Capsid assembly modulator dosing regimen
阅读说明：本技术 衣壳组装调节剂给药方案 (Capsid assembly modulator dosing regimen ) 是由 O·伦茨 C·E·巴尔曼 J·斯诺伊斯 J·J·范登博舍 D·J·W·韦斯特拉特 J·Z· 于 2019-03-13 设计创作，主要内容包括：本披露涉及使用衣壳组装抑制剂来治疗乙型肝炎病毒感染的方法。(The present disclosure relates to methods of treating hepatitis b virus infection using capsid assembly inhibitors.)
1. A pharmaceutical composition comprising a compound having formula 1:
or a pharmaceutically acceptable salt thereof,
wherein:
a is N or CH;
at each occurrence, R1Independently selected from halo, CF3And CN;
R2is C1-C3An alkyl group;
at each occurrence, R3Independently selected from C1-C3Alkyl and halo;
R4is independently halogenated or CF3C substituted 1 or 2 times1-C4An alkyl group;
n is 0, 1, 2 or 3; and is
M is 0, 1, or 2;
wherein the amount of the compound having formula 1 is 50mg to 500 mg.
2. The pharmaceutical composition of claim 1, further comprising at least one polymer selected from HPMC-AS and HPMC, more particularly from HPMC-AS and HPMC E5, and wherein the at least one polymer is in an amount of 50mg-1500 mg.
3. The pharmaceutical composition according to claim 1 or 2, wherein the amount of the compound having formula 1 is 75mg-300mg, more particularly 75-250mg, more particularly 100-250 mg.
4. The pharmaceutical composition of any one of claims 1-3, wherein the compound having formula 1 is compound A:
or a pharmaceutically acceptable salt thereof.
5. The pharmaceutical composition of any one of claims 1-3, wherein the compound having formula 1 is compound B:
Or a pharmaceutically acceptable salt thereof.
6. Use of the pharmaceutical composition of any one of claims 1-3 for preventing or treating an HBV infection, or for preventing or treating an HBV-induced disease, in a subject, wherein said use comprises administering to said subject a compound having formula 1:
or a pharmaceutically acceptable salt thereof,
wherein:
a is N or CH;
at each occurrence, R1Independently selected from halo, CF3And CN;
R2is C1-C3An alkyl group;
at each occurrence, R3Independently selected from C1-C3Alkyl and halo;
R4is independently halogenated or CF3C substituted 1 or 2 times1-C4An alkyl group;
n is 0, 1, 2 or 3; and is
M is 0, 1, or 2;
wherein the compound having formula 1 is administered at a daily dose of 50mg-500 mg.
7. The pharmaceutical composition for use of claim 6, wherein the daily dose is 75mg-250 mg.
8. The pharmaceutical composition for use of claim 6 or 7, wherein the daily dose is 250 mg.
9. The pharmaceutical composition for use of any one of claims 6-8, wherein at least one dosage form of the pharmaceutical composition comprises at least one polymer selected from HPMC and HPMC-AS, more particularly selected from HPMC E5 and HPMC-AS.
10. The pharmaceutical composition for use of claim 9, wherein the amount of the compound having formula 1 and the amount of said at least one polymer are present in the dosage form in a ratio of 1: 3 by weight.
11. The pharmaceutical composition for use according to any one of claims 6-10, wherein the compound having formula 1 is administered in a single dosage form.
12. The pharmaceutical composition for use of any one of claims 6-11, wherein the compound having formula 1A is administered to prevent HBV infection in a subject.
13. The pharmaceutical composition for use of any one of claims 6-12, wherein the use further comprises administering a transcription inhibitor.
14. The pharmaceutical composition for use of claim 13, wherein the transcription inhibitor is a nucleoside analog.
15. The pharmaceutical composition for use of claim 14, wherein the nucleoside analog is denofovir disoproxil fumarate or denofovir alafenamide or entecavir monohydrate.
16. The pharmaceutical composition for use of claim 14, wherein the nucleoside analog is qinofovir, or a pharmaceutically acceptable salt, or prodrug thereof.
17. The pharmaceutical composition for use according to claim 16, wherein tenofovir is administered in an amount of 60mg-600 mg.
18. The pharmaceutical composition for use of claim 14, wherein the nucleoside analog is entecavir, or a pharmaceutically acceptable salt thereof.
19. The pharmaceutical composition for use according to claim 18, wherein entecavir is administered in an amount of 0.1mg to 1 mg.
20. The pharmaceutical composition for use of any one of claims 6-19, wherein the use further comprises administering an immunomodulator, or at least one siRNA or antisense oligonucleotide, or at least one nucleic acid polymer, more particularly at least one immunomodulator.
21. The pharmaceutical composition for use of claim 20, wherein the immunomodulatory agent is an interferon.
22. The pharmaceutical composition for use of any one of claims 6-21, wherein the subject is HBV naive.
23. The pharmaceutical composition for use of any one of claims 6-22, wherein the HBV-induced disease is cirrhosis, liver failure or hepatocellular carcinoma.
24. The pharmaceutical composition for use of any one of claims 6-23, wherein administration of the compound having formula 1 reduces HBV cccDNA formation in a subject infected with or at risk of infection with HBV.
25. The pharmaceutical composition for use of any one of claims 6-24, wherein administration of the compound having formula 1 reduces HBsAg in a subject infected with or at risk of infection with HBV.
26. The pharmaceutical composition for use of any one of claims 6-25, wherein administration of the compound having formula 1 reduces HBeAg in a subject infected with or at risk of infection with HBV.
27. The pharmaceutical composition for use of any one of claims 6-26, wherein administration of the compound having formula 1 induces seroconversion.
28. The pharmaceutical composition for use of any one of claims 6-27, wherein the compound having formula 1 is administered so as to achieve a maximum concentration (Cmax) in the subject's plasma of more than 3,000ng/mL-15,000ng/mL, particularly 3,900ng/mL-13,500ng/mL, and/or an AUC in the subject's plasma of 50,000ng.h/mL-300,000ng.h/mL, more particularly 80,000ng.h/mL-250,000 ng.h/mL.
29. The pharmaceutical composition for use of any one of claims 6-28, wherein the compound having formula 1 is compound a:
Or a pharmaceutically acceptable salt thereof.
30. The pharmaceutical composition for use of any one of claims 6-28, wherein the compound having formula 1 is compound B:
or a pharmaceutically acceptable salt thereof.
Background
Chronic Hepatitis B Virus (HBV) infection is a persistent, potentially progressive necrotic inflammatory (neoinfluenza) liver disease associated with chronic HBV infection. Worldwide, approximately 2.4-4 million people are chronically infected with HBV, and chronic HBV infection is a major global cause of severe liver morbidity and liver-related mortality (Hepatitis B Factsheet [ Hepatitis B live report ], World Health Organization [ World Health Organization ], 2013; Hoofnagle JH et al, Management of Hepatitis B: Summary of the Clinical Research institute [ Management of Hepatitis B ]; Hepatology [ hepatopathy ], 2007, 45 (4): 1056-1075; EASL Clinical practice Guidelines: Management of chronic Hepatitis B virus infection ], J.hepatology [ journal of Hepatitis B virus ], 167: 167; regional Research of Hepatitis B virus infection [ Japanese Clinical practice review of Hepatitis B virus 2012 ]; Japanese Hepatitis B infection, Japanese Hepatitis B virus infection, Japanese Hepatitis B infection, Japanese Hepatitis B infection, Japanese Hepatitis B infection, Japanese Hepatitis infection, LiverInternational [ journal of international liver ], 2006, 26: 3-10; lok ASF and McMahon BJ, chronichepatis B: update [ chronic hepatitis b: update ]2009, Hepatology, 2009, 9 months: 1-36(Lok 2009)).
In the case of a continuing worldwide prevalence of HBV-related deaths and severe morbidity, there remains a need for improved HBV antiviral therapies that can achieve a sustained viral response during and after treatment.
Disclosure of Invention
The present disclosure relates to methods of treating hepatitis b virus infection using capsid assembly inhibitors. In one aspect, provided herein is a method of preventing or treating HBV infection in a subject, the method comprising administering to the subject a compound having formula 1:
or a pharmaceutically acceptable salt thereof,
wherein:
a is N or CH;
at each occurrence, R1Independently selected from halo, CF3And CN;
R2is C1-C3An alkyl group;
at each occurrence, R3Independently selected from C1-C3Alkyl and halo;
R4is independently halogenated or CF3C substituted 1 or 2 times1-C4An alkyl group;
n is 0, 1, 2 or 3; and is
M is 0, 1, or 2;
the
In some embodiments, the compound having formula I is compound a:
or a pharmaceutically acceptable salt thereof.
In other embodiments, the compound having formula I is compound B:
or a pharmaceutically acceptable salt thereof.
In an embodiment of the method, the daily dose is 75mg to 250 mg.
In another embodiment of the method, the daily dose is 250 mg.
In yet another embodiment of the method, the stabilizer is at least one of Hypromellose (HPMC) and hypromellose acetate succinate (HPMC-AS). For example, the Hypromellose (HPMC) may be HPMC E5 (i.e. HPMC having a viscosity of 5 mpa.s).
In an embodiment of the method, the amount of the
In an embodiment of the method, the
In an embodiment of the method, the
In embodiments of the method, the method further comprises administering to the subject a transcription inhibitor. In an embodiment of the method, the transcription inhibitor is a nucleoside analog. In an embodiment of the method, the nucleoside analog is tenofovir or a pharmaceutically acceptable salt or prodrug thereof, tenofovir alafenamide or a pharmaceutically acceptable salt or prodrug thereof, or entecavir or a pharmaceutically acceptable salt thereof. In embodiments of the method, the nucleoside analog is tenofovir disoproxil fumarate or entecavir monohydrate. In an embodiment of the method, the nucleoside analogue is tenofovir disoproxil fumarate. In an embodiment of the method, the nucleoside analog is entecavir monohydrate.
In an example of the method, tenofovir disoproxil fumarate is administered in an amount of 60mg to 600 mg. In another embodiment of the method, tenofovir disoproxil fumarate is administered in an amount of 300 mg. In yet another embodiment of the method, entecavir monohydrate is administered in an amount from 0.1mg to 1 mg. In yet another embodiment of the method, entecavir monohydrate is administered in an amount of 0.5 mg.
In embodiments of the method, the method further comprises administering an immunomodulatory agent. In embodiments of the method, the immunomodulatory agent is an interferon, such as interferon alpha or pegylated interferon alpha. In embodiments of the method, the subject is treatment naive.
In some embodiments, the method further comprises administering at least one Nucleic Acid Polymer (NAP), more particularly, at least one NAP that inhibits release of subviral particles from hepatocytes.
In some embodiments, the method further comprises administering at least one short interfering rna (siRNA), or antisense oligonucleotide (ASO), more particularly, at least one siRNA or ASO selected from the group consisting of siRNA and ASO that inhibits expression of one or more genes essential for replication or pathogenesis of HBV.
In another aspect, provided herein is a pharmaceutical composition comprising a
The pharmaceutical composition may comprise at least one polymer selected from HPMC-AS and HPMC E5, and wherein the at least one polymer is in an amount of 50mg to 1500 mg. In embodiments, at least one dosage form of the pharmaceutical composition comprises at least one polymer selected from HPMC (e.g., HPMC E5) and HPMC AS.
In another aspect, provided herein is a method of reducing HBV cccDNA formation in a subject infected with HBV or at risk of infection with HBV, the method comprising administering to the subject a
In another aspect, provided herein is a method of reducing HBsAg in a subject infected with, or at risk of infection with, HBV, the method comprising administering to the subject a compound of
In yet another aspect, provided herein is a method of preventing HBV infection in a subject at risk of being infected with HBV by reducing the formation of HBVcccDNA, the method comprising administering to the subject a
In various embodiments of the methods provided herein, the method further comprises administering a nucleoside (nucleotide) analog.
Drawings
Figure 1 depicts the study design of the first human study of compound a in healthy patients and patients with HBV.
Figure 2 depicts the plasma concentration of compound a in human subjects after 28 days of treatment.
FIG. 3 depicts the effect of Compound A on HBV DNA. And refers to one and three patients, respectively, in which HBV DNA is below the lower limit of quantitation in HBV DNA assays. Placebo data were pooled from two treatment sessions. Values are mean ± SD.
Figure 4 depicts a study design for testing the safety and tolerability of compound a in healthy human subjects.
Figure 5 depicts the pharmacokinetics of compound a in healthy human subjects.
Detailed Description
The present disclosure relates to methods of treating hepatitis b virus infection using capsid assembly inhibitors. It has now been found that administration of Capsid Assembly Modulators (CAMs) can interfere with HBV capsid assembly, which is a key step in virus production and is therefore an attractive new area of development. Unexpectedly, it has been found that administration of a
Definition of
As used in this specification and claims, the term "comprising" may include embodiments "consisting of and" consisting essentially of. As used herein, the terms "comprising," "including," "having," "can," "containing," "contains," and variants thereof mean an open transition phrase, term, or word that requires the presence of named components/steps and allows for the presence of other components/steps. However, such description should be understood as also describing the composition or method as "consisting of and" consisting essentially of: the compounds listed, which allow the presence of only the named compound, along with any pharmaceutically acceptable carrier, and the exclusion of other compounds.
All ranges disclosed herein are inclusive of the recited endpoint and independently combinable (e.g., ranges of "from 50mg to 500 mg" are inclusive of the endpoints 50mg and 500mg, and all intermediate values). The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are not sufficiently accurate to include values close to these ranges and/or values.
As used herein, approximating language may be applied to modify any quantitative representation that may vary without resulting in a change in the basic function to which it is related. Accordingly, a value modified by a term or terms, such as "about" and "substantially," is not to be limited to the precise value specified, in some cases. In at least some instances, the language of the approximation may correspond to the accuracy of the instrument used to measure the value. The modifier "about" should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression "from about 50 to about 500" also discloses the range "from 50 to 500". The term "about" may refer to plus or minus 10% of a number. For example, "about 10%" may mean a range of 9% to 11%, and "about 1" may mean from 0.9 to 1.1. From the context, other meanings of "about" may become apparent, such as rounding off, so, for example, "about 1" may also mean from 0.5 to 1.4.
As used herein, the term "treatment" is defined as the application or administration of a therapeutic agent, i.e., a compound of the present invention (alone or in combination with another agent), to a patient suffering from or having a symptom of HBV infection or having a likelihood of developing HBV infection, with the purpose of curing, healing, alleviating, altering, remediating, ameliorating, improving or affecting HBV infection, a symptom of HBV infection or a likelihood of developing HBV infection, or the application or administration of a therapeutic agent, i.e., a compound of the present invention (alone or in combination with another agent), or to an isolated tissue or cell line from a patient having HBV infection or having a likelihood of developing HBV infection (e.g., for diagnostic or ex vivo applications). Such treatments can be specifically tailored or modified based on knowledge gained from the pharmacogenomics field.
As used herein, the term "preventing" includes the prevention of at least one symptom associated with or caused by the condition, disease or disorder being prevented.
As used herein, the term "patient", "individual" or "subject" refers to a human or non-human mammal. Non-human mammals include, for example, farm animals as well as companion animals such as ovine, bovine, porcine, canine, feline, and murine mammals. Preferably, the patient, subject or individual is a human.
As used herein, the term "pharmaceutically acceptable" refers to a material (e.g., carrier or diluent) that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of a composition in which it is contained.
As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds wherein the parent compound is modified by conversion of an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; an alkali metal or organic salt of an acidic residue such as a carboxylic acid; and the like. Pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts is found in Remington's Pharmaceutical Sciences [ Remington's Pharmaceutical Sciences ], 17 th edition, Mack Publishing Company [ Mark Publishing Company ], Iston, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science [ Journal of Pharmaceutical Sciences ], 66, 2(1977), each of which is incorporated herein by reference in its entirety.
As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful in the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. There are a variety of techniques in the art for administering compounds including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.
As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material, involved in carrying or transporting or carrying or delivering a compound useful in the present invention in a patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compounds useful in the present invention, and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered gum tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; a surfactant; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol; a phosphate buffer solution; and other non-toxic compatible materials used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coating agents, antibacterial and antifungal agents, and absorption delaying agents, and the like, that are compatible with the activity of the compounds useful in the present invention and are physiologically acceptable to a patient. Supplementary active compounds may also be incorporated into the compositions. The "pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of the compounds useful in the present invention. Other additional ingredients that may be included in Pharmaceutical compositions for practicing the present invention are known in the art and are described, for example, in Remington's Pharmaceutical Sciences [ Remington Pharmaceutical science ] (genano editors, Mack Publishing Co. [ mark Publishing company ], 1985, easton, pa), which is incorporated herein by reference.
As used herein, the term "stabilizer" refers to a polymer that is capable of chemically inhibiting or preventing the degradation of a
As used herein, "combination," "therapeutic combination," "pharmaceutical combination," or "combination product" refers to a non-fixed combination or kit of parts for combined administration, wherein two or more therapeutic agents may be administered independently, either simultaneously or separately, over time intervals, particularly wherein the time intervals allow the combination partners to exhibit a synergistic, e.g., synergistic, effect.
As used herein, "treatment-naive" refers to patients not previously receiving treatment with drugs (particularly nucleoside (nucleotide) drugs) studied or approved for HBV infection. "treatment naive" also means that within six months of entry into the clinical study, the patient was not treated with the HBV antiviral drug.
Alternatively, a patient treated according to the methods of the present disclosure may be "undergoing treatment. As used herein, "undergoing treatment" refers to a patient having received at least one prior course of HBV antiviral therapy, particularly a nucleoside (nucleotide) drug. In some embodiments, the last administration in this prior course of treatment occurs at least three months prior to the practice of a method according to the present disclosure.
HBV infections that can be treated according to the disclosed methods include HBV genotype A, B, C, and/or D infection. However, in the examples, the disclosed methods can treat any HBV genotype ("pan-genotypic) therapy"). HBV genotyping can be performed using methods known in the art, e.g.
The term "synergistic effect" refers to the effect produced by two agents (e.g., such as a capsid assembly modulator and a nucleoside (nucleotide) analog), e.g., the effect of slowing the progression of symptoms of HBV infection or symptoms thereof, which is greater than the simple addition of the effects of each drug administered alone. For example, synergistic effects can be calculated using suitable methods, such as the Sigmoid-Emax equation (Holford, N.H.G., and Scheiner, L.B., Clin. Pharmacokinet. [ clinical pharmacokinetics ] 6: 429-453(1981)), the Loewe additivity equation (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. [ experimental pathology and pharmacology archives ] 114: 313-326(1926)) and the median effect equation (Chou, T.C., and Talalay, P., Adv. enzyme Regul. [ enzyme regulation progression ] 22: 27-55(1984) and Chou, Phacol. Rev. [ Pha ] 58: 621- (2006)). Each of the above-mentioned equations can be applied to experimental data to generate a corresponding graph to help assess the effect of the drug combination. The corresponding graphs associated with the above equations are the concentration-effect curve, the isobologram curve, and the joint index curve, respectively. In some embodiments, the combination of compounds exhibits a synergistic effect (i.e., greater than additive effect) in the treatment of HBV infection.
The volumes of synergy of < -100, -100 to-50, -50 to-25, -25 to 25, 25 to 50, 50 to 100, and >100 represent strong antagonism, moderate antagonism, mild antagonism, insignificant synergy/antagonism (additivity), mild synergy, moderate synergy, and strong synergy, respectively.
Synergy can be defined as an improvement in any beneficial effect of each of the compounds or nucleoside (nucleotide) analogs of
For administration/rotation
In one aspect, the present disclosure relates to methods of treating HBV infection in a patient in need thereof, comprising administering to the patient a compound having formula 1:
or a pharmaceutically acceptable salt thereof,
wherein:
a is N or CH;
at each occurrence, R1Independently selected from halo, CF 3And CN;
R2is C1-C3An alkyl group;
at each occurrence, R3Independently selected from C1-C3Alkyl and halo;
R4is independently halogenated or CF3C substituted 1 or 2 times1-C4An alkyl group;
n is 0, 1, 2 or 3; and is
M is 0, 1, or 2.
In some embodiments, the amount of the
In some embodiments, the dose or daily dose of the compound having formula 1 (more particularly, compound (a) or (B)) is 5 to 300mg, more particularly 25mg to 300mg, more particularly 50mg to 300mg, more particularly 75mg to 300mg, more particularly 80mg to 300mg, more particularly 100mg to 250 mg.
In some embodiments, the dose or daily dose of the compound having formula 1 (more particularly, compound (a) or (B)) is 5mg to 250mg, more particularly 25mg to 250mg, more particularly 50mg to 250mg, more particularly 75mg to 250mg, more particularly 80mg to 250mg, more particularly 100mg to 250 mg.
In some embodiments, the dose or daily dose of the compound having formula 1 (more particularly, compound (a) or (B)) is 50mg to 300mg, more particularly 75mg to 250mg, more particularly 100mg to 250 mg.
In embodiments of the methods provided herein for treating HBV infection in a patient in need thereof, the
or a pharmaceutically acceptable salt thereof (hereinafter "compound a"), in an amount of from about 50mg per day to about 500mg per day (e.g., 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500 mg). In some embodiments, the amount of compound a is from 75mg per day to 250mg per day. In some embodiments, the amount of compound a is 75mg per day. In some embodiments, the amount of compound a is 150mg per day. In some embodiments, the amount of compound a is 250mg per day.
Compound A, including its synthesis, is disclosed in PCT publication No. WO/2014/184350 (or its U.S. counterpart publication No.), which is hereby incorporated by reference in its entirety.
In another embodiment of the methods provided herein for treating HBV infection in a patient in need thereof, the
or a pharmaceutically acceptable salt thereof (hereinafter "compound B"), in an amount of from about 50mg per day to about 500mg per day (e.g., 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500 mg). In some embodiments, the amount of compound B is from 75mg per day to 250mg per day. In some embodiments, the amount of compound B is 75mg per day. In some embodiments, the amount of compound B is 150mg per day. In some embodiments, the amount of compound B is 250mg per day.
Compound B, including its synthesis, is disclosed in PCT publication No. WO/2015/118057 (or its U.S. counterpart publication No.), which is incorporated herein by reference in its entirety.
The methods of the present disclosure are directed to reducing serum HBV DNA, serum HBV RNA, and quantifying serum HBsAg and HBeAg in a patient. The methods of treating HBV infection provided herein, in particular, treating HBV infection by reducing serum HBV DNA in a patient, by reducing serum HBV RNA in a patient, and/or by reducing serum HBsAg and HBeAg in a patient, and/or by inducing seroconversion (against sAg and/or eAg) in a patient.
In certain embodiments of the methods of treating HBV infection provided herein, the treatment is therapeutic and the patient does not have to continue treatment after the specified treatment time. In particular embodiments of the methods of treating HBV provided herein, the treatment is limited.
The present disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient a compound of
In an alternative embodiment, the present disclosure provides methods of preventing HBV infection in a patient at risk of HBV infection, comprising administering to the patient a compound of
In some embodiments, the methods further comprise administering an immunomodulatory agent, such as an interferon. In some embodiments, the subject is treatment naive.
In some embodiments, the methods further comprise administering at least one Nucleic Acid Polymer (NAP), more particularly, at least one NAP that inhibits release of subviral particles from hepatocytes.
In some embodiments, the method further comprises administering at least one short interfering rna (siRNA), or antisense oligonucleotide (ASO), more particularly, at least one siRNA or ASO selected from the group consisting of siRNA and ASO that inhibits expression of one or more genes essential for replication or pathogenesis of HBV.
In some embodiments of these methods, the
In another embodiment, the disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient a
In another embodiment, the disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient a
In another embodiment, the present disclosure provides methods of treating HBV infection in a patient in need thereof comprising administering to the patient a
In some embodiments, the present disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient a
In another embodiment, the disclosure provides methods of treating HBV infection in a patient in need thereof comprising administering to the patient a
In another embodiment, the present disclosure provides methods of treating HBV infection in a patient in need thereof comprising administering to the patient a
In some embodiments, the present disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient a
In another embodiment, the disclosure provides methods of treating HBV infection in a patient in need thereof comprising administering to the patient a
In some embodiments, the present disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient a
In another embodiment, the disclosure provides methods of treating an HBV infection in a patient in need thereof comprising administering to the patient a
Also provided herein are methods of treating HBV infection in a patient in need thereof, comprising administering compound a, or a pharmaceutically acceptable salt thereof, to the patient (in an amount from 50mg per day to 500mg per day), wherein compound a is administered once per day. In an embodiment, compound a is administered to the patient for a duration of 28 days. In some embodiments, the amount of compound a administered to the patient is from 75mg per day to 250mg per day. In some embodiments, the amount of compound a administered to the patient is 75mg per day. In some embodiments, the amount of compound a or a pharmaceutically acceptable salt thereof is 150mg per day. In a particular embodiment, the amount of compound a administered to the patient is 250mg per day.
In an alternative embodiment, the present disclosure provides methods of preventing HBV infection in a patient at risk of HBV infection, comprising administering compound a, or a pharmaceutically acceptable salt thereof (in an amount from 50mg per day to 500mg per day), to the patient, wherein compound a is administered once per day. Thus, in particular embodiments, the disclosure provides methods of preventing HBV infection in a patient at risk of HBV infection, comprising administering compound a, or a pharmaceutically acceptable salt thereof, to the patient (in an amount of 250mg per day).
In some embodiments of these methods, compound a is co-administered with a transcription inhibitor. In some embodiments, the transcription inhibitor is a nucleoside (nucleotide) analog. In some embodiments, the nucleoside (nucleotide) inhibitor is tenofovir or a pharmaceutically acceptable salt thereof or a prodrug thereof (e.g., Tenofovir Disoproxil Fumarate (TDF), Tenofovir Alafenamide (TAF), or a pharmaceutically acceptable salt thereof), or entecavir or a pharmaceutically acceptable salt thereof. In some embodiments, compound a is co-administered with tenofovir disoproxil fumarate. In some embodiments, compound a is co-administered with tenofovir alafenamide. In other embodiments, compound a is co-administered with entecavir monohydrate.
In another embodiment, the disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient compound a, or a pharmaceutically acceptable salt thereof, in an amount from 50mg per day to 500mg per day, and a transcription inhibitor.
In another embodiment, the disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient compound a, or a pharmaceutically acceptable salt thereof, in an amount of from 50mg per day to 500mg per day, and a nucleoside (nucleotide) analog.
In another embodiment, the present disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient compound a, or a pharmaceutically acceptable salt thereof (in an amount from 50mg per day to 500mg per day), and tenofovir, or a pharmaceutically acceptable salt, or a prodrug thereof (in an amount from 60mg per day to 600mg per day).
In some embodiments, the present disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient compound a, or a pharmaceutically acceptable salt thereof (in an amount from 50mg per day to 500mg per day), and tenofovir alafenamide, or a pharmaceutically acceptable salt thereof (in an amount from 60mg per day to 600mg per day).
In another embodiment, the disclosure provides methods of treating an HBV infection in a patient in need thereof, comprising administering to the patient compound a, or a pharmaceutically acceptable salt thereof, in an amount from 50mg daily to 500mg daily, and entecavir, or a pharmaceutically acceptable salt thereof, in an amount from 0.1mg daily to 1mg daily.
In another embodiment, the present disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient compound a, or a pharmaceutically acceptable salt thereof (in an amount from 75mg per day to 250mg per day), and tenofovir, or a pharmaceutically acceptable salt or prodrug thereof (in an amount of 300mg per day). In embodiments, co-administration of compound a, or a pharmaceutically acceptable salt thereof, with tenofovir, or a pharmaceutically acceptable salt or prodrug thereof produces a synergistic effect.
In some embodiments, the present disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient compound a, or a pharmaceutically acceptable salt thereof, in an amount from 75mg per day to 250mg per day, and tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, in an amount of 300mg per day. In embodiments, co-administration of compound a, or a pharmaceutically acceptable salt thereof, with tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, produces a synergistic effect.
In another embodiment, the disclosure provides methods of treating an HBV infection in a patient in need thereof, comprising administering to the patient compound a, or a pharmaceutically acceptable salt thereof, in an amount from 75mg per day to 250mg per day, and entecavir, or a pharmaceutically acceptable salt thereof, in an amount of 0.5mg per day. In embodiments, co-administration of compound a, or a pharmaceutically acceptable salt thereof, with entecavir, or a pharmaceutically acceptable salt thereof, produces a synergistic effect.
In another embodiment, the present disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient compound a, or a pharmaceutically acceptable salt thereof (in an amount of 250mg per day), and tenofovir, or a pharmaceutically acceptable salt thereof, or a prodrug thereof (in an amount of 300mg per day).
In some embodiments, the present disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient compound a, or a pharmaceutically acceptable salt thereof (in an amount of 250mg per day), and tenofovir alafenamide, or a pharmaceutically acceptable salt thereof (in an amount of 300mg per day).
In another embodiment, the disclosure provides methods of treating an HBV infection in a patient in need thereof comprising administering to the patient compound a, or a pharmaceutically acceptable salt thereof, in an amount of 250mg per day, and entecavir, or a pharmaceutically acceptable salt thereof, in an amount of 0.5mg per day.
Also provided herein are methods of treating HBV infection in a patient in need thereof, comprising administering compound B, or a pharmaceutically acceptable salt thereof, to the patient (in an amount of from 50mg per day to 500mg per day), wherein compound a is administered once per day. In an embodiment, compound B is administered to the patient for a duration of 28 days. In some embodiments, the amount of compound B administered to the patient is from 75mg per day to 250mg per day. In some embodiments, the amount of compound B administered to the patient is 75mg per day. In some embodiments, the amount of compound B or a pharmaceutically acceptable salt thereof is 150mg per day. In a particular embodiment, the amount of compound B administered to the patient is 250mg per day.
In an alternative embodiment, the present disclosure provides methods of preventing HBV infection in a patient at risk of HBV infection, comprising administering compound B, or a pharmaceutically acceptable salt thereof (in an amount from 50mg per day to 500mg per day), to the patient, wherein compound B is administered once per day. Thus, in particular embodiments, the disclosure provides methods of preventing HBV infection in a patient at risk of HBV infection, comprising administering compound B, or a pharmaceutically acceptable salt thereof, to the patient (in an amount of 250mg per day).
In some embodiments of these methods, compound B is co-administered with a transcription inhibitor. In some embodiments, the transcription inhibitor is a nucleoside (nucleotide) analog. In some embodiments, the nucleoside (nucleotide) inhibitor is tenofovir or a pharmaceutically acceptable salt thereof or a prodrug thereof (e.g., Tenofovir Disoproxil Fumarate (TDF), Tenofovir Alafenamide (TAF), or a pharmaceutically acceptable salt thereof), or entecavir, or a pharmaceutically acceptable salt thereof. In some embodiments, compound B is co-administered with tenofovir disoproxil fumarate. In some embodiments, compound B is co-administered with tenofovir alafenamide. In other embodiments, compound B is co-administered with entecavir monohydrate.
In another embodiment, the disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient compound B, or a pharmaceutically acceptable salt thereof, in an amount from 50mg per day to 500mg per day, and a transcription inhibitor.
In another embodiment, the disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient compound B, or a pharmaceutically acceptable salt thereof, in an amount of from 50mg per day to 500mg per day, and a nucleoside (nucleotide) analog.
In another embodiment, the present disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient compound B, or a pharmaceutically acceptable salt thereof (in an amount from 50mg per day to 500mg per day), and tenofovir, or a pharmaceutically acceptable salt, or prodrug thereof (in an amount from 60mg per day to 600mg per day).
In some embodiments, the present disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient compound B, or a pharmaceutically acceptable salt thereof (in an amount from 50mg per day to 500mg per day), and tenofovir alafenamide, or a pharmaceutically acceptable salt thereof (in an amount from 60mg per day to 600mg per day).
In another embodiment, the disclosure provides methods of treating an HBV infection in a patient in need thereof, comprising administering to the patient compound B, or a pharmaceutically acceptable salt thereof, in an amount from 50mg per day to 500mg per day, and entecavir, or a pharmaceutically acceptable salt thereof, in an amount from 0.1mg per day to 1mg per day.
In another embodiment, the present disclosure provides methods of treating HBV infection in a patient in need thereof comprising administering to the patient compound B, or a pharmaceutically acceptable salt thereof (in an amount from 75mg per day to 250mg per day), and tenofovir, or a pharmaceutically acceptable salt or prodrug thereof (in an amount of 300mg per day). In embodiments, co-administration of compound B, or a pharmaceutically acceptable salt thereof, with tenofovir, or a pharmaceutically acceptable salt or prodrug thereof produces a synergistic effect.
In another embodiment, the present disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient compound B, or a pharmaceutically acceptable salt thereof, in an amount from 75mg per day to 250mg per day, and tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, in an amount of 300mg per day. In embodiments, co-administration of compound B, or a pharmaceutically acceptable salt thereof, with tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, produces a synergistic effect.
In another embodiment, the disclosure provides methods of treating an HBV infection in a patient in need thereof comprising administering to the patient compound B, or a pharmaceutically acceptable salt thereof, in an amount from 75mg per day to 250mg per day, and entecavir, or a pharmaceutically acceptable salt thereof, in an amount of 0.5mg per day. In embodiments, co-administration of compound B, or a pharmaceutically acceptable salt thereof, with entecavir, or a pharmaceutically acceptable salt thereof, produces a synergistic effect.
In another embodiment, the present disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering to the patient compound B, or a pharmaceutically acceptable salt thereof (in an amount of 250mg per day), and tenofovir, or a pharmaceutically acceptable salt thereof, or a prodrug thereof (in an amount of 300mg per day).
In another embodiment, the present disclosure provides methods of treating HBV infection in a patient in need thereof, comprising administering compound B, or a pharmaceutically acceptable salt thereof, to the patient in an amount of 250mg per day, and tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, in an amount of 300mg per day.
In another embodiment, the disclosure provides methods of treating an HBV infection in a patient in need thereof comprising administering to the patient compound B, or a pharmaceutically acceptable salt thereof, in an amount of 250mg per day, and entecavir, or a pharmaceutically acceptable salt thereof, in an amount of 0.5mg per day.
In some embodiments, the patient that can be treated using the described methods is a human. Other warm-blooded animals may also be treated.
In embodiments of the methods of treating HBV infection provided herein, the patient in need thereof is a patient with chronic HBV infection with or without evidence of potential liver inflammation. In some embodiments, the patient has a chronic HBV infection. In other embodiments, the patient has HBV-induced disease. In some embodiments, the HBV-induced disease is cirrhosis, liver failure, or hepatocellular carcinoma. In other embodiments, the patient is a treatment naive patient. More particularly, the patient is a treatment naive patient to chronic HBV infection. In further embodiments, the patient is HBeAg positive. In further embodiments, the patient is treatment naive and HBeAg positive.
HBV infections that can be treated according to the disclosed methods include HBV genotype A, B, C, and/or D infection. However, in the examples, the disclosed methods can treat any HBV genotype ("pan-genotype treatment"). HBV genotyping can be performed using methods known in the art, e.g.
The methods of treating HBV infection as provided herein, particularly by reducing serum HBV DNA in a patient, by reducing serum HBV RNA in a patient, and/or by reducing HBeAg in a patient.
Thus, in further embodiments, provided herein are methods of reducing serum HBV DNA in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBV DNA in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBV DNA in a patient, comprising administering to a patient in need thereof a
In further embodiments, provided herein are methods of reducing serum HBV DNA in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBV DNA in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBV DNA in a patient, comprising administering to a patient in need thereof a
In further embodiments, provided herein are methods of reducing serum HBV DNA in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBV DNA in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBV DNA in a patient, comprising administering to a patient in need thereof a
In further embodiments, provided herein are methods of reducing serum HBV DNA in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBV DNA in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBV DNA in a patient, comprising administering to a patient in need thereof a
In some embodiments of the methods of reducing serum HBV DNA provided herein, the
In further embodiments, the disclosure relates to a method of reducing serum HBV RNA in a patient comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBV RNA in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBV RNA in a patient, comprising administering to a patient in need thereof a
In further embodiments, provided herein are methods of reducing serum HBV RNA in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBV RNA in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBV RNA in a patient, comprising administering to a patient in need thereof a
In further embodiments, provided herein are methods of reducing serum HBV RNA in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBV RNA in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBV RNA in a patient, comprising administering to a patient in need thereof a
In further embodiments, provided herein are methods of reducing serum HBV RNA in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBV RNA in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBV RNA in a patient, comprising administering to a patient in need thereof a
In some embodiments of the methods of reducing serum HBV RNA provided herein, the
In further embodiments, the disclosure relates to a method of reducing serum HBeAg in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBeAg in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBeAg in a patient, comprising administering to a patient in need thereof a
In further embodiments, provided herein are methods of reducing serum HBeAg in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBeAg in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBeAg in a patient, comprising administering to a patient in need thereof a
In further embodiments, provided herein are methods of reducing serum HBeAg in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBeAg in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBeAg in a patient, comprising administering to a patient in need thereof a
In further embodiments, provided herein are methods of reducing serum HBeAg in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBeAg in a patient, comprising administering to a patient in need thereof a
In another embodiment, provided herein is a method of reducing serum HBeAg in a patient, comprising administering to a patient in need thereof a
In some embodiments of the methods of reducing serum HBeAg provided herein, the
Serum HBV DNA quantification can be performed according to methods known in the art, e.g., using Polymerase Chain Reaction (PCR) based assaysHBV test v2.0 (Ochro diagnostics), which has been validated for different HBV genotypes (A-H), including pronuclear mutant HBV strains, was performed using a WHO mixed serum reference standardQuantitative, reported lower limit of detection was 35IU/mL, and quantitative linear dynamic range was 1.7X 102To 8.5x 108IU/mL IU/mL。
For example, using the investigational Abbott ARCHITECTTMSerum HBsAg and HBeAg levels were measured (Abbott Laboratories, Arbert scientific, Ill., USA).
In another aspect, provided herein is a method of reducing HBV cccDNA formation in a subject infected with HBV or at risk of infection with HBV, comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBV cccDNA formation in a subject infected with or at risk of infection with HBV, comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBV cccDNA formation in a subject infected with or at risk of infection with HBV, comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBV cccDNA formation in a subject infected with or at risk of infection with HBV, comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBV cccDNA formation in a subject infected with or at risk of infection with HBV, comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBV cccDNA formation in a subject infected with HBV or at risk of infection with HBV, comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBV cccDNA formation in a subject infected with or at risk of infection with HBV, comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBV cccDNA formation in a subject infected with or at risk of infection with HBV, comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBV cccDNA formation in a subject infected with HBV or at risk of infection with HBV, comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBV cccDNA formation in a subject infected with or at risk of infection with HBV, comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBV cccDNA formation in a subject infected with or at risk of infection with HBV, comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBV cccDNA formation in a subject infected with HBV or at risk of infection with HBV, comprising administering to the subject a
In an example of a method of reducing the formation of HBV cccDNA, a
In some embodiments of the methods of reducing the formation of HBV cccDNA provided herein, the
In another aspect, provided herein is a method of reducing HBsAg in a subject infected with, or at risk of infection with, HBV, the method comprising administering to the subject a
In embodiments, provided herein are methods of reducing HBsAg in a subject infected with, or at risk of infection with, HBV, the method comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBsAg in a subject infected with, or at risk of infection with, HBV, the method comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBsAg in a subject infected with, or at risk of infection with, HBV, the method comprising administering to the subject a
In embodiments, provided herein are methods of reducing HBsAg in a subject infected with, or at risk of infection with, HBV, the method comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBsAg in a subject infected with, or at risk of infection with, HBV, the method comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBsAg in a subject infected with, or at risk of infection with, HBV, the method comprising administering to the subject a
In embodiments, provided herein are methods of reducing HBsAg in a subject infected with, or at risk of infection with, HBV, the method comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBsAg in a subject infected with, or at risk of infection with, HBV, the method comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBsAg in a subject infected with, or at risk of infection with, HBV, the method comprising administering to the subject a
In embodiments, provided herein are methods of reducing HBsAg in a subject infected with, or at risk of infection with, HBV, the method comprising administering to the subject a
In another embodiment, provided herein is a method of reducing HBsAg in a subject infected with, or at risk of infection with, HBV, the method comprising administering to the subject a
In some embodiments of the method of reducing HBsAg, the
In some embodiments of the methods of reducing HBsAg provided herein, the
In yet another aspect, provided herein is a method of preventing HBV infection in a subject at risk of being infected with HBV by reducing the formation of HBVcccDNA, the method comprising administering to the subject a
In embodiments, provided herein are methods of preventing HBV infection in a subject at risk of being infected with HBV by reducing the formation of HBVcccDNA, comprising administering to the subject a
In another embodiment, provided herein is a method of preventing HBV infection in a subject at risk of being infected with HBV by reducing HBV cccDNA formation, comprising administering to the subject a
In embodiments, provided herein are methods of preventing HBV infection by reducing HBVcccDNA formation in a subject at risk of HBV infection, comprising administering to the subject a
In embodiments, provided herein are methods of preventing HBV infection by reducing HBVcccDNA formation in a subject at risk of HBV infection, comprising administering to the subject a
In another embodiment, provided herein is a method of preventing HBV infection in a subject at risk of being infected with HBV by reducing HBV cccDNA formation, comprising administering to the subject a
In embodiments, provided herein are methods of preventing HBV infection by reducing HBVcccDNA formation in a subject at risk of HBV infection, comprising administering to the subject a
In embodiments, provided herein are methods of preventing HBV infection by reducing HBVcccDNA formation in a subject at risk of HBV infection, comprising administering to the subject a
In another embodiment, provided herein is a method of preventing HBV infection in a subject at risk of being infected with HBV by reducing HBV cccDNA formation, comprising administering to the subject a
In embodiments, provided herein are methods of preventing HBV infection by reducing HBVcccDNA formation in a subject at risk of HBV infection, comprising administering to the subject a
In embodiments, provided herein are methods of preventing HBV infection by reducing HBVcccDNA formation in a subject at risk of HBV infection, comprising administering to the subject a
In another embodiment, provided herein is a method of preventing HBV infection in a subject at risk of being infected with HBV by reducing HBV cccDNA formation, comprising administering to the subject a
In some embodiments of the method of preventing HBV infection by reducing HBV cccDNA formation, the
In some embodiments of the methods provided herein for preventing HBV infection by reducing HBV cccDNA formation, the
In one aspect of the methods provided herein, a particular dosing strategy results in inhibition of DANE particles (DANE particles), RNA-containing particles, and double-stranded DNA particles, but not subviral particles containing HBsAg.
In another aspect of the methods provided herein, the particular dosing strategy results in inhibition of cccDNA, which results in inhibition of subviral particles containing HBsAg.
In some embodiments, the
In an embodiment, the tablet comprises a
In another embodiment, the tablet comprises 50mg to 500mg of the compound having formula 1 (more particularly, at the above dose or daily dose) and 150mg to 1500mg of the stabilizer, more particularly, 50mg to 1500mg of the stabilizer. In another embodiment, the tablet comprises 75mg to 250mg of the compound having formula 1 (more particularly, at the above dose or daily dose) and 225mg to 750mg of the stabilizer, more particularly, 75mg to 750mg of the stabilizer. In another embodiment, the tablet comprises 250mg of the
The tablets of the present application may further comprise one or more agents selected from the group consisting of: fillers, disintegrants, glidants and lubricants. For example, the tablets of the present application may further comprise at least one filler selected from the group consisting of: microcrystalline cellulose, silicified microcrystalline cellulose, and pregelatinized corn starch, at least one disintegrant (e.g., croscarmellose sodium), at least one glidant (e.g., colloidal anhydrous silicon dioxide), and at least one lubricant (e.g., magnesium stearate).
In some embodiments, administration of the
In some embodiments, the co-administration of the
In some embodiments, co-administration of the
In some embodiments, the co-administration of the
In some embodiments, the co-administration of the
In some embodiments, co-administration of a
In some embodiments, administration of compound a is performed for an administration period of about 24 weeks. In another embodiment, administration of compound a is performed for an administration period of longer than 24 weeks. In yet another embodiment, administration of compound a is performed for an administration period of less than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In the examples, compound a was administered for a duration of 28 days. In the examples, compound a was administered for a duration of about 48 weeks. In the examples, compound a was administered for a duration of longer than 48 weeks.
In some embodiments, the co-administration of compound a and the transcription inhibitor is performed for an administration period of about 24 weeks. In another embodiment, administration of compound a and the transcription inhibitor is carried out for an administration period longer than 24 weeks. In yet another embodiment, administration of compound a and the transcription inhibitor is performed for an administration period of less than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In the examples, compound a and a transcription inhibitor were administered for a duration of 28 days. In embodiments, compound a and the transcription inhibitor are administered for a duration of about 48 weeks. In embodiments, compound a and the transcription inhibitor are administered for a duration of longer than 48 weeks.
In some embodiments, co-administration of compound a and the nucleoside (nucleotide) analog is performed for an administration period of about 24 weeks. In another embodiment, the administration of compound a and the nucleoside (nucleotide) analog is carried out for an administration period longer than 24 weeks. In yet another embodiment, the administration of compound a and the nucleoside (nucleotide) analog is performed for an administration period of less than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In the examples, compound a and nucleoside (nucleotide) analogs were administered for a duration of 28 days. In the examples, compound a and nucleoside (nucleotide) analogs were administered for a duration of about 48 weeks. In the examples, compound a and nucleoside (nucleotide) analogs were administered for a duration of longer than 48 weeks.
In some embodiments, the co-administration of compound a and tenofovir is performed for an administration period of about 24 weeks. In another embodiment, the administration of compound a and tenofovir is performed for an administration period longer than 24 weeks. In yet another embodiment, the administration of compound a and tenofovir is performed for an administration period of less than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In the examples, compound a and tenofovir were administered for a duration of 28 days. In the examples, compound a and tenofovir are administered for a duration of about 48 weeks. In the examples, compound a and tenofovir are administered for a duration of longer than 48 weeks.
In some embodiments, the co-administration of compound a and tenofovir alafenamide is performed for an administration period of about 24 weeks. In another embodiment, the administration of compound a and tenofovir alafenamide is performed for an administration period longer than 24 weeks. In yet another embodiment, the administration of compound a and tenofovir alafenamide is performed for an administration period of less than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In the examples, compound a and tenofovir alafenamide were administered for a duration of 28 days. In the examples, compound a and tenofovir alafenamide are administered for a duration of about 48 weeks. In the examples, compound a and tenofovir alafenamide are administered for a duration of longer than 48 weeks.
In some embodiments, co-administration of compound a and entecavir is performed for an administration period of about 24 weeks. In another embodiment, administration of compound a and entecavir is performed for an administration period longer than 24 weeks. In yet another embodiment, administration of compound a and entecavir is performed for an administration period of less than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In the examples, compound a and entecavir were administered for a duration of 28 days. In an embodiment, compound a and entecavir are administered for a duration of about 48 weeks. In the examples, compound a and entecavir are administered for a duration of greater than 48 weeks.
In some embodiments, administration of compound B is performed for an administration period of about 24 weeks. In another embodiment, administration of compound B is performed for an administration period of longer than 24 weeks. In yet another embodiment, administration of compound B is performed for an administration period of less than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In the examples, compound B was administered for a duration of 28 days. In an embodiment, compound B is administered for a duration of about 48 weeks. In the examples, compound B was administered for a duration of longer than 48 weeks.
In some embodiments, the co-administration of compound B and the transcription inhibitor is performed for an administration period of about 24 weeks. In another embodiment, administration of compound B and the transcription inhibitor is carried out for an administration period longer than 24 weeks. In yet another embodiment, administration of compound B and the transcription inhibitor is performed for an administration period of less than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In the examples, compound B and the transcription inhibitor were administered for a duration of 28 days. In embodiments, compound B and the transcription inhibitor are administered for a duration of about 48 weeks. In embodiments, compound B and the transcription inhibitor are administered for a duration of longer than 48 weeks.
In some embodiments, co-administration of compound B and the nucleoside (nucleotide) analog is performed for an administration period of about 24 weeks. In another embodiment, the administration of compound B and the nucleoside (nucleotide) analog is carried out for an administration period longer than 24 weeks. In yet another embodiment, administration of compound B and the nucleoside (nucleotide) analog is performed for an administration period of less than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In the examples, compound B and nucleoside (nucleotide) analogs were administered for a duration of 28 days. In the examples, compound B and nucleoside (nucleotide) analogs were administered for a duration of about 48 weeks. In the examples, compound B and nucleoside (nucleotide) analogs were administered for a duration of longer than 48 weeks.
In some embodiments, the co-administration of compound B and tenofovir is performed for an administration period of about 24 weeks. In another embodiment, the administration of compound B and tenofovir is performed for an administration period longer than 24 weeks. In yet another embodiment, the administration of compound B and tenofovir is performed for an administration period of less than 24 weeks (e.g. 10, 12, 14, 16, 18, 20, or 22 weeks). In the examples, compound B and tenofovir were administered for a duration of 28 days. In the examples, compound B and tenofovir were administered for a duration of about 48 weeks. In the examples, compound B and tenofovir were administered for a duration of longer than 48 weeks.
In some embodiments, the co-administration of compound B and tenofovir alafenamide is performed for an administration period of about 24 weeks. In another embodiment, the administration of compound B and tenofovir alafenamide is performed for an administration period longer than 24 weeks. In yet another embodiment, the administration of compound B and tenofovir alafenamide is performed for an administration period of less than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In the examples, compound B and tenofovir were administered for a duration of 28 days. In the examples, compound B and tenofovir alafenamide were administered for a duration of about 48 weeks. In the examples, compound B and tenofovir were administered for a duration of longer than 48 weeks.
In some embodiments, co-administration of compound B and entecavir is performed for an administration period of about 24 weeks. In another embodiment, administration of compound B and entecavir is performed for an administration period longer than 24 weeks. In yet another embodiment, administration of compound B and entecavir is performed for an administration period of less than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In the examples, compound B and entecavir were administered for a duration of 28 days. In an embodiment, compound B and entecavir are administered for a duration of about 48 weeks. In the examples, compound B and entecavir were administered for a duration of longer than 48 weeks.
In some embodiments of the methods provided herein, the
In embodiments of the methods provided herein, the
In embodiments of the methods provided herein, compound a is administered such that a maximum concentration (Cmax) of at least 3,000ng/mL in the patient's plasma is achieved, and/or an AUC of at least 50,000ng h/mL in the patient's plasma is achieved.
In embodiments of the methods provided herein, compound B is administered such that a maximum concentration (Cmax) of at least 3,000ng/mL in the patient's plasma is achieved, and/or an AUC of at least 50,000ng h/mL in the patient's plasma is achieved.
The daily doses described herein are calculated for an average body weight of about 60kg to about 70kg and should be recalculated in the case of pediatric applications, or when used for patients with substantially deviating body weights.
Pharmaceutical composition and kit
In one aspect, provided herein is a pharmaceutical composition comprising a
In another aspect, the present disclosure provides a pharmaceutical product comprising a pharmaceutical composition comprising a
In an embodiment of the pharmaceutical composition, the composition further comprises at least one stabilizer. In some embodiments of the pharmaceutical composition, the one or more stabilizing agents are selected from HPMC (e.g., HPMC E5) or HPMC-AS. In embodiments, at least one of these stabilizers is HPMC (e.g., HPMC E5). In embodiments, at least one of these stabilizers is HPMC-AS.
In an embodiment of the pharmaceutical composition, the tablet comprises the
In another embodiment of the pharmaceutical composition, the composition comprises 50mg to 500mg of the
The pharmaceutical composition may be formulated as a solid formulation, such as a tablet, pill or capsule, or as a liquid formulation, such as a polyethylene glycol solution.
The pharmaceutical composition may be formulated for oral administration.
In another aspect, the present disclosure provides a kit of parts for treating HBV infection, comprising a
In some embodiments, the kit of parts comprises a pharmaceutical composition comprising a
For example, the additional HBV antiviral agent may be an immunomodulatory agent (e.g., an interferon), at least one nucleic acid polymer (more particularly, at least one NAP that inhibits the release of subviral particles from hepatocytes), or at least one small interfering RNA (siRNA) or antisense oligonucleotide (more particularly, at least one siRNA or ASO selected from the group consisting of siRNA and ASO that inhibits the expression of one or more genes essential for replication or pathogenesis of HBV).
In another embodiment, the kit of parts comprises a pharmaceutical product comprising:
a pharmaceutical composition comprising a compound having formula 1:
or a pharmaceutically acceptable salt thereof,
wherein:
a is N or CH;
at each occurrence, R1Independently selected from halo, CF3And CN;
R2is C1-C3An alkyl group;
at each occurrence, R3Independently selected from C1-C3Alkyl and halo;
R4is independently halogenated or CF3C substituted 1 or 2 times1-C4An alkyl group;
n is 0, 1, 2 or 3; and is
M is 0, 1, or 2;
an amount of from 50mg to 500mg (more particularly, at the above dose or daily dose), and a pharmaceutically acceptable carrier or diluent; and
nucleoside (nucleotide) analogs;
a sealed container for containing the pharmaceutical composition;
a sealed container for containing the nucleoside (nucleotide) analog; and
instructions for use.
In further embodiments, a pharmaceutical kit is provided. The kit comprises a sealed container approved for storage of pharmaceutical compositions, the container containing one of the above-described pharmaceutical compositions. In some embodiments, the sealed container minimizes air contact with the composition, such as a vacuum bottle. In other embodiments, the sealed container is a sealed tube. Instructions for using the composition and information about the composition are also included in the kit.
In some embodiments of the kits of parts provided herein, the
or a pharmaceutically acceptable salt thereof.
In other embodiments of the kits provided herein, the
or a pharmaceutically acceptable salt thereof.
The following examples are illustrative only and are not intended to limit the disclosure to the materials, conditions, or process parameters set forth herein.
Examples of the invention
Example 1: safety, pharmacokinetics and antiviral activity of Compound A in treatment naive patients with chronic HBV
In
In
HBeAg positive or negative
Plasma HBV DNA > 2.0log10IU/mL
·ALT/AST＜2.5x ULN
METAVIR phase < F3.
1.1 patient Baseline characteristics
The baseline characteristics of the patients in this study are described in table 1 below.
Table 1: baseline patient characteristics
Studies have shown that there are no Serious Adverse Events (SAE) or Adverse Events (AE) of clinical concern and no treatment discontinuation. In addition, no patients showed clinically significant changes in ECG or persistent/worsening vital sign abnormalities (see table 2 below). Although none of the patients had
Table 2: assessment of adverse events
1.2 pharmacokinetics
Figure 2 shows that in both treatment arms, the pharmacokinetics is dose proportional and apparent clearance is low. Exposure (Cmax, AUC) increased in a dose-dependent manner with time-linear PK. The pharmacokinetics of compound a did not differ significantly between healthy volunteers and patients. The mean compound a exposure in patients with CHB can be predicted from data in healthy volunteers. Mean (± SD) exposures in 75mg arms were within the 90% prediction interval. The mean dose normalized Cmax at steady state was 56.6ng/mL (25mg) and 53.2ng/mL (75 mg). For the 25mg and 75mg groups, the mean dose normalized AUC 0-24h was 1109 ng.h/mL. In both dosing groups, apparent clearance was low and similar (1L/h and 0.9L/h at 25mg and 75mg, respectively).
1.3 HBV reduction
HBV DNA was assessed weekly for each patient during this study (see figure 3). After 28 days, a mean 2.16 (+ -0.49 SD) log reduction in plasma HBV DNA levels from baseline was observed10IU/mL (25mg of Compound A) and 2.89 (+ -0.48 SD) log10IU/mL (75mg of Compound A). Three patients dosed with 75mg QD achieved levels below quantification of HBV DNA assay, while none achieved this level in the 25mg compound a group. In the 75mg group, more significant and consistent HBV DNA was observed in the patients compared to the 25mg group And (5) reducing. In line with HBV DNA, substantial reduction in HBV RNA levels was observed with compound a treatment despite low baseline levels (see table 3 below).
Table 3: HBV DNA and RNA analysis
1.4 conclusion
In both dose groups (n-24), patients had a median age of 36 years (range: 21-58 years), of which 88% were male and 75% caucasian. Overall, 38% of patients were HBeAg positive and the mean (± SD) baseline HBV DNA was 5.88(± 1.82) log10 IU/mL. AE grade > 3 or laboratory abnormalities were rare (< 2 patients/dose). During treatment, 56% (9/16) of patients treated with compound a experienced at least one Adverse Event (AE) (5 patients in 25mg arm, and 4 patients in 75mg arm) compared to 63% (5/8) in placebo arm. There were no serious AEs, no discontinuations due to AEs, and no dose-limiting toxicity. After 28 days, a mean (± SD) reduction in HBV DNA levels from baseline of 2.16(± 0.49) log10IU/mL (25mg QD) and 2.89(± 0.48) log10IU/mL (75mg QD) was observed. Three patients dosed with 75mg QD achieved a level of quantitation below the HBV DNA assay, but patients not dosed with 25mg QD achieved sub-quantitative HBV DNA. In addition, a decrease in HBV RNA levels was observed in both compound a treated groups; although the reduction of HBV RNA in the 25mg group was higher than in the 75mg group, more patients in 75mg (n-6) compared to the 25mg group (n-3) achieved HBV RNA at quantitative levels lower than that of HBV RNA assay.
Example 2: safety, tolerability and pharmacokinetics of single ascending doses of compound a in healthy subjects
A double-blind placebo-controlled study was conducted to evaluate the safety, tolerability, and Pharmacokinetics (PK) of compound a. Thirty-two healthy adult Japanese volunteers were randomized into four groups. Volunteers were randomized 3: 1 and received a single dose of compound a or placebo in the fasted state (see figure 4). After each dose, compound a was evaluated for safety, tolerability, and PK plasma profile. Complete plasma PK profiles were determined up to 28 days after each single dose of compound a. Urine elimination was evaluated in group C for 7 days (see fig. 4).
2.1 baseline characteristics of healthy volunteers
The baseline characteristics of the subjects are summarized in table 4 below.
Table 4: baseline patient characteristics
Compound a is well tolerated. No volunteers underwent SAE, or the study was discontinued prematurely because of AE. Reported Treatment Emergent Adverse Events (TEAEs) were hiccups, upper respiratory tract infections, nasal congestion, and coughing. All TEAEs were mild and all resolved before the end of the study. AE is summarized in table 5 below.
Table 5: adverse events
No significant laboratory abnormalities were found, most of which were
Table 6: laboratory abnormalities
2.2 pharmacokinetics
In all four treatment groups, PK was dose dependent. PK data are summarized in figure 5 and table 7 below. CL/F, Vd/F and T1/2term were comparable between dose levels. Inter-subject variability (expressed as% CV) was low to moderate and similar between dose levels. In group C, 53.9mg of the unaltered drug was excreted in the urine after a single dose administration of 300mg of Compound A. Compound a is a low clearance drug, with 18% of the administered dose excreted via the kidney.
Table 7: pharmacokinetics
Example 3: formulations of Compound A
The quantitative and qualitative composition of compound a 250mg/G spray-dried powder (G001) is provided in table 8 below.
The qualitative and quantitative compositions of compound a 100-mg (G009)25-mg (G008) and 5-mg (G007) oral tablets are provided in table 9 below.
The quantitative and qualitative composition of compound a 250mg/G spray dried powder (G021) is provided in table 10 below.
The qualitative and quantitative composition of compound a 100-mg (G022) oral tablets is provided in table 11 below.
Table 11: qualitative and quantitative composition of Compound A100-mg oral tablet (G022), 100-mg oral tablet (G024), and 25-mg oral tablet (G025)
aPlant grade
Example 4: bioavailability of tablets G009 and G022
A
Tablet G009 or tablet G022 (see, tablets 10 and 11 of example 3 above) was administered as a 300-mg single oral dose in healthy adult subjects under fasting and fed conditions. A total of 28 subjects were enrolled in the study and divided into 2 groups on average (14 subjects/group).
In part I of the study, all subjects in one group (n ═ 14) received a single oral 300-mg dose of the compound of formula (1) (formulated as a 3x100-mg test tablet in treatment period 1) (tablet G022, treatment a) followed by a single oral 300mg dose of the compound of formula (1) (formulated as a 3x100-mg tablet in treatment period 2) (tablet G009, treatment B). On
In part I, study drug intake in individual subjects for
In part II, all subjects in one group (n ═ 14) received a single oral 300-mg dose of the compound of formula (1) formulated as a 3x100-mg G022 tablet in treatment phase 1 (treatment C). On
The complete Pharmacokinetic (PK) profile of the compound of formula (a) was determined approximately 864 hours (37 days) after drug administration of the compound of formula (a) on
Table 12:
table 13: effect of the formulations
Geometric mean number
aFor Cmax，n＝13
Table 14: effects of food
aFor CmaxAnd AUC72h，n＝14
Table 15:
Cmaxthe maximum analyte concentration observed;
tmaxactual sampling time to reach the maximum observed analyte concentration;
Clastlast observed measurable (not less than quantitative limit [ non-BQL ]]) Plasma analyte concentration;
tlast(non-BQL) plasma analyte concentrations can be measured last;
AUC72harea under analyte concentration-time curve (AUC) from
AUClasttime from
AUC∞area under the analyte concentration-time curve from
t1/2apparent terminal elimination half-life, calculated as 0.693/λz；
λzAn apparent terminal elimination rate constant, estimated by linear regression using the terminal log linear phase of the log-transformed concentration-time curve;
CL/F Total apparent oral clearance, calculated as dose/AUC∞；
VdzVolume of apparent distribution,/F, calculated as dose/(λ)z*AUC∞)。
Non-compartmental analysis (model type: plasma [200- > 202], administration type: extravascular) was applied to the PK analysis. In addition, SAS (version 9.3, SAS Institute Inc., california, north carolina, usa) was used for PK table generation.
Effect of the preparation (G022 comparative G009)
At a 300mg dose, both under fasting conditions, tablet G022 provided a 1.49-fold higher Cmax compared to tablet G009, based on the geometric mean ratio. AUC72h, AUClast, and AUC ∞ were similar for both tablet formulations (90% CI of the geometric mean ratio was within 80% -125%).
Median tmax was the same for tablet G022(3.00 hours) and tablet G009(2.99 hours) under fasting conditions.
In the fasted state, mean t1/2 was 124.6 hours for tablet G022 and mean t1/2 was 142.2 hours for tablet G009.
Effects of food
Based on the geometric mean ratio between the intake of tablet G022 under fed and fasted conditions, Cmax, AUClast, and AUC ∞ were all reduced appropriately after intake (19.82%, 8.81% and 9.79% respectively) under fed conditions, while AUC72h was similar (300 mg-dose) for both treatments. The lower limit of 90% CI of the geometric mean ratio of Cmax, AUClast, and AUC ∞ falls below 80%. In
For tablet G022, median tmax appeared later under fed conditions (3.00 and 4.00 hours after dosing, respectively) compared to administration under fasting conditions.
Under fasting and fed conditions, after the intake of tablet G022, the mean t1/2 was within the same range, with values of 124.6 hours (fasting) and 95.7 hours (fed).
Example 5: bioavailability of tablets G009 and G024
The protocol for the bioavailability study that has been described for tablets G009 and G022 (in example 4 above) can be applied to tablets G009 and G024.
Example 6:
the primary objective was to assess the oral bioavailability of compound a in healthy adult subjects when administered as follows: under fasting and fed conditions, e.g., as a single dose of 150mg, consisting of 6x25-mg oral tablets; and under fasting conditions, e.g. in a single dose of 300mg, consisting of 3x100-mg oral tablets.
In healthy adult subjects, part I was performed to assess the bioavailability of a new 25mg oral tablet of compound a under fasting and fed conditions, and the bioavailability of a new 100mg oral tablet of compound a under fasting conditions. During
On
In part I, 16 healthy adult subjects were included. Following treatment a (150mg compound a, fed) in
Healthy male and female subjects who meet the following criteria are eligible for enrollment for the study: age between 18 and 55 years (including 18 and 55), Body Mass Index (BMI) between 18.0kg/m2 and 30.0kg/m2 (limits included), and body weight no less than 50.0 kg. The subjects must be healthy based on medical and surgical history, physical examination, 12-lead Electrocardiogram (ECG), vital signs and clinical laboratory tests performed at the time of screening. Male and female subjects must adhere to contraceptive requirements as specified by the regimen.
Table 16:
The study consisted of: screening phase, admission phase, treatment phase, and follow-up phase (post-treatment phase). During the follow-up period, subjects returned to the study site for follow-up 10-14 days and 30-35 days after study drug administration for the last treatment period. The duration of each treatment period was 33 ± 3 days and the study duration for each individual subject was at least 61 days (including the admission and follow-up periods), excluding the screening period.
Research population
A total of 16 subjects were enrolled and received treatment a in
Table 17:
table 18:pharmacokinetic results
Food effect
Statistics comparing PK of compound a between treatment a and treatment B (food effect) are presented in the table below.
Table 19:
based on the geometric mean ratio between treatment a (fed, test, n ═ 16) and treatment B (fasted, reference, n ═ 8), Cmax was 14.2% (GMR, 85.8%; 90% CI, 77.0-95.7%) lower under fed conditions, while AUClast and AUC ∞ were similar under fasted or fed conditions. The upper limit of 90% CI for the geometric mean ratio of Cmax drops below 100%.
Effect of tablet Strength
Statistics comparing dose normalized PK parameters for compound a between treatment B and treatment C (effect of tablet strength) are presented in the table below.
Table 20:
the geometric mean ratio between treatment C and treatment B based on dose normalized PK parameters was 21.6% (GMR, 78.4%; 90% CI, 67.4-91.2%) lower for 100mg tablet strength compared to 25mg tablet strength. The upper limit of 90% CI for the geometric mean ratio of Cmax drops below 100%. AUClast and AUC ∞ are similar under fasting or fed conditions.
When 150mg of compound was administered as a 6x25mg oral tablet, the median (range) tmax was 1.75(1.00-3.00) hours, and when 300mg of compound a was administered as a 3x100mg oral tablet, the median (range) tmax was 3.00(1.00-4.02) hours.
The median (range) t1/2term was similar between treatments. For treatments A, B, and C, the values varied between subjects, namely 134.3(65.7-221.6) hours, 123.9(72.3-195.7) hours, and 161.1(111.5-257.3), respectively.
Clearance (CL/F) varied between 0.47L/h and 1.55L/h for all treatments and individuals.
Example 7: therapeutic exploratory phase II study on Compound A in patients with chronic HBV infection
A double-blind placebo-controlled study was performed to evaluate the efficacy of compound a treatment (alone or in combination with a nucleoside analogue) for 24 weeks in terms of changes in hepatitis b surface antigen (HBsAg) levels.
7.1 patient Baseline characteristics
Naive adult patients with chronic HBV infection were randomized into groups for study.
7.2 administration and combination
Compound a was administered by oral administration at 250 mg/day in a tablet formulation. Compound a is administered alone or in combination with a nucleoside analog. Nucleoside analogues are tenofovir disoproxil fumarate (virreed, girlidd science (Gilead Sciences International)) administered at 300 mg/day by oral administration, or entecavir monohydrate (Bristol-Myers Squibb Pharma) administered at 0.5 mg/day by oral administration, film-coated tablet by oral administration, by oral administration.
7.3 results
This study evaluated the safety and tolerability of 24 weeks of study treatment. Efficacy was evaluated in the following respects: an alteration in the level of HBsAg, an HBV DNA level, an alteration in the level of HBeAg (in HBeAg positive subjects only), and HBsAg (in all subjects) or HBeAg (in HBeAg positive subjects only) sero clearance and/or sero conversion. This study also evaluated the frequency of subjects with biochemical responses and HBV virological breakthrough. This study also evaluated the potential effect of compound a on the pharmacokinetics of nucleoside (nucleotide) analogs (NA) when co-administered. This study also evaluated the pharmacokinetics of compound a when administered as monotherapy. This study also evaluated the potential effect of NA on the pharmacokinetics of compound a when co-administered. This study evaluated the change in HBV genomic sequence following treatment with compound a (alone or in combination with NA).
Finally, this study evaluated the synergistic effect of compound a and NA. Synergy, additivity, and antagonism were assessed using the Pritchard and Shipman models. The synergy or antagonism of the concentration combination was determined based on the following 2 rules: first, the 95% CI of the mean difference between the observed and predicted fractions of inhibition at each concentration combination was calculated. If the lower limit of 95% CI is greater than zero, the drug combination will be considered to have a synergistic effect; if the upper limit of 95% CI is less than zero, the drug combination will be considered to have an antagonistic effect; in addition, there was no significant antagonism or synergy at this combination of concentrations. Second, the synergistic or antagonistic effect must have its relative mean difference divided by its corresponding observed mean inhibition of greater than 1%. By doing so, small differences of statistical significance caused by very small variances can be excluded.
The disclosure of each and every patent, patent application, and publication cited herein is hereby incorporated by reference in its entirety.
While the invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of the invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. It is intended that the following claims be interpreted to embrace all such embodiments and equivalents.
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