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WO2018172759A1 - Procédé d'identification de patients résistants au sofosbuvir - Google Patents

Procédé d'identification de patients résistants au sofosbuvir Download PDF

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Publication number
WO2018172759A1
WO2018172759A1 PCT/GB2018/050718 GB2018050718W WO2018172759A1 WO 2018172759 A1 WO2018172759 A1 WO 2018172759A1 GB 2018050718 W GB2018050718 W GB 2018050718W WO 2018172759 A1 WO2018172759 A1 WO 2018172759A1
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Prior art keywords
hcv
mutations
sofosbuvir
nucleic acid
drug
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PCT/GB2018/050718
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English (en)
Inventor
Graham Foster
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Queen Mary University of London
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Queen Mary University of London
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
    • C12Q1/701—Specific hybridization probes
    • C12Q1/706—Specific hybridization probes for hepatitis
    • C12Q1/707—Specific hybridization probes for hepatitis non-A, non-B Hepatitis, excluding hepatitis D
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
    • G01N2333/08—RNA viruses
    • G01N2333/18—Togaviridae; Flaviviridae
    • G01N2333/183—Flaviviridae, e.g. pestivirus, mucosal disease virus, bovine viral diarrhoea virus, classical swine fever virus (hog cholera virus) or border disease virus
    • G01N2333/186—Hepatitis C; Hepatitis NANB
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to a method for the identification of patients receiving treatment for Hepatitis C Virus infection who are resistant to sofosbuvir.
  • HCV Hepatitis C virus
  • the HCV genome is a positive sense single-stranded RNA molecule consisting of a 9600 base pair long single open-reading frame (ORF). Translation of the single ORF of HCV yields a single protein product which can then be processed to produce smaller active proteins that allow viral replication within a host cell or permit assembly of viral particles, for example core proteins E1 and E2, and non-structural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.
  • Sofosobuvir is an inhibitor of the hepatitis C virus polymerase and is the main therapeutic drug for the treatment of genotype 3 HCV. It is usually combined with another drug, usually an NS5A inhibitor such as daclatasvir or velpatasvir and around 90% of patients are cured. It is not clear why some patients do not respond to sofosbuvir based therapies and it is not clear whether re-treating such patients with extended duration of therapy will be beneficial or not. New, sofosbuvir free, antiviral therapies are in development and a test that would identify which patients were unlikely to respond to sofosbuvir would be of clinical value.
  • a method for the identification of a subject infected with a hepatitis C virus (HCV) and resistant to treatment with sofosbuvir comprising determining the presence of one of more mutations in the NS5B protein of hepatits C virus selected from the group consisting: A150V, I85V, K206E, K100R, A150S, G188D, T213N and N244I.
  • the determination may be performed on a biological sample from the subject.
  • the sample may be physioloigcal fluid such as blood, plasma, saliva, urine, tears, milk, or semen, or a biopsy or cell sample, for example a blood cell such as erythrocytes, leucocytes, monocytes, macrophages or a sample of liver tissue.
  • the sample may be prepared by co-culturing a physioloigcal fluid sample containing HCV from the patient with a cell from a cell line, and then subsequently analysing the HCV captured by the cell.
  • the HCV infection may be a genotype 3 HCV infection or co-infection with multiple genotypes of HCV.
  • the subject to be identified according to the methods of the invention may be a human subject.
  • the subject according to the first aspect of the invention may also be referred to as a patient.
  • the method of the invention may suitably be practiced in various embodiments.
  • Some suitable mutations or combinations of mutations at least are as follows: (i) A150V;
  • the mutations described herein use the preferred terminology for amino acid substitutions as set out in J. T. den Dunnen and S. E. Antonarakis, Hum. Genet 109(1 ), 121-124 (2001 )), in which the amino acids are identified using the single-letter code. The amino acid which is replaced is indicated first, then the residue number, then followed by the amino acid which is present instead in the mutation.
  • the invention may be a method for the identification of a subject infected with a hepatitis C virus (HCV) having one of more mutations in genes present in the NS5B protein of hepatits C virus selected from the group consisting: 185V, K206E, A150V, K100R, A150S, G188D. T213N and N244I.
  • HCV hepatitis C virus
  • a reference sequence for genotype 3 HCV may be the sequence shown at https :/7www. neb I . n I m . n i h .qov/n uccore/HW 121682.1 identified as GenBank Accession no. HW121682, Version HW121682.1 and deposited on 13 November 2013 (see Figure 7) and as published in WO 2013/031956.
  • the determination of the presence of one of more mutations in genes present in the NS5B protein of hepatits C virus in the subject selected from the group consisting: I85V, K206E, A150V, K100R, A150S, G188D, T213N and N244I may be completed by sequencing the genome of the HCV in the cells of an infected individual.
  • the invention can also be performed by probing for the presence of one of more of the mutations in genes present in the NS5B protein of hepatits C virus in the subject selected from the group consisting: I85V, K206E, A150V, K100R, A150S, G188D, T213N and N244I.
  • the mutations in the sequence of the NS5B protein of HCV may be identified using whole genome sequencing or PCR, for example nested PCR. Where PCR is used the oligonucleotide primers may be sequence specific primers selected according to one or more the mutations referred to above.
  • the primer is a synthetic DNA sequence designed according to the considerations set out herein and may be referred to as a cDNA primer.
  • the oligonucleotide may of from 18 to 22 base pairs in length and may be any contiguous sequence of 18 to 22 base pairs selected from the mutated nucleic acid sequences as shown in Figure 8(a), 8(b), 8(c) or Table 1 below (in which the mutated residue is indicated with an underline), or a sequence complementary or homologous thereto.
  • Identity as known in the art is the relationship between two or more polypeptide sequences or two or more polynucleotide sequences, as determined by comparing the sequences. In the art, identity also means the degree of sequence relatedness (homology) between polypeptide or polynucleotide sequences, as the case may be, as determined by the match between strings of such sequences. While there exist a number of methods to measure identity between two polypeptides or two polynucleotide sequences, methods commonly employed to determine identity are codified in computer programs.
  • Preferred computer programs to determine identity between two sequences include, but are not limited to, GCG program package (Devereux, et al., Nucleic acids Research, 12, 387 (1984), BLASTP, BLASTN, and FASTA (Atschul et al., J. Molec. Biol. 215, 403 (1990).
  • the nucleic acid sequence of the HCV isolate has at least 50% identity, using the default parameters of the BLAST computer program (Atschul et al., J. Mol. Biol. 215, 403-410 (1990) provided by HGMP (Human Genome Mapping Project), at the nucleic acid level to the sequences described herein. More preferably, the nucleic acid sequence may have at least 60%, 70%, 80%, 90% and still more preferably 95% (still more preferably at least 99%) identity, at the nucleic acid level.
  • the nucleic acid sequence may also comprise a sequence which has at least 50%, 60%, 70%, 80%, 90%, 95% or 99% identity with a sequence as described herein using the default parameters of the BLAST computer program provided by HGMP.
  • a capture fusion HCV replication assay as described in WO 2013/064833 and Cunningham ef al (Hepatology, 61 , 1 192-1204 (2015)) can further be used as part of a method of the present invention to identify patients resistant to sofsobuvir.
  • the capture fusion assay provides a method for replicating HCV virus in vitro which comprises the following steps: (i) fusing an HCV-infected white blood cell with a hepatocyte cell to produce a fused cell; and
  • the HCV-infected white blood cell may be suitably isolated from an HCV patient.
  • the hepatocyte may be from any suitable source of hepatocytes, including hepatocyte cell lines, for example the hepatoma cell line Huh7.5.
  • the HCV-infected white blood cell can be made by infecting a white blood cell with HCV virus in vitro.
  • the white blood cell may be derivable from a white blood cell (e.g. a monocyte) cell line, for example THP-1 .
  • the white blood cell may be pre-treated with at least one proinflammatory reagent prior to infection in vitro.
  • the white blood cell may be pre-treated with a cocktail of pro-inflammatory reagents.
  • the pro-inflammatory reagent may be, for example, interferon- ⁇ (IFNy) and/or PMA.
  • the pro-inflammatory reagent may be lipopolysaccharide and other Toll Like receptor agonists including flagellin, imiquimod and IL-1 .
  • the white blood cell may be any white blood cell which has the capacity to capture HCV virus. Suitable white blood cell types include: monocytes, polymorphs, macrophages and B cells.
  • the method may comprise the following steps:
  • a fused cell or a plurality of cells prepared according to this method can then be used permit analysis of the genome of the HCV in accordance with a method of the present invention.
  • Detection of a mutated HCV sequence in accordance with the invention may be carried out by any suitable technique. For example, whole genome sequencing may be performed on an isolated viral genomic. However, techniques such as polymerase chain reaction (PCR) may be used conveniently also. Appropriate oligonucleotide probes can be designed to hybridise to the specific mutated HCV sequences referred to herein. Other suitable assays may include dot-blot, ELISA or other antibody based assays also if specific regions of the HCV DNA sequences containing the mutations are translated into protein.
  • PCR polymerase chain reaction
  • the subject may be further treated with an anti- Hepatitis C Virus (HCV) drug wherein the drug is not sofosbuvir.
  • HCV Hepatitis C Virus
  • the drug may be selected from the group consisiting of daclatasvir, velpatasvir, elbasvir or grazoprevir, or a combination thereof.
  • an oligonucleotide probe or a set of oligonucleotide probes having nucleic acid sequences which hybridise to a nucleic acid sequence of Table 1 , or a sequence having 75% identity thereto.
  • more than one set of oligonucleotide probes can be used if more than one mutation is to be detected.
  • the probe or set of probes can be used as a primer or set of primers in a method according to the first aspect.
  • a kit comprising a set of oligonucleotide probes described above. In some instances, more than one set of oligonucleitide probes can be used if more than one mutation is to be detected.
  • the kit of parts may additionally comprise aqueous media for sample preparation, such as isotonic saline.
  • a method of treatment for a patient infected with Hepatitis C Virus comprising the step of administering an anti-HCV drug wherein the drug is not sofosbuvir and wherein the patient has previously been determined to be infected with an HCV strain having one or mutations in the NS5B protein of HCV selected from
  • an anti-Hepatitis C Virus (HCV) drug for use in the treatment of HCV in a patient wherein the drug is not sofosbuvir and the patient is infected with a HCV strain having one or more mutations in the NS5B protein of HCV selected from
  • the HCV infection is a genotype 3 Hepatitis C virus (HCV) infection.
  • the anti-HCV-drug may be IFN, PEG-IFN, ribavirin, or any HCV direct-acting antiviral (DAA) agent.
  • DAA HCV direct-acting antiviral
  • the HCV direct-acting antiviral (DAA) agent may be for example daclatasvir, velpatasvir, elbasvir or grazoprevir, or a combination thereof.
  • Methods in accordance with this aspect of the invention therefore include combinations of anti-HCV drugs which may be administered simultaneously, separately or sequentially to a patient.
  • Such combinations of drugs may therefore extend to the provision of a kit of parts which may additionally comprise an administration vehicle including, but not limited to, tablets for oral administration, inhalers for lung administration and injectable solutions for intravenous administration.
  • the anti-HCV drug may be administered by any convenient route, for example intravenously, intradermally, intramuscularly, orally or by other routes.
  • the active agent may be administered to an individual as an injectable composition, for example as a sterile aqueous dispersion, preferably isotonic.
  • Oral forms of the active substance include controlled-release and/or sustained release table formulations which may be additionally enteric coated.
  • the daily dosage of the active agent will be from 0.01 mg/kg up to 10mg/kg body weight, typically around 1 mg/kg.
  • the physician in any event will determine the actual dosage which will be most suitable for an individual which will be dependent on factors including the age, weight, sex and response of the individual.
  • the above dosages are exemplary of the average case. There can, of course, be instances where higher or lower dosages are merited, and such are within the scope of this invention
  • the sequence of the virus was analysed in patients by full genome sequencing which identified clusters of mutations associated with treatment failure.
  • sofosbuvir resistance is associated with the following mutations or combinations of mutations in the NS5B protein of HCV of at least:-
  • FIGURE 1 shows NS5B Mutations Identified in Drug Insensitive samples.
  • FIGURE 2 shows RBV and SOF sensitivity in G3 treatment non-responders to new DAA therapy.
  • Individual IC50 values for SOF (A) and RBV (B) were compared between the SVR and relapse groups. Capture fusion data for SOF and RBV was grouped by clinical outcome into patients who achieved SVR (C, D) or relapsed (E-H). Relapse samples were further divided in to SOF and RBV sensitive (E, F) and insensitive (G, H).
  • IC50 values for each drug represent the average of the indicated number of patients in each group. Graphs show mean ⁇ SEM.
  • FIGURE 3 shows analysis of NS5B sequences from drug sensitive and insensitive HCV isolates. Schematic of NS5B with indicated amino acid positions. Viral genomes from drug sensitive and insensitive relapse isolates were compared by sequence alignment.
  • FIGURE 4 shows effect of mutations on SOF sensitivity in a transient replicon assay.
  • FIGURE 5 shows effect of mutations on RBV sensitivity in a transient replicon assay. Engineered mutations were also tested for sensitivity to RBV. Sensitivity of each replicon was compared to the un-modified, wild-type replicon (Wt) The above is representative of 3 independent experiments performed in Huh7.5-SEC14L2 cell. Error bars depict mean ⁇
  • FIGURE 6 shows luciferase activity of mutated G3 replicons. Luciferase levels for each replicon were quantified 3 days post electroporation in a similar fashion to drug sensitivity experiments. Luciferase activity was normalised to a sample taken 4 hrs post electroporation. Error bars depict mean ⁇ SEM.
  • FIGURE 7 shows the reference nucleic acid sequence for HCV from:
  • FIGURE 8 shows the mutations found in HCV isolates from patients with resistance to sofosbuvir
  • Figure 8(a) shows I85V and K206E
  • Figure 8(b) shows A150V and K206E
  • Figure 8(c) shows K100R, A150S, G188D, T213N, and N244I
  • FIGURE 9 shows the full length nucleic acid sequence and corresponding presumed amino acid coding regions for HCV genotype 3a fui!-iength genome (DBNSacc) with the mutations in the NS5B region identified and stop codons shown by
  • the S5B region starts at nucleotide residue 7633 and finishes at nucleotide residue 9404 in the genome sequence.
  • the numbering of amino acid residue in the NS5B protein therefore starts from the corresponding initial residue in the DS5B region as shown.
  • Example 1 Comparison of Sofosbuvir and ribavirin sensitivity
  • Sofosbuvir and ribavirin sensitivity were carried out.
  • the 'capture-fusion' assay was used to assess sensitivity of HCV to sofosbuvir and ribavirin from patients with decompensated cirrhosis who relapsed following 12 weeks therapy with sofosbuvir and an NS5A inhibitor as part of the English Early Access Programme (Cheung ef al., Journal of hepatology 65, 741 -747 (2016); Foster et al., Journal of hepatology 64, 1224-1231 (2016)).
  • Example 3 Effect of identified NS5B substitutions on drug sensitivity in a transient replicon assay
  • SOF dose response curves for the mutated replicons were compared to the wild type replicon (Wt) and a control replicon containing the well-described S282T mutation (Table 2 which shows which effect of mutations on sofosbuvir sensitivity). Individually most of the mutations had only a modest effect on sofosbuvir sensitivity but in combination the effect was much more pronounced.
  • Example 4 Prevalence and impact of NS5B mutations in a second patient cohort To further examine the impact of the substitutions, their frequency was examined in a second, independent cohort of patients with genotype 3 HCV receiving sofosbuvir based therapies.

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Abstract

La présente invention concerne un procédé d'identification d'un sujet infecté par un virus de l'hépatite C (VHC) et résistant au traitement par le sofosbuvir, comprenant la détermination de la présence d'une ou de plusieurs mutations dans la protéine NS5B du virus de l'hépatite C choisie dans le groupe constitué de : A150V, I85V, K206E, K100R, A150S, G188D, T213N et N244I. L'invention concerne une sonde oligonucléotidique ou un ensemble de sondes oligonucléotidiques destiné à être utilisé dans un tel procédé. L'invention concerne également des méthodes de traitement d'un patient infecté par le VHC identifié par un procédé de l'invention et des médicaments anti-VHC destinés à être utilisés dans de tels méthodes.
PCT/GB2018/050718 2017-03-20 2018-03-20 Procédé d'identification de patients résistants au sofosbuvir Ceased WO2018172759A1 (fr)

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GBGB1704386.0A GB201704386D0 (en) 2017-03-20 2017-03-20 Method for identification of sofosbuvir resistant patients
GB1704386.0 2017-03-20

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WO2024123010A1 (fr) * 2022-12-05 2024-06-13 국립암센터 Plateforme luminescente pour la double mesure de l'activité du vhc/mir-122 et utilisation d'une substance rigosertib dérivée pour le traitement contre le vhc résistant au sofosbuvir

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024123010A1 (fr) * 2022-12-05 2024-06-13 국립암센터 Plateforme luminescente pour la double mesure de l'activité du vhc/mir-122 et utilisation d'une substance rigosertib dérivée pour le traitement contre le vhc résistant au sofosbuvir

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