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Conference Paper: Resistance monitoring data from treatment-naïve chronic HBV infected patients treated for 28 days with a new class a core protein allosteric modulator RO7049389 monotherapy

TitleResistance monitoring data from treatment-naïve chronic HBV infected patients treated for 28 days with a new class a core protein allosteric modulator RO7049389 monotherapy
Authors
Issue Date2020
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep
Citation
Digital International Liver Congress (Digital ILC 2020), 27-29 August 2020. In Journal of Hepatology, 2020, v. 73 n. Suppl. 1, p. S850-S851 How to Cite?
AbstractBackground and Aims: RO7049389 is a small molecule, Class A HBV core protein allosteric modulator being developed for the treatment of chronic hepatitis B. In a Phase Ib clinical study (NCT02952924), treatment-naive chronic HBV infected HBeAg-positive and -negative patients received 4 weeks oral administration of RO7049389 or placebo (200 mg to 1000 mg daily). Potent antiviral effects were observed and no subject experienced virologic breakthrough. Here, we present the resistance monitoring data of this study. Methods: A near full-length HBV genome was amplified and underwent next generation sequencing using HBV DNA extracted from the baseline samples of all 37 patients and from the end of treatment (EoT, day 28) and subsequent last follow-up visit (LFU) samples of all 22 patients who had a quantifiable HBV DNA (>20 IU/ mL) at EoT. The mutations in each sample were determined by comparing with the HBV reference sequence (HBV genotype A, NCBI ID X02763). The analyses focused on amino acid substitutions in the core protein, especially the 24 positions located within the putative compound-binding pocket suggested by cocrystal structures. The impact of mutations on the susceptibility to RO7049389 was assessed in a transient transfection assay using corresponding point-mutants. Results: A total of 71 samples, 34 baseline (28 active: 6 placebo), 16 EoT (11 active: 5 placebo), and 21 LFU (17 active: 4 placebo), were successfully amplified and sequenced. Among them, only 5 samples from 3 patients contained amino acid substitutions of >5% frequency in any of the 24 amino acids of the putative compound-binding pocket. One patient (active) harbored 99.9% T109C at baseline, which decreased to 67.8% at LFU. The second patient (placebo) harbored 15.8% T109M at baseline, which increased to 99.8% at EoT. The LFU sample of this patient failed amplification. The third patient (active) harbored 8.0% I105 V at baseline and HBV DNA went below 20 IU/mL at EoT. In vitro assays with the corresponding point-mutants showed that T109C and I105 V did not confer resistance to RO7049389, while T109M led to reduced susceptibility to RO7049389 (5.4 fold change in EC50), at the cost of reduced replication capacity (22% of the wild type). The reason why T109M was enriched during placebo treatment remains unclear. Conclusions: In this study, a low occurrence of polymorphisms within the 24 amino acids in the putative binding pocket of RO7049389 was observed in all sequenced samples. Baseline polymorphisms known to reduce RO7049389 activity were observed in only 1 of the 34 (3%) patients with baseline sequence data, as this was a placebo-treated patient, no conclusion on reduced in vivo susceptibility can be drawn. No mutations known to reduce RO7049389 activity in vitro emerged or were enriched after 28 days of treatment, which is consistent with the robust decline in plasma HBV DNA among all patients who received RO7049389 monotherapy.
DescriptionPoster presentation - Viral Hepatitis A, B, C, D, E: Virology - no. SAT395
Persistent Identifierhttp://hdl.handle.net/10722/289187
ISSN
2019 Impact Factor: 20.582
2015 SCImago Journal Rankings: 4.570

 

DC FieldValueLanguage
dc.contributor.authorZhou, X-
dc.contributor.authorKazma, R-
dc.contributor.authorMeinel, D-
dc.contributor.authorZhou, Y-
dc.contributor.authorYuen, RMF-
dc.contributor.authorGane, E-
dc.contributor.authorSchwabe, C-
dc.contributor.authorTanwandee, T-
dc.contributor.authorCao, L-
dc.contributor.authorZhou, J-
dc.contributor.authorBo, Q-
dc.date.accessioned2020-10-22T08:09:05Z-
dc.date.available2020-10-22T08:09:05Z-
dc.date.issued2020-
dc.identifier.citationDigital International Liver Congress (Digital ILC 2020), 27-29 August 2020. In Journal of Hepatology, 2020, v. 73 n. Suppl. 1, p. S850-S851-
dc.identifier.issn0168-8278-
dc.identifier.urihttp://hdl.handle.net/10722/289187-
dc.descriptionPoster presentation - Viral Hepatitis A, B, C, D, E: Virology - no. SAT395-
dc.description.abstractBackground and Aims: RO7049389 is a small molecule, Class A HBV core protein allosteric modulator being developed for the treatment of chronic hepatitis B. In a Phase Ib clinical study (NCT02952924), treatment-naive chronic HBV infected HBeAg-positive and -negative patients received 4 weeks oral administration of RO7049389 or placebo (200 mg to 1000 mg daily). Potent antiviral effects were observed and no subject experienced virologic breakthrough. Here, we present the resistance monitoring data of this study. Methods: A near full-length HBV genome was amplified and underwent next generation sequencing using HBV DNA extracted from the baseline samples of all 37 patients and from the end of treatment (EoT, day 28) and subsequent last follow-up visit (LFU) samples of all 22 patients who had a quantifiable HBV DNA (>20 IU/ mL) at EoT. The mutations in each sample were determined by comparing with the HBV reference sequence (HBV genotype A, NCBI ID X02763). The analyses focused on amino acid substitutions in the core protein, especially the 24 positions located within the putative compound-binding pocket suggested by cocrystal structures. The impact of mutations on the susceptibility to RO7049389 was assessed in a transient transfection assay using corresponding point-mutants. Results: A total of 71 samples, 34 baseline (28 active: 6 placebo), 16 EoT (11 active: 5 placebo), and 21 LFU (17 active: 4 placebo), were successfully amplified and sequenced. Among them, only 5 samples from 3 patients contained amino acid substitutions of >5% frequency in any of the 24 amino acids of the putative compound-binding pocket. One patient (active) harbored 99.9% T109C at baseline, which decreased to 67.8% at LFU. The second patient (placebo) harbored 15.8% T109M at baseline, which increased to 99.8% at EoT. The LFU sample of this patient failed amplification. The third patient (active) harbored 8.0% I105 V at baseline and HBV DNA went below 20 IU/mL at EoT. In vitro assays with the corresponding point-mutants showed that T109C and I105 V did not confer resistance to RO7049389, while T109M led to reduced susceptibility to RO7049389 (5.4 fold change in EC50), at the cost of reduced replication capacity (22% of the wild type). The reason why T109M was enriched during placebo treatment remains unclear. Conclusions: In this study, a low occurrence of polymorphisms within the 24 amino acids in the putative binding pocket of RO7049389 was observed in all sequenced samples. Baseline polymorphisms known to reduce RO7049389 activity were observed in only 1 of the 34 (3%) patients with baseline sequence data, as this was a placebo-treated patient, no conclusion on reduced in vivo susceptibility can be drawn. No mutations known to reduce RO7049389 activity in vitro emerged or were enriched after 28 days of treatment, which is consistent with the robust decline in plasma HBV DNA among all patients who received RO7049389 monotherapy.-
dc.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep-
dc.relation.ispartofJournal of Hepatology-
dc.relation.ispartofDigital International Liver Congress (Digital ILC 2020)-
dc.titleResistance monitoring data from treatment-naïve chronic HBV infected patients treated for 28 days with a new class a core protein allosteric modulator RO7049389 monotherapy-
dc.typeConference_Paper-
dc.identifier.emailYuen, RMF: mfyuen@hku.hk-
dc.identifier.authorityYuen, RMF=rp00479-
dc.description.natureabstract-
dc.identifier.doi10.1016/S0168-8278(20)32144-9-
dc.identifier.hkuros315883-
dc.identifier.volume73-
dc.identifier.issueSuppl. 1-
dc.identifier.spageS850-
dc.identifier.epageS851-
dc.publisher.placeNetherlands-
dc.identifier.issnl0168-8278-

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