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Ombitasvir (ABT267; Viekira Pak)

Alias: Viekira Pak (trade name); ABT-267; Ombitasvir; 1258226-87-7; Ombitasvir [INN]; CHEBI:85183; Ombitasvir [USAN:INN]; ABT 267; UNII-2302768XJ8; Ombitasvir(ABT-267); ABT267; CHEBI:85183; 2302768XJ8; ABT267; ABT 267
Cat No.:V0073 Purity: ≥98%
Ombitasvir (trade name; Viekira Pak; formerly known as ABT-267) is a novel and potent N-phenylpyrrolidine-based inhibitor of hepatitis C virus (HCV) NS5A with excellent potency, metabolic stability, and pharmacokinetics/PK.
Ombitasvir (ABT267; Viekira Pak)
Ombitasvir (ABT267; Viekira Pak) Chemical Structure CAS No.: 1258226-87-7
Product category: HCV Protease
This product is for research use only, not for human use. We do not sell to patients.
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Product Description

Ombitasvir (trade name; Viekira Pak; formerly known as ABT-267) is a novel and potent hepatitis C virus (HCV) NS5A inhibitor based on N-phenylpyrrolidines that exhibits good pharmacokinetics/PK, metabolic stability, and potency. Ombitasvir was discovered to be a pan-genotypic HCV inhibitor, with an EC50 range of 366 pM against GT6a and 1.7-19.3 pM against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a. In treatment-naive HCV GT1-infected subjects, it reduced HCV RNA up to 3.10 log10 IU/mL during a 3-day monotherapy. Under the brand name Viekira Pak, ombitasvir has received FDA approval for use in combination with paritaprevir, ritonavir, and dasabuvir as antiviral medications.

Biological Activity I Assay Protocols (From Reference)
Targets
HCV (IC50 = 0.82 to 19.3 pM); HCV (IC50 = 366 pM)
ln Vitro
Ombitasvir (ABT267) is a picomolar potency, pan-genotypic activity, and 50% effective concentrations (EC50s) of 0.82 to 19.3 pM against HCV genotypes 1 to 5 and 366 pM against genotype 6a hepatitis C virus (HCV) NS5A inhibitor. When it comes to genotype 1a-H77 and genotype 1b-Con1 subgenomic replicons, ombitasvir's EC50 values are 14.1 and 5.0 pM, respectively[1].
Ombitasvir (ABT267) is a hepatitis C virus (HCV) NS5A inhibitor with picomolar potency, pan-genotypic activity, and 50% effective concentrations (EC50s) of 0.82 to 19.3 pM against HCV genotypes 1 to 5 and 366 pM against genotype 6a. Ombitasvir retained these levels of potency against a panel of 69 genotype 1 to 6 chimeric replicons containing the NS5A gene derived from HCV-infected patients, despite the existence of natural sequence diversity within NS5A. In vitro resistance selection identified variants that conferred resistance to ombitasvir in the HCV NS5A gene at amino acid positions 28, 30, 31, 58, and 93 in genotypes 1 to 6.
Activity in HCV replicons. [1]
The activity of Ombitasvir (ABT267) was previously presented by DeGoey et al. Ombitasvir had EC50s of 14.1 and 5.0 pM against genotype 1a-H77 and 1b-Con1 subgenomic replicons, respectively. The antiviral activity of ombitasvir was attenuated 11- to 13-fold in the presence of 40% human plasma through sequestration of compound due to plasma protein binding. The CC50 of ombitasvir was greater than 32 μM, resulting in an in vitro therapeutic index that exceeded two millionfold. Ombitasvir demonstrated broad genotypic activity, with EC50s of 0.82 to 19.3 pM against genotype 2a, 2b, 3a, 4a, and 5a replicons and 366 pM against a genotype 6a replicon (Table 1).
Selection of variants resistant to Ombitasvir (ABT267) in genotype 1a, 1b, 2a, 2b, 3a, 4a, 5a, and 6a replicons. [1]
The amino acid variants selected by ombitasvir across genotypes 1 to 6 are listed in Tables 2 and 3. The resistance profile of ombitasvir in genotype 1 was previously presented briefly by DeGoey et al. In genotype 1a, the predominant variants selected by ombitasvir at 10-, 100-, or 100-fold over the EC50 were M28T, M28V, Q30R, Y93C, and Y93H. In the genotype 1a-H77 background, M28V conferred 58-fold resistance, while the M28T, Q30R, Y93C, and Y93H variants each conferred greater than 800-fold levels of resistance. The predominant variant selected by ombitasvir in genotype 1b was Y93H, which conferred 77-fold resistance to ombitasvir. In contrast to the observations for genotype 1a, single substitutions at amino acid position 28, 30, and 31 in genotype 1b conferred <10-fold resistance. At 100-fold or 1,000-fold over EC50 of ombitasvir, a number of clones contained double amino acid substitutions, primarily Y93H along with an additional substitution in the N-terminal region of NS5A, and the double variants conferred more than 400-fold resistance to ombitasvir. Resistance selection was conducted at 50-fold above the EC50 in genotypes 2 to 5 and at 10-fold above the Ombitasvir (ABT267) EC50 in the genotype 6a cell line, as at concentrations above these values, replicon cells did not survive in the presence of G418, indicating that the cells had been cleared of replicons.

In genotype 2a, the predominant variants selected were T24A and F28S, and in genotype 2b, the predominant variants selected were L31V and Y93H, while the L28F variant was observed in only one out of the 24 clones. In the European HCV database, amino acid position 31 in genotypes 2a and 2b is polymorphic with a prevalence of both methionine and leucine. Therefore, some of the resistant variants were constructed in the background of M31 as well as L31. In genotype 2a, both T24A (plus M31) and T24A (plus L31) were found to confer similar levels of resistance to Ombitasvir (ABT267). The genotype 2b L28F (plus L31) and L31V variants conferred 47-fold and 511-fold resistance, respectively; however, variant L28F in an M31 background was found to confer 248-fold resistance to ombitasvir. The predominant resistance-associated variant detected in genotype 3a was Y93H, which conferred 6728-fold resistance to ombitasvir. In genotype 4a, the only variant selected was L28V, and it conferred 23-fold resistance to ombitasvir. In genotype 5a, variants L28I, L31F, and L31V were observed, of which L28I conferred 79-fold resistance to ombitasvir, while both the L31F and L31V variants conferred over 240-fold resistance. In genotype 6a, L31V and several variants at T58 were selected, and these conferred 18- to 101-fold resistance to ombitasvir.

In summary, the key resistance-associated amino acid positions observed across genotypes 1 to 6 were 28, 30, 31, 58, and 93 in NS5A; however, the resistance conferred by variants at these amino acid positions to Ombitasvir (ABT267) varied by genotype. Figure 2 shows an alignment of amino acids 1 to 100 of NS5A in the wild-type genotype 1 to 6 replicons, highlighting the signature resistance-associated amino acid positions in each genotype.
Activity of Ombitasvir (ABT267) against a panel of HCV genotype 1 to 6 isolates. [1]
Given the genetic diversity of HCV and the degree of amino acid polymorphisms within the N-terminal region of NS5A, the activity of ombitasvir was evaluated against a panel of treatment-naive genotype 1 to 6 isolates in order to characterize its breadth of coverage (Table 4). The variability at signature resistance-associated amino acid positions relative to the consensus in the European HCV database was also analyzed by population sequencing (41), and the polymorphisms observed in the isolates are shown in Table 4. A total of 69 genotype 1 to 6 isolates were included in the panel. The EC50 of ombitasvir ranged from 0.1 to 15.1 pM against NS5A from 66 genotype 1 to 5 isolates. Polymorphisms at amino acid position 31 in NS5A in genotypes 2a and 2b or at amino acid position 28 in genotype 4a had no impact on activity of ombitasvir. In addition, ombitasvir was active against the genotype 2a JFH-1 replicon, with an EC50 of 0.82 pM. The EC50 of ombitasvir was higher against one genotype 2b sample with L28F plus M31 and one genotype 3a sample with the A30K variant. Only one genotype 6a sample, containing L28, was available for analysis. In order to better represent polymorphisms in genotype 6a isolates, L28F was introduced into the available genotype 6a replicon. The EC50s of ombitasvir were 42 pM and 68 pM against the L28 and F28 variants of this genotype 6a replicon, respectively.
As a result of its picomolar potency and good pharmacokinetics, compound 38/Ombitasvir (ABT267) was selected for further in vitro virologic evaluation. As shown in Table 4, 38 demonstrated picomolar potency not only against GT1a and GT1b but also against GT2–GT6. Replicon resistance selection experiments in GT1 with compound 38 identified variants at positions 28, 30, and 93 as the predominant resistance associated variants, although additional minor variants were also observed (Table 5). In GT1a, variants M28V, L31V, and H58D conferred 58- to 243-fold resistance to 38. Single variants M28T, Q30R, and Y93C/S conferred 800- to 8965-fold resistance, while Y93H/N conferred >40000-fold resistance to 38. In GT1b, the predominant variant selected in vitro with 38 was Y93H, which conferred 77-fold resistance. Double variants R30Q + Y93H and L31M + Y93H conferred 142- to 284-fold resistance, whereas all other double substitutions including Y93H in combination with substitutions at position 28, 31, or 58 conferred more than 400-fold resistance to 38. This resistance profile exhibits considerable overlap with BMS-790052, although there are some differences in fold-resistance and variants selected. These observations of highly resistant mutants selected in vitro underscore the need for combination therapy with DAAs that inhibit viral replication through different mechanisms of action in order to increase the barrier to resistance [2].
ln Vivo
Ombitasvir (ABT267) was evaluated in vivo in a 3-day monotherapy study in 12 HCV genotype 1-infected patients at 5, 25, 50, or 200 mg dosed once daily. All patients in the study were HCV genotype 1a infected and were without preexisting resistant variants at baseline as determined by clonal sequencing. Decreases in HCV RNA up to 3.1 log10 IU/ml were observed. Resistance-associated variants at position 28, 30, or 93 in NS5A were detected in patient samples 48 hours after the first dose. Clonal sequencing analysis indicated that wild-type virus was largely suppressed by ombitasvir during 3-day monotherapy, and at doses higher than 5 mg, resistant variant M28V was also suppressed. Ombitasvir was well tolerated at all doses, and there were no serious or severe adverse events. These data support clinical development of ombitasvir in combination with inhibitors targeting HCV NS3/4A protease (ABT-450 with ritonavir) and HCV NS5B polymerase (ABT-333, dasabuvir) for the treatment of chronic HCV genotype 1 infection. (Study M12-116 is registered at ClinicalTrials.gov under registration no. NCT01181427.)[1].
To assess the safety, tolerability, pharmacokinetics, and antiviral activity of compound 38/Ombitasvir (ABT267), it was dosed for 3 days in HCV GT1-infected treatment naive patients, with patients receiving once-daily doses of 38 for 3 days at doses ranging from 5 to 200 mg. On day 3, dose-normalized Cmax and AUC values were similar across doses. Compound 38 demonstrated Cmax values ranging from 5.7 to 442 ng/mL and a half-life ranging from 25 to 32 h across the dose groups. As shown in Figure 3, 38 decreased HCV RNA up to 3.10 log10 IU/mL during 3-day monotherapy with a nearly 3 log reduction observed in all dose groups. Compound 38 was generally well tolerated at all doses, and there were no serious or severe adverse events, no clinically significant laboratory abnormalities, and no subjects discontinued. Most adverse events were mild and were not dose related. [2]

Three-day monotherapy pharmacokinetics and antiviral efficacy.[1]
In study M12-116, six treatment-naive patients infected with HCV genotype 1 were in each dose group (5, 50 or 200 mg once daily [QD]), with 4 patients administered active drug and 2 patients receiving a matched placebo for 3 days. Sixteen of the 18 patients enrolled in this study were infected with HCV genotype 1a, while 2 patients were infected with HCV genotype 1b, both of whom were randomized to the placebo group. Two of the patients randomized to the 50-mg group actually received 25 mg during monotherapy due to a dosing error. At baseline, the mean HCV RNA in the 18 patients was 6.32 log10 IU/ml. On day 3, Ombitasvir (ABT267) dose-normalized maximum concentration (Cmax) and area under the concentration-time curve (AUC) values were similar across all doses. The Cmax ranged from 5.7 to 442 ng/ml, and the half-life ranged from 25.5 to 32.0 h. Figure 3 shows the individual HCV RNA viral load declines for the 12 HCV-infected patients who were administered ombitasvir. Similar robust antiviral responses were observed across all doses studied, with mean maximum decreases in HCV RNA of up to 3.10 log10 IU/ml observed during the 3-day monotherapy, while the mean decrease in HCV RNA was 0.15 log10 IU/ml in the placebo arm of the study. In general, ombitasvir was well tolerated across all doses administered. Most adverse events were mild, self-limiting, and of short duration and were considered not related or probably not related to ombitasvir. There was no dose-responsive pattern to the adverse events. No deaths or serious adverse events were reported.
Evaluation of in vivo resistance development.[1]
Clonal sequencing and phenotypic analysis of the NS5A-coding region were performed on all patients who received Ombitasvir (ABT267) in this study for whom the viral titer at baseline, day 3, and/or day 6 was ≥1,000 IU/ml (Fig. 3 and Table 5). All 12 patients given Ombitasvir (ABT267) in the 3 dose groups were infected with genotype 1a virus, and variants at resistance-associated amino acid position 28, 30, 31, 58, or 93 were not detected at baseline in any patient by clonal sequence analysis.

In the 5-mg QD dose group, 2 of the 4 patients had HCV RNA viral loads of ≥1,000 IU/ml at both day 3 and day 6. Patient 1 had predominantly M28V at day 3 but had a mixture of M28T, M28V, and Q30R at day 6. Patient 2 had predominantly wild-type virus with M28V and Q30R as minor variants at both day 3 and day 6. Of the 2 patients who received the 25-mg dose, one (patient 3) had HCV RNA viral loads of ≥1,000 IU/ml at day 3 and day 6. In the sample from this patient, M28T, M28V, Q30R, and Y93C were observed on day 3; however, the M28V variant was no longer detected on day 6. Consistent with these sequencing observations, day 6 samples from patients 1, 2, and 3 conferred 98-, 4-, and 36-fold resistance to Ombitasvir (ABT267), respectively, in the phenotypic assay.

Of the 2 patients receiving the 50-mg dose of Ombitasvir (ABT267), M28T was the predominant variant in patient 4 at both days 3 and 6, although M28V, Q30E, Q30R, and Y93C were also detected. Patient 5 in the 50-mg dose group had an HCV RNA viral load nadir at 36 h after initiation of ombitasvir dosing, which was only a 1.52 log10 IU/ml decrease from the baseline value. Although preexisting resistance-associated variants were not detected at baseline, patient 5 had a complex mixture of variants at day 3 and day 6. Y93S and Q30L plus Y93H were the predominant variants, while Y93H and Q30L plus Y93S were also detected as minor variants. In vitro analysis of these variants in the HCV genotype 1a-H77 replicon (Table 2) indicated that resistance conferred by Q30L plus Y93H (416-fold) or Q30L plus Y93S (218-fold) was lower that that conferred by Y93H or Y93S alone. Consistent with the presence of resistant variants, day 6 samples from patients 4 and 5 conferred 353- and 406-fold resistance to ombitasvir, respectively, in the phenotypic assay.

In the 200-mg dose group, 3 of the 4 patients dosed with active drug had viral loads of ≥1,000 IU/ml HCV RNA at day 3 and/or day 6. M28T and Q30R were the predominant variants in all 3 patients at both day 3 and day 6, while Y93C and Y93H were observed as minor variants. Consistent with the presence of resistant variants, day 6 samples from patients 6, 7, and 8 conferred 927- to 2,238-fold resistance to Ombitasvir (ABT267) in the phenotypic assay.

The clinical samples at days 3 or 6 usually contained a mixture of NS5A variants (including the wild type). Each of these variants may have differing replication fitness and variable susceptibility to Ombitasvir (ABT267), and the EC50 against clinical isolates is therefore a reflection of the multiple variants present in the quasispecies. The EC50s from reference replicons harboring single or multiple defined resistant variants are, in many cases, different from those for the clinical isolates.
Enzyme Assay
The techniques previously described were used to quantify how different amino acid variants affected an inhibitor's activity in HCV replicon cell culture assays. In short, using the Change-IT multiple-mutation site-directed mutagenesis kit, the resistance-associated variants in NS5A were each introduced into the genotype 1a-H77 or 1b-Con1 or one of the chimeric genotype 2 to 6 replicons. After sequence analysis verified the variant's existence, the plasmid was linearized and the HCV subgenomic RNA was extracted using the TranscriptAid T7 high-yield transcription kit. Through electroporation, a Huh-7 cell line was transfected with the variant-containing replicon RNA in a temporary experiment. As mentioned in the earlier sections, the EC50s were computed.
Replicon cell lines and measurement of in vitro activity.[1]
The inhibitory effect of Ombitasvir (ABT267) on HCV replication was determined in DMEM containing 5% FBS with or without 40% human plasma by measuring the activity of the luciferase reporter gene. The cells were incubated for 3 days in the presence of ombitasvir and were subsequently lysed and processed according to the manufacturer's instructions. The luciferase activity in the cells was measured using a Victor II luminometer. The 50% effective concentration (EC50) was calculated using nonlinear regression curve fitting to the 4-parameter logistic equation and GraphPad Prism 4 software. The cytotoxicity of ombitasvir was determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (5 mg/ml) colorimetric assay. The 50% cytotoxicity concentration (CC50) was calculated from the optical density data using nonlinear regression curve fitting to the 4-parameter logistic equation and GraphPad Prism 4 software. Activity of ombitasvir against genotype 2a JFH-1 was evaluated by Southern Research Institute, using a subgenomic replicon that did not contain a luciferase reporter, using a quantitative RT-PCR (qRT-PCR) assay.
Phenotype against NS5A gene from clinical isolates.[1]
A genotype 1b-Con1 HCV replicon-based shuttle vector cassette with the luciferase reporter but without the Neo gene was constructed for assessing the phenotypes of NS5A genes derived from individuals infected with HCV genotypes 1 to 6. A NotI restriction site was cloned into the 1b-Con1 subgenomic replicon vector 90 nucleotides upstream of NS5A in the 3′ end of NS4B, and a ClaI site was cloned after the NS5A amino acid 413 codon. The NS5A region from genotype 1-infected patients was inserted between the NotI and ClaI restriction sites. The 1b-Con1 shuttle vector with NotI and BlpI restriction sites (described in the previous section) was used to evaluate the ability of Ombitasvir (ABT267) to inhibit the NS5A region encompassing amino acids 1 to 214 from non-genotype 1 HCV. The NS5A gene from clinical samples was amplified and ligated into the shuttle vector. In a transient assay, the HCV subgenomic replicon RNA containing the NS5A gene from each clinical sample was transfected via electroporation into a Huh-7 derived cell line. The cells were incubated in the presence of ombitasvir for 4 days. The luciferase activity in the cells was measured, and the EC50 was calculated as described above.
In vitro resistance analysis.[1]
In order to characterize replicon variants with reduced susceptibility to Ombitasvir (ABT267), resistance selection was conducted in the chimeric genotype 1 to 6 HCV replicon-containing stable cell lines described above. Replicon cells (5 × 104 to 1 × 106) were plated in 150-mm cell culture plates and grown in the presence of G418 (400 μg/ml) and ombitasvir at a concentration that was 10-fold, 50-fold, 100-fold, or 1,000-fold above the EC50 for the respective cell line. After 3 weeks of treatment, the majority of replicon cells were cleared of replicon RNA and were therefore unable to survive in the G418-containing medium. The cells containing resistant replicon variants survived and formed colonies, and each of these colonies was picked and further expanded. In order to characterize the genotype of the resistant replicon variants, the expanded colonies were lysed in CellsDirect resuspension and lysis buffer to yield total RNA. The NS5A-coding region was amplified by RT-PCR, and the amplified samples were sequenced using the ABI Prism dye terminator cycle sequencing ready-reaction kit and were analyzed on an Applied Biosystems 3100 genetic analyzer.
Cell Assay
A genotype 1b-Con1 HCV replicon-based shuttle vector cassette lacking the Neo gene but containing a luciferase reporter was created to evaluate the NS5A gene phenotypes in patients infected with HCV genotypes 1 through 6. 90 nucleotides upstream of NS5A in the 3′ end of NS4B, a NotI restriction site was cloned into the 1b-Con1 subgenomic replicon vector, and a ClaI site was cloned after the NS5A amino acid 413 codon. The NotI and ClaI restriction sites were crossed with the NS5A region from patients with genotype 1 infection. Ombitasvir's ability to inhibit the NS5A region of non-genotype 1 HCV, which contains amino acids 1 through 214, was assessed using the 1b-Con1 shuttle vector with NotI and BlpI restriction sites (discussed in the preceding section). An amplified copy of the NS5A gene was ligated into the shuttle vector using clinical samples. One transient assay involved electroporating each clinical sample's HCV subgenomic replicon RNA containing the NS5A gene into a cell line derived from Huh-7. Ombitasvir was present during the four days that the cells were cultured. Following the procedure previously mentioned, the luciferase activity in the cells was determined.
The GT1a replicon construct (GenBank accession number NC004102) contained the 5′ nontranslated region (NTR) from 1a-H77 followed by a firefly luciferase reporter gene and the neomycin phosphotransferase (Neo) gene, which together comprised the first cistron of the bicistronic replicon construct. This was followed by the EMCV IRES and then the second cistron containing the 1a-H77 NS3-NS5B coding region with adaptive mutations E1202G, K1691R, K2040R, and S2204I and finally the 1a-H77 3′ NTR. The GT1b-Con1 replicon construct (GenBank accession number AJ238799) contained the 5′ nontranslated region (NTR) from 1b-Con1 followed by a firefly luciferase reporter gene and the neomycin phosphotransferase (Neo) gene, which together comprised the first cistron of the bicistronic replicon construct. This was followed by the EMCV IRES and the second cistron containing the 1b-Con1 NS3-NS5B coding region with adaptive mutations K1609E, K1846T, and Y3005C and finally the 1b-Con1 3′ NTR. In addition, the 1b-Con1 replicon construct contained a poliovirus IRES between the HCV 5′ NTR and the firefly luciferase gene. In order to assess the ability of compounds to inhibit NS5A from non-GT1 HCV, a 1b-Con1 replicon shuttle vector was constructed that containing restriction sites just upstream of NS5A in the C-terminus of NS4B and just after NS5A amino acid 214. Six chimeric subgenomic replicon cell lines were generated for evaluation of the activity of compounds. The NS5A regions for generation of chimeric replicons were derived from genotypes 2a, 2b, 3a, 4a, 5a, and 6a HCV-infected patient sera. RT-PCR was conducted on the viral RNA from each of these patient serum samples to generate a DNA fragment encoding the first 214 amino acids of NS5A. The fragment was ligated into the replicon shuttle vector and in vitro transcribed into replicon RNA. This RNA was introducing into human hepatoma cells (Huh-7) to create stable replicon cell lines. The inhibitory effect of compounds on HCV replication was determined (in the presence or absence of 40% HP) by measuring the decrease in luciferase signal. The percent inhibition of HCV replicon replication was calculated for each compound concentration, and the EC50 value was calculated using nonlinear regression curve fitting to the four-parameter logistic equation in the GraphPad Prism 4/5 software. The methods describing the measurement of the effects of individual amino acid variants on the activity of an inhibitor in HCV replicon cell culture assays were described previously. Briefly, the resistance-associated variants in NS5A were each introduced into GT 1a-H77, GT 1b-Con1, or chimeric replicons. In transient assays, the replicon containing the variant was transfected via electroporation into a Huh-7 derived cell line. The percent inhibition of HCV replicon replication as determined by decreased luciferase signal was calculated for each compound concentration, and the EC50 values were calculated as described above. Replication capacity was calculated as a percentage of wild-type replication using the following equation, 100 × {(variant 4 day luciferase counts/wild-type 4 day luciferase counts)/(variant 4 h luciferase counts/wild-type 4 h luciferase counts)}[2].
Animal Protocol
Clinical study design. Study M12-116 (ClinicalTrials.gov registration no. NCT01181427) was the first study to evaluate the pharmacokinetics, safety, tolerability, antiviral activity, and resistance of ombitasvir in HCV-infected treatment-naive adults. All of the patients provided written informed consent. The study was performed in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki, and the study protocol was approved by the relevant institutional review boards and regulatory agencies. Inclusion criteria included chronic HCV genotype 1 infection for at least 6 months prior to study enrollment, plasma HCV RNA level of >100,000 IU/ml at screening, and a liver biopsy within the past 3 years with histology consistent with HCV-related inflammation and fibrosis but no evidence of cirrhosis. Exclusion criteria included positive antibodies for hepatitis A or B virus or human immunodeficiency virus type 1 (HIV-1) or a history of clinically significant comorbidities. The primary endpoint was the maximum change from baseline in HCV RNA. The patients in the ombitasvir dose groups were enrolled sequentially, and within each group, patients were randomized (2:1) to either ombitasvir or placebo and treated under nonfasting conditions for 3 days while confined to the study site. The 200-mg dose group received a different formulation with higher bioavailability. Patients who received at least one dose of ombitasvir or placebo were provided the option to receive treatment with pegIFN/RBV for approximately 48 weeks once treatment with ombitasvir was completed. HCV RNA was measured using the Roche COBAS TaqMan HCV Test v2.0 real-time reverse transcriptase PCR assay (with a lower limit of quantification of 25 IU/ml and a lower limit of detection of 10 IU/ml). The virologic response was assessed as HCV RNA decrease from baseline in log10 IU/ml[1].
ADME/Pharmacokinetics
Absorption, Distribution and Excretion
Ombitasvir reaches peak plasma concentration 5 hours after administration. It has an absolute bioavailability of 48%. Taking ombitasvir with high or normal fat meals increases exposure by 1.76 or 1.82 fold respectively.
Ombitasvir is mainly excreted in the feces (90.2%) with very little excreted in the urine (1.91%). 87.8% and 0.03% of the dose excreted in the feces and urine respectively is present as the parent compound.
Ombitasvir has a volume of distribution at steady state of 173 liters.
Clearance of Ombitasvir has not been determined.
Metabolism / Metabolites
Ombitasvir is mainly metabolized by amide hydrolysis followed by CYP2C8-mediated oxidative metabolism.
Biological Half-Life
Ombitasvir has a half life of elimination of 21-25 hours
Compound 38/Ombitasvir (ABT267) demonstrated high stability in RLM and long half-lives in rat (6, 4, and 9 h, respectively), although they suffered from low oral bioavailability. However, compound 38 demonstrated significantly higher oral bioavailability and exposures in the dog compared to compound 32 and 33. Unlike compounds 13 and 16, compound 38 also demonstrated a reasonable half-life with low clearance and moderate oral bioavailability in monkey. The tert-butylglycine analogues 40 and 41 showed comparable rat PK to the valine analogues 38 and 39, including low oral bioavailability, likely a result of their high lipophilicity (log D = 5.5) and low aqueous solubility. [2]
Toxicity/Toxicokinetics
Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Ombitasvir has not been studied in nursing mothers being treated for hepatitis C infection. Because it is 99.9% bound to maternal plasma proteins, amounts in breastmilk are likely to be very low. Some sources recommend against breastfeeding when ombitasvir is used with ribavirin.
Ritonavir used as a booster has been studied in several studies of breastfeeding mothers. It is excreted into milk in measurable concentrations and low levels can be found in the blood of some breastfed infants. No reports of adverse reactions in breastfed infants have been reported. For more information, refer to the LactMed record on ritonavir.
Hepatitis C is not transmitted through breastmilk and breastmilk has been shown to inactivate hepatitis C virus (HCV). However, the Centers for Disease Control recommends that mothers with HCV infection should consider abstaining from breastfeeding if their nipples are cracked or bleeding. It is not clear if this warning would apply to mothers who are being treated for hepatitis C.
Infants born to mothers with HCV infection should be tested for HCV infection; because maternal antibody is present for the first 18 months of life and before the infant mounts an immunologic response, nucleic acid testing is recommended.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.
Protein Binding
Ombitasvir is 99.9% bound to human plasma proteins.
References

[1]. In vitro and in vivo antiviral activity and resistance profile of ombitasvir, an inhibitor of hepatitis C virus NS5A. Antimicrob Agents Chemother. 2015 Feb;59(2):979-87.

[2]. Discovery of ABT-267, a pan-genotypic inhibitor of HCV NS5A. J Med Chem. 2014 Mar 13;57(5):2047-57.

Additional Infomation
Pharmacodynamics
Ombitasvir is classified as a direct acting antiviral and acts against HCV to inhibit viral replication.
Ombitasvir is a dipeptide derivative which is used which is in combination with dasabuvir sodium hydrate, paritaprevir and ritonavir (under the trade name Viekira Pak) for treatment of chronic hepatitis C virus genotype 1 infection as well as cirrhosis of the liver. It has a role as an antiviral drug and a hepatitis C virus nonstructural protein 5A inhibitor. It is a member of pyrrolidines, a carbamate ester, an aromatic amide and a dipeptide. It is functionally related to a Val-Pro.

Ombitasvir is a direct acting antiviral medication used as part of combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as Ombitasvir. Ombitasvir is an inhibitor of NS5A, a protein essential for viral replication and virion assembly. The barrier for develoment of resistance to NS5A inhibitors is lower than that of NS5B inhibitors, another class of DAAs. In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend Ombitasvir as a first line therapy option when used in combination with other antivirals for genotypes 1a, 1b, and 4. Depending on the genotype, Ombitasvir is often used in combination with other antivirals such as [DB09183], [DB09297], [DB00503], and [DB00811] with the intent to cure, or achieve a sustained virologic response (SVR), after 12 weeks of daily therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality. Treatment with direct acting antivirals such as Ombitasvir is associated with very minimal side effects, with the most common being headache and fatigue. Lack of significant side effects and short duration of therapy is a considerable advantage over older interferon-based regimens, which were limited by infusion site reactions, reduced blood count, and neuropsychiatric effects. Ombutasvir first came on the market as a fixed-dose combination product with [DB09183], [DB09297], and [DB00503] as the FDA-approved product Viekira Pak. First approved in December 2014, Viekira Pak is indicated for the treatment of HCV genotype 1b without cirrhosis or with compensated cirrhosis, and when combined with Ribavirin for the treatment of HCV genotype 1a without cirrhosis or with compensated cirrhosis. Ombutasvir is also available as a fixed-dose combination product with [DB09297] and [DB00503] as the FDA- and Health Canada-approved product Technivie. First approved in July 2015, Technivie is indicated in combination with Ribavirin for the treatment of patients with genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis. In Canada, Ombutasvir is also available as a fixed-dose combination product with [DB09183], [DB09297], and [DB00503] as the Health Canada-approved, commercially available product Holkira Pak. First approved in January 2015, Holkira Pak is indicated for the treatment of HCV genotype 1b with or without cirrhosis, and when combined with [DB00811] for the treatment of HCV genotype 1a with or without cirrhosis.

Ombitasvir is a Hepatitis C Virus NS5A Inhibitor. The mechanism of action of ombitasvir is as an UGT1A1 Inhibitor.
Ombitasvir is an orally available inhibitor of the hepatitis C virus (HCV) non-structural protein 5A (NS5A) replication complex, with potential activity against HCV. Upon oral administration and after intracellular uptake, ombitasvir binds to and blocks the activity of the NS5A protein. This results in the disruption of the viral RNA replication complex, blockage of HCV RNA production, and inhibition of viral replication. NS5A, a zinc-binding and proline-rich hydrophilic phosphoprotein, plays a crucial role in HCV RNA replication. HCV is a small, enveloped, single-stranded RNA virus belonging to the Flaviviridae family; HCV infection is associated with the development of hepatocellular carcinoma (HCC).
OMBITASVIR is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 2014 and is indicated for hepatitis c virus infection and chronic hepatitis c virus infection and has 1 investigational indication.
Ombitasvir (ABT267) is a hepatitis C virus (HCV) NS5A inhibitor with picomolar potency, pan-genotypic activity, and 50% effective concentrations (EC50s) of 0.82 to 19.3 pM against HCV genotypes 1 to 5 and 366 pM against genotype 6a. Ombitasvir retained these levels of potency against a panel of 69 genotype 1 to 6 chimeric replicons containing the NS5A gene derived from HCV-infected patients, despite the existence of natural sequence diversity within NS5A. In vitro resistance selection identified variants that conferred resistance to ombitasvir in the HCV NS5A gene at amino acid positions 28, 30, 31, 58, and 93 in genotypes 1 to 6. Ombitasvir was evaluated in vivo in a 3-day monotherapy study in 12 HCV genotype 1-infected patients at 5, 25, 50, or 200 mg dosed once daily. All patients in the study were HCV genotype 1a infected and were without preexisting resistant variants at baseline as determined by clonal sequencing. Decreases in HCV RNA up to 3.1 log10 IU/ml were observed. Resistance-associated variants at position 28, 30, or 93 in NS5A were detected in patient samples 48 hours after the first dose. Clonal sequencing analysis indicated that wild-type virus was largely suppressed by ombitasvir during 3-day monotherapy, and at doses higher than 5 mg, resistant variant M28V was also suppressed. Ombitasvir was well tolerated at all doses, and there were no serious or severe adverse events. These data support clinical development of ombitasvir in combination with inhibitors targeting HCV NS3/4A protease (ABT-450 with ritonavir) and HCV NS5B polymerase (ABT-333, dasabuvir) for the treatment of chronic HCV genotype 1 infection. (Study M12-116 is registered at ClinicalTrials.gov under registration no. NCT01181427.).[1]
Ombitasvir (ABT267) was evaluated in the dose-ranging clinical study M12-116, in which the maximum change from baseline in HCV RNA was evaluated along with a thorough resistance analysis of samples obtained within the first few days after initiation of ombitasvir dosing. In M12-116, 12 treatment-naive patients infected with HCV genotype 1 were administered 5, 25, 50, or 200 mg once daily of ombitasvir for 3 days, followed by an optional regimen of pegIFN and RBV for 48 weeks. All ombitasvir-treated patients were genotype 1a infected, and the mean maximum declines in HCV RNA observed across the doses studied were up to 3.10 log10 IU/ml during the 3-day monotherapy. None of the patients had preexisting resistance-conferring variants at signature amino acid position 28, 30, 31, 58, or 93 in NS5A detectable by clonal sequencing. Postbaseline samples from 8 patients were available for resistance analyses. Variants M28T, M28V, and Q30R in NS5A were the predominant treatment-emergent variants, while Y93C and Y93H were detected as minor variants. On day 3 of treatment or day 6 (48 h posttreatment), greater than 90% of the clones from each of the patient samples contained variants at signature resistance-conferring amino acid positions, indicating that in most patients, the wild-type virus had been suppressed. At the 5-mg dose, M28V was detected in two patients at day 3 and day 6; however, at higher doses where the Cmax values also increased, M28T or Q30R was the predominant variant. This is consistent with the observation in vitro that the M28V variant, which confers 58-fold resistance to ombitasvir, can be suppressed at higher doses of ombitasvir. In line with the genotypic observations, phenotypic analysis indicated that samples from patients in the 5-mg and 25-mg dose groups conferred 1- to <100-fold resistance to ombitasvir, while most samples from patients receiving 50 or 200 mg of ombitasvir conferred >500-fold resistance to ombitasvir. Although ombitasvir demonstrated similarly robust antiviral responses across all doses studied, the in vivo resistance profile suggest a benefit of using a dose higher than 5 mg of ombitasvir in order to suppress prevalent preexisting variants such as M28V in genotype 1a or Y93H in genotype 1b. The in vitro profile Ombitasvir (ABT267) and the results in the 3-day monotherapy study M12-116 provided the basis for investigating the combination of ombitasvir with the NS3/4A protease inhibitor ABT-450 and nonnucleoside NS5B polymerase inhibitor dasabuvir (ABT-333) in treatment of chronic genotype 1 HCV infection. The combination of these 3 DAAs provides a barrier to resistance in patients, as evidenced by the high SVR rate in the six phase 3 clinical trials using an interferon-free combination of ombitasvir/ABT-450/ritonavir and dasabuvir with or without ribavirin.[1]
We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds with 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2R,5R analogues. Furthermore, the attachment of substituents at the 4-position of the central N-phenyl group resulted in compounds with improved potency. Substitution with tert-butyl, as in compound 38/Ombitasvir (ABT267), provided compounds with low-picomolar EC50 values and superior pharmacokinetics. It was discovered that compound 38 was a pan-genotypic HCV inhibitor, with an EC50 range of 1.7-19.3 pM against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a and 366 pM against GT6a. Compound 38 decreased HCV RNA up to 3.10 log10 IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects and is currently in phase 3 clinical trials in combination with an NS3 protease inhibitor with ritonavir (r) (ABT-450/r) and an NS5B non-nucleoside polymerase inhibitor (ABT-333), with and without ribavirin. [2]
There is a tremendous unmet medical need to discover new treatments for HCV infection with improved efficacy, tolerability, and convenience relative to the current standard of care. The addition of inhibitors of HCV NS5A to the arsenal of DAAs that are available for use in combination therapy holds significant promise for delivering such therapies. We discovered compound 38/Ombitasvir (ABT267), based on a chiral pyrrolidine core, which demonstrates picomolar potency against GT1a and GT1b. Compound 38 is a pan-genotypic HCV inhibitor, with an EC50 range of 1.7–19.3 pM against genotypes 1a, 1b, 2a, 2b, 3a, 4a, and 5a and 366 pM against genotype 6a. Subsequent to its discovery, compound 38 has demonstrated excellent human pharmacokinetics with a long 25–32 h half-life, consistent with once-daily dosing. Compound 38 decreased HCV RNA up to 3.10 log10 IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects, and it is currently undergoing phase 3 clinical trials in combination with an NS3 protease inhibitor and an NS5B non-nucleoside polymerase inhibitor, with and without ribavirin.[2]
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C50H67N7O8
Molecular Weight
894.11
Exact Mass
893.505
Elemental Analysis
C, 67.17; H, 7.55; N, 10.97; O, 14.32
CAS #
1258226-87-7
Related CAS #
1258226-87-7
PubChem CID
54767916
Appearance
White to light yellow solid powder
Density
1.2±0.1 g/cm3
Boiling Point
1065.6±65.0 °C at 760 mmHg
Flash Point
598.2±34.3 °C
Vapour Pressure
0.0±0.3 mmHg at 25°C
Index of Refraction
1.595
LogP
6.29
Hydrogen Bond Donor Count
4
Hydrogen Bond Acceptor Count
9
Rotatable Bond Count
16
Heavy Atom Count
65
Complexity
1540
Defined Atom Stereocenter Count
6
SMILES
CC(C)(C)C(C=C1)=CC=C1N2[C@H](C3=CC=C(NC([C@H]4N(C([C@@H](NC(OC)=O)C(C)C)=O)CCC4)=O)C=C3)CC[C@H]2C5=CC=C(NC([C@@H]6CCCN6C([C@@H](NC(OC)=O)C(C)C)=O)=O)C=C5
InChi Key
PIDFDZJZLOTZTM-KHVQSSSXSA-N
InChi Code
InChI=1S/C50H67N7O8/c1-30(2)42(53-48(62)64-8)46(60)55-28-10-12-40(55)44(58)51-35-20-14-32(15-21-35)38-26-27-39(57(38)37-24-18-34(19-25-37)50(5,6)7)33-16-22-36(23-17-33)52-45(59)41-13-11-29-56(41)47(61)43(31(3)4)54-49(63)65-9/h14-25,30-31,38-43H,10-13,26-29H2,1-9H3,(H,51,58)(H,52,59)(H,53,62)(H,54,63)/t38-,39-,40-,41-,42-,43-/m0/s1
Chemical Name
methyl N-[(2S)-1-[(2S)-2-[[4-[(2S,5S)-1-(4-tert-butylphenyl)-5-[4-[[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]phenyl]pyrrolidin-2-yl]phenyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate
Synonyms
Viekira Pak (trade name); ABT-267; Ombitasvir; 1258226-87-7; Ombitasvir [INN]; CHEBI:85183; Ombitasvir [USAN:INN]; ABT 267; UNII-2302768XJ8; Ombitasvir(ABT-267); ABT267; CHEBI:85183; 2302768XJ8; ABT267; ABT 267
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: >100 mg/mL
Water: N/A
Ethanol: N/A
Solubility (In Vivo)
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.80 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

Solubility in Formulation 2: ≥ 2.5 mg/mL (2.80 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.1184 mL 5.5922 mL 11.1843 mL
5 mM 0.2237 mL 1.1184 mL 2.2369 mL
10 mM 0.1118 mL 0.5592 mL 1.1184 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

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Clinical Trial Information
Understanding HCV Reinfection Rates in an Incarcerated Population After Cure With Interferon Free HCV Treatment
CTID: NCT02460133
Phase: Phase 4    Status: Active, not recruiting
Date: 2024-08-23
A Study to Evaluate the Safety and Effect of Co-administration of ABT-450 With Ritonavir (ABT-450/r) and ABT-267 in Adults With Chronic Hepatitis C Virus Infection
CTID: NCT01685203
Phase: Phase 2    Status: Completed
Date: 2021-07-30
Study to Assess the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of ABT-267 in HCV Infected Subjects
CTID: NCT01563536
Phase: Phase 2    Status: Completed
Date: 2018-07-02
Study of ABT-267 in Treatment Naive Hepatitis C Virus (HCV) Genotype 1 Infected Subjects
CTID: NCT01314261
Phase: Phase 2    Status: Completed
Date: 2018-07-02
A Study to Evaluate the Safety and Effect of Treatment With Experimental Antiviral Drugs in Combination With Peginterferon Alpha-2a and Ribavirin in People With Hepatitis C Virus Who Did Not Respond to Treatment in a Previous AbbVie/Abbott Combination Study
CTID: NCT01609933
Phase: Phase 2    Status: Completed
Date: 2018-06-19
View More

A Follow up Study Designed to Obtain Long Term Data on Participants Who Either Achieved a Sustained Virologic Response or Did Not Achieve a Sustained Virologic Response in an AbbVie Sponsored Hepatitis C Study
CTID: NCT01773070
Phase: Phase 3    Status: Completed
Date: 2017-12-06


A Study to Evaluate Paritaprevir With Ritonavir (ABT-450/r) When Given Together With Ombitasvir and With and Without Ribavirin (RBV) in Treatment-Naïve Participants With Genotype 1, 2 or 3 Chronic Hepatitis C Virus (HCV)
CTID: NCT01458535
Phase: Phase 2    Status: Completed
Date: 2016-07-11
ABT-450 With Ritonavir and ABT-267 and/or ABT-333 With and Without Ribavirin in Genotype 1 Hepatitis C Virus Infected Patients
CTID: NCT01464827
Phase: Phase 2    Status: Completed
Date: 2015-04-22
------------------------
Open-label Study to Evaluate the Safety and Efficacy of the Combination of Ombitasvir, Paritaprevir/r ± Dasabuvir with Ribavirin (RBV) in Adult Patients with GT1 or GT4 Chronic HCV Infection and Response to Prior Treatment of Early Stage Hepatocellular Carcinoma
CTID: null
Phase: Phase 3    Status: Prematurely Ended
Date: 2015-09-24
An Open-Label Study to Evaluate the Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir With or Without Dasabuvir in Adults With Genotype 1a or Genotype 4 Chronic Hepatitis C Virus (HCV) Infection, With Severe Renal Impairment or End-Stage Renal Disease (RUBY-II)
CTID: null
Phase: Phase 3    Status: Completed
Date: 2015-09-24
A Follow-up Study to Assess Resistance and Durability of Response to AbbVie Direct-Acting Antiviral Agent (DAA) Therapy in Subjects Who Participated in Phase 2 or 3 Clinical Studies for the Treatment of Chronic Hepatitis C Virus (HCV) Infection
CTID: null
Phase: Phase 3    Status: Prematurely Ended, Completed
Date: 2013-10-22
An Open-Label Study to Evaluate the Safety, Antiviral Activity and Pharmacokinetics of Direct-Acting Antiviral Agent (DAA) Treatment in Combination with Peginterferon α-2a and Ribavirin (pegIFN/RBV) in Chronic Hepatitis C Virus (HCV) Infected Subjects Who Have Experienced Virologic Failure in a Previous AbbVie or Abbott DAA Combination Study
CTID: null
Phase: Phase 2    Status: Prematurely Ended, Completed
Date: 2012-08-10
A Randomized, Open-Label Study to Evaluate the
CTID: null
Phase: Phase 2    Status: Completed
Date: 2012-05-31
A Randomized, Open-Label, Multicenter Study to Evaluate the Antiviral Activity, Safety, and Pharmacokinetics, of ABT-450 with Ritonavir (ABT 450/r) in Combination with ABT-267 and/or ABT 333 With and Without Ribavirin (RBV) in Treatment-Naïve and Null Responder Subjects with Genotype 1 Chronic Hepatitis C Virus Infection.
CTID: null
Phase: Phase 2    Status: Completed
Date: 2011-12-12

Biological Data
  • Ombitasvir (ABT-267)

    Alignment of amino acids 1 to 100 of NS5A in the replicon cell lines. Amino acid changes relative to the 1b-Con1 sequence are indicated. Amino acids within each genotype where variants resistant to ombitasvir were selected are highlighted in gray.2015 Feb;59(2):979-87.

  • Ombitasvir (ABT-267)

    HCV RNA viral load during 3-day monotherapy with ombitasvir in HCV genotype 1-infected treatment-naive patients.2015 Feb;59(2):979-87.


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