Treatment of hepatitis delta virus infection

Abstract

To provide a method for treating viral hepatitis caused by infection with hepatitis delta virus (HDV).SOLUTION: The present invention provides a method for reducing hepatitis delta virus (HDV) viral load in a human patient with an HDV infection. The method comprises treating the patient with lonafarnib-ritonavir co-therapy for at least 30 days, where the patient has a baseline viral load of at least 105 IU / mL serum before the initiation of treatment, and the treatment results in a reduction of viral load to less than 103 IU / mL serum. In the method, the HDV viral load remains at the level less than 103 IU / mL serum for at least one month after the treatment.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention provides methods for treating viral hepatitis caused by Hepatitis Delta Virus (HDV) infection and relates to the fields of chemistry, medicinal chemistry, medicine, molecular biology and pharmacology. [Background technology]

[0002] Hepatitis delta virus (HDV) causes the most severe form of viral hepatitis and has no effective drug therapy (see Lau, 1999, Hepatology 30:546-549). HDV always presents as a coinfection with hepatitis B virus (HBV), and coinfected patients are much more likely to die from complications of the viral infection than patients infected with HBV alone.

[0003] The HDV large delta antigen protein contains a CXXX box (see Zhang and Casey, 1996, Annu. Rev. Biochem. 65:241-269), making it a substrate for prenylation by prenyllipid farnesyltransferase (see Glenn et al., 1992, Science 256:1331-1333, and Otto and Casey, 1996, J. Biol. Chem. 271:4569-4572). Protein farnesylation, catalyzed by FTase, is an essential step in the processing of a variety of proteins and occurs by the transfer of the farnesyl group of farnesyl diphosphate to a cysteine ​​in the C-terminal tetrapeptide of the protein in a structural motif sometimes referred to as the CAAX box. Further post-translational modifications of farnesylated proteins generally follow farnesylation, including proteolytic cleavage at the cysteine ​​residue of the CAAX box and methylation of the cysteine ​​carboxyl. Molecular genetic experiments have shown that specific mutations in the prenylation region in the large delta antigen suppress both prenylation and HDV particle formation (Glenn et al., 1992, supra; see also Glenn et al., 1998 J. Virol. 72(11):9303-9306; Bordier et al., 2002 J. Virol. 76(20):10465-10472). There remains a need for agents to treat HDV infection. Summary of the Invention [Means for solving the problem]

[0004] In one embodiment, the present invention provides a method for treating hepatitis delta virus (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 at a dose of about 25mgBID or 50mgBID in combination with administration of ritonavir at 100mgBID or 100mgQD.In one embodiment, the present invention provides a method for treating HDV infection by oral administration of lonafarnib at a dose of about 25mgQD or BID, 50mgQD or BID, 75mgQD or BID in combination with QD or BID administration of ritonavir in a therapeutically effective amount. In some embodiments, the present invention provides methods for treating HDV infection by oral administration of lonafarnib at a dose of about 25 mg QD or BID, 50 mg QD or BID, 75 mg QD or BID, in combination with QD or BID administration of a therapeutically effective amount of ritonavir, further in combination with QW administration of a therapeutically effective amount of interferon (e.g., non-pegylated or pegylated interferon alpha or interferon lambda).

[0005] In another aspect, a method for reducing HDV viral load in a human patient is provided. In some embodiments, the method comprises treating the patient with lonafarnib-ritonavir co-therapy for at least 30 days. In some embodiments, the patient has chronic HDV infection. In some embodiments, the method comprises treating the patient with lonafarnib, ritonavir, and interferon (e.g., non-pegylated or pegylated interferon alpha or interferon lambda) for at least 30 days. In some embodiments, the method comprises treating the patient with lonafarnib-ritonavir co-therapy for at least 30 days, and the patient has been in the treatment for at least 10 days prior to the start of treatment. 5 The subjects had a baseline viral load of 10 IU / mL serum and treatment consisted of 3 This results in a reduction of viral load to less than IU / mL serum.

[0006] In some embodiments, the method includes administering (e.g., orally) lonafarnib in a daily dose ranging from 50 mg to 150 mg. In some embodiments, lonafarnib is administered in a daily dose of 50 mg. In some embodiments, lonafarnib is administered in a daily dose of 100 mg. In some embodiments, lonafarnib is administered in a dose of 25 mg BID. In some embodiments, lonafarnib is administered in a dose of 50 mg QD. In some embodiments, lonafarnib is administered in a dose of 50 mg BID. In some embodiments, lonafarnib is administered in a dose of 75 mg QD. In some embodiments, lonafarnib is administered in a dose of 75 mg BID.

[0007] In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 60 days. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 90 days. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 1 year.

[0008] In one embodiment, a patient receiving lonafarnib-ritonavir co-therapy is administered lonafarnib at a daily dose of 50 mg / day to 150 mg / day, or at a daily dose of 50 mg / day to 100 mg / day, e.g., 25 mg / day, 50 mg / day, 75 mg / day or 100 mg / day, preferably with each administration of lonafarnib being 75 mg or less, e.g., 25 mg or 50 mg, and ritonavir at a daily dose of 100 mg / day to 200 mg / day, preferably with each administration of ritonavir being 100 mg or less.

[0009] In one embodiment, patients may receive 75 mg lonafarnib BID and 100 mg ritonavir BID.

[0010] In one embodiment, patients may receive 50 mg lonafarnib BID and 100 mg ritonavir BID.

[0011] In one embodiment, patients may receive 25 mg lonafarnib BID and 100 mg ritonavir BID.

[0012] In one embodiment, patients may receive 75 mg lonafarnib BID and 100 mg ritonavir QD.

[0013] In one embodiment, a patient is administered a daily dose of 100 mg lonafarnib and 200 mg ritonavir. For example, a patient may be administered 50 mg lonafarnib BID and 100 mg ritonavir BID.

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

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

[0016] In one embodiment, a patient is administered a daily dose of 50 mg lonafarnib and 200 mg ritonavir. For example, a patient may be administered 25 mg lonafarnib BID and 100 mg ritonavir BID.

[0017] In some embodiments, in the treatment described herein, lonafarnib and ritonavir are administered together in a single unit dosage form. In some embodiments, the unit dosage form comprises amorphous lonafarnib. In some embodiments, the unit dosage form comprises lonafarnib (e.g., amorphous lonafarnib), ritonavir, and a copolymer. In some embodiments, the copolymer is povidone.

[0018] In some embodiments, in the treatments described herein, lonafarnib and ritonavir are administered at about the same time as separate unit dosage forms.

[0019] In some embodiments, in the treatments described herein, lonafarnib and ritonavir are administered together in a liquid formulation containing both lonafarnib and ritonavir.

[0020] In one embodiment, a patient is administered oral lonafarnib administered BID or QD at a dose of 50 mg / day, 75 mg / day, or 100 mg / day, and oral ritonavir administered BID or QD at a daily dose of 100 mg / day, e.g., 100 mg / day. This treatment results in serum lonafarnib concentrations greater than 2,000 ng / mL, preferably greater than 4,000 ng / mL, and more preferably in the range of about 3,500 ng / mL to about 7,500 ng / mL.

[0021] In one embodiment, patients are administered oral lonafarnib BID or QD at daily doses of 50 mg / day, 75 mg / day, or 100 mg / day, optionally with a boosting agent. This treatment produces serum lonafarnib concentrations greater than 2,000 ng / mL, preferably greater than 4,000 ng / mL, and more preferably in the range of about 3,500 ng / mL to about 7,500 ng / mL.

[0022] In some embodiments, the patient has at least 10 4 had a baseline viral load of HDV RNA copies per mL of serum and treatment consisted of 2 In some embodiments, patients have a viral load of at least 10 HDV RNA copies per mL of serum prior to treatment. 7 had a baseline viral load of HDV RNA copies per mL of serum and treatment consisted of 5 Produces a viral load less than HDV RNA copies.

[0023] In some embodiments, the treatment comprises administering 10 2 The patient received an additional course of lonafarnib-ritonavir co-treatment for 30 days, resulting in a viral load of less than 10 HDV RNA copies per mL of serum after the additional course of treatment. 2 HDV RNA copies remain below

[0024] In some embodiments, the treatment further comprises administering an interferon. In some embodiments, the interferon is interferon alpha or interferon lambda. In some embodiments, the interferon is a pegylated interferon. In some embodiments, the interferon is a pegylated interferon alpha-2a or a pegylated interferon lambda-1a.

[0025] In some embodiments, lonafarnib and ritonavir or similar enhancer, optionally in combination with interferon, are administered to the patient for a course of treatment that lasts 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, lonafarnib and ritonavir or similar enhancer are administered to the patient for a course of treatment that lasts for at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, or more.In some embodiments, administration is discontinued after a period of time (such as 1-3 months or more) when the viral level falls below 3 log HDV RNA copies / mL (below 1,000 copies / mL) or below detection level.

[0026] In some embodiments, the treatment methods disclosed herein result in HDV RNA levels below 1,000 copies / mL serum or below 1,000 IU / mL serum, and in some cases may remain at low levels for at least one month. In some embodiments, after the HDV RNA level is determined to be below a threshold level (e.g., below 1,000 copies / mL serum or below 1,000 IU / mL serum), lonafarnib-ritonavir co-treatment is continued.

[0027] In some embodiments, the treatment methods disclosed herein result in HDV RNA levels below 100 copies / mL serum or below 100 IU / mL serum, and in some cases may remain at low levels for at least one month. In some embodiments, after the HDV RNA level is determined to be below a threshold level (e.g., below 100 copies / mL serum or below 100 IU / mL serum), lonafarnib-ritonavir co-treatment is continued.

[0028] In some embodiments, the therapeutic approaches disclosed herein result in HDV RNA levels that are below detection levels, and in some cases may remain at low levels for at least one month. In some embodiments, after the HDV RNA level is determined to be below a threshold level (e.g., below detection levels), lonafarnib-ritonavir co-treatment is continued.

[0029] In some embodiments, the patient is administered at least 10 5 had a baseline viral load of HDV RNA copies per mL of serum and treatment consisted of 2 This results in a reduction in viral load to fewer than HDV RNA copies.

[0030] In some embodiments, the patient is at least 10 5 The subjects had a baseline viral load of 10 IU / mL serum and treatment consisted of 2This results in a reduction in viral load to IU / mL serum.

[0031] In some embodiments, the patient receives 10 2 HDV RNA copies or less (or 10 2 After a patient is determined to have a viral load of less than 1 IU / mL serum, lonafarnib-ritonavir co-treatment will be continued for at least 30 days.

[0032] In some embodiments, the patient receives at least 10 7 HDV RNA copies (or 10 7 and treatment consisted of a baseline viral load of 10 IU / mL serum or less. 5 HDV RNA copies or less (or 10 5 It produces a viral load of less than 1 IU / mL serum.

[0033] In some embodiments, the therapeutic approach disclosed herein comprises administering lonafarnib at a first dose, followed by administering lonafarnib at a second dose, the second dose being lower than the first dose.In some embodiments, the therapeutic approach disclosed herein comprises an escalating dosing regimen comprising administering lonafarnib at a first dose in a first treatment period, and then administering lonafarnib at a second dose higher than the first dose in a second treatment period.In some embodiments, the patient is administered lonafarnib at a first dose of 25mg BID in a first treatment period, followed by lonafarnib at a second dose of 50mg BID in a second treatment period. In some embodiments, the therapeutic approach involves administering lonafarnib at a first dose for a first treatment period, then administering a second dose of lonafarnib higher than the first dose for a second treatment period if the patient does not experience unacceptable gastrointestinal side effects during the first treatment period, or administering lonafarnib at a first dose for a first treatment period, then administering a second dose of lonafarnib lower than the first dose for a second treatment period if the patient experiences unacceptable gastrointestinal side effects during the first treatment period.

[0034] In another aspect, a method is provided for inducing immune reactivation in patients infected with HDV and HBV. In some embodiments, the method comprises administering lonafarnib at a total daily dose ranging from 50 mg to 150 mg for at least 12 weeks and / or until a hepatitis flare is observed. In some embodiments, the hepatitis flare is accompanied by a transient increase in the patient's HBV viral load. In some embodiments, the method comprises administering lonafarnib-ritonavir co-therapy, in which ritonavir is administered at a total daily dose of 100-200 mg. Following immune reactivation, HDV viral load can be reduced by at least 3 logs, at least 2 logs, or reduced to undetectable levels.

[0035] In one embodiment, inducing immune reactivation in patients infected with HDV and HBV comprises administering lonafarnib at a first dose, followed by administering lonafarnib at a second dose, the second dose being lower than the first dose.For example, in some cases, the first dose is administered for at least 8 weeks, and the second dose is administered for at least 2 weeks, and optionally at least 4 weeks.In some cases, the first dose of lonafarnib is 50mg BID, and the second dose of lonafarnib is 50mg QD.In some cases, the first dose of lonafarnib and the second dose of lonafarnib are administered in combination with ritonavir at a dose of 100mg BID.

[0036] In another aspect, the lonafarnib-ritonavir co-therapy described herein is discontinued after a treatment period of 10 to 24 weeks, and the lonafarnib-ritonavir co-therapy is not administered to the patient for at least 4 weeks. In some embodiments, the lonafarnib-ritonavir co-therapy is discontinued after a treatment period of 10 to 14 weeks, or the lonafarnib-ritonavir co-therapy is discontinued at 12 weeks of treatment.

[0037] In some embodiments, the therapeutic approach disclosed herein includes detecting the occurrence of a hepatitis flare and / or detecting a transient increase of at least 3 logs in the patient's Hepatitis B Virus (HBV) viral load. In some embodiments, the hepatitis flare is characterized by an abrupt rise in serum alanine aminotransferase (ALT) to levels greater than 200 U / L. In some embodiments, the hepatitis flare is characterized by an abrupt rise in serum alanine aminotransferase (ALT) to levels greater than 800 U / L. In some embodiments, the treatment is discontinued within 25 weeks (e.g., within 20 weeks or within 12 weeks) following the hepatitis flare. In some embodiments, the treatment is discontinued at 12 weeks of treatment. In some embodiments, the treatment is discontinued after 10-14 weeks of treatment. In some embodiments, therapy is discontinued after a treatment period (e.g., after a 10-24 week treatment period, after a 10-14 week treatment period, or after a 12 week treatment period) and therapy (e.g., lonafarnibritonavir co-therapy) is not administered to the patient for at least 4 weeks, e.g., at least 8 weeks, at least 12 weeks, or more. In some embodiments, therapy is discontinued prior to detecting the occurrence of a hepatitis flare and / or prior to detecting a transient increase.

[0038] In yet another aspect, a method is provided for reducing HBV viral load in a patient infected with HBV and HDV. In some embodiments, the patient has chronic HBV infection, and the course of treatment results in a reduction in the patient's HBV viral load compared to the baseline level at the start of treatment. In one approach, the method includes administering lonafarnib at a total daily dose ranging from 50 mg to 150 mg for at least 12 weeks, optionally administering lonafarnib and ritonavir, and detecting at least a 1 log reduction in HBV viral load. In some cases, the treatment results in at least a 2 log reduction in HBV viral load. In some cases, the patient is not treated with an antiviral nucleotide or nucleoside analog. In some embodiments, the patient is also treated by administration of interferon, which may be pegylated interferon lambda, and may be administered at a dose of 120 mcg QW or 180 mcg QW.

[0039] In yet another aspect, a method is provided for reducing the viral load of hepatitis delta virus (HDV) in a human patient with chronic HDV infection, in which the patient receives lonafarnib-interferon co-treatment for at least 30 days, where the co-treatment includes oral administration of lonafarnib at a total daily dose ranging from 50mg to 150mg, and oral administration of interferon lambda-1a at a total weekly dose ranging from 120mcg to 180mcg. Exemplary lonafarnib doses are 25mg BID and 50mg BID. In certain embodiments, the interferon lambda-1a is pegylated interferon lambda-1a.

[0040] In one embodiment, prior to initiation of oral administration of lonafarnib and ritonavir, the patient is prophylactically treated with at least one GI modifying agent, and typically a combination of at least two GI modifying agents (one or more of an antiemetic, an antidiarrheal, and an antacid).

[0041] In another embodiment, the GI modifier is administered simultaneously with lonafarnib and ritonavir, and the lonafarnib is administered as a delayed release formulation, not released until after the GI modifier has begun to take effect.

[0042] In yet another aspect, a unit dosage form is provided that includes lonafarnib and ritonavir. In some embodiments, the unit dosage form is formulated for oral administration. In some embodiments, the unit dosage form includes lonafarnib and ritonavir in a ratio of about 1:2 (w / w) or about 1:4 (w / w), and the unit dosage form is formulated for oral administration. In some embodiments, the unit dosage form includes lonafarnib in an amount of about 25 mg to about 100 mg and ritonavir in an amount of about 50 mg to about 100 mg. In some embodiments, the unit dosage form includes amorphous lonafarnib. In some embodiments, the unit dosage form includes 25 mg of amorphous lonafarnib and 100 mg of ritonavir. In some embodiments, the unit dosage form includes 50 mg of amorphous lonafarnib and 100 mg of ritonavir. In some embodiments, the unit dosage form comprises a mixture of lonafarnib and ritonavir, a multiparticulate formulation, or a bilayer formulation. In some embodiments, the unit dosage form further comprises a copolymer. In some embodiments, the copolymer is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose phthalate, polyvinylpyrrolidone-vinyl acetate copolymer, hypromellose-acetate-succinate, and mixtures thereof. In some embodiments, the copolymer is not povidone. In some embodiments, the copolymer is povidone. In some embodiments, the povidone is povidone K30. In some embodiments, the unit dosage form is formulated as a capsule or tablet. In some embodiments, one or both of lonafarnib and ritonavir are formulated for immediate release. In some embodiments, one or both of lonafarnib and ritonavir are formulated for controlled release.

[0043] In another aspect, a liquid formulation is provided comprising lonafarnib and ritonavir. In some embodiments, the liquid formulation comprises lonafarnib and ritonavir in a ratio of 1:4 or 1:2.

[0044] In yet another embodiment, a pharmaceutical package containing lonafarnib and ritonavir in unit dosage form is provided.

[0045] These and other aspects and embodiments of the invention are described in more detail below. [Brief description of the drawings]

[0046] [Figure 1] 1 shows the time course of HDV RNA levels (copies / mL) in patients treated with 100 mg lonafarnib BID for 28 days. See Example 1.

[0047] [Diagram 2] 1 shows the change in HDV RNA viral load versus serum level of lonafarnib in patients treated with 100 mg lonafarnib BID for 28 days. See Example 1.

[0048] [Diagram 3] HDV RNA viral titers in human patients treated with lonafarnib at doses of either 200 mg BID or 300 mg BID for 28 days. See Example 2.

[0049] [Figure 4] 4. Change in HDV RNA viral titers in patients treated with lonafarnib and interferon (Pegasys) at the doses described in Example 3.

[0050] [Diagram 5] HDV RNA viral titers in patients treated with lonafarnib at a dose of 100 mg BID and ritonavir at 100 mg QD for 28 days. See Example 4.

[0051] [Figure 6A-C] Change in HDV RNA viral titer. Figure 6A shows the change in HDV RNA viral titer from normalized baseline in patients treated with lonafarnib and ritonavir for 28 days at doses described in Example 5. Figure 6B shows the change in HDV RNA viral titer in patients treated with lonafarnib and ritonavir for 56 days at doses described in Example 5. Figure 6C shows the change in HDV RNA viral titer in patients treated with lonafarnib and ritonavir for 84 days at doses described in Example 5.

[0052] [Figure 7] Inverse correlation between higher lonafarnib serum levels and HDV viral load in patients receiving 100 mg lonafarnib BID and 100 mg ritonavir QD.

[0053] [Figure 8] Decreased correlation between lower lonafarnib serum levels and HDV viral load in patients receiving 150 mg lonafarnib QD and 100 mg ritonavir QD.

[0054] [Figure 9] Relationship between lonafarnib serum concentrations and change in viral load in patients receiving 100 mg lonafarnib BID and 100 mg ritonavir QD.

[0055] [Figure 10] Changes in HDV RNA viral titers in patients treated with lonafarnib and pegylated interferon or lonafarnib and ritonavir.

[0056] [Figure 11] Changes in ALT levels in patients treated with lonafarnib and pegylated interferon.

[0057] [Figure 12] 4. Change in HDV RNA viral titers in patients treated with lonafarnib, ritonavir and interferon using the combinations, doses and schedules described in Example 6.

[0058] [Figure 13] 4. Change in HDV RNA viral titers in patients treated with lonafarnib, ritonavir and interferon using the combinations, doses and schedules described in Example 7.

[0059] [Figure 14] 4. Change in HDV RNA viral titers in patients treated with lonafarnib, ritonavir and interferon using the combinations, doses and schedules described in Example 8.

[0060] [Figure 15A-B] Change in HDV RNA viral titer in patients treated with lonafarnib-ritonavir cotherapy with or without pegylated interferon-α as described in Example 12. (A) Change in HDV RNA viral titer measured after 4 weeks. (B) Change in HDV RNA viral titer measured after 8 weeks.

[0061] [Figure 16] 13 shows the change in HDV RNA viral titers at various time points in patients treated with lonafarnib-ritonavir cotherapy with or without pegylated interferon-α, as described in Example 12.

[0062] [Figure 17] 13 is a graph showing the time course of HDV RNA levels (copies / mL) in patients treated with 50 mg BID lonafarnib and 100 mg BID ritonavir, as described in Example 12.

[0063] [Figure 18]13 is a graph showing the time course of HDV RNA levels (copies / mL) in patients treated with 50 mg BID lonafarnib, 100 mg BID ritonavir, and 180 mcg QW pegylated interferon-α, as described in Example 12.

[0064] [Figure 19] 13 is a graph showing the time course of HDV RNA levels (copies / mL) in patients treated with 25 mg BID lonafarnib and 100 mg BID ritonavir, as described in Example 12.

[0065] [Figure 20] 13 is a graph showing the time course of HDV RNA levels (copies / mL) in patients treated with 25 mg BID lonafarnib, 100 mg BID ritonavir, and 180 mcg QW pegylated interferon-α, as described in Example 12.

[0066] [Figure 21] 12 is the change in ALT levels after 12 weeks of treatment as described in Example 12.

[0067] [Figure 22] A titration regimen of lonafarnib / ritonavir co-therapy over 24 weeks of treatment as described in Example 14. No adjustment of ritonavir is shown.

[0068] [Diagram 23] Changes in HDV RNA viral titers in patients treated with lonafarnib and ritonavir using the combinations, doses and schedules described in Example 14.

[0069] [Figure 24] 13 is a graph showing changes in HDV RNA levels (copies / mL) and ALT levels (U / L) over time in patients treated with lonafarnib / ritonavir cotherapy, as described in Example 14.

[0070] [Diagram 25]13 is the change in ALT levels at 24 weeks of treatment as described in Example 14.

[0071] [Figure 26] 26-30. Post-treatment ALT flare for patient A-001-5 treated with 200 mg BID lonafarnib as described in Example 15, showing HDV-RNA negativity and ALT normalization following ALT flare and suppression of HDV RNA and HBV DNA. In Figures 26-30, the limit of quantification (LOQ) for the HDV assay is 3.2 logIU / mL and the LOQ for the HBV assay is 2 logIU / mL. Thus, for HDV, measurements graphed as >0 log and <3.2 log would indicate the presence of HDV at concentrations greater than 0 IU / mL and less than 3.2 log uL / mL, but do not indicate precise amounts within this range. Similarly, for HBV, measurements graphed as >0 log and <2 log would indicate the presence of HBV at concentrations greater than 0 IU / mL and less than 2 logIU / mL, but do not indicate precise amounts within this range.

[0072] [Figure 27] 13 is a post-treatment ALT flare for patient A-001-1 treated with 300 mg BID lonafarnib as described in Example 15, showing ALT flare and HDV-RNA negativity and ALT normalization following suppression of HDV RNA and HBV DNA.

[0073] [Figure 28] Post-treatment ALT flare in patient A-002-3 treated with 100 mg BID lonafarnib in combination with 50 mg BID ritonavir for approximately 10 weeks, followed by 2 weeks of lonafarnib (150 mg QD) and ritonavir (50 mg BID), as described in Example 15, showing ALT flare and parallel reduction in HDV RNA and HBV DNA followed by HDV-RNA negativity and ALT normalization.

[0074] [Figure 29]Post-treatment ALT flare for patient A-002-14 treated with 75 mg BID lonafarnib in combination with 100 mg BID ritonavir for weeks 1-12, 50 mg BID lonafarnib in combination with 100 mg BID ritonavir for weeks 13-24, and pegylated interferon alpha for weeks 16-24 as described in Example 15, showing reduction in HDV-RNA and ALT following suppression of ALT flare and HDV RNA and HBV DNA.

[0075] [Diagram 30] 13 is a post-treatment ALT flare for patient A-002-23 treated with 50 mg BID lonafarnib in combination with 100 mg BID ritonavir as described in Example 15, showing ALT flare and HDV-RNA negativity and ALT normalization following suppression of HDV RNA and HBV DNA.

[0076] [Diagram 31] 4A-4C are characteristic X-ray powder diffraction (XRPD) patterns of ritonavir-lonafarnib-povidone compositions in ratios of 1:1:2 (w / w), 1:2:3 (w / w), and 1:1:5 (w / w) prepared as described in Example 16.

[0077] [Fig. 32A-B] 1 is a thermogravimetric analysis. (A) Characteristic powder TGA thermograms of ritonavir-povidone (1:1) and ritonavir-lonafarnib-povidone (1:1:2), (1:2:3) and (1:1:5) co-precipitates prepared as described in Example 16. (B) Characteristic powder TGA thermograms comparing ritonavir-lonafarnib-povidone (1:1:2) and ritonavir-lonafarnib-HPMC (1:1:2) co-precipitates prepared as described in Example 16. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0078] This detailed description of the invention is divided into sections for the convenience of the reader. As will be apparent to one of skill in the art upon reading this disclosure, each of the individual embodiments described and exemplified herein has individual components and features that can be easily separated or combined with any of the features of several other embodiments (whether described in the same or different sections in this disclosure) without departing from the scope or spirit of the present disclosure. Any described method may be carried out in the order of events described or in any other order that is logically possible. The embodiments of the present disclosure employ techniques within the skill of the art, such as organic synthetic chemistry, biochemistry, biology, molecular biology, recombinant DNA technology, pharmacology, and the like, unless otherwise indicated. Such techniques are fully described in the literature. This disclosure is not limited to the specific embodiments described, and actual embodiments of the present invention may, of course, differ from those described herein.

[0079] I. Definition The scope of the present invention is limited only by the appended claims, and therefore the terms used herein are for the purpose of describing only specific embodiments and are not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In this specification and the claims that follow, reference is made to a number of terms that shall be defined to have the following meanings unless a contrary intention is apparent. In some cases, terms that have commonly understood meanings are defined herein for clarity and / or ready reference, and the inclusion of such definitions herein should not be interpreted as representing a substantial difference to the definition of the term as commonly understood in the art.

[0080] Although any method and material similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices and materials are described herein.All technical and patent literature cited herein is incorporated herein by reference in its entirety.Nothing in this specification should be construed as an admission that the present invention is not entitled to antedate such disclosure by prior invention.

[0081] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations which are varied (+) or (-) by increments of 0.1 or 1.0, as appropriate. All numerical designations should be understood as being preceded by the term "about," even if not always explicitly stated.

[0082] HDV levels are generally calculated as log 10 The HDV RNA level is presented using units. HDV RNA levels can be presented in units of "RNA copies per mL" or "International Units (IU) per mL". See Chudy et al., 2013, Collaborative Study to Establish World Health Organization International Standards for Hepatitis D Virus RNA for Nucleic Acid Amplification Technology (NAT)-Based Assays" WHO Expert Committee on Biological Standardization WHO / BS / 2013.2227. Both units are used herein. As used herein, a statement of "HDV RNA copies per mL" (e.g., as shown in the Examples, but not including discussion related to clinical trial results) should be read as "HDV RNA copies / mL or HDVIU / mL" for purposes of description or basis of the specification. When a specific amount of HDV RNA copies per mL is described, a multiplier of 1.2 can be applied to convert the amount of HDV RNA copies / mL to an amount of IU / mL for description and support of the specification. For example, "120 HDV RNA copies per mL" should be read as "120 copies / mL or 100 IU / mL."

[0083] HBV DNA levels are commonly described in the art using the IU rule (see Saldanha et al., 2001, International Collaborative Study to Establish International Health Organization Standards for Hepatitis B Virus DNA Nucleic Acid Amplification Techniques, Vox Sanguinis 80(1) 63-71).

[0084] Changes in HDV RNA levels can be expressed as "log reductions" following the usual conventions of virology. For example, a 1 log reduction (i.e., -1 log) in viral load (e.g., from 7 log to 6 log) is a 10-fold reduction, and a 2 log reduction (i.e., -2 log) in viral load (e.g., from 7 log to 5 log) is a 100-fold reduction. A reduction from 7 log RNA copies / mL to 6 log RNA copies / mL is equivalent to a reduction from 7 log IU / mL to 6 log IU / mL. Changes in HBV DNA levels can be described using the same terms.

[0085] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of compounds.

[0086] The term "administration" refers to the introduction of a compound, composition or agent of the present disclosure into a host, such as a human. One preferred route of administration of an agent is oral administration. Other routes are intravenous administration and subcutaneous administration.

[0087] "Antidiarrheal drugs" can be of two types: those that thicken the stool and those that slow intestinal spasms. Stool thickening compounds (such as psyllium) absorb water. This helps to make the stool clump and harder. Antispasmodic antidiarrheal preparations slow intestinal spasms by acting on μ-opioid receptors in the intersegmental plexus of the large intestine. By decreasing the activity of the myenteric plexus, this in turn decreases the tone of the longitudinal and circular smooth muscles of the intestinal wall, increasing the time that material remains in the intestinal tract and allowing more water to be absorbed from the feces. Antispasmodics also decrease mass motility in the colon and inhibit the gastrocolic reflex.

[0088] The term "antacid" refers to agents that reduce gastric acid secretion or reduce the effects thereof, and includes H2-receptor antagonists and proton pump inhibitors.

[0089] The term "baseline" refers to measurements (eg, of viral load, patient status, ALT level) taken before a course of treatment, unless otherwise specified or apparent from the context.

[0090] The terms "BID" (twice daily), "QD" (once daily), "QW" (once weekly), etc. have their ordinary meaning in the medical arts.

[0091] The term "comprising" is intended to mean that the compounds, compositions, and methods include the recited elements, but do not exclude others. "Consisting essentially of," when used to define compounds, compositions, and methods, is intended to mean excluding other elements that would materially affect the basic and novel characteristics of the claimed invention. "Consisting of" is intended to mean excluding any element, step, or ingredient not specified in the claim. Embodiments defined by each of these transitional phrases are within the scope of the invention.

[0092] The terms "course of treatment" and "course of therapy" are used interchangeably herein and refer to medical intervention after a patient has been diagnosed, for example, with HDV infection and requires medical intervention, which may include, but is not limited to, administration of medication for a period of time, typically at least one month, several months, or even many months or years for an HDV-infected patient.

[0093] The term "GI intolerance" refers to any one of diarrhea, nausea and vomiting individually or in combination.

[0094] The terms "hepatitis flare", "ALT flare" and "immune reactivation" are used interchangeably and refer to a sudden rise in serum alanine aminotransferase (ALT) to levels greater than twice the baseline ALT of a hepatitis patient. In some embodiments, hepatitis flare is characterized by a sudden rise in serum ALT to levels greater than 5 times the upper limit of normal (ULN). In some cases, serum ALT levels are 200 U / L or greater. See Liaw, Journal of Gastroenterology and Hepatology, 2003, 18:246-252. Methods for measuring serum ALT levels are known in the art. See, for example, J.Clin.Chem.Clin.Biochem., 1986, 24:481-495. In some embodiments, hepatitis flare may indicate a therapeutic effect in HDV patients undergoing treatment with lonafarnib.

[0095] The term "HDV RNA viral load" or "viral load" of a human serum or plasma sample refers to the amount of HDV RNA in a given volume of human serum or plasma sample. HDV RNA is generally detected by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) assays. In such assays, the amount of signal generated during the assay is proportional to the amount of HDV RNA in the sample. The signal from the test sample is compared to the signal of a dilution series of quantified Hepatitis Delta RNA standards, and the copy number of genome copies is calculated. See, e.g., Kodani et al., 2013, J. Virol. Methods, 193(2), 531; Karatayli et al., 2014, J. Clin. Virol, 60(1), 11. HDV RNA viral load may be reported using RNA copies per mL serum (or plasma) or International Units (IU) per mL serum (or plasma) (Chudy et al., 2013, see above). A commercial assay is available from ARUP Laboratories (Salt Lake City, UT). The detection limit of the ARUP HDV RNA assay is reported to be 31 IU / mL. Analytik Jena AG (Germany) offers the RoboGene® HDV RNA Quantitation Kit 2.0, which is CE-IVD certified to WHO standards, to assess response to antiviral treatment. The detection limit of the RoboGene® assay is reported to be 6 IU / mL. "Viral load" without a specific unit (e.g., "viral load less than 100") refers to copies of HDV RNA per mL of serum unless otherwise indicated or clear from the context. Unless otherwise stated, reference to below detection level means less than 6 IU / mL.

[0096] The term "HDV infection" with respect to a human (host) refers to the fact that the host is suffering from HDV infection. Typically, a HDV-infected human host has at least about 2 log HDV RNA copies per mL of host serum or plasma, or 10 HDV-RNA copies per mL of host serum or plasma. 2copies, often at least about 3 log HDV RNA copies per mL of host serum or plasma, or 10 3 copies, and in many cases, especially for patients not receiving any treatment, at least about 4 log HDV RNA copies per mL of host serum or plasma, or 10 4 copies, for example, about 4 log HDV RNA copies per mL of host serum or plasma to 8 log HDV RNA copies per mL of host serum or plasma, or 10 4 ~10 8 The human host has an HDV RNA viral load, such as copies. As used herein, the term "chronic HDV infection" refers to a HDV infection that has persisted in the human host for at least 6 months, as described by a positive HDV antibody (Ab) test and / or detectable by qRT-PCR. The diagnosis and pathogenesis of HDV are described, for example, in Wedemeyer et al., Nat.Rev.Gastroenterol.Hepatol, 2010,7:31-40.

[0097] The term "HBV infection" refers to Hepatitis B (HBV) infection. It will be understood by those skilled in the art that HDV infection can only occur in individuals who are also infected with HBV. Thus, a human host with HDV infection also has HBV infection. Diagnosis of HBV infection can be based on the presence of HBV serological markers, such as hepatitis B surface antigen (HBsAg), hepatitis B core IgM antibody (anti-HBc IgM), and / or the presence of HBV DNA. Methods for detecting and quantifying HBV serological markers and HBV DNA have been described in the art. See, for example, Liu et al., 2015, World J Gastroenterol 21:11954-11963. In some embodiments, a human host with HDV infection and HBV infection has at least about 2 log HBV DNA copies / mL host serum or plasma, or 10 2copies of HBV-DNA / mL of host serum or plasma, and often at least about 3 log HBV DNA copies / mL of host serum or plasma, or 10 3 copies of HBV-DNA / mL host serum or plasma, or at least about 4 log HBV DNA copies / mL host serum or plasma, or 10 4 copies of HBV-DNA / mL of host serum or plasma viral load.

[0098] The term "HBV viral load" of a human serum or plasma sample refers to the number of copies of human HBV DNA in a given volume of human serum or plasma sample. Real-time PCR can be used to detect and quantify HBV DNA. Commercial assays for quantifying HBV DNA are available. In the United States, Abbott offers the Real-time HBV Assay, an in vitro PCR assay for the quantification of HBV DNA in human serum or plasma. A CE-certified kit for real-time PCR-based detection of HBV is commercially available from Analytik Jena, Germany (RoboGene® HBV DNA Quantitation Kit 2.0).

[0099] "H2-receptor antagonists" are a class of drugs used to block the action of histamine on parietal cells (specifically the histamine H2 receptors) in the stomach, reducing acid production by these cells. H2 antagonists are used to treat indigestion.

[0100] "5-HT3 antagonists" are a class of drugs that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in several key sites involved in emesis, including vagus afferents, the nucleus of the solitary tract (STN) and the area postrema itself. 5-HT3 receptor antagonists suppress emesis and nausea by inhibiting the binding of serotonin to the 5-HT3 receptor.

[0101] The term "lonafarnib" or "LNF" or "EBP994", also known by the trade name Sarasar (Schering), refers to the FTase inhibitor 4 (2[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2b]pyridin-11yl]-piperidino]-2-oxoethyl]-1-piperidinecarboxamide) (also identified as Sch-66336 or SCH 66336), having the structural formula shown below. [ka]

[0102] Lonafarnib is a crystalline solid with a melting point of approximately 200°C and is non-hygroscopic. Its molecular weight is 638.7. In the solid state, the compound is thermally stable. In solution, lonafarnib is stable at neutral pH, but is hydrolyzed under acidic or basic conditions. Lonafarnib is a poorly water-soluble tricyclic compound, which when formulated in crystalline form results in low and variable bioavailability in animals. To improve oral bioavailability, considerable efforts have been directed toward formulation development. In addition to the drug substance, a suitable pharmaceutical formulation of lonafarnib for administration in capsules contains povidone, poloxamer 188, croscarmellose sodium, silicon dioxide, and magnesium stearate. The product is formulated with a drug:povidone (1:1) co-precipitate to achieve optimal bioavailability. These are safe and well-tested excipients commonly used in commercial products.

[0103] A patient is considered "HDV-RNA negative" or equivalently "cleared of HDV" if the amount of HDV RNA per mL serum or plasma is below the detection limit of the assay used (i.e., qRT-PCR assay). A patient is considered "persistently HDV-RNA negative" if the amount of HDV RNA per mL serum or plasma is below the detection limit in one viral load measurement and remains below the detection limit in subsequent viral load measurements or measurements taken over an extended period of time, such as at least 6 weeks, at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, or at least 1 year. If not otherwise specified, a patient is considered "persistently HDV-RNA negative" if two viral load measurements at least 24 weeks apart do not detect HDV virus and no viral RNA is detected in the intervening viral load measurements. It will be understood that measurements obtained from serum samples may not detect the presence of low levels of virus in liver cells ("reservoirs"). In many cases, the presence of low levels does not cause any symptoms. In some instances, the reservoir virus population expands and the patient relapses, requiring further treatment.

[0104] "NK1" is a G protein-coupled receptor located in the central and peripheral nervous system. This receptor has a dominant ligand known as substance P (SP). SP is a neuropeptide composed of 11 amino acids that sends and receives impulses and messages from the brain. It is found in high concentrations in the vomiting center of the brain and causes emetic regurgitation when activated. NK-1 receptor antagonists block the signal emitted by the NK1 receptor.

[0105] The term "oral dosage form" as used herein refers to a dosage form suitable for oral administration, such as tablets, capsules, gel capsules, syrups, elixirs, and suspensions. "Solid oral dosage forms" include tablets, capsules, caplets, and the like.

[0106] The term "oral unit dosage form" as used herein refers to a unit dosage form intended for oral administration.

[0107] The terms "patient," "host," or "subject" are used interchangeably and refer to a human infected with HDV, including patients who have been previously infected with HDV and have been cleared of the virus.

[0108] The term "pharmaceutical composition" is meant to encompass compositions suitable for administration to a subject. Generally, a "pharmaceutical composition" is preferably sterile and free of contaminants that may induce an undesired reaction in a subject (e.g., one or more compounds in the pharmaceutical composition are of pharmaceutical grade). Pharmaceutical compositions can be designed for administration to a subject or patient in need thereof by a number of different routes of administration, including oral, intravenous, buccal, rectal, parenteral, intraperitoneal, intradermal, intratracheal, intramuscular, subcutaneous, inhalation, and the like.

[0109] The term "pharmacologically acceptable excipient", "pharmacologically acceptable diluent", "pharmacologically acceptable carrier" or "pharmacologically acceptable adjuvant" means an excipient, diluent, carrier and / or adjuvant that is generally safe, non-toxic and not otherwise biologically undesirable for use in preparing pharmaceutical compositions, and includes excipients, diluents, carriers and adjuvants that are acceptable for veterinary and / or human medicine. As used in the specification and claims, "a pharma- ceutical acceptable excipient, diluent, carrier and / or adjuvant" includes one or more such excipients, diluents, carriers and adjuvants. A wide variety of pharma- ceutical acceptable excipients, such as vehicles, adjuvants, carriers or diluents, and auxiliary agents, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents, and the like, are known in the art. Pharmaceutically acceptable excipients have been widely described in various publications, including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., eds., 7th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et al., eds., 3rd ed. Amer. Pharmaceutical Assoc.For oral formulations, lonafarnib and / or ritonavir may be used in the pharmaceutical formulations of the invention which comprise, consist essentially of, or consist of lonafarnib, alone or in combination with suitable excipients for making tablets, powders, granules, or capsules, e.g., conventional excipients such as lactose, mannitol, corn starch, or potato starch; binders such as microcrystalline cellulose, cellulose derivatives, gum arabic, corn starch, or gelatin; disintegrants such as corn starch, potato starch, or sodium carboxymethylcellulose; lubricants such as talc or magnesium stearate; and, optionally, diluents, buffers, wetting agents, preservatives, and flavorings.

[0110] The term "pharmacologically acceptable salt" refers to salts that retain the biological effectiveness and optionally other properties of the free salt, as well as those obtained by reaction with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, 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, etc. When embodiments of the disclosed agents form salts, these salts are within the scope of the present disclosure. Reference to any agent in the formulations herein is understood to include reference to its salt, unless otherwise indicated.

[0111] As used herein, the term "polymer" refers to an organic substance consisting of multiple repeats of structural units (monomer units) covalently bonded together. As used herein, the term "copolymer" encompasses organic and inorganic polymers. In some embodiments, the polymer is a compound of natural origin (e.g., a protein-based polymer such as collagen, albumin, or gelatin, or a polysaccharide such as alginic acid, cyclodextrin, dextran, agarose, chitosan, hyaluronic acid, starch, or cellulose). In some embodiments, the polymer is a semi-synthetic compound (e.g., a cellulose derivative). In some embodiments, the polymer is a synthetic compound (e.g., polyethylene glycol, poloxamer, polylactide, acrylic acid polymer, or polyamide). In some embodiments, the polymer is a natural biodegradable polymer (e.g., albumin, collagen, gelatin, or starch). In some embodiments, the polymer is a synthetic biodegradable polymer (e.g., polylactide, polyamide). In some embodiments, the polymer is a non-biodegradable polymer (eg, polyethylene, polymethylmethacrylate, polyvinylpyrrolidine, or a cellulose derivative).

[0112] "Proton pump inhibitors" are a class of antisecretory compounds that suppress gastric acid secretion by specific inhibition of the H+ / K+ATPase enzyme system at the secretory surface of the gastric parietal cells. Because this enzyme system is regarded as 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 step of acid production. This effect is dose-dependent and causes inhibition of basal and stimulated acid secretion regardless of the stimulus.

[0113] The term "therapeutically effective amount," as used herein, refers to an amount of an embodiment of an agent (which may also be referred to as a compound, inhibitor, and / or drug) being administered that treats to some extent a disease, disorder, or condition, e.g., alleviates one or more of the symptoms of the disease or infection being treated, and / or prevents to some extent one or more of the symptoms of the disease or infection that the subject being treated has or is at risk of developing.

[0114] The terms "treatment", "treating" and "treat" are defined as addressing a disease, disorder or condition with an agent to reduce or ameliorate the pharmacological and / or physiological effects of the disease, disorder or condition and / or its symptoms. "Treatment" as used herein includes any treatment of disease in a human subject, and includes (a) reducing the risk of disease development in a subject determined to be susceptible to the disease but not yet diagnosed as infected with the disease, (b) preventing the development of the disease, and / or (c) relieving the disease, i.e., causing regression of the disease and / or relieving one or more disease symptoms. "Treatment" is also meant to include the delivery of inhibitors that provide a pharmacological effect even in the absence of disease or condition. For example, "treatment" includes the delivery of disease or pathogen inhibitors that provide enhanced or desirable effects in a subject (e.g., reduction in pathogenic viral load, reduction in disease symptoms, etc.).

[0115] The term "undetectable" used in reference to HDV RNA levels means that no HDV RNA copies are detected by the assay method used. In some embodiments, the assay is quantitative RT-PCR. The term "essentially undetectable" used in reference to HDV RNA levels means that the HDV RNA copies / mL serum or plasma that can be detected by the assay method used (e.g., quantitative RT-PCR) is less than 50, sometimes less than 25, and sometimes less than 10 HDV RNA copies / mL.

[0116] The term "unacceptable gastrointestinal side effect" refers to a gastrointestinal side effect that prevents a patient from completing a recommended course of treatment.

[0117] The term "unit dosage form" as used herein refers to physically discrete units suitable as single doses for a human subject, each unit containing a predetermined amount of one or more compounds (e.g., an antiviral compound and / or a potentiator as described herein) calculated in an amount sufficient to produce the desired therapeutic effect, in association with a pharma- ceutically acceptable diluent, carrier, or vehicle.

[0118] All deuterated analogs of any active pharmaceutical ingredient described herein, including, but not limited to, lonafarnib, and the potentiators ritonavir and cobicistat (when a compound differs from a parent compound only by the replacement of one or more hydrogen atoms with one or more deuterium atoms, it is a deuterated analog of another compound, the "parent compound"), are encompassed by reference to the parent compound for purposes of this invention.

[0119] All stereoisomers of any of the agents described herein, including but not limited to lonafarnib, ritonavir, cobicistat, and any other active pharmaceutical substances described herein, including, for example, enantiomeric forms (which may exist even in the absence of asymmetric carbons) and diastereomeric forms, that may exist due to asymmetric carbons on various substituents, are contemplated within the scope of the present disclosure. Individual stereoisomers of the compounds of the present disclosure may, for example, be essentially free of other isomers, or may, for example, be mixed as racemates or with all other or selected stereoisomers. The stereocenters of the compounds of the present disclosure may have the S or R configuration as defined by the IUPAC 1974 Recommendations.

[0120] II. Introduction In one embodiment, the present invention relates to the treatment of patients infected with Hepatitis D virus (HDV) by co-administering the prenyltransferase inhibitor lonafarnib and the CYP3A4 inhibitor ritonavir. As described below, 28 days of 100mg BID lonafarnib administration has been found to reduce viral load, but this reduction was not sufficient to develop as a treatment. Higher doses of lonafarnib were poorly tolerated and produced unacceptable levels of adverse events. Thus, when administered at 200mg BID, lonafarnib serum levels declined after about one month of treatment, which is believed to be due in general to poor tolerability, poor patient compliance, and loss of drug through the GI tract. When administered at 300mg BID, lonafarnib serum levels were lower than expected, which is also believed to be the result of poor tolerability. See, for example, Table 11 below. Thus, while 100 mg BID lonafarnib was not fully effective, higher doses were associated with significant GI-related adverse effects, making it unsuitable for routine treatment of patients infected with HDV.

[0121] The present invention relates, in part, to the discovery that administration of lonafarnib in combination with ritonavir according to the dosing regimen described herein ("lonafarnib-ritonavir co-therapy") is effective in treating HDV and produces superior efficacy compared to lonafarnib monotherapy. Surprisingly, administration of 100 mg lonafarnib BID and 100 mg ritonavir QD produced higher serum concentrations of lonafarnib measured after 56 days of treatment than those seen with lonafarnib monotherapy, but with a lower frequency of adverse effects (see, e.g., Tables 10 and 11 below). It has also been discovered that lower doses of lonafarnib (e.g., 25 mg lonafarnib BID or 50 mg lonafarnib BID) administered in combination with ritonavir are effective in reducing HDV RNA viral load and are better tolerated (see, e.g., Figures 15A-B and Table 16 below).

[0122] It has also been found that lonafarnib-ritonavir co-therapy can be supplemented or combined with prophylactic administration of a GI modifier (particularly prophylactic administration of one or more of an antiemetic, antidiarrheal, and antacid) to improve the therapeutic effect of the patient. Thus, one aspect of the present invention relates to lonafarnib-ritonavir co-therapy in combination with prophylactic administration of a combination of GI modifiers.

[0123] In one embodiment, a patient undergoing lonafarnib-ritonavir co-treatment is administered a daily dose of lonafarnib of 50-150 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-200 mg / day, e.g., 100 mg / day or 200 mg / day. Certain of the above doses can be achieved by administering lonafarnib QD or BID and administering ritonavir QD or BID. Preferably, each dose of lonafarnib is 75 mg or less, e.g., 50 mg or less, and each dose of ritonavir is 100 mg or less. In one approach, lonafarnib is administered BID and ritonavir is administered QD. In one approach, both lonafarnib and ritonavir are administered BID. In one approach, both lonafarnib and ritonavir are administered QD.

[0124] III. HDV Treatment In one aspect, the present invention provides a method for treating HDV infection, in which HDV-infected patients are treated with oral administration of lonafarnib and ritonavir (which may also be referred to as "lonafarnib administration", "lonafarnib-ritonavir co-therapy", etc.). In some embodiments, lonafarnib and ritonavir are administered according to the doses and administration schedules described herein. In some embodiments, HDV-infected patients are prophylactically treated with one, two, or three or more classes of gastrointestinal (GI) modifiers. In some embodiments, patients receiving lonafarnib-ritonavir co-therapy are also treated with interferon (e.g., non-pegylated or pegylated interferon-alpha or interferon-lambda).

[0125] Lonafarnib has been studied for the treatment of solid and hematologic malignancies, Hutchinson-Gilford progeria syndrome, and chronic hepatitis delta virus infection, but is not approved for any indication. The majority of reports of lonafarnib administration involve its administration to patients with cancer in combination with one or more antineoplastic agents.

[0126] Ritonavir (CAS Registry Number 155213-67-5) is sold by AbbVie, Inc. under the trade name Norvir® and is administered as an antiretroviral in combination with other antiviral drugs for the treatment of HIV-1 infected individuals. See Miller et al., 2015, Infection and Drug Resistance, 8:19-29. The recommended dose of ritonavir for the treatment of HIV-1 in adult patients is 600 mg orally twice daily with food. See Norvir® package insert. Ritonavir is also used as a pharmacological potentiator or booster. Pharmacokinetic "boosting" refers to the pharmacological enhancement of orally administered drugs by coadministration with a pharmacological booster that makes these drugs more effective. Ritonavir is used to enhance the Cmax of proteases used to treat HIV infection. The boosting effect of ritonavir results from several properties of the drug. Ritonavir inhibits two key steps of metabolism.

[0127] First, ritonavir inhibits first-pass metabolism during absorption. The enterocytes lining the intestine contain both CYP3A4, one of the key cytochrome P450 isoenzymes involved in drug metabolism, and P-glycoprotein, an efflux transporter that can effectively pump drugs through the intestinal wall back into the intestinal lumen. Ritonavir inhibits both of these proteins. Thus, coadministration of ritonavir with drugs that are transported by P-glycoprotein and / or metabolized by enterocyte CYP3A4 can increase the Cmax of the coadministered drug. Second, ritonavir inhibits CYP3A4 in the liver, thereby preserving the plasma half-life of the drug.

[0128] Several factors make it impossible and difficult to predict what an acceptable dose of ritonavir for use as a booster would be.

[0129] First, the potentiating effect of ritonavir varies widely and unpredictably depending on the first (i.e., co-administered) drug. This is illustrated by the Norvir® package insert (available on the FDA website at www.rxabbvie.com / pdf / norvirtab_pi.pdf), which shows that the effect of co-administering ritonavir with the first drug can range from a 350-fold increase in the AUC of the first drug (fluticasone propionate, delivered as a water-soluble nasal spray), to an 11-fold increase (sidenafil), to a 1.2-fold increase (trimethoprim). Large differences also exist within a single drug class. For example, in a meta-study of 17 dose-ranging pharmacokinetic studies of protease inhibitors, Hill et al. evaluated the potentiation of ritonavir at doses of 50 to 800 mg daily with seven protease inhibitors: amprenavir, atazanavir, darunavir, indinavir, lopinavir, saquinavir, and tipranavir. Hill concluded that ritonavir has a dose-dependent potentiating effect on indinavir, tipranavir, and lopinavir, but the potentiating effect of ritonavir on darunavir or saquinavir does not correlate with dose.

[0130] Also, the pharmacokinetics of ritonavir in patients with hepatitis is likely to be more unpredictable compared to other treatment populations. Li et al. reported that hepatic CYP3A4 expression is decreased in individuals with chronic HBV infection. Although the subpopulation of HBV-infected patients co-infected with HDV was not separately studied, it is likely that a decrease in CYP3A4 occurs in HDV-positive individuals. See Li et al., 2006, Zhonghua Yi Xue Za Zhi, 86:2703-2706.

[0131] It has also been reported that ritonavir can inhibit P-glycoprotein found in peripheral blood lymphocytes. See Lucia et al., 2001, J Acquir Immune Defic Syndr. 27:321-30. If lonafarnib is a substrate for P-glycoprotein, co-administration of ritonavir may result in less lonafarnib being transported back out of the cell, thereby increasing the intracellular half-life of the drug.

[0132] Furthermore, the HDV patient subpopulation is characterized by a higher level of cirrhosis (occurring in approximately 60-70% of patients with chronic hepatitis D) than patients infected with HBV alone. The pharmacokinetics of ritonavir in the HDV patient population is more unpredictable compared to other populations with lower levels of cirrhosis or no cirrhosis.

[0133] The therapeutic effect of co-administration of lonafarnib and ritonavir to patients with chronic HDV was not known prior to the present invention, and no dosing regimens (e.g., doses and dosing schedules) that were safe, tolerable, and effective for treating patients with HDV and chronic HDV infection were described in the medical literature prior to the present invention.

[0134] Additionally, the side effect profile of lonafarnib administration and coadministration of lonafarnib with ritonavir has not been determined to date. Diarrhea, nausea, and vomiting have been reported as side effects of both lonafarnib (see Schering IB) and ritonavir (see Norvir package insert). In cancer patients, lonafarnib at 200 mg BID was characterized as "well tolerated." See 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. 32:274-279 (describing lonafarnib treatment after platinum-based therapy for recurrent SCCHN) and List et al., 2002, Blood, 100:789A (lonafarnib at 200 mg BID was well tolerated in patients with advanced hematologic malignancies). However, the side effect profile of therapeutically effective levels of lonafarnib administered to patients with chronic HDV infection was not known, and the side effect profile of lonafarnib-ritonavir cotreatment was not known for either population.

[0135] Effect of lonafarnib treatment on HDV infection As described in Example 1 below, a cohort of patients with chronic hepatitis delta (HDV) was treated with 100 mg lonafarnib BID for 28 days and showed a mean change in HDV RNA levels from baseline to nadir of -0.74 log HDV RNA copies / mL compared to -0.24 log HDV RNA copies / mL in patients receiving placebo. See also Table 1 below. Plasma levels of lonafarnib ranged from 200 ng / mL to 1,100 ng / mL during treatment, with subjects with higher lonafarnib plasma levels experiencing a greater reduction in HDV RNA titers during treatment. See Figure 2. However, a stronger reduction in viral load would have been desirable.

[0136] As described in Example 2 below, administration of higher doses of lonafarnib to HDV-infected patients resulted in more dramatic reductions in viral load, but was unacceptably tolerated. In patients receiving 200 mg BID lonafarnib for 28 days, the mean change in viral load was -1.63 log HDV RNA copies / mL. In patients receiving 300 mg BID lonafarnib for 28 days, the mean change in viral load was -2.00 log HDV RNA copies / mL. See also Table 1 below.

[0137] Although daily administration of 200 mg or 300 mg BID lonafarnib produced superior viral load reductions in HDV patients compared with daily administration of 100 mg BID lonafarnib, administration of 200 mg or 300 mg BID lonafarnib produced significant side effects that make these dosing regimens unsuitable for long-term treatment.

[0138] Effect of lonafarnib-coadministration on HDV infection As shown in Examples 4-6 and 12 below, lonafarnib-ritonavir co-treatment substantially reduced HDV viral load in patients at different dose combinations. Example 4 describes the superior efficacy observed with lonafarnib-ritonavir co-treatment compared to lonafarnib monotherapy. In patients receiving 100 mg BID lonafarnib in combination with 100 mg QD ritonavir for 28 days, the mean change in viral load was -2.2 log HDV RNA copies / mL. See also Table 1 below. Example 12 shows that for patients receiving 25 mg BID or 50 mg BID lonafarnib in combination with 100 mg BID ritonavir, a reduction in HDV RNA viral load was observed with lonafarnib-ritonavir co-treatment comparable to patients receiving higher doses of lonafarnib. Furthermore, in some instances, lonafarnib-ritonavir co-treatment reduced HDV viral load to undetectable levels at week 8. See Figures 5 and 17. Thus, in accordance with the present invention, by using lower doses of lonafarnib alone or in combination with interferon, along with a potentiator, patients can achieve significant therapeutic benefit at lower doses of lonafarnib doses 25 mg QD to 100 mg BID in combination with 100 mg BID ritonavir, and at the preferred dose of 50 mg BID lonafarnib. [Table 1]

[0139] Thus, in various methods of the present invention, each of lonafarnib and ritonavir is orally administered to HDV patients in combination with the other continuously, daily, at least once a day (QD), in various embodiments twice a day (BID). In some embodiments, lonafarnib-ritonavir co-treatment is administered daily for at least 30 consecutive days. In some embodiments, lonafarnib-ritonavir co-treatment is administered daily for at least several months. In some embodiments, patients can receive lonafarnib-ritonavir co-treatment for the rest of their lives.

[0140] As shown in Figure 2, HDV viral load decreases with increasing plasma concentration of lonafarnib. A correlation between lonafarnib serum levels and viral load in patients undergoing lonafarnib-ritonavir co-treatment is also found by comparing the viral load of patients who maintained serum lonafarnib concentrations in the range of about 3,500-5,000 ng / mL for about 21 days (see Figure 7) with the viral load of patients who maintained serum lonafarnib concentrations in the range of about 1500-2500 ng / mL for about 21 days (see Figures 7 and 8), with the former patients doing significantly better. Also referring to Table 12, it is shown that patients with the highest lonafarnib serum levels after 4 weeks of co-treatment have the greatest reduction in viral load, and that patients with lonafarnib serum levels above 2,000 ng / mL generally have more dramatic reductions in viral load than patients with serum levels below 2,000 ng / mL (Patient 4 is an exception to this trend).

[0141] Thus, in certain embodiments, lonafarnib and ritonavir are co-administered according to a schedule that results in a serum lonafarnib level of 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 schedule that results in a serum lonafarnib level 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 6,500 ng / mL to about 7,500 ng / mL).

[0142] As used herein, serum lonafarnib levels or concentrations can be measured from serum samples obtained from a subject periodically (such as weekly, biweekly, monthly, or according to other schedules) and levels can be estimated during the intervening period. For example, if a measurement of 4,000 ng / mL is obtained at 4 weeks and a measurement of 6,000 ng / mL is obtained at 6 weeks, for purposes of this analysis, it is concluded that the serum levels for the intervening 2 weeks were in the range of 4,000-6,000 ng / mL. In some embodiments, the first measurement is made one week or later after the start of oral treatment.

[0143] Serum levels of lonafarnib may be measured using methods known in the art, including radioimmunoassay, chromatographic assay, mass spectrometry, and the like. In some embodiments of the present invention, patient serum samples were extracted using protein precipitation (acetonitrile). Samples were then loaded onto a Waters CSH C18, 2.1x50mm, 1.7μm column for separation, followed by LC-MS / MS in positive ion mode for detection of lonafarnib. The assay range for lonafarnib was 1-2500ng / mL.

[0144] Lonafarnib and Ritonavir Dosage In some embodiments, lonafarnib-ritonavir co-therapy includes administering lonafarnib at a total daily dose ranging from 50 mg to 150 mg (e.g., a total daily dose of about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg) and administering ritonavir at a total daily dose ranging from 100 mg to 200 mg (e.g., a total daily dose of about 100 mg, about 150 mg, or about 200 mg). In some embodiments, the total daily dose of lonafarnib is 50 mg and the total daily dose of ritonavir is 200 mg. In some embodiments, the total daily dose of lonafarnib is 100 mg and the total daily dose of ritonavir is 200 mg. In some embodiments, the total daily dose of lonafarnib is 150 mg and the total daily dose of ritonavir is 200 mg.

[0145] In some embodiments, lonafarnib is administered BID. In some embodiments, lonafarnib is administered QD. In some embodiments, lonafarnib is administered at a dose of 25 mg BID. In some embodiments, lonafarnib is administered at a dose of 50 mg BID. In some embodiments, lonafarnib is administered at a dose of 50 mg QD. In some embodiments, lonafarnib is administered at a dose of 75 mg BID. In some embodiments, lonafarnib is administered at a dose of 75 mg QD. In some embodiments, lonafarnib is administered at a dose of 100 mg QD.

[0146] In some embodiments, ritonavir is administered BID. In some embodiments, ritonavir is administered QD. In some embodiments, ritonavir is administered at a dose of 100 mg BID. In some embodiments, ritonavir is administered at a dose of 100 mg QD. In some embodiments, ritonavir is administered at a dose of 75 mg BID. In some embodiments, ritonavir is administered at a dose of 50 mg BID.

[0147] Exemplary doses are provided, by way of illustration and not limitation, in Table 2. Typically, lonafarnib and ritonavir are administered together (e.g., self-administered by the patient) at approximately the same time (e.g., simultaneously or within about 15 minutes of each other). [Table 2]

[0148] Each of embodiments 1-8 in Table 2 may be administered with prophylactic GI modifiers (e.g., antiemetics, antidiarrheals, and antacids) and / or interferons (e.g., interferon alpha or interferon lambda). See Sections V and VI below.

[0149] In some embodiments, lonafarnib and ritonavir (or a similar potentiator such as cobicistat) are administered to a patient, with both ritonavir and lonafarnib doses being at least 50 mg QD or at least 100 mg QD for at least 30 days, usually at least about 60 days, or 90 days or more, including 6 months to 1 year or more. In some embodiments, administration is discontinued after a period of time (such as 1 to 3 months or more) during which the viral levels have decreased to undetectable levels. In one approach, suitable doses of lonafarnib / ritonavir include at least 30 days, more often at least 60 days, and typically at least 90 days, or more than 90 days. In one approach, treating hepatitis delta virus (HDV) infection in humans includes administering a daily dose of about 50 mg / day, about 100 mg / day, or about 150 mg / day of lonafarnib (e.g., about 25 mg BID, 50 mg BID, 50 mg QD, 75 mg BID, 74 mg QD, or 100 mg QD of lonafarnib) for at least about 30 days, and a therapeutically effective amount of a CYP3A4 inhibitor (e.g., ritonavir or cobicistat), thereby treating the HDV infection. In one approach, ritonavir is administered at 100 mg QD.

[0150] In some embodiments, treatment with lonafarnib-ritonavir co-therapy results in serum lonafarnib concentrations greater than 2,000 ng / mL when measured after 4 weeks of treatment. In some embodiments, treatment with lonafarnib-ritonavir co-therapy results in serum lonafarnib concentrations greater than 3,000 ng / mL when measured after 4 weeks of treatment.

[0151] Patient population In some embodiments, the patient treated with the co-therapy described herein is a patient with chronic HDV infection. In some embodiments, the patient treated has a persistent chronic HDV infection for at least 6 months, documented by a positive HDV antibody (Ab) test and / or detectable HDV RNA by qRT-PCR. In some embodiments, the patient treated with the co-therapy method described herein is a patient with an acute HDV infection that is newly diagnosed or otherwise considered to have been absent in the patient for 6 months or more. The diagnosis and pathogenesis of HDV are described, for example, in Wedemeyer et al., Nat. Rev. Gastroenterol. Hepatol, 2010, 7:31-40. HDV is known to exist in various subtypes. The methods described herein are suitable for treating all HDV patients, regardless of HDV subtype.

[0152] In some embodiments, the patient being treated receives at least 10 4 HDV RNA copies, e.g., at least 10 per mL serum or plasma 5 HDV RNA copies, at least 10 per mL of serum or plasma 6 HDV RNA copies, at least 10 per mL of serum or plasma 7 HDV RNA copies or at least 10 per mL serum or plasma 8 The viral load of HDV RNA copies is. In some embodiments, the HDV viral load is measured using serum samples from patients. In some embodiments, the HDV viral load is measured using plasma samples from patients. In some embodiments, the viral load is measured by quantitative RT-PCR. The qRT-PCR assay for quantifying HDV RNA in serum or plasma is known in the art, for example as described above.

[0153] In some embodiments, the patient to be treated exhibits one or more symptoms of liver dysfunction. In some embodiments, the patient exhibits one or more liver function parameters that are outside the normal parameters of healthy controls (e.g., subjects not infected with HDV or HBV). In some embodiments, the liver function parameters are selected from the group consisting of serum albumin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and prothrombin activity. In some embodiments, the patient has a serum ALT level that is at least twice (e.g., at least twice, at least three times, at least four times, at least five times, at least six times, at least seven times, at least eight times, or more) the upper limit of normal (ULN). Liver function parameters are described in the art. See, for example, Limdi et al., Postgrad Med J, 2003, 79:307-312. Methods for measuring these liver function parameters are known in the art and are commercially available.

[0154] Dose escalation and deescalation In one embodiment, a patient treated for HDV infection receives an escalating dosing regimen of lonafarnib, with one or more later doses being higher than one or more earlier doses. In some embodiments, the escalating dosing regimen can increase the patient's tolerance to the drug and minimize side effects. In some embodiments, the dose escalation comprises administering lonafarnib at a first dose for a first treatment period, followed by administering lonafarnib at a second dose higher than the first dose for a second treatment period. In some embodiments, the length of time of the first treatment period is the same as the length of time of the second treatment period. In some embodiments, the first treatment period and the second treatment period are of different lengths of time. In some embodiments, the dose escalation further comprises administering one or more additional doses of lonafarnib for one or more additional treatment periods.

[0155] In some embodiments, the duration of administration of each dose in the titration regimen is within 1-4 weeks. The duration of each administration may be adjusted (e.g., accelerated) by the clinician based on the patient's response. For example, but not limited to, a patient may receive lonafarnib 25 mg BID for the first 2 weeks, followed by 50 mg BID for the next 2 weeks until a predetermined desired final dose is reached. Typically, the titration dose is co-administered with an appropriate dose, e.g., 100 mg QD or BID, of ritonavir. Dose escalation may continue up to 75 mg BID or more (e.g., 75 mg BID), including 100 mg BID or more (e.g., 100 mg BID).

[0156] In some embodiments, lonafarnib-ritonavir co-therapy involves administering lonafarnib at a first dose in a first treatment period, and then administering a second dose of lonafarnib higher than the first dose in a second treatment period if the patient does not experience unacceptable gastrointestinal side effects in the first treatment period. As a non-limiting example, in some embodiments, lonafarnib is administered at a first dose of 50 mg BID in a first treatment period, and at a second dose of 75 mg BID in a second treatment period if the patient does not experience unacceptable gastrointestinal side effects in the first treatment period.

[0157] In some embodiments, lonafarnib-ritonavir co-therapy involves administering lonafarnib at a first dose in a first treatment period, and then administering a second dose of lonafarnib lower than the first dose in a second treatment period if the patient experiences unacceptable gastrointestinal side effects in the first treatment period. As a non-limiting example, in some embodiments, lonafarnib is administered at a first dose of 75 mg BID in the first treatment period, and a second dose of 50 mg BID in the second treatment period if the patient experiences unacceptable gastrointestinal side effects during the first treatment period.

[0158] Duration of Treatment, Induction of Immunological Reactivation, and Treatment Endpoints The patient may receive lonafarnib-ritonavir co-therapy for a predetermined period of time, an indefinite period of time, or until an endpoint is reached. Treatment may be continued continuously daily for at least 2-3 months. Treatment is typically for at least 30 days or 1 month, more often for at least 60 days or 2 months, or at least 90 days or 3 months, even more often for at least 120 days or 4 months, sometimes for at least 150 days or 5 months, and sometimes for at least 180 days or 6 months. 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 low enough level to provide a meaningful therapeutic benefit.

[0159] According to the methods of the present invention, some HDV patients respond to co-treatment herein by clearing the virus to undetectable levels, often after experiencing a hepatitis flare, after which treatment may be discontinued unless and until HDV levels return to detectable levels. Other patients experience a reduction in viral load and improvement in symptoms, but do not clear the virus to undetectable levels, but remain on "long-term treatment" as long as it provides therapeutic benefit.

[0160] In some cases, during the first course of treatment, the patient will achieve a particular endpoint (e.g., 10 2 or 10 3The patient is treated to a viral load below 100 mg / kg / day, hepatitis flare, or viral clearance. When the patient achieves the endpoint, the healthcare provider may choose to discontinue treatment, such as lonafarnib-ritonavir co-therapy. Alternatively, when the patient achieves the endpoint, the healthcare provider may choose to continue treatment, such as lonafarnib-ritonavir co-therapy. For convenience, post-endpoint treatment is sometimes referred to as a "second (or "additional") course of treatment." The first and second courses of treatment may (and typically do) include administration of the same dosing regimen (i.e., the same dose and frequency of administration). Although the terminology is sometimes convenient, for the avoidance of doubt, the patient may receive a "single course of treatment" that extends to the endpoint.

[0161] In some embodiments, patients receiving lonafarnib-ritonavir co-treatment have at least 10 4 had a baseline viral load of HDV RNA copies per mL of serum and treatment consisted of 2 In some embodiments, the viral load is at least 10 HDV RNA copies per mL of serum. 4 Patients with a baseline viral load of HDV RNA copies 10 per mL of serum 2 A subject receives a first treatment course that results in a viral load of less than 10 HDV RNA copies per mL of serum, followed by an additional treatment course, and the viral load is less than 10 HDV RNA copies per mL of serum after the additional treatment course. 2 HDV RNA copies remain below detection levels. In some embodiments, the treatment results in an HDV viral load below detection levels.

[0162] In some embodiments, patients receiving lonafarnib-ritonavir co-treatment have at least 10 5 had a baseline viral load of HDV RNA copies per mL of serum and treatment consisted of 3 In some embodiments, the viral load is at least 10 HDV RNA copies per mL of serum. 5Patients with a baseline viral load of HDV RNA copies 10 per mL of serum 3 A subject receives a first treatment course that results in a viral load of less than 10 HDV RNA copies per mL of serum, followed by an additional treatment course, and the viral load is less than 10 HDV RNA copies per mL of serum after the additional treatment course. 3 In some embodiments, patients receiving lonafarnib-ritonavir co-treatment have at least 10 HDV RNA copies per mL of serum. 5 had a baseline viral load of HDV RNA copies per mL of serum and treatment consisted of 2 Resulting in a viral load below HDV RNA copies. In some embodiments, the treatment results in a HDV viral load below detection levels.

[0163] In some embodiments, patients receiving lonafarnib-ritonavir co-treatment have at least 10 6 had a baseline viral load of HDV RNA copies per mL of serum and treatment consisted of 4 HDV RNA copies, less than 10 3 HDV RNA copies or less than 10 2 In some embodiments, patients receiving lonafarnib-ritonavir co-treatment have a reduced viral load of less than 10 HDV RNA copies per mL of serum. 7 had a baseline viral load of HDV RNA copies per mL of serum and treatment consisted of 5 HDV RNA copies, less than 10 4 HDV RNA copies, less than 10 3 HDV RNA copies or less than 10 2 Resulting in a reduced viral load below HDV RNA copies. In some embodiments, the treatment results in an HDV viral load below detection levels.

[0164] In some embodiments, treatment with lonafarnib-ritonavir co-therapy results in a reduction in HDV viral load in patients of at least 1.5 log HDV RNA copies / mL serum when measured after 8 weeks of treatment. In some embodiments, treatment with lonafarnib-ritonavir co-therapy results in a reduction in HDV viral load in patients of at least 2.0 log HDV RNA copies / mL serum when measured after 8 weeks of treatment. In some embodiments, treatment with lonafarnib-ritonavir co-therapy results in a reduction in HDV viral load in patients of at least 2.5 log HDV RNA copies / mL serum when measured after 8 weeks of treatment.

[0165] In some embodiments, treatment with lonafarnib-ritonavir cotherapy results in a reduction in HDV viral load in a patient of at least -1 log, or at least -2 log, or at least -3 log, or at least -5 log, or at least -6 log, when measured several weeks (e.g., 12, 24, 36, 48, 60, 72, or 90 weeks) after initiation of treatment.

[0166] In some embodiments, treatment with lonafarnib-ritonavir co-therapy results in a sustained reduction in HDV RNA levels. For example, in some embodiments, treatment results in a reduction in HDV RNA levels in the serum or plasma of the patient, and the reduced levels persist for a period of time (e.g., 1 month, 2 months, 3 months, 6 months, 9 months, 1 year, or more). In some embodiments, the reduced HDV RNA levels persist for a period of time (e.g., 1 month, 3 months, 1 year, or more) after the treatment course is completed. In some embodiments, the reduced HDV RNA levels persist for a period of time (e.g., 1 month, 3 months, 1 year, or more) while the treatment course is ongoing. In some embodiments, the treatment course results in HDV RNA levels (e.g., serum HDV RNA levels or plasma HDV RNA levels) of less than 1,000 copies / mL. In some embodiments, the HDV RNA levels remain less than 1,000 copies / mL for at least 1 month, at least 3 months, at least 1 year, or more. In some embodiments, the course of treatment results in an HDV RNA level (e.g., serum HDV RNA level or plasma HDV RNA level) of less than 100 copies / mL. In some embodiments, the HDV RNA level remains less than 100 copies / mL for at least one month, at least three months, at least one year or more. The phrase "remains less than" an initial measurement (e.g., 100 copies / mL or 100 IU / mL) for one month (or another specified period) means that viral load measurements taken are not higher than the initial value for at least one month (or another specified period) after the measurement of the initial measurement. In some embodiments, the patient does not receive lonafarnib or lonafarnib-ritonavir co-treatment for a specified period. In some embodiments, the patient does not receive any anti-HDV treatment for a specified period.

[0167] In some embodiments, the treatment described herein is continued for a period of time until HDV RNA levels are less than 3 log HDV RNA copies / mL (less than 1,000 copies / mL), or sometimes until HDV RNA levels are less than 2 log HDV RNA copies / mL (less than 100 copies / mL) or below detection levels. In some cases, treatment may be continued for a period of time (such as 1-3 months or more) after viral load has fallen to an acceptably low level (e.g., undetectable). In some embodiments, treatment is continued until HDV viral load has fallen to undetectable levels.

[0168] In some cases, treatment is continued until a "hepatitis flare" or "ALT flare" is observed in the patient. Hepatitis flare (or acute exacerbation) is a sudden rise in serum alanine aminotransferase (ALT) above 5 times the upper limit of normal, approximately 40 U / L, observed in chronic hepatitis B virus (HBV) infection. HBV flare in HBV patients occurs due to an HLA-I restricted, cytotoxic T lymphocyte (CTL) mediated immune response to HBV and its downstream mechanisms. Higher ALT levels reflect more robust immune clearance of HBV. See Liaw, 2003, "Hepatitis flares and hepatitis B antigen seroconversion: implications in anti-hepatitis B virus therapy," J Gastroenterol Hepatol 18:246-52. Although hepatitis flares have not been previously reported in response to anti-HDV treatment, signs of flare were observed in response to lonafarnib-ritonavir co-treatment described herein. For example, two patients who received lonafarnib 100 mg BID and ritonavir 50 mg BID orally administered 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 who received lonafarnib 200 mg BID or 300 mg BID monotherapy, and in patients who received lower doses of lonafarnib in lonafarnib-ritonavir co-treatment (e.g., 75 mg BID lonafarnib combined with 100 mg BID ritonavir, and 50 mg BID lonafarnib combined with 100 mg BID ritonavir). See Example 15 below.

[0169] The observation of flares in HDV patients suggests that co-treatment with ritonavir at doses described herein and lonafarnib may have unprecedented beneficial therapeutic effects in clearing HDV from patients. Without being bound to a particular theory or mechanism, it is believed that in at least a subset of HDV patients, treatment with lonafarnib or lonafarnib-ritonavir co-treatment results in reactivation of the immune system that was suppressed as a result of HDV viral infection. Concurrent HBV / HDV infection often results in suppression of HBV replication in human patients, and in at least a portion of HDV patients, suppression of HDV infection using the methods described herein results in at least a transient increase in HBV levels. Without being bound to a particular theory, it is also believed that HDV suppresses the patient's immune response in parallel with suppression of HBV. Suppression of HDV by lonafarnib treatment suppresses suppression of HBV and HBV replication. Some patients who have undergone immune reactivation and have not received anti-HBV therapy (e.g., antiviral nucleotide or nucleoside analogs) have been found to typically exhibit at least a 3-log transient increase in HBV DNA levels within about 12 weeks of starting treatment. See, for example, Table 15 below. According to the present invention, the increase in HBV can be used as a surrogate marker to monitor the degree of immune reactivation in response to treatment (e.g., the effectiveness of anti-HDV treatment). For example, as described in Example 15 below, ALT flares observed in at least a subset of HDV patients in response to HDV treatment indicate a reactivated immune response. Without being bound to a particular mechanism, it is believed that upon immunological reactivation, the immune system begins to clear in response to HDV infection, resulting in ALT release from targeted HDV-infected hepatocytes, which appears as an ALT flare. Furthermore, in at least some patients, immunological reactivation can result in a decrease in HBV levels or clearance of HBV infection. As described below in Example 15, patients from various lonafarnib-treated cohorts who exhibited ALT flares subsequently demonstrated suppression or clearance of HDV infection and suppression of HBV DNA levels.Without being bound by a particular theory, it is believed that in patients experiencing immune reactivation, as evidenced by the presence of ALT flares, suppression of HBV is due, at least in part, to an immune-mediated response. Thus, although HBV is often suppressed by HDV prior to LNF treatment, the continued or even more pronounced suppression of HBV observed after immunological reactivation results in suppression or clearance of HDV reflects a newly improved immune-mediated response to HBV.

[0170] As described in Example 15 below, patients who experience immunological reactivation have been found to exhibit certain characteristics with respect to HDV RNA levels and HBV DNA levels. For example, patients who experience immunological reactivation exhibit a decrease in HDV RNA levels (e.g., at least 1 log) within the first two weeks of treatment, and then the decreased HDV RNA levels are maintained (if not further decreased) for at least another two weeks before the HDV levels increase by at least 50% or more from the nadir. In some embodiments, patients who experience immunological reactivation exhibit a transient increase of at least 3 logs in HBV viral load.

[0171] In some embodiments, the method of inducing immune reactivation in a patient includes administering lonafarnib or lonafarnib-ritonavir co-therapy at a first dose in a first treatment course, followed by administering lonafarnib or lonafarnib-ritonavir co-therapy at a second dose in a second treatment course, the second dose being different from the first dose. In some embodiments, the second dose is a lower lonafarnib dose ("step-down"). In some embodiments, the first treatment course is in the range of about 4-12 weeks, e.g., about 8-12 weeks. In some embodiments, the second treatment course is about 2-4 weeks. In some embodiments, the first treatment course is about 8 weeks and the second treatment course is about 4 weeks.

[0172] In some embodiments, within about 12-24 weeks after the onset of an ALT flare, the patient is HDV-RNA negative. In some embodiments, within about 12-24 weeks after the onset of an ALT flare, the patient has normalized ALT levels (i.e., ALT levels within the upper limit of normal as defined in the art). In some embodiments, following immune reactivation, the patient's HDV viral load is reduced by at least 3 logs compared to the patient's baseline level at the start of treatment. In some embodiments, following immune reactivation, the patient's HBV viral load is reduced by at least 2 logs compared to the patient's baseline level at the start of treatment. In some embodiments, the patient's HDV viral load and / or HBV viral load is reduced to undetectable levels.

[0173] In some embodiments, treatment with lonafarnib-ritonavir co-therapy results in an improvement in the patient's liver function. In some embodiments, the improved liver function is an improvement in one or more liver function parameters (e.g., one, two, three, four or more parameters) selected from the group consisting of serum albumin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and prothrombin activity. In some embodiments, treatment results in at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more improvement in one or more liver function parameters selected from the group consisting of serum albumin, bilirubin, ALT, AST, and prothrombin activity. In some embodiments, treatment results in an improvement in one or more liver function parameters selected from the group consisting of serum albumin, bilirubin, ALT, AST, and prothrombin activity to the level of a healthy control subject not infected with HDV or HBV. In some embodiments, treatment with lonafarnib-ritonavir cotherapy results in improved liver biopsies (e.g., as assessed by histological staining, immunohistochemical staining, and / or fibrosis grading).

[0174] In some embodiments, treatment with lonafarnib-ritonavir co-therapy delays the need for liver transplant in patients.In some embodiments, treatment delays the need for liver transplant for at least 3 months, at least 6 months, at least 9 months, or at least 12 months.In some embodiments, treatment delays the need for liver transplant indefinitely.

[0175] Induction of ALT flare and subsequent HDV suppression In one embodiment, a method for inducing ALT flare in patients infected with HDV is provided. As described herein, in at least some patients with chronic HDV treated with lonafarnib therapy (e.g., lonafarnib monotherapy or lonafarnib and ritonavir cotherapy), ALT flare is induced followed by a significant decrease in HDV RNA titer (see, e.g., Figures 26-30). In at least some patients within about 12-24 weeks after the onset of ALT flare, the patient tests negative for HDV RNA. In some patients, after a period of HDV RNA negativity, a subsequent increase in HDV RNA levels is observed. Without intending to be bound by a particular theory, it is believed that low levels of virus remain in the "viral reservoir" of patients who test negative for HDV RNA using certain assays. In some situations, persistent virus may expand (see, e.g., Figure 26) and further antiviral treatment may be required if not eliminated by the patient's immune response. This additional antiviral treatment is typically with lonafarnib, optionally as a co-treatment with ritonavir and / or interferon. Generally, the additional treatment involves administering lonafarnib at a lower dose and / or for a shorter period of time than the initial pre-flare treatment regimen, optionally as a co-treatment with ritonavir and / or interferon.

[0176] By way of example and not limitation, Table 3 shows an exemplary treatment protocol. [Table 3]

[0177] As described above, in addition to or as an alternative to monitoring ALT flares, HBV DNA levels can be used to assess the efficacy of initial treatment. As an example, a patient with chronic HDV and a fibrosis score of ≦F3 is administered 50 mg BID lonafarnib in combination with 100 mg BID ritonavir for a first treatment course of 8 weeks (weeks 1-8). The patient is then administered 50 mg QD lonafarnib in combination with 100 mg BID ritonavir for a second treatment course of 4 weeks (weeks 9-12). At week 12, the patient's HBV DNA level is measured. In one approach, if the patient has an increase in HBV DNA of greater than 3 logs, anti-HBV treatment (e.g., with ETV or TNF) for 36 weeks (weeks 13-48) is initiated.

[0178] If the patient shows no evidence of immunological reactivation (e.g., HBV DNA increase is <3 log), the patient will receive a treatment course of anti-HBV therapy (e.g., ETV (or TNF)) in combination with 50 mg BID lonafarnib and 100 mg BID ritonavir for 36 weeks (weeks 13-48).

[0179] Reduction of Hepatitis B virus (HBV) viral load In one aspect, the present invention relates to the treatment of patients infected with chronic hepatitis B virus (HBV), in which a course of lonafarnib treatment or lonafarnib-ritonavir treatment (as described herein) results in a reduction in the patient's HBV viral load, compared to baseline levels at the start of treatment and / or compared to similarly infected patients not receiving treatment effective in reducing the patient's HDV viral load. See Example 15 below. In some embodiments, a method of reducing HBV viral load in patients infected with HBV and HDV includes administering lonafarnib treatment as described herein and detecting at least a 1 log reduction in HBV viral load. In some embodiments, the treatment results in at least a 2 log reduction in HBV viral load. In some embodiments, the patient has not been treated with an antiviral nucleotide or nucleoside analog.

[0180] Without intending to be bound by any theory, it is believed that at least some patients will experience a reduction in HBV viral load upon receiving treatment in accordance with the present invention, and while some patients will not clear the virus, they will maintain the virus at a lower level than if they were not receiving treatment, and as a result experience health benefits.

[0181] IV. Pharmaceutical Compositions and Unit Dosage Forms In another aspect, the present invention provides unit dosage forms and pharmaceutical compositions for providing lonafarnib and ritonavir co-therapy. In some embodiments, the lonafarnib or pharmaceutical composition in the unit dosage form is amorphous lonafarnib. In other embodiments, the lonafarnib is crystalline. In some embodiments, the ritonavir or pharmaceutical composition in the unit dosage form is amorphous ritonavir. In other embodiments, the ritonavir is crystalline. In some embodiments, the lonafarnib and ritonavir co-administration is combined with prophylactic administration of one, two or three GI stabilizers, as described in Section VI below. In some embodiments, the lonafarnib and ritonavir co-administration is combined with interferon co-therapy, as described in Section V below.

[0182] Generally, for convenience, lonafarnib and ritonavir are formulated for oral administration and administered orally. However, in some embodiments, other routes are preferred, and the present invention provides methods and compositions for administering lonafarnib and / or ritonavir to humans for the treatment of HDV infection, using one or more other routes, such as intravenous (IV) administration or subcutaneous (SQ) formulation. As another example, the method of the present invention can be carried out using patch technology, particularly patch technology using microneedles, to administer the drug subcutaneously. Parenteral administration can avoid or at least reduce GI and other side effects. Other routes suitable for drug delivery can be used, including systemic and local administration routes.

[0183] However, in many embodiments, lonafarnib and / or ritonavir are orally administered in a solid dosage form (e.g., capsules, caplets, tablets, etc.). In certain embodiments, lonafarnib and / or ritonavir are orally administered as a soft gel capsule containing a liquid. In some embodiments, lonafarnib and / or ritonavir are administered as a liquid dosage form (oral suspension, syrup, or elixir). A liquid dosage form for oral administration may be provided in which each unit dose, e.g., teaspoon, table spoon, milliliter, etc., contains a predetermined amount of a composition containing lonafarnib and / or ritonavir. In some embodiments, lonafarnib and ritonavir are administered as a combination of two different dosage forms (e.g., lonafarnib tablets and ritonavir solution).

[0184] In carrying out the methods described herein, lonafarnib and ritonavir can be co-administered separately (as separate unit dosage forms) or can be combined in an oral unit dosage form that contains both lonafarnib and ritonavir.When administered as separate unit forms, typically, lonafarnib and ritonavir doses are administered (e.g., self-administered) at about the same time, for example, at the same time or within about 3 minutes of each other, or within about 10, 30 or 60 minutes of each other.In some embodiments, ritonavir is administered before lonafarnib is administered.

[0185] Lonafarnib is manufactured as 50 mg and 75 mg capsules, however, preparing dosage forms with different amounts of lonafarnib and ritonavir active ingredients is provided by the present invention and is within the ability of one of skill in the art in view of this disclosure. In one embodiment, the pharmaceutical formulation of the present invention contains lonafarnib formulated for oral administration as a unit dosage form containing 25 mg, 50 mg, or 75 mg of lonafarnib, including forms in which 50-100 mg of ritonavir is also present. When salts or solvates are used, equivalent amounts are required to be used, as would be readily understood by one of skill in the art.

[0186] Ritonavir is commercially available in 100 mg tablets, 100 mg soft gelatin capsules, and 80 mg / mL oral solution, although preparing different amounts of active ingredient and dosage forms is within the ability of one of ordinary skill in the art in view of this disclosure. In various embodiments, unit dosage forms useful in the methods of the invention contain 50 mg or 100 mg, or any amount between 50 mg and 100 mg of ritonavir. When a salt or solvate is used, an equivalent amount is used, as would be readily understood by one of ordinary skill in the art.

[0187] Pharmaceutical formulations and unit dosage forms suitable for oral administration are particularly useful in the treatment of chronic conditions and therapies where patients self-administer the drug. However, as mentioned above, in some cases, including but not limited to acute infectious diseases and life-threatening conditions, particularly those requiring hospitalization, intravenous formulations are desirable, and the present invention also provides such formulations. The present invention provides pharmaceutical formulations in which lonafarnib and / or ritonavir can be formulated into injectable preparations according to the present invention by dissolving, suspending or emulsifying the active pharmaceutical substance in an aqueous or non-aqueous solvent, such as vegetable or other similar oils, synthetic fatty acid glycerides, esters of higher fatty acids or propylene glycol, and optionally with conventional additives, such as solubilizers, isotonicity agents, suspending agents, emulsifiers, stabilizers and preservatives. Unit dosage forms for injection or intravenous administration may be included in the composition as a solution in sterile water, saline or another pharmacologically acceptable carrier. The appropriate amount of active pharmaceutical ingredient for unit dosage forms of lonafarnib and / or ritonavir is provided herein.

[0188] Lonafarnib-ritonavir coformulation In some embodiments of the present invention, lonafarnib and ritonavir are delivered to a patient in the same unit dosage form (i.e., "co-formulated"). For example, the dosage form may include lonafarnib and ritonavir (with excipients and adjuvants). Without limitation, lonafarnib and ritonavir may be provided as a mixture, a multiparticulate formulation (which may include small particles of lonafarnib in a matrix containing ritonavir), a bilayer formulation, a tablet-within-a-tablet formulation, and the like. Such forms for co-administration are well known for other drugs (see, e.g., U.S. Patent Application Publication Nos. 2009 / 0142393 and 2008 / 0021078, and International Patent Publication No. WO2009 / 042960, each of which is incorporated herein by reference), and such methodologies may be used in accordance with the present disclosure to prepare suitable unit dosage forms. Liquid formulations containing lonafarnib and ritonavir provided herein may also be used for co-administration.

[0189] In some embodiments, lonafarnib and ritonavir are formulated with a copolymer. In some embodiments, the copolymer is selected from the group consisting of povidone (polyvinylpyrrolidone), hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), hypromellose phthalate, polyvinylpyrrolidone-vinyl acetate copolymer, hypromellose-acetate-succinate, and mixtures thereof. In some embodiments, the copolymer is any one of povidone, hydroxypropyl cellulose, HPMC, hypromellose phthalate, polyvinylpyrrolidone-vinyl acetate copolymer, or hypromellose-acetate-succinate. In some embodiments, the copolymer is a mixture of two or more of povidone, hydroxypropyl cellulose, HPMC, hypromellose phthalate, polyvinylpyrrolidone-vinyl acetate copolymer, and hypromellose-acetate-succinate. In some embodiments, the copolymer is povidone, hydroxypropyl cellulose, or hydroxypropyl methylcellulose (HPMC). In some embodiments, the copolymer is a polyvinylpyrrolidone-vinyl acetate copolymer. In some embodiments, the copolymer is not povidone.

[0190] In some embodiments, the copolymer is povidone (also known as polyvinylpyrrolidone or PVP). In some embodiments, the copolymer is polyvinylpyrrolidone K12 (povidone K12), polyvinylpyrrolidone K17 (povidone K17), polyvinylpyrrolidone K25 (povidone K25), polyvinylpyrrolidone K30 (povidone K30) or polyvinylpyrrolidone K90 (povidone K90). In some embodiments, the polyvinylpyrrolidone is polyvinylpyrrolidone K30. In some embodiments, the copolymer is polyvinylpyrrolidone-vinyl acetate copolymer. In some embodiments, the polyvinylpyrrolidone-vinyl acetate copolymer is Kollidon® VA64 copovidone.

[0191] In some embodiments, a unit dosage form or pharmaceutical composition comprising lonafarnib and ritonavir contains lonafarnib in an amount of about 20 mg to about 100 mg, e.g., about 25 mg to about 100 mg, or about 50 mg to about 100 mg, and ritonavir in an amount of about 50 mg to about 100 mg. In some embodiments, lonafarnib is present in an amount of about 25 mg, about 50 mg, about 75 mg, or about 100 mg, and ritonavir is present in an amount of about 50 mg, about 75 mg, or about 100 mg.

[0192] In some embodiments, the unit dosage form or pharmaceutical composition is formulated for oral administration and comprises lonafarnib and ritonavir in a ratio of about 1:2 (w / w) or about 1:4 (w / w). In some embodiments, the unit dosage form or pharmaceutical composition comprises lonafarnib and ritonavir in a ratio of about 1:2 (w / w). In some embodiments, the unit dosage form or pharmaceutical composition comprises lonafarnib and ritonavir in a ratio of about 1:4 (w / w). In some embodiments, the unit dosage form or pharmaceutical composition comprises lonafarnib and ritonavir in a ratio of about 0.75:1 (w / w).

[0193] In some embodiments, the unit dosage form or pharmaceutical composition comprises lonafarnib, ritonavir and the copolymer in a ratio of about 1:1:2 (w / w), 1:2:3 (w / w), or 1:1:5 (w / w).

[0194] In some embodiments, the unit dosage form or pharmaceutical composition comprising lonafarnib, ritonavir and the copolymer is prepared according to the method described in International Application No. PCT / US2016 / 028651, which is incorporated herein by reference. In some embodiments, the unit dosage form or pharmaceutical composition is prepared by a process comprising providing a spray solution of lonafarnib, ritonavir and the copolymer in a solvent (e.g., an organic solvent such as dichloromethane, chloroform, isopropyl alcohol, methanol, ethanol, acetone, ethyl methyl ketone, methyl isobutyl ketone, DMSO, water, or a mixture thereof); optionally filtering the spray solution to remove insoluble matter; and substantially removing the solvent from the spray solution. In some embodiments, the solvent is removed by distillation or complete evaporation of the solvent, spray drying, vacuum drying, tray drying, lyophilization or freeze drying, stirred thin film drying, or a combination thereof.

[0195] Specific release formulations Lonafarnib and / or ritonavir dosage forms, including co-formulations comprising lonafarnib and ritonavir, may be formulated for a predetermined elution profile, including immediate release and controlled release (e.g., delayed or sustained release). For example, lonafarnib may be formulated for delayed release and ritonavir may be formulated for immediate release (whether administered as separate dosage forms or as a combined dosage form(s)).

[0196] In some embodiments, the unit dosage form or pharmaceutical composition containing lonafarnib, ritonavir, or lonafarnib and ritonavir as a co-formulation is formulated as a controlled or delayed release formulation. Methods for making controlled or delayed release formulations are known in the art. By way of example and not limitation, in some cases, lonafarnib, and optionally ritonavir, may be formulated with a release retardant. The lonafarnib in this formulation may have zero or relatively low release of drug during a lag phase after administration to a subject, and then achieve a rapid release ("burst") of drug after the end of the lag phase. The lag phase typically ranges from about 0.25 to 3 hours, more often from about 0.5 to 2 hours. Many methods are known in the art for providing a delayed burst release, such as by diffusion, swelling, osmotic burst, or erosion (e.g., based on the inherent dissolution of the drug and excipients incorporated). See U.S. Patent Application Publication No. 2011 / 0313009, which is incorporated herein by reference.

[0197] In some cases, by way of example and not limitation, the release retardant is designed to release lonafarnib and / or ritonavir upon exposure to a given pathological condition in the body. In one embodiment, the release retardant is an enteric release agent that can release the drug upon exposure to a particular aspect of the digestive tract. In certain embodiments, the enteric release agent is pH sensitive and is affected by changes in pH encountered in the digestive tract (pH sensitive release). The enteric material typically remains insoluble at stomach pH and then allows for release of the active ingredient in the higher pH environment of the downstream digestive 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 digestive tract, particularly the colon. Optionally, the unit dosage form is formulated with a pH sensitive enteric material designed to produce release within about 0.25 to 2 hours when at or above a particular pH. In various embodiments, the particular pH can be, for example, about 4.5, 5, 5.5, 6, or 6.5. In certain embodiments, the pH sensitive material allows for at least 80% release of the drug within 1 hour when exposed to a pH of about 5.5 or greater, hi another embodiment, the pH sensitive material allows for at least 80% release of the drug within 1 hour when exposed to a pH of about 6 or greater.

[0198] Materials used for enteric release formulations, for example as coating agents, are known in the art, for example as described in US Patent Application Publication No. 2011 / 0313009. Combinations of different enteric materials can also be used. Multi-layer coatings using different polymers can also be applied. In some instances, the enteric material causes a delay in drug release in the range of about 0.25 to about 3 hours, sometimes about 0.5 to about 4 hours.

[0199] One skilled in the art can adjust the lag phase before the delayed burst release from the enteric coated multiparticulates by varying the coating weight and composition of the enteric layer. For example, if the time in the stomach is less than 4 hours and some protection (1-3 hours) is desired after the dosage form leaves the stomach, an appropriate level of coating can be prepared that provides up to 4 hours of protection between administration and drug release. To identify the exact coating weight, samples of the multiparticulates would be pulled from a fluid bed coater over a range of coating weights and tested by in vitro dissolution to identify the appropriate coating level. Based on these results, the exact coating weight would be selected. Examples of enteric coated multiparticulates can be found in U.S. Pat. No. 6,627,223.

[0200] The lonafarnib and / or ritonavir may be mixed (e.g., blended, intermixed, or in a continuous phase) with and / or contained within (e.g., encapsulated within or coated with) one or more release retardants. For example, the delayed burst release formulation may be in the form of one or more capsules containing lonafarnib and / or ritonavir. In other examples, the lonafarnib and / or ritonavir may be in a multiparticulate form, such as granules, microparticles (beads), or nanoparticles, coated with a release retardant.

[0201] As described below in Section VI, in one approach, it is contemplated that patients receiving lonafarnib will receive prophylactic administration of one or a combination of GI modifiers. In one approach, one or more GI modifiers are provided as co-formulations with lonafarnib and / or ritonavir. For example, but not limited to, lonafarnib, ritonavir and GI modifiers can be formulated as a tri-layer tablet. In another approach, one or more GI modifiers are provided in a common pharmaceutical package ("co-packaged"), as described below in Section VII. In one approach, one or more GI modifiers are provided as an immediate release formulation, and lonafarnib (and optionally ritonavir) is provided as a controlled release formulation. Formulated agents with different releases can be co-packaged and / or co-formulated in various combinations, so long as at least one GI modifier is formulated for immediate release and lonafarnib is formulated for controlled release (e.g. delayed release). In a preferred embodiment, the formulation allows the patient to self-administer lonafarnib and at least one GI modifier substantially simultaneously (e.g., simultaneously or within about 5 minutes of each other) with the formulation allowing the GI modifier to take effect before the release of lonafarnib. Using this approach, the patient can receive the pre-release benefit of the GI modifier without increasing the number of times per day the patient must self-administer the therapeutic agent.

[0202] V. Interferon Co-treatment In some embodiments, lonafarnib is used in combination with interferon to treat HDV infection (i.e., HBV and HDV co-infection) or to reduce HDV viral load. In some embodiments, lonafarnib-ritonavir co-therapy is used in combination with interferon to treat HDV infection or to reduce HDV viral load.

[0203] Based on the type of receptor through which they signal, human interferons are classified into three major types. In various embodiments, any type I-III interferon is 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 type II interferon in humans is IFN-gamma. The recently classified type III interferon group consists of three IFN-lambda molecules, called IFN-lambda 1, IFN-lambda 2 and IFN-lambda 3 (also called IL29, IL28A and IL28B, respectively). These IFNs signal through a receptor complex consisting of IL10R2 (also called CRF2-4) and IFNLR1 (also called CRF2-12). Interferons suitable for use in the treatment methods described herein are described below.

[0204] In one embodiment, lonafarnib is administered in combination with other agents (such as interferon alpha or interferon lambda, and optionally ritonavir) at a lonafarnib dose of 100mg QD or less. In one embodiment, the present invention provides a method for treating HDV infection by administering at least 50mg / day of lonafarnib (e.g., 25mg BID, 50mg BID, 75mg BID, 100mg BID, 50mg QD, 75mg QD, or 100mg QD of lonafarnib) in combination with ritonavir and / or interferon. In one embodiment, the present invention provides a method for treating HDV infection by administering at least 100mg lonafarnib QD or BID in combination with interferon and / or ritonavir.

[0205] In one approach, patients receiving lonafarnib (alone or in combination with a booster such as ritonavir) are also treated with interferon (e.g., interferon alpha or interferon lambda). In some embodiments, both lonafarnib and interferon (e.g., interferon alpha or interferon lambda) are administered to the patient, and the lonafarnib dose is at least about 50 mg BID or QD, at least about 75 mg BID or QD, or about 100 mg BID or QD. In some embodiments, the administration of lonafarnib and interferon (e.g., interferon alpha or interferon lambda) is simultaneous. In some embodiments, the administration of lonafarnib and interferon (e.g., interferon alpha or interferon lambda) is sequential. In some embodiments, the interferon is interferon alpha. In some embodiments, the interferon alpha is pegylated interferon alpha (e.g., pegylated interferon alpha-2a, also referred to herein as "Pegasys"). In some embodiments, the interferon is interferon lambda. In some embodiments, the interferon lambda is pegylated interferon lambda (e.g., pegylated interferon lambda-1a). Thus, it is contemplated that HDV-infected patients receiving lonafarnib-ritonavir co-therapy may also be treated with interferon.

[0206] Administration of lonafarnib in combination with other agents such as interferon (e.g., interferon alpha or interferon lambda) and ritonavir (Norvir) provides effective treatment at lower doses and / or reduced dosing frequency. In some cases, patients are administered lonafarnib, ritonavir and interferon (e.g., interferon alpha or interferon lambda). In some embodiments, interferon is administered weekly at a dose of 120 micrograms (mcg) per week or 180 mcg per week.

[0207] In some embodiments, interferon alpha (e.g., Pegasys®, Genentech) is administered weekly. In some embodiments, interferon alpha is administered at a dose of 120mcg QW or 180mcg QW. In some embodiments, pegylated interferon (Pegasys®) is administered at a dose of 180 μg per week.

[0208] In some embodiments, interferon lambda (e.g., pegylated lambda, e.g., pegylated lambda-1a) is administered weekly. In some embodiments, interferon lambda is administered at a dose of 120mcg QW or 180mcg QW. In some embodiments, interferon lambda is administered at a dose of 120μg per week.

[0209] In these embodiments, administration of lonafarnib (e.g., alone or in combination with ritonavir) and interferon continues for at least 30 days, usually at least about 60 days, or even 90 days or more, including 6 months to 1 year or more. In some procedures, administration continues for about 30 days, more typically 30 or 60 days, and often for 6 months, 9 months, and 12 months. In some embodiments, administration is discontinued after a period of time (such as 1 to 3 months or more) during which viral levels have decreased to undetectable levels.

[0210] interferon In one embodiment, the present invention provides a combination therapy in which interferon-alpha or interferon-lambda is used in combination with lonafarnib. The terms "interferon-alpha" or "IFN-α" and "interferon-lambda" or "IFN-λ" as used herein refer to a family of related polypeptides that inhibit viral replication and cell proliferation and regulate immune response. Suitable interferons for the purpose of the present invention include, but are not limited to, pegylated IFN-α-2a, pegylated IFN-α-2b, consensus IFN, IFN-λ (e.g., IFN-λ1, such as IFN-λ1a), or pegylated IFN-λ (e.g., pegylated IFN-λ1, such as pegylated IFN-λ1a).

[0211] Interferon alfa The term "IFN-α" includes natural IFN-α; synthetic IFN-α; derivatized IFN-α (e.g., pegylated IFN-α, glycosylated IFN-α, etc.); and analogs of natural or synthetic IFN-α. The term "IFN-α" also encompasses consensus IFN-α. Thus, essentially any IFN-α or IFN-λ that has antiviral properties as described for natural IFN-α may be used in the combination therapy of the present invention.

[0212] The term "IFN-α" encompasses derivatives of IFN-α that have been derivatized (e.g., chemically modified compared to the native peptide) to alter certain properties, such as serum half-life. Thus, the term "IFN-α" includes IFN-α that has been derivatized with polyethylene glycol ("PEGylated IFN-α"), and the like. Pegylated IFN-α, and methods for making same, are described, for example, in U.S. Patent Nos. 5,382,657; 5,951,974; and 5,981,709. Pegylated IFN-α encompasses conjugates of PEG with any of the above IFN-α molecules, including, but not limited to, PEG conjugated to interferon alpha-2a (Roferon, Hoffman La-Roche, Nutley, NJ), interferon alpha-2b (Intron, Schering-Plough, Madison, NJ), interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon defined by determination of the consensus sequence of natural interferon alpha (Infergen®, InterMune, Inc., Brisbane, Calif.).

[0213] Thus, in some embodiments of the combination therapy of the invention, IFN-α is modified with one or more polyethylene glycol moieties, i.e., PEGylated. Two forms of pegylated interferon are commercially available, pegylated interferon α-2a (40 kD) (Pegasys®, Genentech) and pegylated interferon α-2b (12 kD) (PegIntron®, Merck), which differ in pharmacokinetics, viral kinetics, tolerability profiles, and therefore administration.

[0214] Peginterferon alpha-2a (Pegasys) consists of interferon alpha-2a (approximately 20 kD) covalently bound to a 40 kD branched polyethylene glycol (PEG). The PEG moiety is attached at a single site to the interferon alpha moiety by a stable amide bond to a lysine. Peginterferon alpha-2a has an approximate molecular weight of 60,000 daltons. The biological activity of peginterferon-alpha-2a comes from its interferon alpha-2a moiety, which influences both adaptive and innate immune responses to certain viruses. This alpha interferon binds to and activates the human type 1 interferon receptor on hepatocytes, which activates multiple intracellular signaling pathways that maximize the expression of interferon-stimulated genes resulting in a range of antiviral actions, such as blocking viral protein synthesis and inducing viral RNA mutagenesis. Compared to native interferon alpha-2a, peginterferon alpha-2a has sustained absorption and delayed clearance. Peginterferon alpha-2a is administered as a fixed weekly dose. After injection, it has relatively constant absorption and is distributed mostly to the blood and organs.

[0215] Pegylated interferon alpha-2b (PegIntron) consists of interferon alpha-2b covalently attached to a 12 kD linear polyethylene glycol (PEG). The average molecular weight of the molecule is approximately 31,300 daltons. Pegylated interferon alpha-2b is made up primarily of mono-PEGylated species (one PEG molecule is attached to one interferon molecule) and a small amount of di-PEGylated species. Fourteen different PEG attachment sites on the interferon molecule have been identified. The biological activity of pegylated interferon alpha-2b comes from the interferon alpha-2b moiety, which influences both adaptive and innate immune responses to certain viruses. This alpha interferon binds to and activates the human type 1 interferon receptor on hepatocytes, which activates multiple intracellular signaling pathways that maximize the expression of interferon-stimulated genes resulting in a series of antiviral actions, such as blocking viral protein synthesis and inducing viral RNA mutagenesis. Compared with natural interferon alpha-2b, pegylated interferon alpha-2b has sustained absorption, delayed clearance, and extended half-life. Peginterferon alpha-2b is administered as a weekly dose based on the patient's weight. Peginterferon alpha-2b has rapid absorption and wider distribution in the body.

[0216] 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 one embodiment, the PEGylated IFN-α contains a PEG moiety at only one amino acid. In another embodiment, the PEGylated IFN-α contains a PEG moiety at two or more amino acids, for example, the IFN-α contains PEG moieties attached to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 different amino acid residues. The IFN-α can be conjugated to PEG directly (i.e., without a linking group) through an amino group, a sulfhydryl group, a hydroxyl group, or a carboxyl group.

[0217] The term "IFN-α" also includes consensus IFN-α. Consensus IFN-α (also referred to as "CIFN" and "IFN-con" and "consensus interferon") includes, but is not limited to, consensus interferons (e.g., Infergen®, Three Rivers Pharmaceuticals, Warrendale, PA) defined by the amino acid sequences designated IFN-con1, IFN-con2 and IFN-con3 as disclosed in U.S. Pat. Nos. 4,695,623 and 4,897,471 and by determining the consensus sequence of natural interferon alpha. IFN-con1 is the consensus interferon agent in the Infergen® alfacon-1 formulation. The Infergen® consensus interferon formulation is referred to herein by its trade name (Infergen®) or by its generic name (interferon alfacon-1). DNA sequences encoding IFN-con can be synthesized as described in the above patents or by other standard methods. In certain embodiments, the at least one additional therapeutic agent is CIFN.

[0218] Various embodiments of the combination therapy of the invention utilize a fusion polypeptide comprising IFN-α and a heterologous polypeptide. Suitable IFN-α fusion polypeptides include Albuferon-alfa TM(a fusion product of human albumin and IFN-α; Human Genome Sciences; see, e.g., Osborn et al., 2002, J. Pharmacol. Exp. Therap. 303:540-548). Also suitable for use in the present methods are gene-shuffled forms of IFN-α. See, e.g., Masci et al., 2003, Curr. Oncol. Rep. 5:108-113. Other suitable interferons include Multiferon (Viragen), Medusa Interferon (Flamel Technology), Locteron (Octopus), and Omega Interferon (Intarcia / Boehringer Ingelheim).

[0219] In one embodiment of these combination therapies, pegylated interferon alpha-2a (Pegasys) is administered subcutaneously (SQ) weekly at a dose of 180 micrograms (mcg) or 120 mg or 135 mcg (used for patients with a negative response to higher doses). In another embodiment of these combination therapies, pegylated interferon alpha-2b (PegIntron) is administered SQ weekly at a dose of 1.5 mcg / kg / wk. In other embodiments of these methods, alpha-interferons are used as follows: consensus interferon (Infergen) administered at 9mcg-15mcg daily or 3x per week SQ; interferon-alpha 2a recombinant administered at 1MIU-9MIU 3x per week SQ; interferon-alpha 2b (Intron A) recombinant administered at 3MIU-25MIU 3x per week SQ; and pegylated interferon lambda (IL-28) administered at 80mcg-240mcg SQ weekly.

[0220] In some embodiments, the interferon is pegylated IFN-alpha 2a or pegylated IFN-alpha 2b. Suitable doses of lonafarnib / pegylated IFN-alpha 2a include but are not limited to 100mg BID / 180mcg QW; 75mg BID / 180mcg QW; 50mg BID / 180mcg QW; or 25mg BID / 180mcg QW. Suitable doses of lonafarnib / pegylated IFN-alpha 2b include but are not limited to 100mg BID / 1.5mcg / kg patient weight QW; 75mg BID / 1.5mcg / kg patient weight QW; 50mg BID / 1.5mcg / kg patient weight QW; or 25mg BID / 1.5mcg / kg patient weight QW.

[0221] Interferon lambda The term "IFN-lambda" encompasses IFN-lambda-1 (including IFN-lambda-1a), IFN-lambda-2 and IFN-lambda-3. These proteins are also known as interleukin-29 (IL-29), IL-28A and IL-28B, respectively. Collectively, these three cytokines comprise the type III subset of IFNs. They are distinct from both type I and type II IFNs for a number of reasons, including the fact that they signal through heterodimeric receptor complexes that are distinct from the receptors used by type I or type II IFNs. Although type I IFNs (IFN-alpha / beta) and type III IFNs (IFN-lambda) signal through distinct receptor complexes, they activate many of the same intracellular signaling pathways and biological activities, including antiviral activity, in a wide variety of target cells. Interferon lambda can be administered at any therapeutically appropriate dose, including, but not limited to, 80, 120 or 180 mcg QW. In some embodiments, the dose for an adult is 120 micrograms once a week.

[0222] In some embodiments, interferon lambda (e.g., interferon lambda-1 or interferon lambda-1a) is administered with lonafarnib and optionally ritonavir to treat HDV infection in patients. In some embodiments, interferon lambda is a pegylated form of interferon lambda (e.g., pegylated interferon lambda-1 or pegylated interferon lambda-1a). In some embodiments, interferon lambda is an interferon disclosed in U.S. Patent No. 7,157,559, which is incorporated herein by reference. In some embodiments, interferon lambda is administered at a dose of 120 μg per week. In some embodiments, interferon lambda is administered at a dose of 180 μg per week. In some embodiments, interferon lambda is administered subcutaneously. In some embodiments, interferon lambda therapy is administered with lonafarnib and optionally ritonavir to treat a patient's HDV infection for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or more. Example 15 describes a prophetic example of administration of interferon lambda in combination with lonafarnib and optionally ritonavir.

[0223] In some embodiments, the interferon is pegylated IFN lambda-1a. Suitable doses of lonafarnib / pegylated IFN lambda-1a include, but are not limited to, 100mg BID / 180mcg QW; 75mg BID / 180mcg QW; 50mg BID / 180mcg QW; 25mg BID / 180mcg QW; 100mg BID / 120mcg QW; 75mg BID / 120mcg QW; 50mg BID / 120mcg QW; or 25mg BID / 120mcg QW.

[0224] Triple therapy In some embodiments, interferon lambda as described herein is administered in combination with lonafarnib and ritonavir to treat HDV infection in patients.In some embodiments, lonafarnib dose is 50mg BID, ritonavir dose is 100mg BID, and interferon lambda dose is 120mcg QW.In some embodiments, lonafarnib dose is 50mg BID, ritonavir dose is 100mg BID, and interferon lambda dose is 180mcg QW.In some embodiments, lonafarnib dose is 25mg BID, ritonavir dose is 100mg BID, and interferon lambda dose is 120mcg QW.In some embodiments, lonafarnib dose is 25mg BID, ritonavir dose is 100mg BID, and interferon lambda dose is 180mcg QW. In some embodiments, the lonafarnib dose is 75mg BID, the ritonavir dose is 100mg BID, and the interferon lambda dose is 120mcg QW. In some embodiments, the lonafarnib dose is 75mg BID, the ritonavir dose is 100mg BID, and the interferon lambda dose is 180mcg QW. In some embodiments, the lonafarnib dose is 50mg QD, the ritonavir dose is 100mg QD, and the interferon lambda dose is 120mcg QW. In some embodiments, the lonafarnib dose is 50mg QD, the ritonavir dose is 100mg QD, and the interferon lambda dose is 180mcg QW. In some embodiments, the lonafarnib dose is 75mg QD, the ritonavir dose is 100mg QD, and the interferon lambda dose is 120mcg QW. In some embodiments, the lonafarnib dose is 75 mg QD, the ritonavir dose is 100 mg QD, and the interferon lambda dose is 180 mcg QW. In some embodiments, the lonafarnib dose is 100 mg QD, the ritonavir dose is 100 mg QD, and the interferon lambda dose is 120 mcg QW.In some embodiments, the lonafarnib dose is 100 mg QD, the ritonavir dose is 100 mg QD, and the interferon lambda dose is 180 mcg QW.

[0225] VI. Prevention in Digestive Tract Modification Therapy As described in Examples 2 and 4 below, some lonafarnib monotherapy and lonafarnib-ritonavir cotherapy HDV-infected patients experienced gastrointestinal (GI) side effects. GI side effects are not unexpected for compounds in the farnesyltransferase class. GI intolerance is also a known side effect of ritonavir, even though ritonavir can be administered at doses as high as 1200 mg / day when used as a protease inhibitor. However, the severity and persistence of these symptoms in HDV patients receiving lonafarnib, given relatively modest doses of lonafarnib and ritonavir, was unexpected. Medications for the treatment of GI irritation include antiemetics, antacids (H2-receptor antagonists and proton pump inhibitors), and antidiarrheals. Exemplary medicaments (by way of illustration and not limitation) are listed in Table 4 below.

[0226] 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 drug to allow for continued compliance of the patient during lonafarnib treatment. In one embodiment, an antidiarrheal drug is administered. In one embodiment, an antidiarrheal drug and an antacid are administered. In one embodiment, an antidiarrheal drug and an antiemetic drug are administered. In one embodiment, an antidiarrheal drug, an antacid and an antiemetic drug are administered. In one embodiment, the antidiarrheal drug is Lomotil (atropine / diphenoxylate) and / or the antacid is famotidine and / or the antiemetic drug is ondansetron. [Table 4]

[0227] In one approach, GI modifying therapy is administered as needed (symptomatically). In one approach, GI modifying therapy is administered prophylactically. As used herein in this context, "prophylactically" refers to administration to a patient in the absence or prior to the onset of symptoms. Typically, prophylactic treatment requires administration according to a fixed schedule (e.g., daily) during the course of lonafarnib treatment.

[0228] In one approach, prophylactic treatment includes administration of ondansetron (an antiemetic), lomotil (atropine / diphenoxylate) (an antidiarrheal drug) and famotidine (an antacid). For example, ondansetron 8 mg BID may be administered, lomotil (atropine / diphenoxylate) 5 mg QID or 5 mg BID may be administered, and famotidine 20 mg BID may be administered.

[0229] In one approach, the GI modifier is administered daily prior to administration of lonafarnib. In one approach, the GI modifier is administered 30 minutes to 2 hours prior to administration of lonafarnib treatment.

[0230] In one approach, the GI modifier is administered at the same time each day that lonafarnib is administered, but lonafarnib (and optionally ritonavir) is administered as a delayed release formulation (e.g., including an enteric coating) such that the GI modifier begins to work before lonafarnib is released.

[0231] Prophylactic administration of GI modifiers is generally continued throughout lonafarnib treatment.

[0232] In one approach, prophylactic administration of GI modifiers begins on the first day of lonafarnib administration.In another approach, administration of one or more GI modifiers begins before the start of oral lonafarnib-ritonavir treatment.For example, in one embodiment, the patient is administered ondansetron the day before the start of lonafarnib treatment.In one approach, one or more GI modifiers are administered daily, beginning 2 or more days before the start of oral lonafarnib-ritonavir treatment.

[0233] In a preferred embodiment, the GI modifier is administered according to a BID or QD schedule.

[0234] H2-receptor antagonists In one embodiment of the GI modifying treatment, the GI modifying treatment is an H2-receptor antagonist. In one embodiment of the GI modifying treatment, ranitidine (Zantac®) is administered during lonafarnib treatment at a dose of 150 mg twice daily, up to 150 mg four times daily. In another embodiment of the GI modifying treatment, famotidine (Pepcid®) is administered during lonafarnib treatment at a dose of 40 mg once daily, up to 20 mg twice daily, up to 40 mg twice daily. In another embodiment of the GI modifying treatment, cimetidine (Tagamet®) is administered during lonafarnib treatment at a dose of 400 mg once daily, up to 800 mg once daily, up to 1600 mg once daily, up to 800 mg twice daily, up to 300 mg four times daily, up to 400 mg four times daily, up to 600 mg four times daily. In another embodiment of the GI modifying treatment, nizatidine (Axid) is administered during lonafarnib treatment at a dose of 150 mg once daily, up to 300 mg once daily, up to 150 mg twice daily.

[0235] 5-HT3 antagonists In one embodiment of a GI modifying therapy, the therapy is a 5-HT3 receptor antagonist. In one embodiment of a GI modifying therapy, ondansetron (Zofran®) is administered at 8 mg once daily, up to 8 mg twice daily, up to 8 mg three times daily, 30 minutes to 2 hours prior to the initiation of lonafarnib therapy. In this embodiment, administration is continued for at least the duration of lonafarnib treatment. In another embodiment of a GI modifying therapy, granisetron (oral Kytril®) is administered at 2 mg or 1 mg twice daily given up to 1 hour prior to the initiation of lonafarnib treatment. In this embodiment, administration is continued for at least the duration of lonafarnib treatment.

[0236] NK-1 receptor antagonist In one embodiment of the GI modifying therapy, the GI modifying therapy is an NK-1 receptor antagonist. In one embodiment of the GI modifying therapy, aprepitant (Emend®) is administered in combination with a 5-HT3 receptor antagonist and a corticosteroid as a 3-day treatment consisting of a 125 mg dose on day 1, followed by an 80 mg dose on days 2 and 3, given 1 hour before the start of lonafarnib therapy. In another embodiment of these GI modifying therapies, fosaprepitant (Emend® IV) is administered in combination with a 5-HT3 receptor antagonist and a corticosteroid (dexamethasone) as a daily treatment consisting of a single 150 mg dose of fosaprepitant given up to 30 minutes prior to the start of lonafarnib treatment, followed by a single 12 mg dose of dexamethasone and a single dose of a 5-HT3 receptor antagonist (such as ondansetron), up to a single 150 mg dose of fosaprepitant given up to 30 minutes prior to the start of lonafarnib treatment, followed by a single 8 mg dose of dexamethasone and a single dose of a 5-HT3 receptor antagonist (such as ondansetron) on day 1, and a single 8 mg dose of dexamethasone on days 2-4.

[0237] Proton pump inhibitors In one embodiment of the GI modifying therapy, the GI modifying therapy is a proton pump inhibitor (PPI). In one embodiment of the GI modifying therapy, omeprazole (Prilosec®) is administered in combination with an antacid at a dose of 20 mg once daily up to 4 days prior to the initiation of lonafarnib therapy, up to 40 mg once daily during lonafarnib treatment. In another embodiment of the GI modifying therapy, omeprazole / sodium bicarbonate (Zegerid®) is administered at a dose of 20 mg once daily up to 40 mg once daily at least 1 hour prior to the initiation of meals and lonafarnib treatment, up to 40 mg once daily during lonafarnib treatment. In another embodiment of the GI modifying therapy, esomeprazole magnesium (Nexium®) is administered at a dose of 20 mg once daily up to 40 mg once daily up to 40 mg twice daily at least 1 hour prior to the initiation of lonafarnib treatment, up to 40 mg twice daily during lonafarnib treatment. In another embodiment of the GI modifying therapy, esomeprazole strontium is administered at a dose of 24.65 mg once daily, up to 49.3 mg once daily, up to 49.3 mg twice daily at least 1 hour prior to lonafarnib treatment during the lonafarnib treatment period. In another embodiment of the GI modifying therapy, lansoprazole (Prevacid®) is administered at a dose of 15 mg once daily, up to 30 mg once daily, up to 60 mg once daily, up to 30 mg twice daily up to 2 hours prior to lonafarnib treatment for up to 14 days, and at a dose of up to 30 mg three times daily during the lonafarnib treatment period. In another embodiment of the GI modifying therapy, dexlansoprazole (Dexilant®) is administered up to 2 hours prior to lonafarnib treatment at a dose of 30 mg once daily and up to 60 mg once daily of dexlansoprazole during lonafarnib treatment. In another embodiment of the GI modifying therapy, pantoprazole sodium (Protonix®) is administered up to 7 days prior to lonafarnib treatment at a dose of 40 mg once daily and up to 40 mg twice daily during lonafarnib treatment.

[0238] In some embodiments of the present invention, the GI modification treatment comprises a proton pump inhibitor (PPI) selected for its inhibitory effect on CYP3A4. PPI-mediated inhibition can help maintain therapeutically effective lonafarnib serum levels. Such inhibitory PPIs include, but are not limited to, omeprazole and rebeprazole.

[0239] Antidiarrheal medication In one embodiment of GI modifying treatment, the treatment is an antidiarrheal drug. In one embodiment of GI modifying treatment, atropine / diphenoxylate (Lomotil®, Lonox®) is administered at a dose of two Lomotil tablets four times a day or 10 ml Lomotil® liquid four times a day (20 mg / day) until initial control is achieved, after which the dose can be reduced to as little as 5 mg (two tablets or 10 ml liquid) per day. In another embodiment of GI modifying treatment, loperamide HCl (Imodium®) is administered at a dose of 4 mg (two capsules), followed by 2 mg (one capsule) for each loose stool, up to 16 mg (eight capsules). In another embodiment of GI modifying therapy, bismuth subsalicylate (Kaopectate®, Pepto-Bismol®) is administered as two tablets or 30 mL every 30 minutes to 1 hour as needed, up to 8 doses per 24 hours.

[0240] VI. Kits and Packaging The lonafarnib, and / or ritonavir, and / or interferon and / or one or more GI modifiers used to treat HDV patients can be delivered to physicians and patients, such as HDV patients, in a pharmaceutical package or kit. Such packages are intended to improve patient convenience and compliance with treatment plans. Typically, the packages comprise paper (cardboard) or plastic. In some embodiments, the kit or pharmaceutical package further comprises instructions for use (e.g., for administration according to the methods described herein).

[0241] In some embodiments, the pharmaceutical package or kit includes 25, 50, 75, or 100 mg of lonafarnib per unit dose, or a unit dosage form of lonafarnib containing 25 mg to 100 mg of lonafarnib per unit dose, and 50 mg or 100 mg of ritonavir per unit dose, or a unit dosage form of ritonavir containing 50 mg to 100 mg of ritonavir per unit dose. In some embodiments, the pharmaceutical package or kit includes a unit dosage form of interferon in addition to, or instead of, ritonavir. In some embodiments, the pharmaceutical package or kit includes a unit dosage form of interferon containing 120 mcg or 180 mcg of interferon (e.g., pegylated interferon lambda-1a) per unit dose. In some embodiments, the pharmaceutical package or kit further comprises a unit dosage form of one or more GI modifiers (e.g., one or more antiemetics, antacids (H2 receptor antagonists and proton pump inhibitors) or antidiarrheal medications).

[0242] In one embodiment, the kit or pharmaceutical pack contains lonafarnib and ritonavir in predetermined therapeutically effective doses, either combined in a single unit dosage form or as individual unit doses. The doses (e.g., in mg) and unit dose forms (e.g., tablet, capsule, immediate release, delayed release, etc.) of each drug can be in any dose or form as described herein (e.g., Section IV).

[0243] In one embodiment, the kit or pharmaceutical package contains doses suitable for multi-day administration, such as weekly, monthly or quarterly, etc. In a preferred approach, in a multi-day package, the doses (e.g., tablets) for each administration (e.g., once daily for QD administration, twice daily for BID administration, etc.) are split from the dose to be administered on different days or at different times.

[0244] In another embodiment, the package contains predetermined therapeutically effective doses of lonafarnib, ritonavir, or a combination of lonafarnib and ritonavir, and one or more GI modifying drugs combined in a single package, but separated into distinct compartments from each other within said package.

[0245] VIII. Other Antiviral Treatments It is contemplated that HDV-infected patients receiving lonafarnib-ritonavir cotherapy may also be treated with other antiviral agents, such as nucleoside and nucleotide analogs, compounds used to treat HBV infection, as well as other agents.

[0246] Nucleoside and Nucleotide Analogues Antiviral nucleoside or nucleotide analogs that may be used in combination with the lonafarnib-ritonavir co-treatment described herein include adefovir (Hepsera®), entecavir (Baraclude®), lamivudine (Epivir-HBV®, Heptovir®, Heptodin®), telbivudine (Tyzeka®), tenofovir (Viread®) and ribavirin (such as Rebetol® or Copegus®).

[0247] Compounds used to treat HBV In various combination therapies of the present invention, lonafarnib is combined with antiviral drugs against HBV for the treatment of HDV.Except for interferon, currently approved anti-HBV drugs inhibit reverse transcriptase and are nucleoside or nucleotide analogues.Although these drugs are effective against HBV, they are not effective against HDV because they do not clear the HBsAg that HDV needs to replicate.However, when used in the combination therapy of the present invention, improved therapeutic outcomes for patients can be achieved. Currently approved anti-HBV drugs include interferon alpha (Intron A®), pegylated interferon (Pegasys®), lamivudine (Epivir-HBV®, Zeffix® or Heptodin®), adefovir pivoxil (Hepsera®), entecavir (Baraclude®), telbivudine (Tyzeka®, Sebivo®), clevudine (Korea / Asia), tenofovir (Viread®). Truvada® is a combination of tenofovir and emtricitabine, which has not yet been approved but has been shown to be effective in reducing HBV viral titers in early clinical trials and is useful in the combination therapy of the present invention.

[0248] Other Therapeutic Compounds Other therapeutic compounds that may be administered with beneficial effect to HDV-infected patients being treated according to the present invention include nucleoside or nucleotide analogs; thiazolides; protease inhibitors; polymerase inhibitors; helicase inhibitors; class C CpG Toll-like receptor 7 and / or 9 antagonists; amphipathic helix disruptors or NS4B inhibitors; statins or other HMGCoA reductase inhibitors; immunomodulators; anti-inflammatory agents; secondary prenylation inhibitors; cyclophilin inhibitors; and alpha-glucosidase inhibitors.

[0249] Other Treatment Modules Oral lonafarnib-ritonavir co-treatment may be one module in a course of treatment for rapid and complete clearance of HDV infection. Thus, the treatment regimen described herein may be preceded or followed by a complementary treatment.

[0250] As an example, some patients may benefit from an initial IV infusion of lonafarnib to rapidly achieve high blood levels of the drug. This level may be maintained by continuous or regular IV infusions for a period of time (one to several days or perhaps a week) before the patient is placed on oral therapy as more specifically described herein. In these embodiments, the patient may be infused with the drug to achieve the therapeutic effect associated with the serum levels achieved with 50 mg BID dosing (and higher doses). IV administration is done under the care of a physician or other trained medical professional (e.g., in a hospital) with preventative treatment and monitoring to avoid or ameliorate AEs associated with oral administration at these high doses or to discontinue IV administration if necessary. In other embodiments, subcutaneous injections to provide a depot form of the drug that maintains the drug at therapeutically effective blood levels for days or weeks may be used to achieve therapeutically effective results similar to those described herein for oral therapy.

[0251] IX. Use of Cobicistat as a Potentiator While ritonavir is the most widely used CYP3A4 inhibitor, the present invention also provides combination treatments and therapies of lonafarnib with other CYP3A4 inhibitors. In one alternative, the present invention provides an embodiment in which the pharmacokinetic enhancer cobicistat, as described elsewhere herein, is used in combination with lonafarnib instead of ritonavir.

[0252] Cobicistat (sold by Gilead Sciences under the trade name Tybost®) is a strong inhibitor of CYP3A. Like ritonavir, cobicistat "boosts" blood levels of other substrates of this enzyme, but unlike ritonavir, it has no antiviral activity. Also, while it has a pronounced effect on the enzyme system (CYP3A) involved in breaking down certain drugs, it does not affect other enzyme systems used by many other drugs that may contribute to a large number of potentially harmful drug interactions.

[0253] In one aspect, the present invention provides treatment of HDV patients using the methods and compositions described herein, except that a potentiator other than ritonavir is used. In one embodiment, the potentiator cobicistat is used in the methods and compositions described herein. Cobicistat is useful in the combination therapy of the present invention at its approved dose in combination with lonafarnib at any dose and frequency of administration described herein, or at any lower dose. In an alternative embodiment, cobicistat is administered at a lower (e.g., 75 mg) and / or more frequent (e.g., BID) dose than the dose approved for use in treating HIV infection. In some embodiments, a lower dose of cobicistat is used (e.g., 50 mg QD or 50 mg BID).

[0254] Exemplary doses of lonafarnib-cobicistat co-therapy are provided by way of illustration and not limitation in Table 5. In some embodiments, lonafarnib is administered at 100 mg QD or 100 mg BID and cobicistat (Tybost®) is administered at 150 mg once daily.

[0255] Each of dosing schedules A-G may be administered with prophylactic GI modifiers (e.g., antiemetics, antidiarrheals, and antacids), and / or interferons (e.g., interferon alpha or interferon lambda). See Sections V and VI above. In one embodiment, lonafarnib-cobicistat co-treatment is administered in combination with an interferon. [Table 5] EXAMPLES

[0256] X. Example The following examples are offered to illustrate, but not to limit, the claimed invention.

[0257] Example 1. Treatment of HDV Patients with 100 mg Lonafarnib Administered BID This example demonstrates the efficacy of lonafarnib in reducing HDV RNA levels in patients with chronic HDV. Eight group 1 patients (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 administered placebo for 28 days. The six patients in the active treatment group were administered 100 mg BID (administered orally) for 28 days. The mean change in HDV RNA levels from baseline to nadir in the lonafarnib active treatment group was -0.74 log HDV RNA copies / mL, and in the placebo group, it was -0.24 log HDV RNA copies / mL.

[0258] Patients 4, 5, 6, and 8 were responsive to treatment as defined by a ≥0.5 log HDV RNA copy / mL decline in quantitative serum HDV RNA levels from baseline to nadir during active treatment. See Table 6 (showing the change in HDV RNA viral load for each patient during and after treatment) and Figure 1 (showing the change in log HDV RNA copies / mL levels over time for patients 4, 5, and 6). The change in HDV RNA level for patient 4 from baseline to end of treatment (EOT) was -1.34 log HDV RNA copies / mL. The change in HDV RNA level for patient 5 from baseline to EOT was -0.82 log HDV RNA copies / mL. The change in HDV RNA level for patient 6 from baseline to EOT was -1.41 log HDV RNA copies / mL. [Table 6]

[0259] HDV RNA viral load correlates with lonafarnib plasma concentrations. Figure 2 shows the correlation between plasma levels of lonafarnib and viral load. Subjects with higher plasma levels of lonafarnib experienced a greater decline in HDV RNA titers during treatment. Plasma levels during treatment ranged from 200 ng / mL to 1,100 ng / mL.

[0260] Viral rebound after treatment Patients 4, 5, and 6 showed viral rebound or an increase in serum HDV RNA levels after lonafarnib treatment was discontinued on day 28. After lonafarnib discontinuation, patient 4's HDV RNA level increased by 1.7 log HDV RNA copies / mL. After lonafarnib discontinuation, patient 5's HDV RNA level increased by 1.4 log HDV RNA copies / mL. Patient 6's HDV RNA level increased after lonafarnib discontinuation. Patients 4, 5, and 6 showed a subsequent decline in HDV RNA levels, beginning approximately 4 to 8 weeks after lonafarnib treatment was interrupted, which is likely due to virus to virus dynamics between HDV RNA and HBV DNA.

[0261] Example 2. Treatment of HDV Patients with 200 mg and 300 mg Lonafarnib Administered BID Six human subjects with known HDV infection, as documented by baseline HDV RNA viral titers ranging from 5.8 log HDV RNA copies / mL to 8.78 log HDV RNA copies / mL, were treated with lonafarnib at doses of either 200 mg BID or 300 mg BID for 84 days.

[0262] Effects of 28-day treatment At the end of 28 days of treatment, the mean change in viral load across the six subjects from baseline to day 28 was -1.63 log copies / mL for the 200 mg BID group and -2.00 log copies / mL for the 300 mg BID group. See Table 7 and Figure 3. [Table 7]

[0263] Day 28 results showed superior efficacy for the 200 mg BID and 300 mg BID dosing schedules versus the 100 mg BID dosing schedule, however, additional efficacy with fewer side effects was believed to be required for significant therapeutic benefit.

[0264] Treatment effects in 56-84 days When 200 mg BID and 300 mg BID dosing was continued for 56 days (days 29-56 may be referred to as 2 months) and 84 days (days 57-84 may be referred to as 3 months), the change in viral load across the six patients plateaued or increased from the 28-day viral load level. This lack of change or increase in viral load was attributed to poor GI tolerability to lonafarnib, making poor compliance associated with the protocol. These six patients did not receive prophylactic GI modifying medications to alleviate GI distress. Compliance or drug absorption or both are believed to be suboptimal due to GI intolerance and associated side effects.

[0265] Example 3. Combination Treatment of HDV Patients with 100 mg BID Lonafarnib and Interferon Three human subjects known to be infected with HDV were treated with lonafarnib at a dose of 100 mg BID in combination with Pegasys (PEG interferon alpha-2a) at 180 μg per week for 56 days (2 months), as described by baseline HDV RNA viral titers ranging from 4.34 log HDV RNA copies / mL to 5.15 log HDV RNA copies / mL, and ALT values ​​ranging from 155 to 174 IU / L.

[0266] At the end of 28 days, HDV RNA viral titers in all three patients had declined from baseline with a range of declines in HDV-RNA of -1.04 log HDV RNA copies / mL to -2.00 log HDV RNA copies / mL, with a mean decline across the three subjects of -1.8 log HDV RNA copies / mL. At the end of 56 days, HDV RNA viral titers in all three patients continued to decline with a mean viral load decline of 3 log copies / mL at day 56. ALT values ​​in all three patients also declined from baseline through day 56 and continued to decline after treatment was discontinued, normalizing by 4 weeks after treatment was discontinued for two of the three patients. The upper limit of normal for ALT values ​​is estimated to be 40 U / L.

[0267] The changes in HDV RNA viral load and ALT values ​​for each patient are shown in Table 8 below. See also Figure 4. [Table 8]

[0268] These viral load results demonstrate comparable efficacy to the 200 mg BID lonafarnib regimen and superior efficacy to the 100 mg BID lonafarnib regimen, and fewer grade 2 adverse events (AEs) compared to the 200 mg BID lonafarnib.

[0269] Example 4. Combination Treatment of HDV Patients with 100 mg BID Lonafarnib and 100 mg QD Ritonavir Three human subjects known to be infected with HDV, as documented by baseline HDV RNA viral titers ranging from 5.14 log HDV RNA copies / mL to 6.83 log HDV RNA copies / mL, and ALT values ​​ranging from 84 to 195 U / L, were treated with lonafarnib at a dose of 100 mg BID in combination with ritonavir 100 mg QD for 8 weeks essentially as otherwise described in Example 1.

[0270] At the end of week 4, HDV RNA viral titers in all three patients had declined from baseline ranging from -1.71 log HDV RNA copies / mL to at least a -2.76 log HDV RNA copies / mL decline in HDV-RNA, with a mean decline across the three patients of -2.2 log HDV RNA copies / mL. At the end of week 8, HDV RNA viral titers in all three patients continued to decline, with patient 2 having an undetectable viral titer. See Figure 5. The mean viral load decline across the three patients at week 8 was -3.2 log HDV-RNA.

[0271] Additionally, ALT levels in all three subjects decreased from baseline in the range of 35-50 U / L. The upper limit of normal for ALT levels is estimated to be 40 U / L. See Table 9, which also shows the change in HDV RNA viral load for each patient. [Table 9]

[0272] These results show superior efficacy compared to 200mg BID and 300mg BID lonafarnib monotherapy, and compared to the combination treatment of 100mg BID lonafarnib and 180μg Pegasys (PEG interferon α-2a) per week. Also, fewer grade 2 AEs were observed compared to 200mg BID lonafarnib. See Table 10. [Table 10]

[0273] Table 11 below shows the mean serum concentrations obtained with lonafarnib monotherapy (200 mg BID or 300 mg BID), lonafarnib-ritonavir cotherapy (100 mg BID lonafarnib combined with 100 mg QD ritonavir), and lonafarnib-ritonavir cotherapy (100 mg BID lonafarnib combined with 180 mcg QW pegylated interferon) at specific time points. [Table 11]

[0274] Example 5. Treatment of HDV Patients with Lonafarnib and Ritonavir In the examples, the anti-HDV effect of combination therapy of lonafarnib and ritonavir is shown. Eight patients with chronic HDV infection are treated with four different dose combinations of lonafarnib and ritonavir (administered orally) for 84 days under the regimen outlined in Table 12.

[0275] result The changes in patient HDV RNA levels from baseline as a result of lonafarnib and ritonavir combination treatment are summarized in Table 12 below. [Table 12]

[0276] Time courses showing changes in HDV RNA levels in patients 1-8 through days 28, 56, and 84 are shown in Figures 6A, 6B, and 6C, respectively (changes relative to normalized baseline). The mean change in log viral load was -1.89 after day 28, -1.86 after day 56, and -1.62 after day 84. Nadir was reached in 4-6 weeks, after which viral load (VL) plateaued or in some cases rose slightly. Group 4 may have reached a saturable uptake point, potentially supporting greater efficacy of lower lonafarnib doses.

[0277] Groups 1 and 2 have the highest C min maintained. These two groups received either BID lonafarnib (group 1) or BID ritonavir (group 2). These results support the conclusion that higher or more frequent ritonavir doses, e.g., BID administration, are beneficial. Figure 10 shows that QD administration of ritonavir (shown in the graph) provides lonafarnib (LNF) serum concentrations in the range of 2500-3500 ng / mL. Increasing ritonavir dosing BID in patients may achieve higher lonafarnib serum concentrations of >5000 ng / mL.

[0278] The correlation between decreasing HDV RNA levels and increasing serum levels of lonafarnib in hepatitis delta-infected patients treated with lonafarnib-ritonavir cotherapy is exemplified in patient 2 (Figure 7) and patient 8 (Figure 8). Patients with serum lonafarnib levels below 2000 ng / mL, such as patient 8, may experience lower viral load reductions (<1.5 log HDV-RNA) compared with patients with lonafarnib levels approaching or exceeding 5,000 ng / mL (>2 log HDV-RNA).

[0279] Adverse effects Table 13 summarizes patient adverse events during the first 6 weeks of treatment and shows that 75% of patients in the study (6 of 8 patients) required at least one dose reduction between weeks 7 and 10. Dose reductions often resulted in an increase or plateau in HDV RNA levels. [Table 13]

[0280] The lonafarnib dose was reduced in 6 of 8 patients (patients 1, 2, 3, 4, 5, and 8) due to side effects. Dose reductions correlated with viral load plateau or increase. Lomotil and ondansetron were used in 3 of 8 patients (starting at week 4). Two of these 3 patients did not require a lonafarnib dose reduction.

[0281] Example 6. Treatment of HDV patients with low-dose lonafarnib-ritonavir co-therapy and lonafarnib-ritonavir-pegylated interferon alpha triple co-therapy Figure 12 shows HDV values ​​in three patients with chronic HDV infection (patients 13, 14, and 15) treated with lonafarnib (75 mg BID) in combination with ritonavir (100 mg BID) for 12 weeks. At week 12, ritonavir was discontinued and PEG-IFN-α was administered (180 mcg QW). At week 16, ritonavir (100 mg BID) was resumed.

[0282] result Time courses showing changes in HDV RNA levels in patients 13, 14, and 15 are shown in Figure 12 (changes compared to normalized baseline). At weeks 12 and 16 (lonafarnib-interferon cotreatment), viral load remained roughly constant (patients 13 and 15) or increased (patient 14). From weeks 16 to 20, patients received triple therapy, which resulted in a significant decrease in viral load (patients 13 and 14).

[0283] Example 7. Triple therapy with low dose (50 mg BID) lonafarnib Three patients with chronic HDV infection (patients 25, 26, and 27) were treated with lonafarnib (50 mg BID), ritonavir (100 mg BID) and pegylated interferon alpha (180 mcg QW) for 4 weeks. See Figure 13. A significant reduction in viral load was observed at 2 weeks. At 4 weeks, all patients had significantly reduced viral load versus baseline. These results support the conclusion that low doses of lonafarnib can be administered in combination with a potentiator (e.g., ritonavir) and an interferon (e.g., interferon alpha or interferon lambda) that allows patients to achieve significant therapeutic benefit.

[0284] Example 8. Triple therapy with low dose (50 mg BID) and very low dose (50 mg QD) lonafarnib Figure 14 shows the effect of triple therapy on viral load in three patients with chronic HDV infection. Patients 2 and 3 received 50mg BID lonafarnib, 100mg BID ritonavir, and 180mcg QW pegylated interferon alpha for 8 weeks. Patient 1 received 50mg BID lonafarnib, 100mg BID ritonavir, and 180mcg QW pegylated interferon alpha for approximately 3 weeks, at which point the lonafarnib dose was reduced to 50mg QD (except for one day in week 8, when 50mg BID was administered). Patients received proton pump inhibitors (esomeprazole or rabeprazole on a QD basis) and antidiarrheal medications (lomotil or loperamide BID or TID).

[0285] As shown in Figure 14, after 8 weeks with a 50 mg BID dose, the mean reduction in log HDV viral load was greater than 2 (patient 3) or greater than 3 (patient 2), and with a 50 mg QD dose, it was greater than 3 (patient 1). The treatment was well tolerated, with diarrhea being the most significant side effect, indicating that the triple therapy is well suited for long-term treatment (greater than 6 months).

[0286] Example 9: Exemplary Treatment Regimens This prophetic example describes treating HDV infection by administration of various doses of lonafarnib and ritonavir, as disclosed below in Table 14. Patients infected with HDV self-administer the following regimen daily for 90-180 days: During the course of treatment, the patient's lonafarnib serum levels and HDV viral load are measured periodically. After 90 days of treatment, the patient's viral load decreases above baseline. [Table 14]

[0287] Example 10. A Phase 2 Study Evaluating the Safety, Tolerability, and Pharmacodynamics of Pegylated Interferon Lambda-1a (PEG-IFN-λ) Monotherapy in Patients with Chronic Hepatitis D Virus Infection This predictive example describes a phase 2 clinical trial protocol to evaluate the safety, tolerability, and pharmacodynamics of pegylated interferon lambda monotherapy in patients with chronic HDV infection. The efficacy demonstrated by interferon lambda monotherapy in this protocol indicates that interferon lambda therapy in combination with lonafarnib, and optionally in combination with an additional booster such as ritonavir, is effective in treating HDV infection.

[0288] Two dose levels of PEG-IFN-λ (120 μg per week or 180 μg per week) will be administered by subcutaneous injection over a 48-week treatment period, and the safety and tolerability of the treatment will be assessed based on HDV, ALT, and Hepatitis B surface antigen (HBsAg) levels.

[0289] At least one patient from a cohort of patients who receive at least 80% of the total study drug dose over the entire 48-week treatment period and have HDV viral load data available at day 1 (baseline) and end of treatment (week 48) demonstrates improvement in one or more of the endpoints described in the protocol at the study visit. In some embodiments, patients treated with interferon lambda monotherapy demonstrate a reduction in HDV viral load at end of treatment compared to baseline. In some embodiments, patients treated with interferon lambda monotherapy demonstrate a reduction in HBV viral load at end of treatment compared to baseline. In some embodiments, patients treated with interferon lambda monotherapy demonstrate a reduction in HBsAg levels at end of treatment compared to baseline. In some embodiments, patients treated with interferon lambda monotherapy demonstrate improved clearance of HBsAg antigen.

[0290] Example 11. Triple therapy This prophetic example describes the treatment of HDV infection by administration of interferon lambda in combination with lonafarnib and ritonavir. Administration of pegylated interferon lambda in combination with lonafarnib and ritonavir provides effective treatment at lower doses and / or reduced dosing frequency.

[0291] Patients infected with HDV will receive pegylated interferon lambda at 120mcg QW or 180mcg QW in combination with one of the following lonafarnib + ritonavir dose combinations: Lonafarnib 50mg BID + Ritonavir 100mg BID Lonafarnib 25mg BID + Ritonavir 100mg BID Lonafarnib 75mg BID + Ritonavir 100mg BID Lonafarnib 50mg QD + Ritonavir 100mg QD Lonafarnib 75mg QD + Ritonavir 100mg QD Lonafarnib 100mg QD + Ritonavir 100mg QD Lonafarnib 50mg QD + Ritonavir 100mg BID Lonafarnib 75mg QD + Ritonavir 100mg BID Lonafarnib 100mg QD + Ritonavir 100mg BID

[0292] During the course of treatment, the patient's HDV viral load is measured periodically. After 90 days of treatment, the patient's viral load decreases above baseline.

[0293] Example 12. Lonafarnib-Ritonavir Co-Therapy Combination Regimen This example shows the efficacy and tolerability of various combination regimens of lonafarnib and ritonavir with or without pegylated interferon-α in patients known to be infected with HDV. Thirty-eight patients were dosed as shown in Table 15 below. Treatment duration was 12-24 weeks. 72-hour pharmacokinetic (PK) and pharmacodynamic (PD) assessments were performed on days 1 and 28 of treatment. In addition, biochemical parameters and HDV RNA levels (measured by quantitative real-time PCR) were measured on days 1, 2, 3, 7, 14 and 28, and then every 4 weeks thereafter, during treatment. [Table 15]

[0294] For all treatment groups, HDV RNA viral load was measured after 4 weeks and 8 weeks of treatment and compared to baseline HDV RNA viral load.As shown in Figure 15A, when HDV RNA viral load was measured after 4 weeks, a similar reduction in viral load was observed for patients who received 25mgBID or 50mgBID lonafarnib in combination with 100mgBID ritonavir with or without pegylated interferon-α, compared to patients who received higher doses in lonafarnib-ritonavir co-treatment.As shown in Figure 15B, when HDV RNA viral load was measured after 8 weeks, a similar reduction in viral load was observed for patients who received 25mgBID or 50mgBID lonafarnib in combination with 100mgBID ritonavir with or without pegylated interferon-α, compared to patients who received higher doses in lonafarnib-ritonavir co-treatment.

[0295] Figure 16 shows that a rapid decline in HDV viral levels was observed in patients receiving 25mgBID or 50mgBID lonafarnib in combination with 100mgBID ritonavir with or without pegylated interferon-α.Furthermore, for patients receiving 50mgBID lonafarnib in combination with 100mgBID ritonavir and patients receiving 50mgBID lonafarnib in combination with 100mgBID ritonavir and 180mcgQW PEG IFN-α, the HDV RNA viral load after 8 weeks was comparable to the change in HDV RNA viral load after 48 weeks of treatment with 180mcgQW PEG IFN-α in combination with tenofovir. Additionally, HDV RNA viral negativity (clearance) was observed for a subset of patients receiving 50 mg BID lonafarnib in combination with 100 mg BID ritonavir, 50 mg BID lonafarnib in combination with 100 mg BID ritonavir and 180 mcg QW PEG IFN-a, or 25 mg BID lonafarnib in combination with 100 mg BID ritonavir and 180 mcg QW PEG IFN-a. See Figures 17 and 18.

[0296] For the group of patients receiving 50 mg BID lonafarnib in combination with 100 mg BID ritonavir, patients 2, 3, 4, and 5 were responsive to treatment as defined by a decline in quantitative serum HDV RNA levels from baseline to nadir of 0.5 log HDV RNA copies / mL or greater during active treatment. See Figure 17 (showing the time course of HDVIU / mL over 12 weeks of treatment).

[0297] For the group of patients receiving 50mg BID lonafarnib in combination with 100mg BID ritonavir and 180mcg QW PEG IFN-α, patients 7 and 8 were responsive to treatment as defined by a ≥0.5 log HDV RNA copies / mL decline in quantitative serum HDV RNA levels from baseline to nadir during active treatment. See Figure 18 (showing time course of HDVIU / mL over 32 weeks of treatment).

[0298] For the group of patients receiving 25 mg BID lonafarnib in combination with 100 mg BID ritonavir, patients 9, 10, 11, 12, 13, and 14 were responsive to treatment as defined by a decline in quantitative serum HDV RNA levels from baseline to nadir of 0.5 log HDV RNA copies / mL or greater during active treatment. See Figure 19 (showing the time course of log HDVIU / mL over 8 weeks of treatment).

[0299] For the group of patients receiving 25 mg BID lonafarnib in combination with 100 mg BID ritonavir and 180 mcg QW PEG IFN-α, patients 15, 16, 17, 19, and 20 were responsive to treatment as defined by a decline in quantitative serum HDV RNA levels from baseline to nadir of 0.5 log HDV RNA copies / mL or greater during active treatment. See Figure 20 (showing the time course of log HDVIU / mL over 20 weeks of treatment).

[0300] Additionally, normalization of ALT levels was observed in 65% of patients at week 12. As shown in Figure 21, 17 patients had elevated ALT levels at baseline, but only 6 patients had elevated ALT levels at week 12. The upper limit of normal for ALT levels was 45 for men and 34 for women.

[0301] Dosing regimens with lower dosages are also better tolerated, as shown in Table 16 below. The numbers in the table indicate the number of patients experiencing adverse events. Mostly grade 1 gastrointestinal AEs were observed at the lower doses. [Table 16]

[0302] Example 13. Lonafarnib-ritonavir co-treatment duration study This example demonstrates the efficacy and tolerability of three doses (50 mg, 75 mg, and 100 mg) of lonafarnib administered once daily in combination with ritonavir administered once daily for 12 or 24 weeks. Twenty-one patients with chronic HDV infection were randomized into one of six treatment groups, as summarized in Table 17 below: [Table 17]

[0303] Lonafarnib / ritonavir co-treatment is expected to produce a 2-log mean HDV-RNA reduction after 12 weeks of co-treatment. Doses of 50 mg QD lonafarnib in combination with 100 mg QD ritonavir and 75 mg QD lonafarnib in combination with 100 mg QD ritonavir are expected to be tolerable allowing dosing for more than 24 weeks. The addition of interferon (e.g., pegylated interferon alpha or pegylated interferon lambda) for more than 24 weeks is expected to achieve HDV-RNA negativity in a subset of patients.

[0304] Example 14. Lonafarnib-ritonavir co-therapy dose-finding study This example demonstrates the efficacy, safety, and tolerability of lonafarnib and ritonavir co-treatment administered twice daily. Fifteen patients (11 males) were enrolled in a 24-week open-label study that included the option of dose escalation at the investigator's discretion. The study was a phase 2 study of 24 weeks of treatment with a titrated regimen of lonafarnib / ritonavir in patients chronically infected with HDV. Lonafarnib was administered in combination with ritonavir administered at 100 mg BID, starting at 50 mg BID, up to 75 mg BID, then up to 100 mg BID, as tolerated. The initial doses of lonafarnib (50 mg BID) and ritonavir (100 mg BID) were maintained for at least 4 weeks. Subsequent dose escalations occurred at intervals of 2 weeks or more after the patient first received a specific dose.

[0305] At baseline (BL), patients had a mean HDV RNA viral load of 6.53 log 10 IU / mL (4.43 to 8.31 log 10 The mean serum ALT level was 111 U / L (range 53-362 U / L). Liver stiffness (fibrosis) was also assessed by FibroScan®. Two patients had cirrhosis on biopsy. Eleven patients received nucleoside or nucleotide analogues (NUC) at BL.

[0306] By week 8 of treatment, 10 of 15 patients (66%) were able to dose-escalate to 100 mg BID lonafarnib in combination with ritonavir. All patients achieved a 1.87 log 10 IU / mL (0.88 to 3.13 log 10The study showed a decline in HDV RNA viral load, with a mean reduction from BL to 8 weeks of 100 mg / mL (range: 1.0 IU / mL). Three patients showed HBV DNA rebound associated with HDV RNA reduction, and two patients initiated treatment with the anti-HBV drug tenofovir. AEs were primarily grade 1-2 intermittent diarrhea. Three patients had grade 3 AEs (2 diarrhea, 1 asthenia), all of which were transient and non-recurrent. No patient had grade 4 AEs. This data from 8 weeks of treatment indicates that dose escalation of lonafarnib in combination with ritonavir is feasible and leads to an early decline in HDV RNA in all patients. HDV RNA reduction was associated with HBV DNA rebound in patients not receiving NUC, suggesting an inhibitory effect of HDV on HBV replication. These data support the use of longer treatment durations.

[0307] The titration regimen through 24 weeks of treatment is outlined in Figure 22. As shown in Figure 22, after 24 weeks of treatment, 5 of 15 patients (33%) maintained the 100 mg BID lonafarnib combination through week 24 (EOT). Patients who maintained a dose of 100 mg BID lonafarnib in combination with ritonavir had a 2.9 log 10 The mean reduction in HDV RNA viral load of 1.5 log IU / mL was shown in Figure 23. Of these five patients, one patient (Patient 3) achieved HDV-RNA negativity at 24 weeks and one patient achieved a HDV-RNA viral load of 32 IU / mL (i.e., 1.5 log 10 IU / mL) (the lower limit of detection is 14 IU / mL). See FIG.

[0308] Of the 10 patients who were dose escalated to 100 mg BID lonafarnib with ritonavir by week 8 of treatment, 5 patients were tapered to a lower dose. See Figure 23. These patients experienced less decline in HDV-RNA viral load than patients who maintained a dose of 100 mg BID lonafarnib in combination with ritonavir through week 24. The remaining 5 patients either received a "partial" dose escalation from 50 mg BID lonafarnib in combination with ritonavir (patients were not successfully escalated to 100 mg BID lonafarnib) or did not receive a dose escalation and experienced a BL of 2.3 logs of mean HDV RNA viral load at week 24. 10 The decrease was as low as IU / mL.

[0309] Normalization of ALT levels was observed in 53% of patients at week 24. As shown in FIG. 25, all 15 patients had elevated ALT levels at baseline, but only 7 patients had elevated ALT levels at week 24. As shown in Table 18 below, patients experienced mostly grade 1-2 GI adverse events. Table 18 shows the number of patients experiencing an AE of a particular grade at least once during the 24-week study. The most common AE was grade 1-2 intermittent diarrhea. No grade 4 AEs were observed. [Table 18]

[0310] Example 15. Induction of post-treatment ALT flare with lonafarnib therapy This example describes post-treatment ALT flare and its therapeutic effect in patients treated with lonafarnib for 12 or 24 weeks in various treatment regimens, such as the regimen described in Example 12 above. 27 patients were analyzed who had detectable HDV RNA after receiving lonafarnib for 12 or 24 weeks in various doses of lonafarnib, in some cases in combination with ritonavir and / or pegylated interferon alpha. Post-treatment ALT flare was defined as an increase in ALT greater than 2-fold above baseline ALT levels.

[0311] To date, 5 of 27 patients (18.5%) studied have experienced post-treatment ALT flares. These post-treatment flares (median ALT 190 U / L, range 110-1355 U / L) led to ALT normalization and HDV RNA negativity within 12-24 weeks. These 5 patients were from the following lonafarnib-treated cohorts: Patient A-001-5. 12 weeks of BID lonafarnib 200 mg (Figure 26); Patient A-001-1. 12 weeks of BID lonafarnib 300 mg (Figure 27); Patient A-002-3. Lonafarnib 100mg BID in combination with ritonavir 50mg BID for 12 weeks (Figure 28); Patient A-002-14. 12 weeks of lonafarnib 75 mg BID in combination with ritonavir 100 mg BID, followed by the addition of pegylated interferon alfa for 12 weeks (Figure 29); and Patient A-002-23. 24 weeks of lonafarnib 50mg combined with ritonavir 100mg BID (Figure 30);

[0312] One patient (patient A-002-3) cleared HBV DNA and subsequently HBsAg. See Figure 28. Two other patients (patient A-001-5 and patient A-002-23) showed HBV DNA reductions of 2 logs or more. See Figures 26 and 30. All five patients showed rapid initial declines in HDV RNA upon initiation of lonafarnib treatment. These rapid initial declines were followed by gradual increases upon treatment upon reduction in lonafarnib exposure (due to dose reductions or excessive GI side effects).

[0313] As shown in Figure 26 for patient A-001-5, a 12-week treatment course with lonafarnib (200 mg BID) resulted in ALT flare and suppression of HDV RNA to undetectable levels. The subsequent rise in HDV viral load (at approximately week 50) was suppressed by a second treatment course with lonafarnib (50 mg BID) and ritonavir (100 mg BID). As shown in Figure 26, HDV became undetectable in this patient, and the patient remained apparently virus-free when measured at week 132. Remarkably, HBV VL (i.e., HBV DNA level) was also suppressed from a baseline of approximately 4 logIU / mL to approximately 1.5 logIU / mL (i.e., below the LOQ). See Figure 26.

[0314] As shown in Figure 27 for patient A-001-1, a 12-week treatment course with lonafarnib (300 mg BID) resulted in ALT flare and suppression of HDV RNA by approximately 3 logs or less (weeks 30-54). An increase in HDV VL was observed (e.g., week 78), which was suppressed by a second treatment course with low-dose lonafarnib treatment (50 mg BID) and ritonavir (100 mg BID). A transient increase in HBV DNA levels was also suppressed following the ALT flare. The patient remained apparently virus-free when measured at 125 weeks.

[0315] As shown in Figure 28 for patient A-002-3, treatment with lonafarnib (100 mg BID) and ritonavir (50 mg BID) for approximately 10 weeks, followed by 2 weeks with lonafarnib (150 mg QD) and ritonavir (50 mg BID) resulted in an ALT flare. HDV RNA and HBV DNA levels declined to undetectable levels. The patient remained apparently virus-free when measured at 95 weeks.

[0316] As shown in FIG. 29 for patient A-002-14, a 24-week course of treatment with lonafarnib, ritonavir and pegylated interferon alpha resulted in ALT flare and suppression of HDV RNA VL from greater than 6 logIU / mL to below the limit of quantitation of the assay (i.e., less than 3.2 logIU / mL), as shown in the figure.

[0317] As shown in FIG. 30 for patient A-002-23, a 24-week course of treatment with lonafarnib (50 mg BID) and ritonavir (100 mg BID) resulted in no ALT flare and suppression of HDV RNA to approximately 0 logIU / mL.

[0318] The data presented herein suggest that a short course of lonafarnib may contribute to the effective resetting and activation of immune responses in chronic delta hepatitis, which, surprisingly, may extend to HBV in some cases.Thus, there are thought to be at least two routes to achieve HDV negativity with lonafarnib treatment.First, lonafarnib-induced gradual suppression of HDV negativity by ALT normalization during the course of treatment (more classical antiviral approach), and second, lonafarnib-induced anti-HDV ALT flare that occurs after treatment and results in HDV clearance.

[0319] Example 16. Preparation of lonafarnib-ritonavir-copolymer composition (A) 1:1:2 coprecipitate 5.0 grams of ritonavir, 5.47 grams of lonafarnib, and 10.0 grams of povidone K30 were dissolved in 600 mL of dichloromethane with stirring at room temperature. The solution was spray dried using a Model GB22 Yamato Lab spray dryer with the following operating parameters: internal nozzle diameter 711 μm; pump speed 12-14 mL / min; inlet temperature 60 °C; outlet temperature NMT 45 °C; atomizing air pressure 0.15 MPa and air flow 0.5 m. 3 / min. Of the 20.47 g of solids in the spray solution, 15.9 g were collected in the receiving flask for a yield of 77%. The total solids in the spray solution was 3% (w / v).

[0320] (B) 1:2:3 coprecipitate 6.5 grams of (A) (corresponding to 1.6 grams of ritonavir, 1.6 grams of lonafarnib, and 3.3 grams of povidone K30) ritonavir-lonafarnib-providone (1:1:2) co-precipitate, an additional 1.6 grams of ritonavir (total amount of ritonavir was 3.2 grams), and an additional 1.5 grams of povidone K30 (total amount of povidone K30 was 4.8 grams) were dissolved in 300 mL of dichloromethane with stirring at room temperature. The solution was spray dried using a Model GB22 Yamato Lab spray dryer with the following operating parameters: internal nozzle diameter 711 μm; pump speed 12-14 mL / min; inlet temperature 60 °C; outlet temperature NMT 45 °C; atomizing air pressure 0.15 MPa and air flow 0.5 m. 3 / min. Of the 9.6 g of solids in the spray solution, 5.6 g was collected in the receiving flask for a yield of 58%. The total solids in the spray solution was 3% (w / v).

[0321] (C) 1:1:5 coprecipitate 7.5 grams of (A) (corresponding to 1.9 grams of ritonavir, 1.9 grams of lonafarnib, and 3.8 grams of povidone K30) ritonavir-lonafarnib-providone (1:1:2) co-precipitate and an additional 5.0 grams of povidone K30 (total amount of povidone K30 was 8.8 grams) were dissolved in 390 mL of dichloromethane with stirring at room temperature. The solution was spray dried using a Model GB22 Yamato Lab spray dryer with the following operating parameters: internal nozzle diameter 711 μm; pump speed 12-14 mL / min; inlet temperature 60 °C; outlet temperature NMT 45 °C; atomizing air pressure 0.15 MPa and air flow 0.5 m. 3 / min. Of the 12.5 g of solids in the spray solution, 8.8 g were collected in the receiving flask for a yield of 70%. The total solids in the spray solution was 3% (w / v).

[0322] (D) 1:1:2 coprecipitate with HPMC polymer 2.5 grams of ritonavir, 2.61 grams of lonafarnib, and 5.0 grams of hydroxymethylcellulose (HPMC) were dissolved in 340 mL of dichloromethane with stirring at room temperature. The solution was spray dried using a Model GB22 Yamato Lab spray dryer with the following operating parameters: internal nozzle diameter 711 μm; pump speed 12-14 mL / min; inlet temperature 60 °C; outlet temperature NMT 45 °C; atomizing air pressure 0.15 MPa and air flow 0.5 m. 3 / min. Of the 10.1 g of solids in the spray solution, 7.2 g were collected in the receiving flask for a yield of 71%. The total solids in the spray solution was 3% (w / v).

[0323] Analysis of Lonafarnib-Ritonavir-Copolymer Composition X-ray powder diffraction (XRPD) confirmed the amorphous state of each of the coprecipitates (A)-(D). Diffraction patterns were confirmed by X-ray diffraction using a Bruker D2 Phaser X-ray diffractometer equipped with a Lynxeye detector, CuKα radiation (λ=1.5406 Å). Acquisition was performed in the range of 5-55°2θ, with an increment of 0.05°2θ, a step time of 1.0 s, and a 0.6 mm aperture slit, and a 2.5 mm detection window. Samples were analyzed using a low volume sample holder and kept under constant rotation of 15 rpm during analysis. Figure 31 shows the powder X-ray patterns of amorphous 1:1:2, 1:2:3, and 1:1:5 ritonavir-lonafarnib-copolymer coprecipitates with povidone as the copolymer. Consistent with the characteristics of an amorphous solid form, the amorphous 1:1:2, 1:2:3, and 1:1:5 coprecipitates show no crystalline diffraction peaks. The amorphous 1:1:2 co-precipitate with HPMC also shows no crystalline diffraction peaks (data not shown).

[0324] Residual solvent from the spray dried material was confirmed by thermogravimetric analysis (TGA). The analysis was performed using a TA Instrument Q50 thermogravimetric analyzer over the temperature range of 25°C to 200°C at a scan rate of 10°C / min. Samples were heated in platinum open pans under a nitrogen purge (60 mL / min).

[0325] Figure 32A shows the sample weight (percentage of original weight) as a function of temperature. The material showed clear weight loss steps. The first step (4.8-5.6% weight loss) at temperatures between 25 and 100 °C corresponds to the material decomposition starting at about 180 °C, followed by the loss of volatile compounds (water and dichloromethane). Identification and quantification of residual solvents using more sophisticated techniques should be employed to ensure compliance with ICH Q3C guidelines.

[0326] Figure 32B compares samples with similar API (active pharmaceutical ingredient) composition, but different polymers, 1:1:2 ritonavir-lonafarnib-povidone-containing sample and 1:1:2 ritonavir-lonafarnib-HPMC-containing sample. As shown in Figure 23B, the HPMC-containing sample contains 1.7% volatiles, which is much lower compared to 4.8% for the povidone-containing sample. This difference is likely related to the higher hygroscopicity and / or dichloromethane affinity of povidone versus HPMC.

[0327] Example 17: Exemplary Co-Therapeutic Doses By way of illustration and not limitation, this example provides exemplary doses for lonafarnib-ritonavir co-therapy and lonafarnib-interferon lambda co-therapy. For lonafarnib-ritonavir co-therapy, exemplary doses include the following combinations (see Table 19): L1+(R1 or R2 or R3), where L1 and R are from the same row. [Table 19]

[0328] For lonafarnib-interferon lambda co-therapy, exemplary doses include, by way of example and not limitation, the following combinations (see Table 20): [Table 20]

[0329] All publications and patents cited in this specification are incorporated by reference herein to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference, and are incorporated by reference herein to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0330] While the present invention is specifically disclosed by certain aspects, embodiments and optional features, it should be understood that modifications, improvements and variations of such aspects, embodiments and optional features may be made by those skilled in the art, and such modifications, improvements and variations are considered to be within the scope of the present disclosure.

[0331] The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. Also, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention thereby also relates to any individual member or subgroup of members of the Markush group.

Claims

1. 1. A method of reducing hepatitis delta virus (HDV) viral load in a human patient having HDV infection, comprising treating the patient with lonafarnib-ritonavir co-therapy for at least 30 days, wherein the patient has been administered lonafarnib-ritonavir co-therapy for at least 10 days prior to initiation of treatment. ５ IU / mL serum baseline viral load, and treatment was ３ The method results in a reduction of viral load to less than IU / mL serum.

2. For at least one month after treatment, the HDV viral load is 10 ３ 2. The method of claim 1, wherein the IL-10 concentration remains below 1U / mL serum.

3. 10. The method of claim 1, wherein the treatment results in an HDV viral load below detection levels.

4. 4. The method of claim 3, wherein the HDV viral load remains below detectable levels for at least one month following treatment.

5. The patient had 10 ３ 10. The method of claim 1, wherein treatment with lonafarnib-ritonavir-cotherapy continues for at least 30 days after being determined to have a viral load of less than HDV RNA copies.

6. The method of any one of claims 1-5, wherein said lonafarnib is administered at a dose of 25 mg BID and said ritonavir is administered at a dose of 100 mg BID.

7. The method of any one of claims 1 to 6, wherein the patient is treated with lonafarnib-ritonavir co-therapy for at least 60 days.

8. The method of claim 7, wherein the patient is treated with lonafarnib-ritonavir co-therapy for at least 90 days.

9. 9. The method of any one of claims 1-8, comprising administering a first dose of lonafarnib followed by a second dose of lonafarnib, said second dose being lower than said first dose.

10. A method according to any one of claims 1 to 9, comprising detecting the occurrence of a hepatitis flare.

11. 11. The method of claim 10, wherein the hepatitis flare is characterized by a sudden rise in serum alanine aminotransferase (ALT) to levels above 200 U / L.

12. 12. The method of any one of claims 1 to 11, comprising detecting a transient increase of at least 3 log in the patient's Hepatitis B virus (HBV) viral load.

13. The method of any one of claims 10 to 12, wherein the lonafarnib-ritonavir co-treatment is discontinued prior to detecting the onset of the hepatitis flare or prior to detecting the transient increase.

14. 1. A method of inducing immune reactivation in patients infected with Hepatitis Delta Virus (HDV) and Hepatitis B Virus (HBV), comprising administering lonafarnib-ritonavir co-therapy for at least 12 weeks and / or until a hepatitis flare is observed, wherein the lonafarnib is administered at a total daily dose ranging from 50 mg to 150 mg and the ritonavir is administered at a total daily dose ranging from 100 mg to 200 mg.

15. 15. The method of any one of claims 1-14, wherein the lonafarnib-ritonavir co-therapy is discontinued after 10-24 weeks of treatment, and lonafarnib-ritonavir co-therapy is not administered to the patient for at least 4 weeks.

16. The method of claim 15, wherein the lonafarnib-ritonavir co-therapy is discontinued after 10 to 14 weeks of treatment.

17. 17. The method of claim 16, wherein the lonafarnib-ritonavir co-therapy is discontinued after 12 weeks of treatment.

18. 18. The method of any one of claims 14 to 17, wherein the hepatitis flare is characterized by a sudden rise in serum alanine aminotransferase (ALT) to levels above 200 U / L.

19. The method of any one of claims 14 to 18, wherein the hepatitis flare is accompanied by a transient increase in the patient's HBV viral load.

20. The method of any one of claims 14 to 19, wherein the immune reactivation is followed by at least a 3 log reduction in HDV viral load.

21. The method of any one of claims 14 to 20, wherein after said immune reactivation, there is at least a 2 log reduction in HBV viral load.

22. 22. The method of claim 20 or 21, wherein the HDV viral load and / or HBV viral load is reduced to an undetectable level.

23. 23. The method of any one of claims 14-22, wherein inducing immune reactivation in a patient infected with HDV and HBV comprises administering a first dose of lonafarnib followed by a second dose of lonafarnib, said second dose being lower than said first dose.

24. 24. The method of claim 23, wherein the first dose is administered for at least 8 weeks and the second dose is administered for at least 2 weeks, and optionally, for at least 4 weeks.

25. 25. The method of claim 23 or 24, wherein the first dose of lonafarnib is 50 mg BID and the second dose of lonafarnib is 50 mg QD.

26. 26. The method of claim 25, wherein the first dose of lonafarnib and the second dose of lonafarnib are administered in combination with ritonavir at a dose of 100 mg BID.

27. 27. The method of any one of claims 1 to 26, wherein the patient has a chronic HBV infection and the course of treatment results in a reduction in the patient's HBV viral load compared to the baseline level at the start of treatment.

28. A method of reducing HBV viral load in a patient infected with HBV and HDV, comprising administering lonafarnib at a total daily dose ranging from 50 mg to 150 mg for at least 12 weeks and detecting at least a 1 log reduction in HBV viral load.

29. 29. The method of claim 28, comprising administering lonafarnib and ritonavir.

30. 30. The method of claim 28 or 29, wherein the patient has not been treated with an antiviral nucleotide or nucleoside analogue.

31. The method of any one of claims 28 to 30, wherein the treatment results in at least a 2 log reduction in HBV viral load.

32. 32. The method of any one of claims 1 to 31, further comprising administering to the patient an interferon.

33. 33. The method of claim 32, wherein the interferon is pegylated interferon lambda.

34. 34. The method of claim 32 or 33, wherein the interferon is administered at a dose of 120mcg QW or 180mcg QW.

35. 1. A method of reducing hepatitis delta virus (HDV) viral load in a human patient with chronic HDV infection, said method comprising treating the patient with lonafarnib-interferon co-therapy for at least 30 days, said co-therapy comprising oral administration of lonafarnib in a total daily dose range of 50 mg to 150 mg, and oral administration of interferon lambda-1a in a total weekly dose range of 120 mcg to 180 mcg.

36. 36. The method of claim 35, wherein the interferon lambda-1a is pegylated interferon lambda-1a.

37. 37. The method of claim 35 or 36, wherein the lonafarnib is administered at a dose of 25 mg BID.

38. 37. The method of claim 35 or 36, wherein the lonafarnib is administered at a dose of 50 mg BID.

39. 39. The method of any one of claims 1 to 38, wherein treatment results in an improvement in liver function in said patient.

40. 40. The method of claim 39, wherein the improved liver function is improvement in one or more liver function parameters selected from the group consisting of serum albumin level, bilirubin level, alanine aminotransferase (ALT) level, aspartate aminotransferase (AST) level, and prothrombin activity.

41. 41. The method of claim 39 or 40, wherein the treatment results in an improvement in one or more liver function parameters to levels typical of healthy subjects not infected with HDV or Hepatitis B virus (HBV).

42. 39. The method of any one of claims 1 to 38, wherein treatment delays the need for a liver transplant in said patient.

43. A unit dosage form comprising lonafarnib and ritonavir, wherein said lonafarnib and ritonavir are present in a ratio of about 1:2 (w / w) or about 1:4 (w / w), and said unit dosage form is formulated for oral administration.

44. 44. The unit dosage form of claim 43 comprising lonafarnib in an amount of about 25 mg to about 100 mg and ritonavir in an amount of about 50 mg to about 100 mg.

45. 45. The unit dose form of claim 43 or 44, comprising a mixture, a multiparticulate formulation, or a bilayer formulation of lonafarnib and ritonavir.

46. 46. ​​The unit dosage form of any one of claims 43 to 45, formulated as a capsule or tablet.

47. 47. The unit dosage form of any one of claims 43-46, wherein one or both of the lonafarnib and the ritonavir are formulated for immediate release.

48. 47. The unit dosage form of any one of claims 43-46, wherein one or both of the lonafarnib and the ritonavir are formulated for controlled release.

49. A liquid formulation comprising lonafarnib and ritonavir in a ratio of 1:4 or 1:2.

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