EP3937928A1

EP3937928A1 - Capsid assembly modulator solid formulation

Info

Publication number: EP3937928A1
Application number: EP20709618.1A
Authority: EP
Inventors: Michaël Bertil S ANNÉ; Claire Elisabeth BALMAIN; Maria JANSENS; Oliver Lenz; Abhishek Singh; Jan SNOEYS; Joris Jozef VANDENBOSSCHE; Frederic Anne R VAN DYCKE; Dominique Josiane W VERSTRAETE
Original assignee: Janssen Sciences Ireland ULC
Current assignee: Janssen Sciences Ireland ULC
Priority date: 2019-03-13
Filing date: 2020-03-13
Publication date: 2022-01-19
Also published as: BR112021017525A2; MA55280A; CA3132095A1; IL286209A; SG11202109710QA; KR20210137484A; ECSP21067052A; JOP20210250A1; MX2021011030A; CR20210481A; WO2020183020A1; JP2022524819A; AU2020235442A1; PE20212107A1; CN113557016A

Abstract

The present disclosure is directed to solid oral dosage forms of a capsid assembly inhibitor for the treatment of hepatitis B virus infection.

Description

CAPSID ASSEMBLY MODULATOR SOLID FORMULATION

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Chronic hepatitis B virus (HBV) infection is a persistent, potentially progressive necroinflammatory liver disease associated with chronic HBV infection. Worldwide about 240-400 million persons 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, World Health Organization, 2013; Hoofnagle JH, et al. , Management of Hepatitis B: Summary of a Clinical Research Workshop, Hepatology, 2007, 45(4):1056- 1075; EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection, J. Hepatology, 2012, 57:167-185 (EASL 2012); Lesmana LA, et al. Hepatitis B: overview of the burden of disease in the Asia-Pacific region, Liver International, 2006, 26:3-10; Lok ASF and McMahon BJ, Chronic Hepatitis B: Update 2009, Hepatology, September 2009:1-36 (Lok 2009)).

With the continued worldwide prevalence of HBV-associated mortality and severe morbidity, there remains a need for improved HBV antiviral therapies that can achieve sustained viral response during and after treatment.

Because of their pharmacokinetic properties and the need to keep plasma levels above a minimum level, some antiviral drugs require frequent administration of relatively high doses. The number and/or volume of dosage forms that need to be administered are commonly referred to as the "pill burden". A high pill burden is undesirable for many reasons, such as the number of dosage forms to intake, often combined with the inconvenience of having to swallow large dosage forms, as well as the need to store and transport a large number or volume of pills.

A high pill burden increases the risk of patients not taking their entire dose, thereby failing to comply with the prescribed dosage regimen. As well as reducing the effectiveness of the treatment, this also leads to the emergence of viral resistance. The problems associated with this pill burden are increased where a patient must take a combination of different antiviral agents or agents in combination.

Providing high dosage forms that have a relatively small size contributes to the convenience of intake and therefore also helps to overcome problems of pill burden. WO 2014/184350 discloses compound A, and synthesis thereof, as a compound having HBV inhibitory activity:

(A).

A tablet containing 100 mg of compound A as active ingredient and having a total weight of 1200 mg per tablet is disclosed in PCT/IB2019/000231. The oral dosage forms are formed by spray drying of the compound with a stabiliser, dry granulation and compression of the ingredients. In order to achieve a total dosing of 250-300 mg of compound A, intake of at least three dosage forms of acceptable size are required when using that tablet composition.

Therefore, it would be desirable to provide HBV inhibitory therapy that involves the administration of dosage forms of a practical size while reducing the number of dosage forms.

The present invention is based on the unexpected finding that a higher weight% load of compound A per dosage form is feasible while maintaining an acceptable stability of product upon storage and an acceptable bioavailability.

The present invention thus provides an anti-HBV therapy involving the

administration of dosage forms of compound A having acceptable size and/or number of dosage forms. Hence, the present dosage forms are beneficial in terms of pill burden and drug compliance of the patient.

SUMMARY OF THE INVENTION

In one aspect, the invention relates to a solid dispersion comprising compound A:

or a pharmaceutically acceptable salt or solvate thereof, and a stabiliser selected from at least one of Hypromellose (HPMC) and Hypromellose acetate succinate (HPMC-AS) at a ratio of 1 : 1 to less than 1 :3 by weight, with the proviso that the ratio is not 1 :2 by weight. Hypromellose (HPMC) may e.g. be Hypromellose E5 (HPMC E5) (i.e. , HPMC with a viscosity of 5 mPa.s).

Said solid dispersion can be further incorporated into an oral dosage form, in particular a solid oral dosage form, more in particular, a tablet.

Therefore, the invention also relates to a solid oral dosage form, in particular a tablet, comprising a solid dispersion comprising compound A

(A), or a pharmaceutically acceptable salt or a solvate thereof, and a stabiliser selected from at least one of Hypromellose (HPMC) and Hypromellose acetate succinate (HPMC-AS) at a ratio of 1 :1 to less than 1 :3 by weight, and additional pharmaceutical excipients, with the proviso that the ratio compound A: stabiliser is not 1 :2 by weight.

In yet another aspect, the invention relates to a process for preparing an oral dosage form according to the invention, comprising the steps of:

providing a spray-dried powder by preparing a solution of the compound with the stabiliser and spray drying the solution to form a spray dried powder;

mixing the spray-dried powder with part of tablet excipients;

performing dry granulation of the mixture;

adding part of tablet excipients to the granulate and mixing until homogeneous; compressing the mixture to provide the oral dosage form, said oral dosage form then being optionally film-coated.

In a further aspect, the invention relates to a process for preparing an oral dosage form according to the invention, comprising the steps of:

providing a spray-dried powder by preparing a solution of the compound with the stabiliser and spray drying the solution to form a spray dried powder; mixing the spray-dried powder with tablet excipients; and

compressing the mixture to provide the oral dosage form, said oral dosage form then being optionally film-coated.

In yet another aspect, the present invention relates to an oral dosage form according to the invention for use in medicine, more specifically for use in the treatment of HBV infection.

In yet another aspect, the invention relates to a method for the treatment of an HBV infection in a subject which comprises administering to the subject a therapeutically effective amount of an oral dosage form according to the invention.

BRIEF DESCRIPTION OF THE FIGURES

Fig. 1 depicts the geometric mean concentration (cone) (ng/mL) as a function of time (hours) (initial 24 hours) in two pharmacokinetic studies in healthy volunteers evaluating different formulations.

DESCRIPTION OF THE INVENTION

The present invention provides a solid dispersion comprising compound A or a pharmaceutically acceptable salt or solvate thereof, and a stabiliser selected from at least one of Hypromellose (HPMC) and Hypromellose acetate succinate (HPMC-AS) at a ratio of 1 :1 to less than 1 :3 by weight, with the proviso that the ratio is not 1 :2 by weight. In a particular embodiment, compound A or a pharmaceutically acceptable salt or solvate thereof, and the stabilizer selected from at least one of Hypromellose (HPMC) and Hypromellose acetate succinate (HPMC-AS) are present at a ratio of 1 :1 to less than 1 :2 by weight.

In a particular embodiment, the invention relates to a solid dispersion as described herein, comprising compound A

or a pharmaceutically acceptable salt or solvate thereof, and a stabiliser selected from at least one of Hypromellose (HPMC) and Hypromellose acetate succinate (HPMC-AS) at a ratio of 1 :1.5 by weight. Hypromellose (HPMC) may e.g. be Hypromellose E5 (HPMC E5) (i.e., HPMC with a viscosity of 5 mPa.s).

In a further particular embodiment, compound A is present in the solid dispersion in amorphous form, more in particular, as an amorphous, base form. In yet a further embodiment, the solid dispersion of compound A and stabilizer as described herein, is a solid solution.

The present invention also provides a solid oral dosage form, in particular a tablet, of compound A, that is manufactured by first providing a solid dispersion as described herein, comprising compound A or a pharmaceutically acceptable salt or a solvate thereof, and a stabiliser selected from at least one of Hypromellose (HPMC) and

Hypromellose acetate succinate (HPMC-AS) at a ratio of 1 : 1 to less than 1 :3 by weight, with the proviso that the ratio is not 1 :2 by weight, more in particular, at a ratio of 1 : 1 to less than 1 :2.

In a particular embodiment, the invention also relates to a solid oral dosage form, in particular a tablet, comprising a solid dispersion comprising compound A

(A),

or a pharmaceutically acceptable salt or a solvate thereof, and a stabiliser selected from at least one of Hypromellose (HPMC) and Hypromellose acetate succinate (HPMC-AS) at a ratio of 1 :1.5 by weight and additional pharmaceutical excipients.

Hypromellose (HPMC) may e.g. be Hypromellose E5 (HPMC E5) (i.e., HPMC with a viscosity of 5 mPa.s).

The oral dosage form, in particular the tablet, according to the invention, may further comprise one or several agents selected from fillers, disintegrants, glidants, and lubricants. For example, a tablet of the invention may further comprise at least one filler selected from microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate and pre-gelatinized maize starch, at least one disintegrant such as croscarmellose sodium, at least one glidant such as colloidal anhydrous silica, hydrophobic colloidal silica, and at least one lubricant such as magnesium stearate.

In another embodiment, the tablet comprises 50-300 mg of compound A, in particular 50-250 mg of compound A (more particularly at the above-mentioned doses or daily doses) and 75-450 mg of stabilizer, in particular, 75-375 mg of stabiliser. In a further embodiment, the tablet comprises 250 mg of compound A.

By making use of this composition, the weight percentage of compound A compared to the 100 mg tablet described in PCT/IB2019/000231 can be increased per dosage form by about 60%, thus generating oral dosage forms with a higher drug load of compound A (e.g. tablet having 160 mg compound A and having a total weight of 1200 mg per tablet). Alternatively, the size and weight of existing dosage forms (e.g. tablets having 100 mg compound A and having a total weight of 750 mg per tablet) may be reduced by about 38%.

The size of the dosage forms of the invention, i.e. the total weight of the dosage forms, in particular a tablet, should be below a limit of convenience which is below the size at which a number of patients start having difficulty taking in the dosage form.

Definitions

As used in the specification and in the claims, the term“comprising” can include the embodiments“consisting of” and“consisting essentially of.” The terms“comprise(s),” “include(s),”“having,”“has,”“can,”“contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients/steps and permit the presence of other ingredients/steps.

However, such description should be construed as also describing compositions or processes as“consisting of” and“consisting essentially of” the enumerated components, which allows the presence of only the named components, along with any

pharmaceutically acceptable carriers, and excludes other components.

All ranges disclosed herein are inclusive of the recited endpoint and independently combinable (for example, the range of“from 50 mg to 250 mg” is inclusive of the endpoints, 50 mg and 250 mg, and all the intermediate values). The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and/or values.

As used herein, approximating language can be applied to modify any quantitative representation that can 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,” can not be limited to the precise value specified, in some cases. In at least some instances, the approximating language can correspond to the precision of an instrument for measuring 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 250” also discloses the range“from 50 to 250.” The term“about” can refer to plus or minus 10% of the indicated number. For example, “about 10%” can indicate a range of 9% to 11 %, and“about 1” can mean from 0.9 to 1.1. Other meanings of“about” can be apparent from the context, such as rounding off, so, for example“about 1” can also mean from 0.5 to 1.4.

As used herein, the term“treatment” or“treating,” is defined as the application or administration of a therapeutic agent, i.e., a compound of the invention (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has HBV infection, chronic HBV infection, a symptom of HBV infection or the potential to develop HBV infection, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect HBV infection, the symptoms of HBV infection or the potential to develop HBV infection. Such treatments can be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

The term“prevent,”“preventing,” or“prevention” as used herein comprises the prevention of at least one symptom associated with or caused by the state, disease or disorder being prevented.

As used herein, the term“patient,”“individual” or“subject” refers to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. Preferably, the patient, subject or individual is human.

As used herein, the term“pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which 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 the composition in which it is contained.

As used herein, the term‘compound A’ is meant to comprise the base form, any pharmaceutically acceptable acid addition salt thereof, as well as any pharmaceutically acceptable solvate thereof. The pharmaceutically acceptable addition salts as mentioned hereinabove are the therapeutically active non-toxic acid addition salt forms, which compound A is able to form. In one embodiment, the term‘compound A’ is meant to comprise the base form, as well as any pharmaceutically acceptable solvate thereof. The term‘pharmaceutically acceptable solvate’ comprises the hydrates and the solvent addition forms that compound A can form. Examples of such forms are e.g.

hydrates, and the like.

As used herein, the term“composition” or“pharmaceutical composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.

Oral dosage forms according to the invention will preferably comprise

pharmaceutically acceptable carriers and excipients. Such inactive ingredients are added to help hold the tablet together and give it strength, and are selected among binders, fillers, disintegrants, glidants and lubricants.

As used herein, the term“pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabiliser, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it can perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be“acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the patient.

As used herein, the term“lubricant” means a pharmaceutically acceptable material which avoids manufacturing probles such as tablet sticking when the drug product blend is compressed into tablets. A tablet formulation may also contain a disintegrant to aid disintegration and dissolution of the formulation upon administration to the patients.

Other additional ingredients that can be included in the pharmaceutical

compositions used in the practice of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

The term“stabiliser,” as used herein, refers to polymers capable of chemically inhibiting or preventing degradation or conversion to crystalline state of compound A.

Stabilisers are added to formulations of compounds to improve chemical and physical stability of the compound. A tablet formulation can be used to make tablet cores in a conventional manner for example by initially dry blending the ingredients, that preferably having been sieved or by dry granulation, in order to improve blend flow. Subsequently, the lubricant is added to the dry-blended mixture for final dry-blending of the total tablet core blend, which is then compressed into tablets having the desired size and weight. For taste masking and cosmetic reasons the tablet cores according to the invention are generally provided with a film coating. Different coloring agents may be used in the film coating in order to differentiate between tablet strengths. The coating can be applied to the core in coating suspension for example in purified water, followed by drying of the coated cores.

The term“combination,”“therapeutic combination,”“pharmaceutical combination,” or“combination product” as used herein refer to a non-fixed combination or a kit of parts for the combined administration where two or more therapeutic agents can be

administered independently, at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g., synergistic, effect.

As used herein,“treatment naive” refers to a patient not having previously received treatment with a drug, investigational or approved, for HBV infection, in particular a nucleos(t)ide drug. “Treatment naive” also refers to a patient not having been on treatment with HBV antiviral medicines within six months of entering a clinical study.

Alternatively, patients treated according to the methods of the disclosure can be “treatment experienced.” As used herein,“treatment experienced” refers to a patient who has had at least one previous course of an HBV antiviral therapy, in particular a nucleos(t)ide drug. In some embodiments, the last dose in this previous course occurred at least three months prior to implementing a method according to the present disclosure.

HBV infections that may be treated according to the disclosed methods include HBV genotype A, B, C, and/or D infections. However, in an embodiment, the methods disclosed may treat any HBV genotype (“pan-genotypic treatment”). HBV genotyping may be performed using methods known in the art, for example, IN NO-LI PA® HBV Genotyping, Innogenetics N.V., Ghent, Belgium).

The term“synergistic effect” refers to the action of two agents, such as, for example, a capsid assembly modulator and a nucleos(t)ide analogue, producing an effect, for example, slowing the symptomatic progression of HBV-infection or symptoms thereof, which is greater than the simple addition of the effects of each drug administered alone.

A synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)) and the median-effect equation (Chou, T.

C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984) and Chou, Pharmacol. Rev. 58: 621-681 (2006). Each equation referred to above can be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively. In some embodiments, the combination of compounds exhibits a synergistic effect (/.e., greater than additive effect) in the treatment of HBV infection.

Synergy volumes of <-100, -100 to -50, -50 to -25, -25 to 25, 25 to 50, 50 to 100, and >100 indicate strong antagonism, moderate antagonism, slight antagonism, insignificant synergism/antagonism (additivity), slight synergism, moderate synergism, and strong synergism respectively.

Synergy can be defined as an improvement in any beneficial effect of compound A or a nucleos(t)ide analogue, alone or in combination. The improvement may exceed an additive effect of the combination or may only occur as a result of the combination. For example, in an embodiment, the effect is complete or sustained reduction of viral load, HBsAg and/or anti-HBsAb during and/or after treatment. For example, in an embodiment, the effect is sustained virological response (SVR) and/or sustained viral clearance.

For application in adults, the estimated daily dose of compound A is 250 mg compound A once per day. On the basis of existing tablet formulations, manufactured by first providing a spray dried powder composition consisting of compound A or a pharmaceutically acceptable salt thereof, and a stabiliser selected from Hypromellose acetate succinate (HPMC-AS) and Hypromellose (HPMC) at a ratio of 1 :3 by weight in the form of a spray dried powder composition, ingestion of two tablets of 1200 mg nominal weight, containing 100 mg of compound A and one or two smaller tablets containing 50 or 25 mg of compound A, respectively, is required. Such tablets have a drug load of 0.083 mg compound A per mg tablet.

One option in order to reduce the tablet size and/or number of tablets required to achieve a particular dose, could be to increase the drug load, and/or decrease the amount of excipients. Decreasing the amount of stabiliser in a given formulation however, could have a detrimental impact in the physical stability of the active pharmaceutical ingredient (API), as well as decrease the amount of API dissolved in the gastrointestinal tract, and therefore bioavailability of the active pharmaceutical ingredient. By providing a solid dispersion obtained by spray drying compound A with the stabilizer, compound A is present in amorphous form, which in turn improves the solubility and bioavailability of compound A. The stabilizer must be present in a sufficient amount in order to prevent compound A from converting to a crystalline form, but also to prevent it from precipitating in the gastrointestinal tract, which in turn might affect the bioavailability of compound A. It has now been unexpectedly discovered that the amount of stabiliser can be reduced and, by using the composition of the invention, tablets with a drug load of 0.133 mg compound A per mg tablet can be made available. In order to ensure appropriate exposure levels, dose adjustment may therefore be necessary.

The present invention provides a solid oral dosage form according to the invention for use in medicine, more specifically for use in the treatment of HBV infection. In yet another aspect, the invention relates to a method for the treatment of an HBV infection in a subject which comprises administering the subject an effective amount of an oral dosage form according to the invention. In particular, the invention relates to a method of preventing or treating HBV infection in a subject, said method comprising administering to said subject compound A at a daily dose of 50-300 mg, in particular 50-250 mg, wherein compound A is administered in at least one dosage form comprising a solid dispersion comprising compound A or a pharmaceutically acceptable salt or a solvate thereof, and a stabiliser selected from at least one of Hypromellose (HPMC) and Hypromellose acetate succinate (HPMC-AS) at a ratio of 1 : 1 to less than 1 :3 by weight with the proviso that the ratio is not 1 :2 by weight; more in particular at a ratio of 1 : 1 to less than 1 :2 by weight, yet more in particular, at a ratio of 1 :1.5 by weight.

In certain embodiments of the use or method of treating HBV infection provided herein, the treatment is curative and the patient does not have to continue treatment after the specified treatment time. In a particular embodiment of the use or method of treating HBV provided herein, the treatment is finite.

In an embodiment of the use or method method, the use or method further comprises administering, in particular co-administering, a transcription inhibitor to the subject. In a particular embodiment, the transcription inhibitor is a nucleoside analog. In a particular embodiment, the nucleoside analog is administered at the approved daily dosing regimen for the nucleoside analogue. In a more particular embodiment, the nucleoside analog is tenofovir, or a pharmaceutically acceptable salt or prodrug thereof (e.g. tenofovir disoproxil fumarate or tenofovir alafenamide), or entecavir, or a

pharmaceutically acceptable salt or prodrug thereof (e.g. entecavir monohydrate). In a particular embodiment, the nucleoside analog is tenofovir disoproxil fumarate. In a particular embodiment, the nucleoside analog is tenofovir alafenamide. In a particular embodiment, the nucleoside analog is entecavir monohydrate. In a further particular embodiment, the tenofovir disoproxil fumarate is administered in an amount of 60-600 mg. In another further embodiment, the tenofovir disoproxil fumarate is administered in an amount of 300 mg. In yet another further embodiment, the entecavir monohydrate is administered in an amount of 0.1-1 g. In still another embodiment, the entecavir monohydrate is administered in an amount of 0.5 mg.

In an embodiment of the use or method, the use or method further comprises administering an immune modulator. In a particular embodiment, the immune modulator is interferon, for example interferon alpha or pegylated interferon alpha.

In a further embodiment of the use or method, the subject is treatment naive.

In some embodiments, the use or method further comprises administering at least one Nucleic Acid Polymer (NAP), more particularly at least one NAP which inhibits the release of subviral particles from hepatocytes.

In some embodiments, the use or method further comprises administering at least one short interfering RNA (siRNA) or antisense oligonucleotide (ASO), more particularly at least one siRNA or ASO sleeted from the group of siRNAs and ASOs which inhibit the expression of one or more genes that are necessary for replication or pathogenesis of HBV.

In some embodiments, the administration of compound A is performed for an administration period of about 24 weeks. In another embodiment, the administration of compound A is performed for an administration period of longer than 24 weeks. In yet another embodiment, the administration of compound A is performed for an administration period shorter than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In embodiments, compound A is administered for a duration of 28 days. In embodiments, compound A is administered for a duration of about 48 weeks. In embodiments, compound A is 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, the administration of compound A and the transcription inhibitor is performed for an administration period of longer than 24 weeks. In yet another embodiment, the administration of compound A and the transcription inhibitor is performed for an administration period shorter than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In embodiments, compound A and the transcription inhibitor is

administered for a duration of 28 days. In embodiments, compound A and the

transcription inhibitor is administered for a duration of about 48 weeks. In embodiments, compound A and the transcription inhibitor is administered for a duration of longer than 48 weeks.

In embodiments of the methods provided herein, compound A is administered to reach a maximal concentration (Cmax) of at least 3,000 ng/mL (e.g., at steady state), in the plasma of the patient and/or an AUC of at least 50,000 ng.h/mL (e.g., at steady state), in the plasma of the patient. In embodiments of the methods provided herein, Compound A is administered to reach a maximal concentration (Cmax) of at least 3,000 ng/mL, in the plasma of the patient and/or an AUC of at least 50,000 ng.h/mL, in the plasma of the patient.

The daily doses described herein are calculated for an average body weight of about 60 to about 70 kg and should be recalculated in case of paediatric applications, or when used with patients with a substantially diverting body weight.

In another aspect, the present disclosure provides a kit of parts for treating HBV infections, comprising a pharmaceutical composition comprising compound A, or a pharmaceutically acceptable salt or a solvate thereof, as described herein. In some embodiments, the kit of parts further comprises packaging and instructions.

In some embodiments, the kit of parts comprises a pharmaceutical composition comprising compound A, or a pharmaceutically acceptable salt or solvate thereof, as described herein; an additional HBV antiviral agent; and a pharmaceutically acceptable carrier or diluent.

The additional HBV antiviral agent can e.g., be a nucleos(t)ide analogue (such as tenofovir or a pharmaceutically acceptable salt or prodrug thereof, or entecavir or a pharmaceutically acceptable salt thereof); an immune modulator (such as interferon), at least one Nucleic Acid Polymer (more particularly at least one NAP which 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 sleeted from the group of siRNAs and ASOs which inhibit the expression of one or more genes that are necessary for replication or pathogenesis of HBV).

In additional embodiments, pharmaceutical kits are provided. The kit includes a sealed container approved for the storage of pharmaceutical compositions, the container containing one of the above-described pharmaceutical compositions. In some embodiments, the sealed container minimizes the contact of air with the ingredients, e.g. an airless bottle. In other embodiments, the sealed container is a sealed tube. An instruction for the use of the composition and the information about the composition are to be included in the kit.

The following examples are merely illustrative and are not intended to limit the disclosure to the materials, conditions, or process parameters set forth therein. EXAMPLES

Reference Example 1: Existing Formulations of Compound A

The quantitative and qualitative composition of the Compound A 250 mg/g spray dried powder (G001) is provided in Table 1 below.

The qualitative and quantitative composition of the Compound A 100-mg (G009) 25- mg (G008) and 5-mg (G007) oral tablets is provided in Table 2 below. The tablets contain compound A and a stabiliser at a ratio of 1 :3 by weight.

The quantitative and qualitative composition of the Compound A 250 mg/g spray dried powder (G021) is provided in Table 3 below.

The qualitative and quantitative composition of the Compound A 100-mg (G022) oral tablets, Compound A 100-mg (G024) oral tablets and Compound A 25-mg (G-25) oral tablets are provided in Table 4 below. The tablets contain compound A and a stabiliser at a ratio of 1 :3 by weight.

Table 4: Qualitative and Quantitative Composition of Compound A 100-mg oral tablets (G022), 100-mg oral tablets (G024) and 25-mg oral tablets (G025)

Quantity Quantity Quantity per per per

Component Quality Reference Function Tablet Tablet Tablet

(mg) (mg) (mg)

G022 G024 G025

Intragranular Phase

250 mg/g spray dried Company

Active 400.00 400.00 100.00 powder (G021) specifications

Microcrystalline Ph.Eur. Filler

400.00 256.00 64.00 cellulose

Croscarmellose sodium Ph.Eur. Disintegrant 30.00 30.00 7.50 Colloidal anhydrous Ph.Eur. Glidant

6.00 6.00 1.50 silica

Magnesium stearate, Ph.Eur. Lubricant

3.00 3.00 0.75 NF^a

Extragranular Phase

Silicified NF Filler

Microcrystalline 316.00 394.00 98.50 Cellulose

6.00 6.00 1.50 silica

Magnesium stearate, Ph.Eur. Lubricant

9.00 9.00 2.25 NF^a

Pre-gelatinized Maize Ph.Eur Filler

66.00 16.50 Starch _

Nominal Weight _ 1 ,200.00 1 ,200.00 300.00 ^a Vegetable grade

Example 1: New formulations according to the invention

The quantitative and qualitative composition of the Compound A 400 mg/g spray dried powder (G028) is provided in Table 5 below.

The quantitative and qualitative composition of the Compound A 400 mg/g spray dried powder (G028) is provided in Table 6 below.

The qualitative and quantitative composition of the Compound A 100-mg (G030) oral tablets and 100-mg (G031) oral tablets is provided in Table 7 below. The tablets contain compound A and a stabiliser at a ratio of 1 : 1.5 by weight. Table 7: Qualitative and Quantitative Composition of Compound A 100-mg oral tablets (G030) and (G031)

Quantity

Quantity per

per Tablet

Component Quality Reference Function Tablet (mg)

(mg) G030

G031

Intragranular Phase

Company

400 mg/g spray dried powder (G028) Active 250.00

specifications

Company

400 g/g spray dried powder (G029) Active 250.00 specifications

Microcrystalline cellulose Ph.Eur. Filler 370.00 310.00 Croscarmellose sodium Ph.Eur. Disintegrant 25.00 25.00 Hydrophobic colloidal silica Ph.Eur. Glidant 5.00 5.00 Lactose monohydrate Ph.Eur. Filler 90.00 Magnesium stearate³ Ph.Eur. Lubricant 2.50 2.50 Extragranular Phase

Silicified Microcrystalline Cellulose NF Filler 255.00 280.00 Croscarmellose sodium Ph.Eur. Disintegrant 25.00 25.00 Colloidal anhydrous silica Ph.Eur. Glidant 5.00 5.00 Magnesium stearate, IMF³ Ph.Eur. Lubricant 7.50 7.50 Pre-gelatinized Maize Starch Ph.Eur Filler 55.00

Nominal Weight 1 ,000.00 1 ,000.00 ³ Vegetable grade Example 2: Phase 1, open-label studies in healthy adult subjects to assess the

bioavailability of Compound A

Phase 1 open-label studies were performed to assess the safety, tolerability, and

pharmacokinetics (PK) of Compound A after oral administration of a single dose in a fasted state or in a fed state. Full plasma PK profiles were determined.

Study 1 evaluated the exposure of G020, a 10 mg/mL aqueous suspension of Compound A in a crystalline form, as well as the exposure of G009, a 100-mg tablet containing an amorphous solid dispersion of compound A and HPMC as a stabiliser at a ratio of 1 :3 by weight. Study 2 evaluated the exposure of G024, a 100-mg tablet containing an

amorphous solid dispersion of compound A and HPMC-AS as a stabiliser at a ratio of 1 :3 by weight, in a fasted state in 2 separate cohorts (n=13, n=10) and in a fed state in 1 cohort Study 2 also evaluated the exposure of G030, a 100-mg tablet containing an amorphous solid dispersion of compound A and HPMC-AS as a stabiliser at a ratio of 1 : 1.5 by weight and of G031 , a 100-mg tablet containing an amorphous solid dispersion of compound A and HPMC as a stabiliser at a ratio of 1 :1.5 by weight.

The PK data is summarized in Fig. 1 and table 8.

Table 8: Pharmacokinetic results in healthy volunteers

Tablet formulations containing an amorphous solid dispersion of compound A and HPMC or HPMC-AS as a stabiliser at a ratio of 1 :3 by weight (G009, G024) result in exposures in healthy subjects that can result in treatment regimen in cHBV patients with acceptable pill burden.

Tablet formulations containing an amorphous solid dispersion of compound A and HPMC or HPMC-AS as a stabiliser at a ratio of 1 :1.5 by weight (G030, G031) result in exposures that can result in treatment regimen in cHBV patients with comparable exposures as formulations with the higher stabilizer amount and allow for formulation of a tablet with higher concentration of Compound A and thus reduced pill burden. Exposure of the tablet formulations containing an amorphous solid dispersion of compound A and HPMC or HPMC-AS as a stabiliser at a ratio of 1 :1.5 or 1 :3 by weight is significantly higher compared to exposure of a crystalline aqueous suspension of Compound A. Exposure of the crystalline suspension formulation was approximately 16 fold lower compared to the tablet formulation G024 after dosing in fed state. The dose of the crystalline suspension would need to be approximately 16 fold higher to reach the same exposure as the oral tablet G024; based on this, and without wishing to be bound by theory, a tablet formulation with the compound in a crystalline form could therefore result in treatment regimen in cHBV patients with a high pill burden. High pill burden can affect patient adherence as it is not convenient for the patient and certainly not for a treatment regimen that has to be administered for a prolonged period of time.

The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety.

While the invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention can be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

1. A solid dispersion comprising compound A:

(A),

or a pharmaceutically acceptable salt or solvate thereof, and a stabiliser selected from at least one of Hypromellose (HPMC) and Hypromellose acetate succinate (HPMC-AS) at a ratio of 1 : 1 to less than 1 :3 by weight, with the proviso that the ratio is not 1 :2 by weight.

2. The solid dispersion according to claim 1 , wherein compound A and the stabiliser selected from at least one of Hypromellose (HPMC) and Hypromellose acetate succinate (HPMC-AS) are present at a ratio of at a ratio of 1 :1 to less than 1 :2 by weight.

3. The solid dispersion according to claim 1 or 2, wherein compound A and the stabiliser selected from at least one of Hypromellose (HPMC) and Hypromellose acetate succinate (HPMC-AS) are present at a ratio of 1 :1 to 1 :1.5 by weight.

4. The solid dispersion according to any one of claims 1 to 3, wherein compound A is in amorphous form.

5. The solid dispersion according to any one of claims 1 to 4, wherein compound A is in amorphous base form.

6. The solid dispersion according to any one of claims 1 to 5, wherein the stabiliser is HPMC.

7. The solid dispersion according to any one of claims 1 to 5, wherein the stabiliser is HPMC-AS.

8. The solid dispersion according to any one of claims 1 to 7, wherein the solid dispersion is a solid solution.

9. A solid oral dosage form, comprising a solid dispersion as claimed in any one of claims 1 to 8.

10. The solid oral dosage form according to claim 9, wherein the solid oral dosage form is a tablet.

11. A process for preparing an oral dosage form according to claim 10, comprising the steps of:

mixing the spray-dried powder with part of tablet excipients;

performing dry granulation of the mixture;

adding part of tablet excipients to the granulate and mixing until homogeneous;

- compressing the mixture to provide the oral dosage form, said oral dosage form then being optionally film-coated;

or alternatively, comprising the steps of:

mixing the spray-dried powder with tablet excipients; and

12. The oral dosage form as claimed in claim 9 or 10, for use as a medicament.

13. The oral dosage form as claimed in any claim 9 or 10, for use in the treatment of HBV infection.

14. A product containing (a) the oral dosage form as claimed in claim 9 or 10, and (b) another HBV inhibitor, in particular, a nucleoside analogue, as a combined preparation for simultaneous, separate or sequential use in the treatment of HBV infections.

15. A method for the treatment of an HBV infection in a subject which comprises administering to the subject a therapeutically effective amount of an oral dosage form as claimed in claim 9 or 10.