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WO2003050129A1 - Utilisation d'analogue de nucleotide phosphonate dans le traitement des infections par le virus de l'hepatites b - Google Patents

Utilisation d'analogue de nucleotide phosphonate dans le traitement des infections par le virus de l'hepatites b Download PDF

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WO2003050129A1
WO2003050129A1 PCT/US2002/033641 US0233641W WO03050129A1 WO 2003050129 A1 WO2003050129 A1 WO 2003050129A1 US 0233641 W US0233641 W US 0233641W WO 03050129 A1 WO03050129 A1 WO 03050129A1
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purine
patient
methoxyphenylthio
trifluoroethoxy
bis
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PCT/US2002/033641
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English (en)
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Stephen Douglas Wise
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Eli Lilly And Company
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Priority to JP2003551153A priority Critical patent/JP2005511749A/ja
Priority to AU2002343556A priority patent/AU2002343556A1/en
Publication of WO2003050129A1 publication Critical patent/WO2003050129A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present invention relates to novel doses and dosing regimens for the administration of 2-amino-9-[2-[bis(2,2,2-trifiuoroethoxy)phosphonylmethoxy]ethyl]- 6-(4-methoxyphenylthio) purine (LY582563) to treat hepatitis B virus (HBV) infections in human patients.
  • the invention is particularly advantageous for lowering the plasma HBN D ⁇ A levels of patients infected with HBV, and ameliorating symptoms, conditions, or disorders associated with HBV infections in humans.
  • Hepatitis B is a potentially fatal liver disease caused by infection with hepatitis B virus, a partially double-stranded D ⁇ A virus of the Hepadnaviridae family. It is estimated that some 350 million individuals in the world are chronically infected with HBV, and about 1 million individuals die annually as a direct result of HBV-induced cirrhosis or liver cancer.
  • HBV is a hepatotropic virus that replicates in the liver, resulting in acute and chronic liver disease including liver fibrosis, cirrhosis, inflammatory liver disease, and hepatic cancer that can lead to death in some patients ( W.K. Joklik, Virology, Third Edition, Appleton & Lange, ⁇ orwalk, Comiecticut, 1988).
  • the virus is a blood- borne pathogen, which is transmitted by exposure to infectious body fluids in a fashion similar to human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • HBV is much more infectious than HIV.
  • effective vaccines are available, they have no therapeutic value for those already infected with the virus.
  • Alpha-interferon therapy has been available for the treatment of chronic hepatitis B for some time. However, it is effective in fewer than 40% of patients, and has dose-limiting side effects such as flu-like symptoms, weight loss, depression, and cytopenias.
  • Lamivudine and adefovir are new compounds currently in development for us ⁇ in HBV treatment. Unfortunately, the emergence of lamivudine-resistant viruses developing in up to 70% of patients after four years has been observed. It is therefore necessary and of high priority to find improved and effective anti-HBV anti- hepatitis therapies (Loca ⁇ iini et. al. (1996) Antiviral Chemistry & Chemotherapy 7(2): 53-64).
  • LY582563 (2-amino-9-[2-[bis(2,2,2-trifluoroethoxy)phosphonyl- methoxy]ethyl]-6-(4-methoxyphenylthio) purine) is a recently discovered phosphonate nucleotide analog (see U. S. Patent No. 5,840,716) currently under development as an anti-HBV agent.
  • LY582563 is a derivative of 9-[2-(phosphonyl- methoxy)ethyl]adenine (PMEA; adefovir) with improved oral absorption and antiviral activity. In vitro, LY582563 has demonstrated greater activity against HBV than lamivudine or PMEA. Although some of the beneficial effects of LY582563 in the treatment of HBV infections are known, optimization of treatment with this agent would be of significant therapeutic value.
  • the present invention is directed to novel pharmaceutical compositions comprising LY582563, as well as novel methods of treating HBV infections in humans, including optimal dosing regimens for the administration of LY582563 to treat HBV infected patients.
  • the present invention provides a pharmaceutical composition for oral administration in dosage unit form, comprising: about 2.5 mg to about 20 mg of 2-amino-9-[2-[bis(2,2,2- trifluoroethoxy)phosphonylmethoxy]ethyl]-6-(4-methoxyphenylthio) purine per dosage unit, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the composition can be in the form of a tablet or capsule containing the purine in an amount of about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, or about 20 mg per dosage unit, or in an amount in the range between about 5 mg and about 10 mg, or between about 7.5 mg and about 10 mg, per dosage unit. In each case, the upper limit of these ranges may be extended to about 12 or about 12.5 mg per dosage unit.
  • the present invention provides the use of 2-amino-9-[2- [bis(2,2,2-trifluoroethoxy)phosphonylmethoxy]ethyl]-6-(4-methoxyphenylthio) purine for the preparation of a medicament for treating a human patient suffering from a hepatitis B virus infection, wherein: the medicament is formulated for oral administration, and the medicament is in dosage unit form and comprises, per dosage unit, about 2.5 mg to about 20 mg of this purine.
  • the medicament can be in the form of a tablet or capsule containing the purine in an amount of about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, or about 20 mg per dosage unit, or in an amount in the range between about 5 mg and about 10 mg, or between about 7.5 mg and about 10 mg, per dosage unit. In each case, the upper limit of these ranges may be extended to about 12 or about 12.5 mg per dosage unit.
  • the present invention provides a method of treating a human patient suffering from a hepatitis B virus infection, comprising administering to said patient a total amount of 2-amino-9-[2-[bis(2,2,2-trifluoroethoxy)phosphonyl- methoxy]ethyl]-6-(4-methoxyphenylthio) purine in the range of from about 2.5 mg to about 20 mg of the purine per day.
  • the purine can be administered to the patient for a period of time sufficient to lower the plasma level of HBV DNA of the patient compared to the plasma level of HBV DNA of the patient prior to administering the purine.
  • the plasma level of HBV DNA of said patient is lowered to at least about 10 4 copies/mL compared to the plasma level of HBV DNA of the patient prior to administering the purine.
  • the purine can be administered to the patient for a period of time sufficient to treat or ameliorate a symptom, condition, or disorder caused by a hepatitis B virus in the patient, for example liver fibrosis, cirrhosis, inflammatory liver disease, or hepatic cancer.
  • the purine can be administered to the patient in the form of a pharmaceutically acceptable oral composition, which can be a tablet or capsule.
  • the period of time over which the purine is administered can be several days, several weeks,, several months, or several years, and the purine can be administered to the patient in a total amount of about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, or about 20 mg per day, or in an amount in the range between about 5 mg and about 10 mg per day, or between about 7.5 mg and about 10 mg per day. In each case, the upper limit of these ranges may be extended to about 12 or about 12.5 mg per day.
  • These amounts of purine can be administered in a single dose, or in divided subdoses totaling the total amount per day.
  • Figure 1 shows the Profile of Mean Log-change in HBV DNA with standard deviation bars: (BID groups).
  • Figure 2 shows the Profile of Mean Log-change in HBV DNA with standard deviation bars: (QD groups).
  • Figure 3 is a scatter plot showing the Log-Change in HBV DNA on Day 29 with mean and standard deviation bars.
  • the individual open symbols, i.e., squares, triangles, etc., represent individual patient data points. These differ to show some differences between the columns of data at different daily doses, although this is not really necessary as the columns are clearly differentiated.
  • the solid symbol in each column represents the mean. The outer limits of the bars represent the standard deviation from that mean.
  • Figure 4 shows the Log-Change in HBV DNA on Day 29 with Fitted E max model based on Total Daily Dose (TDD).
  • Figure 5 shows the Maximum Log-Change in HBV DNA during treatment period with fitted E m ax model based on Total Daily Dose (TDD).
  • Figure 6 shows the area under the curve (AUC) of Log-Change in HBV DNA after first dose with fitted E m a ⁇ model based on Total Daily Dose (TDD).
  • LY582563 the structure of which is shown below, is a new purine nucleotide analogue prodrug that has shown potent activity against HBV in preclinical studies (Ono-Nita et. al. (2002) Antimicrob. Agents Chemother. 46(8): 2602-5; Wise et. al.(2002) J. Gastroenterol. Hepatol. 17(suppl): A46).
  • LY582563 For oral administration of LY582563, U.S. Patent 5,840,716 teaches that the clinical dose may generally be 0.1 mg to 500 mg/kg per day, preferably 1 mg to 50 mg/kg per day, of the compound for an adult. For an adult weighing 68 kg (approximately 150 lbs), these ranges are approximately 6.8 mg to approximately 34 g per day, preferably approximately 68 mg to approximately 3.4 g per day. The '716 patent notes that these doses may be appropriately increased or decreased depending on age, conditions or symptoms, or the presence or absence of a co-administered drug. In addition, U.S. Patent 5,840,716 teaches that the above daily doses may be administered once a day, or dividedly administered twice or several times a day with appropriate intervals. Finally, continual administration may be carried out at intervals of several days.
  • Determination of a safe and effective dose of any new pharmaceutical agent, and an appropriate treatment regimen employing the drug is an empirical process. This process generally requires treating afflicted patients with varying doses of the agent, one or more times daily, over varying time periods, and monitoring effectiveness by accepted diagnostic methods.
  • diagnostic methods can include measurement of plasma or tissue levels of HBV DNA or various antigens that comprise part of the virus, or patient response such as antibody formation (for example hepatitis B e antibody) or biochemical improvement such as decreased alanine aminotransferase (ALT) levels.
  • one can also measure the effectiveness of treatment by monitoring the amelioration of symptoms, conditions, or disorders caused by the virus.
  • HBV human diseases
  • these include fatigue, anorexia, jaundice, liver fibrosis and inflammation, cirrhosis, and hepatic cancer (hepatocellular carcinoma).
  • acceptable safety which includes acceptable toxicity.
  • Toxicities that have been observed with other HBV antivirals include mitochondrial toxicity, renal toxicity, and bone marrow toxicity.
  • the relationship between dose and treatment regimen for a new drug entity, and effectiveness and safety, can only be determined by clinical testing in humans. Therefore, determination of dose and treatment regimen parameters cannot be predicted or deduced, and the results are necessarily novel and unobvious. Particular attention must be paid to selecting treatment parameters that, while being effective to treat a disease, do not cause other harm to the patient.
  • Safety data e.g., clinical signs (e.g., blood pressure, pulse, respiratory rate, and general physical findings), adverse events (e.g., upper abdominal pain, diarrhea, nausea, headache, fatigue, and alopecia), ECGs, hematology, biochemistry measures in blood (e.g., aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactic acid, blood urea nitrogen (BUN), creatinine, and bilirubin), as well as highly sensitive urinary markers of renal tubular toxicity (lactate dehydrogenase (LDH), urinary creatinine, and urinary beta-N-acetyl glucosaminidase (beta-NAG)), were also measured.
  • clinical signs e.g., blood pressure, pulse, respiratory rate, and general physical findings
  • adverse events e.g., upper abdominal pain, diarrhea, nausea, headache, fatigue, and alopecia
  • ECGs e.g., hematology
  • LY582563 exhibits a favorable safety profile and effective HBV antiviral activity in chronically infected patients, and suggest optimal dose levels and dosing regimes for long term safe and effective use of this new HBV antiviral agent. Based on the present results, an appropriate dose of LY582563 balancing both safety and efficacy is between about 2.5 mg and about 20 mg per patient per day. These doses may have to be administered to patients over the course of several days, several weeks, or several months or years in order to ameliorate or control undesirable pathogenic consequences of HBV infection.
  • the oral dosing regimen for treating a patient suffering from HBV with LY582563 is generally selected in accordance with a variety of factors, including the age, weight, sex, diet, and medical condition of the patient, genotype of the infecting virus, the severity of the infection, and pharmacological considerations such as the activity, efficacy, pharmacokinetic, and toxicology profiles of LY582563.
  • Administration of LY582563 should generally be continued over a period of several hours, days, or weeks to several months or years until virus titers reach acceptable levels, or until one or more indicia, symptoms, conditions, or disorders present in a patient due to hepatitis B virus infection has been ameliorated or completely eliminated, indicating that infection has been controlled or eradicated.
  • the long term goal is currently a matter of debate, with some workers in the field proposing that a desirable level is below 10 4 copies/mL. The duration for this level of HBV DNA has yet to be defined.
  • Representative indicia of HBV infection other than plasma HBV DNA levels include, but are not limited to, liver fibrosis, cirrhosis, inflammatory liver disease, and hepatic cancer. See Hollinger et al. (2001) in Fields Virology, Fourth Ed., Vol. 2, David M. Knipe et al., Eds., "Hepatitis B Virus," Chapter 87, pp. 2971-3036, Lippincott, Williams, & Wilkins, Philadelphia, PA for a review. In most parts of the world, liver fibrosis, etc., is diagnosed via liver biopsy; in most Asian countries, liver biopsies are not routinely performed, and medical practitioners usually rely on clinical measures to make presumptive diagnoses.
  • HBV antigens such as HBV surface antigen (HBsAg) and HBV e antigen (HBeAg)
  • HBV antigens such as HBV surface antigen (HBsAg) and HBV e antigen (HBeAg)
  • HBeAg HBeAg
  • the terms “ameliorate,” “treat,” “treatment,” “therapeutic use,” or “treatment regimen” as used herein are meant to encompass prophylactic, palliative, and therapeutic modalities of administration of LY582563, and include any and all uses of this purine that remedy an indicium, a disease state, a condition, a symptom, or a disorder caused by a hepatitis B virus, or which prevent, hinder, retard, or reverse the progression of indicia, symptoms, conditions, or disorders associated with HBV infection.
  • any prevention, improvement, alleviation, reversal, or complete elimination of an undesirable are examples of this purine that remedy an indicium, a disease state, a condition, a symptom, or a disorder caused by a hepatitis B virus, or which prevent, hinder, retard, or reverse the progression of indicia, symptoms, conditions, or disorders associated with HBV infection.
  • indicium, disease state, symptom, condition, or disorder associated with HBV infection is encompassed by the present invention.
  • dosage unit refers to an individual delivery vehicle, for example, but not limited to, a tablet or capsule, for administration of a dose of the active LY582563 purine.
  • the following example is provided to illustrate various aspects of the present invention, and should not be construed to be limiting thereof in any way.
  • a randomized, single period, multiple dose-escalation, single-blind study of LY582563 was carried out in 2 parts. Part 1 was conducted in healthy subjects, and Part 2 was conducted in patients with compensated chronic HBV infection (hereafter "patients"). The study was designed to evaluate the safety and pharmacodynamics of multiple doses of LY582563. This was the first multiple dose study in humans.
  • Dose escalation was carried out in conservative increments in healthy subjects who were given BID regimen for a 2-week period. Safety data were reviewed prior to each dose escalation.
  • Plasma concentrations of LY582563 and its metabolites were measured up to 24 hours after a single dose of LY582563 and after the last dose by a validated LC/MS/MS method (Advion BioSciences, Inc., Ithaca, NY). Subjects were followed up at regular intervals for approximately 4 weeks after the last dose of LY582563.
  • Part 2 (Patients) In part 2, there were 7 groups with 8-12 patients in each group. Table 2 shows the characteristics of the subjects in this study.
  • LY582563 day 1
  • multiple BID dosing for approximately 28 days (i.e., day 2 to day 29) of LY582563 was administered, except for the last day (day 29) of dosing, which was QD.
  • LY582563 and its metabolites 602074, 602075 and 602076 were sampled up to 24 hours after a single dose of LY582563 and after the last dose. Subjects were followed up at regular intervals for approximately 12 weeks after the last dose of LY582563.
  • HBV DNA Baseline Geometric mean of HBV DNA at screening, -28 day, -14 day and predose.
  • LY582563 and matching placebos were supplied as either 2.5 mg, 10 mg, or 20 mg tablets.
  • LY582563 and matching placebo tablets were supplied by Mitsubishi Pharma Corporation, Tokyo, Japan.
  • LY582563 and placebo formulations for oral administration were as follows:
  • LY582563, D-mannitol, and corn starch are mixed. Hydroxypropylcellulose dissolved in purified water is added for granulation by fluid-bed granulator. After drying, granules are screened by tornado mill. Screened granules are mixed with magnesium stearate and low substituted hydroxypropylcellulose by V-shaped mixer. Mixed granules are compressed into tablets. Tablets are filmed coated with hydroxypropylmethyl-cellulose 2910, propylene glycol, titanium dioxide, and talc by conventional methods. Finally, tablets are coated with a little hydrogenated oil. Dosing
  • the 2.5 mg dose was administered as 1 tablet of 2.5 mg LY582563 or 1 matching placebo.
  • the 5 mg dose was administered as 2 tablets of 2.5 mg LY582563 or 2 matching placebos.
  • the 10 mg dose was administered as 1 tablet of 10 mg LY582563 or 1 matching placebo.
  • the 15 mg dose was administered as 2 tablets of 2.5 mg LY582563 and 1 tablet of 10 mg LY582563 or matching placebos corresponding to the 2.5 and 10 mg LY582563 tablets.
  • the 20 mg dose was administered as 1 tablet of 20 mg LY582563 or 1 matching placebo.
  • **lsubject of 5A dose group who was randomized to receive LY582563 was withdrawn from the study on day 1 prior to receiving study drug.
  • HBN D ⁇ A Plasma-derived PCR assay
  • Baseline measurements were defined as the geometric mean of the non log-transformed data obtained prior to dosing.
  • Within-subject maximum log-changes in HBN D ⁇ A values from baseline during the treatment period were derived by substracting the minimum HBV D ⁇ A value during treatment period from the baseline value. For two patients (2108 and 3308, both on placebo treatment) where the HBN D ⁇ A values during treatment were all greater than the baseline, the maximum log-change was assigned a value of zero.
  • the area under the curve (AUC) for log change between each HBN D ⁇ A time curve and a horizontal line passing through the baseline score were computed.
  • the HBV D ⁇ A values were first converted to baseline score when they were higher than baseline score, and area between the curve and the horizontal baseline was computed using the trapezoidal rule to adjust for the difference in time interval between measurements.
  • Plasma samples for HBV DNA were quantitated using the validated NGI HBV SuperQuantTM Quantitative PCR assay with a specified assay range of 100 genome copies/mL to 5xl ⁇ 9 genome copies/mL at National Genetics Institute (Los Angeles, CA). Blood samples of approximately 5 mL were collected at screening, at approximately 4 and 2 weeks before dosing, as well as just prior to dosing; measurements were then made during the dosing period (approximately 3 days, then 1, 2, 3, and 4 weeks after the first dosing) and the follow up period ( 5, 6, 8, 12 and 16 weeks after the first dosing). Depending on the level of hepatitis B viral suppression 8 weeks after dosing, subjects would have additional samples taken approximately 10 and 14 weeks after the first dosing.
  • the profiles of mean log-change in HBV DNA are shown in Figures 1 and 2.
  • the placebo group exhibited a consistent mean value of zero (i.e., not significantly different from baseline) at each measurement day.
  • the 2.5, 5, and 10 mg doses of LY582563 resulted in a linear decline in log-scale of HBV DNA during the treatment period ( Figure 1).
  • the same was also observed for QD dosing groups, although the 2.5 mg dose group appeared to have a slower rate of decline, and the 5 mg group exhibited a slower rate of decline after Day 7 ( Figure 2).
  • the HBV DNA values gradually returned to baseline after the last dose of LY582563, and the time of return to the baseline or 1/2 log change of baseline appeared to increase with higher doses.
  • the mean HBV DNA for 10 mg BID, 10 mg QD, and 20 mg QD groups was lower compared to the baseline at day 112 ( Figures 1 and 2), indicating that the viral load did not return to baseline after a 3-month period.
  • N n Emax model was fitted to the log-change with total daily dose as the explanatory variable (Figure 4), facilitating understanding the relationship between pharmacodynamic effects and total daily dose.
  • the fitted regression curve suggests that a plateau was achieved for HBV DNA drop at approximately 10 mg total daily dose.
  • Confidence interval (shown in parenthesis) that does not contain zero indicates a statistically significant difference between two treatments at the 5% level.
  • the mean maximum log-changes during the treatment period were observed to be 2.39, 1.82, and 2.93 for the 2.5, 5, and 10 mg dose groups, respectively. All mean maximum log-drops were statistically significant when . compared to that of the placebo group. Although there appeared to be a significant 5 difference in mean log-change between the 10 mg and 5 mg dose groups, there was no significant difference between the 10 mg and 2.5 mg dose groups.
  • QD dosing the observed mean maximum log-changes during the treatment period were 1.53, 2.19, 2.58, and 2.68 for the 2.5, 5, 10, and 20 mg dose groups, respectively. All mean log- drops were statistically significant when compared to that of the placebo group.
  • the 10 mean log-change for the 5, 10, and 20 mg dose groups appeared to be similar, and were significantly different from that of 2.5 mg group.
  • Figure 4 shows the log-change in HBV DNA on day 29 with fitted E max model based on total daily dose (TDD);
  • Figure 5 shows the 20 maximum log-change in HBV DNA over the treatment period with fitted E max model based on TDD.
  • Both figures need to be taken into consideration as the maximum log- change for some patients occurred at times other than at day 29.
  • these figures permit a better understanding of the profile of pharmacodynamic effect, i.e., HBV DNA change, with dose.
  • 25 The pair- wise comparisons of mean change in AUC after the first dose until the end of the study period (day 112) within each dosing regimen are listed in Table 11. Pair- wise differences were tested at the 5% level of significance without any multiplicity adjustments.
  • Table 11 Mean AUC of Log-Change from Baseline of HBV DNA Value with 95% Confidence Interval After First Dose (Day 1 to Last Visit)
  • Confidence interval (shown in parenthesis) that does not contain zero indicates a statistically significant difference between two treatments at the 5% level.
  • the mean AUC for log-change after the first dose for the 2.5, 5, and 10 mg dose groups was observed to be statistically significant when compared to that of the placebo group.
  • a significant difference in mean AUC for log-change between the 10 mg and 2.5 mg dose groups was also observed.
  • QD dosing the observed mean AUC for log-change for the 2.5, 5, 10, and 20 mg dose groups was statistically significant compared to that of the placebo group.
  • the mean AUC for log-change for the 10 and 20 mg dose groups appeared to be similar, and were significantly different from that of the 2.5 mg group. A trend of significant difference between the 10 mg and 5 mg doses was also observed.
  • ALT elevations attributable to LY582563 was approximately three times the upper limit of normal. Evaluations of clinical biochemical markers (serum phosphate, urea, and creatinine) as well as of clinical urinary markers (LDH/creatinine and beta- NAG/creatinine ratios) in both healthy subjects and patients did not reveal any dose- related, renal tubular toxicity. Clinical laboratory results of plasma lactate and serum creatine kinase also suggested that there was no dose-related mitochondrial or musculoskeletal toxicity following repeated dosing with the doses of LY582563 examined.
  • LY582563 There were no significant abnormalities of vital signs or ECGs (including assessment for QT C prolongations) in healthy subjects and patients with compensated chronic HBV infection. All doses of LY582563 were associated with a reduction in viral load (plasma HBV DNA) during the treatment period that appeared to be dose-related. The greatest decline was observed in the 10 mg QD, 10 mg BID, and 20 mg QD dose groups, resulting in an approximately 2.5 mean log ⁇ 0 decline after four weeks of therapy. The viral load gradually returned to baseline after cessation of LY582563 treatment. This appeared to be delayed in the higher doses. Based on these results, an appropriate dose of LY582563 that balances safety with efficacy is between about 2.5 mg and about 20 mg per patient per day.

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Abstract

L'invention concerne des compositions acceptables sur le plan pharmaceutique contenant 2-amino-9-[2-[bis(2,2,2-trifluoroéthoxy)phosphonylméthoxy]éthyl]-6-(4-méthoxyphénylthio)purine (LY582563) qui sont destinées, par administration orale, à traiter les infections véhiculées par le virus de l'hépatite B virus chez les patients infectés. Ces compositions se présentent sous la forme de dosages unitaires contenant chacun entre environ 2,5 et environ 20 mg de purine. Ces compositions sont adaptées pour l'administration orale, de préférence sous forme de comprimés ou de capsules, et peuvent être administrées par doses uniques ou multiples, à condition que la dose quotidienne totale de purine soit comprise entre environ 2,5 mg et environ 20 mg par patient et par jour. Ces compositions sont particulièrement avantageuses pour réduire le taux de l'ADN HBV dans le plasma, ou pour atténuer les symptômes, améliorer l'état du malade diminuer les troubles véhiculés par le virus de l'hépatite B, chez les patients humains atteints d'une infection chronique par HBV.
PCT/US2002/033641 2001-12-07 2002-11-15 Utilisation d'analogue de nucleotide phosphonate dans le traitement des infections par le virus de l'hepatites b WO2003050129A1 (fr)

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JP2003551153A JP2005511749A (ja) 2001-12-07 2002-11-15 Ｂ型肝炎ウィルス感染症を治療するためのホスホネートヌクレオチド類似体の使用
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WO2004096286A3 (fr) * 2003-04-25 2005-06-16 Gilead Sciences Inc Analogues de phosphonate antiviraux
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US7273715B2 (en) 2003-10-24 2007-09-25 Gilead Sciences, Inc. Methods and compositions for identifying therapeutic compounds with GS-9005 ester hydrolase A
US7300924B2 (en) 2003-04-25 2007-11-27 Gilead Sciences, Inc. Anti-infective phosphonate analogs
US7407965B2 (en) 2003-04-25 2008-08-05 Gilead Sciences, Inc. Phosphonate analogs for treating metabolic diseases
US7417055B2 (en) 2003-04-25 2008-08-26 Gilead Sciences, Inc. Kinase inhibitory phosphonate analogs
US7427636B2 (en) 2003-04-25 2008-09-23 Gilead Sciences, Inc. Inosine monophosphate dehydrogenase inhibitory phosphonate compounds
US7427624B2 (en) 2003-10-24 2008-09-23 Gilead Sciences, Inc. Purine nucleoside phosphorylase inhibitory phosphonate compounds
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US7432261B2 (en) 2003-04-25 2008-10-07 Gilead Sciences, Inc. Anti-inflammatory phosphonate compounds
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US9775852B2 (en) 2013-03-15 2017-10-03 The Regents Of The University Of California Acyclic nucleoside phosphonate diesters
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US10377782B2 (en) 2015-09-15 2019-08-13 The Regents Of The University Of California Nucleotide analogs
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EA014685B1 (ru) * 2003-04-25 2010-12-30 Джилид Сайэнс, Инк. Фосфонатсодержащие антивирусные соединения (варианты) и фармацевтическая композиция на их основе
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US7429565B2 (en) 2003-04-25 2008-09-30 Gilead Sciences, Inc. Antiviral phosphonate analogs
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WO2005002626A3 (fr) * 2003-04-25 2005-05-26 Gilead Sciences Inc Composes de phosphonate therapeutiques
US7452901B2 (en) 2003-04-25 2008-11-18 Gilead Sciences, Inc. Anti-cancer phosphonate analogs
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US7432273B2 (en) 2003-10-24 2008-10-07 Gilead Sciences, Inc. Phosphonate analogs of antimetabolites
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US7432272B2 (en) 2003-12-22 2008-10-07 Gilead Sciences, Inc. Antiviral analogs
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