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Scientific Publications

Boehringer Ingelheim offers an overview of scientific publications on the following pages. This overview represents all publications of the last three years (YTD) where employees of Boehringer Ingelheim worldwide were involved.

12 publications regarding Infection
  • Author:
    McPherson CJ; Aschenbrenner LM; Lacey BM; Fahnoe KC; Lennon MM; Finegan SM; Tadakamalla B; O'Donnell JP; Mueller JP; Tomaras AP
    Title:
    Clinically relevant Gram-negative resistance mechanisms have no effect on the efficacy of MC-1, a novel siderophone-conjugated monocarbam.
    Source:
    Antimicrob Agents Chemother 56 (12), 6334-6342 (2012)
  • Author:
    Beaulieu P L; Bös M; Cordingley M G; Chabot C; Fazal G; Garneau M; Gillard J R; Jolicoeur E; Laplante S; McKercher G; Poirier M; Poupart M A; Tsantrizos Y S; Duan J; Kukolij G
    Title:
    Discovery of the first thumb pocket 1 NS5B polymerase inhibitor (BILB 1941) with demonstrated antiviral activity in patients chronically infected with genotype 1 hepatitis C virus (HCV)
    Source:
    J Med Chem 55 (17), 7650-7666 (2012)
    Abstract:
    Combinations of direct acting antivirals (DAAs) that have the potential to suppress emergence of resistant virus and that can be used in interferon-sparing regimens represent a preferred option for the treatment of chronic HCV infection. We have discovered allosteric (thumb pocket 1) non-nucleoside inhibitors of HCV NS5B polymerase that inhibit replication in replicon systems. Herein, we report the late-stage optimization of indole-based inhibitors, which began with the identification of a metabolic liability common to many previously reported inhibitors in this series. By use of parallel synthesis techniques, a sparse matrix of inhibitors was generated that provided a collection of inhibitors satisfying potency criteria and displaying improved in vitro ADME profiles. "Cassette" screening for oral absorption in rat provided a short list of potential development candidates. Further evaluation led to the discovery of the first thumb pocket 1 NS5B inhibitor (BILB 1941) that demonstrated antiviral activity in patients chronically infected with genotype 1 HCV. © 2012 American Chemical Society.
  • Author:
    Schernthaner G; Barnett AH; Emser A; Patel S; Troost J; Woerle H-J; von Eynatten M
    Title:
    Safety and tolerability of linagliptin: A pooled analysis of data from randomized controlled trials in 3572 patients with type 2 diabetes melitus.
    Source:
    Diabetes Obes Metab 14 (5), 470-478 (2012)
    Abstract:
    Aims: To assess the safety and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin in patients with type 2 diabetes. Methods: Data were pooled from eight randomized, double-blind, placebo-controlled Phase III clinical trials lasting ?24 weeks. Incidences were calculated with descriptive statistics for the overall population and for subgroups of elderly and renally impaired patients. Results: A total of 2523 patients received linagliptin 5 mg once daily and 1049 patients received placebo. The overall incidence of adverse events (AEs) or serious AEs with linagliptin was similar to placebo (AEs 55.8% vs. 55.0%; serious AEs 2.8% vs. 2.7%). Overall aggregated infection incidence was 19.5% for linagliptin and 21.4% for placebo. Similar or reduced incidence of AEs versus placebo were seen with linagliptin for upper respiratory tract infection (3.3% vs. 4.9%), headache (2.9% vs. 3.1%), urinary tract infection (2.2% vs. 2.7%), blood and lymphatic disorders (1.0% vs. 1.2%), hypersensitivity (0.1% vs. 0.1%), hepatic enzyme increase (0.1% and 0.1%) and serum creatinine increase (0.0% and 0.1%). There was a slight increased frequency of nasopharyngitis (5.9% vs. 5.1%) and cough (1.7% vs. 1.0%) with linagliptin. Hypoglycaemia incidence was 8.2% for linagliptin and 5.1% for placebo; incidence was higher in patients with a background of sulphonylurea therapy (20.7% and 13.3%, respectively). In patients not receiving concomitant sulphonylurea, the hypoglycaemic incidence with linagliptin was very low in both the total population (<1%), and elderly and renally impaired patients (both <1%). Conclusions: This pooled analysis shows that linagliptin is well tolerated, with a low risk of hypoglycaemia.
  • Author:
    Ibrisimovic M; Nagl U; Kneidinger D; Rauch M; Lion T; Klein R
    Title:
    Targeted expression of herpes simplex virus thymidine kinase in adenovirus-infected cells reduces virus titers upon treatment with ganciclovir in vitro.
    Source:
    J Gene Med 14 (1), 3-19 (2012)
    Abstract:
    Background: Adenoviruses are a frequent cause of life-threatening infections in immunocompromised patients. Available therapeutics still cannot completely prevent fatal outcomes. By contrast, herpes viruses are well treatable with prodrugs such as ganciclovir (GCV), which are selectively activated in virus-infected cells by virus-encoded thymidine kinases. This effective group of prodrugs is not applicable to adenoviruses and other DNA viruses because they lack those kinases. Methods: To render adenoviruses amenable to GCV treatment, we generated an adenoviral vector-based delivery system for targeted expression of herpes simplex virus thymidine kinase (HSV-TK) in wild-type adenovirus 5 (wt Ad5)-infected cells. HSV-TK expression was largely restricted to wt virus-infected cells by transcription of the gene from the Ad5 E4 promoter. Its activity is dependent on the adenoviral E1A gene product which is not produced by the vector but is only provided in cells infected with wt adenovirus. The anti-adenoviral effect of HSV-TK expression and concomitant treatment with GCV was assessed in vitro in four different cell lines or primary cells. Results: E4 promoter-mediated HSV-TK background expression was sufficiently low to prevent cytotoxicity in the presence of low-levels GCV in cells not infected with wt Ad5. However, expression was several-fold increased in wt Ad5-infected cells and treatment with low levels of GCV efficiently inhibited wt Ad5 DNA replication. Genome copy numbers and output of infectious particles were reduced by up to>99.99% and cell viability was greatly increased. Conclusions: We extended the concept of enzyme/prodrug therapy to adenovirus infections by selectively sensitizing adenovirus-infected cells to treatment with GCV.
  • Author:
    Zeuzem St; Soriano V; Asselah T; Bronowicki J-P; Ceausu E; Lohse AW; Streinu-Cercel A; Preotescu L; Moussalli J; Mullhaupt B; Schuchmann M; Bourliere M; Calinas F; Buti M; Roberts StK; Gane EJ; Stern JO; Mensa FJ; Nehmiz G; Bonaventura H; Boecher WO
    Title:
    Virologic response to an interferon-free regimen of BI201335 and BI207127, with and without ribavirin, in treatment-naive patients with chronic genotype-1 HCV infection: week 12 interim results of the sound-C2 study.
    Source:
    Hepatology 54 (Supp.[1]), 1436 A (2011)
  • Author:
    Dieterich D; Asselah T; Guyader D; Berg Th; Biermer M; Ceausu E; Preotescu L; Schuchmann M; Mauss St; Ratsiu V; Ferenci P; Larrey DG; Maieron A; Stern JO; Scherer J; Kubiak R; Boecher WO
    Title:
    SILEN-C3: treatment for 12 and 24 weeks with BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in treatment naive patients with chronic genotype-1 HCV infection.
    Source:
    Hepatology 54 (Supp.[1]), 378a (2011)
  • Author:
    Sulkowski MS; Asselah T; Ferenci P; Stern JO; Scherer J; Kukolj G; Boecher WO
    Title:
    Treatment with the second generation HCV protease inhibitor BI201355 results in high and consistent SVR rates - results from SILEN-C1 in treatment-naive patients across different baseline factors.
    Source:
    Hepatology 54 (Supp.[1]), 473A (2011)
  • Author:
    Zeuzem St; Asselah T; Angus PW; Zarski J-PH; Larrey DG; Mullhaupt B; Gane EJ; Schuchmann M; Lohse AW; Pol St; Moussalli J; Bronowicki J-P; Roberts SK; Arasteg K; Zoulim F; Stern JO; Mensa FJ; Nehmiz G; Haefner C; Boecher WO
    Title:
    High sustained virologic response following interferon-free treatment of chronic HCV GT1 infection for 4 weeks with HCV protease inhibitor BI201335, polymerase inhibitor BI207127 and ribavirin, followed by BI201335 and pegifn/ribavirin - the sound-C1 study.
    Source:
    Hepatology 54 (Suppl.[1), 486A-487A (2011)
  • Author:
    Bohnhorst B; Lange M; Bartels DB; Bejo L; Hoy L; Peter C
    Title:
    Procalcitonin and valuable clinical symptoms in the early detection of neonatal late-onset bacterial infection.
    Source:
    Acta Paediatr 101 (1), 19-29 (2012)
    Abstract:
    Aim: To evaluate which clinical symptoms indicate proven neonatal bacterial infection (NBI) and whether measuring procalcitonin aside from C-reactive protein and interleukin 6 improves sensitivity and specificity in diagnosis. Methods: In a prospective observational study, clinical symptoms and procalcitonin, C-reactive protein and interleukin 6 were simultaneously determined from the 4th day of life in 170 preterm and term neonates at the first time of suspicion of NBI. Proven NBI was defined as a positive culture of otherwise sterile body fluids or radiologically verified pneumonia in combination with elevated inflammatory markers. Results: Fifty-eight (34%) patients were diagnosed with proven late-onset NBI. In case of proven NBI, odds ratio and 95% confidence intervals were 2.64 (1.06-6.54) for arterial hypotension, 5.16 (2.55-10.43) for feeding intolerance and 9.18 (4.10-20.59) for prolonged capillary refill. Sensitivity of combined determination of C-reactive protein (>10 mg/L) and interleukin 6 (>100 pg/mL) was 91.4%, specificity 80.4%, positive predictive value 70.7% and negative predictive value 94.7%. The additional determination of procalcitonin (>0.7 ng/mL) resulted in 98.3%, 65.2%, 58.8% and 98.6%, respectively. Conclusion: Arterial hypotension, feeding intolerance and especially prolonged capillary refill indicate proven neonatal late-onset bacterial infection, even at the time of first suspicion. Additional measurement of procalcitonin does indeed improve sensitivity to nearly 100%, but is linked to a decline in specificity. Nevertheless, in the high-risk neonatal population, additional procalcitonin measurement can be recommended because all infants with NBI have to be identified.
  • Author:
    Zeuzem S; Asselah T; Angus P; Zarski JP; Larrey D; Mullhaupt B; Gane E; Schuchmann M; Lohse A; Pol S; Bronowicki JP; Roberts S; Arasteh K; Zoulim F; Heim M; Stern JO; Kukolj G; Nehmiz G; Haefner C; Boecher WO
    Title:
    Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection.
    Source:
    Gastroenterology 141 (6), 2047-2055 (2011)
    Abstract:
    BACKGROUND & AIMS: Therapeutic regimens are being developed for patients with hepatitis C virus (HCV) infection that do not include the combination of peginterferon alfa and ribavirin. We investigated the antiviral effect and safety of BI 201335 (an inhibitor of the NS3/4A protease) and BI 207127 (an inhibitor of the NS5B non-nucleoside polymerase) with ribavirin. METHODS: Thirtytwo treatment-naive patients with chronic HCV genotype 1 infection were randomly assigned to groups that were given 400 mg or 600 mg BI 207127 3 times daily plus 120 mg BI 201335 once daily and 1000 to 1200 mg/day ribavirin for 4 weeks. The primary efficacy end point was virologic response (HCV RNA level <25 IU/mL at week 4). Thirty-two patients received treatment; 31 completed all 4 weeks of assigned combination therapy. RESULTS: In the group given BI 207127 400 mg 3 times daily, the rates of virologic response were 47%, 67%, and 73% at days 15, 22, and 29; a higher rate of response was observed in patients with genotype-1b compared with genotype-1a infections. In the group given BI 207127 600 mg 3 times daily, the rates of virologic response were 82%, 100%, and 100%, respectively, and did not differ among genotypes. One patient in the group given 400 mg 3 times daily had virologic breakthrough (>= 1 log(10) rebound in HCV RNA) at day 22. The most frequent adverse events were mild gastrointestinal disorders, rash, and photosensitivity. There were no severe or serious adverse events; no patients discontinued therapy prematurely. CONCLUSIONS: The combination of the protease inhibitor BI 201335, the polymerase inhibitor BI 207127, and ribavirin has rapid and strong activity against HCV genotype-1 and did not cause serious or severe adverse events.
  • Author:
    Huang F; Scholl P; Huang DB; MacGregor TR; Vinisko R; Castles MA; Berger F; Robinson P
    Title:
    Coadministration with lopinavir and ritonavir decreases exposure to BILR 355, a nonnucleoside reverse transcriptase inhibitor, in healthy volunteers.
    Source:
    J Clin Pharmacol 51 (7), 1061-1071 (2011)
    Abstract:
    The objective of this investigation was to evaluate the pharmacokinetic interaction of lopinavir/ritonavir (LPV/r) with BILR 355. In group A, 26 healthy participants were administered LPV/r (400mg/100mg) twice daily for 14 days, followed by coadministration of BILR 355, 150 mg twice daily for an additional 7 days. Pharmacokinetic assessments were performed on days 14 and 21. In group B, 8 healthy participants were given BILR 355/ritonavir (BILR 355/r, 150mg/100mg) twice daily for 7 days. The pharmacokinetic data from group B (BILR 355/r-alone group) were also pooled with group B subjects from 3 similar phase I drug-drug interaction trials performed in parallel to this study. Coadministration with LPV/r resulted in a 51% decrease in steady-state area under plasma concentration-time curve from 0 to 12 hours (AUC0-12,ss) and steady-state maximum measured plasma concentration over a dosing interval (Cmax,ss) and a 50% decrease in steady-state plasma concentration 12 hours post last dosing (C12,ss) for BILR 355. Exposure to LPV was not changed after coadministration. BILR 355/r was well tolerated in this study. There was no evidence of increased risk of lopinavir or ritonavir toxicity upon coadministration with BILR 355. - DERWENT Abstract - This single-center, open-label, randomized, phase I study evaluated the pharmacokinetic interaction of lopinavir (LP) + ritonavir (RV) with BILR 355 (all p.o.) tablets in 34 healthy volunteers. Coadministration with LP + RV resulted in a 51% decrease in steady-state AUC0-12 hr and steady-state maximum measured plasma concentration (PC) over a dosing interval and a 50% decrease in steady-state PC 32 hr post last dosing for BILR 355. Exposure to LP was not changed after coadministration. BILR 355 + RV are well tolerated. There is no evidence of increased risk of LP or RV toxicity upon coadministration with BILR 355. Methods 34 Healthy volunteers were treated with LP (400 mg b.i.d.) + RV (100 mg b.i.d.) + BILR 355 (150 mg b.i.d., all p.o.) tablets for 14 days followed by BILR 355 for 7 days (n = 26, 13 male, median age 34.5 yr, range 21-59 yr) or BILR 355 + RV for 7 days (n = 8, 4 male, median age 25 yr, range 19-42 yr). Results Peak PC of BILR 355 were achieved about 4 hr after administration, irrespective of whether BILR 355 + RV were given alone or as BILR 355 + LP + RV. The terminal half-lives were similar, with a mean half-life of 17.9 hr for BILR 355 + LP + RV and 18.5 hr for BILR 355 + RV alone. Following administration of LP + RV + BILR 355, the exposures to RV were somewhat higher vs. LP + RV. However, the exposures to RV after coadministration were significantly lower than those when BILR 355 + RV was given alone. Following administration, LP was rapidly absorbed, with peak concentrations achieved within 4 hr of administration regardless of whether the drug was administered alone or with BILR 355. PC-time profiles of LP administered alone and concomitantly with BILR 355 were nearly superimposable. Mean pharmacokinetic parameter values following the administration of LP alone were similar to those observed after treatment with LP + RV and BILR 355. The median tmax for LP was similar with or without concomitant administration of BILR 355. Adverse events were headache, diarrhea, fatigue, upper abdominal pain, chest discomfort, insomnia, nausea, abdominal pain, flatulence, pharyngolaryngeal pain, dysmenorrhea, hunger, hypersensitivity, somnolence, abdominal discomfort, dizziness, frequent bowel movements, asthenia, abnormal bowel sounds, and sunburn.
  • Author:
    Manns MP; Bourliere M; Benhamou Y; Pol S; Bonacini M; Trepo C; Wright D; Berg T; Calleja JL; White PW; Stern JO; Steinmann G; Yong C-L; Kukolj G; Scherer J; Boecher WO
    Title:
    Potency safety and pharmacokinetic of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection.
    Source:
    J Hepatol 54 (6), 1114-1122 (2011)
    Abstract:
    Background &amp; Aims: BI201335 is a highly specific and potent HCV protease inhibitor. This multiple rising dose trial evaluated antiviral activity and safety in chronic HCV genotype-1 patients. Methods: Thirty-four treatment-naïve patients were randomized to monotherapy with placebo or BI201335 at 20-240 mg once-daily for 14 days, followed by combination with pegylated interferon alfa/ribavirin (PegIFN/RBV) through Day 28. Nineteen treatment-experienced patients received 48-240 mg BI201335 once-daily with PegIFN/RBV for 28 days. HCV-RNA was measured with Roche COBAS TaqMan. Results: In treatment-naïve patients, median maximal viral load (VL) reductions during 14-day monotherapy were -3.0, -3.6, -3.7, and -4.2 log10 for the 20, 48, 120, and 240 mg groups. VL breakthroughs (?1 log10 from nadir) were seen in most patients on monotherapy and were caused by NS3/4A variants (R155K, D168V) conferring in vitro resistance to BI201335. Adding PegIFN/RBV at Days 15-28 led to continuous viral load reductions in most patients. In treatment-experienced patients, treatment with BI201335 and PegIFN/RBV achieved VL &lt;25 IU/ml at Day 28 in 3/6, 4/7, and 5/6 patients in the 48, 120, and 240 mg dose groups. VL breakthroughs were observed during triple combination in only 3/19 patients. BI201335 was generally well tolerated. Mild rash or photosensitivity was detected in four patients. Mild unconjugated hyperbilirubinemia was the only dose-dependent laboratory abnormality of BI201335. BI201335 elimination half-life supports once-daily dosing. Conclusions: BI201335 combined with PegIFN/RBV was well tolerated and induced strong antiviral responses. These results support further development of BI201335 in HCV genotype-1 patients.
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