Treatment of hepatitis delta virus infection

Abstract

Lonafarnib, a phenyltransferase inhibitor, and ritonavir, a CYP3A4 inhibitor, are used in combination to treat hepatitis delta virus (HDV) infection. HDV infection is treated by orally administering a therapeutically effective dose of lonafarnib and a therapeutically effective dose of a CYP3A4 inhibitor to the patient for at least 30 days. Optionally, treatment includes the prophylactic administration of one or more GI modifiers.

Description

Technology Field

[0001] Cross-reference of related applications

[0002] This application claims priority to U.S. provisional applications No. 62 / 151,349 (filed April 22, 2015), 61 / 987,315 (filed May 1, 2014), 62 / 044,766 (filed September 2, 2014), and 62 / 073,413 (filed October 31, 2014). The full contents of each of the aforementioned provisional applications are incorporated herein by reference.

[0003] Field of invention

[0004] The present invention provides a method for treating a viral infection caused by Delta Hepatitis Virus (HDV) infection, and thus relates to the fields of chemistry, medicinal chemistry, medicine, molecular biology and pharmacology. Background Technology

[0005] Background of the Invention

[0006] Delta hepatitis virus (HDV) causes the most severe form of viral infection, and there is no effective medical treatment for it (see literature [Lau, 1999, Hepatology 30:546-549]). HDV always manifests as a co-infection with HBV, and co-infected patients are much more likely to die from complications of the viral infection than patients infected with HBV alone. Currently available anti-HBV agents include the following nucleotide or nucleoside reverse transcriptase (RT) inhibitors: lamivudine, adefover, entecarber, telbivudine, clevudine, and tenofover. HBV / HDV co-infection can be treated with alpha interferon therapy or therapy with pegylated interferon alpha-2a (alone or in combination with one of the above RT inhibitors).

[0007] The HDV large delta antigen protein contains a CXXX box that serves as a substrate for prenylation by prenyl lipid farnesyltransferase (see reference [Zhang and Casey, 1996, Annu.Rev.Biochem. 65: 241-269]) (see reference [Glenn et al., 1992, Science 256: 1331-1333, and Otto and Casey, 1996, J. Biol. Chem. 271: 4569-4572]). Farnesylation of proteins catalyzed by FTase is an essential step in the processing of various proteins and occurs through the transfer of the farnesyl group of farnesyl pyrophosphate to cysteine ​​in the C-terminal tetrapeptide of the protein at a structural motif often referred to as the CAAX box. Further post-translational modifications of farnesylated proteins, including proteolytic cleavage at cysteine ​​residues in the CAAX box and methylation of cysteine ​​carboxylates, generally follow farnesylation. Molecular genetic experiments have demonstrated that specific mutations in the prenylation site of the large delta antigen prevent both its prenylation and HDV particle formation (see [Glenn et al., 1992, supra]; also see [Glenn et al., 1998 J. Virol. 72(11): 9303-9306]; also see [Bordier et al., 2002 J. Virol. 76(20): 10465-10472]). There is a continuing need for agents to treat HDV infections.

[0008] Brief Summary of the Invention

[0009] In one embodiment, the present invention provides a method for treating HDV infection by oral administration of lonafarnib in combination with a CYP3A4 inhibitor (e.g., ritonavir or cobicistat). In one embodiment, the present invention provides a method for treating HDV infection by oral administration of lonafarnib in doses of about 50 mg QD or BID, about 75 mg QD or BID, or about 100 mg QD, in combination with ritonavir administered in a therapeutically effective dose QD or BID or another CYP3A4 inhibitor administered in a therapeutically effective dose BID or QD. In one embodiment, the present invention provides a method for treating HDV infection by oral administration of at least about 50 mg QD or BID or at least about 100 mg QD or BID, in combination with ritonavir administered in a therapeutically effective dose QD or BID or another CYP3A4 inhibitor administered in a therapeutically effective dose BID or QD.

[0010] In one embodiment, a patient treated with lonafarnib-ritonavir combination therapy is administered a daily dose of lonafarnib of 50 mg / day to 150 mg / day, e.g., 50 mg / day, 75 mg / day, 100 mg / day, or 150 mg / day, and a daily dose of ritonavir of 100 mg / day to 200 mg / day, e.g., 100 mg / day or 200 mg / day.

[0011] In one embodiment, the patient is administered a daily dose of 150 mg of lonafarnib and 200 mg of ritonavir. For example, the patient may be administered 75 mg of lonafarnib BID and 100 mg of ritonavir BID.

[0012] In one embodiment, the patient receives a daily dose of 100 mg of lonafarnib and 200 mg of ritonavir. For example, the patient may receive 50 mg of lonafarnib BID and 100 mg of ritonavir BID.

[0013] In one embodiment, the patient receives a daily dose of 150 mg of lonafarnib and 100 mg of ritonavir. For example, the patient may receive 75 mg of lonafarnib BID and 100 mg of ritonavir QD.

[0014] In one embodiment, the patient receives a daily dose of 75 mg of lonafarnib and 100 mg of ritonavir. For example, the patient may receive 75 mg of lonafarnib QD and 100 mg of ritonavir QD.

[0015] In one embodiment, the patient receives a daily dose of 50 mg of lonafarnib and 100 mg of ritonavir. For example, the patient may receive 50 mg of lonafarnib QD and 100 mg of ritonavir QD.

[0016] In one embodiment, the patient is administered lonafarnib orally at a daily dose of 50 mg / day, 75 mg / day to 150 mg / day administered BID or QD, and linotavir orally at a daily dose of 100 mg / day to 200 mg / day administered BID or QD, e.g., 100 mg / day or 200 mg / day administered daily, wherein the treatment induces a serum concentration of lonafarnib greater than 2,000 ng / mL, preferably greater than 4,000 ng / mL, more preferably in the range of about 3,500 ng / mL to about 7,500 ng / mL.

[0017] In one embodiment, the patient optionally receives an oral dose of lonafarnib of 75 mg / day to 150 mg / day administered BID or QD with a boosting agent, wherein this treatment induces serum lonafarnib concentrations greater than 2,000 ng / mL, preferably greater than 4,000 ng / mL, more preferably in the range of about 3,500 ng / mL to about 7,500 ng / mL.

[0018] In some embodiments, lonafarnib and ritonavir or similar boosting agents are administered to the patient during an extended therapy course of at least 30 days, more often at least 60 days or at least 90 days, even more often at least 120 days, sometimes at least 150 days and sometimes at least 180 days. In some embodiments, administration will be discontinued after viral levels have decreased to less than 3 log HDV RNA copies / mL (less than 1,000 copies / mL) or below detectable levels for a certain period (e.g., 1 to 3 months or more).

[0019] In one embodiment, prior to the initiation of oral administration of lonafarnib and ritonavir, the patient is prophylactically treated with at least one GI modifier, and typically a combination of at least two GI modifiers (one or more of antiemetics, antidiarrheals, and antacids).

[0020] In another embodiment, a GI modifier is administered simultaneously with lonafarnib and ritonavir, and lonafarnib is administered as a sustained-release formulation and is not released until after the GI modifier begins to exert its effect.

[0021] These and other aspects and embodiments of the present invention are described in more detail below. Brief explanation of the drawing

[0022] Figure 1 graphs the time course of HDV RNA levels (copy / mL) in patients 4, 5, and 6. See Example 1. Figure 2 graphs the HDV RNA virus load in patients against serum levels of lonafarnib in patients treated with 100 mg lonafarnib BID for 28 days. Figure 3 graphs HDV RNA virus titers in human patients treated with lonafarnib at doses of 200 mg BID or 300 mg BID for a period of 28 days. See Example 2. Figure 4 graphs the change in HDV RNA virus titers in patients treated with the doses of lonafarnib and interferon described in Example 3. Figure 5 graphs HDV RNA virus titers in patients treated with a dose of 100 mg BID of lonafarnib or 100 mg QD of ritonavir for a period of 28 days. See Example 4. Figure 6a graphs the change in HDV RNA virus titers from a standardized reference in patients treated with the doses of lonafarnib and ritonavir described in Example 5 over a period of 28 days. Figure 6b graphs the change in HDV RNA virus titers in patients treated with the doses of lonafarnib and ritonavir described in Example 5 over a period of 56 days. Figure 6c graphs the change in HDV RNA virus titers in patients treated with the doses of lonafarnib and ritonavir described in Example 5 over a period of 84 days. Figure 7 graphs the inverse correlation between higher lonafarnib serum levels and HDV virus load. Figure 8 graphs the reduced correlation between lower lonafarnib serum levels and HDV virus load. Figure 9 graphs the relationship between lonafarnib serum concentration and changes in viral load. Figure 10 graphs the change in HDV RNA virus titers in patients treated with lonafarnib and pegylated interferon or lonafarnib and ritonavir. Figure 11 graphs the change in ALT values ​​in patients treated with lonafarnib and pegylated interferon. Specific details for implementing the invention

[0023] Detailed description of the invention

[0024] This detailed description of the invention is divided into sections for the convenience of the reader. As will be apparent to those skilled in the art when reading this disclosure, each individual embodiment described and illustrated herein has individual components and features that can be easily separated from or combined with the features of any of the other embodiments without departing from the scope or spirit of this description (regardless of whether they are described in the same or different sections of this description). Any method mentioned may be performed in the order of the enumerated events or in any other logically possible order. Unless otherwise indicated, the embodiments of this description utilize synthetic organic chemistry, biochemistry, biology, molecular biology, recombinant DNA technology, pharmacology, and the like, and these technologies belong to the field. These technologies are sufficiently described in the literature. This description is not limited to the specific embodiments described, and, of course, embodiments of the invention may actually differ from those described herein.

[0025] I. Definition

[0026] The terms used herein are for the purpose of describing specific embodiments only and are not intended to limit the scope of the invention, as the scope of the invention is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by those skilled in the art to which the invention pertains. In this specification and the following claims, references will be made to many terms that are defined as having the following meanings, unless otherwise evident. In some cases, terms having the generally understood meaning have been defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not be interpreted as representing a substantial difference from the definitions of terms as generally understood in the art.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by those skilled in the art to which the present invention pertains. Any method and material similar or equivalent to that described herein may be used to practice or test the present invention, but preferred methods, apparatuses, and materials are described hereafter. All technical and patent publications cited herein are incorporated herein by reference in their entirety. It should not be construed that the present invention does not precede such descriptions by prior art.

[0028] All numerical notations including ranges, e.g., pH, temperature, time, concentration, and molecular weight, are approximations that change (+) or (-) by increments of 0.1 or 1.0, as appropriate. Although not always explicitly stated, all numerical notations should be understood as being preceded by the term "approx."

[0029] The singular form includes plural objects unless the context clearly indicates otherwise. Thus, for example, a reference to "compound" includes plural compounds.

[0030] The term "administration" refers to the introduction of the compound, composition, or preparation described herein into a host, e.g., a human. One preferred route of administration of the preparation is oral administration. Other routes are intravenous administration and subcutaneous administration.

[0031] The term "comprising" is intended to mean that the compound, composition, and method include the cited elements but do not exclude other elements. When used to define the compound, composition, and method, "essentially constituting" means excluding other elements that substantially affect the fundamental and novel characteristics of the claimed invention. "Constituting" means excluding any elements, steps, or components not specified in the claims. The embodiments defined by each of these conjunction terms are within the scope of the invention.

[0032] The term "lonafarnib" or "EBP994," also known by the trademark Sarasar (Schering), refers to FTase inhibitor 4 (2[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5Hbenzo[5,6]-cyclohepta[1,2b]pyridine-11yl]-piperidino]-2-oxoethyl]-1-piperidinecarboxamide) having the structure presented below (also identified as Sch-66336 or SCH 66336):

[0033]

[0034] Lonafarnib

[0035] Lonafarnib is a crystalline solid with a melting point of approximately 200°C and is non-absorbent. Its molecular weight is 638.7. In the solid state, the compound is thermally stable. In solution, it is stable at neutral pH but hydrolyzes under acidic or basic conditions. It is a tricyclic compound with low water solubility, which leads to low and variable bioavailability in animals when formulated in a crystalline form. Considerable efforts have been made to develop formulations to improve oral bioavailability. In addition to the drug substance, suitable pharmaceutical formulations of lonafarnib for administration in capsules contain povidone, poloxamer 188, sodium croscarmellose, silicon dioxide, and magnesium stearate. The product is formulated as a drug:povidone (1:1) co-precipitation to achieve optimal bioavailability. These are safe and well-tested excipients commonly used in commercially available products.

[0036] The terms "HDV RNA viral load" or "viral load" in human serum or plasma samples refer to the number of copies of human HDV RNA in a given amount of human serum or plasma sample. Currently, while there are commercially available tests for the detection of HDV RNA (Quest Therapeutics), there are no commercially available clinical tests for the quantification of HDV RNA in clinical samples. However, several such assays reported in the literature (e.g., [Kodani et al., 2013, J. Virol. Methods, 193 (2), 531; and Karatayli et al., 2014, J. Clin. Virol, 60 (1), 11]) utilize quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) assays for the quantification of HDV RNA in serum or plasma that are suitable for use according to the method of the present invention. The amount of signal generated during the assay is proportional to the amount of HDV RNA in the sample. The signal from the evaluation sample is compared to that of the dilution series of the quantified delta hepatitis RNA standard, and the number of genomic copies is calculated.

[0037] The term "HDV infection" related to humans (hosts) indicates that the host is suffering from an HDV infection. Typically, an HDV-infected human host will have a viral load of at least about 2 log HDV RNA copies / host serum or plasma mL or 102 copies of HDV RNA / host serum or plasma mL, often at least about 3 log HDV RNA copies / host serum or plasma mL or 103 copies of HDV RNA / host serum or plasma mL, and, in particular, in patients who have not received any treatment, often at least about 4 log HDV RNA copies / host serum or plasma mL or 104 copies of HDV RNA / host serum or plasma mL, e.g., about 4 log HDV RNA copies / host serum or plasma mL to 7 log HDV RNA copies / host serum or plasma mL or 104-107 copies of HDV RNA / host serum or plasma mL of HDV RNA.

[0038] The terms "patient," "host," or "subject" are used interchangeably and refer to a human infected with HDV, including a patient previously infected with HDV from which the virus has been cleared.

[0039] The term "drug composition" means comprising a composition suitable for administration to a subject. In general, the "drug composition" is sterile and, preferably, does not contain contaminants that could induce undesirable reactions within the subject (e.g., the compound(s) of the drug composition are of pharmaceutical grade). The drug composition may be designed to be administered to subjects or patients requiring it via a number of various routes of administration, including oral, intravenous, oral, rectal, parenteral, intraperitoneal, intradermal, intratracheal, intramuscular, subcutaneous, inhalation, and others.

[0040] The terms “pharmaceuticalally acceptable excipient,” “pharmaceuticalally acceptable diluent,” “pharmaceutically acceptable carrier,” or “pharmaceutically acceptable adjuvant” generally mean an excipient, diluent, carrier, and / or adjuvant that is safe, non-toxic, useful for preparing a desirable pharmaceutical composition for biological or other purposes, and is acceptable for veterinary and / or human pharmaceutical use. As used in the specification and claims, “pharmaceutically acceptable excipient, diluent, carrier, and / or adjuvant” comprises one or more such excipients, diluents, carriers, and adjuvants. A wide range of pharmaceutically acceptable excipients, e.g., vehicles, adjuvants, carriers, or diluents, and auxiliary substances, e.g., pH regulators and buffers, osmotic regulators, stabilizers, wetting agents, and others, are known in the art. Pharmaceutically acceptable excipients are, for example, [A. It is sufficiently described in various public literature, including Gennaro (2000) "Remington: The Science and Practice of Pharmacy", 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) HC Ansel et al., eds., 7th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) AH Kibbe et al., eds., 3rd ed. Amer. Pharmaceutical Assoc.].In the case of oral formulations, lonafarnib and / or ritonavir may be used alone or in combination with suitable additives for making tablets, powders, granules, or capsules, for example, conventional additives such as lactose, mannitol, corn starch, or potato starch; binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch, or gelatin; disintegrants such as corn starch, potato starch, or sodium carboxymethylcellulose; lubricants such as talc or magnesium stearate; and, if necessary, diluents, buffers, wetting agents, preservatives, and flavoring agents.

[0041] The term “pharmaceutically acceptable salt” refers to such salts having biological efficacy and, optionally, other properties of free bases obtained by reaction with inorganic or organic acids such as hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, malic acid, maleic acid, succinic acid, tartaric acid, citric acid, and others. Where specific examples of the described formulations form salts, these salts are within the scope of this description. Unless otherwise noted, any reference to a formulation of any formula of this invention is understood to include a reference to its salt.

[0042] The term “therapeutic effective dose” as used herein refers to such an amount of a specific example of a preparation to be administered (which may be referred to as a compound, inhibitor, and / or drug) that treats a disease, condition, or state to some extent, for example, alleviates one or more of the symptoms of the disease being treated, i.e., infection, and / or such an amount that prevents to some extent one or more of the symptoms of the disease being treated, i.e., infection, which the subject being treated has or is at risk of developing.

[0043] The terms “treatment,” “treating,” and “treat” are defined as acting a preparation on a disease, condition, or state to reduce or improve the pharmacological and / or physiological effects of the disease, condition, or state and / or its symptoms. As used herein, “treatment” encompasses any treatment of a disease in human subjects, including (a) reducing the risk of disease onset in subjects measured as susceptible to disease but not yet diagnosed as infected with the disease; (b) inhibiting the development of the disease and / or (c) remission of the disease, i.e., inducing disease regression and / or alleviating one or more disease symptoms. “Treatment” also implies the delivery of an inhibitor to provide a pharmacological effect, even in the absence of the disease or condition. For example, “treatment” includes the delivery of a disease or pathogen inhibitor to provide an enhanced or desirable effect in a subject (e.g., reduction of pathogen viral load, reduction of disease symptoms, etc.).

[0044] The term “unit dosage form” as used herein refers to a physically separated unit suitable for a single dose to a human subject, each unit containing a predetermined amount of a compound (e.g., an antiviral compound as described herein) or compounds calculated in an amount sufficient to induce a desired therapeutic effect in relation to a pharmaceutically acceptable diluent, carrier, or vehicle.

[0045] As used herein, the term “oral dosage form” refers to a dosage form administered orally, such as tablets, capsules, gel caps, syrups, elixirs, and suspensions. “Solid oral dosage form” includes tablets, capsules, coated tablets, and others.

[0046] The term "oral unit dosage form" as used herein refers to a unit dosage form administered orally.

[0047] For the purposes of the present invention, with reference to the parent compound, all deuterated analogs of any active pharmaceutical ingredient described herein, including lonafarnib, ritonavir, and cobicistat (where the compound is distinguished from the parent compound by the substitution of only one or more hydrogen atoms with one or more deuterium atoms, another compound, i.e., a deuterated analog of the “parent compound”) are included.

[0048] All stereoisomers of any formulation described herein, including, but not limited to, lonafarnib, ritonavir, cobicistat, and any other active agent described herein, that may exist due to asymmetric carbons for various substituents including enantiomer forms (which may exist even in the absence of asymmetric carbons) and diastereomer forms, are considered within the scope of this description. Individual stereoisomers of the compounds described herein may, for example, be substantially absent from other isomers, or may, for example, be mixed with all other or other selected stereoisomers as a racemic mixture. The stereocenters of the compounds described herein may have an S or R configuration as defined in the IUPAC 1974 Recommendations.

[0049] The term "antacid" refers to a preparation that reduces gastric acid secretion or impairs its effects, and includes H2-receptor antagonists and proton pump inhibitors.

[0050] "H2-receptor antagonists" are a class of drugs used to reduce acid production by parietal cells in the stomach (specifically, histamine H2 receptors) by blocking the action of histamine on these cells. H2 antagonists are used to treat indigestion.

[0051] "5-HT3 antagonists" are a class of drugs that act as receptor antagonists on 5-HT3 receptors, which are a subtype of serotonin receptors found in several critical sites involved in vomiting (including the afferent vagus nerve, the nucleus solitary tract (STN), and its own sub-region). Serotonin is released by intestinal chromaffin cells in the small intestine in response to chemotherapy agents and can stimulate the afferent vagus nerve (via 5-HT3 receptors) to initiate the vomiting reflex. 5-HT3 receptor antagonists suppress vomiting and nausea by inhibiting serotonin binding to 5-HT3 receptors. The highest concentrations of 5-HT3 receptors in the central nervous system (CNS) are found in the STN and the chemoreceptor-triggered zone (CTZ), and 5-HT3 antagonists can also suppress vomiting and nausea by acting on these sites.

[0052] "NK1" is a G protein-coupled receptor located in the central and peripheral nervous systems. This receptor possesses a dominant ligand known as Substance P (SP). SP is a neuropeptide composed of 11 amino acids that sends and receives stimuli and messages from the brain. It is found in high concentrations in the brain's vomiting center and triggers vomiting reflux when activated. NK-1 receptor antagonists block the signals emitted by the NK1 receptor.

[0053] "Proton pump inhibitors" are a class of antisecretory compounds that inhibit gastric acid secretion by specifically inhibiting the H+ / K+ ATPase enzyme system at the secretory surface of gastric parietal cells. Since this enzyme system is considered an acid (proton) pump within the gastric mucosa, inhibitors of this system are characterized as gastric acid-pump inhibitors in that they block the final stage of acid production. This effect is dose-dependent and induces inhibition of both irritant-independent basal acid secretion and stimulated acid secretion.

[0054] "Antidiarrheal agents" can be of one of two types: those that thicken the stool and those that slow intestinal spasms. Concentrated mixtures (e.g., psyllium) absorb water. This helps increase the volume of the stool, making it more solid. Antispasmodic antidiarrheal products slow intestinal spasms by acting on μ-opioid receptors in the muscular plexus of the large intestine. By reducing the activity of the muscular plexus and subsequently decreasing the tone of the longitudinal and circular smooth muscles of the intestinal wall, the amount of time substances remain in the intestine increases, which allows more water to be absorbed from the stool. Antispasmodics also reduce the movement of substances in the colon and inhibit the gastrocolic reflex.

[0055] The term "GI intolerance" refers to any one of diarrhea, nausea, and vomiting, individually or in combination.

[0056] II. Introduction

[0057] In one aspect, the present invention relates to the treatment of patients infected with hepatitis D virus (HDV) by co-administration of the prenyltransferase inhibitor lonafarnib and the CYP3A4 inhibitor ritonavir. Although the use of lonafarnib to treat HDV infection was proposed in WO 2011 / 088126, incorporated herein by reference, this publication did not include in vivo efficacy data and described a wide range of dosages (e.g., 25 to 300 mg per day). As described below, the inventors found that administration of lonafarnib at 100 mg BID for 28 days reduced the viral load, but this reduction was insufficient for development as a therapeutic agent. Higher dosages of lonafarnib were poorly tolerated and resulted in unacceptable levels of adverse effects. As such, when administered at 200 mg BID, serum levels of lonafarnib decreased after approximately one month of treatment, likely due to poor tolerability, poor patient compliance, and loss of the agent passing through the GI tract. When administered at 300 mg BID, serum levels of lonafarnib were lower than expected, which also appears to be a result of poor tolerability. See, for example, Table 10 below. Therefore, while administration of lonafarnib at 100 mg BID was not sufficiently effective, higher doses were associated with significant GI-related adverse effects, making this treatment inappropriate as a routine regimen for patients infected with HDV.

[0058] The present invention arises in part from the discovery that the administration of lonafarnib in combination with ritonavir according to the dosing regimen described herein ("lonafarnib-ritonavir combination therapy") is effective in the treatment of HDV and induces superior results compared to lonafarnib monotherapy. Surprisingly, the administration of 100 mg lonafarnib BID and 100 mg ritonavir QD induced higher serum lonafarnib concentrations than observed with lonafarnib monotherapy measured after 56 days of treatment, and the frequency of adverse events was lower (see, for example, Tables 9 and 10 below). Furthermore, it was found that lonafarnib-ritonavir combination therapy can improve patient outcomes when supplemented or combined with the prophylactic administration of GI modifiers (in particular, the prophylactic administration of one or more of antiemetics, antidiarrheals, and antacids). Accordingly, one aspect of the present invention relates to lonafarnib-ritonavir combination therapy in combination with the prophylactic administration of a combination of GI modifiers.

[0059] In one embodiment, a patient treated with lonafarnib-ritonavir combination therapy is administered lonafarnib at a daily dose of 75–150 mg per day, e.g., 75 mg, 100 mg, or 150 mg per day, and ritonavir at a daily dose of 100–200 mg per day, e.g., 100 mg or 200 mg per day. The aforementioned dosages may be achieved by administering lonafarnib QD or BID and ritonavir QD or BID. In one embodiment, lonafarnib is administered BID and ritonavir is administered QD. In one embodiment, both lonafarnib and ritonavir are administered BID. In one embodiment, both lonafarnib and ritonavir are administered QD.

[0060] III. HDV treatment

[0061] The present invention provides a method for treating a disease related to HDV infection, wherein a patient with HDV infection is treated by oral administration of lonafarnib and ritonavir (which may be referred to as "lonafarnib administration," "lonafarnib-ritonavir combination therapy," and others). Preferably, lonafarnib and ritonavir are administered according to the dosage and dosing regimen described herein. In some embodiments, the patient with HDV infection receives prophylactic treatment with one, two, or three or more classes of gastrointestinal (GI) modulators. In some embodiments, the patient treated with lonafarnib-ritonavir combination therapy is also treated with interferon (e.g., interferon-alpha or interferon-lambda).

[0062] Dosage plan for lonafarnib-ritonavir combination therapy

[0063] Lonafarnib has been studied for the treatment of solid tumors and hematological malignancies, Hutchinson-Gilford progeria syndrome, and chronic delta hepatitis virus infection, but it has not been approved for any indication. Most reports regarding the administration of lonafarnib concern the administration of lonafarnib to cancer patients in combination with one or multiple antitumor agents.

[0064] Ritonavir (AbbVie, Inc. trademark Norvir) ® Ritonavir (commercially available) was administered as an antiretroviral agent in combination with other antivirals for the treatment of HIV-1 infected individuals. See reference [Miller et al., 2015, infection and Drug Resistance, 8: 19-29]. For the treatment of HIV-1 in adult patients, the recommended dose of ritonavir is 600 mg, taken orally with meals twice daily. Norvir ®Refer to the packaging instructions. Ritonaver has also been used as a pharmacological modifier or boosting agent. Pharmacokinetic "boosting" refers to the pharmacological improvement of orally administered drugs through co-administration with pharmacological modifiers that make these drugs more effective. Ritonaver is the C of the protease used to treat HIV infection. max It was used to increase. The boosting effect of ritonavir is attributed to various properties of the drug. Ritonavir inhibits two major steps of metabolism:

[0065] First, ritonavir inhibits first-pass metabolism during absorption. Intestinal cells lining the intestine contain both CYP3A4, one of the major cytochrome P450 isoenzymes involved in drug metabolism, and P-glycoprotein, an efflux transporter capable of effectively pumping drugs back from the digestive tract wall into the intestinal lumen. Ritonavir inhibits both of these proteins. Consequently, co-administration of ritonavir with drugs transported by P-glycoprotein and / or metabolized by intestinal cell CYP3A4 can increase the Cmax of the co-administered drugs. Second, ritonavir inhibits CYP3A4 in the liver, thereby maintaining the plasma half-life of the drugs.

[0066] Several factors make it impossible to predict or determine the acceptable dose of ritonavir for use as a boosting agent.

[0067] First, the boosting effect of ritonavir varies widely and unpredictably depending on the principal (i.e., co-administered) drug (PD). This is illustrated by Norvir, which shows that the co-administration effect of the principal drug and ritonavir can range from a 350-fold increase in AUC of the principal drug (fluticasone propionate, delivered as an aqueous nasal spray) to an 11-fold increase (saidnafil) or a 1.2-fold increase (trimethoprim). ®This is described in the package insert (available on the FDA website at http: / / www.rxabbvie.com / pdf / norvirtab_pi.pdf). Furthermore, there are significant differences even within a single drug class. For example, in a meta-study of 17 dose-range pharmacokinetic studies of protease inhibitors, Hill et al. evaluated the boosting effect of ritonavir with the following seven protease inhibitors at doses of 50–800 mg daily: amprenavir, atazanavir, darunavir, indinavir, lopinavir, saquinavir, and tipranavir. Hill concluded that ritonavir has a dose-dependent boosting effect on indinavir, tipranavir, and lopinavir. For example, "there was a significant increase in lopinavir Cmin when the ritonavir dose was increased from 50 mg to 100 mg." However, the boosting effect of ritonavir on darunavir or saquinavir is not correlated with their dosage. For example, a daily dosage of 200 mg of ritonavir has the same effect on serum exposure to the drug as 100 mg daily ("At a once-daily dosage of 200 mg, plasma exposure for these dosages was similar to that of 100 mg of ritonavir once daily"). Similarly, the results of the saquinavir study showed that there was no significant correlation between the dosage of ritonavir used and the achieved Cmax or Cmin of saquinavir.

[0068] Furthermore, the pharmacokinetics of ritonavir in hepatitis patients appear to be more difficult to predict compared to other treatment groups. Li et al. reported that hepatic CYP3A4 expression is downregulated in individuals with chronic HBV infection. Although a subgroup of HBV-infected patients co-infected with HDV has not been studied separately, it is expected that CYP3A4 downregulation may occur in HDV-positive individuals. See [Li et al., 2006, Zhonghua yi xue za zhi, 86: 2703-2706].

[0069] In addition, ritonavir has been reported to inhibit P-glycoprotein found in peripheral blood lymphocytes. See reference [Lucia et al., 2001, J Acquir Immune Defic Syndr. 27:321-30]. When lonafarnib is a substrate of P-glycoprotein, co-administration of ritonavir causes lonafarnib to be transported back out of the cell less, thereby [reducing] the drug 1 It can increase the intracellular half-life of.

[0070] In addition, the HDV patient subgroup is characterized by a higher level of liver cirrhosis than patients infected only with HBV (which occurs in about 60 to 70% of patients with chronic hepatitis D). The pharmacokinetics of ritonavir in the HDV patient subgroup will be more unpredictable compared to other subgroups.

[0071] The therapeutic effect of co-administration of lonafarnib and ritonavir to patients with chronic HDV was unknown prior to the present invention, and medical literature prior to the present invention did not describe an effective administration regimen (e.g., dosage and dosing plan) for the treatment of patients with chronic HDV infection.

[0072] Furthermore, the adverse effect profiles of lonafarnib administration and co-administration of lonafarnib and ritonavir had not been previously measured. Diarrhea, nausea, and vomiting are reported as adverse effects for both lonafarnib administration (see Schering IB) and ritonavir administration (see Norvir packaging leaflet). For cancer patients, the 200 mg BID lonafarnib dosage was characterized as "very well tolerated." Reference [Hanrahan et al., 2009, "A phase II study of Lonafarnib (SCH66336) in patients with chemorefractory, advanced squamous cell carcinoma of the head and neck," Am J Clin Oncol. See [32:274-279] (describes lonafarnib therapy after platinum-based therapy in relapsed SCCHN) and [List et al., 2002, Blood, 100:789A] (200 mg BID lonafarnib dose was very well tolerated in patients with advanced blood cancer). However, the adverse effect profile of lonafarnib administration at therapeutically effective levels in patients with chronic HDV infection is unknown, and the adverse effect profile of lonafarnib-ritonavir combination therapy is unknown for any population.

[0073] Effects of Lonafarnib administration on HDV infection

[0074] A cohort of patients with chronic delta hepatitis (HDV) was treated with 100 mg lonafarnib BID for 28 days and showed an average change in HDV RNA levels from baseline to a trough of -0.74 log HDV RNA copy / mL, compared to -0.24 log HDV RNA copy / mL in patients receiving a placebo. See Example 1 below. Plasma levels of lonafarnib ranged from 200 ng / mL to 1,100 ng / mL during treatment, and this study revealed that subjects with higher plasma levels of lonafarnib experienced a greater reduction in HDV RNA titers during treatment. See Figure 2. However, a more potent reduction in viral load is required.

[0075] As described in Example 2 below, administration of higher doses of lonafarnib to HDV-infected patients induced a more significant reduction in viral load. In patients who received 200 mg BID lonafarnib for 28 days, the mean change in viral load was -1.63 HDV RNA copies / mL. In patients who received 300 mg BID lonafarnib for 28 days, the mean change in viral load was -2.00 HDV RNA copies / mL.

[0076] The inventors concluded that daily administration of 200 mg BID lonafarnib provides a superior reduction in viral load in HDV patients compared to daily administration of 100 mg BID lonafarnib. However, administration of lonafarnib 200 mg / BID or 300 mg / BID causes serious side effects, making these regimens unsuitable for long-term therapy.

[0077] Table 1

[0078] Changes in viral load after 28 days in patients treated with lonafarnib or lonafarnib and ritonavir

[0079]

[0080] The average plasma levels of lonafarnib ranged from 540 ng / mL to 890 ng / mL.

[0081] Effects of Lonafarnib-Ritonavir Administration on HDV Infection

[0082] As exemplified in Examples 5-10, the lonafarnib-ritonavir co-therapy substantially reduced the HDV viral load, including a reduction to undetectable levels in one case at 8 weeks. See Fig. 5. Accordingly, in various methods of the present invention, lonafarnib and ritonavir are each administered orally daily in succession at least once a day (QD) and, in various embodiments, twice a day (BID).

[0083] As illustrated in Fig. 2, the HDV viral load decreases as the serum concentration of lonafarnib increases. The correlation between serum lonafarnib levels and viral load in patients treated with lonafarnib-ritonavir combination therapy is also illustrated by comparing the viral load of a patient maintaining serum lonafarnib concentrations in the range of approximately 3,500 to 5,000 ng / mL for about 21 days (see Fig. 7) with the viral load of a patient maintaining serum lonafarnib concentrations in the range of approximately 1,500 to 2,500 ng / mL for about 21 days (see Figs. 7 and 8). Refer also to Table 9, which shows that after 6 weeks of combination therapy, patients with the highest lonafarnib serolevels had the greatest reduction in viral load, patients with lonafarnib serolevels greater than 2,000 ng / mL generally had a more significant reduction in viral load than patients with serolevels less than 2,000 ng / mL, and patient 4 was excluded from this trend.

[0084] In certain embodiments, lonafarnib and ritonavir are co-administered according to a plan to induce serum levels of lonafarnib greater than 2,000 ng / mL, e.g., greater than 4,000 ng / mL. In some embodiments, lonafarnib and ritonavir are co-administered according to a plan to ensure that lonafarnib serum levels are in the range of about 3,500 ng / mL to about 8,500 ng / mL (e.g., about 4,500 ng / mL to about 7,500 ng / mL, about 5,000 ng / mL to about 6,000 ng / mL, about 5,500 ng / mL to about 6,500 ng / mL, about 6,000 ng / mL to about 7,000 ng / mL, or about 6,500 ng / mL to about 7,500 ng / mL) or about 5,000 ng / mL to about 7,000 ng / mL.

[0085] As used herein, serum levels or concentrations of lonafarnib may be measured from serum samples obtained periodically from subjects (e.g., weekly, every two weeks, monthly, or according to other schedules), and levels during the inter-periods may be inferred. For example, if a measurement of 4,000 ng / mL is obtained at week 4 and a measurement of 6,000 ng / mL is obtained at week 6, for the purposes of this analysis, it is concluded that the serum levels during the inter-week period are in the range of 4,000 to 6,000 ng / mL. In some embodiments, the first measurement is taken one week after the initiation of oral therapy.

[0086] Serum levels of lonafarnib can be measured using methods known in the art, including radioimmunoassays, chromatographic assays, mass spectrometry, and others. In some embodiments of the present invention, patient serum samples were extracted using protein precipitation (acetonitrile). Subsequently, samples were loaded onto a Waters CSH C18, 2.1 x 50 mm, 1.7 µm column for separation, and then LC-MS / MS was performed in cationic mode for the detection of lonafarnib. The assay range for lonafarnib was 1–2500 ng / mL.

[0087] Exemplary dosage

[0088] Non-limiting exemplary dosages for illustrative purposes are provided in Table 2. Generally, lonafarnib and ritonavir are administered together (e.g., at the same time or within about 15 minutes of each other) (e.g., self-administered by the patient).

[0089] Table 2

[0090]

[0091] Each of Specific Examples 1-8 of Table 2 may be administered with a prophylactic GI modifier (e.g., antiemetics, antidiarrheals, and antacids). See Section IV below.

[0092] In some embodiments, lonafarnib and ritonavir (or a similar boosting agent, e.g., cobicistat) are administered to a patient, and both the ritonavir dose and the EBP994 dose are at least 100 mg QD for at least 30 days, typically at least 60 days, or even 90 days or more, including 6 months to 1 year or more. In some embodiments, treatment will be discontinued after viral levels have decreased to undetectable levels for a specified period (e.g., 1 to 3 months or more). In one approach, appropriate doses of lonafarnib / ritonavir include 100 mg QD / 50 mg QD or BID, 100 mg QD / 100 mg QD or BID, or 100 mg QD / 150 mg QD for at least 30 days, more often at least 60 days, and typically at least 90 days, or more than 90 days. In one approach, treatment of human delta hepatitis virus (HDV) infection involves treating the HDV infection by administering a daily dose of about 100 mg QD lonafarnib and a therapeutically effective amount of a CYP3A4 inhibitor (e.g., ritonavir or cobicistat) for at least about 30 days. In one approach, ritonavir is administered as a 100 mg QD.

[0093] Increased dosage

[0094] In one embodiment, a patient treated for HDV infection is administered a dose-escalating regimen of lonafarnib to increase the patient's tolerance to the drug and minimize side effects. In the dose-escalating regimen, the duration of each dose is typically within 1 to 4 weeks, but may be adjusted (e.g., increased) by the clinician based on the patient's response. For example, without limitation, the patient may be provided with lonafarnib 50 mg BID for an initial 2-week period, followed by 75 mg BID for a second 2-week period, and then 100 mg BID for a third 2-week period until a predetermined desired final dose is achieved. Typically, the dose-escalating dose is co-administered with an appropriate dose of ritonavir, e.g., 100 mg QD or BID.

[0095] Treatment period

[0096] Patients may be treated with lonafarnib-ritonavir combination therapy for a specified period, indefinitely, or until an endpoint is reached. Treatment may be continued daily for at least 2 to 3 months. Typically, the regimen is administered for at least 30 days, more often at least 60 days or at least 90 days, even more often at least 120 days, sometimes at least 150 days, and sometimes at least 180 days. In some embodiments, treatment is continued for at least 6 months to 1 year. In other embodiments, treatment is continued for the remainder of the patient's life, or until administration is no longer effective in maintaining the virus at a level low enough to provide a significant therapeutic benefit.

[0097] In some embodiments, the therapy disclosed herein is continued for a period of time until the HDV RNA level is less than 3 log HDV RNA copies / mL (less than 1,000 copies / mL) or, at times, until the HDV RNA level is less than 2 log HDV RNA copies / mL (less than 100 copies / mL) or below a detectable level. In some cases, the therapy may be continued for a period of time (e.g., 1 to 3 months or more) after the viral load has dropped to an acceptable low level (e.g., undetectable level).

[0098] In some cases, therapy is continued until a "hepatitis flare" or "ALT flare" is observed in the patient. A hepatitis flare (or acute exacerbation) is a sudden increase in serum alanine aminotransferase (ALT) exceeding five times the upper limit of normal (approximately 40 U / mL), which is observed in chronic hepatitis B virus (HBV) infection. In HBV patients, an HBV flare arises from a T lymphocyte (CTL)-mediated immune response of HLA-I-limited cytotoxicity against HBV and its downstream mechanisms. Higher ALT levels reflect a more potent immune clearance of HBV. See Literature [Liaw, 2003, "Hepatitis flares and hepatitis B e antigen seroconversion: implication in anti-hepatitis B virus therapy," J Gastroenterol Hepatol 18:246-52]. Although hepatitis flares had not previously been reported in response to anti-HDV treatment, signs of flares were observed in response to the lonafarnib-ritonavir combination therapy described herein. For example, two patients who received oral administration of lonafarnib 100 mg BID and ritonavir 50 mg BID for 12 weeks exhibited ALT flares characterized by ALT levels 10–20 times higher than normal individuals. ALT flares were also observed in some patients treated with lonafarnib 200 mg BID or 300 mg BID monotherapy. The observation of flares in HDV patients suggests that the combination therapy of ritonavir and lonafarnib at the dosages described herein may have unprecedented therapeutic effects.

[0099] IV. Prevention using gastrointestinal regulation therapy

[0100] As described in the examples, HDV-infected patients treated with lonafarnib monotherapy and lonafarnib-ritonavir therapy experienced gastrointestinal (GI) side effects. Gastrointestinal (GI) side effects of compounds in the farnesyl transferase class are not unexpected. GI intolerance is also a known side effect of ritonavir, which can be administered at 1200 mg / day when used as a protease inhibitor. However, the severity and persistence of these symptoms were not expected in HBV patients (particularly when relatively normal doses of lonafarnib and ritonavir are provided). Agents for the treatment of gastrointestinal irritation include antiemetics, antacids (H2-receptor antagonists and proton pump inhibitors), and antidiarrheals. Exemplary agents (exemplary and non-limiting) are listed in Table 3.

[0101] According to the method of the present invention, lonafarnib is used in combination with at least one, at least two, or at least three of an antiemetic, an antacid (H2-receptor antagonist or proton pump inhibitor) and / or an antidiarrheal agent to allow for sustained patient compliance during lonafarnib therapy. In one embodiment, an antidiarrheal agent is administered. In one embodiment, an antidiarrheal agent and an antacid are administered. In one embodiment, an antidiarrheal agent and an antiemetic are administered. In one embodiment, an antidiarrheal agent, an antacid, and an antiemetic are administered. In one embodiment, the antidiarrheal agent is romotil (atropine / diphenoxylate) and / or the antacid is famotidine and / or the antiemetic is ondansetron.

[0102] Table 3

[0103] Exemplary GI modifiers

[0104]

[0105] In one approach, GI modulators are administered as needed (in response to symptoms). In another approach, GI modulators are administered prophylactically. As used herein in this context, "prophylactically" means administration to patients who are asymptomatic or before symptoms appear. Typically, prophylactic treatment involves administration according to a fixed schedule (e.g., daily) during a course of lonafarnib treatment.

[0106] In one approach, prophylactic treatment involves the administration of ondansetron (an antiemetic), romotil (atropine / diphenoxylate) (an antidiarrheal), and famotidine (an antacid). For example, ondansetron may be administered at 8 mg BID, romotil (atropine / diphenoxylate) may be administered at 5 mg QID or 5 mg BID, and famotidine may be administered at 20 mg BID.

[0107] In one approach, a GI regulator is administered daily before lonafarnib administration. In another approach, a GI regulator is administered 30 minutes to 2 hours before the administration of the lonafarnib regimen.

[0108] In one approach, a GI modifier is administered daily at the same time as lonafarnib is administered, but lonafarnib (and optionally ritonavir) is administered as a sustained-release formulation (e.g., including an enteric coating) so that the GI modifier begins to exert its effect before the release of lonafarnib.

[0109] Prophylactic administration of GI regulators is generally continued during the period of lonafarnib therapy.

[0110] In one approach, prophylactic administration of a GI modifier is initiated on the first day of lonafarnib administration. In another approach, administration of one or more GI modifiers is initiated prior to the initiation of oral lonafarnib-ritonavir therapy. For example, in one embodiment, the patient takes ondansetron the day before the start of lonafarnib treatment. In one approach, one or more GI modifiers are administered daily, starting more than one day prior to the start of oral lonafarnib-ritonavir treatment.

[0111] In a preferred embodiment, the GI modifier is administered according to a BID or QD schedule.

[0112] H2-receptor antagonists

[0113] In one embodiment of this GI modulation therapy, this GI modulator is an H2-receptor antagonist. In one embodiment of this GI modulation therapy, ranitidine (Zantac ® ) is administered at a dosage of 150 mg twice daily and 150 mg four times daily or less during the lonafarnib therapy period. In another embodiment of this GI control therapy, famotidine (Pepcid®) is administered at a dosage of 40 mg once daily, 20 mg twice daily or less, and 40 mg twice daily or less during the lonafarnib therapy period. In another embodiment of this GI control therapy, cimetidine (Tagamet ® ) is administered during the lonafarnib therapy period at doses of 400 mg once daily, 800 mg or less once daily, 1600 mg or less once daily, 800 mg or less twice daily, 300 mg or less four times daily, 400 mg or less four times daily, and 600 mg or less four times daily. In another embodiment of this GI control therapy, nizatidine (Axid) is administered during the lonafarnib therapy period at doses of 150 mg once daily, 300 mg or less once daily, and 150 mg or less twice daily.

[0114] 5-HT 3 antagonist

[0115] In one embodiment of this GI control therapy, the therapeutic agent is a 5-HT3 receptor antagonist. In one embodiment of this GI control therapy, ondansetron (Zofran®) is administered 8 mg once daily, 8 mg twice daily, or 8 mg three times daily, 30 minutes to 2 hours before the start of lonafarnib therapy. In this embodiment, administration continues for at least the duration of the lonafarnib treatment. In another embodiment of this GI control therapy, granisetron (oral Kytril®) is administered 2 mg or 1 mg twice daily up to 1 hour before the start of lonafarnib therapy. In this embodiment, administration continues for at least the duration of the lonafarnib treatment.

[0116] NK-1 receptor antagonist

[0117] In one embodiment of this GI modulation therapy, this GI modulator is an NK-1 receptor antagonist. In one embodiment of this GI modulation therapy, aprepritant (Emend ® ) is combined with a 5-HT3 receptor antagonist and a corticosteroid and is administered as a 3-day treatment consisting of a 125 mg dose 1 hour prior to the start of lonafarnib therapy on Day 1, followed by 80 mg doses on Days 2 and 3. In another embodiment of this GI control therapy, fosaprepitant (Emend ®IV) is administered as a single treatment consisting of a single dose of the corresponding 150 mg fosaprepitant up to 30 minutes before the start of lonafarnib therapy, followed by a single dose of 12 mg dexamethasone and a single dose of a 5-HT3 receptor antagonist, such as odansetron, in combination with a 5-HT3 receptor antagonist and a corticosteroid (dexamethasone), up to 30 minutes before the start of lonafarnib therapy, followed by a single dose of the corresponding 150 mg fosaprepitant up to 30 minutes before the start of lonafarnib therapy, followed by a single dose of 8 mg dexamethasone and a single dose of a 5-HT3 receptor antagonist, such as odansetron, on day 1, and a single dose of 8 mg dexamethasone on days 2 to 4.

[0118] Proton pump inhibitor

[0119] In one embodiment of this GI modulation therapy, this GI modulator is a proton pump inhibitor (PPI). In one embodiment of this GI modulation therapy, omeprazole (Prilosec ® ) is combined with an antacid and administered at a dose of 20 mg once daily up to 4 days prior to the start of lonafarnib therapy and up to 40 mg once daily during the lonafarnib therapy period. In another embodiment of this GI control therapy, omeprazole / sodium bicarbonate (Zegerid ® ) is administered at a dose of 20 mg once daily at least 1 hour before meals and the start of lonafarnib therapy, and up to 40 mg once daily during the period of lonafarnib therapy. In another embodiment of this GI control therapy, esomeprazole magnesium (Nexium ® ) is administered at a dose of 20 mg once daily at least 1 hour before lonafarnib treatment, up to 40 mg once daily, and up to 40 mg twice daily during the period of lonafarnib therapy. In another embodiment of this GI control regimen, esomeprazole strontium (Nexium ®) is administered at a dose of 24.65 mg once daily at least 1 hour prior to lonafarnib treatment, up to 49.3 mg once daily, and up to 49.3 mg twice daily during the period of lonafarnib therapy. In another embodiment of this GI control regimen, lansoprazole (Prevacid) ® ) is administered up to 2 hours prior to lonafarnib therapy at a dose of lansoprazole 15 mg once daily, up to 30 mg once daily, up to 60 mg once daily, up to 30 mg twice daily for a period of up to 14 days, and up to 30 mg three times daily during the lonafarnib therapy period. In another embodiment of this GI control regimen, dexlansoprazole (Dexilant ® ) is administered at a dose of 30 mg of dextransoprazole once daily up to 2 hours prior to lonafarnib therapy, and up to 60 mg once daily during the lonafarnib therapy period. In another embodiment of this GI control regimen, pantoprazole sodium (Protonix ® ) is administered at a dose of 40 mg once daily up to 7 days prior to lonafarnib therapy, and at a dose of up to 40 mg twice daily during lonafarnib therapy.

[0120] In some embodiments of the present invention, GI modulation therapy involves the administration of a proton pump inhibitor (PPI) selected due to its inhibitory effect on CYP3A4. PPI-mediated inhibition can help maintain therapeutically effective serum levels of lonafarnib. Such inhibitory PPIs include, but are not limited to, omeprazole and rabeprazole.

[0121] antidiarrheal medicine

[0122] In one embodiment of this GI control therapy, the therapeutic agent is an antidiarrheal. In one embodiment of this GI control therapy, atropine / diphenoxylate (Lomotil ® , Lonox ®) 2 Lomotil tablets 4 times daily or 10 ml of Lomotil 4 times daily until initial control is achieved ® It is administered as a liquid dose (20 mg per day), and thereafter the dose may be reduced by 5 mg per day (2 tablets or 10 ml of liquid). In another embodiment of this GI control therapy, loperamide HCl (Imodium ® ) is administered at a dose of 4 mg (2 capsules), followed by 2 mg after each diarrhea, up to a maximum of 16 mg (8 capsules). In another embodiment of this GI control therapy, bismuth subsalicylate (Kaopectate ® , Pepto-Bismol ® ) is administered as needed, up to 8 times within 24 hours, as 2 tablets or 30 mL every 30 minutes to 1 hour.

[0123] V. Pharmaceutical composition and unit dosage form

[0124] The present invention provides a pharmaceutical composition for providing a lonafarnib and ritonavir combination therapy. In one approach, the co-administration of lonafarnib and ritonavir is combined with the prophylactic administration of one, two, or three GI stabilizers as discussed in Section IV above. In another approach, the co-administration of lonafarnib and ritonavir is combined with interferon combination therapy as discussed in Section VII below.

[0125] Generally, lonafarnib and ritonavir are formulated for oral administration and administered orally. However, the present invention provides a method and composition for administering lonafarnib and / or ritonavir to humans for the treatment of HDV infection by one or more other routes, such as administration of an IV or subcutaneous (SQ) formulation. As another example, the method of the present invention may be carried out using patch technology, particularly patch technology using micro-needles, to administer the drug subcutaneously. Non-oral administration may avoid or at least improve GI and other side effects. Other routes suitable for drug delivery, including systemic and local administration routes, may be utilized.

[0126] In certain embodiments, lonafarnib and / or ritonavir may be administered orally in solid dosage forms (e.g., capsules, coated tablets, tablets, etc.). In certain embodiments, lonafarnib and / or ritonavir may be administered orally as soft gel capsules containing liquid. In some embodiments, the formulation is administered as a liquid dosage form (oral suspension, syrup, or elixir) or a combination (e.g., lonafarnib tablet and ritonavir solution). Liquid dosage forms for oral administration may be provided, wherein each dosage unit, e.g., teaspoon, spoon, milliliter, etc., contains a predetermined amount of composition containing lonafarnib and / or ritonavir.

[0127] Lonafarnib and ritonavir may be co-administered separately (as separate unit dosage forms) or combined into an oral unit dosage form containing both lonafarnib and ritonavir. When administered as separate unit dosage forms, typically the doses of lonafarnib and ritonavir are administered approximately simultaneously, e.g., simultaneously or within about 3 minutes of each other, or alternatively within about 10, 30, or 60 minutes of each other (e.g., self-administered). In some embodiments, ritonavir is administered before lonafarnib.

[0128] Lonafarnib has been manufactured in 50 mg, 75 mg, and 100 mg capsules, but this is within the capability of those skilled in the art to manufacture dosage forms having varying amounts of the active ingredient. In one embodiment, the pharmaceutical formulation of the present invention contains lonafarnib formulated for oral administration as a unit dosage form containing 50 mg, 75 mg, or 100 mg. Where a salt or solvate is used, an equally larger amount will be required as readily understood by those skilled in the art.

[0129] Ritonavir is commercially available as 100-mg tablets, 100-mg soft gelatin capsules, and an 80-mg / mL oral solution, but this is within the capability of those skilled in the art to manufacture dosage forms having various amounts of the active ingredient. In various embodiments, the unit dosage form useful for the method of the present invention contains 50 mg or 10 mg. If a salt or solvate is used, an equally larger amount will be required, as is readily understood by those skilled in the art.

[0130] In some embodiments of the present invention, lonafarnib and ritonavir are delivered in the same dosage form (i.e., "co-formulated"). For example, the dosage form may contain lonafarnib and ritonavir (along with excipients and adjuvants). Non-limitingly, lonafarnib and ritonavir may be provided as a mixture, a multiply particulate formulation (which contains small particles of lonafarnib in a matrix containing ritonavir), a bilayer formulation, a table-within-table formulation, and others. Such forms for co-administration are well known (see, e.g., US 20090142393, US 20080021078, WO2009042960). Liquid formulations containing both lonafarnib and ritonavir may also be used for co-administration.

[0131] Lonafarnib and / or ritonavir dosage forms may be formulated for prescribed release profiles, including immediate release and controlled release (e.g., delayed release or sustained release). For example, lonafarnib may be formulated for delayed release, and ritonavir may be formulated for immediate release (whether administered separately or as a combination dosage form(s)).

[0132] As described above in Section IV, in one approach, patients receiving lonafarnib are considered to receive one GI modifier or a combination of GI modifiers prophylactically. In one approach, one or more GI modifiers are provided as co-formulations with lonafarnib and / or ritonavir. For example, lonafarnib, ritonavir, and GI modifiers may be formulated as a trilayer tablet. In another approach, as described below in Section VI, one or more GI modifiers are provided in a standard pharmaceutical package ("co-packaged"). In one approach, one or more GI modifiers are provided as immediate-release formulations, and lonafarnib (and optionally ribonavir) is provided as a controlled-release formulation. Formulations formulated with different releases may be co-packaged and / or co-formulated in various combinations, provided that at least one GI modifier is formulated for rapid release and lonafarnib is formulated for controlled (e.g., delayed) release. In a preferred embodiment, these formulations allow a patient to self-administer lonafarnib and at least one GI modifier substantially simultaneously (e.g., simultaneously or within about 5 minutes of each other) using a formulation in which the effect of the GI modifier(s) occurs before the release of lonafarnib. Using this approach, the patient can benefit from the pre-release of the GI modifier without increasing the number of times the patient must self-administer the treatment per day.

[0133] Methods for manufacturing controlled or delayed-release formulations are well known in the art. For the sake of non-limiting examples, in some cases, lonafarnib and optionally ritonavir are formulated with a release-delay agent. In such formulations, lonafarnib may have zero or relatively low drug release during a delay period after administration to a subject; followed by rapid release ("burst") of the drug after the end of the delay period. The delay period is typically in the range of about 0.25 to 3 hours, more often in the range of about 0.5 to 2 hours. Many methods for providing delayed-burst release by, for example, diffusion, expansion, osmotic burst, or erosion (e.g., based on the intrinsic dissolution of the formulation and incorporated excipients) are known in the art; see US Patent Publication No. 20110313009.

[0134] In some cases, for the sake of example and without limitation, a retardant-release agent is designed to allow the release of lonafarnib and / or ritonavir upon exposure to defined conditions within the body. In one embodiment, the retardant-release agent is an enteric-release agent that allows the release of the drug upon exposure to a characteristic side of the gastrointestinal tract. In an embodiment, the enteric-release agent is pH-sensitive and is affected by changes in pH encountered within the gastrointestinal tract (pH-sensitive release). The enteric material typically remains insoluble at gastric pH and subsequently allows the release of the active ingredient in a higher pH environment of the downstream gastrointestinal tract (e.g., often the duodenum or sometimes the colon). In another embodiment, the enteric material comprises an enzymatically degradable polymer that is degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly the colon. Optionally, a unit dosage form is formulated with a pH-sensitive enteric material designed to induce release within about 0.25–2 hours at a specific pH or higher. In various embodiments, a specific pH may be, for example, about 4.5, 5, 5.5, 6, or 6.5. In a specific embodiment, the pH-sensitive material allows for the release of at least 80% of the drug within one hour when exposed to a pH of about 5.5 or higher. In another embodiment, the pH-sensitive material allows for the release of at least 80% of the drug within one hour when exposed to a pH of about 6 or higher.

[0135] Materials used in enteric-release formulations, for example, coatings, are well known in the art (those described in U.S. Patent Publication No. 20110313009). Combinations of various enteric materials may also be used. Multilayer coatings using various polymers may also be applied. In some cases, the enteric material causes a drug release delay in the range of about 0.25 to about 3 hours, sometimes about 0.5 to about 4 hours.

[0136] A person skilled in the art can control the delay period before delayed-burst release from enteric-coated multiply particles by varying the weight and composition of the enteric layer coating. For example, if the time in the stomach is <4 hours and some degree of protection (1-3 hours) is desired after the dosing form leaves the stomach, an appropriate coating level can be manufactured to provide protection of up to 4 hours between administration and drug release. To determine the correct coating weight, multiply particle samples will be removed from a fluid bed coater across various coating weight ranges and examined via in vitro dissolution to determine the appropriate coating level. Based on these results, the correct coating weight will be selected. An example of enteric-coated multiply particles can be found in U.S. Patent No. 6,627,223.

[0137] Lonafarnib and / or ritonavir may be mixed with one or more release retardants (e.g., blended, mixed, or mixed in a continuous phase) and / or contained within one or more release retardants (e.g., encapsulated within or coated with them). For example, a delayed-burst-release formulation may be in the form of one or more capsules containing lonafarnib and / or ritonavir. In other cases, lonafarnib and / or ritonavir may be in the form of multiple microparticles, such as granules, microparticles (beads), or nanoparticles, coated with a release retardant.

[0138] Pharmaceutical formulations and unit dose forms suitable for oral administration are particularly useful for patient self-administration therapy and the treatment of chronic conditions. However, as mentioned above, in some cases (including, but not limited to, acute infections and life-threatening conditions, particularly those requiring hospitalization), an intravenous formulation is preferred, and the present invention also provides such formulations. The present invention provides pharmaceutical formulations that can be formulated into infusion preparations according to the present invention by dissolving, suspending, or emulsifying lonafarnib and / or ritonavir in an aqueous or non-aqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids, or propylene glycol, with, as needed, conventional additives, such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers, and preservatives. Unit dose forms for infusion or intravenous administration may be included in the composition as a solution in sterile water, physiological saline, or other pharmaceutically acceptable carriers. An amount of active pharmaceutical ingredient suitable for a unit dosage form of lonafarnib and / or ritonavir is provided herein.

[0139] VI. Kit and packaging

[0140] Lonafarnib, ritonavir, and optionally one or more GI modifiers used in the treatment of HDV patients may be delivered to HDV patients in a pharmaceutical package. Such packages are intended to improve patient convenience and adherence to the treatment plan. Typically, the packaging material includes paper (cardboard) or plastic.

[0141] In one embodiment, the delivery package comprises lonafarnib and ritonavir as a therapeutically effective amount combined with a single unit dosage form or as separate unit doses. The dosage of each drug (e.g., mg) and the form of the unit dosage (e.g., tablet, capsule, immediate release, delayed release, etc.) may be in accordance with the recommendations of the present invention.

[0142] In one approach, the package contains a dosage suitable for multi-day administration, such as one week or one month. In a preferred approach, in a multi-day pack, the dosage (e.g., tablet) for each administration (e.g., once a day for QD administration, twice a day for BID administration, etc.) is separated from the dosage to be administered on other days or at other times.

[0143] In another embodiment, the package comprises a prescribed therapeutically effective amount of lonafarnib, ritonavir, or a combination of lonafarnib and ritonavir and one or more GI modifiers, which are combined into a single package but separated from each other into individual compartments within the package.

[0144] VII. Interferon co-therapy

[0145] Current medical practice for treating HBV infection and / or HBV and HDV co-infection often involves interferon-alpha or interferon-gamma monotherapy (including treatment with interferon-alpha-2b or pegylated interferons, e.g., Pegasys sold by Roche or PEG-Intron sold by Merck) or interferon-alpha with nucleoside or nucleotide analogs, e.g., adefover (Hepsera ® ), Entecover (Baraclude ® ), Lamivudine (Epivir-HBV ® , Heptovir ® , Heptodin ® ), Telbivudine (Tyzeka ® ), Tenofover (Viread ® ), and ribavirin (e.g., Rebetol ® or Copegus ®A combination therapy with ) is used. According to the method of the present invention, lonafarnib is used in combination with one of these standard therapies to treat HDV infection (i.e., HBV and HDV co-infection). In one embodiment, lonafarnib is administered in combination with other agents (e.g., interferon alpha and ritonavir) at a lonafarnib dose of 100 mg QD. In an embodiment, the present invention provides a method for treating HDV infection by administering at least 100 mg lonafarnib QD or BID in combination with interferon or ritonavir.

[0146] Thus, in one approach, patients receiving lonafarnib (e.g., lonafarnib combined with a booster, e.g., ritonavir) are also treated with interferon (e.g., interferon-α). In some embodiments, both lonafarnib and interferon-α are administered to the patient, and the lonafarnib dose is at least about 50 mg BID or at least about 75 mg BID or QD. In some embodiments, the lonafarnib dose is 100 mg BID. In some embodiments, the administration of lonafarnib and interferon-α is simultaneous. In some embodiments, the administration of lonafarnib and interferon-α is sequential. In some embodiments, interferon-α is pegylated interferon (hereinafter, "Pegasys"). Therefore, HDV-infected patients treated with lonafarnib-ritonavir co-therapy are also considered to be treatable with interferon.

[0147] Administration of lonafarnib in combination with other agents such as interferon alpha and ritonavir (Norvir) provides an effective regimen with lower dosages and / or reduced dosing frequency. In some cases, this involves administering lonafarnib, ritonavir, and interferon-α to the patient. In some embodiments, Pegasys is administered weekly. In some embodiments, pegylated interferon (Pegasys) is administered at a dose of 180 micrograms per week. In these embodiments, administration of lonafarnib and interferon continues for at least 30 days, generally at least about 60 days, or even 90 days or more, including 6 months to 1 year or more. In one approach, administration will continue for about 30 days, more commonly 30 or 60 days, and often as long as 6, 9, and 12 months. In some embodiments, administration will be stopped after the virus level has decreased to an undetectable level for a certain period (e.g., 1 to 3 months or more).

[0148] Interferon

[0149] Based on the type of receptor they signal, human interferons have been classified into three main types. In various embodiments, any of the types I through III interferons are used in combination with lonafarnib to treat HDV infection. All type I IFNs bind to a specific cell surface receptor complex known as the IFN-alpha receptor (IFNAR), which consists of IFNAR1 and IFNAR2 chains. The type I interferons present in humans are IFN-alpha, IFN-beta, IFN-epsilon, and IFN-omega. Type II IFNs bind to the IFN-gamma receptor (IFNGR), which consists of IFNGR1 and IFNGR2 chains. The human type II interferon is IFN-gamma. The recently classified group of type III interferons consists of three IFN-lambda molecules called IFN-lambda1, IFN-lambda2, and IFN-lambda3 (also referred to as IL29, IL28A, and IL28B, respectively). These IFNs signal through a receptor complex composed of IL10R2 (also called CRF2-4) and IFNLR1 (also called CRF2-12).

[0150] Accordingly, the present invention provides a combination therapy in which interferon-alpha or interferon-lambda is used in combination with lonafarnib. As used herein, the terms “interferon-alpha” or “IFN-α” and “interferon-lambda” or “IFN-λ” refer to a family of related polypeptides that inhibit viral replication and cell proliferation and regulate immune responses. The term “IFN-α” includes naturally occurring IFN-α; synthetic IFN-α; derivatized IFN-α (e.g., pegylated IFN-α, glycosylated IFN-α, and others); and analogs of naturally occurring or synthetic IFN-α. The term “IFN-α” also includes consensus IFN-α. Thus, any IFN-α or IFN-λ having antiviral properties, as described for naturally occurring IFN-α, may be used in the combination therapy of the present invention.

[0151] Interferons suitable for the purposes of the present invention include, but are not limited to, pegylated IFN-α-2a, pegylated IFN-α-2b, consensus IFN, and IFN-λ.

[0152] The term "IFN-α" includes derivatives of IFN-α that have been derivatized (e.g., chemically modified compared to naturally occurring peptides) to alter specific properties such as serum half-life. As such, the term "IFN-α" includes IFN-α derivatized with polyethylene glycol (“pegylated IFN-α”) and others. Pegylated IFN-α and methods for its preparation are discussed, for example, in U.S. Patents 5,382,657; 5,951,974; and 5,981,709. Pegylated IFN-α is, but is not limited to, interferon alpha-2a (Roferon, Hoffman La-Roche, Nutley, NJ), interferon alpha-2b (Intron, Schering-Plough, Madison, NJ), and interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon as defined by the measurement of the consensus sequence of naturally occurring interferon alpha (Infergen ® It includes any of the IFN-α molecules described above, including PEG conjugated to , InterMune, Inc., Brisbane, CA, and a conjugate of PEG.

[0153] Accordingly, in some embodiments of the combination therapy of the present invention, IFN-α is modified into one or more polyethylene glycol moieties, i.e., pegylated. Two forms of pegylated interferon, namely pegylated interferon alpha-2a (40 kD) (Pegasys, Hoffmann-La Roche) and pegylated interferon alpha-2b (12 kD) (PegIntron, Merck), are commercially available and differ in their pharmacokinetics, virological kinetics, tolerability profiles, and thus, dosage.

[0154] Pegylated interferon alpha-2a (Pegasys) consists of interferon alpha-2a (~20 kD) covalently bonded to 40 kD branched polyethylene glycol (PEG). The PEG moiety is linked at a single site to the interferon alpha moiety via a stable amide bond to lysine. Pegylated interferon alpha-2a has a molecular weight of approximately 60,000 daltons. The biological activity of pegylated interferon alpha-2a is derived from its interferon alpha-2a moiety, which influences both adaptability to specific viruses and natural immune responses. These alpha interferons bind to and activate human type 1 interferon receptors on hepatocytes, which activate multiple intracellular signaling pathways, thereby inducing the expression of interferon-stimulated genes that produce numerous antiviral effects, such as blocking viral protein synthesis and inducing viral RNA mutagenesis. Compared to natural interferon alpha-2a, pegylated interferon alpha-2a exhibits sustained absorption and delayed elimination. Pegylated interferon alpha-2a is used at a fixed weekly dose. It has relatively constant absorption after infusion and is mostly distributed in the blood and organs.

[0155] Pegylated interferon alpha-2b (PegIntron) consists of interferon alpha-2b covalently bonded to 12 kD linear polyethylene glycol (PEG). The average molecular weight of the molecule is approximately 31,300 daltons. Pegylated interferon alpha-2b is composed primarily of monopegylated species (one PEG molecule is attached to one interferon molecule) and contains only a small amount of dipegylated species. Fourteen different PEG attachment sites on the interferon molecule have been identified. The biological activity of pegylated interferon alpha-2b originates from its interferon alpha-2b moiety, which influences both adaptability to specific viruses and natural immune responses. This alpha interferon binds to and activates human type 1 interferon receptors on hepatocytes, which activate multiple intracellular signaling pathways, thereby inducing the expression of interferon-stimulated genes that produce numerous antiviral effects, such as blocking viral protein synthesis and inducing viral RNA mutagenesis. Compared to natural interferon alpha-2b, pegylated interferon alpha-2b has delayed absorption, delayed elimination, and an extended half-life. Pegylated interferon alpha-2b is administered weekly based on the patient's body weight. Pegylated interferon alpha-2b has rapid absorption and wider dispersion in the body.

[0156] The PEG molecule of the pegylated IFN-α polypeptide is conjugated to one or more amino acid side chains of the IFN-α polypeptide. In a specific embodiment, the pegylated IFN-α contains a PEG moiety on only one amino acid. In another embodiment, the pegylated IFN-α contains a PEG moiety on two or more amino acids, for example, the IFN-α contains a PEG moiety attached to 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, or 14 different amino acid residues. The IFN-α can be directly coupled to PEG (i.e., without a linker) through an amino group, a sulfhydryl group, a hydroxyl group, or a carboxyl group.

[0157] Pegylated interferon has been used as monotherapy for the management of HDV, but it cleared HDV in less than one-quarter of patients treated for one year. The combination therapy provided by the present invention comprises administering an immunomodulator such as interferon and lonafarnib as provided herein as a direct antiviral agent (optionally in combination with other antiviral drugs). Exemplary interferons include those discussed above. In one embodiment of this combination therapy, pegylated interferon alpha-2a (Pegasys) is administered subcutaneously (SQ) weekly at a dose of 180 micrograms (mcg) or 135 mcg (for patients who respond negatively to higher doses). In another embodiment of this combination therapy, pegylated interferon alpha-2b (PegIntron) is administered SQ at a dose of 1.5 mcg / kg / week. In other embodiments of these methods, alpha-interferon is used as follows: Consensus interferon (Infergen) administered at 9 mcg to 15 mcg SQ daily or three times a week; interferon-alpha 2a recombinant administered at 3 MIU to 9 MIU SQ three times a week; interferon-alpha 2b (Intron A) recombinant administered at 3 MIU to 25 MIU SQ three times a week; and pegylated interferon lambda (IL-28) administered at 80 mcg to 240 mcg SQ weekly.

[0158] The term "IFN-α" also includes Consensus IFN-α. Consensus IFN-α (also referred to as "CIFN," "IFN-Con," and "Consensus Interferon") is, without limitation, the amino acid sequences designated as IFN-Con1, IFN-Con2, and IFN-Con3 as described in U.S. Patents Nos. 4,695,623 and 4,897,471; and naturally occurring interferon alpha (e.g., Infergen ®It contains a consensus interferon as defined by the determination of the consensus sequence of Three Rivers Pharmaceuticals (Warrendale, PA). IFN-con1 is Infergen ® Alphacon-1 is a consensus interferon preparation. Infergen ® Consensus Interferon Products is its trademark (Infergen ® ) or is referred to herein by its generic name (interferon alpha-con-1). A DNA sequence encoding IFN-con can be synthesized as described in the aforementioned patent or other standard methods. In one embodiment, at least one additional therapeutic agent is CIFN.

[0159] The term "IFN-λ" includes IFN-lambda1, IFN-lambda2, and IFN-lambda3. These proteins are also known as interleukin-29 (IL-29), IL-28A, and IL-28B, respectively. Collectively, these three cytokines comprise a type III subset of IFN. They are distinguished from both type I and type II IFN for many reasons, including the fact that they signal through heterodimer receptor complexes different from the receptors used by type I or type II IFN. Although type I IFN (IFN-alpha / beta) and type III IFN (IFN-lambda) signal through distinct receptor complexes, they activate many of the same biological activities, including antiviral activity, and the same intracellular signaling pathways in a wide range of target cells. Interferon lambda may be administered without restriction at any therapeutically appropriate dose, including 80, 120, or 180 mcg QW.

[0160] In various embodiments of the combination therapy of the present invention, a fusion polypeptide comprising IFN-α and a heteropeptide is used. Suitable IFN-α fusion polypeptides are, without limitation, Albuferon-alpha TM(Includes fusion products of human albumin and IFN-α; Human Genome Sciences; see, e.g., [Osborn et al., 2002, J. Pharmacol. Exp Therap., 303: 540-548]). Additionally, a gene-shuffled form of IFN-α is suitable for use in this method. See, e.g., [Masci et al., 2003, Curr. Oncol. Rep. 5:108-113]. Other suitable interferons include Multiferon (Viragen), Medusa Interpron (Flamel Technology), Locteron (Octopus), and Omega Interoperron (Intarcia / Boehringer Ingelheim).

[0161] As such, in various embodiments, lonafarnib is administered in combination with interferon to treat HDV infection according to the present invention. In various embodiments, the interferon is pegylated IFN-alpha 2a or pegylated IFN-alpha 2b. An appropriate dose of lonafarnib / pegylated IFN-alpha 2a is 100 mg BID / 180 mcg QW. An appropriate dose of lonafarnib / pegylated IFN-alpha 2b is 100 mg BID / 1.5 mcg / patient body weight kg QW.

[0162] VIII. Other antiviral therapies

[0163] It is considered that HDV-infected patients treated with lonafarnib-ritonavir combination therapy may also be treated with other antiviral agents, such as nucleoside and nucleotide analogs, compounds used to treat HBV infection, and other agents.

[0164] Nucleosides and nucleotide analogs

[0165] Antiviral nucleoside or nucleotide analogs that can be used in combination with the lonafarnib-ritonavir combination therapy described herein are, for example, adefover (Hepsera ® ), Entecover (Baraclude ® ), Lamivudine (Epivir-HBV ® , Heptovir ® , Heptodin ® ), Telbivudine (Tyzeka ® ), Tenofover (Viread ® ), and ribavirin (e.g., Rebetol ® or Copegus ® Includes ).

[0166] Compounds used to treat HBV

[0167] In the various combination therapies of the present invention, for the treatment of HDV, lonafarnib is combined with an antiviral drug for HBV. With the exception of interferon, currently approved anti-HBV drugs inhibit reverse transcriptase and are nucleoside or nucleotide analogs. These drugs, which are effective against HBV, are not effective against HDV because they do not lower HBsAg, which is necessary for HDV replication; however, when used in the combination therapy of the present invention, improved patient outcomes can be achieved. Currently approved anti-HBV drugs include the following: interferon alpha (Intron A ® ), pegylated interferon (Pegasys ® ), Lamivudine (Epivir-HBV ® , Zeffix ® , or Heptodin ® ), Adepover dipivoxil (Hepsera ® ), Entecover (Baraclude ® ), Telbivudine (Tyzeka ® , Sebivo ® ), Clebudin (Korea / Asia), Tenofover (Viread ®Truvada, a combination of tenofobor and emtricitabine. ® Although it has not yet been approved, it has been proven effective in reducing HBV virus titers in early clinical trials and is useful for the combination therapy of the present invention.

[0168] Other therapeutic compounds

[0169] Other therapeutic compounds that may be administered to have a beneficial effect on HDV-infected patients treated according to the present invention include nucleosides or nucleotide analogs; thiazolids; protease inhibitors; polymerase inhibitors; helicase inhibitors; class C CpG Toll-like receptor 7 and / or 9 antagonists; amphiphilic helix inhibitors or NS4B inhibitors; statins or other HMG CoA reductase inhibitors; immunomodulators; anti-inflammatory agents; second-generation prenylation inhibitors; cyclophylline inhibitors; and alpha-glucosidase inhibitors.

[0170] Other therapeutic modules

[0171] Oral lonafarnib-ritonavir combination therapy can be a module in the treatment course for the rapid and complete elimination of HDV infection. Therefore, the treatment regimen described herein may be preceded by or followed by complementary therapy.

[0172] For example, some patients may benefit from an initial IV infusion of ronifarnib to rapidly achieve high blood levels of the drug, and these levels may be sustained by continuous or periodic IV infusion(s) for a period (from one day to several days or possibly one week) before applying the oral therapy more specifically described herein to the patient. In these embodiments, the drug may be infused to the patient to achieve therapeutic efficacy associated with serum levels achieved with a 200 mg BID administration (and higher doses). IV administration is performed under the supervision of another medical specialist (e.g., in a hospital) and is carried out in conjunction with prophylactic therapy and monitoring to avoid or mitigate AEs associated with oral administration at these high doses as needed, or to discontinue IV administration. In other embodiments, a subcutaneous infusion to provide a reservoir form of the drug maintaining therapeutically effective blood levels of the drug for several days or weeks may be used to achieve the same therapeutic efficacy results as described herein for oral therapy.

[0173] IX. Use of Cobicistat as a Boosting Agent

[0174] Although ritonavir is the most widely used CYP3A4 inhibitor, the findings described herein allow for the implementation of lonafarnib combination therapy with CYP3A4 inhibitors. In an alternative embodiment, the present invention provides an embodiment as described elsewhere in this invention in which cobicistat, a pharmacokinetic boosting agent, is used in combination with lonafarnib instead of ritonavir.

[0175] Cobicistat (Gilead Sciences' trademark Tybost ®Cobicistat (marketed as is) is another potent inhibitor of CYP3A. Like ritonavir, it "boosts" blood levels of other substrates of this enzyme, but unlike ritonavir, it does not have antiviral activity. Additionally, while it has a significant effect on the enzyme system (CYP3A) responsible for the breakdown of certain drugs, it does not affect other enzyme systems used in many other medicines (which can contribute to many potentially harmful drug interactions). Cobicistat is useful in the combination therapy of the present invention when combined with lonafarnib at any dosage and frequency described herein, at any of its acceptable or any lower doses.

[0176] In one embodiment, the present invention considers the treatment of HDV patients using the methods and compositions described herein, except that a boosting agent other than ritonavir is used. In one embodiment, the boosting agent is cobicistat. In some embodiments, a lower dose of cobicistat is used (e.g., 50 mg QD or 50 mg BID).

[0177] Table 4 illustrates, but is not limited to, four exemplary dosing regimens (ADs) for lonafarnib-cobicistat combination therapy. Cobicistat is useful in combination with lonafarnib at any dosage and dosing frequency described herein, at any of its acceptable or any lower doses, for the combination therapy of the present invention. In alternative embodiments, cobicistat is administered at a lower (e.g., 75 mg) and / or more frequent (e.g., BID) dose.

[0178] Table 4

[0179]

[0180] In another specific example, cobicistat (Tybost ®) is administered once daily at 150 mg. In a specific example, lonafarnib may be selectively combined with interferon as described above and administered at 100 mg QD or 100 mg BID.

[0181] X. Examples

[0182] Example 1. Treatment of HDV patients using 100 mg lonafarnib administered BID

[0183] This example demonstrates the efficacy of lonafarnib in reducing HDV RNA levels in patients with chronic HDV. Eight patients in Group 1 (all with chronic HDV) were treated as follows: Six patients with chronic delta hepatitis (HDV) (patients 1, 2, 4, 5, 6, and 8) were treated with lonafarnib, and two patients (patients 3 and 7) were given a placebo for a period of 28 days. The six patients in the active treatment group were administered 100 mg BID (oral) for 28 days. The mean change in HDV RNA levels from baseline to trough in the lonafarnib active treatment group was -0.74 log HDV RNA copy / mL, and in the placebo group, it was -0.24 log HDV RNA copy / mL.

[0184] Patients 4, 5, 6, and 8 are responsive to therapy as defined by a decrease in quantitative serum HDV RNA levels of 0.5 log HDV RNA copy / mL or greater from baseline to the lowest level during active treatment. Refer to Table 5 (showing changes in HDV RNA viral load in each patient during and after treatment) and Figure 1 (showing the time course of log HDV RNA copy / mL levels in patients 4, 5, and 6). The change in HDV RNA levels in patient 4 from baseline to end of treatment (EOT) was -1.34 log HDV RNA copy / mL. The change in HDV RNA levels in patient 5 from baseline to EOT was -0.82 log HDV RNA copy / mL. The change in HDV RNA levels in patient 6 from baseline to EOT was -1.41 log HDV RNA copy / mL.

[0185] Table 5

[0186] 100 mg BID lonafarnib monotherapy

[0187] Rx vs Post Standard vs EOT

[0188]

[0189] HDV RNA virus load is correlated with plasma concentration of lonafarnib.

[0190] Figure 2 shows the correlation between lonafarnib plasma levels and viral load. Patients with higher lonafarnib plasma levels experienced a greater decrease in HDV RNA titers during treatment. During treatment, plasma levels ranged from 200 ng / mL to 1,100 ng / mL.

[0191] Viral rebound after treatment

[0192] After lonafarnib therapy was discontinued on day 28, patients 4, 5, and 6 exhibited a viral rebound or an increase in serum HDV RNA levels. Patient 4's HDV RNA level increased by 1.7 log HDV RNA copy / mL after discontinuation of lonafarnib. Patient 5's HDV RNA level increased by 1.4 log HDV RNA copy / mL after discontinuation of lonafarnib. Patient 6's HDV RNA level increased after discontinuation of lonafarnib. Patients 4, 5, and 6 showed a subsequent decrease in HDV RNA levels, which began approximately 4–8 weeks after discontinuation of lonafarnib therapy, and this is believed to be due to viral-viral dynamics between HDV RNA and HBV DNA.

[0193] Example 2. Treatment of HDV patients using 200 mg and 300 mg lonafarnib administered BID

[0194] Six human subjects known to be infected with HDV were treated with lonafarnib at doses of 200 mg BID or 300 mg BID for a period of 84 days, as recorded with reference HDV RNA viral titers ranging from 5.8 log HDV RNA copy / mL to 8.78 log HDV RNA copy / mL.

[0195] 28-day treatment effect

[0196] At the end of the 28-day treatment, the mean change in viral load across 6 subjects from baseline to day 28 was -1.63 log copy / mL in the 200 mg BID group and -2.00 log copy / mL in the 300 mg BID group. See Table 6 and Figure 3.

[0197] Table 6

[0198]

[0199] The results on day 28 recorded the superior efficacy of the 200 mg BID and 300 mg BID regimens compared to the 100 mg BID regimen. However, additional efficacy is required for significant therapeutic benefit. Based on the treatment results of HDV patients administered 200 mg and 300 mg lonafarnib BID, the inventors decided to include continuing administration in combination with a boosting agent for at least an additional 30 days or for an additional 60 days or more in a strategy to achieve significant therapeutic benefit. In some embodiments, the use of a boosting agent alone or in combination with interferon may enable patients to achieve significant therapeutic benefit with a lower lonafarnib dose (e.g., 100 mg QD or 100 mg BID) or a shorter duration of treatment (e.g., 30 days).

[0200] 56-84 days of treatment effect

[0201] When 200 mg BID and 300 mg BID administration was continued for 56 days (days 29–56 may be referred to as the second month) or 84 days (days 57–84 may be referred to as the third month), the change in viral load across 6 patients reached a steady state or increased from the viral load level at day 28. The absence of change or increase in viral load was due to poor gastrointestinal intolerance to lonafarnib. These 6 patients were not prophylactically administered GI modifiers to relieve gastrointestinal distress. Due to GI intolerance, compliance with 200 mg BID and 300 mg BID lonafarnib treatment appears to be poor during the second and third months (days 29–84).

[0202] Example 3. Combination therapy of HDV patients using 100 mg BID lonafarnib and interferon

[0203] Three human subjects known to be infected with HDV, as recorded by reference HDV RNA viral titers in the range of 4.34 log HDV RNA copy / mL to 5.15 log HDV RNA copy / mL and ALT values ​​in the range of 155-174 IU / L, were treated with a 100 mg BID dose of lonafarnib combined with 180 µg of Pegasys (pegylated interferon alpha-2a) per week for a period of 56 days (2 months).

[0204] At the end of day 28, the HDV RNA viral titers of all 3 patients decreased from baseline, with a decline range of -1.04 log HDV RNA copy / mL and -2.00 log HDV RNA copy / mL, and the average decline across the 3 subjects was -1.8 log HDV RNA copy / mL. At the end of day 56, the HDV RNA viral titers of all 3 patients continued to decrease, and the average viral load reduction on day 56 was 3 log copy / mL. Additionally, the ALT values ​​of all 3 patients decreased from baseline over day 56 and continued to decrease after discontinuation of treatment, and for 2 of the 3 patients, the values ​​averaged 4 weeks after discontinuation of treatment. The upper limit of the normal for ALT values ​​is estimated to be 40 U / L.

[0205] Changes in HDV RNA virus load and ALT values ​​for each patient are shown in Table 7 below.

[0206] Table 7

[0207] Lonafarnib 100mg BID + PEG IFN 180 mcg QW

[0208]

[0209] *Sailing ship upper limit = 40 U / L

[0210] **4 weeks later indicates the end of the first week after the end of treatment.

[0211] These viral load results record efficacy comparable to 200 mg BID lonafarnib therapy, superior efficacy compared to 100 mg BID lonafarnib therapy, and grade 2 lower adverse events (AE) compared to 200 mg BID lonafarnib.

[0212] Example 4. Combination therapy of HDV patients using 100 mg BID lonafarnib and 100 mg QD ritonavir

[0213] Three human subjects known to be infected with HDV, as recorded by reference HDV RNA viral titers in the range of 5.14 log HDV RNA copy / mL to 6.83 log HDV RNA copy / mL and ALT values ​​of 84-195 U / L, were treated with a 100 mg BID dose of lonafarnib combined with a 100 mg QD dose of ritonavir for a period of 8 weeks, essentially differently from what is described in Example 1.

[0214] At the end of week 4, the HDV RNA viral titers of all 3 patients decreased from baseline, with a decline in HDV RNA ranging from -1.71 log HDV RNA copy / mL to at least -2.76 log HDV RNA copy / mL, and the average decline across the 3 patients was -2.2 log HDV RNA copy / mL. At the end of week 8, the HDV RNA viral titers of all 3 patients continued to decrease, and the viral titer of patient 2 was undetectable. At week 8, the average viral load reduction across all 3 patients was -3.2 log HDV RNA.

[0215] In addition, the ALT values ​​of all three subjects decreased from the reference and ranged from 35 to 50 U / L. The upper limit of the normal for ALT is estimated to be 40 U / L. See Table 8.

[0216] Changes in HDV RNA virus load for each patient were prepared in Table 8 below and illustrated in Figure 5.

[0217] Table 8

[0218] 100mg Lonafarnib BID + 100mg Ritonavir QD

[0219]

[0220] *Sailing ship upper limit = 40 U / L

[0221] Below the detection limit.

[0222] These results demonstrated superior efficacy compared to 200 mg BID and 300 mg BID lonafarnib monotherapy and combination therapy of 100 mg BID lonafarnib and 180 µg of Pegasys (pegylated interferon alpha-2a) per week. Additionally, grade 2 lower AEs were observed compared to 200 mg BID lonafarnib. See Table 9.

[0223] Table 9

[0224]

[0225] Table 10

[0226] Average serum concentration (ng / mL)

[0227]

[0228] Example 5. Treatment of HDV patients using lonafarnib and ritonavir

[0229] This example describes the anti-HDV effects of a combination therapy of lonafarnib and ritonavir. Eight patients with chronic HDV infection were treated with four different dosage combinations of lonafarnib and ritonavir (oral administration) for 84 days according to the regimen summarized in Table 10.

[0230] result

[0231] Changes in patients' HDV RNA levels from baseline as a result of lonafarnib and ritonavir combination therapy are summarized in Table 11.

[0232] Table 11

[0233] Lonafarnib-Ritonavir combination therapy

[0234]

[0235] *Refer to Table 11 for the discussion on dosage reduction at weeks 7–12.

[0236] The time course showing changes in HDV RNA levels in patients 1–8 over 28, 56, and 84 days is illustrated in Figures 6a.1, 6a.2, and 6a.3, respectively (averaged change relative to baseline). The mean change in log viral load is -1.89 after 28 days, -1.86 after 56 days, and -1.62 after 84 days. Troughs are reached between 4 and 6 weeks, after which VL is stable or, in some cases, slightly elevated. Group 4 may reach a saturation absorption point, suggesting that a lower lonafarnib dose is preferable.

[0237] Groups 1 and 2 maintained the highest Cmin. These two groups received either BID lonafarnib (Group 1) or BID ritonavir (Group 2). This suggests that higher or more frequent ritonavir administration, such as BID, may be beneficial. Figure 10 illustrates that a QD dose of ritonavir (as shown in the graph) provides LNF serum concentrations in the range of 2500–3500 ng / mL. Increasing the ritonavir dose to BID in patients can achieve higher lonafarnib serum concentrations of >5000 ng / mL.

[0238] The correlation between the decrease in HDV RNA levels and the increase in serum levels of lonafarnib in patients with delta hepatitis infected with lonafarnib-ritonavir combination therapy is exemplified in Patient 2 (Fig. 7) and Patient 8 (Fig. 8). For example, in Patient 8, patients with serum lonafarnib levels of less than 2,000 ng / mL appear to have a lower viral load reduction (<1.5 log HDV-RNA) compared to patients with lonafarnib levels approaching or exceeding 5,000 ng / mL (>2 log HDV-RNA).

[0239] side effect

[0240] Table 12 summarizes the adverse effects of patients during the first 6 weeks of therapy and shows that 75% of patients (6 out of 8 patients) in the study required at least one dose reduction between weeks 7 and 10. Dose reduction often induced an increase in HDV RNA levels or a steady state.

[0241] Table 12

[0242] Reduction of lonafarnib dosage in patients with side effects

[0243]

[0244] The lonafarnib dosage was reduced in 6 out of 8 patients (patients 1, 2, 3, 4, 5, and 8) due to adverse effects. Dose reduction correlated with viral load stabilization or increase. Lomotil and ondansetron were used in 3 out of 8 patients (starting at week 4). 2 out of 3 patients did not require a reduction in the lonafarnib dosage.

[0245] Example 6

[0246] These preliminary examples describe the treatment of HDV infection by administration of lonafarnib 50 mg QD + ritonavir 100 mg QD. Patients infected with HDV self-administered daily in the following manner for 90–180 days:

[0247] Lonafarnib 50mg QD

[0248] Ritonavir 100mg QD

[0249] During the course of treatment, the patient's lonafarnib serum levels and HDV viral load were measured periodically. After 90 days of treatment, the patient's viral load decreased compared to baseline.

[0250] Example 7

[0251] These preliminary examples describe the treatment of HDV infection by administration of lonafarnib 50 mg BID + ritonavir 50 mg BID. Patients infected with HDV self-administered daily in the following manner for 90–180 days:

[0252] Lonafarnib 50mg BID

[0253] Ritonavir 50mg BID

[0254] Ondansetron 8mg BID

[0255] Lomotil 5mg BID

[0256] Famotidine 20mg BID.

[0257] During the course of treatment, the patient's lonafarnib serum levels and HDV viral load were measured periodically. After 90 days of treatment, the patient's viral load decreased compared to baseline.

[0258] Example 8

[0259] These preliminary examples describe the treatment of HDV infection by administration of lonafarnib 75 mg QD + ritonavir 100 mg QD. Patients infected with HDV self-administered daily for 90–180 days in the following manner:

[0260] Lonafarnib 75mg QD

[0261] Ritonavir 100mg QD

[0262] Ondansetron 8mg BID

[0263] Lomotil 5mg BID

[0264] Famotidine 20mg BID.

[0265] During the course of treatment, the patient's lonafarnib serum levels and HDV viral load were measured periodically. After 90 days of treatment, the patient's viral load decreased compared to baseline.

[0266] Example 9

[0267] These preliminary examples describe the treatment of HDV infection by administration of lonafarnib 75 mg BID + ritonavir 50 BID. Patients infected with HDV self-administered daily for 90–180 days in the following manner:

[0268] Lonafarnib 75mg BID

[0269] Ritonavir 50mg BID

[0270] Ondansetron 8mg BID

[0271] Lomotil 5mg BID*

[0272] Famotidine 20mg BID

[0273] Omeprazole 20 mg BID

[0274] *Adjust according to dosage

[0275] During the course of treatment, the patient's lonafarnib serum levels and HDV viral load were measured periodically. After 90 days of treatment, the patient's viral load decreased compared to baseline.

[0276] All publications and patents cited in this specification are incorporated herein by reference as specifically and individually indicated so that each individual publication or patent may be incorporated by reference, and methods and / or materials related to the cited publications are described and explained by reference incorporated herein.

[0277] Although the present invention has been specifically described by specific embodiments, embodiments, and optional features, it should be understood that variations, improvements, and changes to these embodiments, embodiments, and optional features may be made by those skilled in the art, and that such variations, improvements, and changes are considered to be within the scope of this description.

[0278] The invention has been described broadly and generally herein. Each of the narrower types and subgenus groupings included in the general description also forms part of the invention. Furthermore, where a feature or aspect of the invention is described in terms of a group of markers, those skilled in the art will recognize that the invention is also described in terms of any individual member of the group of markers or a subgroup of a member.

Claims

Claim 1 A pharmaceutical composition for treating a delta hepatitis virus (HDV) infection in a human patient, wherein the pharmaceutical composition comprises a therapeutically effective amount of lonafarnib and a therapeutically effective amount of a CYP3A4 inhibitor, wherein the pharmaceutical composition is administered orally to a patient to treat the HDV infection, and the CYP3A4 inhibitor is ritonavir. Claim 2 A pharmaceutical composition according to claim 1, wherein the viral load of human HDV is reduced by at least 2 log HDV-RNA copy / mL or at least 3 log HDV-RNA copy / mL. Claim 3 delete Claim 4 A pharmaceutical composition according to claim 1, wherein one or more gastrointestinal (GI) modifiers are administered prophylactically to the human patient. Claim 5 A pharmaceutical composition according to claim 4, wherein lonafarnib is administered as a sustained-release formulation and released after a GI modifier begins to show effect. Claim 6 A pharmaceutical composition according to claim 4, wherein one or more GI modifiers are selected from the group consisting of antiemetics, antacids, and antidiarrheals. Claim 7 A pharmaceutical composition according to claim 4, wherein one or more GI modifiers are selected from the group consisting of ondansetron, romotil, and famotidine. Claim 8 A pharmaceutical composition according to claim 7, wherein ondansetron is administered at 8 mg BID or TID, lomotil is administered at 5 mg QID or BID, and famotidine is administered at 20 mg BID. Claim 9 delete

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