WO1998023285A1 - Use of a combination of penciclovir and alpha-interferon in the manufacture of a medicament for the treatment of hepatitis b - Google Patents

Use of a combination of penciclovir and alpha-interferon in the manufacture of a medicament for the treatment of hepatitis b Download PDF

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Publication number
WO1998023285A1
WO1998023285A1 PCT/GB1997/003236 GB9703236W WO9823285A1 WO 1998023285 A1 WO1998023285 A1 WO 1998023285A1 GB 9703236 W GB9703236 W GB 9703236W WO 9823285 A1 WO9823285 A1 WO 9823285A1
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WO
WIPO (PCT)
Prior art keywords
penciclovir
interferon
famciclovir
treatment
alpha
Prior art date
Application number
PCT/GB1997/003236
Other languages
French (fr)
Inventor
Ronald James Boon
Gillian Frances Atkinson
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9624801.8A external-priority patent/GB9624801D0/en
Priority claimed from GBGB9700900.5A external-priority patent/GB9700900D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to AU51270/98A priority Critical patent/AU5127098A/en
Publication of WO1998023285A1 publication Critical patent/WO1998023285A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha

Definitions

  • the present invention relates to the use of a penciclovir or a bioprecusor therefor and alpha interferon in the treatment of hepatitis B virus infections and to pharmaceutical compositions containing the two compounds.
  • EP-A-271270 (Beecham Group p. I.e.) discloses the use of penciclovir or a pro- drug therefor and an interferon as a combined preparation for simultaneous, separate or sequential use in antiviral therapy, in particular in the treatment of herpesvirus infections.
  • EP-A-388049 (Beecham Group p.l.c.) discloses the use of penciclovir/famciclovir in the treatment of hepatitis B virus infection.
  • penciclovir/famciclovir include pharmaceutically acceptable salts, such as the hydrochlorides. and solvates. such as hydrates.
  • penciclovir or its oral form, famciclovir is particularly effective in treatment of Hepatitis B virus infections when administered in combination with alpha interferon.
  • the present invention provides a pharmaceutical product comprising a penciclovir or a bioprecusor therefor, such as famciclovir. and alpha interferon as a combined preparation for simultaneous, separate or sequential use in the treatment and/or prevention of hepatitis B virus infections.
  • the present invention also provides a method of treatment and/or prophylaxis of hepatitis B virus infections, which method comprises administering to a human or animal subject penciclovir or a bioprecusor therefor, such as famciclovir. and alpha interferon or a pharmaceutically acceptable salt or ester thereof.
  • penciclovir or a bioprecusor therefor such as famciclovir
  • the invention further provides the use of penciclovir or a bioprecusor therefor, such as famciclovir, in the manufacture of a medicament for administration in conjunction with alpha interferon for the treatment and/or prevention of hepatitis B virus infections.
  • Co-administration of penciclovir/famciclovir with alpha interferon is particularly useful for the treatment of prolonged hepatitis B virus infections.
  • Penciclovir/famciclovir and alpha interferon or a pharmaceutically acceptable salt or ester thereof may be administered as a single, pharmaceutical composition comprising effective amounts of the two active ingredients.
  • the two active ingredients may be co-administered in the form of two separate, pharmaceutical compositions for simultaneous or sequential use.
  • a usual dose of alpha interferon for use according to the invention is 3-10 MU (million units) three times per week. Famciclovir or penciclovir may be given before, after, during or continued after cessation of interferon treatment or any combination of these.
  • the unit doses may be administered, for example, 1 to 4 times per day.
  • the exact dose will depend on the route of administration and the severity of the condition being treated, and it will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient and immunocompromised patients may require an increased dosage.
  • the two active ingredients are administered as separate preparations, they are preferably given enterally, such as orally or parenterally (e.g. intramuscularly or, more particularly, intravenously).
  • the dose of famciclovir administered may be 0.5 or 1 to 5 g per day, typically 1.5 g to 2.25 g per day.
  • the invention provides a pharmaceutical composition, for use in human or veterinary medicine, which pharmaceutical composition comprises penciclovir or a bioprecusor therefor, such as famciclovir, and alpha interferon.
  • compositions according to the invention may be formulated in conventional manner using one or more physiologically acceptable carriers or excipients.
  • the compositions may, for example, be formulated for oral, buccal, parenteral or rectal administration.
  • Compositions for administration by the oral route in the form of, for example, tablets or capsules are preferred.
  • compositions for oral use such as tablets and capsules may be prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, micro -crystalline cellulose or calcium hydrogen phosphate); lubricant (e.g. magnesium stearate. talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate) or wetting agent (e.g. sodium lauryl sulphate). Tablets may be coated by methods well known in the art.
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, micro -crystalline cellulose or calcium hydrogen phosphate
  • lubricant e.g. magnesium stearate. talc or silica
  • disintegrants e.
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils) and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid).
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of one or both active ingredients.
  • compositions may be presented in a form suitable for bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in syringes, ampoules or in multi-dose containers with added preservative.
  • compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredients may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • compositions may be formulated as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the pharmaceutical compositions of the invention may be prepared according to conventional techniques well known in the pharmaceutical industry.
  • the penciclovir/famciclovir and the alpha interferon may be admixed together, if desired, with suitable excipients.
  • Tablets may be prepared, for example, by direct compression of such a mixture.
  • Capsules may be prepared by filling the blend along with suitable excipients into gelatin capsules using a suitable filling machine.
  • Controlled release forms for oral or rectal administration may be formulated in a conventional manner associated with controlled release forms.
  • compositions for use according to the invention may. if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • penciclovir/famciclovir and the alpha interferon are intended for administration as two separate compositions these may be presented in the form of, for example, a twin pack.
  • Examples of pharmaceutically acceptable salts are as described in the aforementioned patent references in the name of Beecham Group p. I.e. and references quoted therein, the subject matter of which is incorporated herein by reference.
  • anti-hepatitis B virus nucleoside analogue and alpha interferon of this invention may be administered in combination with other pharmacologically active agents, in particular, other antivirals.
  • Example 1

Abstract

The invention provides a method for the treatment or prophylaxis of hepatitis B virus infections in a human or animal patient which comprises administering to the patient effective or prophylactic amounts of penciclovir (or a bioprecursor thereof such as famciclovir) and alpha-interferon.

Description

USE OF A COMBINAΗON OF PENCICLOVI AND ALPHA-INTERFERON
IN THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF HEPATITIS B
The present invention relates to the use of a penciclovir or a bioprecusor therefor and alpha interferon in the treatment of hepatitis B virus infections and to pharmaceutical compositions containing the two compounds.
EP-A-271270 (Beecham Group p. I.e.) discloses the use of penciclovir or a pro- drug therefor and an interferon as a combined preparation for simultaneous, separate or sequential use in antiviral therapy, in particular in the treatment of herpesvirus infections. EP-A-388049 (Beecham Group p.l.c.) discloses the use of penciclovir/famciclovir in the treatment of hepatitis B virus infection.
All references herein to penciclovir/famciclovir include pharmaceutically acceptable salts, such as the hydrochlorides. and solvates. such as hydrates.
It has now been discovered that penciclovir or its oral form, famciclovir. is particularly effective in treatment of Hepatitis B virus infections when administered in combination with alpha interferon.
Accordingly, the present invention provides a pharmaceutical product comprising a penciclovir or a bioprecusor therefor, such as famciclovir. and alpha interferon as a combined preparation for simultaneous, separate or sequential use in the treatment and/or prevention of hepatitis B virus infections.
The present invention also provides a method of treatment and/or prophylaxis of hepatitis B virus infections, which method comprises administering to a human or animal subject penciclovir or a bioprecusor therefor, such as famciclovir. and alpha interferon or a pharmaceutically acceptable salt or ester thereof. The invention further provides the use of penciclovir or a bioprecusor therefor, such as famciclovir, in the manufacture of a medicament for administration in conjunction with alpha interferon for the treatment and/or prevention of hepatitis B virus infections.
Co-administration of penciclovir/famciclovir with alpha interferon is particularly useful for the treatment of prolonged hepatitis B virus infections.
Penciclovir/famciclovir and alpha interferon or a pharmaceutically acceptable salt or ester thereof may be administered as a single, pharmaceutical composition comprising effective amounts of the two active ingredients. Alternatively the two active ingredients may be co-administered in the form of two separate, pharmaceutical compositions for simultaneous or sequential use.
A usual dose of alpha interferon for use according to the invention is 3-10 MU (million units) three times per week. Famciclovir or penciclovir may be given before, after, during or continued after cessation of interferon treatment or any combination of these.
The unit doses may be administered, for example, 1 to 4 times per day. The exact dose will depend on the route of administration and the severity of the condition being treated, and it will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient and immunocompromised patients may require an increased dosage.
When the two active ingredients are administered as separate preparations, they are preferably given enterally, such as orally or parenterally (e.g. intramuscularly or, more particularly, intravenously).
The dose of famciclovir administered may be 0.5 or 1 to 5 g per day, typically 1.5 g to 2.25 g per day.
According to a further aspect the invention provides a pharmaceutical composition, for use in human or veterinary medicine, which pharmaceutical composition comprises penciclovir or a bioprecusor therefor, such as famciclovir, and alpha interferon.
Compositions according to the invention may be formulated in conventional manner using one or more physiologically acceptable carriers or excipients. Thus the compositions may, for example, be formulated for oral, buccal, parenteral or rectal administration. Compositions for administration by the oral route in the form of, for example, tablets or capsules are preferred.
Compositions for oral use such as tablets and capsules may be prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, micro -crystalline cellulose or calcium hydrogen phosphate); lubricant (e.g. magnesium stearate. talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate) or wetting agent (e.g. sodium lauryl sulphate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils) and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of one or both active ingredients.
For parenteral administration the compositions may be presented in a form suitable for bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g. in syringes, ampoules or in multi-dose containers with added preservative.
The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredients may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
For rectal administration the compositions may be formulated as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides. The pharmaceutical compositions of the invention may be prepared according to conventional techniques well known in the pharmaceutical industry. Thus, for example, the penciclovir/famciclovir and the alpha interferon may be admixed together, if desired, with suitable excipients. Tablets may be prepared, for example, by direct compression of such a mixture. Capsules may be prepared by filling the blend along with suitable excipients into gelatin capsules using a suitable filling machine. Controlled release forms for oral or rectal administration may be formulated in a conventional manner associated with controlled release forms.
The compositions for use according to the invention may. if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Where the penciclovir/famciclovir and the alpha interferon are intended for administration as two separate compositions these may be presented in the form of, for example, a twin pack. Examples of pharmaceutically acceptable salts are as described in the aforementioned patent references in the name of Beecham Group p. I.e. and references quoted therein, the subject matter of which is incorporated herein by reference.
It will be appreciated that the anti-hepatitis B virus nucleoside analogue and alpha interferon of this invention may be administered in combination with other pharmacologically active agents, in particular, other antivirals. Example 1
Two patients suffering from chronic hepatitis B infection were studied. In each case, interferon (IFN) monotherapy had failed. However, both patients showed complete suppression of HBV-DNA during famciclovir therapy. As a relapse occurred (raised ALT, AST, HBV-DNA, HBe-Ag.+, positive histology) after stopping famciclovir monotherapy, a combination therapy was introduced. Famciclovir was administered 500-750mg tid. After a significant suppression of HBV-DNA was achieved, IFN was added in a dosage of 9-10 MU 3 times weekly for 6 months. During combination therapy liver function tests returned to normal and HBV-DNA became undetectable by hybridisation assay. One of the patients showed seroconversion from HBe-Ag to anti-HBe. Combination therapy was well tolerated with only interferon induced adverse events. In the patient with seroconversion a relapse was observed 8 months after the end of therapy with spontaneous recovery after 2 months. In the second patient famciclovir therapy was continued after stopping interferon. as seroconversion did not occur, although HBV-DNA remained undetectable by hybridisation. In conclusion, combination therapy was safe and well tolerated in both patients. (See H Hinrichsen et al., 48th AASLD, 7-11 November 1997, Chicago.)
Example 2
A R Marques et al. report (37th ICAAC, 28 September - 1 October 1997, Toronto) that the combination of famciclovir and interferon appears to be at least additive on suppressing HBV-DNA and resulted in the apparent clearance of HBe-Ag in two of five patients suffering from chronic hepatitis B. despite their prior failure on alpha- interferon alone.

Claims

Claims
1. A pharmaceutical product comprising a penciclovir or a bioprecursor therefor and alpha-interferon or a pharmaceutically acceptable salt or ester thereof as a combined preparation for simultaneous, separate or sequential use in the treatment or prophylaxis of hepatitis B infections.
2. A pharmaceutical product as claimed in claim 1, when said bioprecursor is famciclovir.
3. A method of treatment or prophylaxis of hepatitis B virus infections in a human or animal patient, which method comprises administering to the patient an effective or prophylactic amount of penciclovir or a bioprecursor thereof and alpha- interferon or a pharmaceutically acceptable salt or ester thereof.
4. A method as claimed in claim 3, wherein said alpha-interferon and penciclovir are administered simultaneously or sequentially.
5. A method as claimed in claim 3 or claim 4 wherein said bioprecursor is famciclovir.
6. A method as claimed in any of claims 3-5, wherein the dose of alpha- interferon is 3-10 MU/2-5 times per week.
7. A method as claimed in any of claims 3-6, wherein the dose of penciclovir is 0.5-5g/day.
8. A method as claimed in any of claims 3-7, wherein famciclovir or penciclovir is given before interferon treatment.
9. A method as claimed in any of claims 3-8, wherein famciclovir or penciclovir is given during interferon treatment.
10. A method as claimed in any of claims 3-9, wherein famciclovir or penciclovir is given after interferon treatment.
11. A method as claimed in claim 8 or 9, wherein famciclovir or penciclovir is continued after cessation of interferon treatment.
12. A method as claimed in any of claims 3-7, wherein famciclovir is given before and during interferon treatment.
13. A pharmaceutical composition for use in human or veterinary medicine. which pharmaceutical composition comprises penciclovir or a bioprecursor therefor and alpha-interferon or a pharmaceutically acceptable salt or ester thereof.
14. The use of penciclovir or a bioprecursor thereof in the manufacture of a medicament for the administration in conjunction with alpha-interferon or a pharmaceutically acceptable salt or ester thereof for the treatment or prophylaxis of hepatitis B virus infections.
PCT/GB1997/003236 1996-11-29 1997-11-26 Use of a combination of penciclovir and alpha-interferon in the manufacture of a medicament for the treatment of hepatitis b WO1998023285A1 (en)

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AU51270/98A AU5127098A (en) 1996-11-29 1997-11-26 Use of a combination of penciclovir and alpha-interferon in the manufacture of a medicament for the treatment of hepatitis

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GBGB9624801.8A GB9624801D0 (en) 1996-11-29 1996-11-29 Pharmaceuticals
GB9624801.8 1996-11-29
GBGB9700900.5A GB9700900D0 (en) 1997-01-17 1997-01-17 Pharmaceuticals
GB9700900.5 1997-01-17

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WO2000025797A1 (en) * 1998-11-02 2000-05-11 Triangle Pharmaceuticals, Inc. Combination therapy to treat hepatitis b virus
US6723728B2 (en) 2001-03-01 2004-04-20 Gilead Sciences, Inc. Polymorphic and other crystalline forms cis-FTC
WO2015120178A1 (en) * 2014-02-05 2015-08-13 Novira Therapeutics, Inc. Combination therapy for treatment of hbv infections
US9181288B2 (en) 2014-01-16 2015-11-10 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9505722B2 (en) 2014-01-16 2016-11-29 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
CN106939042A (en) * 2016-01-22 2017-07-11 华南农业大学 A kind of porcine alpha-IFN and its application
US9884831B2 (en) 2015-03-19 2018-02-06 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US9884818B2 (en) 2013-05-17 2018-02-06 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9895349B2 (en) 2013-04-03 2018-02-20 Janssen Sciences Ireland Us N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10071961B2 (en) 2013-10-23 2018-09-11 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10077239B2 (en) 2015-09-29 2018-09-18 Novira Therapeutics, Inc. Crystalline forms of a hepatitis B antiviral agent
US10125094B2 (en) 2013-02-28 2018-11-13 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10196376B2 (en) 2011-12-21 2019-02-05 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10441589B2 (en) 2016-04-15 2019-10-15 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10676429B2 (en) 2012-08-28 2020-06-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10973801B2 (en) 2018-03-14 2021-04-13 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
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US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases

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US6528515B1 (en) 1998-11-02 2003-03-04 Triangle Pharmaceuticals, Inc. Combination therapy to treat hepatitis B virus
EP1380303A1 (en) * 1998-11-02 2004-01-14 Triangle Pharmaceuticals Inc. Combination therapy to treat hepatitis B virus
US7572800B2 (en) 1998-11-02 2009-08-11 Gilead Sciences, Inc. Combination therapy to treat hepatitis B virus
WO2000025797A1 (en) * 1998-11-02 2000-05-11 Triangle Pharmaceuticals, Inc. Combination therapy to treat hepatitis b virus
US6723728B2 (en) 2001-03-01 2004-04-20 Gilead Sciences, Inc. Polymorphic and other crystalline forms cis-FTC
US7544692B2 (en) 2001-03-01 2009-06-09 Gilead Sciences, Inc. Polymorphic and other crystalline forms of cis-FTC
US8637535B2 (en) 2001-03-01 2014-01-28 Gilead Sciences, Inc. Polymorphic and other crystalline forms of cis-FTC
US10196376B2 (en) 2011-12-21 2019-02-05 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US10676429B2 (en) 2012-08-28 2020-06-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10995064B2 (en) 2012-08-28 2021-05-04 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10941113B2 (en) 2013-02-28 2021-03-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10125094B2 (en) 2013-02-28 2018-11-13 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US9895349B2 (en) 2013-04-03 2018-02-20 Janssen Sciences Ireland Us N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10398677B2 (en) 2013-04-03 2019-09-03 Janssen Sciences Ireland Uc N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10457638B2 (en) 2013-05-17 2019-10-29 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9884818B2 (en) 2013-05-17 2018-02-06 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10071961B2 (en) 2013-10-23 2018-09-11 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10377709B2 (en) 2013-10-23 2019-08-13 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9505722B2 (en) 2014-01-16 2016-11-29 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9181288B2 (en) 2014-01-16 2015-11-10 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9873671B2 (en) 2014-01-16 2018-01-23 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
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