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WO2013062959A2 - Administration continue sous-cutanée d'interféron alpha à des patients infectés par le virus de l'hépatite b - Google Patents

Administration continue sous-cutanée d'interféron alpha à des patients infectés par le virus de l'hépatite b Download PDF

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Publication number
WO2013062959A2
WO2013062959A2 PCT/US2012/061467 US2012061467W WO2013062959A2 WO 2013062959 A2 WO2013062959 A2 WO 2013062959A2 US 2012061467 W US2012061467 W US 2012061467W WO 2013062959 A2 WO2013062959 A2 WO 2013062959A2
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Prior art keywords
interferon
patient
hepatitis
week
therapeutic regimen
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WO2013062959A3 (fr
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William P. Van Antwerp
Eric A. Grovender
Rachael M. Scherer
Jeffrey Lande
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Medtronic Inc
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Medtronic Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • 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
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • This invention relates to therapies involving the administration of interferon-a for the treatment of pathological conditions (e.g. Hepatitis B virus infections).
  • this invention relates to methods and systems for administering interferon-a in a manner that controls the in vivo levels of interferon- ⁇ in the patient in order to optimize the outcome of a therapeutic regimen(s).
  • Hepatitis B virus (HBV) infection is a major public health challenge, with an estimated 730,000 chronically infected adults in the United States alone and an annual financial burden of $1.3 billion.
  • Currently available therapeutic options include both parenteral and oral agents, which act on various host and viral targets. These include medications such as standard interferon and pegylated interferon (peg-interferon), which target receptors on the host cell membranes, and nucleotide and nucleoside analogues, which inhibit HBV RNA-dependent DNA polymerase.
  • peg-interferon standard interferon and pegylated interferon
  • nucleotide and nucleoside analogues which inhibit HBV RNA-dependent DNA polymerase.
  • the HBV virus is transmitted by blood and blood products, contamination of needles in IV drug abusers, sexually and vertically from infected or carrier mothers to infants.
  • the disease is most common in Southeast Asia, Africa and parts of South America. In these areas, vertical transmission to infants at an early age results in a high proportion of infected individuals becoming chronic carriers of hepatitis B.
  • HBV can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive sections of the liver are destroyed.
  • Males acquiring hepatitis B as infants have approximately a 40% chance of dying from cirrhosis or primary hepatocellular carcinoma as a result of chronic hepatitis B infection.
  • Chronic hepatitis B infection Females infected at birth have about a 15% chance of dying a similar death from chronic hepatitis B infection. While patients typically recover from acute hepatitis, in some patients high levels of viral antigen persist in the blood for an extended, or indefinite, period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Chronic persistent hepatitis can cause fatigue, cirrhosis of the liver, and hepatocellular carcinoma, a primary liver cancer. The mechanism by which HBV induces cancer is unknown, although it is postulated that it may directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis, and cell regeneration associated with the infection.
  • the disclosure provided herein includes results obtained from a clinical trial designed to study the continuous subcutaneous administration of interferon- ⁇ combined with ribavirin in chronic hepatitis C treatment experienced patients.
  • Clinical data obtained from this trial shows that the continuous subcutaneous administration of interferon- ⁇ can be used to maintain in vivo concentrations of interferon- ⁇ above a critical efficacy threshold for an extended period of time and that this furthers viral clearance in the host.
  • interferon-a has potent antiviral activity but does not act directly on the virus or replication complex. Instead, interferon- ⁇ acts by inducing IFN-stimulated genes (ISGs), which establish a non-virus specific antiviral state within the cell (see, e.g. Bekisz et al., Growth Factors 22, 243-251 (2004) and Sen, Annu. Microbiol. 55, 255-281 (2001).
  • ISGs IFN-stimulated genes
  • Microarray analysis show that hundreds of genes are induced by interferon- ⁇ , many related to antiviral activity but others involved in lipid metabolism, apoptosis, protein degradation and inflammatory cell responses.
  • interferon- ⁇ promotes memory T-cell proliferation, prevent T-cell apoptosis and stimulate natural-killer-cell activation and dendritic cell maturation.
  • cytokine e.g. via a continuous infusion pump
  • Interferon- ⁇ has been approved as a therapeutic agent in methods for treating hepatitis B infection and the invention disclosed herein provides specific therapeutic methodologies for the treatment of this infection.
  • One illustrative embodiment of the invention is a method of administering interferon- ⁇ to a patient infected with hepatitis B virus, the method comprising administering interferon- ⁇ to the patient using a continuous infusion apparatus, wherein the interferon- ⁇ is administered to the patient using a therapeutic regimen sufficient to maintain circulating levels of the interferon- ⁇ in the serum of the patient above a certain steady state concentration threshold for a period of time, for example a concentration of at least 100 picograms per milliliter (pg/ mL) for at least 1 week to at least 52 weeks.
  • such therapeutic regimens are sufficient to reduce levels of HBV in the patient by at least 100- fold.
  • Embodiments of the invention include personalized therapeutic regimens tailored to consider one or more characteristics specific to the patient and/ or the virus infecting the patient. For example, the presence or absence of specific single nucleotide polymorphisms can be used to assess the likelihood of chronic hepatitis B (CHB) susceptibility. Consequently, certain methodological embodiments of the invention comprise the steps of determining a polynucleotide sequence on in the patient for example, one or more single nucleotide polymorphisms such as those designated rs2856718, rs7453920, rs3077, rs9277535, rs2284553, rs9808753 or rsl 7401966 (e.g.
  • the patient is examined in order to identify the genotype of the virus and/or the presence or status of one or more HBV antigens (e.g. HBsAg or HBeAg) and/or antibodies to one or more HBV antigens (e.g. anti-HBsAg, IgM anti-HBc or anti-HBeAg) prior to initiating the therapeutic regimen.
  • HBV antigens e.g. HBsAg or HBeAg
  • antibodies to one or more HBV antigens e.g. anti-HBsAg, IgM anti-HBc or anti-HBeAg
  • the interferon- ⁇ is not conjugated to a polyol.
  • these methods further comprise administering a small molecule inhibitor of viral replication such as a nucleoside/ nucleotide analog.
  • Another illustrative embodiment of the invention that considers one or more characteristics specific to the patient is a method of administering an interferon- ⁇ to a patient infected with hepatitis B virus, the method comprising administering a test dose of an interferon- ⁇ to the patient and then observing a concentration of circulating interferon- ⁇ in the serum of the patient that results from the test dose.
  • the concentration of circulating interferon- ⁇ observed in response to the test dose is then used to design a patient-specific therapeutic regimen, one that comprises administering interferon- ⁇ to the patient subcutaneously using a continuous infusion apparatus in an amount sufficient to maintain circulating levels of interferon- ⁇ in the serum of the patient above a specific in vivo concentration for a specific period of time, for example above 100 pg/mL for at least 1 week to at least 52 weeks.
  • the patient- specific therapeutic regimen is selected to maintain serum interferon- ⁇ concentrations in the patient at a value greater than a critical concentration threshold that induces and/ or facilitates a patient's sustained response to a therapeutic regimen.
  • inventions include systems for administering interferon- ⁇ to a patient having a hepatitis B infection.
  • the system can comprise for example: a continuous infusion pump having a medication reservoir comprising interferon- ⁇ ; a processor operably connected to the continuous infusion pump and comprising a set of instructions that causes the continuous infusion pump to administer the interferon- ⁇ to the patient according to a therapeutic regimen comprising administering interferon- ⁇ to the patient subcutaneously; wherein the therapeutic regimen is sufficient to maintain circulating levels of interferon-a in the serum of the patient above a steady state concentration of at least 100-700 pg/mL.
  • the system for administering interferon- ⁇ is coupled to an electronic system for managing medical data on an electronic communication network.
  • one such electronic system can comprise at least one electronic server connectable for communication on the communication network, the at least one electronic server being configured for: receiving a first physiological parameter observed in a patient (e.g. a patient's viral load) setting a first dose of the interferon- ⁇ for infusion by the continuous infusion pump, based on the first physiological parameter; receiving second physiological parameter information of the patient indicative of a response of the patient to the interferon- ⁇ of the first dose; and then setting a second dose of the interferon- ⁇ for infusion by the continuous infusion pump, based on the second physiological parameter.
  • a first physiological parameter observed in a patient e.g. a patient's viral load
  • the at least one electronic server being configured for: receiving a first physiological parameter observed in a patient (e.g. a patient's viral load) setting a first dose of the interferon- ⁇ for infusion by the continuous infusion pump,
  • Figures 1A and IB provide analyses of data from HCV infected patients treated with interferon-a following the therapeutic regimens disclosed herein.
  • the data provided in the graphs shown in Figures 1A and IB show that there is a strong dose response observed in patients in response to interferon- ⁇ administration following the disclosed therapeutic regimens.
  • the data shown in Figures 1A and IB further show that delivering higher concentrations of interferon- ⁇ following the therapeutic regimens disclosed herein leads to correspondingly higher sustained concentrations of interferon- ⁇ in vivo.
  • Figure 2 provides viral decay analyses from a subset of HCV infected patients that were previously shown to be severely interferon- ⁇ resistant and were subsequently treated using the therapeutic regimens disclosed herein.
  • the viral decay curves in the 6 MIU/ day treatment group treatment failures are illustrated in the graphic data shown in this Figure.
  • the 6 MlU/day therapeutic regimen group there were 5 subjects that showed significant resistance. Of these 5 subjects, patient 8 showed a robust response at week 8 with subsequent rebound. In previous therapy, all of these 5 subjects were either therapy failures at week 12 or week 24.
  • Five subjects in this 6 MlU/day therapeutic regimen group with more clinically significant HCV declines are shown in Figure 3.
  • subjects in the 6 MIU per day group were previously shown to be severely resistant to conventional HCV therapies using pegylated interferon-a.
  • Figure 3 provides viral decay analyses of a subset of HCV infected patients in the 6 MIU per day therapeutic regimen group, robust response group, all of whom were previously shown to be severely resistant to conventional HCV therapies using pegylated interferon-a.
  • viral decay curves in response to this treatment show a clinically significant response following the therapeutic regimens disclosed herein.
  • Figures 4A and 4B provide viral decay analyses of a subset HCV infected patients in the 9 MIU per day therapeutic regimen group, all of whom were previously shown to be severely resistant to conventional HCV therapies using pegylated interferon- a.
  • the data provided in Figure 4A shows that there were 4 subjects who remained interferon- ⁇ resistant.
  • the data provided in Figure 4B shows that that 6 of the 10 subjects in the 9 MIU per day therapeutic regimen group show a robust response even though these patients were found to be previously resistant to pegylated interferon-a treatment.
  • Figure 5 provides viral decay analyses of a subset of HCV infected patients in the 12 MIU per day therapeutic regimen group, all of whom were previously shown to be severely resistant to conventional HCV therapies using pegylated interferon- ⁇ . In this 12 MlU/day therapeutic regimen group, there are no interferon- ⁇ resistant subjects to the current therapy. Three patients have withdrawn from the trial. 9 patients show a robust response.
  • Figure 6 provides viral decay data at the four- week timepoint for the 6, 9, and 12 MIU per day therapeutic regimen groups. As shown by the curves in this graph, at four weeks there is a significant difference in viral load that relates to differences in the doses.
  • Figure 7 provides data comparing viral decay by dosing in patient groups receiving the 6, 9 or 12 MIU per day therapeutic regimens. As shown by the data presented in these bar graphs at four weeks there is a significant difference in viral decay observed with different doses of interferon-a.
  • Figure 8 provides information on how the serum interferon-a concentrations in vivo that result from the therapeutic regimens disclosed herein influences the viral decay data at the four week timepoint.
  • Figure 9A presents an exemplary generalized computer system 202 that can be used to implement elements of the present invention.
  • Figure 9B presents one embodiment of a specific illustrative computer system embodiment that can be used with embodiments of the invention in the treatment of Hepatitis C virus infection.
  • interferon-a By the term “at least 100-700 pg/mL" of interferon-a it is understood that values such as at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675 or 700 pg/mL can be used to create any specific range of values.
  • the therapeutic regimen is administered for a duration of at least 7, 14, 21 or 28 days, while time periods of at least 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 54, 58, 62, 66, 70, 72 or more weeks can also be selected.
  • the therapeutic regimen is administered for a duration of at least 6, 8 or 10 weeks to at least 48 weeks.
  • the therapeutic regimen is administered for a duration of at least 6 weeks to at least 32, 36, 40 or 44 weeks.
  • the therapeutic regimen is administered for a duration of at least 6 weeks to at least 52, 54, 58, 62, 66, 70, 72 or more weeks.
  • administer means to introduce a therapeutic agent into the body of a patient in need thereof to treat a disease or condition.
  • treating refers to the management and care of a patient having a pathology such as a viral infection or other condition for which administration of one or more therapeutic compounds is indicated for the purpose of combating or alleviating symptoms and complications of those conditions. Treating includes administering one or more formulations of the present invention to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • treatment or “therapy” refer to both therapeutic treatment and prophylactic or preventative measures.
  • treating does not require complete alleviation of signs or symptoms, does not require a cure, and specifically includes protocols which have only a marginal effect on the patient.
  • terapéuticaally effective amount refers to an amount of an agent (e.g. a cytokine such as interferon-a or small molecule inhibitors such as a nucleoside/ nucleotide analog) effective to treat at least one sign or symptom of a disease or disorder in a human.
  • Amounts of an agent for administration may vary based upon the desired activity, the diseased state of the patient being treated, the dosage form, method of administration, patient factors such as the patient's sex, genotype, weight and age, the underlying causes of the condition or disease to be treated, the route of administration and bioavailability, the persistence of the administered agent in the body, the formulation, and the potency of the agent. It is recognized that a therapeutically effective amount is provided in a broad range of concentrations. Such range can be determined based on in vitro and/ or in vivo assays.
  • profile is used according to its art accepted meaning and refers to the collection of results of one or more analyses or examinations of: (1) the presence of; or (2) extent to which an observed phenomenon exhibits various characteristics.
  • Illustrative profiles typically include the results from a series of observations which, in combination, offer information on factors such as, for example, the presence and/or levels and/or characteristics of one or more agents infecting a patient (e.g. the hepatitis B virus), as well as the pharmacokinetic and/or pharmacodynamic characteristics of one or more therapeutic agents administered to a patient as part of a treatment regimen (e.g. interferon-a), as well as the physiological status or functional capacity of one or more organs or organ systems in a patient (e.g. the liver), as well as the genotype of one or more single nucleotide polymorphisms in a patient etc.
  • agents infecting a patient e.g. the hepatitis B virus
  • terapéutica regimen refers to, for example, a part of treatment plan for an individual suffering from a pathological condition (e.g. chronic hepatitis B infection) that specifies factors such as the agent or agents to be administered to the patient, the doses of such agent(s), the schedule and duration of the treatment etc.
  • a pathological condition e.g. chronic hepatitis B infection
  • factors such as the agent or agents to be administered to the patient, the doses of such agent(s), the schedule and duration of the treatment etc.
  • pharmacokinetics is used according to its art accepted meaning and refers to the study of the action of drugs in the body, for example the effect and duration of drug action, the rate at they are absorbed, distributed, metabolized, and eliminated by the body etc. (e.g. the study of a concentration of interferon-a in the serum of the patient that results from its administration via a therapeutic regimen).
  • pharmacodynamics is used according to its art accepted meaning and refers to the study of the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body, the mechanisms of drug action and the relationship between drug concentration and effect etc. (e.g. the study of a concentration of hepatitis B virus present in a patient's plasma following one or more therapeutic regimens).
  • continuous administration and “continuous infusion” are used interchangeably herein and mean delivery of an agent such as interferon- ⁇ in a manner that, for example, avoids significant fluctuations in the in vivo concentrations of the agent throughout the course of a treatment period.
  • This can be accomplished by constantly or repeatedly injecting substantially identical amounts of interferon-a (typically with a continuous infusion pump device), e.g., at least every hour, 24 hours a day, seven days a week for a period such as at least 1 week to at least 48 weeks, such that a steady state serum level is achieved for the duration of treatment.
  • Continuous interferon-a may be administered according to art accepted methods, for example via subcutaneous or intravenous injection at appropriate intervals, e.g. at least hourly, for an appropriate period of time in an amount which will facilitate or promote in vivo inactivation of hepatitis B virus.
  • continuous infusion system refers to a device for continuously administering a fluid to a patient parenterally for an extended period of time or for intermittently administering a fluid to a patient parenterally over an extended period of time without having to establish a new site of administration each time the fluid is administered.
  • the fluid typically contains a therapeutic agent or agents.
  • the device typically has one or more reservoir(s) for storing the fluid(s) before it is infused, a pump, a catheter, cannula, or other tubing for connecting the reservoir to the administration site via the pump, and control elements to regulate the pump.
  • the device may be constructed for implantation, usually subcutaneously. In such a case, the reservoir will usually be adapted for percutaneous refilling.
  • patients or humans having hepatitis B infections means any patient-including a pediatric patient-having hepatitis B and includes treatment- naive patients having hepatitis B infections and treatment-experienced patients having hepatitis B infections as well as those pediatric, treatment-naive, and treatment- experienced patients having chronic hepatitis B infections.
  • These patients having chronic hepatitis B include those who are infected with multiple HBV genotypes.
  • interferon means the family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation and modulate immune response. Human interferons are typically grouped into three classes based on their cellular origin and antigenicity: interferon- ⁇ (leukocytes), interferon- ⁇ (fibroblasts), interferon- ⁇ (T cells) and interferon- ⁇ . Both naturally occurring and recombinant a-interferons may be used in the practice of the invention (e.g. recombinant interferon- ⁇ 2a or recombinant interferon-a 2b).
  • Interferons such as interferon-a can be quantified a number of ways, for example in picograms per milliliter (e.g. 100 pg/mL) or international units ("IU", see, e.g. Meager et al.,(2001) Establishment of new and replacement World Health Organisation International Biological Standards for human interferon- ⁇ and omega. Journal of Immunological Methods, 257, 17-33).
  • picograms per milliliter e.g. 100 pg/mL
  • IU international units
  • antibody when used for example in reference to an "antibody capable of binding HBV” is used in the broadest sense and specifically covers intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies ⁇ e.g. bispecific antibodies) formed from at least two intact antibodies, and antibody fragments so long as they retain their ability to immunospecifically recognize a target polypeptide.
  • the instant disclosure includes the results from a clinical trial studying new therapeutic regimens comprising the continuous subcutaneous administration of interferon- ⁇ combined with ribavirin in chronic hepatitis C treatment experienced patients.
  • Clinical data obtained from this trial shows that the continuous subcutaneous administration of interferon- ⁇ can be used to maintain in vivo concentrations of this therapeutic agent above a critical efficacy threshold for an extended period of time.
  • This clinical data further shows that these therapeutic regimens can eliminate hepatitis C virus in patients previously shown to be refractory to conventional antiviral therapy. Consequently, the therapeutic regimens disclosed herein address a long-felt but unresolved need, specifically the need to optimize the dosing of interferon- ⁇ in a manner that overcomes problems associated with conventional therapeutic regimens.
  • interferon-a has potent antiviral activity but does not act directly on the virus or replication complex. Instead, interferon- ⁇ acts by inducing IFN-stimulated genes (ISGs), which establishes a non-virus specific antiviral state in the patient. For example, interferon- ⁇ is observed to generally promote memory T-cell proliferation, prevent T- cell apoptosis and stimulate natural-killer-cell activation and dendritic cell maturation.
  • ISGs IFN-stimulated genes
  • HBsAg clearance and seroconversion characterized by the loss of serum HBsAg with or without anti-HBs antibody development, are the main markers of a successful immunological response to HBV infection and the closest outcome to clinical cure.
  • HBsAg clearance is defined as the disappearance of HBsAg from the serum.
  • HBsAg seroconversion is defined as HBsAg disappearance and anti-HBs antibody appearance.
  • interferon-a e.g. non-pegylated interferon
  • interferon- ⁇ e.g. non-pegylated interferon
  • Embodiments of the invention involve the continuous subcutaneous administration of interferon- ⁇ in order to maintain in vivo concentrations of this therapeutic agent in patients infected with the hepatitis B virus above a critical efficacy threshold in vivo for a sustained period of time.
  • illustrative embodiments of the invention involve the continuous subcutaneous administration of interferon- ⁇ in order to maintain in vivo concentrations of this therapeutic agent above at least 100-700 pg/mL (e.g. 300 pg/mL) for at least 1 to at least 48 weeks.
  • the interferon- ⁇ concentrations e.g.
  • 100-700 pg/mL refer to non- pegylated embodiments of interferon- ⁇ 2a or interferon- ⁇ 2b (e.g. INTRO N® A made by the Schering Corporation).
  • the interferon- ⁇ can be pegylated.
  • equivalent concentrations can be calculated using art accepted methodologies, for example by calculating the ratio of specific activities and/ or molecular weights of: 1) non-pegylated interferon- ⁇ such as INTRON®A and 2) pegylated interferon- ⁇ such as Peglntron® and then using correlations from such analysis to determine appropriate concentrations of, for example, a pegylated interferon-a.
  • the surprising response observed in patients refractory to conventional therapy may result from interferon- ⁇ having a efficacy threshold that is: (1) met in only about 50% of patients treated according to conventional therapeutic regimens; and (2) met in a greater number of patients when administered via a continuous infusion apparatus so as to maintain circulating levels of interferon- ⁇ in the serum of the patient above a steady state concentration (e.g. at least 100-700 pg/mL) for a sustained period of time (e.g. at least 1 to 48 weeks).
  • a steady state concentration e.g. at least 100-700 pg/mL
  • a sustained period of time e.g. at least 1 to 48 weeks.
  • Example 2 Because the clinical trial disclosed herein comprises patients shown to be refractory to conventional HCV antiviral therapy, the data disclosed in Example 2 below and shown in associated Figures demonstrates the surprising efficacy of therapeutic regimens disclosed herein.
  • the continuous subcutaneous administration of interferon- ⁇ appears to contribute to the reduction of the number and/ or the severity of dose dependent side effects observed in patients administered interferon- ⁇ according to conventional therapeutic regimens, for example by continuously administering interferon- ⁇ in a manner that improves patient tolerance to doses of interferon- ⁇ (e.g. as compared to conventional therapeutic regimens that comprise, for example, thrice weekly or daily bolus injections of this cytokine).
  • interferon- ⁇ has does not act directly on the virus or replication complex and instead induces potent global antiviral activities.
  • interferon- ⁇ prevents immune exhaustion and enhances the adaptive immune response that is directed towards certain infectious agents including the hepatitis B virus.
  • One illustrative embodiment of the invention is a method of administering interferon- ⁇ to a patient infected with hepatitis B virus, the method comprising administering interferon- ⁇ to the patient subcutaneously using a continuous infusion apparatus, wherein the interferon- ⁇ is administered to the patient using a therapeutic regimen sufficient to maintain circulating levels of the interferon- ⁇ in the serum of the patient above a steady state concentration of at least 100 pg/mL for at least 1 to at least 48 weeks.
  • the therapeutic regimen used is sufficient to maintain circulating levels of the interferon- ⁇ in the serum of the patient above a steady state concentration of at least 100-700 pg/ mL.
  • the therapeutic regimen used is sufficient so that mean circulating levels of the interferon- ⁇ in the serum of the patient are above a steady state concentration of at least 100-700 pg/mL for a period of at least 1 to at least 48 weeks.
  • the mean circulating levels of the interferon- ⁇ in the serum of the patient comprise the average interferon- ⁇ serum concentration value of a set of interferon- ⁇ serum concentration values measured weekly during the course of therapy (or daily or bimonthly or monthly).
  • the therapeutic regimen used is sufficient so that median circulating levels of the interferon- ⁇ in the serum of the patient are above a steady state concentration of at least 100-700 pg/mL for a period of at least 1 to at least 48 weeks.
  • the median circulating levels of the interferon-a in the serum of the patient comprise the middle interferon- ⁇ serum concentration value from a set of interferon- ⁇ serum concentration values measured weekly during the course of therapy (or daily or bimonthly or monthly).
  • embodiments of the invention include personalized therapeutic regimens tailored to consider one or more characteristics specific to the patient and/or the virus infecting the patient.
  • Embodiments of the invention also include therapeutic regimens tailored to use therapeutic compositions selected to have certain properties (e.g. properties that control the bioavailability profile of a therapeutic agent in the composition).
  • One such embodiment is a method of subcutaneously administering an interferon-a to a patient using a continuous infusion apparatus where the patient is identified as being infected with hepatitis B virus having a specific genotype, for example genotype A, B ,C, D, E, F, G, or H.
  • the patient is examined in order to identify the presence or status of one or more HBV antigens (e.g. HBsAg or HBeAg) and/ or antibodies to one or more HBV antigens (e.g. anti-HBsAg, IgM anti-HBc or anti- HBeAg) prior to initiating the therapeutic regimen.
  • HBV antigens e.g. HBsAg or HBeAg
  • HBeAg HBsAg or HBeAg
  • anti-HBsAg, IgM anti-HBc or anti- HBeAg anti-HBsAg
  • Embodiments of the invention can further use selected compositions in the therapeutic regimens disclosed herein, for example interferon-a that has undergone a chemical modification process designed to modify one or more bioavailability characteristics, for example conjugation to a polyol (e.g. polyethylene glycol).
  • a polyol e.g. polyethylene glycol
  • embodiments of the invention can use interferon- ⁇ having a pharmacodynamic and pharmacokinetic profile that more closely mimic interferon- ⁇ as found in vivo (e.g. interferon- ⁇ not conjugated to a polyol) than the interferon species used in conventional HBV therapies (e.g. Pegasys, Peg-Intron etc.).
  • interferon species used in conventional HBV therapies e.g. Pegasys, Peg-Intron etc.
  • interferon- ⁇ is administered to the patient using a therapeutic regimen determined to be sufficient to maintain circulating levels of interferon-a in the serum of the patient above a steady state concentration of at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675 or 700 pg/mL for at least 1 to at least 48 weeks.
  • One illustrative embodiment of the invention that considers one or more characteristics specific to the patient, for example a patient's unique rate of exogenous interferon- ⁇ clearance or metabolism, is a method of administering an interferon- ⁇ to a patient infected with hepatitis B virus, the method comprising administering a test dose of interferon- ⁇ to the patient and then observing a concentration of circulating interferon- ⁇ in the serum of the patient that results from the dose of interferon- ⁇ .
  • the dose of interferon-a e.g. in a first therapeutic regimen for administering interferon- ⁇
  • the concentration of circulating interferon- ⁇ that results from the test dose is then used to design a patient-specific therapeutic regimen, one that considers patient specific factors and comprises administering interferon- ⁇ to the patient subcutaneously using a continuous infusion apparatus in an amount sufficient to maintain circulating levels of interferon- ⁇ in the serum of the patient above a specific in vivo concentration for a specific period of time, for example at least 100 pg/mL for at least 1 to at least 48 weeks.
  • the patient- specific therapeutic regimen is selected to: maintain serum interferon- ⁇ concentrations in the patient at a value greater than C crit , a concentration threshold that coordinates a patient's sustained response to a therapeutic regimen and/or maintain serum interferon-a concentrations in the patient at a value where the actual efficacy of interferon- ⁇ in the patient is greater than the critical efficacy of interferon- ⁇ and/ or maintain circulating levels of interferon- ⁇ in the serum of the patient above a steady state concentration of at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675 or 700 pg/mL
  • One specific illustrative embodiment of the invention is a method of administering an interferon-a to a patient infected with hepatitis B virus having genotype A, B, C, D, E, F, G, or H, the method comprising administering oral nucleoside/nucleotide inhibitor to the patient in combination with interferon- ⁇ 2a/2b administered subcutaneously using a continuous infusion apparatus, wherein: the patient is examined in order to identify the genotype of the virus and/ or the presence or status of one or more HBV antigens (e.g. HBsAg or HBeAg) and/ or antibodies to one or more HBV antigens (e.g.
  • HBV antigens e.g. HBsAg or HBeAg
  • antibodies to one or more HBV antigens e.g.
  • the interferon-a is not conjugated to a polyol
  • the interferon- ⁇ is administered to the patient using a therapeutic regimen sufficient to maintain circulating levels of interferon- ⁇ in the serum of the patient above a steady state concentration of at least 100-700 pg/mL for at least 1 to at least 48 weeks; and the therapeutic regimen reduces levels of HBV in the patient by at least 2 logs (100-fold).
  • Certain embodiments of the invention also comprise observing in vitro proliferation of T cells from the patient in response to exposure to interferon- ⁇ .
  • a number of assays of T cell proliferation in response to interferon- ⁇ are known in the art that can be adapted for such observations (see, e.g. Folgori et al., Gut, (2006) 55(7): 914-916).
  • Embodiments of the invention include systems for administering interferon- ⁇ to a patient having a hepatitis B infection.
  • the system can comprise for example: a continuous infusion pump having a medication reservoir comprising interferon- ⁇ ; a processor operably connected to the continuous infusion pump and comprising a set of instructions that causes the continuous infusion pump to administer the interferon- ⁇ to the patient according to a therapeutic regimen comprising administering interferon- ⁇ to the patient subcutaneously; wherein the therapeutic regimen is sufficient to maintain circulating levels of interferon- ⁇ in the serum of the patient above a steady state concentration of at least 100-700 pg/mL for at least 1 week to at least 48 weeks.
  • a related embodiment of the invention is a system for administering interferon-a to a patient having a hepatitis B infection, the system comprising: a continuous infusion pump having a medication reservoir comprising interferon- ⁇ ; a processor operably connected to the continuous infusion pump and comprising a set of instructions that causes the continuous infusion pump to administer the interferon- ⁇ to the patient.
  • the system administers interferon- ⁇ according to a patient-specific therapeutic regimen made by: administering interferon- ⁇ to the patient following a first therapeutic regimen; observing a concentration of circulating interferon- ⁇ in the blood of the patient that results from the first therapeutic regimen; and then using the concentration of circulating interferon- ⁇ observed to result from the first therapeutic regimen to make a patient- specific therapeutic regimen.
  • the patient specific therapeutic regimen comprises administering interferon- ⁇ to the patient subcutaneously in an amount sufficient to maintain circulating levels of interferon- ⁇ in the serum of the patient above a steady state concentration of at least 100-700 pg/ mL for at least 1 week to at least 48 weeks.
  • System embodiments of the invention can be designed for use where the hepatitis B virus is of a specific genotype, for example genotype A, B, C, D, E, F, G, or H.
  • the patient is examined in order to identify the genotype of the virus and/ or the presence or status of one or more HBV antigens (e.g. HBsAg or HBeAg) and/or antibodies to one or more HBV antigens (e.g. anti-HBsAg, IgM anti-HBc or anti-HBeAg) prior to administering the interferon- ⁇ (e.g. interferon-a that is not conjugated to a polyol).
  • HBV antigens e.g. HBsAg or HBeAg
  • antibodies to one or more HBV antigens e.g. anti-HBsAg, IgM anti-HBc or anti-HBeAg
  • interferon- ⁇ e.g. interferon-a that is not conjugated to a
  • the therapeutic regimen is sufficient to maintain circulating levels the interferon- ⁇ in the patient above a concentration of at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675 or 700 pg/mL
  • the therapeutic regimen is administered for a duration of at least at least 1 week to at least 48 weeks.
  • the therapeutic regimen is sufficient to reduce levels of HBV in the patient by at least 2 logs (100-fold) or 3 logs (1000 fold).
  • interferon-a e.g. non-pegylated interferon-a 2a
  • a continuous infusion apparatus e.g. subcutaneously
  • the interferon- ⁇ is administered to the patient using a therapeutic regimen sufficient to maintain circulating levels of the interferon- ⁇ in the serum of the patient above a mean steady state concentration of at least 100 pg/mL (or at least 200, 300, 400, 500, 600 or 700 pg/mL) for at least four weeks (or at least 5, 6, 7, 8, 12, 24, 36 or 48 weeks).
  • the interferon- ⁇ is used in a method of administering interferon- ⁇ to a patient infected with hepatitis B virus in combination with an antiviral nucleotide/ nucleoside analog.
  • a related embodiment comprises interferon- ⁇ for use in a method of administering an interferon- ⁇ to a patient infected with hepatitis B virus (HBV), the method comprising administering a test dose of interferon- ⁇ to the patient (e.g.
  • HBV hepatitis B virus
  • the patient specific therapeutic regimen comprises administering interferon- ⁇ to the patient subcutaneously using a continuous infusion apparatus in an amount sufficient to maintain circulating levels of interferon- ⁇ in the serum of the patient above a steady state concentration of at least 100 pg/mL.
  • This use can further comprise, for example steps such as: identifying the hepatitis B virus as being a genotype A or a genotype D virus; observing in vitro proliferation of T cells from the patient in response to exposure to interferon- ⁇ ; and/ or administering interferon- ⁇ to the patient using a patient-specific therapeutic regimen sufficient to maintain circulating levels of interferon- ⁇ in the serum of the patient above a steady state concentration of at least 200, 300, 400, 500, 600 or 700 pg/ mL for at least 4 weeks.
  • Embodiments of the invention also include a system for administering interferon to a patient having a hepatitis B infection, the system comprising a continuous infusion pump having a medication reservoir comprising interferon- ⁇ ; a processor operably connected to the continuous infusion pump and comprising a set of instructions that causes the continuous infusion pump to administer the interferon- ⁇ to the patient according to a therapeutic regimen comprising administering interferon- ⁇ to the patient subcutaneously; wherein the therapeutic regimen is sufficient to maintain circulating levels of interferon- ⁇ in the serum of the patient above a steady state concentration of at least 100 pg/mL for at least 4 weeks.
  • the processor in the system is used to modulate a parameter of the patient-specific therapeutic regimen using determined polynucleotide sequence information, wherein the parameter comprises a duration of interferon- ⁇ administration; or an interferon- ⁇ dose.
  • Yet another embodiment of the invention comprises the use of interferon- ⁇ in the manufacture of a composition for treating hepatitis B infection for use in a continuous infusion apparatus, wherein the interferon- ⁇ composition is manufactured to allow the continuous infusion apparatus to maintain circulating levels of interferon- ⁇ in serum of a patient above a steady state concentration of at least 100 pg/mL for at least 24, 48, 72, 96, 120, 144 or 168 hours (and/or from at least 1 week to at least 48 weeks) when administered subcutaneously.
  • the interferon- ⁇ composition is used in a patient for at least 5, 6, 7, 8, 12, 24, 36 or 48 weeks to maintain circulating levels of the interferon- alpha in a patient above a mean steady state concentration threshold of at least 100, 200, 300, 400, 500, 600 or 700 pg/mL.
  • the interferon- ⁇ is not conjugated to a polyol.
  • the interferon- ⁇ is used in a patient identified as having a single nucleotide polymorphism (SNP) associated with chronic HBV infection, wherein the SNP is selected from the group consisting of rs2856718, rs7453920, rs3077, rs9277535, rs2284553, rs9808753 or rsl7401966.
  • SNP single nucleotide polymorphism
  • the interferon- ⁇ is used in a patient infected with a hepatitis B genotype A or a genotype D virus.
  • use of the interferon-a reduces levels of HBV in a patient by at least 2 logs (100-fold) or 3 logs (1000 fold) after 1, 2, 4, 8 10, 12, 14 or 16 weeks.
  • the continuous infusion apparatus is designed for ambulatory use and for example has dimensions smaller than 15 x 15 centimeters (and typically smaller than 15 x 15 x 5 centimeters) and/or is operably coupled to an interface that facilitates the patient's movements while using the continuous infusion pump, wherein the interface comprises a clip, a strap, a snap, a clamp or an adhesive strip.
  • embodiments of the invention are designed to maintain circulating levels of interferon- ⁇ in the serum of the patient above a target steady state concentration (e.g. at least 100-700 pg/mL) so as to increase the efficacy of this polypeptide.
  • a target steady state concentration e.g. at least 100-700 pg/mL
  • steady state is used herein to describe situations in which a variable (e.g. the concentration of circulating interferon- ⁇ that results from a therapeutic regimen) remains above a set threshold and/ or essentially constant in spite of ongoing processes that strive to change them (e.g. in vivo clearance of exogenous interferon- ⁇ by the liver and kidneys).
  • a steady state is typically reached when the rate of elimination approximates the rate of administration.
  • a related embodiment of the invention is a method of administering an interferon- ⁇ to a patient infected with hepatitis B virus, the method comprising administering interferon- ⁇ to the patient subcutaneously using a continuous infusion apparatus, wherein the therapeutic regimen is sufficient to maintain circulating levels of interferon- ⁇ in the serum of the patient above a target concentration (e.g. 100-700 pg/mL).
  • a target concentration e.g. 100-700 pg/mL
  • Such embodiments of the invention can be used to administer interferon- ⁇ for a period of at least 1 week to at least 48 weeks.
  • Some embodiments of the invention include methods for obtaining patient- specific regimen responsiveness profiles based upon individualized patient factors such as infection parameters (e.g. hepatitis B viral load) and therapeutic agent responsiveness parameters (e.g. in vivo concentrations of interferon-a that result from its administration to the patient) and then using the regimen responsiveness profiles to design optimized therapeutic regimens for patients suffering from pathological conditions (e.g. Hepatitis B infections).
  • such methods comprise determining patient- specific pharmacokinetic (pK) and pharmacodynamic (pD) parameters (e.g. the concentration of circulating of interferon- ⁇ in vivo that results from a specific dose being administered to that patient) and then utilizing these parameters to design new therapeutic regimens.
  • the invention provides a computer implemented system for: (1) delivering interferon- ⁇ according to an initial dosing parameter (e.g. one disclosed in the Examples below); and/or (2) constructing patient- specific regimen responsiveness profiles based upon a patient's response to the initial dosing parameters; and/ or (3) delivering therapeutic agent(s) using optimized therapeutic regimens designed in response to such profiles (e.g. regimens that comprise variations of initial dosing parameters).
  • an initial dosing parameter e.g. one disclosed in the Examples below
  • constructing patient- specific regimen responsiveness profiles based upon a patient's response to the initial dosing parameters
  • therapeutic agent(s) using optimized therapeutic regimens designed in response to such profiles e.g. regimens that comprise variations of initial dosing parameters.
  • a patient is administered interferon-a following a set of initial dosing parameters (e.g. those disclosed in the Example below) and the levels of circulating interferon- ⁇ in vivo that result from this set of initial dosing parameters are then observed.
  • the levels of circulating interferon-a in vivo observed in the individual patient are then used to construct one or more further dosing parameters, for example those designed to modulate levels of circulating interferon- ⁇ in vivo in that specific patient for some period of time during the course of therapy (e.g. to increase concentrations of circulating interferon- ⁇ above a target threshold).
  • therapeutic modelling parameters such as those disclosed in International Application Numbers PCT/US2008/078843 and PCT/US2009/038617, the contents of which are incorporated by reference.
  • One illustrative embodiment of the invention is a method of using a patient- specific regimen responsiveness profile obtained from a patient infected with hepatitis B virus to design a patient-specific therapeutic regimen such as those disclosed in the Examples below.
  • Embodiments of this method comprise administering at least one therapeutic agent (e.g. interferon-a) to the patient as a test dose (optionally a dose that is part of a first therapeutic regimen) and then obtaining pharmacokinetic or pharmacodynamic parameters from the patient in order to observe a patient- specific response to the test dose.
  • at least one therapeutic agent e.g. interferon-a
  • pharmacokinetic or pharmacodynamic parameters observed comprise a concentration of the therapeutic agent in the blood of the patient that results from the test dose and/ or a concentration of hepatitis B virus present in the patient.
  • practitioners can then use the pharmacokinetic or pharmacodynamic parameters observed in the patient in response to the test dose (e.g. the concentration of circulating of interferon- ⁇ in vivo that results from a specific dose being administered to that patient) to obtain a patient-specific regimen responsiveness profile.
  • This patient-specific regimen responsiveness profile is based upon an HBV infected patient's individualized physiology and necessarily takes into account a variety of host factors such as ethnicity, obesity, insulin resistance, hepatic fibrosis as well as viral factors such as genotype and baseline viral load.
  • This patient-specific regimen responsiveness profile is then used to design a patient-specific therapeutic regimen (e.g. one comprising administering interferon- ⁇ to the patient subcutaneously in an amount sufficient to maintain circulating levels of interferon- ⁇ in the serum of the patient above a steady state concentration of at least 100-700 pg/ mL for at least 1 week to at least 48 weeks).
  • a therapeutic regimen is selected to control serum interferon- ⁇ concentrations in the patient.
  • a therapeutic regimen is selected to maintain serum interferon-a concentrations in a patient at a value greater than a critical concentration "C crit " that is associated with therapeutic efficacy, i.e. a concentration threshold that induces and/or facilitates a patient's sustained response to a therapeutic regimen.
  • C crit critical concentration
  • the term critical concentration "C crit" is used according to its art accepted meaning of: the concentration of a substance (e.g. the concentration of circulating exogenous interferon-a) at and above which functional changes occur in a cell or an organ (see, e.g. Nordberg et al., Pure Appl.
  • C crit parameter information can be obtained using assessments of a patient or a group of patients' response to one or more predefined therapeutic regimens (e.g. 6 MlU/day, 9 MlU/day and 12 MlU/day as disclosed in Example 2).
  • C crit parameter information may be determined empirically and can, for example, consider the pharmacokinetics/pharamacodynamics of the interferon used as well as patient specific factors that can influence this threshold (e.g. the HBV genotype(s) infecting the patient, and/or a patient's weight, treatment history, health status and the like).
  • the patient-specific therapeutic regimen is designed to maintain plasma interferon- ⁇ levels in the patient above a set-point, e.g. above a concentration of at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675 or 700 pg/mL
  • the patient-specific therapeutic regimen is selected to modulate interferon- ⁇ concentrations in the patient so as to reduce dose-dependent side effects observed during the administration of interferon- ⁇ .
  • the patient-specific therapeutic regimen is selected to maintain serum interferon-a concentrations in the patient at a value where the actual efficacy of interferon- ⁇ in the patient is greater than the critical efficacy of interferon- ⁇ .
  • the patient-specific therapeutic regimen is selected to modulate interferon- ⁇ concentrations in the patient so that the patient is administered different interferon-a dosing regimens during different phases of hepatitis B viral load decline.
  • measurements of phenomena such as the in vivo levels of an administered agent, the actual efficacy and limits of critical efficacy of such agents, as well as the in vivo levels of HBV are determined.
  • determinations are made 0, 1, 2, 3, 4, 6, or 7 days (e.g. week 1) after the administration of a therapeutic regimen and/or any day of weeks 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 etc. up to for example week 48.
  • Certain embodiments of the methods and systems of the invention comprise the administration of interferon-a in a therapeutic regimen that lasts for more than 48 weeks, for example, ones where the therapeutic regimen is administered for 50, 54, 58, 62, 66, 70 or 72 weeks.
  • patients can return for safety and efficacy evaluations on a weekly basis up to week 4 and every 28 days thereafter throughout a 48 week treatment duration, with weekly or monthly follow-up visits up to week 72.
  • determinations of actual efficacy and limits of critical efficacy occur between 0 and 7 days, and more preferably around between 0 to 2 days.
  • this determination may be made intermittently throughout therapy, to take into account for example individualized patient response to various therapeutic regimens.
  • pharmacokinetic, pharmacodynamic, and viral kinetic models such as those described herein may be used to achieve this.
  • parameters relating to HBV infection and/or parameters relating to therapeutic regimens for treating HBV infection are examined before the initiation of a therapeutic regimen and/or at one or more times during the administration of a therapeutic regimen and/or after the conclusion of a therapeutic regimen.
  • Such parameters include for example baseline viral load as well as other parameters associated with Hepatitis B infection such as, liver fibrosis or cirrhosis, and/or the presence of serum markers such as alanine transaminase (ALT).
  • Such parameters further include biochemical markers that are induced in response to interferon- ⁇ (e.g.
  • interferon-a administered according to a therapeutic regimen such as neopterin and 2',5'-oligoadenylate synthetase (OAS).
  • a therapeutic regimen such as neopterin and 2',5'-oligoadenylate synthetase (OAS).
  • exemplary embodiments of the invention that comprise the observation of one or more parameters relating to HBV infection and/ or parameters relating to therapeutic regimens for treating HBV infection include methods and/ or systems for administering interferon-a to a patient infected with hepatitis B virus that are sufficient to increase levels of neopterin by at least 10, 20, 30, 40 or 50% as compared to pretreatment levels.
  • the therapeutic regimen is sufficient to increase levels of neopterin by at least 1, 2, 3, or 4 ng/mL (see, e.g. Figure 1).
  • a method and/or system for administering interferon-a to a patient infected with hepatitis B virus uses a therapeutic regimen sufficient to increase levels of 2',5' oligo-adenylate synthetase by at least 2, 4, 6, 8 or 10-fold as compared to pretreatment levels.
  • the therapeutic regimen is sufficient to increase levels of 2',5' oligo-adenylate synthetase by at least 25, 50, 75 or 100 pg/ dL.
  • neopterin tests include those offered by Quest laboratories Teterboro, New Jersey, test number 97402P and HENNING test, BRAHMS Diagnostica GmbH, D- 12064, Berlin, Germany. Methods and materials used in the measurement of 2', 5' oligo- adenylate synthetase are described for example in Podevin et al., J Hepatol. 1997 (2):265- 71). Methods and materials used in the measurement of beta-2-microglobulin are described for example in Malaquarnera Eur J Gastroenterol Hepatol. 2000 Aug;12(8):937-9.
  • ALT serum alanine aminotransferase
  • a therapeutic regimen disclosed herein reduces ALT levels to less than about 200 IU/L, less than about 150 IU/L, less than about 125 IU/L, less than about 100 IU/L, less than about 90 IU/L, less than about 80 IU/L, less than about 60 IU/L, or less than about 40 IU/L.
  • Certain embodiments of the invention comprises a method and/ or system for administering interferon- ⁇ to a patient infected with hepatitis B virus sufficient to decrease levels of alanine transaminase (ALT) by at least 2, 3, 4 or 5-fold as compared to pretreatment levels.
  • the therapeutic regimen is sufficient to decrease levels of alanine transaminase by at least 25, 50, 75 or 100 IU/L.
  • embodiments of the invention can examine for example, levels of neopterin and/ or 2',5' oligo-adenylate synthetase and/ or ALT in a patient as well as the other markers disclosed herein and/ or known in the art to, for example, examine the pretreatment status of a patient and/ or assess the course of a therapeutic regimen and/ or design patient specific therapeutic regimens.
  • Embodiments of the invention can also examine a combination of these parameters and/ or additional parameters such as a level of beta-2 -microglobulin in plasma of the patient; a genotype or subtype of the hepatitis B virus; a patient's prior medical treatment history; and/ or a presence or degree of a side effect that results from the first therapeutic regimen and/or the presence of serum markers associated with liver fibrosis.
  • Serum markers of liver fibrosis further include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin.
  • Additional biochemical markers of liver fibrosis include ⁇ -2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.
  • Methods and materials used in the measurement of depression are well known in the art (e.g. the Beck Depression Inventory) and are described for example in Golub et al., J Urban Health. 2004 Jun;81 (2):278-90).
  • Methods and materials used in the measurement of neutropenia and thrombocytopenia are well known in the art and described for example in Koskinas et al., Med Virol.
  • embodiments of the invention provide technical advantages in this art by eliminating HBV in a greater number of infected individuals than possible using conventional therapeutic regimens.
  • Other technical advantages of embodiments of the invention include, for example, the reduction or elimination of detrimental side effects that can result from the interferon-a administered according to conventional therapeutic regimens.
  • the continuous infusion of interferon-a allows this cytokine to reach high circulating concentrations in vivo while concurrently reducing or eliminating the adverse immunological and/or hematological reactions that can occur for example when this cytokine is administered in a bolus (e.g. a bolus of interferon- ⁇ that is administered 3 times a week etc.).
  • a bolus of interferon- ⁇ e.g. a bolus of interferon- ⁇ that is administered 3 times a week etc.
  • embodiments of the invention include the administration of a dose of interferon- ⁇ to a patient using a continuous infusion apparatus in order to reduce or eliminate the incidence of neutropenia, and/or thrombocytopenia and/ or the induction of autoimmune diseases that are observed when this cytokine is administered in a bolus (e.g.
  • Exemplary embodiments of the invention include the administration of a dose of interferon- ⁇ to a patient using a continuous infusion apparatus so as to reduce or eliminate the incidence of adverse immunological and/ or hematological reactions such as neutropenia, and/ or thrombocytopenia and/ or the induction of autoimmune diseases (e.g. thyroiditis) by at least 10, 20, 30, 40 or 50% as compared to therapeutic regimens where this cytokine is administered in a bolus.
  • adverse immunological and/ or hematological reactions such as neutropenia, and/ or thrombocytopenia and/ or the induction of autoimmune diseases (e.g. thyroiditis)
  • a therapeutic regimen e.g. one disclosed in Example 1 or 2 below
  • practitioners can then obtain a patient-specific regimen responsiveness profile that results from the administration of this therapeutic regimen.
  • the patient-specific regimen responsiveness profiles can then be used to design further patient-specific therapeutic regimens.
  • certain embodiments of the invention comprise obtaining pharmacokinetic or pharmacodynamic parameters from the patient so as to observe a patient-specific response to a first therapeutic regimen as discussed above, wherein the pharmacokinetic or pharmacodynamic parameters comprise at least one of: a concentration of administered interferon-a in the plasma of the patient; or a concentration of hepatitis B virus in the plasma of the patient; using the pharmacokinetic or pharmacodynamic parameters observed in the patient in response to the first patient- specific therapeutic regimen to obtain a second patient-specific regimen responsiveness profile; and using the second patient-specific regimen responsiveness profile to design a second (or third or fourth etc.) patient-specific therapeutic regimen.
  • a concentration of administered interferon-a in the plasma of the patient or a concentration of hepatitis B virus in the plasma of the patient
  • using the pharmacokinetic or pharmacodynamic parameters observed in the patient in response to the first patient- specific therapeutic regimen to obtain a second patient-specific regimen responsiveness profile
  • the second patient-specific regimen responsiveness profile to
  • the computer is operatively coupled to an infusion pump that delivers interferon-a to a patient according to instructions provided by the computer.
  • the systems include a controller programmed with mathematical models representing a viral response in a patient receiving a therapeutic regimen and programmed to regulate the dosing rate of therapeutic agent based on the models and the measurements of clinical parameters (e.g. in vivo concentrations of an administered therapeutic agent or viral load).
  • the controller program is use to modulate the dose of interferon- ⁇ administered to the patient, the interferon- ⁇ administration profile, the duration of interferon- ⁇ administration or the like.
  • One such embodiment of the invention is a method of administering interferon-a to a patient suffering from a Hepatitis B infection, the method comprising: administering interferon- ⁇ to the patient following a first therapeutic regimen; obtaining pharmacokinetic or pharmacodynamic parameters from the patient to observe a patient- specific response to the first therapeutic regimen wherein the parameters comprise a concentration of interferon- ⁇ in the blood of the patient that results from the first therapeutic regimen; or a concentration of hepatitis B virus present in the patient.
  • the pharmacokinetic or pharmacodynamic parameters so observed in the patient in response to the first therapeutic regimen are then used to design a patient- specific therapeutic regimen; one which can, for example, be programmed into a controller that operably coupled to a continuous infusion pump.
  • the continuous infusion pump having this program can then be used to administer interferon-a to the patient according to the controller programming, programming that, for example, controls one or more aspects of an administration profile (e.g. the timing of the administration, the rate of administration etc.
  • embodiments of the invention include systems such as those that comprise computer processors and the like coupled to a medication infusion pump and adapted to deliver interferon- ⁇ according to a specific therapeutic regimen.
  • these systems comprise one or more control mechanisms designed to modulate delivery of interferon- ⁇ , for example those that allow its delivery according to a predetermined infusion profile.
  • a processor is programmed to control a therapeutic regimen that includes an infusion profile designed to take into account one or more characteristics of the patient (e.g. weight) and/or one or more characteristics of the hepatitis virus infecting the patient (e.g. genotype) and/or one or more characteristics of the therapeutic agent administered to the patient (e.g. the presence or absence of a polyethylene glycol moiety).
  • such profiles are selected from a plurality of predetermined infusion profiles that are stored in the computer system.
  • a system comprising one or more computer processors is coupled to a medication infusion pump in order to administer a therapeutic regimen designed in accordance with the total interferon- ⁇ per kilogram and/or total interferon- ⁇ per day that is administered to the patient.
  • a system administers a therapeutic regimen designed to consider the weight and/or body-mass index (BMI) of the patient (e.g. to increase or, alternatively, decrease the dose or duration of interferon- ⁇ administered in accordance with a patient's current weight).
  • BMI body-mass index
  • a therapeutic regimen designed to consider the weight of the patient can consider selecting a weight-based dose of continuously administered interferon- ⁇ (e.g.
  • INTRON A 80 klU/kg/day, or alternatively 120 klU/kg/day, or alternatively 160 klU/kg/day.
  • a system administers a therapeutic regimen designed to consider the past and/ or current viral load observed in the patient (e.g. to increase or, alternatively, decrease the dose or duration of interferon-a administered in accordance with the patient's current viral load).
  • a system administers a therapeutic regimen designed to consider the specific genotype of the hepatitis virus that infects the patient (e.g. to increase or, alternatively, decrease the dose or duration of interferon- ⁇ administered in accordance with the patient's HBV genotype).
  • a system administers a therapeutic regimen designed to consider the presence and/or past or current levels of serum markers such as alanine transaminase, neopterin, 2', 5'- oligoadenylate synthetase and the like in the patient (e.g. to increase or, alternatively, decrease the dose or duration of interferon- ⁇ administered in accordance with the patient's past and/or current levels of serum markers).
  • the therapeutic regimen may be based on a single factor, e.g., the patient's weight only. In other embodiments, therapeutic regimen is based upon multiple factors.
  • the controller is programmed so that the continuous infusion pump administers interferon- ⁇ in a manner that: maintains serum interferon- ⁇ concentrations in the patient at a value greater than C crit , a concentration threshold that coordinates a patient's sustained response to a therapeutic regimen; maintains serum interferon- ⁇ concentrations in the patient at a value where the actual efficacy of interferon- ⁇ in the patient is greater than the critical efficacy of interferon- ⁇ ; modulates interferon- ⁇ concentrations in the patient so that the patient is administered different interferon- ⁇ dosing regimens during different phases of hepatitis B viral load decline; modulates interferon- ⁇ concentrations in the patient so that a difference between the actual efficacy of interferon- ⁇ and the critical efficacy of interferon- ⁇ in the patient is increased; or modulates interferon- ⁇ concentrations in the patient so as to reduce adverse side effects observed during the administration of interferon- ⁇ .
  • the controller is operatively coupled to the continuous infusion pump and programmed so that the pump administers interferon-a to a patient infected with HBV according to a therapeutic regimen in a manner that: maintains serum interferon- ⁇ concentrations in the patient at a value less than a EC 50 a concentration at which the effectiveness of interferon- ⁇ is 50% of its maximum.
  • the controller is operatively coupled to the continuous infusion pump and programmed so that the pump administers interferon- ⁇ at a dose and for a period of time (e.g. at least 1 to at least 48 weeks) selected to maintain a plasma interferon- ⁇ concentration above a set-point (e.g.
  • the therapeutic regimen further comprises administering a nucleoside analog that interferes with Hepatitis B viral replication (e.g. a nucleoside analog such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disproxil).
  • a nucleoside analog such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disproxil.
  • the system for administering interferon- ⁇ is coupled to an electronic system for managing medical data on an electronic communication network.
  • an electronic system for managing medical data on an electronic communication network.
  • one such electronic system can comprise at least one electronic server connectable for communication on the communication network, the at least one electronic server being configured for: receiving a first physiological parameter observed in a patient (e.g. a patient's viral load or a patient's serum concentration of interferon- ⁇ ) setting a test dose of the interferon- ⁇ for infusion by the continuous infusion pump (e.g.
  • Yet another embodiment of the invention is a program code storage device, comprising: a computer-readable medium; a computer-readable program code, stored on the computer-readable medium, the computer-readable program code having instructions, which when executed cause a controller operably coupled to a medication infusion pump to administer the interferon-a to a patient infected with the hepatitis B virus according to a patient- specific therapeutic regimen made by: administering interferon-a to the patient following a first therapeutic regimen obtaining pharmacokinetic or pharmacodynamic parameters from the patient so as to observe a patient-specific response to the first therapeutic regimen wherein the pharmacokinetic or pharmacodynamic parameters comprise at least one of: a concentration of interferon-a in the blood of the patient that results from the first therapeutic regimen; or a concentration of hepatitis B virus present in the patient; using the pharmacokinetic or pharmacodynamic parameters observed in the patient in response to the first therapeutic regimen to obtain a patient-specific regimen responsiveness profile; and then using the patient-specific regimen responsiveness profile to
  • the methods of the invention can be practiced on a wide variety of individuals infected with HBV including those previously treated for HBV infection or having a specific HBV strain.
  • some embodiments of the invention include the step of selecting the patient for treatment by identifying them as one previously treated with a course of interferon- ⁇ therapy, wherein the previous course interferon- ⁇ therapy was observed to be ineffective to treat one or more symptoms associated with the HBV infection.
  • Other embodiments of the invention include the step of selecting the patient for treatment by identifying the patient as one infected with a specific HBV genotype, for example one infected with Genotype A, B, C, D, E, F, G, or H.
  • Hepatitis B virus is a species of the genus Orthohepadnavirus, which is likewise a part of the Hepadnavmdae family of viruses. There are eight known genotypes labeled A through H and a number of subtypes of these genotypes. Different genotypes may respond to treatment in different ways (see, e.g. Palumbo E (2007). "Hepatitis B genotypes and response to antiviral therapy: a review”. Am J Ther 14 (3): 306-9; and Mahtab MA, Rahman S, Khan M, Karim F (October 2008). "Hepatitis B virus genotypes: an overview”. Hbpd Int 7 (5): 457-64. PMID 18842489.
  • HBV genotypes have different polynucleotide sequences and have distinct geographical distributions.
  • Type A is prevalent in Europe, Africa and South-east Asia, including the Philippines.
  • Type B and C are predominant in Asia; type D is common in the Mediterranean area, the Middle East and India; type E is localized in sub-Saharan Africa; type F (or H) is restricted to Central and South America.
  • Type G has been found in France and Germany. Genotypes A, D and F are predominant in Brazil and all genotypes occur in the United States with frequencies dependent on ethnicity.
  • a person suffering from chronic hepatitis B infection may exhibit one or more of the following signs or symptoms which can be examined (typically in addition to other factors) in order to obtain a patient-specific profile: (a) elevated serum alanine aminotransferase (ALT), (b) positive test for anti-HBV antibodies, (c) presence of HBV as demonstrated by a positive test for HBV-RNA, (d) clinical stigmata of chronic liver disease, (e) hepatocellular damage.
  • ALT serum alanine aminotransferase
  • HBV-RNA positive test for anti-HBV antibodies
  • HBV-RNA a positive test for HBV-RNA
  • Such criteria may not only be used to diagnose hepatitis B, but can be used to evaluate a patient's response to drug treatment.
  • certain embodiments of the invention include the step of monitoring the HBV viral load in a subject and to adjust the therapeutic regimen based upon the observed result.
  • whether a particular method or methodological step e.g. a specific regimen
  • one can measure another parameter associated with HBV infection including, but not limited to, liver fibrosis.
  • Viral load can be measured by a variety of procedures known in the art, for example, by measuring the titer or level of virus in serum. These methods include, but are not limited to, a quantitative polymerase chain reaction (PCR) and/or a branched DNA (bDNA) test. Many such assays are available commercially, including a quantitative reverse transcription PCR (RT-PCR).
  • PCR polymerase chain reaction
  • bDNA branched DNA test.
  • RT-PCR quantitative reverse transcription PCR
  • a therapeutic agent such as interferon-a and/ or a small molecule inhibitor such as a nucleoside analog such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disproxil and the response to such agents is then observed by monitoring changes in the levels of HBV-RNA or HBV-DNA that are detectable in vivo.
  • a therapeutic regimen will reduce this number so that there is no longer any detectable HBV-DNA.
  • liver fibrosis reduction is determined by analyzing a liver biopsy sample.
  • An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by "grade” as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by "stage” as being reflective of long-term disease progression. See, e.g., Brunt (2000) Hepatol.
  • METAVIR Hepatology 20:15-20, the contents of which are incorporated by reference. Based on analysis of the liver biopsy, a score is assigned.
  • Another alternative but indirect method of determining viral load is by measuring the level of serum antibody to HBV.
  • Methods of measuring serum antibody to HBV are standard in the art and include enzyme immunoassays, and recombinant immunoblot assays, both of which involve detection of antibody to HBV by contacting a serum sample with one or more HBV antigens, and detecting any antibody binding to the HBV antigens using an enzyme labeled secondary antibody (e.g., goat anti-human IgG).
  • an enzyme labeled secondary antibody e.g., goat anti-human IgG
  • Embodiments of the invention can use a wide variety of therapeutic agents known in the art to both construct patient-specific profiles and then deliver therapeutic agent(s) using optimized regimens based upon these profiles.
  • Typical embodiments of the methods disclosed herein include the administration of interferon-a (also termed "interferon-alpha") to an individual infected with HBV.
  • Such embodiments of the invention optimize regimens for treating HBV infection using a nucleoside/nucleotide analog such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disproxil and an interferon-a treatments that are well known in the art.
  • a nucleoside/nucleotide analog such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disproxil and an interferon-a treatments that are well known in the art.
  • interferon- alpha (interferon-a) as used herein means the highly homologous cytokine polypeptides that inhibit viral replication and cellular proliferation and modulate immune response.
  • interferon- ⁇ includes human interferon- ⁇ 2a and 2b (collectively designated herein “interferon- ⁇ 2a/2b”), almost identical interferon- ⁇ polypeptides that bind to the same specific cell surface receptor complex known as the IFN-a receptor (IFNAR) and which differ by only a single basic amino acid (lysine versus arginine). Due to their extreme similarity, medical practitioners can use either interferon- ⁇ 2a or interferon- ⁇ 2b in combination with a nucleoside analog such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disproxil to treat HBV infection.
  • a nucleoside analog such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disproxil to treat HBV infection.
  • Interferon-alphas include, but are not limited to, recombinant interferon alfa-2b such as Intron-A interferon available from Schering Corporation, Kenilworth, N.J., recombinant interferon alfa-2a such as Roferon interferon available from Hoffmann-La Roche, Nutley, N.J., recombinant interferon-a2c such as Berofor alpha 2 interferon available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn., interferon alpha-nl , a purified blend of natural alpha interferons such as Sumiferon available from Sumitomo, Japan or as Wellferon interferon alpha-nl (INS) available from the Glaxo- Welicome Ltd., London, Great Britain, or a consensus alpha interferon such as those described in U.S.
  • recombinant interferon alfa-2b such as Intron-A interferon available from Schering Corporation, Ken
  • interferons available on the market include, but are not limited to alpha interferons ((IFN-oc): Roferon®-A, Intron®-A; consensus IFN: Infergen®, and the like)); and beta interferons ((IFN-Ps): Betaseron®, Rebif®, Avonex®, Cinnovex® and Berlex)).
  • IFN-oc alpha interferons
  • IFN-Ps beta interferons
  • Pegylated interferon- alpha-2b was approved in January 2001 and pegylated interferon-alpha-2a was approved in October 2002.
  • Examples of commercially available pegylated interferons include, but are not limited to, PEGASYS®, PegIntron tm and Reiferon Retard®.
  • Intron-a interferon-a 2b, Schering Plough
  • Roferon interferon-a 2a, Roche
  • Infergen interferon- ⁇ consensus, Valeant
  • Peg-Intron interferon- ⁇ 2b pegylated with a 12kD PEG (polyethylene glycol), Schering Plough
  • Pegylation of the interferon- ⁇ leads to a molecule with reduced biological activity but a greatly increased circulating half -life in-vivo.
  • Peg-Intron is labeled for weight based dosing with a single weekly injection.
  • Peg-intron is only labeled for naive patients.
  • the half -life of Peg-Intron is about 48 hours, so plasma levels of interferon- ⁇ are essentially zero by the end of day 7 following bolus injection.
  • Pegasys (interferon- ⁇ 2a pegylated with a 40kD PEG, Roche) was the second pegylated interferon- ⁇ approved for clinical use. In contrast to Peg-Intron, Pegasys is typically delivered at the same dose for all patients. Like Peg-Intron, Pegasys is only indicated for interferon- ⁇ naive patients. The pharmacokinetics of Pegasys are considerably different than Peg-intron due to the larger molecular weight of the PEG attached to the interferon- ⁇ . The circulating half-life of Pegasys is about 3 weeks, which might have considerable safety implications in the case of overdosing but does not allow for significantly reduced trough levels in the plasma.
  • interferon- ⁇ conjugates can be prepared by coupling an interferon alpha to a variety of water-soluble polymers.
  • polymers include polyethylene and polyalkylene oxide homopolymers such as polypropylene glycols, polyoxyethylenated polyols, copolymers thereof and block copolymers thereof.
  • the typical poly ethylene-glycol-interferon alfa-2b conjugate is PEG 12000 -interferon alpha 2b.
  • the phrases "12,000 molecular weight polyethylene glycol conjugated interferon alpha" and "PEG 1200 o-IFN alpha" as used herein mean conjugates such as are prepared according to the methods of International Application No. WO 95/ 13090 and containing urethane linkages between the interferon alfa-2a or -2b amino groups and polyethylene glycol having an average molecular weight of 12000.
  • an interferon-a administered in one or more sequential phases of a therapeutic regimen is not conjugated to a polyol.
  • the interferon- ⁇ so administered comprises two interferon- ⁇ species: a first interferon- ⁇ species that is conjugated to a polyol; and a second interferon- ⁇ species that is not conjugated to a polyol.
  • different species of interferon- ⁇ are administered in one or more of the different sequential phases of the invention.
  • the supply of interferon- ⁇ in the pump may last for an extended period of time. Because the loadable amount of interferon- ⁇ is fixed by the drug reservoir volume, to increase the amount of time the interferon- ⁇ supply may last, potency of interferon, as well as concentration of interferon- ⁇ may be increased. Accordingly, in some embodiments, the interferon-a may comprise a highly potent interferon.
  • highly potent means an interferon- ⁇ that may exhibit favorable characteristics such as antiviral activity, antiproliferative activity, efficacy in clearing hepatitis virus from cells, increased ratio of antiviral activity to antiproliferative activity, or increased ratio of T h l differentiation activity to antiproliferative activity. Due to these characteristics, less volume of interferon- ⁇ is required to cause the same therapeutic effect on the patient, and thus highly potent interferon- ⁇ formulation may be administered at a lower flow rate. Alternatively, a highly soluble interferon- ⁇ may be used to prepare formulations with increased concentration of interferon, which can also be administered at a lower flow rate.
  • the term "highly soluble” means interferon-a with a solubility of between at least 5 mg/ mL to at least 10 mg/ mL
  • the interferon- ⁇ concentration may be at least 10 MIU/mL, 20 MIU/mL, 30 MIU/mL, 40 MIU/mL, 50 MIU/mL, 60 MIU/mL, 70 MIU/mL, 80 MIU/mL, 90 MIU/mL, 100 MIU/mL, 125 MIU/mL, 150 MIU/mL, 175 MIU/mL, 200 MIU/mL and 225 MIU/mL to at least 1500 MIU/mL
  • the interferon- ⁇ concentration is at least 25 MIU/ mL
  • the therapeutic regimen(s) e.g. the therapeutic agent(s), the dosage amount(s), dosage period(s), dosage schedule(s), dosage route(s), and so on, for agents such as interferon- ⁇ and/or a nucleoside analog such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disproxil, encompass those generally used in the art to administer these agents in a manner that typically produces an improvement in one or more physiological conditions associated with a chronic hepatitis B infection.
  • a variety of therapeutic regimens known in the art can be employed in and/or adapted to the methods of the invention (e.g. those described in United States Patent Applications 2006/0088502 and 2006/0024271 and U.S. Patent No. 6,849,254).
  • Medical personnel can control and/or modify an interferon- ⁇ dosage regimen depending on the constellation of clinical factors observed in a specific individual (factors which are known to change during treatment).
  • factors which are known to change during treatment are typically those that are individually designed in view of various factors observed in a specific individual.
  • medical personnel may select a specific interferon- ⁇ dosage regimen based upon the genotype or subtype of HBV that is observed to be infecting the patient and/ or the amount of HBV-DNA per ml of serum in the patient as measured by a quantitative PCR method.
  • the dosage regimen may be selected or controlled depending on the weight and age of a patient, whether the patient is observed to have another pertinent pathological condition (e.g. cirrhosis of the liver, hepatocarcinoma, HIV infection, or the like).
  • another pertinent pathological condition e.g. cirrhosis of the liver, hepatocarcinoma, HIV infection, or the like.
  • interferon-a can be administered via a variety of routes, for example subcutaneously, intramuscularly or intravenously.
  • the interferon-a administered is selected from one or more of interferon alpha-2a, interferon alpha-2b, a consensus interferon, a purified interferon alpha product (e.g.
  • an interferon- ⁇ dose can be characterized in international units (IU) or milligrams of polypeptide, optionally in the context of amount of agent per kilogram of patient weight and/or another measure of patient size (e.g. m 2 ).
  • the interferon- ⁇ can be selected from consensus interferon, interferon alpha-2a, interferon alpha-2b, or a purified interferon- ⁇ product and the amount of interferon-a administered can be from at least 1 to at least 20 million IU per day via continuous infusion.
  • interferon- ⁇ can be administered in different doses during different phases of the viral cycle that are observed in HBV therapy.
  • different doses of interferon- ⁇ are administered during the first and/or second phases of viral decline and/ or shoulder and/ or final phase of viral decline and can include for example a first dose between 6-20 MIU (e.g. at least 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5 or 20 MIU) daily for a first specific time period (e.g. 2 weeks), followed by a second different dose between 6- 20 MIU daily for another time period (e.g.
  • Such dosage regimes can use an infusion delivery device (e.g. a medication infusion pump) programmed to deliver different doses of interferon-a during different stages of a treatment regimen.
  • an infusion delivery device e.g. a medication infusion pump
  • interferon- ⁇ may be exposed to elevated temperatures and/ or mechanical stresses for an extended period of time, it may be desirable to prepare interferon-a compositions that enhance the stability of the interferon- ⁇ and prevent its degradation.
  • interferon- ⁇ may be stabilized in an aqueous medium by a mixed buffer system.
  • a mixed buffer system For example, U.S. Patent No. 6,734,162 discloses methods and materials that may be employed to prepare such compositions. Various other methods known and used in the art may also be used.
  • interferons may cause adverse side effects, in some embodiments, they may be delivered in a manner that provides increased levels of the drug in liver tissues and decreased levels in non-liver tissues. In one embodiment, it may be accomplished by chemically modifying the interferon- ⁇ to render it inactive until the modification is cleaved off by a liver-specific enzyme.
  • a liver-specific enzyme One example of such technology, known as HepDirect, is offered by Metabasis Therapeutics, Inc, La Jolla, CA.
  • the interferons may be modified to enhance its site-specific delivery to target cells. Suitable compounds for modifying the interferons in this manner include, but are not limited to, lactosaminated albumin, (Stefano, J. Pharmacol. Exp.
  • interferon- ⁇ may be delivered via a drug delivery device either intraperitoneally or directly to the liver, slightly upstream from the liver vascular bed, such as into the hepatic artery.
  • In vivo samples may be assayed for interferon- ⁇ concentrations using a variety of different methods known and used in the art.
  • One suitable example is an electrochemiluminescence-based assay and an ORIGEN analyzer (IGEN International, Inc. Gaithersburg, MD) as disclosed for example in Obenauer-Kutner et al., Journal of Immunological Methods, Volume 206, Issues 1-2, 7 August 1997, Pages 25-33.
  • Other methods used in the art include those disclosed for example in Niewold et al., Genes Immun.
  • ELISA kits designed to provide quantitative assays of interferon-a concentrations in serum (e.g.
  • 100-700 pg/mL are commercially available from vendors, including for example the Human IFN-alpha Platinum ELISA CE available from Bender MedSystems® (e.g. Product # BMS216CE) and The Human IFN alpha colorimetric ELISA Kit (Serum Samples) available from Thermo Scientific Life Science Research Products (e.g. Product # 411101).
  • Bender MedSystems® e.g. Product # BMS216CE
  • the Human IFN alpha colorimetric ELISA Kit serum Samples
  • Thermo Scientific Life Science Research Products e.g. Product # 411101
  • interferon- ⁇ may be administered to a patient in combination with other antiviral agent(s) such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disoproxil.
  • antiviral agent(s) such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disoproxil.
  • Suitable anti-viral agents include, for example HBV polymerase or protease inhibitors. These anti-viral agents are typically administered orally.
  • Embodiments of the methods disclosed herein include the administration of lamivudine (CAS number 134678-17-4).
  • Lamivudine (2',3'-dideoxy-3'-fhiacytidine, commonly called 3TC) is an analogue of cytidine that inhibits the reverse transcriptase of hepatitis. It is marketed by GlaxoSmithKline with the brand names Zeffix, Heptovir, Epivir, and Epivir-HBV.
  • Lamivudine improves the seroconversion of e-antigen positive hepatitis B and also improves histology staging of the liver. Long term use of lamivudine can lead to the emergence of resistant hepatitis B virus (YMDD) mutants.
  • YMDD resistant hepatitis B virus
  • Embodiments of the methods disclosed herein include the administration of, adefovir dipivoxil (CAS number 106941-25-7).
  • Adefovir dipivoxil previously called bis- POM PMEA, with trade names Preveon and Hep sera, is an orally- administered nucleotide analog reverse transcriptase inhibitor (ntRTI).
  • ntRTI nucleotide analog reverse transcriptase inhibitor
  • Adefovir works by blocking reverse transcriptase, an enzyme that is crucial for the hepatitis B virus (HBV) to reproduce in the body. It is approved for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (primarily ALT) or histologically active disease.
  • the main benefit of adefovir over lamivudine (the first NRTI approved for the treatment of hepatitis B) is that it takes a much longer period of time before the virus develops
  • Embodiments of the methods disclosed herein include the administration of entecavir (CAS number 142217-69-4).
  • Entecavir is an oral antiviral drug used in the treatment of hepatitis B infection. It is marketed under the trade name Baraclude (BMS) & by Entavir (Cipla).
  • Entecavir is a guanine analogue that inhibits reverse transcription, DNA replication and transcription in the HBV viral replication process.
  • Embodiments of the methods disclosed herein include the administration of telbivudine (CAS number 3424-98-4). Telbivudine is a synthetic thymidine nucleoside analogue used in the treatment of hepatitis B infection.
  • Embodiments of the methods disclosed herein include the administration of tenofovir disoproxil (CAS number 147127-20-6).
  • Tenofovir disoproxil fumarate (TDF or PMPA) marketed by Gilead Sciences under the trade name Viread, is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate.
  • compositions of the invention for pharmaceutical administration are known to those of skill in the art. See, for example, Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro (ed.) 1995, Mack Publishing Company, Easton, PA.
  • therapeutic agents used in the methods of the invention combined with at pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is used according to its art accepted meaning and is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • compositions of the invention can be used in the compositions of the invention.
  • Supplementary active compounds can also be incorporated into the compositions.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • compositions of cytokines such as interferon-a can be prepared by mixing the desired cytokine having the appropriate degree of purity with optional pharmaceutically acceptable carriers, excipients, or stabilizers in the form of lyophilized formulations, aqueous solutions or aqueous suspensions (see, e.g. Remington: The Science and Practice of Pharmacy Lippincott Williams & Wilkins; 21 edition (2005), and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems Lippincott Williams & Wilkins; 8th edition (2004)).
  • compositions of pegylated interferon alpha-suitable for parenteral administration may be formulated with a suitable buffer, e.g., Tris-HCl, acetate or phosphate such as dibasic sodium phosphate/monobasic sodium phosphate buffer, and pharmaceutically acceptable excipients (e.g., sucrose), carriers (e.g. human plasma albumin), toxicity agents (e.g. NaCl), preservatives (e.g. thimerosol, cresol or benylalcohol), and surfactants (e.g. tween or polysorabates) in sterile water for injection.
  • a suitable buffer e.g., Tris-HCl, acetate or phosphate such as dibasic sodium phosphate/monobasic sodium phosphate buffer
  • pharmaceutically acceptable excipients e.g., sucrose
  • carriers e.g. human plasma albumin
  • toxicity agents e.g. NaCl
  • Acceptable carriers, excipients, or stabilizers are typically nontoxic to recipients at the dosages and concentrations employed, and include buffers such as Tris, HEPES, PIPES, phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3- pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glut
  • Solutions or suspensions used for administering a cytokine can include the following components: a sterile diluent such as water for injection, saline solution; fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution
  • fixed oils polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants such as ascorbic acid or sodium bisulfite
  • chelating agents such as EDTA
  • buffers such as acetates,
  • Suitable carriers for formulations of interferons in liquid form include, but are not limited to, water, saline solution, buffered solutions, blood, glucose, concentrated plasma, concentrated or fractioned blood, glycerol or any combination thereof.
  • Acceptable excipients or stabilizers that may be added to interferon-a formulations are nontoxic to recipients at the dosages and concentrations employed, and include buffers and preservatives typically used in the art.
  • the formulations herein may also comprise other active molecules as necessary for the particular indication being treated. A person with ordinary skill in the art is capable of selecting active molecules with complementary activities that do not adversely affect each other in amounts that are effective for the purpose intended.
  • the formulation may also include bioactive agents including, neurotransmitter and receptor modulators, anti-inflammatory agents, anti-viral agents, anti-tumor agents, antioxidants, anti-apoptotic agents, nootropic and growth agents, blood flow modulators and any combinations thereof.
  • bioactive agents including, neurotransmitter and receptor modulators, anti-inflammatory agents, anti-viral agents, anti-tumor agents, antioxidants, anti-apoptotic agents, nootropic and growth agents, blood flow modulators and any combinations thereof.
  • interferon-a may be incorporated into a sustained release composition designed to continuously administer interferon- ⁇ over a period of time.
  • the interferons may, for example, be entrapped in a microsphere prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • macroemulsions for example, Remington's Pharmaceutical Sciences, Lippincott Williams & Wilkins; 21 edition (May 1, 2005).
  • the interferons may be incorporated into semipermeable matrices of biodegradable solid polymers.
  • the matrices may be in the form of shaped articles, e.g., films, rods, or pellets.
  • Suitable materials for sustained-release matrices include, but are not limited to, poly(alpha-hydroxy acids), poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PG), polyethylene glycol (PEG) conjugates of poly(alpha-hydroxy acids), polyorthoesters, polyaspirins, polyphosphagenes, collagen, starch, chitosans, gelatin, alginates, dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (polyactive), methacrylates, poly( -isopropylacrylamide), PEO- PPO-PEO (pluronics), P
  • one or more algorithms is used to obtain a regimen responsiveness profile that can be used for example to design and/ or modify a therapeutic regimen administered to a patient (see, e.g. International Application Number PCT/US2009/038617, the contents of which are incorporated by reference).
  • an algorithm is used to determine patient-specific parameters such as the in vivo concentrations of therapeutic agent(s) administered to a patient, the baseline viral load, liver fibrosis or cirrhosis, or presence (e.g. in the serum of the patient) of markers associate with a pathological condition such as alanine transaminase (ALT) or aspartate transaminase (AST).
  • ALT alanine transaminase
  • AST aspartate transaminase
  • the algorithm(s) can further be used to design an optimized therapeutic regimen (e.g. an interferon-a dose that is, for example, calculated to avoid severe side effects that can be associated with interferon- ⁇ therapy).
  • the patient may then be tested a plurality of times for the interferon- ⁇ serum concentration or the viral load or any other relevant parameters known to those of ordinary skill in the art.
  • a plurality of patient-specific pharmacokinetic and pharmacodynamic parameters may be obtained by fitting the pharmacokinetic and pharmacodynamic models known in the art (and described herein) to this data.
  • a wide variety of statistical techniques known and used in the art such as for example, linear or non-linear regressions, may be employed in embodiments of the invention.
  • the models or their solutions in analytical or numerical form may be combined or substituted into each other as is commonly done by artisans skilled in this technology.
  • a first therapeutic regimen can include a dose interferon-a given to the patient in order to obtain information on the rate at which the patient metabolizes the interferon- ⁇ (e.g. to ascertain the dose of interferon- ⁇ in that patient that is required to produce a median concentration in serum of at least 100-700 pg/ mL.
  • a first therapeutic regimen can include a dose of an interferon- ⁇ , either alone, or in combination with a nucleoside/nucleotide analog such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disproxil that is therapeutically effective yet calculated to avoid substantial adverse side effects, and can be determined by one with ordinary skill in the art from experience, population data, journal articles, etc.
  • a nucleoside/nucleotide analog such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disproxil that is therapeutically effective yet calculated to avoid substantial adverse side effects, and can be determined by one with ordinary skill in the art from experience, population data, journal articles, etc.
  • regular interferon- ⁇ can be administered at a dosing rate at, or approximately at, a rate of 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5 or 20 million or more international units (MIU) per day via a continuous infusion apparatus.
  • MIU international units
  • the levels of circulating interferon- ⁇ that result from this first therapeutic regimen can then be observed and, if necessary, the regimen can then be modified to, for example, maintain circulating levels of interferon- ⁇ in that patient above a target threshold, for example 100-700 pg/mL.
  • interferon-a may be administered by more than one method, i.e., bolus injection and continuous infusion.
  • different routes of administration may be employed, such as, subcutaneous bolus and intravenous bolus.
  • the amount of interferon- ⁇ may be changed, such as, administering interferon- ⁇ at a different dosing rate or different concentration.
  • the dose may be varied at any time during the therapy, such as hours, days, weeks or even months after commencement of therapy.
  • efficacy is defined as the ability of a drug to produce a desired therapeutic effect or a clinical outcome.
  • the efficacy of interferon- ⁇ treatment may be described in terms of overall efficacy ( ⁇ ), in terms of blocking virion production ( ⁇ ⁇ ) or in terms of reducing new infections ( ⁇ ).
  • Efficacy may also indicate the rate of sustained virological response, early virological response, rapid virological response, and so forth.
  • actual efficacy means an efficacy achieved by administering to a patient an interferon dose.
  • the actual efficacy may be calculated from the clinical outcome, such as interferon serum concentration or viral load data.
  • critical efficacy means a critical value of efficacy such that for efficacies above the critical value the virus is ultimately cleared in a significant number of patients, while for efficacies below it, virus is not cleared in a significant number of patients.
  • critical efficacy means a critical value of efficacy such that for efficacies above the critical value the virus is ultimately cleared in a significant number of patients, while for efficacies below it, virus is not cleared in a significant number of patients.
  • the term "desired efficacy” means a value of efficacy that is estimated to result in a desired clinical outcome including, for example, desired value of, rate of change of, or trend of change in viral load, number of infected target cells, number of uninfected target cells and so forth.
  • the desired efficacy is typically set to maximize the difference between the actual efficacy and the critical efficacy while minimizing the side effects on the patient.
  • Efficacy of interferon may be varied by varying the dosing rate of interferon-a.
  • the term "dosing rate" as contemplated herein depends on a quantity of interferon-a delivered over time, and may be optimized by changing interferon's administration rate or interferon's concentration.
  • the term "dosing rate” as used herein may also depend on a quality of interferon-a, and may be changed by switching to a more potent interferon-a formulation.
  • the dosing rate may be varied rapidly or gradually from one constant rate to another, or according to an approximately sinusoidal function.
  • the blood samples for determination of pK and pD parameters may be taken throughout the therapy. More specifically, the samples may be taken from 0 to at least 48 weeks after commencement of therapy. Typically, the blood samples may be taken more frequently around the peak and less frequently around the tail. Furthermore, the duration of sampling may also depend on the type of interferon- ⁇ used as well as on the individual's response to therapy.
  • the samples for determination of may be taken at 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 36, 38, 40, 42, 44, 46, 48, 52, 56, 60, 72, 96, 120, 144, and 168 hours during week 1, and then at week 2, 4, 8, 16, 24, 36 and 48.
  • samples are taken every week up to week 48 or 72. Data for concentration and viral load may be obtained according to the same or different schedule. It will also be understood that samples may be taken more frequently in order to provide adequate feedback to the controller, and these samples may also be used to determine or optimize the pK and pD parameters.
  • the dosing rates may be dependent or independent of each other. If dependent, the dosing of the first stage may be set to fall between at least 5 to 95%, or at least 20% and 80%, or at least 20 and 50%, or at least 25% of the dosing rate of the second stage (dosing rate resulting in a higher efficacy).
  • the second stage may last for the remainder of the therapy or, alternatively, may be followed by one or more additional stages.
  • the efficacy during the additional stages may be higher or lower than the efficacy during the second stage.
  • the second stage of the therapy would always provide a higher level of the actual efficacy as compared to the actual efficacy during the first stage of the therapy.
  • FIG. 9A illustrates an exemplary generalized computer system 202 that can be used to implement elements the present invention, including the user computer 102, servers 112, 122, and 142 and the databases 114, 124, and 144.
  • the computer 202 typically comprises a general purpose hardware processor 204A and/or a special purpose hardware processor 204B (hereinafter alternatively collectively referred to as processor 204) and a memory 206, such as random access memory (RAM).
  • the computer 202 may be coupled to other devices, including input/ output ( ⁇ / O) devices such as a keyboard 214, a mouse device 216 and a printer 228.
  • ⁇ / O input/ output
  • the computer 202 operates by the general purpose processor
  • the computer program 210 and/ or the operating system 208 may be stored in the memory 206 and may interface with the user 132 and/ or other devices to accept input and commands and, based on such input and commands and the instructions defined by the computer program 210 and operating system 208 to provide output and results. Output/ results may be presented on the display 222 or provided to another device for presentation or further processing or action.
  • the display 222 comprises a liquid crystal display (LCD) having a plurality of separately addressable liquid crystals.
  • LCD liquid crystal display
  • Each liquid crystal of the display 222 changes to an opaque or translucent state to form a part of the image on the display in response to the data or information generated by the processor 204 from the application of the instructions of the computer program 210 and/or operating system 208 to the input and commands.
  • the image may be provided through a graphical user interface (GUI) module 218A.
  • GUI graphical user interface
  • the instructions performing the GUI functions can be resident or distributed in the operating system 208, the computer program 210, or implemented with special purpose memory and processors.
  • Some or all of the operations performed by the computer 202 according to the computer program 110 instructions may be implemented in a special purpose processor 204B.
  • the some or all of the computer program 210 instructions may be implemented via firmware instructions stored in a read only memory (ROM), a programmable read only memory (PROM) or flash memory in within the special purpose processor 204B or in memory 206.
  • the special purpose processor 204B may also be hardwired through circuit design to perform some or all of the operations to implement the present invention.
  • the special purpose processor 204B may be a hybrid processor, which includes dedicated circuitry for performing a subset of functions, and other circuits for performing more general functions such as responding to computer program instructions.
  • the special purpose processor is an application specific integrated circuit (ASIC).
  • the computer 202 may also implement a compiler 212 which allows an application program 210 written in a programming language such as COBOL, C++, FORTRAN, or other language to be translated into processor 204 readable code. After completion, the application or computer program 210 accesses and manipulates data accepted from 1/ O devices and stored in the memory 206 of the computer 202 using the relationships and logic that was generated using the compiler 212.
  • the computer 202 also optionally comprises an external communication device such as a modem, satellite link, Ethernet card, or other device for accepting input from and providing output to other computers.
  • instructions implementing the operating system 208, the computer program 210, and the compiler 212 are tangibly embodied in a computer- readable medium, e.g., data storage device 220, which could include one or more fixed or removable data storage devices, such as a zip drive, floppy disc drive 224, hard drive, CD-ROM drive, tape drive, etc.
  • the operating system 208 and the computer program 210 are comprised of computer program instructions which, when accessed, read and executed by the computer 202, causes the computer 202 to perform the steps necessary to implement and/or use the present invention or to load the program of instructions into a memory, thus creating a special purpose data structure causing the computer to operate as a specially programmed computer executing the method steps described herein.
  • Computer program 210 and/or operating instructions may also be tangibly embodied in memory 206 and/or data communications devices 230, thereby making a computer program product or article of manufacture according to the invention.
  • article of manufacture “program storage device” and “computer program product” as used herein are intended to encompass a computer program accessible from any computer readable device or media.
  • a user computer 102 may include portable devices such as medication infusion pumps, analyte sensing apparatuses, cellphones, notebook computers, pocket computers, or any other device with suitable processing, communication, and input/ output capability.
  • Fig. 9B presents a specific illustrative embodiment system 10 for performing methods disclosed herein.
  • the interferon-a may be administered at a dosing rate Q(t) 12 from an infusion device 11 including, but not limited to, a pump, a depot, an infusion bag, or the like.
  • the interferon- ⁇ serum concentration 14, represented as C(t) may be determined by sampling a patient's blood by assay or sensor 16, and communicated to a controller 18, as represented by a concentration feedback loop 20.
  • the system 10 may also include a viral load feedback loop 22.
  • patient's viral load 24, represented as V(t) may be determined by sampling patient's blood by assay or sensor 26 and may be communicated to the controller 18. Based on C(t), V(t) or both, controller 18 may calculate the dosing rate 12, which may then be adjusted if necessary either automatically by the controller or manually by an individual administering the therapy. In addition, patient-specific pK parameters 13 and pD parameters 15 may be determined from this data.
  • the controller 18 may be a conventional process controller such as a PID controller, one can also utilize an adaptive model predictive process controller or model reference adaptive control.
  • a model predictive controller may be programmed with mathematical models of a "process" to predict "process" response to proposed changes in the inputs. These predictions are then used to calculate appropriate control actions. In response to control actions, the model predictions are continuously updated with measured information from the "process" to provide a feedback mechanism for the controller.
  • the mathematical models may be continuously optimized to match the performance of the "process.”
  • the controller 18 may be programmed with patient-specific pK or pD parameters, population or subpopulation averages, or a combination thereof together with pharmacokinetic and pharmacodynamic models to calculate the dosing rate necessary to achieve desired clinical outcome.
  • the controller continuously processes the data received from the feedback loops to optimize the dosing rate based on a patient's response to the therapy.
  • the controller 18 may also manipulate the pharmacokinetic and pharmacodynamic parameters, as well as the mathematical models based on concentration and viral load data to adopt or customize the models for individual patients and specific conditions.
  • the controller 18 may use patient- specific pharmacokinetic or pharmacodynamic parameters, population or subpopulation averages, or combination thereof together with pharmacokinetic, pharmacodynamic, or viral kinetic models to calculate the dosing rate for desired efficacy based on C(t), V(t) or both.
  • pK refers to the physical pharmacokinetic system of a real patient.
  • the parameter pK 19 refers to the pharmacokinetic model and parameter values used by the controller to describe pK, and which may be drawn from the real patient, population, or subpopulation averages. Similar notation is used for pD, C, V and Q.
  • a given patient is assumed to have a set of individual pharmacokinetic parameters, represented as pK, and thus actual efficacy may be represented as a function of concentration, which is a function of the dosing rate Q(t).
  • the controller 18 may use pharmacokinetic and pharmacodynamic models to calculate the suitable dosing rate for desired efficacy based on the concentration or other physiological characteristic data. Such models are known and are disclosed in, for example, Bonate, P.L. (2006). Pharmacokinetic- Pharmacodynamic Modeling and Simulation. New York, Springer Science&Business Media; Andrew H Talal, et al. (2006).
  • therapeutic agents e.g. interferon- a
  • substantially continuous manner means that the dosing rate is constantly greater than zero during the periods of administration.
  • the term includes embodiments when the drug is administered at a steady rate, e.g. via a continuous infusion apparatus.
  • interferon-a may be administered only in a substantially continuous manner throughout the entire treatment period. In other embodiments, these manners of interferon-a administration may be combined during the same stage or altered during different stages of the treatment.
  • the therapeutic agent is administered in a "substantially continuous manner".
  • the therapeutic agent is administered in a substantially continuous manner via a continuous infusion pump, for example a pump typically used to administer insulin to diabetic patient.
  • a continuous infusion pump for example a pump typically used to administer insulin to diabetic patient.
  • Suitable types of pumps include, but are not limited to, osmotic pumps, interbody pumps, infusion pumps, implantable pumps, peristaltic pumps, other pharmaceutical pumps, or a system administered by insertion of a catheter at or near an intended delivery site, the catheter being operably connected to a pharmaceutical delivery pump. It is understood that such pumps can be implanted internally (e.g. into a patient's abdominal (peritoneal) cavity) or worn externally (e.g. clipped to belt loop) as appropriate. Typical methods of the invention employ a programmable pump for the methods described herein.
  • biocompatibility both the drug/ device and device/ environment interfaces
  • reliability both the drug/ device and device/ environment interfaces
  • durability both the drug/ device and device/ environment interfaces
  • environmental stability accuracy
  • delivery scalability flow delivery (continuous vs. pulse flow)
  • portability portability
  • reusability back pressure range and power consumption.
  • biocompatibility is always an important consideration, other considerations vary in importance depending on the device application.
  • a person with ordinary skill in the art is capable of selecting an appropriate pump for the methods described herein.
  • a variety of external or implantable pumps may be used to administer the interferon.
  • an external pump is Medtronic MiniMed ® pump and one example of a suitable implantable pump is Medtronic SynchroMed ® pump, both manufactured by Medtronic, Minneapolis, Minnesota.
  • the therapeutic agent is pumped from the pump chamber and into a drug delivery device, which directs the therapeutic agent to the target site.
  • the rate of delivery of the therapeutic agent from the pump is typically controlled by a processor according to instructions received from the programmer. This allows the pump to be used to deliver similar or different amounts of the therapeutic agent continuously, at specific times, or at set intervals between deliveries, thereby controlling the release rates to correspond with the desired targeted release rates.
  • the pump is programmed to deliver a continuous dose of interferon-a to prevent, or at least to minimize, fluctuations in interferon-a serum level concentrations.
  • interferon- ⁇ may be delivered subcutaneously, intramuscularly, parenterally, intraperitoneally, transdermally, or systemically.
  • interferon-a may be delivered subcutaneously or for a systemic infusion.
  • a drug delivery device may be connected to the pump and tunneled under the skin to the intended delivery site in the body. Suitable drug delivery devices include, but are not limited to, those devices disclosed in United States Patent Numbers 6,551,290 and 7,153,292.
  • a wide variety of continuous infusion devices known in the art can be used to deliver one or more antiviral agents to a patient infected with HBV.
  • Continuous interferon-a administration may for example be accomplished using an infusion pump for the subcutaneous or intravenous injection at appropriate intervals, e.g.
  • the continuous infusion device used in the methods of the invention has the highly desirably characteristics that are found for example in pumps produced and sold by the Medtronic corporation.
  • the cytokine is administered via an infusion pump such as a Medtronic MiniMed model 508 infusion pump.
  • the Model 508 is currently a leading choice in insulin pump therapy, and has a long history of safety, reliability and convenience.
  • the pump includes a small, hand-held remote programmer, which enables diabetes patients to program cytokine delivery without accessing the pump itself.
  • continuous administration can by accomplished by, for example, another device known in the art such as a pulsatile electronic syringe driver (Provider Model PA 3000, Pancretec Inc., San Diego Calif), a portable syringe pump such as the Graseby model MS 1 6A (Graseby Medical Ltd., Watford, Herts England), or a constant infusion pump such as the Disetronic Model Panomat C-S Osmotic pumps, such as that available from Alza, may also be used. Since use of continuous subcutaneous injections allows the patient to be ambulatory, it is typical chosen for use over continuous intravenous injections.
  • Infusion pumps and monitors for use in embodiments of the invention can be designed to be compact (e.g. less than 15 x 15 centimeters) as well as water resistant, and may thus be adapted to be carried by the user, for example, by means of a belt clip.
  • important medication can be delivered to the user with precision and in an automated manner, without significant restriction on the user's mobility or life-style.
  • the compact and portable nature of the pump and/or monitor affords a high degree of versatility in using the device.
  • the ideal arrangement of the pump can vary widely, depending upon the user's size, activities, physical handicaps and/or personal preferences.
  • the pump includes an interface that facilitates the portability of the pump (e.g. by facilitating coupling to an ambulatory user).
  • Typical interfaces include a clip, a strap, a clamp or a tape.
  • formulations tailored for use with continuous infusion pumps are known in the art.
  • formulations which simulate a constant optimized dose injection such as, but not limited to, short- acting unconjugated forms of interferon-a as well as long-acting interferon-a -polymer conjugates and various-sustained release formulations, are contemplated for use.
  • Typical routes of administration include parenteral, e.g., intravenous, intradermal, intramuscular and subcutaneous administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution; fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution
  • fixed oils polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants such as ascorbic acid or sodium bisulfite
  • chelating agents such as EDTA
  • buffers such as
  • a interferon- ⁇ , and/ or a nucleoside analog such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disproxil or other therapeutic agents
  • the HBV burden in the individual can be monitored in various ways well known to the skilled practitioner familiar with the hallmarks of HBV infection.
  • a therapeutically effective amount of the drug may reduce the numbers of viral particles detectable in the individual and/or relieve to some extent one or more of the signs or symptoms associated with the disorder.
  • hepatitis DNA or RNA may be measured in serum samples by, for example, an PCR procedure such as one in which a nested polymerase chain reaction assay uses two sets of primers derived from a hepatitis genome.
  • PCR procedure such as one in which a nested polymerase chain reaction assay uses two sets of primers derived from a hepatitis genome.
  • an article of manufacture containing materials useful for the treatment of HBV infection as described above.
  • the article of manufacture can comprise a container and a label.
  • Suitable containers include, for example, continuous infusion pumps, infusion tubing sets, catheters, bottles, vials, syringes, and test tubes.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container can hold a composition (e.g. cytokine or other therapeutic composition) which is effective for treating the condition (e.g.
  • the article of manufacture may further comprise a second container comprising a pharmaceutically- acceptable buffer, such as phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
  • a pharmaceutically- acceptable buffer such as phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
  • kits containing materials useful for treating pathological conditions with interferon comprising a container with a label.
  • Suitable containers include, for example, bottles, vials, and test tubes.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container holds a composition having an active agent which is effective for treating pathological conditions such as HBV infection.
  • the active agent in the composition is typically interferon-a and/or a nucleoside analog such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disproxil.
  • the label on the container indicates that the composition is used for treating pathological conditions with interferon-a and/ or a nucleoside analog such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disproxil.
  • EXAMPLE 1 GENERAL THERAPEUTIC REGIMENS FOR THE CONTINUOUS ADMINISTRATION OF INTERFERON-a TO PATIENTS
  • illustrative therapeutic regimens can comprise the use of an ambulatory infusion pump (e.g.
  • MiniMed® model 508 micro infusion pump for the continuous administration of interferon-a so as to maintain circulating levels of administered interferon-a above a certain threshold, for example a therapeutic regimen sufficient to maintain circulating levels of the interferon-a in the serum of the patient above a steady state concentration of at least 100, 200, 300, 400, 500, 600 or 700 pg/ mL
  • Such regimens can include, for example, administering 6, 9 or 12 MIU of IFN-a (e.g. Intron A®) per day for at least 1 week to at least 48 weeks, for example as discussed in detail in Example 2 below.
  • Another illustrative regimen comprises the continuous administration of IFN-a 80,000 IU/kg/day for at least 1 week to at least 48 weeks.
  • Another illustrative regimen comprises the continuous administration of IFN-a 120,000 IU/kg/day for at least 1 week to at least 48 weeks.
  • Another illustrative regimen comprises the continuous administration of IFN-a 160,000 IU/kg/day for at least 1 to at least 48 weeks.
  • Yet another illustrative regimen comprises the continuous administration of Peglntron 1.5 ⁇ g/kg SC weekly for at least 1 week to at least 48 weeks.
  • patents also receive oral a nucleoside analog such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disoproxil.
  • a first therapeutic regimen for a first time period e.g. 1, 2, 3, 4, 5, 6 or 7 days, 1, 2, 3, or 4 weeks etc.
  • an analysis can be performed to observe for example, serum interferon-a levels, as well as safety/ tolerability data and outcomes measures such as the illustrative measures disclosed herein.
  • patient specific therapeutic regimen can then be designed based on the results of this analysis. For example, assuming that the analysis shows circulating levels of interferon- ⁇ to be within a target range, a patient can continue with an assigned treatment for the remainder of the treatment course. Alternatively, the patient can be administered a patient specific therapeutic regimen designed for example to increase serum interferon- ⁇ levels as compared to the first therapeutic regimen administered to the patient.
  • Embodiments of the invention further include systems such as those that comprise computer processors and the like coupled to a medication infusion pump and adapted to deliver interferon- ⁇ according to a specific therapeutic regimen.
  • the system includes one or more control mechanisms designed to modulate delivery of interferon- ⁇ , for example those that allow its delivery according to a predetermined infusion profile.
  • a processor controls a therapeutic regimen that includes an infusion profile designed to take into account one or more characteristics of the patient (e.g. weight) and/or one or more characteristics of the hepatitis virus infecting the patient (e.g. genotype) and/ or one or more characteristic of the therapeutic agent administered to the patient (e.g.
  • the system can be operably coupled to an input that provides information on the concentrations of exogenous IFN-a in a patient's serum (e.g. an input coupled to a sensor) and then uses the processor to modulate the dose of interferon-a administered to the patient so as to modulate the resulting in vivo serum concentrations up or down (e.g. so as to fall with an predetermined target ranges of concentrations).
  • EXAMPLE 2 CLINICAL STUDIES ON THE SUBCUTANEOUS CONTINUOUS INFUSION OF INTERFERON-a TO HCV INFECTED PATIENTS THAT FAIL TO RESPOND TO CONVENTIONAL THERAPEUTIC REGIMENS
  • IFN alfa Pegylation of interferon (IFN) alfa has improved the pharmacokinetic profile of conventional interferon- ⁇ by maintaining constant blood levels. This has enabled once- weekly IFN-a dosing and resulted in higher response rates. However, it has been shown that the IFN-a volume of distribution due to pegylation is considerably restricted (see, e.g. Zeuzem et al. Semin Liver Dis 2003;23 Suppl 1:23-8), a factor which decreases biological activity and potentially decreases treatment efficacy.
  • the continuous administration of IFN-a that has not been chemically modified via conjugation to a polyol can overcome these problems by providing sustained and constant levels of a fully potent IFN-a protein, one having a pharmacokinetic profile equivalent to endogenous interferon.
  • This example provides data from a clinical trial designed to examine the effects of the continuous administration of IFN-a to patients shown to be refractory to (PEG- )IFN-a/RBV combination therapy.
  • PEG- refractory to previous (PEG-)IFN-a/RBV combination therapy.
  • IFN-a2b Intron A®
  • RBV Rebetol®
  • This study uses a continuous infusion apparatus such as the MiniMed® model 508 micro infusion pump device to investigate therapeutic regimens which can optimize the dose, safety, and tolerability of continuous subcutaneous administration of high-dose IFN-a2b/ ribavirin combination therapy in HCV (e.g. genotype 1) patients, such as those unresponsive to previous (peg)interferon/ ribavirin combination therapy.
  • HCV e.g. genotype 1
  • IFN-a2b • Biological activity of IFN-a2b represented as 2'5'-oligoadenylate synthetase (2'5'- OAS) and p 2 -microglobulin activity.
  • Hepatitis C genotype 1 or 4 unresponsive to (peg)interferon-a /ribavirin therapy.
  • (peg)interferon-a or conventional interferon-a plus ribavirin combination therapy for at least 12 weeks and less than 2-log HCV RNA decrease at week 12, HCV RNA positivity at week 24, breakthrough during therapy or relapse after therapy. At least 12 weeks between end of (peg)interferon/ribavirin therapy and start of high-dose IFN-a/ribavirin therapy.
  • Persistent indication for antiviral therapy such as persistently elevated serum ALT or histological evidence of continuing or progressive fibrosis.
  • decompensated cirrhosis defined as jaundice in the presence of cirrhosis, ascites, gastric bleeding, esophageal varices or encephalopathy.
  • Hepatic imaging US, CT or MRI
  • hepatic imaging should be performed within 3 months prior to screening
  • an alpha fetoprotein >20 ng/ mL
  • liver disease activity • Other acquired or inherited causes of liver disease that could explain liver disease activity.
  • Severe psychiatric disorder such as major psychoses, suicidal ideation, suicidal attempt and/or manifest depression during previous (peg)interferon-a therapy.
  • Severe depression would include the following: (a) subjects who have been hospitalized for depression, (b) subjects who have received electroconvulsive therapy for depression, or (c) subjects whose depression has resulted in a prolonged absence of work and/or significant disruption of daily functions.
  • Subjects with a history of mild depression may be considered for entry into the protocol provided that a pretreatment assessment of the subject's mental status supports that the subject is clinically stable and that there is ongoing evaluation of the patient's mental status during the study.
  • Substance abuse such as alcohol ( ⁇ 80 gm/ day) and I.V. drugs. If the subject has a history of substance abuse, to be considered for inclusion into the protocol, the subject must have abstained from using the abused substance for at least 2 years. Any other condition which in the opinion of the investigator would make the patient unsuitable for enrollment, or could interfere with the patient participating in and completing the study.
  • Ribavirin is available in tablets of 200 mg and was weight-based dosed (approximately 15 mg/kg/day, see Table 1 below). TABLE 1: RIBAVIRIN DOSING
  • ribavirin The most frequent reported side effects are: nausea, anorexia, dyspepsia, dizziness, rash, pruritus, skin eruptions, cough, nasal congestion, dyspnea. Most of these events are of mild to moderate severity in previous studies.
  • the primary toxicity of ribavirin is hemolytic anemia, which is observed in approximately 13% of PEG-IFN- a/ribavirin treated patients. Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin.
  • paracetamol can be given to minimize the side-effects of IFN- a2b.
  • the total daily dose of paracetamol should not exceed 4 gram.
  • erytropoietin can be administered and blood transfusion is allowed.
  • SSRIs selective serotonin reuptake inhibitors
  • Concomitant medication apart from drugs or therapies mentioned in the exclusion criteria, is permitted during the study, provided this pre-supposes no effect on the study outcome. The use of concomitant medication must be documented on the CRF (stating type, dosage and duration). If possible, existing concomitant medication should not be changed during the study.
  • HCV RNA • Virology: HCV RNA:
  • the percentage of EVR and SVR in the three dosages regimes of continuous subcutaneous IFN-a2b therapy can be compared using Chi-Square test.
  • the log viral decline and pharmacokinetics over time can be analysed with nonlinear regression applying repeated measurement analysis techniques.
  • ALT, biological activity, immunological response and quality of life assessment can be analysed with linear regression applying repeated measurement analysis.
  • AEs adverse events
  • SAEs severe adverse events
  • dose reductions can be compared between all groups using Chi-Square test.
  • IFN-a Pegylation of IFN-a is known to improve the PK profile with higher SVRs compared to standard IFN-a. The volume of distribution and biological activity, however, are substantially reduced.
  • primary clinical data from the clinical trial provides evidence that the continuous exposure to therapeutic IFN-a levels not only prevents peaks associated with adverse events, but also troughs associated with subtherapeutic drug levels and viral breakthrough.
  • TaqMan HCV Test (LLD ⁇ 15 IU/mL) at week 24 were allowed to complete 48 weeks of therapy.
  • AEs were mostly mild to moderate and typically IFN-a-related.
  • SAEs led to temporary suspension of therapy in 3 patients and permanent discontinuation in 3; 4 of them had cirrhosis. No problems with regard to pump handling by patients were seen.
  • This disclosure establishes some parameters important in treating hepatitis with interferon-a via continuous subcutaneous infusion.
  • the SCIN-C trial conducted in the Netherlands in the city of Rotterdam at the Erasmus Medical Center was a three arm (treatment regimen) study with 10 subjects in each arm/regimen.
  • the interferon-a dosages in the trial were 6 MIU, 9 MIU, and 12 MIU daily via pump with concomitant weight based oral ribavirin.
  • the patients in the study are all previous therapy failures and are all Genotype 1 or 4. Previous therapy and certain subject specific data are in Table 2 below.
  • Genotype 1 24/30 (80%), Interferon-a non-responder week 12 10/30 (33%), HCV Positive week 24 12/30 (40%), Relapse/Rebound 8/30 (26.7%).
  • non-responders at week 12 are the most difficult to retreat, while relapsers and rebounders are the least difficult to treat.
  • Figure 2 shows viral decay curves in patients that are severely interferon-a resistant (and these patients are consequently difficult to treat).
  • Figure 2 shows viral decay curves in patients that are severely interferon-a resistant (and these patients are consequently difficult to treat).
  • in the 6 MIU/ day treatment group there were 5 subjects that showed significant resistance. Of these 5 subjects, only patient 8 showed a robust response at week 8 with subsequent rebound. In previous therapy all of these 5 subjects were either therapy failures at week 12 or week 24. Five subjects with more robust HCV declines are shown in Figure 3.
  • Figure 3 provides data showing a robust response in the 6 MIU treatment group.
  • patients 2 and 3 both were viral negative by quantitative RNA testing at week 24 but tested positive by qualitative highly sensitive testing at week 24 and are out of the study. The other subjects continued in the study.
  • EVR Early virologic response
  • SCIN-C trial 4 of 8 patients with measured viral data (50%) achieved EVR in the 6 MIU/ day treatment group and 3 of 6 patients with measured viral data (50%) achieved EVR in the 9 MlU/day treatment group.
  • all 6 subjects (100%) of subjects who reached 12 weeks showed EVR.
  • Viral negativity (VN) at week 24 is a continuation requirement for the SCIN-C protocol. Patients who were not viral negative at week 24 were discontinued from the study. In the 6 MlU/day treatment group, 1 of 8 (12.5%) subjects who had 24 week data was viral negative while 2 subjects are still on treatment. In the intermediate dose of 9 MlU/ml, 2 of 8 (25%) subjects who had 24 week measurements were viral negative and 3 subjects are still on treatment. In the 12 MlU/day treatment group, 2 subjects had achieved VN at week 24, 2 subjects were viral positive at week 24 and 3 subjects remained on therapy.
  • Viral decay data at the four week time point is shown in Figure 6. As shown by the curves in this graph, at four weeks there is a significant difference between the doses. This is shown more clearly by Figure 7, which shows viral decay by dosing (all patients).
  • OAS 2,5-oligoadenylate synthetase
  • Virological responses are shown in Table 6 below.
  • a mean HCV RNA decline of 1.19 (95%CI 0.55-1.83), 1.21 (95%CI 0.38-2.04) and 2.67 (95%CI 2.38-2.97) log 10 IU/ml was found with 6, 9, and 12MIU IFN-a/day, respectively (12MIU vs. 9MIU/6MIU, p ⁇ 0.0001).
  • Out of the 20 previous non-responders 9 became HCV RNA negative by PCR during therapy and 3 achieved SVR (2 received 12 MlU/day and 1 received 9 MlU/day).
  • All patients achieving sustained virological response after 48 weeks of therapy (n 5) had >2 log drop of HCV RNA at week 4.
  • IFN-a levels increased dose-dependently, reaching peak-levels between 48hrs and week 1 followed by steady-state.
  • Responders achieved higher IFN-a levels than nonresponders (mean 304.0 vs 160.2 pg/ml at week 4).
  • Neopterin increased equally among all patients between 48 and 96 hrs, with higher steady-state levels in patients receiving 12MIU/day.
  • Beta 2-microglobulin increased moderately in all patients; higher baseline levels were seen in responders (mean 16.9 vs 13.4 ug/ml). 2,5-OAS levels peaked between 24 and 96 hrs followed by slow decline, without differences in responders and nonresponders.
  • Baseline T cell proliferation was strongly reduced when cultured in vitro with IFN-alfa in most patients, suggesting responsiveness to IFN-a irrespective of treatment outcome.
  • AEs were mostly mild to moderate and were typical of IFN-a therapy but 5 patients developed irritation and/or abscesses at the injection site.
  • Six serious adverse events (SAEs) were reported in 5 subjects, this led to permanent discontinuation in 3 subjects. All SAEs were consistent with high dose IFN-a therapy. Of the discontinuations due to SAEs, 2 subjects received the 12 MlU/day and 1 patient received the 9 MlU/day dose
  • the clinical trial data shows that a strong HCV RNA decline at week 4 can be induced by high dose continuous IFN-a therapy in patients who failed previous PeglFN- a/RBV therapy. Serum interferon-a levels, but no other immune activation markers, predict response.
  • Table 6 Virological response: (undetectable HCV RNA by COBAS® Ampliprep/COBAS® TaqMan® HCV test, LLD ⁇ 15 IU/mL).
  • delivering concentrations of interferon-a following the therapeutic regimens disclosed herein leads to concentrations of interferon- ⁇ that are sustained in vivo and that these sustained in vivo concentrations of interferon- ⁇ can be used to eliminate HCV in a greater number of infected individuals than is possible following conventional therapeutic regimens.
  • SVR was achieved in patients in each of the groups that received either 6, 9 or 12 MIU IFN alfa-2b daily by continuous subcutaneous administration for 48 weeks.
  • the surprising response observed in patients refractory to conventional therapy may result from interferon- ⁇ having a efficacy threshold that is: (1) met in only about 50% of patients treated according to conventional therapeutic regimens (perhaps due in part to different rates of exogenous interferon-a metabolism/clearance in different individuals); and (2) met in a greater number of patients when administered via a continuous infusion apparatus so as to maintain circulating levels of interferon- ⁇ in the serum of the patient above a steady state concentration (e.g. at least 100-700 pg/mL) for a sustained period of time (e.g. at least 1 to 48 weeks).
  • a steady state concentration e.g. at least 100-700 pg/mL
  • a sustained period of time e.g. at least 1 to 48 weeks.
  • interferon- ⁇ in this manner can reduce the dose dependent adverse side effects that typically occur with the administration of these doses of interferon- ⁇ following conventional therapeutic regimens.
  • a dose of interferon- ⁇ administered in this manner does not produce the same degree of adverse side effects typically experienced with a dose of interferon- ⁇ administered following conventional IFN-a based HCV therapies because the continuous administration of this therapeutic molecule can avoid the very high serum concentrations of interferon- ⁇ and continual fluctuations in serum levels of this therapeutic molecule that can occur with conventional HCV therapies and which are believed to contribute to the severity of adverse reactions and/ or the general discomfort that can occur with such therapies (e.g. weekly boluses of interferon, daily boluses of interferon- ⁇ etc.).
  • the data from the clinical trial shows that SVR can be attained in patients refractory to conventional IFN-a/ribavirin HCV therapy by administering ribavirin in combination with 6 MIU IFN-a/ day infused by continuous subcutaneous administration for 48 weeks.
  • the data from the clinical trial further shows that serum interferon-a levels are predictive of a patient's response. As shown in FIG.
  • the data from the clinical trial shows that SVR can be attained in patients refractory to conventional IFN-a/ribavirin HCV therapy by administering ribavirin in combination with 9 MIU IFN-a/ day infused by continuous subcutaneous administration for 48 weeks.
  • the data from the clinical trial further shows that serum levels of exogenous interferon- ⁇ are predictive of a patient's response.
  • FIG. 1A over a period of four weeks, patients receiving 9 MIU IFN-a/day by continuous infusion attained mean serum IFN-a concentrations above 200 pg/mL, typically above 300 pg/mL Similarly, the data shown in FIG.
  • the data from the clinical trial shows that SVR can be attained in patients refractory to conventional IFN-a /ribavirin HCV therapy by administering ribavirin in combination with 12 MIU IFN-a/day infused by continuous subcutaneous administration for 48 weeks.
  • the data from the clinical trial further shows that serum interferon- ⁇ levels are predictive of a patient's response.
  • FIG. 1A over a period of four weeks, patients receiving 12 MIU IFN-a/day by continuous infusion attained mean serum IFN-a concentrations above 300 pg/mL, typically above 400 pg/mL Similarly, the data shown in FIG.
  • embodiments of the invention address a long-felt but unresolved need, specifically the need to eliminate HCV in a greater number of infected individuals than is possible using conventional therapeutic regimens.
  • the clinical trial focused on patients refractory to conventional IFN-a/ ribavirin HCV therapy, those of skill in this art understand that embodiments of the invention are useful for treatment naive patients as well.
  • therapeutic protocols following parameters disclosed herein disclosed herein can be tailored to take into account patient specific factors that can influence a patients' response to treatment such as the HBV genotype(s) infecting the patient, and/or a patient's weight, treatment history, health status, individual rate of exogenous interferon-a clearance, and the like.
  • a patient is administered interferon- ⁇ following a first therapeutic regimen that endeavors to produce mean or median circulating levels of interferon- ⁇ that fall within a target range, for example 100-200 pg/mL (or 150-250 pg/mL), 200-300 pg/mL (or 250- 350 pg/mL), 300-400 pg/ mL (or 350-450 pg/mL) up to 700 pg/mL, etc.
  • Pharmacokinetic and/or pharmacodynamic parameters can then be obtained from the patient so as to observe a patient-specific response to this first therapeutic regimen (e.g.
  • Embodiments of the invention include personalized therapeutic regimens designed to produce a sustained virological response while simultaneously reducing or avoiding one or more of the adverse side effects that are observed to arise with lengthy treatment regimens comprising doses of interferon- ⁇ .
  • embodiments of the invention consider factors such as: indicators of the patient's overall physiological health (e.g. Body Mass Index, the presence or absence of metabolic diseases such as diabetes etc.); and/ or the genotype of the HBV virus and/ or a patient's rate of exogenous interferon- ⁇ metabolism and/ or the extent of an individual patient's desensitization of their T cells (with regard to T cell proliferation) in response to interferon- ⁇ etc.
  • Personalized therapeutic regimens include those designed to avoid administering amounts of interferon-a that are greater than the critical amounts required to attain sustained virological response and/or avoid administering interferon-a for a period of time longer than the critical period required to attain sustained virological response. In this way, personalized therapeutic regimens can effectively treat patients while simultaneously reducing or avoiding the occurrence of one or more of the adverse side effects that are observed to arise in treatment regimens comprising doses of interferon-a.
  • the Entrez SNP database provides a library of single nucleotide polymorphisms such as those disclosed in Mbarek et al.
  • the sequences of various polymorphism are cataloged with a SNP designation (e.g. rs2856718 and rs 7453920).
  • Illustrative SNP sequences obtained using such SNP designations as a query are provided in Table 8.
  • Table 8 the polymorphic nucleotide in these SNP sequences is bracketed (nucleotide position 27).
  • TTCTTCTCACTTCATGTGAAAACTAC [C/T] CCAGTGGCTGACTGAATTGCTGACC (SEQ ID NO 3)

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Abstract

La présente invention concerne des méthodes et des systèmes de traitement d'infections par le virus de l'hépatite B. D'une manière générale, la méthode comprend l'administration d'interféron alpha au patient par voie sous-cutanée en utilisant un appareil à perfusion continue, ce régime thérapeutique étant suffisant pour maintenir le taux d'interféron alpha en circulation dans le sérum du patient au-dessus d'une concentration cible pendant une certaine période de temps.
PCT/US2012/061467 2011-10-26 2012-10-23 Administration continue sous-cutanée d'interféron alpha à des patients infectés par le virus de l'hépatite b Ceased WO2013062959A2 (fr)

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WO2017009303A1 (fr) * 2015-07-15 2017-01-19 F. Hoffmann-La Roche Ag Biomarqueurs pour la réponse au traitement du hbv
JP2020178556A (ja) * 2019-04-23 2020-11-05 ジェネシスヘルスケア株式会社 角膜疾患のリスクを判定する方法
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US20110027229A1 (en) * 2009-07-31 2011-02-03 Medtronic, Inc. Continuous subcutaneous administration of interferon-alpha to hepatitis c infected patients
WO2011059824A2 (fr) * 2009-10-29 2011-05-19 Medtronic, Inc. Méthodes et matériels pour des régimes thérapeutiques contre l'hépatite c optimisés

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