavirin, and specifically targeted antiviral therapy for hepatitis C (STAT-C) drugs. There is no cross-resistance with protease and polymerase inhibitors. In humans, Debio 025 has shown activity against genotypes 1, 2, 3, and 4, and displays an additive antiviral effect with pegylated interferon (peg-IFN)alpha2a in genotype 1 and 4 patients. The most prominent side effect is reversible hyperbilirubinaemia caused by inhibition of biliary transporters. Debio 025 is a potent anti-HCV drug, with a novel mechanism of action and an efficacy profile that makes it an attractive candidate for combination with current and future HCV treatments.
GLP-1 (glucagon-like peptide-1) is a potent insulin
secretagogue released from L cells in the intestine. The regulation of
GLP-1 secretion has been described both in
vivo and in vitro in several ...animal species, but
data from human cellular models are lacking. For this purpose, factors
and cell-signaling pathways regulating GLP-1 secretion
were investigated in the NCI-H716 human intestinal cell line. After
differentiation, these cells homogeneously produced 16.8 pmol
GLP-1/mg protein with a basal release of 4.2% during a
2-h incubation period. Nutrients, such as palmitic acid, oleic acid,
and meat hydrolysate, stimulated GLP-1 secretion in a
dose-dependent manner, as did the cholinergic agonist carbachol and the
neuromediator gastrin-releasing peptide. Along with stimulating
GLP-1 release, gastrin-releasing peptide, like ionomycin,
increased intracellular calcium levels. Activators of PKA and PKC were
able to increase GLP-1 secretion in NCI-H716 cells.
However, neither PKA activators nor meat hydrolysate increased
proglucagon mRNA levels. These findings indicate that the NCI-H716 cell
line constitutes a unique model to study the cellular mechanism of
GLP-1 secretion in humans and suggest potential
interspecies divergence in the regulation of proglucagon gene
expression in enteroendocrine cells.
Erythropoietin (Epo) is required for the production of mature red blood cells. The requirement for Epo and its receptor (EpoR) for normal heart development and the response of vascular endothelium ...and cells of neural origin to Epo provide evidence that the function of Epo as a growth factor or cytokine to protect cells from apoptosis extends beyond the hematopoietic lineage. We now report that the EpoR is expressed on myoblasts and can mediate a biological response of these cells to treatment with Epo. Primary murine satellite cells and myoblast C2C12 cells, both of which express endogenous EpoR, exhibit a proliferative response to Epo and a marked decrease in terminal differentiation to form myotubes. We also observed that Epo stimulation activates Jak2/Stat5 signal transduction and increases cytoplasmic calcium, which is dependent on tyrosine phosphorylation. In erythroid progenitor cells, Epo stimulates induction of transcription factor GATA-1 and EpoR; in C2C12 cells, GATA-3 and EpoR expression are induced. The decrease in differentiation of C2C12 cells is concomitant with an increase in Myf-5 and MyoD expression and inhibition of myogenin induction during differentiation, altering the pattern of expression of the MyoD family of transcription factors during muscle differentiation. These data suggest that, rather than acting in an instructive or specific mode for differentiation, Epo can stimulate proliferation of myoblasts to expand the progenitor population during differentiation and may have a potential role in muscle development or repair.
To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor.
This was a first-in-human, multicenter, open-label study in patients with ...advanced solid tumors harboring
gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks.
A total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were
amplifications (40%) and mutations in
(12%) and
(17%); 12 patients (21%) showed
fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with
fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of ≤30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day.
Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.
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