WO2021092554A1

WO2021092554A1 - Pharmaceutical compositions and methods for treating hbv disorders

Info

Publication number: WO2021092554A1
Application number: PCT/US2020/059666
Authority: WO
Inventors: Richard J. Colonno
Original assignee: Assembly Biosciences, Inc.
Priority date: 2019-11-08
Filing date: 2020-11-09
Publication date: 2021-05-14

Abstract

Provided herein are methods of treating hepatitis B in a subject by administering daily to the subject for example, about 100 mg or a dosage amount as disclosed herein of a compound represented by: Formula (I).

Description

PHARMACEUTICAL COMPOSITIONS AND METHODS FOR TREATING HBV DISORDERS

Cross Reference to Related Applications

[0001] This application claims the benefit of, and priority to, U.S. provisional patent application serial number 62/932,909, filed November 8, 2019, and U.S. provisional patent application serial number 63/020,914, filed May 6, 2020, each of which are hereby incorporated by reference herein in their entirety.

Background

[0002] Hepatitis B (HBV) causes viral hepatitis that can further lead to chronic liver disease and increase the risk of liver cirrhosis and liver cancer (hepatocellular carcinoma). Worldwide, about 2 billion people have been infected with HBV, around 360 million people are chronically infected, and every year HBV infection causes more than one half million deaths (2009; WHO, 2009). HBV can be spread by body fluids: from mother to child, by sex, and via blood products. Children bom to HBV -positive mothers may also be infected, unless vaccinated at birth.

[0003] The vims particle is composed of a lipid enveloped studded with surface protein (HBsAg) that surrounds the viral core. The core is composed of a protein shell, or capsid, built of 120 core protein (Cp) dimers, which in turn contains the relaxed circular DNA (rcDNA) viral genome as well as viral and host proteins. In an infected cell, the genome is found as a covalently closed circular DNA (cccDNA) in the host cell nucleus. The cccDNA is the template for viral RNAs and thus viral proteins. In the cytoplasm, Cp assembles around a complex of full-length viral RNA (the so-called pregenomic RNA or pgRNA and viral polymerase (P). After assembly, P reverse transcribes the pgRNA to rcDNA within the confines of the capsid to generate the DNA-filled viral core. For convenience, we divide the assembly process at the point of capsid assembly and pgRNA-packaging. Steps preceding this event are "upstream"; steps following RNA-packaging are "downstream".

[0004] At present, chronic HBV is primarily treated with nucleos(t)ide analogs (e.g. entecavir) that suppress the vims while the patient remains on treatment but do not eliminate the infection, even after many years of treatment. Once a patient starts taking nucleotide analogs most must continue taking them or risk the possibility of a life threatening immune response to viral rebound. Further, nucleos(t)ide therapy may lead to the emergence of antiviral drug resistance (Deres and Rubsamen-Waigmann, 1999; Tennant et al., 1998; Zhang et al, 2003) and - in rare Subjects- adverse events have been reported (Ayoub and Keeffe , 2011).

[0005] The only FDA approved alternative to nucleos(t)ide analogs is treatment with interferon a or pegylated interferon a. Unfortunately, the adverse event incidence and profile of interferon a can result in poor tolerability, and many Subjects are unable to complete therapy. Moreover, only a small percentage of Subjects are considered appropriate for interferon therapy, as only a small subset of subjects are likely to have a sustained clinical response to a course of interferon therapy. As a result, interferon based therapies are used in only a small percentage of all diagnosed Subjects who elect for treatment.

[0006] Thus, current HBV treatments can range from palliative to watchful waiting. Nucleos(t)ide analogs suppress virus production, treating the symptom, but leave the infection intact. Interferon a has severe side effects and less tolerability among subjects and is successful as a finite treatment strategy in only a small minority of subjects. There is a clear on-going need for more effective treatments for HBV infections.

Summary

[0007] Provided herein, in part, are methods of treating hepatitis B in a subject in need thereof, the method comprising administering daily to the subject for example, about 100 mg or about 300 mg or a dosage amount as disclosed herein, of a compound represented by:

(also referred to as Compound 1) or a pharmaceutically acceptable salt thereof.

[0008] In some aspects, the method comprises administering 300 mg of Compound 1.

[0009] Also provided herein is a method of treating hepatitis B in a subject in need thereof, the method comprising administering daily to the subject a composition comprising for example, about 100 mg or about 300 mg, or a dosage amount as disclosed herein, of a compound represented by:

(also referred to as Compound 1) or a pharmaceutically acceptable salt thereof.

Brief Description of the Drawings [0010] FIG. 1 depicts the study design.

[0011] FIG. 2 depicts baseline demographic and disease characteristics for Cohort 1.

[0012] FIG. 3 depicts the treatment-emergent adverse effects (TEAEs) for Cohort 1. [0013] FIG. 4 depicts the number of subjects with treatment-emergent laboratory abnormalities.

[0014] FIG. 5 depicts the pharmacokinetics at day 14 for Cohort 1.

[0015] FIG. 6 depicts the pharmacokinetics at day 14 for Cohort 1.

[0016] FIG. 7 depicts the HBV DNA change from baseline in Cohort 1. [0017] FIG. 8 depicts HBV pgRNA change from baseline for Cohort 1.

Detailed Description

[0018] As generally described herein, the present disclosure provides methods of treating hepatitis B in a subject in need thereof, by forexample, administering daily to the subject for example, about 100 mg or a dosage amount as disclosed herein of a compound represented by:

(also referred to as Compound 1) or a pharmaceutically acceptable salt thereof.

Definitions

[0019] The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

[0020] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0021] “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g ., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N- methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term “pharmaceutically acceptable cation” refers to an acceptable cationic counter ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g, Berge, etal, ./. Pharm. Sci. (1977) 66(1): 1-79.

[0022] The term “prodrug” is intended to encompass compounds that, under physiological conditions, are converted into the therapeutically active agents of the present disclosure. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the subject.

[0023] The term “AUC” refers to the area under the time/plasma concentration curve after administration of the pharmaceutical composition. AUCO-infmity denotes the area under the plasma concentration versus time curve from time 0 to infinity; AUCO-t denotes the area under the plasma concentration versus time curve from time 0 to time t. As used herein, AUCO-t is the area under the plasma concentration versus time curve from the time of dosing to the last quantifiable concentration. It should be appreciated that AUC values can be determined by known methods in the art.

[0024] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. [0025] The term “Cmax” refers to the maximum concentration of a therapeutic agent (e.g. Compound 1) in the blood (e.g. plasma) following administration of the pharmaceutical composition.

[0026] The term “tmax” refers to the time in hours when Cmax is achieved following administration of the pharmaceutical composition comprising the therapeutic agent (e.g. Compound 1).

[0027] As used herein, “solid dosage form” means a pharmaceutical dose(s) in solid form, e.g. tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewables.

[0028] Where the use of the term “about” is before a quantitative value, the present teachings also include the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred.

[0029] Disease, disorder, and condition are used interchangeably herein.

[0030] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”).

[0031] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat hepatitis B. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.

[0032] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. [0033] As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0034] Viraemic infection refers to Hepatitis B infection associated with presence of virus in the blood (as measured by HBV DNA), and often referred to as active, ongoing or current infection.

Compounds

[0035] In some embodiments, provided herein is a compound represented by:

(also referred to as Compound 1) or a pharmaceutically acceptable salt thereof, for the treatment of hepatitis B in a subject. In some embodiments, hepatitis B is chronic hepatitis B. [0036] In some embodiments, a pharmaceutical composition comprises Compound 1 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In other embodiments, a composition comprises Compound 1 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0037] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject an effective amount of a Compound 1 or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 25 mg to about 50 mg, about 50 mg to about 75 mg, about 75 mg to about 100 mg, about 100 mg, about 90 mg to about 110 mg, about 95 mg to about 115 mg, about 100 mg to about 120 mg, about 90 mg to about 120 mg, about 225mg, about 250 mg, about 275mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400mg, about 425mg, or about 450mg or more, e.g. daily, of Compound 1 or a pharmaceutically acceptable salt thereof, and optionally administering a therapeutically effective amount of a nucleos(t)ide inhibitor such as contemplated herein.

[0039] For example, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 300 mg to about 500mg, e.g., about 225mg, about 250 mg, about 275mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400mg, about 425mg, or about 450mg or more, e.g. daily 300 mg of Compound 1 or a pharmaceutically acceptable salt thereof .

[0040] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof. [0043] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 75 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 125 mg of Compound 1 or a pharmaceutically acceptable salt thereof. [0046] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 130 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject 300 mg of Compound 1 or a pharmaceutically acceptable salt thereof

[0048] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 275 mg to about 300 mg of Compound 1 or a pharmaceutically acceptable salt thereof .

[0049] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 290 mg to about 325 mg of Compound 1 or a pharmaceutically acceptable salt thereof .

[0050] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 90 mg to about 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof. [0051] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 225 mg to about 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof. [0052] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 250 mg to about 300 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 300 mg to about 350 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 280 mg to about 300 mg of Compound 1 or a pharmaceutically acceptable salt thereof. [0055] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 280 mg to about 320 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 300 mg to about 325 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 325 mg to about 350 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 350 mg to about 375 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 375 mg to about 400 mg of Compound 1 or a pharmaceutically acceptable salt thereof. [0060] In some embodiments, provided herein are methods of treating hepatitis B in a subject in need thereof, comprising administering to the subject about 400 mg to about 425 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0061] Exemplary compounds of the disclosure may be synthesized from the following known starting materials using methods known to one skilled in the art or certain references. Pharmaceutical Compositions

[0062] In one aspect, provided herein is a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound disclosed herein is provided in an effective amount in the pharmaceutical composition (e.g. 300 mg of Compound 1). In certain embodiments, the compound of the present disclosure is provided in a therapeutically effective amount. In some embodiments, the Compound 1 is provided in a composition in an amount of about 25 mg to about 50 mg; about 35 mg to about 60 mg; about 40 mg to about 70 mg; about 50 mg to about 75 mg; about 60 mg to about 80 mg; about 70 mg to about 90 mg; about 80 mg to about 100 mg; about 90 mg to about 100 mg; about 90 mg to about 110 mg; about 100 mg to about 110 mg; about 100 mg to about 110 mg about 150 mg to about 200 mg; about 200 mg to about 225 mg; about 200 mg to about 250 mg; about 300 mg to about 320 mg; about 300 mg to about 350 mg; about 280 mg to about 300 mg; about 280 mg to about 320 mg; about 300 mg to about 325 mg; about 325 mg to about 350 mg; about 350 mg to about 375 mg; about 375 mg to about 400 mg; about 400 mg to about 425 mg; and about 425 mg to about 450 mg. In some embodiments, the Compound 1 is provided in a pharmaceutical composition in an amount of about 150 mg to about 200 mg; about 200 mg to about 225 mg; about 200 mg to about 250 mg; about 300 mg to about 320 mg; about 300 mg to about 350 mg; about 280 mg to about 300 mg; about 280 mg to about 320 mg; about 300 mg to about 325 mg; about 325 mg to about 350 mg; about 350 mg to about 375 mg; about 375 mg to about 400 mg; about 400 mg to about 425 mg; and about 425 mg to about 450 mg.

[0063] It should be appreciated that “a pharmaceutical composition” could comprise one oral dose form, two oral dose forms, three oral dose forms, four oral dose forms, etc. For example, a pharmaceutical composition could comprise 100 or 300 mg of Compound 1, but be contained in two oral dose forms (e.g., two tablets or capsules with 50 or 150 mg each).

[0064] The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

[0065] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

[0066] The pharmaceutical compositions provided herein can also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc, or may be continued indefinitely, for example, for the rest of the subject’s life. In certain embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.

[0067] The pharmaceutical compositions of the present disclosure may be further delivered using a variety of dosing methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject’s body. Furthermore, in still yet other embodiments, the pharmaceutical composition may be administered as first as a bolus dose, followed by continuous infusion.

[0068] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.

[0069] Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, preservatives, lubricants and the like, as suited to the particular dosage form desired, e.g., injection. General considerations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0070] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, response of the individual patient, the severity of the patient’s symptoms, and the like.

[0071] Contemplated compositions may be presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre measured ampules or syringes of the liquid compositions. In such compositions, the compound is usually a minor component (from about 0.1% to about 50% by weight or preferably from about 1% to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0072] The compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents. In one aspect, the present disclosure provides a combination of a compound of the present disclosure and another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternating administration.

[0073] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005.

Methods of Use and Treatment

[0074] Provided herein are methods of treating hepatitis B (HBV). Provided herein are methods of treating an acute HBV infection (or a new infection). An acute hepatitis B infection may last up to six months (with or without symptoms) and infected persons are able to pass the virus to others during this time. Provided herein are methods of treating chronic HBV, which is defined as a condition where the virus is not eliminated after six months. Subjects who test positive for the persistence of HBsAg for more than six months (after their first blood test result) are diagnosed as having a chronic HBV infection.

[0075] Subjects may be diagnosed with HBV by the results from a serological assay, which is an assay that detect the presence of either antigens or antibodies, typically in serum or plasma but also in capillary/venous whole blood and oral fluid. These include rapid diagnostic tests (RDTs), and laboratory-based immunoassays, e.g. enzyme immunoassays (EIAs), chemiluminescence immunoassays (CLIAs), and electrochemiluminescence immunoassays (ECLs). A positive or reactive Hepatitis B surface antigen HBsAg test result means that the subject is infected with hepatitis B. This test can detect the actual presence of the hepatitis B virus (called the “surface antigen”) in blood. If a person tests positive, then further testing would be needed to determine if this is a new acute infection or a chronic hepatitis B infection. A positive HBsAg test result means that the subject is infected and can spread the hepatitis B virus to others through blood.

[0076] A positive or reactive anti-HBs (or HBsAb) (Hepatitis B surface antibody) test result indicates that a subject is protected against the hepatitis B virus. This protection can be the result of receiving the hepatitis B vaccine or successfully recovering from a past hepatitis B infection. A positive anti-HBs (or HBsAb) test result means the subject is immune and protected against the hepatitis B virus and cannot be infected. [0077] A positive or reactive anti-HBc (or HBcAb) (Hepatitis B core antibody) test result indicates a past or current hepatitis B infection. The core antibody does not provide any protection against the hepatitis B virus (unlike the surface antibody described above).

[0078] A positive test for the hepatitis B e-antigen (HBeAg), a protein from the hepatitis B virus that circulates in blood, indicates that there is an active infection with the hepatitis B virus and the virus is actively multiplying.

[0079] HBV DNA and HBV RNA are HBV viral genomes that can be detected and quantified in serum by nucleic acid testing (NAT). Serum HBV DNA and HBV RNA is measured in international units (IU)/mL as the recognized international standard or copies/ml by nucleic acid testing (NAT) technologies.

[0080] In some embodiments, provided herein are methods treating hepatitis B in a subject by administering daily to the subject for example, about 100 mg or a dosage amount as disclosed herein of Compound 1 or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, before the subject is administered Compound 1, it is determined that the subject has detectable levels of hepatitis B viral DNA prior to administration. In some embodiments, before the subject is administered Compound 1, it is determined that the subject is positive for the hepatitis B e-antigen (HBeAg) prior to administration.

[0082] In some embodiments, the subject is HBeAg negative prior to daily administration.

[0083] In some embodiments, provided herein are methods treating hepatitis B in a subject by administering daily for at least 4 weeks to the subject for example, about 300 mg or a dosage amount as disclosed herein of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods treating hepatitis B in a subject by administering daily for at least 8 weeks to the subject for example, about 300 mg or a dosage amount as disclosed herein of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods treating hepatitis B in a subject by administering daily for at least 12 weeks to the subject for example, about 300 mg or a dosage amount as disclosed herein of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods treating hepatitis B in a subject by administering daily for at least 16 weeks to the subject for example, about 300 mg or a dosage amount as disclosed herein of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods treating hepatitis B in a subject by administering daily for at least 24 weeks to the subject for example, about 300 mg or a dosage amount as disclosed herein of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods treating hepatitis B in a subject by administering daily for at least 28 weeks to the subject for example, about 300 mg or a dosage amount as disclosed herein of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods treating hepatitis B in a subject by administering daily for at least 32 weeks to the subject for example, about 300 mg or a dosage amount as disclosed herein of Compound 1 or a pharmaceutically acceptable salt thereof;. In some embodiments, provided herein are methods treating hepatitis B in a subject by administering daily for at least 40 weeks to the subject for example, about 300 mg or a dosage amount as disclosed herein of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods treating hepatitis B in a subject by administering daily for at least 44 weeks to the subject for example, about 300 mg or a dosage amount as disclosed herein of Compound 1 or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, provided herein are methods treating hepatitis B in a subject by administering daily for at least 48 weeks to the subject for example, about 300 mg or a dosage amount as disclosed herein of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods treating hepatitis B in a subject by administering daily for at least 1 year to the subject for example, about 300 mg or a dosage amount as disclosed herein of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods treating hepatitis B in a subject by administering daily for at least 18 months to the subject for example, about 300 mg or a dosage amount as disclosed herein of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods treating hepatitis B in a subject by administering daily for at least 2 years to the subject for example, about 300 mg or a dosage amount as disclosed herein of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods treating hepatitis B in a subject by administering daily for at least 2.5 years to the subject for example, about 300 mg or a dosage amount as disclosed herein of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods treating hepatitis B in a subject by administering daily for at least 3 years to the subject for example, about 300 mg or a dosage amount as disclosed herein of Compound 1 or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the subject is assessed after a set time period for HBeAg, HBsAg, HBV DNA, and HBV RNA levels, amounts, or concentrations after the subject has undergone administered daily of for example, about 100 mg or about 300 mg or a dosage amount as disclosed herein of Compound 1 or a pharmaceutically acceptable salt thereof. The set time period can be about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 50 weeks, about 12 months, about 18 months, about 24 months, about 30 months, about 36 months, about 42 months, about 48 months, or about 54 months.

[0086] In some embodiments, after 2 weeks of daily administration the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 4 weeks of daily administration the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 8 weeks of daily administration the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 12 weeks of daily administration the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 16 weeks of daily administration the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 20 weeks of daily administration the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 24 weeks of daily administration the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 28 weeks of daily administration the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 32 weeks of daily administration the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 36 weeks of daily administration the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 40 weeks of daily administration (the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 44 weeks of daily administration the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 12 months of daily administration the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 18 months of daily administration the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 24 months of daily administration the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 30 months of daily administration the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 36 months of daily administration the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 42 months of daily administration the subject has a reduction of HBeAg and/or HBsAg. In some embodiments, after 48 months of daily administration the subject has a reduction of HBeAg and/or HBsAg.

[0087] In some embodiments, after 2 weeks of daily administration, the subject has a reduction in HBV DNA or HBV RNA levels. In some embodiments, after 4 weeks of daily administration, the subject has a reduction in HBV DNA or HBV RNA levels. In some embodiments, after 8 weeks of daily administration, the subject has a reduction in HBV DNA or HBV RNA levels. In some embodiments, after 12 weeks of daily administration, the subject has a reduction in HBV DNA or HBV RNA levels. In some embodiments, after 24 weeks of daily administration the subject has a reduction in HBV DNA or HBV RNA. In some embodiments, after 30 weeks of daily administration the subject has a reduction in HBV DNA or HBV RNA. In some embodiments, the subject after 36 weeks of daily administration the subject has a reduction in HBV DNA or HBV RNA.

[0088] In some embodiments, after 2 weeks of daily administration the subject has greater than 0.51ogl0 decline in HBeAg. In some embodiments, after 4 weeks of daily administration the subject has greater than 0.51ogl0 decline in HBeAg. In some embodiments, after 8 weeks of daily administration the subject has greater than 0.51ogl0 decline in HBeAg. In some embodiments, after 12 weeks of daily administration the subject has greater than 0.51ogl0 decline in HBeAg. In some embodiments, after 16 weeks of daily administration the subject has greater than 0.51ogl0 decline in HBeAg. In some embodiments, after 18 weeks of daily administration the subject has greater than 0.51ogl0 decline in HBeAg. In some embodiments, after 24 weeks of daily administration the subject has greater than 0.51ogl0 decline in HBeAg. In some embodiments, after 30 weeks of daily administration the subject has greater than 0.51ogl0 decline in HBeAg. In some embodiments, after 36 weeks of daily administration the subject has greater than 0.51ogl0 decline in HBeAg. In some embodiments, after 44 weeks of daily administration the subject has greater than 0.51ogl0 decline in HBeAg. In some embodiments, after 12 months of daily administration the subject has greater than 0.51ogl0 decline in HBeAg. In some embodiments, after 18 months of daily administration the subject has greater than 0.51ogl0 decline in HBeAg. In some embodiments, after 24 months of daily administration the subject has greater than 0.51ogio decline in HBeAg. In some embodiments, after 30 months of daily administration the subject has greater than 0.51ogio decline in HBeAg. In some embodiments, after 36 months of daily administration the subject has greater than 0.51ogio decline in HBeAg. In some embodiments, after 42 months of daily administration the subject has greater than 0.51ogio decline in HBeAg. In some embodiments, after 44 months of daily administration the subject has greater than 0.51ogio decline in HBeAg. In some embodiments, after 50 months of daily administration the subject has greater than 0.51ogio decline in HBeAg.

[0089] In some embodiments, after 2 weeks of daily administration the subject has hepatitis B virus levels that are below detection levels in the subject. In some embodiments, after 4 weeks of daily administration the subject has hepatitis B virus levels that are below detection levels in the subject. In some embodiments, after 8 weeks of daily administration the subject has hepatitis B virus levels that are below detection levels in the subject. In some embodiments, after 18 weeks of daily administration the subject has hepatitis B virus levels that are below detection levels in the subject. In some embodiments, after 24 weeks of daily administration the subject has hepatitis B virus levels that are below detection levels in the subject. In some embodiments, after 30 weeks of daily administration the subject has hepatitis B virus levels that are below detection levels in the subject. In some embodiments, after 36 weeks of daily administration the subject has hepatitis B virus levels that are below detection levels in the subject. In some embodiments, after 42weeks of daily administration the subject has hepatitis B virus levels that are below detection levels in the subject. In some embodiments, after 44 weeks of daily administration the subject has hepatitis B virus levels that are below detection levels in the subject. In some embodiments, after 12 months of daily administration the subject has hepatitis B virus levels that are below detection levels in the subject. In some embodiments, after 18 months of daily administration the subject has hepatitis B virus levels that are below detection levels in the subject. In some embodiments, after 24 months of daily administration the subject has hepatitis B virus levels that are below detection levels in the subject. In some embodiments, after 30 months of daily administration the subject has hepatitis B virus levels that are below detection levels in the subject. In some embodiments, after 36 months of daily administration the subject has hepatitis B virus levels that are below detection levels in the subject. In some embodiments, after 42 months of daily administration the subject has hepatitis B virus levels that are below detection levels in the subject. In some embodiments, after 44 months of daily administration the subject has hepatitis B virus levels that are below detection levels in the subject. In some embodiments, after 50 months of daily administration the subject has hepatitis B virus levels that are below detection levels in the subject. Combination Therapy

[0090] In certain aspects, provided herein are methods of treating hepatitis B in a subject in need thereof by administering once daily a pharmaceutical composition comprising about 100 mg to about 500mg, e.g., about 225mg, about 250 mg, about 275mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400mg, about 425mg, or about 450mg or more, e.g. daily, e.g., about 300 mg of Compound 1, in combination with a therapeutically effective amount of a nucleos(t)ide analog. In some aspects, the nucleos(t)ide analog is entecavir or tenofovir.

[0091] In some aspects, provided herein are methods of treating hepatitis B in a subject in need thereof by administering once daily for example, about 300 mg or a dosage amount as disclosed herein of a compound of Compound 1, in combination with a once daily dose of entecavir (ETV). The daily dose of entecavir may be in tablet form or oral solution form.

The tablets may comprise 0.5 mg or 1.0 mg. The oral solution may comprise 0.05 mg/mL. Therefore, 10 mL of the oral solution provides a 0.5 mg dose and a 20 mL provides a 1 mg dose of entecavir. In some embodiments, the subject is administered 0.5 mg of entecavir once daily in combination with for example, about 300 mg or a dosage amount as disclosed herein once daily of Compound 1. In some embodiments, the subject is administered 1.0 mg of entecavir once daily in combination with for example, about 300 mg or a dosage amount as disclosed herein once daily of Compound 1.

[0092] In some embodiments, subjects are administered once daily an oral dosage form comprising for example, about 300 mg or a dosage amount as disclosed herein of Compound 1, and in combination, the subject is administered entecavir according to the label instructions of entecavir.

[0093] In certain aspects, provided herein are methods of treating hepatitis B in a subject in need thereof by administering once daily for example, about 300 mg or a dosage amount as disclosed herein of Compound 1, and administering to the subject a therapeutically effective amount of a nucleos(t)ide inhibitor, or analog, tenofovir disoproxil fumarate (TDF). In some embodiments, the subject is administered about 300 mg of TDF once daily orally. In some embodiments, TDF is in tablet form. In other embodiment, TDF is in an oral powder formulation and the subject is administered 7.5 scoops.

[0094] In some embodiments, subjects are administered once daily an oral dosage form comprising for example, about 300 mg or a dosage amount as disclosed herein of Compound 1, and in combination, the subject is administered TDF according to the label instructions for TDF.

[0095] In certain aspects, provided herein are methods of treating hepatitis B in a subject in need thereof by administering once daily for example, about 300 mg or a dosage amount as disclosed herein of Compound 1, and administering to the subject a therapeutically effective amount of a nucleos(t)ide inhibitor, or analog, tenofovir alafenamide or tenofovir alafenamide fumarate (TAF). In some embodiments, the subject is administered 25 mg of TAF (one tablet) once daily. In some embodiments, the subject is administered 25 mg of TAF (one tablet) once daily with food.

[0096] In some embodiments, subjects are administered daily an oral dosage form comprising for example, about 300 mg or a dosage amount as disclosed herein of Compound 1, and the subject follows the administration of TAF according to the label instructions thereof.

[0097] In some embodiments, Compound l is a tablet formulation in free base and standard pharmaceutical excipients including hypromellose, sodium lauryl sulfate, croscarmellose sodium, microcrystalline cellulose, lactose monohydrate, magnesium stearate, and Opadry film coating.

Examples

[0098] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

Equivalents and Scope

[0099] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0100] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects of the disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0101] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0102] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Example 1: A Study of Compound 1

[0103] Compound 1 was investigated in several cohorts for safety and efficacy. In total, 6 cohorts of 9 subjects each with CHB (chronic hepatitis B) were dosed orally with Compound 1. Within each cohort, subjects were randomized in a ratio of 7 (active):2 (placebo).

Subjects in Cohort 1 were dosed with 100 mg daily of Compound 1 for 14 days. Subjects in Cohort 2 were dosed with 300 mg daily of Compound 1 for 14 days. FIG. 1 depicts the study design.

[0104] Subjects were monitored by physical examination, vital signs, 12-lead ECGs, and laboratory tests. HBV DNA was measured using Roche Ampliprep COBAS TaqMan HBV Test v2.0 and HBV pgRNA was measured using RT-PCR methods. Plasma concentration of Compound 1 was determined using a validated liquid chromatography tandem mass spectrometry method. PK parameters were determined by non-compartmental analysis using Phoenix WinNonLin.

[0105] Subjects were enrolled and recruited at 13 sites in 6 countries: New Zealand, UK, South Korea, Hong Kong, USA and China. Subjects met the following criteria:

*between 18 and 65 years of age;

*BMI > 18 and < 34 kg/m² and a minimum weight of 45 kg;

*no prior treatment within the last 6 months with an investigative or approved therapy for HBV;

*no prior treatment with a core protein targeted therapy;

*negative serology of HIV, HCV, or HDV;

*noncirrhotic (Metavir score F0-F2 or FibroScan <8kPa;

*HBsAg-positive, HBeAg-positive;

*HBV DNA > 2 x 10⁵ IU/mL; and

*ALT and AST <5x upper limit of normal range.

[0106] Baseline demographic and disease characteristics for Cohort 1 are shown in FIG. 2. [0107] Compound 1 was rapidly absorbed with median time to maximum plasma concentration (T_max) ranging between 1 and 4 hours. The extent of exposure, as measured by the AUC, as well as the trough plasma concentration (C24_hr) increased proportionally with the dose. The Cma_x, however, was slightly less than dose proportional. Summary PK parameters following single oral dose administration are summarized in Table 1. In general, the overall systemic exposure to Compound 1 was well-characterized with sampling time capturing more than 95% of the AUC at all dose levels except for the lowest dose, which was greater than 85%. The PK of Compound 1 appears to be linear with similar terminal elimination half life (ti_/2), CL/F, and Vz/F across dose levels, suggesting there are no saturable processes involved within this exposure range.

Table 1:

AUCo-24: Area under the plasma-concentration curve from time 0 to 24 hours postdose; C241₁₁: trough plasma concentration;

Cmax! maximum plasma concentration; ti_/2: terminal elimination half-life; Tma : time to Cmax

Geometric mean (Geometric CV%) are presented for AUCs, Cmax, and C241₁₁; Median (min, max) are presented for Tmax; Mean (SD) are presented for ti_/2.

[0108] Five of the 6 subjects that received Compound 1, 100 mg in the fasted cohort returned to receive Compound 1,100 mg in the fed state. Compound 1 was administered 30 minutes after the start of a high fat breakfast. No evidence of a significant food effect was seen on the PK profile of Compound 1.

[0109] The PK of Compound 1 on Day 1 was consistent with the PK observed in the SAD part of the study, at the same dose level. Accumulation ratios between 1.5 and 2 suggest an effective accumulation half-life ranging from 16 to 24 hours, in line with the observed tl/2 in the SAD part of the study, suggesting that the PK of Compound 1 is not time dependent. The summary noncompartmental PK parameters obtained for Compound 1 in plasma are presented in Table 2.

AR: accumulation ratio Day 10/Day 1;

Area under the plasma-concentration curve from time 0 to 24 hours postdose;

AUCo-inf: Area under the plasma-concentration curve from time 0 extrapolated to infinity;

trough plasma concentration;

Cmax! maximum plasma concentration; ti_/ : terminal elimination half-life; Tma*: time to Cma*

Geometric mean and CV% are presented for AUCs, Cma_*, and

Median (min, max) are presented for Tma_*;

Mean (SD) are presented for ti_/ . a Half-life was not determined since the terminal elimination phase was not sampled.

[0110] All TEAEs were mild (Grade 1). No clinically significant ECG, vital signs, physical exam or laboratory test abnormalities were observed. No serious AEs, dose limiting toxicities, or premature discontinuations were reported. Most treatment-emergent laboratory abnormalities were mild. No clinically significant ALT/AST increase was reported. No trend in laboratory abnormality were observed. FIG. 3 depicts the treatment-emergent adverse effects (TEAEs) for Cohort 1. FIG. 4 depicts the number of subjects with treatment-emergent laboratory abnormalities.

[0111] The pharmacokinetics of Compound 1 in patients with HBV were similar to those in healthy volunteers. Steady state-exposures observed at the lowest dose level of 100 mg daily were in excess of the EC90’s for in vitro antiviral and cccDNA assays. FIGs. 5 and FIG. 6 depict the pharmacokinetics at day 14 for Cohort 1. [0112] Subjects dosed with Compound 1 had mean declines from baseline to Day 15 in

HBVDNA and pgRNA levels of 2.3 log 10 IU/mL [range 1.7-3.0] and 2.1 log 10 IU/mL [range 1.5-2.7] FIG. 7 depicts the HBV DNA change from baseline in Cohort 1. FIG. 8 depicts HBV pgRNA change from baseline for Cohort 1.

[0113] The dose of 100 mg of Compound 1 (100 mg QD PO) demonstrated potent antiviral activity as reflected by 2.3 log 10 and 2.1 log 10 reductions in HBV DNA and pgRNA over the 14 day dosing interval. In Cohort 2 evaluating Compound 1 300 mg QD, the mean reductions in HBV DNA and HBV pgRNA were 2.5 loglO IU/mL and 2.12 loglO IU/mL over the 14-day dosing interval.

Example 2: Combination of Compound 1 and ETV

[0114] Chronic hepatitis B (CHB) subjects are administered Compound 1 in combination with entecavir (ETV), a standard of care nucleos(t)ide analogue (Nrtl), to determine safety and whether the combination therapy reduces viral nucleic acid (ie, HBV DNA and HBV pre- genomic (pg) RNA) to a greater extent than ETV alone, which will lead to subsequent reductions in viral antigens (ie, HBeAg, HBcrAg, and HBsAg). The multicenter, randomized, single-blind, PBO-controlled study explores the safety of Compound 1 in combination with entecavir (ETV) and its antiviral activity as measured by effects on serum HBV DNA, HBV pgRNA, and HBV antigens.

[0115] The subjects are male or female, between 18 to 65 years of age with no evidence of cirrhosis or end-stage liver disease. Cohort 1 enrolls treatment-naive subjects with HBeAg- positive CHB.

[0116] In the study, 300 mg of Compound 1 will be administered orally, once daily, in addition to ETV.

[0117] In Cohort 1 approximately 80 treatment-naive subjects with HBeAg-positive CHB are randomized 3:1 to receive 300 mg of Compound 1 [n=60] or matching PBO [n=20]) in combination with ETV for 72 weeks. Treatment assignments are stratified by the HBV DNA level measured at the Screening visit (ie, >8.0 loglO IU/mL versus <8.0 loglO IU/mL).

Safety, antiviral activity, and PK is assessed during treatment and the 24-week follow-up period. During the follow-up period all subjects remain on ETV.

[0118] The primary objectives of the study are to evaluate the safety and tolerability of Compond 1 when administered in combination with ETV in subjects with CHB and to evaluate the effect of Compond 1 in reducing HBV DNA in subjects with CHB.

[0119] The secondary objectives are to evaluate the PK of Compond 1 and ETV in subjects with CHB; to evaluate the effect of Compond 1 in reducing HBV pgRNA levels in subjects with CHB; to evaluate the effect of Compond 1 in reducing HBV antigens (ie, HBeAg, HBcrAg and HBsAg) in subjects with CHB; to evaluate the effect of Compond Ion normalization of alanine aminotransferase (ALT) in subjects with abnormal ALT; and to evaluate the emergence of resistance to Compond 1 when administered in combination with ETV.

[0120] The exploratory objective is to assess the relationship between viral biomarkers and virologic and/or clinical outcomes. For subjects who provide an optional pharmacogenomic sample, to evaluate the potential contribution of host genomics to clinical or virologic outcomes and/or drug disposition

[0121] The primary endpoints are: the proportion of subjects with adverse events (AEs), premature treatment discontinuation, and abnormal laboratory results and the change in mean loglO HBV DNA from Baseline to Week 24 for Compound 1+ETV and PBO+ETV.

[0122] The secondary endpoints are:

• Analysis of Compound land ETV drug concentrations: o Trough levels and trough to peak ratios of Compound Ion Compound 1+ETV o Trough levels and trough to peak ratios of ETV on Compound 1+ETV and PBO+ETV

• The change in mean logio HBV DNA for Compound 1+ETV and PBO+ETV at each timepoint

• The change in mean logio HBV pgRNA from Baseline to Week 24 and at each timepoint for Compound 1+ETV and PBO+ETV

• The proportion of subjects with a reduction in HBV DNA below the assay lower limit of quantitation (LLOQ) for Compound 1+ETV and PBO+ETV at each timepoint

• The proportion of subj ects with a reduction in HBV pgRNA below the assay LLOQ for Compound 1+ETV and PBO+ETV at each timepoint

• The change in serum viral antigens (ie, HBeAg, HBcrAg and HBsAg) on Compound 1+ETV and PBO+ETV at each timepoint

• The proportion of subjects with abnormal ALT at Baseline who have normal ALT at Week 24 and at each timepoint on Compound 1+ETV and PBO+ETV

• The incidence of HBV variants with reduced susceptibility to Compound 1

The exploratory endpoints are:

• The proportion of subjects with loss (defined as below LLOQ) or decline in HBsAg, HBcrAg, or HBeAg on Compound 1+ETV and PBO+ETV at each timepoint • The proportion of subjects with HBsAg seroconversion (loss of HBsAg and appearance of HBsAb) or HBeAg seroconversion (loss of HBeAg and appearance of HBeAb) on Compound 1+ETV and PBO+ETV at each timepoint

• The proportion of subjects whose HBV DNA is below the assay LLOQ and “target not detected” on Compound 1+ETV and PBO+ETV at each timepoint

• Pharmacogenomic correlations may be performed with clinical or virologic outcomes for subjects who provide optional informed consent. For subjects who provide an optional pharmacogenomic sample, to evaluate known gene variants and Compound 1, its metabolites, and PK and/or safety

[0123] Subjects must meet all the following inclusion criteria in order to be eligible for the study:

1. Willing and able to provide informed consent 2. Male or female between the ages 18 and 65 years (inclusive)

3. Female subjects must be non-pregnant and have a negative serum pregnancy test at Screening and a negative urine pregnancy test predose on Day 1.

4. Chronic hepatitis B infection, defined as HBV infection for >6 months documented, for example, by at least two measurements of HBsAg positivity and/or detectable HBV DNA >6 months apart (inclusive of Screening). For subjects without clear documentation of CHB, serum immunoglobulin M (IgM) antibody to the HBV core-related antigen (HBcrAb) must be negative at Screening to exclude acute HBV infection

5. Body mass index (BMI) 18 to 36 kg/m2 and a minimum body weight of 45 kg (inclusive)

6. HBV DNA >2 x 105 IU/mL

7. HBeAg >500 IU/mL at Screening

8. HBsAg >1000 IU/mL at Screening 9. Lack of cirrhosis or advanced liver disease as documented by the following:

Liver biopsy results of METAVIR F0-F2 (absence of bridging fibrosis or cirrhosis) within 1 year of Screening, or

Fasting FibroScan <8 kPa within 3 months of Screening (including Screening visit) or other Sponsor-approved hepatic imaging study (hepatic magnetic resonance imaging [MRI], or hepatic ultrasound by a ultrasonographer with expertise in evaluation of liver fibrosis) within 6 months of Screening indicating lack of cirrhosis or advanced liver disease (F0-F2 or equivalent). Subjects with a fasting FibroScan >8 kPa and <10 kPa are excluded from study participation unless a liver biopsy within the 1 year before Day 1 confirms the absence of bridging fibrosis and cirrhosis. Subjects with a FibroScan >10 kPa are excluded from study participation.

If results from both liver biopsy and FibroScan are available, then the result reporting the most advanced liver disease will be used to determine eligibility for the study.

10. Agreement to comply with protocol-specified contraceptive requirements

11. Agreement to abstain from alcohol abuse [defined as alcohol consumption exceeding 2 standard drinks per day on average (1 standard drink = 10 grams of alcohol)] and the use of illicit substances from screening until end of the study

12. In good general health, except for CHB

13. Have the ability to take oral medication and, in the opinion of the Investigator, be willing to adhere to study treatment

[0124] Subjects who meet any of the following exclusion criteria will not be eligible for the study.

1. Prior treatment for CHB; specifically lamivudine, telbivudine or adefovir (any duration) Nrtl treatment for >4 weeks HBV core inhibitors (any duration)

Previous treatment with an investigational agent for HBV infection

2. Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis E virus (HEV), or hepatitis D virus (HDV) 3. Females who are lactating, or wish to become pregnant during the course of the study

4. History or evidence of advanced liver disease or hepatic decompensation (including jaundice, ascites, portal hypertension, gastrointestinal bleeding esophageal varices, hepatic encephalopathy,) at any time prior to, or at the time of Screening 5. History of persistent alcohol abuse (alcohol consumption exceeding 2 standard drinks per day on average [1 standard drink = 10 grams of alcohol]) or illicit drug abuse within 3 years before Screening

6. Clinically significant cardiac or pulmonary disease, chronic or recurrent renal or urinary tract disease, liver disease other than CHB, endocrine disorder, autoimmune disorder, diabetes mellitus requiring treatment with insulin or hypoglycemic agents, neuromuscular, musculoskeletal, or mucocutaneous conditions requiring frequent treatment, seizure disorders requiring treatment, ongoing infection or other medical conditions requiring frequent medical management or pharmacologic or surgical treatment that in the opinion of the Investigator or the Sponsor makes the subject unsuitable for study participation

7. History of hepatocellular carcinoma (HCC)

8. A history of malignancy other than HCC unless the subject’s malignancy has been in complete remission off chemotherapy and without additional medical or surgical interventions during the 3 years before Screening 9. Poorly controlled or unstable hypertension; or sustained systolic blood pressure

(BP) >160 mmHg or <90 mmHg, or diastolic BP >95 mmHg or <50 mmHg at Screening

10. History or presence of electrocardiogram (ECG) abnormalities deemed clinically significant including: Personal or family history of prolonged QT syndrome or family history of sudden death

QTcF >450 msec (males) or >470 msec (females) or <300 msec at Screening or Day 1 visit

ECG with QRS and/or T-wave judged to be unfavorable for a consistently accurate QT measurement as judged by the Investigator at Screening

Evidence of atrial fibrillation, atrial flutter, complete bundle branch block, Wolff-Parkinson-White Syndrome, or cardiac pacemaker at Screening or Day 1 visit

11. History of hypersensitivity or idiosyncratic reaction to any components or excipients of the investigational drug or PBO formulation

12. History of any significant food or drug-related allergic reactions such as, anaphylaxis, Stevens- Johnson syndrome, or urticaria

13. The following exclusionary laboratory results at Screening and Baseline visit:

Platelet count <100,000/mm3 Albumin < lower limit of normal (LLN)

Total bilirubin >1.2 x upper limit of normal (ULN) unless known Gilbert’s syndrome; subjects with Gilbert’s syndrome are eligible for study participation if the direct bilirubin is within the normal range

Direct bilirubin >1.2 x ULN

ALT >5 x ULN

Serum alpha fetoprotein (AFP) >100 ng/mL. If AFP at Screening is > ULN but <100 ng/mL, the subject is eligible if a hepatic imaging study prior to initiation of study drug reveals no lesions indicative of possible HCC.

International Normalized Ratio (INR) >1.5 x ULN

Glomerular filtration rate (GFR) <60 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [Levey 2009] Serum hemoglobin Ale (HbAlc) >6.5%

Any other laboratory abnormality deemed clinically significant by the Sponsor or the Investigator

14. Subjects receiving prohibited concomitant medications, grapefruit juice, herbal or over-the-counter medications (Section 6.4.1) within 7 days or 5 half-lives (if known), whichever is longer, prior to administration of the first dose of study drug and for the duration of the study period

15. Participation in another clinical trial of a drug or device whereby the last investigational drug/device administration is within 60 days or 5 half-lives prior to the first study drug administration, whichever is longer

16. Donated or lost >500 mL of blood within 2 months prior to Screening, or plasma donation within 7 days prior to Screening

[0125] All subjects receive an oral administration of 0.5 mg ETV tablets, QD, for the duration of the study.

Claims

1. A method of treating hepatitis B in a subject in need thereof, the method comprising: administering daily to the subject: about 100 mg of a compound represented by:

2. The method of claim 1, wherein hepatitis B is chronic hepatitis B.

3. The method of claim 1 or 2, wherein the subject is positive for HBsAg prior to administering the compound.

4. The method of any one of claims 1-3, wherein the subject has had no prior treatment with a core protein targeted therapy prior to administering the compound.

5. The method of any one of claims 1-4, wherein the subject is positive for HBeAg prior to administering the compound.

6. The method of any one of claims 1-5, wherein after two weeks of daily administration, the subject has a decline in HBV DNA levels.

7. The method of any one of claims 1-6, wherein after two weeks of daily administration, the subject has a decline in HBV pgRNA levels.

8. A method of treating hepatitis B in a subject in need thereof, the method comprising: administering daily to the subject: about 300 mg of a compound represented by:

9. The method of claim 8, wherein hepatitis B is chronic hepatitis B.

10. The method of claim 8 or 9, wherein the subject is positive for HBsAg prior to administering the compound.

11. The method of any one of claims 8-10, wherein the subject has had no prior treatment with a core protein targeted therapy prior to administering the compound.

12. The method of any one of claims 8-11, wherein the subject is positive for HBeAg prior to administering the compound.

13. The method of any one of claims 8-12, wherein after two weeks of daily administration, the subject has a decline in HBV DNA levels.

14. The method of any one of claims 8-13, wherein after two weeks of daily administration, the subject has a decline in HBV pgRNA levels.

15. A method of treating hepatitis B in a subject in need thereof, the method comprising: administering daily to the subject: about 300 mg of a compound represented by:

administering to the subject a therapeutically effective amount of a nucleos(t)ide inhibitor selected from the group consisting of entecavir, tenofovir and tenofovir alafenamide fumarate.

16. The method of claim 15, wherein the nucleos(t)ide inhibitor is entecavir.