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4. Safety, pharmacokinetics, and antiviral effects of ABI-H0731, a hepatitis B virus core inhibitor: a randomised, placebo-controlled phase 1 trial.

Author

Yuen M.-F., Agarwal K., Gane E.J., Schwabe C., Ahn S.H., Kim D.J., Lim Y.-S., Cheng W., Sievert W., Visvanathan K., Ruby E., Liaw S., Yan R., Huang Q., Colonno R., Lopatin U., Yuen M.-F., Agarwal K., Gane E.J., Schwabe C., Ahn S.H., Kim D.J., Lim Y.-S., Cheng W., Sievert W., Visvanathan K., Ruby E., Liaw S., Yan R., Huang Q., Colonno R., and Lopatin U.

Abstract

Background: Therapies with novel mechanisms of action against hepatitis B virus (HBV) infection are being explored with the goal of achieving a functional cure (sustained off-treatment response) without requiring lifelong therapy. We aimed to evaluate the pharmacokinetics, safety, and antiviral activity of ABI-H0731, an investigational inhibitor of the HBV core protein. Method(s): This phase 1, randomised, placebo-controlled study was done in two parts. In part 1, healthy adults without hepatitis B aged 18-65 years at one clinical research centre in New Zealand (eight participants per dose cohort) were randomly assigned (3:1) to receive single oral doses of ABI-H0731 (100, 300, 600, or 1000 mg) or matching placebo, or once-daily or twice-daily doses of ABI-H0731 800 mg or matching placebo for 7 days. In part 2, adults aged 18-65 years at clinical research centres in New Zealand, Australia, the UK, Hong Kong, Taiwan, and South Korea with chronic HBV (12 participants per dose cohort) were randomly assigned (5:1) to receive ABI-H0731 (100, 200, 300, or 400 mg) or matching placebo once daily for 28 days. In part 2, participants were required to have HBeAg-positive or HBeAg-negative chronic HBV infection, with serum HBV DNA concentrations of at least 2 x 104 IU/mL (HBeAg-positive) or 2 x 103 IU/mL (HBeAg-negative) and serum alanine aminotransferase concentrations less than seven times the upper limit of normal. Both parts used simple randomisation, with study participants, site personnel, and study monitors masked to treatment assignments. The primary study objective was dose-related safety and tolerability of ABI-H0731 in healthy volunteers and in participants with chronic HBV infection, assessed in all treated participants. Key secondary assessments included pharmacokinetic analyses and virological responses. This study is registered with ClinicalTrials.gov, identifier NCT02908191 and is completed. Finding(s): 48 [61%] of 79 healthy volunteers were enrolled in the sing

Published
2020

7. Interim safety, tolerability pharmacokinetics, and antiviral activity of ABI-H0731, a novel core protein allosteric modulator, in healthy volunteers and non-cirrhotic viremic subjects with chronic hepatitis B

Author

Yuen, M.-F., primary, Agarwal, K., additional, Gane, E., additional, Schwabe, C., additional, Cheng, W., additional, Sievert, W., additional, Kim, D.J., additional, Ahn, S.H., additional, Lim, Y.-S., additional, Visvanathan, K., additional, Ruby, E., additional, Liaw, S., additional, Colonno, R., additional, and Lopatin, U., additional

Published
2018
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8. Final results of a phase 1b 28-day study of ABI-H0731, a novel core inhibitor, in non-cirrhotic viremic subjects with chronic hepatitis B.

Author

Gane E.J., Ahn S.H., Kim D.J., Sievert W., Visvanathan K., Ruby E., Liaw S., Yan R., Connelly E., Cai D., Huang Q., Colonno R., Lopatin U.A., Yuen M.-F., Agarwal K., Schwabe C., Lim Y.-S., Cheng W., Gane E.J., Ahn S.H., Kim D.J., Sievert W., Visvanathan K., Ruby E., Liaw S., Yan R., Connelly E., Cai D., Huang Q., Colonno R., Lopatin U.A., Yuen M.-F., Agarwal K., Schwabe C., Lim Y.-S., and Cheng W.

Abstract

Background: To achieve higher functional cure rates in chronic hepatitis B (CHB) patients, novel antiviral agents are required. The HBV core protein is involved in multiple steps of the HBV life cycle and an attractive target for direct acting antivirals. ABI-H0731 is a potent and selective Core Inhibitor (also known as a Core protein Allosteric Modifier, or CpAM) being developed to improve cure rates for CHB infection. Here we report final results of study ABI-H0731-101(b), exploring safety, pharmacokinetics (PK) and pharmacodynamics of ABI-H0731 in CHB patients. Method(s): Up to 12 viremic, non-cirrhotic CHB patients/cohort were randomized (10:2) to either ABI-H0731 (100, 200, 300 or 400 mg) or placebo, and treated once daily for up to 28 days in a double-blinded placebo-controlled fashion. Subjects were stratified by HBeAg status (7 HBeAg positive:5 HBeAg negative). Safety, tolerability, and PK were monitored, along with surveillance of pre-existing and emerging resistance by direct sequencing of the Core region, and determination of quantitative changes in HBV DNA, RNA and HBV antigens. Result(s): 38 subjects were treated for up to 28 days. Median (range) age was 40 (26-65) years. Most subjects were male (>=90%), Asian (76%), and genotype B (63%). Overall, ABI-H0731 was safe and well-tolerated. There were no serious adverse events, nor clinically significant drug related dose dependent or treatment-emergent laboratory findings. One subject at 400 mg developed a Grade 3 rash after 10 days of dosing which resolved following drug discontinuation. All other drug related treatment-emergent adverse events were considered mild (Grade 1), and there were no other premature treatment discontinuations nor dose modifications. Few changes in viral antigen levels were seen. A subject with suboptimal DNA response had a known resistance mutation (T109M) at baseline. Excluding this subject, median-maximal (range) log10 IU/mL HBV DNA declines per cohort ranged from 1.5 (0.7-3.6)

Published
2018

9. Interim safety, tolerability pharmacokinetics, and antiviral activity of ABI-H0731, a novel core protein allosteric modulator, in healthy volunteers and non-cirrhotic viremic subjects with chronic hepatitis B.

Author

Schwabe C., Ruby E., Liaw S., Colonno R., Lopatin U., Lim Y.-S., Ahn S.H., Kim D.J., Sievert W., Yuen M.-F., Agarwal K., Gane E., Cheng W., Visvanathan K., Schwabe C., Ruby E., Liaw S., Colonno R., Lopatin U., Lim Y.-S., Ahn S.H., Kim D.J., Sievert W., Yuen M.-F., Agarwal K., Gane E., Cheng W., and Visvanathan K.

Abstract

Background and Aims: Core Protein Allosteric Modifiers (CpAMs) target the HBV core protein, a pleotropic protein involved in multiple steps of the HBV life cycle. ABI-H0731 is a potent and selective CpAM being developed to improve functional cure rates for chronic HBV (CHB) infection. Here we report the interim results on safety, tolerability, pharmacokinetic (PK) and antiviral efficacy in two ongoing studies: ABI-H0731-102 in healthy volunteers and ABIH0731- 101(B) in non-cirrhotic, viremic CHB patients. Method(s): Up to 12 healthy volunteers or viremic CHB patients per cohort were randomized (10:2) and treated with 100-400 mg ABIH0731 or placebo once daily for up to 14 days (Study 102) or up to 28 days (Study 101(B)) in double-blinded, placebo-controlled fashion. Patients were stratified by HBeAg status (7 pos:5 neg). Safety, PK and pharmacodynamic responses were monitored. Result(s): Forty-nine subjects have been dosed to date in studies 102 (n = 24) and 101(B) (n = 25). Median (range) age was 38 (24-61) and 40 (26-55) years, respectively. In both studies, the majority were male (>=90%), with 13% and 76% Asian in studies 102 and 101(B), respectively. Mean baseline HBV DNA levels were 8.0 +/- 1.1 log10 in HBeAg pos and 3.8 +/- 1.5 log10 IU/ml in HBeAg neg patients. No serious adverse events (AEs) and no dose limiting laboratory toxicities have occurred in either study. A single G3 treatment-emergent AE leading to drug discontinuation was seen at 400 mg, otherwise all TEAEs were mild (G1) and/or unrelated to study drug. Treatment emergent laboratory abnormalities were infrequent, mild and/or deemed unrelated to study drug. Exposures increased in a dose proportional manner and were similar between CHB patients and healthy subjects. Steady state was readily achieved (<5 days) with approximately 2-fold accumulation seen in both patients and volunteers. HBV declines of 1.3 +/- 0.3 and 2.2 +/- 1.0 log10 IU/ml were seen in HBeAg pos/neg subjects (respectively) at 100 mg

Published
2018

11. Final Results of the Pyramid 1 Study, a Phase 3 Registrational Trial of Ravidasvir (PPI-668) and Sofosbuvir in HCV Genotype-4 Patients: High Rates of Sustained Viral Clearance in Cirrhotic and Non-Cirrhotic Patients

Author

Esmat, G., primary, El Raziky, M., additional, Gomaa, A., additional, Elbaz, T., additional, Abouelkhair, M., additional, Sabry, A., additional, Gamel, H., additional, Deen, E., additional, Ashour, M., additional, Abdel-Hamid, M., additional, Nada, O., additional, Helmy, S., additional, Abdel-Maguid, H., additional, Colonno, R., additional, Brown, N., additional, Ruby, E., additional, Vig, P., additional, and Waked, I., additional

Published
2016
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12. O65 HIGH RATE OF SUSTAINED VIROLOGIC RESPONSE IN PATIENTS WITH HCV GENOTYPE-1A INFECTION: A PHASE 2 TRIAL OF FALDAPREVIR, DELEOBUVIR AND PPI-668, WITH AND WITHOUT RIBAVIRIN

Author

Lalezari, J., primary, Holland, L., additional, Glutzer, E., additional, Vig, P., additional, Elgadi, M., additional, Stern, J.O., additional, Colonno, R., additional, Halfon, S., additional, Ruby, E., additional, Huang, N., additional, Nash, E., additional, and Brown, N., additional

Published
2014
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13. SAT-161 - Final Results of the Pyramid 1 Study, a Phase 3 Registrational Trial of Ravidasvir (PPI-668) and Sofosbuvir in HCV Genotype-4 Patients: High Rates of Sustained Viral Clearance in Cirrhotic and Non-Cirrhotic Patients

Author

Esmat, G., El Raziky, M., Gomaa, A., Elbaz, T., Abouelkhair, M., Sabry, A., Gamel, H., Deen, E., Ashour, M., Abdel-Hamid, M., Nada, O., Helmy, S., Abdel-Maguid, H., Colonno, R., Brown, N., Ruby, E., Vig, P., and Waked, I.

Published
2016
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15. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B

Author

Chang, T., Gish, R.G., Man, R.A. (Robert) de, Gadano, A., Sollano, J. (José), Chao, Y-C. (You Chen), Lok, A.S. (Anna), Han, K., Goodman, Z. (Zachary), Zhu, J. (Jin), Cross, A. (Anne), DeHertogh, D. (Deborah), Wilber, R. (Richard), Colonno, R. (Richard), Apelian, D. (David), Chang, T., Gish, R.G., Man, R.A. (Robert) de, Gadano, A., Sollano, J. (José), Chao, Y-C. (You Chen), Lok, A.S. (Anna), Han, K., Goodman, Z. (Zachary), Zhu, J. (Jin), Cross, A. (Anne), DeHertogh, D. (Deborah), Wilber, R. (Richard), Colonno, R. (Richard), and Apelian, D. (David)

Abstract

Background: Entecavir is a potent and selective guanosine analogue with significant activity against hepatitis B virus (HBV). Methods: In this phase 3, double-blind trial, we randomly assigned 715 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B who had not previously received a nucleoside analogue to receive either 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks. The primary efficacy end point was histologic improvement (a decrease by at least two points in the Knodell necro-inflammatory score, without worsening of fibrosis) at week 48. Secondary end points included a reduction in the serum HBV DNA level, HBeAg loss and seroconversion, and normalization of the alanine aminotransferase level. Results: Histologic improvement after 48 weeks occurred in 226 of 314 patients in the entecavir group (72 percent) and 195 of 314 patients in the lamivudine group (62 percent, P=0.009). More patients in the entecavir group than in the lamivudine group had undetectable serum HBV DNA levels according to a polymerase-chain-reaction assay (67 percent vs. 36 percent, P<0.001) and normalization of alanine aminotransferase levels (68 percent vs. 60 percent, P=0.02). The mean reduction in serum HBV DNA from baseline to week 48 was greater with entecavir than with lamivudine (6.9 vs. 5.4 log [on a base-10 scale] copies per milliliter, P<0.001). HBeAg seroconversion occurred in 21 percent of entecavir-treated patients and 18 percent of those treated with lamivudine (P=0.33). No viral resistance to entecavir was detected. Safety was similar in the two groups. Conclusions: Among patients with HBeAg-positive chronic hepatitis B, the rates of histologic, virologic, and biochemical improvement are significantly higher with entecavir than with lami vudine. The safety profile of the two agents is similar, and there is no evidence of viral resistance to entecavir. Copyright

Published
2006
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19. ChemInform Abstract: Aminodiol HIV Protease Inhibitors. Synthesis and Structure-Activity Relationships of P1/P1′ Compounds: Correlation Between Lipophilicity and Cytotoxicity.

Author

CHEN, P., primary, CHENG, P. T. W., additional, ALAM, M., additional, BEYER, B. D., additional, BISACCHI, G. S., additional, DEJNEKA, T., additional, EVANS, A. J., additional, GREYTOK, J. A., additional, HERMSMEIER, M. A., additional, HUMPHREYS, W. G., additional, JACOBS, G. A., additional, KOCY, O., additional, LIN, P.-F., additional, LIS, K. A., additional, MARELLA, M. A., additional, RYONO, D. E., additional, SHEAFFER, A. K., additional, SPERGEL, S. H., additional, SUN, C., additional, TINO, J. A., additional, VITE, G., additional, COLONNO, R. J., additional, and ET AL., ET AL., additional

Published
2010
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20. ChemInform Abstract: BMS-200475, a Novel Carbocyclic 2′-Deoxyguanosine Analogue with Potent and Selective anti-Hepatitis B Virus Activity in Vitro.

Author

BISACCHI, G. S., primary, CHAO, S. T., additional, BACHARD, C., additional, DARIS, J. P., additional, INNAIMO, S., additional, JACOBS, G. A., additional, KOCY, O., additional, LAPOINTE, P., additional, MARTEL, A., additional, MERCHANT, Z., additional, SLUSARCHYK, W. A., additional, SUNDEEN, J. E., additional, YOUNG, M. G., additional, COLONNO, R., additional, and ZAHLER, R., additional

Published
2010
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26. Clinical Emergence of Entecavir-Resistant Hepatitis B Virus Requires Additional Substitutions in Virus Already Resistant to Lamivudine

Author

Tenney, D. J., primary, Levine, S. M., additional, Rose, R. E., additional, Walsh, A. W., additional, Weinheimer, S. P., additional, Discotto, L., additional, Plym, M., additional, Pokornowski, K., additional, Yu, C. F., additional, Angus, P., additional, Ayres, A., additional, Bartholomeusz, A., additional, Sievert, W., additional, Thompson, G., additional, Warner, N., additional, Locarnini, S., additional, and Colonno, R. J., additional

Published
2004
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35. BMS-200475, a novel carbocyclic 2′-deoxyguanosine analog with potent and selective anti-hepatitis B virus activity in vitro

Author

Bisacchi, G.S., primary, Chao, S.T., additional, Bachard, C., additional, Daris, J.P., additional, Innaimo, S., additional, Jacobs, G.A., additional, Kocy, O., additional, Lapointe, P., additional, Martel, A., additional, Merchant, Z., additional, Slusarchyk, W.A., additional, Sundeen, J.E., additional, Young, M.G., additional, Colonno, R., additional, and Zahler, R., additional

Published
1997
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42. Genotypic And Phenotypic Analysis Of Human Immunodeficiency Virus Type 1 Isolates From Patients On Prolonged Stavudine Therapy

Author

Lin, P.-F., primary, Samanta, H., additional, Rose, R. E., additional, Patick, A. K., additional, Trimble, J., additional, Bechtold, C. M., additional, Revie, D. R., additional, Khan, N. C., additional, Federici, M. E., additional, Li, H., additional, Lee, A., additional, Anderson, R. E., additional, and Colonno, R. J., additional

Published
1994
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