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WO2013137912A2 - Méthodes de distribution de médicaments inhibant le complément aux patients recevant un inhibiteur de complément - Google Patents

Méthodes de distribution de médicaments inhibant le complément aux patients recevant un inhibiteur de complément Download PDF

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Publication number
WO2013137912A2
WO2013137912A2 PCT/US2012/029499 US2012029499W WO2013137912A2 WO 2013137912 A2 WO2013137912 A2 WO 2013137912A2 US 2012029499 W US2012029499 W US 2012029499W WO 2013137912 A2 WO2013137912 A2 WO 2013137912A2
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WIPO (PCT)
Prior art keywords
patient
complement inhibitor
complement
disorder
inhibitor
Prior art date
Application number
PCT/US2012/029499
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English (en)
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WO2013137912A3 (fr
Inventor
Leonard Bell
Original Assignee
Alexion Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Alexion Pharmaceuticals, Inc. filed Critical Alexion Pharmaceuticals, Inc.
Priority to PCT/US2012/029499 priority Critical patent/WO2013137912A2/fr
Priority to CN201280071445.8A priority patent/CN104205155A/zh
Priority to EA201400950A priority patent/EA201400950A1/ru
Priority to EP12870989.6A priority patent/EP2825989A4/fr
Publication of WO2013137912A2 publication Critical patent/WO2013137912A2/fr
Publication of WO2013137912A3 publication Critical patent/WO2013137912A3/fr
Priority to IL234680A priority patent/IL234680A0/en
Priority to HK15105150.8A priority patent/HK1204693A1/xx

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
    • G16H20/10—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H70/00—ICT specially adapted for the handling or processing of medical references
    • G16H70/40—ICT specially adapted for the handling or processing of medical references relating to drugs, e.g. their side effects or intended usage
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
    • F04C—ROTARY-PISTON, OR OSCILLATING-PISTON, POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; ROTARY-PISTON, OR OSCILLATING-PISTON, POSITIVE-DISPLACEMENT PUMPS
    • F04C2270/00—Control; Monitoring or safety arrangements
    • F04C2270/04—Force
    • F04C2270/041—Controlled or regulated

Definitions

  • Complement is an essential component of the immune system and is of substantial relevance for the destruction of invading microorganisms and for maintaining tissue homeostasis including the protection against autoimmune diseases.
  • excessive or uncontrolled complement activation significantly contributes to undesired tissue damage.
  • Complement activation presents a considerable risk of harming the host by directly and indirectly mediating inflammatory tissue destruction.
  • Clinical and experimental evidence underlines the prominent role of complement in the pathogenesis of numerous inflammatory diseases.
  • complement activation In recent years, great progress has been made in inhibiting complement activation for potential therapies for complement-relevant diseases. A certain degree of inhibition of complement activation may be sufficient to reduce its detrimental effects but still preserve the defense mechanisms against invading pathogens. The redundancy of the three complement activation pathways may reduce the risk of infection if only one pathway is selectively blocked. In addition, the risk of infectious complications is most probably highest when blocking the comparatively upstream complement component C3.
  • Some complement inhibitors including antibodies or antigen-binding fragments specifically recognizing and antagonizing the downstream complement component C5, e.g., eculizumab (Soliris ® ) and pexelizumab, have been prepared and/or tested in clinical trials.
  • the present disclosure generally relates to an unexpected discovery of adverse clinical events, including severe adverse effects, after discontinuing use of a certain drug, such as a
  • the disclosure provides a method for distributing a drug to a patient in need by authorizing distribution of the drug on the condition that the patient or a representative of the patient acknowledges the risk of side effects of the drug, discontinuance of the drug, or both. After acknowledgment of a receipt of a warning regarding such risks, the acknowledgment is registered in a database, for example along with an identification of such risks and side effects, to help evaluate later patient compliance and clinical successes and failures.
  • the disclosure provides a method for distributing a complement inhibitor (CI1) for use in treating a patient: (i) afflicted with, suspected of having, or at risk for developing a complement-associated disorder, and (ii) in need of treatment with the complement inhibitor, the method comprising: i) authorizing distribution of a complement inhibitor to treat the patient, upon certification that:
  • the patient, or the legal guardian or representative of the patient has expressed acknowledgment of the warning and agreement to the treatment; ii) registering via a computer readable medium a database comprising the information that the patient, or the legal guardian or representative of the patient, has received and acknowledged the warning and agreed to the treatment; and iii) following (i) and (ii), distributing the complement inhibitor for use in treating the patient.
  • the present disclosure provides a method of promoting a patient's compliance to a medical treatment for a complement-associated disorder with a complement inhibitor (CIl), comprising: i) advising the patient, or the legal guardian or representative of the patient, via one or both of verbal and written warning as to the risk of adverse clinical events associated with discontinuing use of the complement inhibitor to treat said disorder; ii) obtaining acknowledgement of the warning and agreement to the treatment from the patient, or the legal guardian or representative of the patient; iii) registering via a computer readable medium a database comprising patient information, wherein the patient information includes that the patient, or the legal guardian or representative of the patient, has been provided with the warning, has acknowledged the warning, and has agreed to the treatment; and iv) authorizing distribution of the complement inhibitor for treating the patient.
  • a complement inhibitor CIl
  • the complement-associated disorder is selected from the group consisting of: a complement-associated inflammatory disorder, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), age-related macular degeneration (AMD), rheumatoid arthritis (RA), myasthenia gravis (MG), neuromyelitis optica (NMO), catastrophic anti-phospholipid syndrome (CAPS), anti-phospholipid syndrome (APS), sepsis, a complement-associated pulmonary disorder, asthma, and chronic obstructive pulmonary disease (COPD).
  • PNH paroxysmal nocturnal hemoglobinuria
  • aHUS atypical hemolytic uremic syndrome
  • AMD age-related macular degeneration
  • RA age-related macular degeneration
  • RA rheumatoid arthritis
  • MG myasthenia gravis
  • NMO neuromyelitis optica
  • CAS catastrophic anti-phospholipid syndrome
  • APS anti-phospholipid syndrome
  • the patient is treated by re-initiation of the complement inhibitor (CIl) treatment or with an alternative therapy to treat the adverse clinical events after discontinuing use of the complement inhibitor (CIl).
  • the alternative therapy comprises treating with a different complement inhibitor (CI2) or with a different regimen of the same complement inhibitor (CIl).
  • the alternative therapy comprises plasma therapy, or organ-specific supportive measures, or any combination thereof.
  • the plasma therapy is selected from the group consisting of: plasmapheresis, plasma exchange, and fresh frozen plasma infusion.
  • the complement inhibitor (CI1) is an inhibitor of complement protein C5.
  • the complement inhibitor (CI1) is an antibody or antigen- binding fragment thereof recognizing C5.
  • the antibody or antigen-binding fragment thereof is eculizumab (Soliris®), pexelizumab, or a biosimilar equivalent of eculizumab or pexelizumab.
  • the adverse clinical events associated with discontinuation comprise thrombotic microangiopathy (TMA) or a TMA-related complication.
  • TMA-related complication is selected from the group consisting of: changes in mental status, seizures, angina, dyspnea, and thrombosis.
  • the TMA-related complication can be identified by comparing two or more measurements of a laboratory parameter selected from the group consisting of: platelet count, serum creatinine level, and serum LDH level.
  • a TMA-related complication is indicated by i) a 25% or greater decrease in platelet count compared to baseline or the peak platelet count during treatment; ii) an increase of 25% or greater in serum creatinine level compared to baseline or nadir level during treatment; or iii) an increase of 25% or greater in serum LDH level compared to baseline or nadir level during treatment.
  • the present disclosure provides a method of creating a database of patients who have a complement-associated disorder, wherein said method comprises registering via a computer readable medium a database containing information of the patients, wherein the information includes that the patients, or the patients' legal guardians or representatives, have received one or both of verbal and written warning as to the risk of adverse clinical events associated with discontinuing use of a complement inhibitor to treat the disorder.
  • the complement-associated disorder is selected from the group consisting of: a complement-associated inflammatory disorder, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), age-related macular degeneration (AMD), rheumatoid arthritis (RA), myasthenia gravis (MG), neuromyelitis optica (NMO), catastrophic anti-phospholipid syndrome (CAPS), anti-phospholipid syndrome (APS), sepsis, a complement- associated pulmonary disorder, asthma, and chronic obstructive pulmonary disease (COPD).
  • PNH paroxysmal nocturnal hemoglobinuria
  • aHUS atypical hemolytic uremic syndrome
  • AMD age-related macular degeneration
  • RA age-related macular degeneration
  • RA rheumatoid arthritis
  • MG myasthenia gravis
  • NMO neuromyelitis optica
  • CAS catastrophic anti-phospholipid syndrome
  • APS anti-phospholipid syndrome
  • the information further comprises that the patients, or the patients' legal guardians or representatives, have acknowledged the warning and agreement to the complement inhibitor treatment. In one preferred embodiment, the patients receive the warning prior to the distribution of the complement inhibitor.
  • the complement inhibitor disclosed herein is an inhibitor of complement protein C5.
  • the complement inhibitor is an antibody or antigen-binding fragment thereof recognizing C5.
  • the antibody or antigen-binding fragment thereof is eculizumab (Soliris ® ), pexelizumab, or a biosimilar equivalent of eculizumab or pexelizumab.
  • the present disclosure also provides a database of patients created by the methods described herein.
  • the present disclosure provides a method for reporting at least one adverse event to a government regulatory agency, the method comprising searching the database disclosed herein to determine information about patients having a complement-associated disorder and experiencing at least one adverse clinical event upon discontinuation of a therapy with a complement inhibitor (CI1) and communicating the information to a government regulatory agency.
  • searching the database disclosed herein to determine information about patients having a complement-associated disorder and experiencing at least one adverse clinical event upon discontinuation of a therapy with a complement inhibitor (CI1) and communicating the information to a government regulatory agency.
  • CI1 complement inhibitor
  • the present disclosure provides a method for distributing a complement inhibitor (CI1) for treating a complement-associated disorder, wherein at least one adverse clinical event may occur upon discontinuation of the treatment with the complement inhibitor, the method comprising: i) obtaining an approval from a government regulatory agency for distributing the complement inhibitor, wherein the government regulatory agency has been previously notified of the at least one potential adverse clinical event; and ii) providing the complement inhibitor together with a document providing a warning comprising the information of the at least one potential adverse clinical event to a distributor, a prescriber, an authorized dispenser, or a patient having the disorder, or the legal guardian or representative of the patient.
  • CI1 complement inhibitor for treating a complement-associated disorder, wherein at least one adverse clinical event may occur upon discontinuation of the treatment with the complement inhibitor
  • the method comprising: i) obtaining an approval from a government regulatory agency for distributing the complement inhibitor, wherein the government regulatory agency has been previously notified of the at least one potential adverse clinical event; and ii) providing the complement inhibitor together with
  • the present disclosure provides a method for treating a patient with a complement inhibitor, wherein the patient is: (i) afflicted with, suspected of having, or at risk for developing a complement-associated disorder, and (ii) in need of treatment with the complement inhibitor, the method comprising:
  • the present disclosure provides a method for treating a patient who has a complement-associated disorder and has discontinued therapy with a complement inhibitor (CI1), the method comprising:
  • the present disclosure provides a method of warning a patient who has a complement-associated disorder and is prescribed a complement inhibitor (CI1) of the risk of an adverse clinical event if the patient discontinues treatment with said complement inhibitor, the method comprising placing a written warning on the package label or package insert of said complement inhibitor.
  • CI1 complement inhibitor
  • the complement-associated disorder disclosed herein is selected from the group consisting of: a complement-associated inflammatory disorder, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), age-related macular degeneration (AMD), rheumatoid arthritis (RA), myasthenia gravis (MG), neuromyelitis optica (NMO), catastrophic anti-phospholipid syndrome (CAPS), anti-phospholipid syndrome (APS), sepsis, a complement-associated pulmonary disorder, asthma, and chronic obstructive pulmonary disease (COPD).
  • PNH paroxysmal nocturnal hemoglobinuria
  • aHUS atypical hemolytic uremic syndrome
  • AMD age-related macular degeneration
  • RA age-related macular degeneration
  • RA rheumatoid arthritis
  • MG myasthenia gravis
  • NMO neuromyelitis optica
  • CAS catastrophic anti-phospholipid syndrome
  • APS anti-phospholipid
  • the patient is treated by re -initiation of the complement inhibitor (CIl) treatment or with an alternative therapy for the adverse clinical events after the
  • the alternative therapy comprises treating with a different complement inhibitor (CI2) or with a different regimen of the same complement inhibitor (CIl).
  • the alternative therapy comprises plasma therapy, or organ-specific supportive measures, or any combination thereof.
  • the plasma therapy is selected from the group consisting of: plasmapheresis, plasma exchange, and fresh frozen plasma infusion.
  • the complement inhibitor (CIl) of the present disclosure is an inhibitor of complement protein C5.
  • the complement inhibitor (CIl) is an antibody or antigen-binding fragment thereof recognizing C5.
  • the antibody or antigen-binding fragment thereof is eculizumab (Soliris ® ), pexelizumab, or a biosimilar equivalent to eculizumab or pexelizumab.
  • the antibody or antigen-binding fragment thereof binds to the cleavage site of C5 and thereby inhibits cleavage of C5 by preventing the C5 convertase from accessing the cleavage site in C5.
  • the adverse clinical events associated with discontinuation comprise thrombotic microangiopathy (TMA) or a TMA-related complication.
  • TMA thrombotic microangiopathy
  • the TMA-related complication is selected from the group consisting of: changes in mental status, seizures, angina, dyspnea, and thrombosis.
  • the TMA-related complication can be identified by comparing two or more measurements of a laboratory parameter selected from the group consisting of: platelet count, serum creatinine level, and serum LDH level.
  • a TMA-related complication is indicated by: i) a 25% or greater decrease in platelet count compared to baseline or the peak platelet count during treatment; ii) an increase of 25% or greater in serum creatinine level compared to baseline or nadir during treatment; or iii) an increase of 25% or greater in serum LDH level compared to baseline or nadir during treatment.
  • the present disclosure provides a method for distributing a complement inhibitor (Cll) for use in treating a patient: (i) afflicted with, suspected of having, or at risk for developing a complement-associated disorder, and (ii) in need of treatment with the complement inhibitor, the method comprising: i) authorizing distribution of a complement inhibitor to a physician or a pharmacy who will further distribute the inhibitor to the patient, upon certification from the physician or pharmacy that:
  • the physician or pharmacy will distribute the warning to the patient, or the legal guardian or representative of the patient; ii) registering via a computer readable medium a database comprising the information that the physician or pharmacy has received and acknowledged the warning and agreed to distributing the warning to the patient, or the legal guardian or representative of the patient; and iii) following (i) and (ii), distributing the complement inhibitor to the physician or pharmacy for use in treating the patient.
  • the present disclosure provides a method of creating a database of physicians or pharmacies who will distribute a complement inhibitor (CIl) for use in treating a complement-associated disorder, wherein said method comprises registering via a computer readable medium a database containing information that the physicians or pharmacies have received and acknowledged one or both of verbal and written warning as to the risk of adverse clinical events associated with discontinuing use of a complement inhibitor to treat the disorder and agreed to distributing the warning to the patient who has the disorder, or the legal guardian or representative of the patient.
  • CIl complement inhibitor
  • the complement-associated disorder disclosed herein is selected from the group consisting of: a complement-associated inflammatory disorder, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), age-related macular degeneration (AMD), rheumatoid arthritis (RA), myasthenia gravis (MG),
  • PNH paroxysmal nocturnal hemoglobinuria
  • aHUS atypical hemolytic uremic syndrome
  • AMD age-related macular degeneration
  • RA rheumatoid arthritis
  • MG myasthenia gravis
  • NMO neuromyelitis optica
  • CPS catastrophic anti-phospholipid syndrome
  • APS anti- phospholipid syndrome
  • sepsis a complement-associated pulmonary disorder
  • asthma chronic obstructive pulmonary disease
  • the present disclosure provides a database of physicians or pharmacies created by the methods disclosed herein.
  • the present disclosure provides a system for distributing a complement inhibitor (CIl) for use in treating a patient: (i) afflicted with, suspected of having, or at risk for developing a complement-associated disorder, and (ii) in need of treatment with the complement inhibitor, the system comprising: a memory or a storage device for storing information about the patient and about whether an instruction to distribute the complement inhibitor is executed; and a processor configured to execute the instruction, wherein the instruction causes the processor to perform the steps comprising: i) searching the memory or storage device for certifications that:
  • the patient, or the legal guardian or representative of the patient is competent to comprehend and assess information and to make decisions;
  • the patient, or the legal guardian or representative of the patient has received one or both of verbal and written warning as to the risk of adverse clinical events associated with discontinuing use of the complement inhibitor to treat the disorder;
  • step i) the patient, or the legal guardian or representative of the patient, has expressed acknowledgment of the warning and agreement to the treatment; ii) upon the identification of certifications in step i), authorizing distribution of the complement inhibitor to treat the patient; and iii) registering via the memory or storage device the distribution of the complement inhibitor.
  • the disorder is selected from the group consisting of: a complement-associated inflammatory disorder, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), age-related macular degeneration (AMD), rheumatoid arthritis (RA), myasthenia gravis (MG), neuromyelitis optica (NMO), catastrophic anti-phospholipid syndrome (CAPS), anti-phospholipid syndrome (APS), sepsis, a complement- associated pulmonary disorder, asthma, and chronic obstructive pulmonary disease (COPD).
  • PNH paroxysmal nocturnal hemoglobinuria
  • aHUS atypical hemolytic uremic syndrome
  • AMD age-related macular degeneration
  • RA age-related macular degeneration
  • RA rheumatoid arthritis
  • MG myasthenia gravis
  • NMO neuromyelitis optica
  • CAS catastrophic anti-phospholipid syndrome
  • APS anti-phospholipid syndrome
  • the information stored in the memory or storage device disclosed herein further comprises the information concerning the patient's discontinuing use of the complement inhibitor (CIl) and that the patient is monitored for adverse clinical events after the discontinuation.
  • the information stored in the memory or storage device disclosed herein further comprises that the patient is treated by re-initiation of the complement inhibitor (CIl) treatment or with an alternative therapy to treat the adverse clinical events after discontinuing use of the complement inhibitor (CIl).
  • the alternative therapy comprises treating with a different complement inhibitor (CI2) or with a different regimen of the same complement inhibitor (CIl).
  • the alternative therapy comprises plasma therapy, or organ-specific supportive measures, or a combination thereof.
  • the plasma therapy disclosed herein is selected from the group consisting of: plasmapheresis, plasma exchange, and fresh frozen plasma infusion.
  • the complement inhibitor (CIl) disclosed herein is an inhibitor of complement protein C5.
  • the complement inhibitor (CIl) is an antibody or antigen-binding fragment thereof recognizing C5.
  • the antibody or antigen-binding fragment thereof includes at least eculizumab (Soliris ® ), pexelizumab, or a biosimilar equivalent of eculizumab or pexelizumab.
  • the adverse clinical events associated with discontinuation disclosed herein comprise thrombotic microangiopathy (TMA) or a TMA-related complication.
  • the TMA-related complication is selected from the group consisting of: changes in mental status, seizures, angina, dyspnea, and thrombosis.
  • the TMA- related complication is identified by comparing two or more measurements of a laboratory parameter, said laboratory parameter being selected from the group consisting of: platelet count, serum creatinine, and serum LDH.
  • a TMA-related complication is indicated by: i) a 25% or greater decrease in platelet count compared to baseline or the peak platelet count during treatment; ii) an increase of 25% or greater in serum creatinine compared to baseline or nadir during treatment; or iii) an increase of 25% or greater in serum LDH compared to baseline or nadir during treatment.
  • the information stored in the memory or storage device disclosed herein is created into a database. In some embodiments, the information stored in the memory or storage device is to be reported to a government regulatory agency. In one embodiment, the complement inhibitor is distributed after obtaining an approval from the government regulatory agency.
  • the information stored in the memory or storage device further comprises that the complement inhibitor is distributed with a document providing a warning about at least one potential adverse clinical event after discontinuing use of the complement inhibitor (CI1).
  • the present disclosure is directed generally to methods for the delivery of drugs, especially drugs inhibiting complement activation pathways, to patients.
  • drug refers to any substance which is intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure or function of the body.
  • the methods of the present disclosure may be desirably and advantageously used to educate and reinforce the actions and behaviors of patients who are taking the drug, as well as prescribers who prescribe the drug and pharmacies which dispense the drug. Such education and reinforcement of actions and behavior are often necessary to ensure proper prescribing and dispensing of the drug, as well as patient compliance with taking the drug. In certain cases it is also necessary to educate patients and prescribers concerning discontinuation of the drug.
  • Discontinuation of a drug may lead to harmful effects and the patient and prescriber need to be educated as to what these harmful effects may be, how to monitor for harmful effects, and how to treat the patient if harmful effects are seen upon discontinuation.
  • a wide variety of educational materials may be employed to ensure proper prescribing, dispensing, patient compliance and follow-up observation according to the methods described herein, including, for example, a variety of literature and other materials, such as, for example, product information, package inserts, educational brochures, continuing education monographs, videotapes and the like which may describe the risks and benefits associated with taking and/or discontinuing the particular drug.
  • complement inhibitor refers to any agent (e.g., any nucleic acids, amino acids, polynucleotides, polypeptides, proteins, chemical compounds, etc.) which is capable of at least partially reducing, neutralizing, antagonizing or completely inhibiting the activation of complement activation pathways, e.g., the classical pathway, the alternative pathway, and the lectin pathway.
  • the complement inhibitor in this application can be any inhibitor that antagonizes any component in the complement activation pathways, resulting in a decreased level of downstream complement activation products.
  • a complement inhibitor may generally and broadly inhibit the complement activation at the level of CI esterase, C3, or selectively block C5 activation with subsequent inhibition of C5a and C5b-9 (TCC) formation.
  • TCC C5a and C5b-9
  • One non-limiting example of such inhibitors is an antibody or antigen-binding fragment thereof or antigen-binding polypeptide which binds to the cleavage site of C5 and thereby inhibits cleavage of C5 by preventing the C5 convertase from accessing the cleavage site in C5.
  • Such inhibitors also include an antibody or antigen-binding fragment thereof or antigen-binding polypeptide which binds to C5a or C5b fragment and inhibits their activities.
  • Another non-limiting example is an antibody or antigen-binding fragment thereof which binds to C5 at a site other than the cleavage site but prevents cleavage of C5.
  • the antibodies eculizumab and pexelizumab are examples of such antibodies.
  • Other complement inhibitors may antagonize or inhibit activators of complement pathways.
  • One non- limiting example of such inhibitors is an antibody, antigen-binding fragment, antigen-binding polypeptide, or agent which recognizes and inhibits factor B or factor D.
  • Some naturally occurring regulators include, for example, CI inhibitors, complement receptor 1 (CR1/CD35), complement receptor 2 (CR2/CD21), membrane cofactor protein (MCP/CD46), decay- accelerating factor (DAF/CD55), factor I, factor H, C4BP, complement receptor 1 related gene/protein (Crry), CD59, microbial proteins, etc.
  • Recombinant regulators may also be designed based on the natural regulators.
  • soluble proteins e.g., soluble CR1, DAF, CD59, etc.
  • tagged proteins e.g., with a glycosylphosphatidylinositol (GPI) anchor for specific targeting to cell surface
  • fusion proteins comprising at least one regulator
  • Dominant negative proteins e.g., containing a dominant negative mutation or truncation
  • of natural regulators can also be used as inhibitors of the corresponding endogenous proteins.
  • chimeric proteins containing at least one inhibitor and at least one other agent could be constructed.
  • the recombinant complement inhibitor is an antibody or antigen-binding fragment thereof specifically recognizing at least one complement pathway component, such as, for example, mannose-binding lectin (MBL), CI, C3, C3 convertase, C5, C5 convertase, C5a, C5b-9 (TCC), factor D, factor B, etc.
  • complement inhibitors may lead to an inhibition of the activation of certain complement pathway components or the formation of various species, such as certain protein complexes.
  • the complement inhibitor of this application also includes small molecule inhibitors, for example, CI binding peptides, compstatin, C3aR antagonists, C5aR antagonists, other small molecule inhibitors of complement components, etc.
  • small molecule inhibitors for example, CI binding peptides, compstatin, C3aR antagonists, C5aR antagonists, other small molecule inhibitors of complement components, etc.
  • the complement inhibitor is an antibody or antigen- binding fragment thereof specifically recognizing C5.
  • the antibody or antigen-binding fragment thereof is the mouse anti-C5 monoclonal antibody BB5.1 (Frei et al., 1987. Generation of a monoclonal antibody to mouse C5 application in an ELISA assay for detection of anti-C5 antibodies. Mol. Cell. Probes 1 : 141-149), the humanized anti-C5 single chain fragment h5Gl . l-scFv (i.e., pexelizumab, Alexion Pharmaceuticals, Cheshire, CT), or the humanized anti-C5 monoclonal antibody eculizumab (with the commercial name Soliris ® , Alexion Pharmaceuticals, Inc.), or an antigen-binding fragment thereof.
  • BB5.1 mouse anti-C5 monoclonal antibody BB5.1
  • the humanized anti-C5 single chain fragment h5Gl . l-scFv i.e., pexelizumab, Alexion Pharmaceuticals, Cheshire, CT
  • C5 binding molecules and anti-C5 antibodies useful as complement inhibitors of the present disclosure include, for example, C5 binding molecules and anti-C5 antibodies described in the U.S. Patent Application Publication Nos. 20100034809 and 20100166748, in U.S. Patent No. 7,999,081, and in Wurzner et al. ((1991). Inhibition of terminal complement complex formation and cell lysis by monoclonal antibodies. Complement Inflamm. 8:328-340).
  • the complement inhibitor is a polypeptide comprising an amino acid sequence with at least about 50% (e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or above 95%) homology (similarity) or identity with that of the instantly disclosed antibody or antigen-binding fragment thereof or antigen- binding polypeptide (e.g., eculizumab or pexelizumab).
  • the complement inhibitor comprises an amino acid sequence with at least about 75% homology or identity therewith.
  • the complement inhibitor may comprise in other instances an amino acid sequence with at least about 80% homology or identity therewith and in other embodiments at least about 85%, 90% or 95% homology or identity therewith.
  • complement activation or similar terms used herein in general refers to the activation of at least one of the complement pathways and at least one of the downstream complement components
  • inhibiting complement activation by antagonizing C5" or similar terms used herein specifically refers to inhibiting the cleavage of C5 into C5a and C5b by C5 convertase and inhibiting downstream C5b-9 complex formation or inhibiting the formation of C5a or the activity of C5a.
  • the complement inhibitor featured in the disclosure is designed for treating or preventing a complement-associated disorder.
  • the method involves administering to a subject (e.g., a human) in need thereof a therapeutic complement inhibitor (e.g., an antibody or antigen-binding fragment thereof) described herein in an amount sufficient to treat a complement-associated disorder afflicting the subject.
  • a therapeutic complement inhibitor e.g., an antibody or antigen-binding fragment thereof
  • the complement-associated disorder can be, e.g., a complement-associated inflammatory disorder, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), age-related macular degeneration (AMD), rheumatoid arthritis (RA), myasthenia gravis (MG), neuromyelitis optica (NMO), catastrophic anti- phospholipid syndrome (CAPS), anti-phospholipid syndrome (APS), or sepsis.
  • the complement-associated disorder is a complement-associated pulmonary disorder.
  • the complement-associated pulmonary disorder can be, e.g., asthma or chronic obstructive pulmonary disease (COPD).
  • the mode of administration which can vary depending on the type of complement-associated disorder to be treated, can be, e.g., intravenous administration, intrapulmonary administration, intraocular administration, subcutaneous administration, or intraarticular administration.
  • the complement inhibitor featured in the disclosure can be performed in conjunction with other therapies for complement-associated disorders.
  • the composition can be administered to a subject at the same time, prior to, or after, plasmapheresis, IVIG therapy, or plasma exchange. See, e.g., Appel et al. (2005) J Am Soc Nephrol 16:1392-1404.
  • the complement inhibitor can be administered to a subject at the same time, prior to, or after, a kidney transplant.
  • a “subject,” as used herein, is a human. In some embodiments, the subject is an infant, adolescent, or adult.
  • a subject “in need of prevention,” “in need of treatment,” or “in need thereof,” refers to one, who by the judgment of an appropriate medical practitioner (e.g., a doctor, a nurse, or a nurse practitioner in the case of humans; a veterinarian in the case of non- human mammals), would reasonably benefit from a given treatment (such as treatment with a composition comprising an anti-C5 antibody or antigen-binding fragment thereof).
  • an appropriate medical practitioner e.g., a doctor, a nurse, or a nurse practitioner in the case of humans; a veterinarian in the case of non- human mammals
  • prevention of a complement-associated disorder such as asthma includes, for example, reducing the extent or frequency of coughing, wheezing, or chest pain in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the occurrence of coughing or wheezing in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
  • terapéuticaally effective amount or “therapeutically effective dose,” or similar terms used herein are intended to mean an amount of an agent (e.g., a complement inhibitor) that will elicit the desired biological or medical response (e.g., an improvement in one or more symptoms of a complement-associated disorder).
  • an agent e.g., a complement inhibitor
  • patient certification is intended to mean that (a) the patient, or the legal guardian or representative of the patient, is competent to comprehend and assess information and to make decisions; (b) the patient, or the legal guardian or representative of the patient, has received one or both of verbal and written warning as to the risk of adverse clinical events associated with discontinuing use of the complement inhibitor to treat the disorder; and (c) the patient, or the legal guardian or representative of the patient, has acknowledged the warning and agreement to the treatment.
  • antibody refers to a whole or intact antibody (e.g., IgM, IgG, IgA, IgD, or IgE) molecule that is generated by any one of a variety of methods that are known in the art and described herein.
  • antibody includes a polyclonal antibody, a monoclonal antibody, a chimerized or chimeric antibody, a humanized antibody, a deimmunized human antibody, and a fully human antibody.
  • the antibody can be made in or derived from any of a variety of species, e.g., mammals such as humans, non-human primates (e.g., monkeys, baboons, or chimpanzees), horses, cattle, pigs, sheep, goats, dogs, cats, rabbits, guinea pigs, gerbils, hamsters, rats, and mice.
  • mammals such as humans, non-human primates (e.g., monkeys, baboons, or chimpanzees), horses, cattle, pigs, sheep, goats, dogs, cats, rabbits, guinea pigs, gerbils, hamsters, rats, and mice.
  • the antibody can be a purified or a recombinant antibody.
  • antibody fragment refers to a fragment of an antibody that retains the ability to bind to an antigen, e.g., a single chain antibody (scFv), an Fd fragment, an Fab fragment, an Fab' fragment, or an F(ab') 2 fragment.
  • scFv single chain antibody
  • An scFv is a single polypeptide chain that includes both the heavy and light chain variable regions of the antibody from which the scFv is derived.
  • diabodies Polyjak ( 1994) Structure 2(12): 1121-1123; Hudson et al.
  • compositions and used in the methods, described herein.
  • Chimeric antibodies and antigen-binding fragments thereof comprise portions from two or more different species (e.g., mouse and human). Chimeric antibodies can be produced with mouse variable regions of desired specificity fused to human constant domains (for example, U.S. Patent No. 4,816,567). In this manner, non-human antibodies can be modified to make them more suitable for human clinical application (e.g., methods for treating or preventing a complement-mediated disorder in a subject).
  • the monoclonal antibodies of the present disclosure include "humanized" forms of the non-human (e.g., mouse) antibodies.
  • Humanized or CDR-grafted mAbs are particularly useful as therapeutic agents for humans because they are not cleared from the circulation as rapidly as mouse antibodies and do not typically provoke an adverse immune reaction.
  • a humanized antibody has one or more amino acid residues introduced into it from a non-human source. These non-human amino acid residues are often referred to as "import” residues, which are typically taken from an “import” variable domain. Methods of preparing humanized antibodies are generally well known in the art.
  • the antibodies and biologically-active fragments described herein can be used to treat a variety of complement-associated disorders such as, but not limited to: rheumatoid arthritis (RA); lupus nephritis; ischemia-reperfusion injury; paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS); typical or infectious hemolytic uremic syndrome (tHUS); myasthenia gravis (MG); neuromyelitis optica (NMO); antiphospholipid syndrome (APS); Degos disease; catastrophic APS (CAPS); dense deposit disease (DDD); scleroderma; multiple sclerosis (MS); macular degeneration (e.g., age-related macular degeneration (AMD)); hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; sepsis; dermatomyositis; diabetic retinopathy; thrombotic thrombocytopenic purpura (TTP); spontaneous
  • the complement-mediated disorder is a complement-mediated vascular disorder such as, but not limited to, a cardiovascular disorder, myocarditis, a cerebrovascular disorder, a peripheral (e.g., musculoskeletal) vascular disorder, a renovascular disorder, a mesenteric/enteric vascular disorder, revascularization to transplants and/or replants, vasculitis, Henoch-Schonlein purpura nephritis, systemic lupus erythematosus-associated vasculitis, vasculitis associated with rheumatoid arthritis, immune complex vasculitis, Takayasu's disease, capillary leak syndrome, dilated cardiomyopathy, diabetic angiopathy, thoracic-abdominal aortic aneurysm
  • a complement-mediated vascular disorder such as, but not limited to, a cardiovascular disorder, myocarditis, a cerebrovascular disorder, a peripheral (e.g.,
  • the complement-associated disorder is myasthenia gravis, cold-agglutinin disease (CAD), paroxysmal cold hemoglobinuria (PCH), dermatomyositis, scleroderma, warm autoimmune hemolytic anemia, Graves' disease,
  • Hashimoto's thyroiditis type I diabetes, psoriasis, pemphigus, autoimmune hemolytic anemia (AIHA), idiopathic thrombocytopenic purpura (ITP), Goodpasture syndrome, myasthenia gravis (MG), neuromyelitis optica (NMO), antiphospholipid syndrome (APS), Degos disease, and catastrophic APS (CAPS).
  • AIHA autoimmune hemolytic anemia
  • ITP idiopathic thrombocytopenic purpura
  • MG myasthenia gravis
  • NMO neuromyelitis optica
  • APS antiphospholipid syndrome
  • Degos disease Degos disease
  • catastrophic APS catastrophic APS
  • the complement inhibitor described herein alone or in
  • RA above
  • inflammatory bowel disease above
  • sepsis above
  • septic shock acute lung injury
  • DIC disseminated intravascular coagulation
  • the second anti-inflammatory agent can be one selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, methotrexate, hydroxychloroquine, anti-TNF agents such as etanercept and infliximab, a B cell depleting agent such as rituximab, an interleukin-1 antagonist, or a T cell costimulatory blocking agent such as abatacept (marketed as Orencia ® by Bristol-Myers Squibb, New York, NY).
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • corticosteroids corticosteroids
  • methotrexate hydroxychloroquine
  • anti-TNF agents such as etanercept and infliximab
  • B cell depleting agent such as rituximab
  • an interleukin-1 antagonist such as interleukin-1 antagonist
  • T cell costimulatory blocking agent such as abatacept (marketed as Orencia ®
  • the complement-associated disorder is a complement-associated neurological disorder such as, but not limited to, amyotrophic lateral sclerosis (ALS), brain injury, Alzheimer's disease, myasthenia gravis (MG), neuromyelitis optica (NMO), and chronic inflammatory demyelinating neuropathy.
  • ALS amyotrophic lateral sclerosis
  • MG myasthenia gravis
  • NMO neuromyelitis optica
  • Complement-associated disorders also include complement-associated pulmonary disorders such as, but not limited to, asthma, bronchitis, a chronic obstructive pulmonary disease (COPD), an interstitial lung disease, a-1 anti-trypsin deficiency, emphysema, bronchiectasis, bronchiolitis obliterans, diffuse interstitial lung disease, alveolitis, sarcoidosis, pulmonary fibrosis, and collagen vascular disorders.
  • complement-associated pulmonary disorders such as, but not limited to, asthma, bronchitis, a chronic obstructive pulmonary disease (COPD), an interstitial lung disease, a-1 anti-trypsin deficiency, emphysema, bronchiectasis, bronchiolitis obliterans, diffuse interstitial lung disease, alveolitis, sarcoidosis, pulmonary fibrosis, and collagen vascular disorders.
  • COPD chronic o
  • the disclosure features treating a patient with the complement inhibitor described herein (e.g., an anti-C5 antibody or antigen-binding fragment thereof), wherein the patient is: (i) afflicted with, suspected of having, or at risk for developing a complement- associated disorder (e.g., PNH or aHUS); and (ii) in need of treatment.
  • the complement inhibitor described herein e.g., an anti-C5 antibody or antigen-binding fragment thereof
  • PNH complement-associated disorder
  • a complement-associated disorder e.g., PNH or aHUS
  • PNH is a debilitating and life-threatening disorder characterized by genetic mutations in hematopoietic stem cells leading to uncontrolled complement activation causing chronic intravascular hemolysis and an inflammatory prothrombotic state.
  • PNH evolves from the clonal expansion of hematopoietic stem cells harboring a somatic mutation causing complete or marked loss of the GPI-linked terminal complement inhibitor DAF/CD55 and CD59 from the surface of hematopoietic cells, rendering red blood cells (RBCs) highly susceptible to uncontrolled terminal complement-mediated hemolysis, and white blood cells and platelets to uncontrolled complement-mediated cell activation.
  • RBCs red blood cells
  • the destruction and loss of these abnormal RBCs results in low RBC counts (anemia), and also fatigue, difficulty in functioning, pain, dark urine, shortness of breath, and blood clots.
  • aHUS is a complement inhibitor deficiency disorder characterized by uncontrolled complement activation, resulting in platelet activation and endothelial cell damage.
  • aHUS is characterized as a thrombotic microangiopathic disease (TMA), which includes a triad of thrombotic thrombocytopenia, microangiopathic hemolysis and impaired renal function as well as other ischemic complications.
  • TMA thrombotic microangiopathic disease
  • patients with aHUS their kidney and blood cells, including platelets, can be inflamed which can lead to low blood counts (thrombocytopenia and anemia), reduced or lost kidney function, blood clots, tiredness and difficulty in functioning.
  • aHUS Most cases of aHUS are secondary to mutations in genes which encode components of the alternative pathway of the complement cascade. Similar to observations in PNH, uncontrolled complement activation may contribute to the TMA process in aHUS by causing inflammation and prothrombotic activity. Patients with aHUS currently face a very poor prognosis with high likelihood of kidney failure, dialysis and/or death within one year from the time of diagnosis unless treated with a complement inhibitor such as Soliris ® . While aHUS is a very rare disorder, the incidence of aHUS has been poorly characterized. From the sparse epidemiologic data in the literature, reports indicate that most patients develop the disease before 10 years of age. See Loirat et al.
  • complement regulatory proteins e.g., factor H (FH), MCP, factor I, factor B and C3, etc.
  • aHUS patients While many aHUS patients report a prodrome of feeling unwell, including fever, malaise, diarrhea, abdominal pain, nausea, vomiting, or neurologic symptoms, aHUS patients are generally only clinically identified when they present with an abrupt onset of signs and symptoms. If they survive this initial disease presentation, they are typically burdened with a chronic thrombotic and inflammatory state characterized by platelet and endothelial cell activation which carries a life-long elevated risk of sudden blood clotting, renal insufficiency with ensuring dialysis, and other severe complications of TMA.
  • Severe TMA complications in aHUS patients include seizures, CNS infarcts, coma, cardiomyopathy, myocardial infarction, pancreatitis, pulmonary distress, diffuse vasculopathy, and multi-organ TMA. These complications frequently lead to premature mortality in aHUS.
  • PT immunosuppressant drugs and supportive care.
  • the rationale for the use of PT in aHUS patients is to remove plasma, which contains mutated complement regulatory proteins or auto-antibodies to complement regulatory proteins, and replace it with fresh frozen plasma from healthy donors in an attempt to transiently restore control of complement activity.
  • PT is a laborious procedure leading to a poor quality of life for patients who receive it. It is also associated with a risk of infection, allergic reactions, thrombosis, and loss of vascular access and provides incomplete reversal of TMA. Kidney transplant has been undertaken in aHUS patients;
  • recurrent aHUS causes kidney transplant failure in up to approximately 60 to 90 percent of patients.
  • eculizumab Soliris ® , Alexion Pharmaceuticals, Inc.
  • eculizumab a humanized monoclonal antibody specifically recognizing human complement protein C5 and preventing the cleavage of C5 and the formation of C5a and the C5b-9 terminal complex
  • Adverse effects resulting from complement inhibition may be directly related to the function of complement, i.e., increased susceptibility to infection and autoimmune- and immune- complex diseases, arising from impaired opsonization, adaptive immune response, tolerance or elimination of immune-complexes.
  • the risk of infectious complications is most probably highest when blocking C3. Blocking of C5b-9 formation, however, could lead to increased susceptibility to certain pathogens, such as Neisseriae.
  • Gram-negative septic shock may result from complement inhibition, while treatment with antibiotics would compensate for short-term complement inhibition.
  • meningococcal infections are the most important adverse reactions experienced by patients while on the drug.
  • the use of Soliris ® increases a patient's susceptibility to serious meningococcal infections (septicemia and/or meningitis).
  • the risk groups or the most known risk factors include: 1) genetic deficiency or therapeutic inhibition of terminal complement (such as Soliris ® therapy); 2) lack of commercially available vaccine against meningococcus serogroup B; and 3) delay or absence of appropriate medical consultation at the appearance of first symptoms.
  • the occurrence of meningococcal infection can be prevented in some cases by means of meningococcal vaccines.
  • meningococcal vaccine For example, patients without a history of meningococcal vaccination can be vaccinated at least 2 weeks prior to receiving the first dose of Soliris or other complement inhibitor. If urgent Soliris ® therapy is indicated in an unvaccinated patient, the meningococcal vaccine should be administered as soon as possible. In patients who cannot receive meningococcal vaccine, including children below the age of two years, antibiotic prophylaxis could prevent meningococcal infection. However, meningococcal vaccination reduces, but does not eliminate, the risk of meningococcal infections. In addition, available meningococcal vaccines do not cover all serogroups, notably serogroup B infection.
  • anti-C5 antibodies or antigen-binding fragments e.g., eculizumab and
  • patients treated with these agents may have increased susceptibility to infections in addition to
  • meningococcal infections especially with encapsulated bacteria.
  • children or adolescent patients may be at increased risk of developing serious infections due to
  • the Soliris ® therapy has been found to increase the number of PNH cells. Actually, the proportion of PNH RBCs increased among Soliris ® -treated PNH patients by a median of 28% from baseline (range from -25% to 69%). Thus, PNH patients who discontinue treatment with Soliris ® may be at increased risk for serious hemolysis.
  • Serious hemolysis is identified by serum lactic dehydrogenase (LDH) levels greater than the pre-treatment level, along with any of the following: greater than 25% absolute decrease in PNH clone size (in the absence of dilution due to transfusion) in one week or less; a hemoglobin level of ⁇ 5 gm/dL or a decrease of >4 gm/dL in one week or less; angina; change in mental status; a 50% increase in serum creatinine level; or thrombosis. Therefore, any PNH patient who discontinues Soliris ® should be monitored for at least 8 weeks to detect serious hemolysis and other reactions.
  • LDH serum lactic dehydrogenase
  • TMA severe thrombotic microangiopathy
  • Severe TMA complications post discontinuation were identified by (i) any two or more measurements of any one of the following: a decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during eculizumab treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during eculizumab treatment; or, an increase in serum LDH of 25% or more as compared to baseline or to nadir during eculizumab treatment; or (ii) any one of the following: a change in mental status or seizures; angina or dyspnea; or thrombosis.
  • Soliris ® treatment 18 patients (5 in the prospective studies) discontinued Soliris ® treatment.
  • baseline for different laboratory parameters used in the present disclosure is the last value available for the patient prior to initiation of treatment.
  • Some clinical parameters may be helpful for laboratory monitoring of PNH and aHUS with or without Soliris ® treatment.
  • serum LDH levels increase during hemolysis and may assist in monitoring Soliris ® effects, including the response to
  • TMA thrombotic microangiopathy
  • TMA complications occur after Soliris ® discontinuation, the re-initiation of the drug, with the same or a different regimen (e.g., dosage, injection method and frequency, etc.) should be considered.
  • other available therapies include, for example, plasma therapy (e.g., plasmapheresis, plasma exchange, fresh frozen plasma infusion, etc.) or appropriate organ- specific supportive measures.
  • aHUS patients For safety concerns, pharmacovigilance has to be maintained for aHUS patients.
  • aHUS patients will be registered into a database and information regarding their risk factors (e.g., laboratory parameters regarding aHUS symptoms, related diseases, adverse reactions during therapy or after therapy discontinuation, therapy regimens, adverse events or state of well-being) may be collected.
  • the information in the database may be updated, if necessary, and provided, if necessary, to any drug manufacturer, supplier, prescriber, aHUS patient (or the patient's legal guardian, representative, or supervising practitioner) as well as regulatory authorities.
  • the drug-distributing methods of the present disclosure preferably involve, inter alia, registering in a computer readable storage medium prescribers who are qualified to prescribe the involved complement inhibitor drugs including, for example, eculizumab (Soliris ® ),
  • pexelizumab biosimilar equivalents of eculizumab or pexelizumab, other C5-binding molecules and anti-C5 antibodies or antigen-binding fragments thereof, e.g., those disclosed in U.S. Patent Application Publication Nos. 20100034809 and 20100166748, in U.S. Patent No. 7,999,081 or in Wurzner et al. (Complement Inflamm. 8:328-340 (1991)).
  • the prescriber may be eligible to prescribe the drug to patients in need of the drug.
  • the prescriber may be required to comply with various aspects of the methods described herein including, for example, providing patient education and counseling, and the like, as described in detail below.
  • the registration of the prescriber in the computer readable storage medium may be achieved by providing the prescriber, for example, by hand, mail, facsimile transmission, or on-line transmission, with a registration card or form, preferably together with appropriate educational materials concerning, for example, the particular drug for which the prescriber is being registered to prescribe, as well as suitable methods for delivering the drug to the patient, including the drug delivery methods described herein.
  • the prescriber will preferably complete the registration card or form by providing information requested therein, and the registration card or form will preferably be returned to the manufacturer or distributor of the drug, or other authorized recipient of the registration materials, for example, by hand, mail, facsimile transmission or on-line transmission.
  • Information which may be requested of the prescriber in the registration card or form may include, for example, the prescriber's name, address, and affiliation, if any, with one or more health care institutions.
  • the prescriber's information in the registration card or form is then entered into the computer readable storage medium. It is contemplated that the registration of the prescriber into the computer readable storage medium may also be achieved, for example, by telephone.
  • Suitable computer readable storage media which may be employed for registration of the prescribers (as well as the pharmacies and patients, as discussed herein) will be apparent to one of ordinary skill in the art, once armed with the teachings of the present application.
  • pharmacies which may fill
  • prescriptions for the particular drug being prescribed herein are also preferably registered in a computer readable storage medium.
  • the computer readable storage medium in which the pharmacies are registered may be the same as, or different from the computer readable storage medium in which the prescribers are registered.
  • the pharmacies Once registered in the computer readable storage medium, the pharmacies may be eligible to dispense the involved drug to patients who are in need of the drug.
  • the pharmacy in order to become registered in the computer readable storage medium, the pharmacy may be required to comply with various aspects of the methods described herein including, for example, registering the patient (preferably also in a computer readable storage medium), as well as other aspects of the present methods, as described in detail below.
  • the registration of the pharmacy may be achieved by providing the pharmacy, for example, by hand, mail, facsimile transmission, or on-line transmission, with a registration card or form, preferably together with appropriate educational materials concerning, for example, the particular drug for which the pharmacy is being registered to dispense, as well as suitable methods for delivering the drug to the patient, including the drug delivery methods described herein.
  • the pharmacy may then have the registration card or form completed by providing the information requested therein, which thereafter may be returned to the
  • Information which may be requested of the pharmacy in the registration card or form may include, for example, the pharmacy's name, address, and affiliation, if any, with any health care institution such as, for example, hospital, health care organization, and the like.
  • the pharmacy's information in the registration card or form is then preferably entered into the computer readable storage medium. It is contemplated that the registration of the pharmacy into the computer readable storage medium may also be achieved, for example, by telephone.
  • the drug-distributing methods described herein also preferably involve the registration of the patient in a computer readable storage medium.
  • the registration of the patient is preferably carried out by the registered pharmacy at the time of the patient's initial visit to the pharmacy or by the prescriber if the prescriber obtains the drug and administers it to the patient.
  • the computer readable storage medium in which the patients are registered may be the same as, or different from the computer readable storage medium in which the prescriber and/or pharmacy is registered.
  • the patient in need of a particular complement inhibitor drug including, for example, a particular anti-C5 antibody or antigen-binding fragment thereof, may be eligible to receive the drug.
  • the patient in order to become registered in the computer readable storage medium, the patient may be required to comply with various aspects of the methods described herein.
  • the pharmacy or prescriber will typically have a registration form filled out for the patient, which includes information on the patient, such as the patient's name, mailing address, date of birth, and the like.
  • Information on the prescriber or dispensing pharmacy such as the information described above for the registration thereof, may also be desirably entered on the patient registration form.
  • the completed form may then be forwarded to the manufacturer or distributor of the drug, or other authorized recipients of the registration form by, for example, hand, mail, facsimile transmission or on-line transmission. It is contemplated that the registration of the patient into the computer readable storage medium may also be achieved, for example, by telephone.
  • the delivery of the drug to the patient may involve the following steps.
  • the prescriber and/or the pharmacy are registered in one or more appropriate computer readable storage media. Suitable computer readable storage media described herein which may be employed for registration will be apparent to one of ordinary skill in the art, once armed with the teachings of the present application. If the prescriber is not registered in the computer readable storage medium, the prescriber will be ineligible to prescribe the drug.
  • the pharmacy will be ineligible to dispense the drug.
  • the prescriber may determine that the patient's condition would be improved by the administration of a drug described herein, including eculizumab (Soliris ® ).
  • the prescriber Prior to prescribing the drug, the prescriber preferably counsels the patient, for example, on the various risks and benefits associated with the drug.
  • the prescriber preferably discusses the benefits associated with taking the drug, while also advising the patient of the various side effects associated therewith.
  • a patient who may acquire or impart a condition or disease for which the drug is contraindicated is preferably counseled by the prescriber on the dangers associated therewith.
  • the prescriber preferably counsels the patient on the dangers of being administered the drug without vaccination against various bacterial-induced infections (e.g., Meningococcal infection) and the dangers of the potential severe hemolysis or severe TMA complications after treatment discontinuation.
  • Such counsel may be provided verbally, as well as in written form.
  • the prescriber provides the patient with literature materials on the drug for which a prescription is contemplated, such as product information, package insert, educational brochures, patient instruction videos, and the like.
  • the prescriber preferably provides patients with literature information, for example, in the form of the aforesaid product information, package insert, educational brochures, patient instruction videos, and the like, warning the patient of the effects and/or the adverse effects during the treatment and/or after treatment discontinuation of the inhibitor.
  • the prescriber preferably counsels aHUS patients that have already discontinued inhibitor treatment or will discontinue the treatment in future.
  • the complement inhibitor drug e.g., eculizumab (Soliris ® ), pexelizumab, biosimilar equivalents of eculizumab or pexelizumab, or other anti-C5 antibodies or antigen-binding fragments thereof described herein
  • the prescriber preferably counsels aHUS patients that have already discontinued inhibitor treatment or will discontinue the treatment in future.
  • the prescriber preferably counsels and/or reminds the patient more frequently as the expected discontinuation date approaches or after the actual discontinuation date. Further, the patient is preferably counseled to have his or her risk factors for the adverse effects after discontinuation (e.g., the various laboratory parameters described herein) measured by himself/herself, a professional personnel, an organization, or a facility authorized by the drug supplier, the prescriber, or the distributor (e.g., a nurse, a doctor, a hospital, a medical laboratory, or a pharmacy).
  • the various laboratory parameters for the adverse effects after discontinuation e.g., the various laboratory parameters described herein
  • the patient is preferably counseled to examine his/her risk factors, more preferably for multiple times or continuously for a reasonable time period, for identification of possible adverse reactions after discontinuation.
  • the drug supplier, the prescriber, and/or the distributor preferably help to provide directions or such professional personnel or organization for measuring the risk factors of the patient, preferably periodically.
  • the diagnosis or the reasonable prediction may be registered in a suitable computer readable storage medium, preferably in the same registry of the patient containing his or her previous clinical information.
  • the patient is preferably informed about the diagnostic result or the reasonable prediction (further including those measured risk factors or laboratory parameters, if any, in support of such diagnosis or prediction). Based on the registry of the diagnosis or the reasonable prediction, the patient will be preferably counseled for possible treatments or therapies for the adverse reaction.
  • Such possible treatments or therapies include, for example, re-initiation of the same complement inhibitor treatment or therapy, substitute treatments or therapies with at least one different complement inhibitor or with a different regimen (e.g., a different dosage, injection method or frequency, etc.) of the same inhibitor, or substitute treatments or therapies involving different mechanisms or target molecules causing the disease or the adverse reaction.
  • a different regimen e.g., a different dosage, injection method or frequency, etc.
  • the possible treatments or therapies include, for example, re-initiation of the same Soliris ® treatment, a Soliris ® treatment with a different regimen, substitute treatments with pexelizumab or a different anti-C5 antibody or antigen- binding fragment thereof or a different complement inhibitor, or substitute therapies including, for example, plasma therapy (e.g., plasmapheresis, plasma exchange, fresh frozen plasma infusion, etc.) or appropriate organ-specific supportive measures. If needed, a combination of the various treatments or therapies can be considered and administered to the patient.
  • plasma therapy e.g., plasmapheresis, plasma exchange, fresh frozen plasma infusion, etc.
  • one or more aspects of the counseling described above may be applicable, in certain circumstances, for complement-inhibiting drugs other than Soliris ® or other anti-C5 antibodies or antigen-binding fragments thereof.
  • the patient, or the legal guardian(s) or representative(s) of the patient should be of an age, as well as being in a physical and psychological state, capable of apprehending the counseling correctly and precisely as a normal person should and additionally be legally responsible for his or her own behavior.
  • the methods of the present disclosure preferably involve requiring the patient, or the legal guardian(s) or
  • the counseling may be through on-site consultation, telephone, mail, facsimile transmission, or on-line transmission.
  • the counseling may, for example, when a patient is not directly supervised by a health professional and/or the prescriber, include literature materials on the drug for which a prescription is contemplated, such as product information, package insert, educational brochures, continuing education monographs, and the like.
  • the content of the counseling is provided in the patient labeling of the drug and is distributed together with the drug.
  • the patient, or the legal guardian(s) or representative(s) of the patient is expected to express acknowledgement of counseling through on-site acknowledgement, telephone, mail, facsimile transmission, or on-line transmission, while at least one legally acceptable form of acknowledgement (for example, an original signature, an electronic signature, an oath or declaration before a notary, etc.) is submitted.
  • the patient or the patient's legal guardian(s) or representative(s) is expected to fill out an informed consent form which is signed by the prescriber, as well as the patient, or the patient's legal guardian(s) or representative(s).
  • the prescriber should retain a copy of the informed consent form for his/her records.
  • the patient, or the patient's legal guardian(s) or representative(s) acknowledges that he/she understands the risks associated with taking the drug or discontinuing the drug.
  • the patient, or the patient's legal guardian(s) or representative(s) preferably agrees to behave, or help the patient to behave, in a manner which is consistent with the preserver's counsel.
  • the patient, or the patient's legal guardian(s) or representative(s) may express agreement to do, or agreement to help the patient to do, at least one of the following: i) monitor at least one risk factor or laboratory parameter for adverse reactions after discontinuing drug treatment; 2) report to the drug prescriber (including, if needed, the drug supplier and the drug distributor) the risk factor or laboratory parameter measurements and the time when the treatment discontinued or will be discontinued; and 3) consider and, if needed, agree to re-initiate the same treatment or a substitute treatment or therapy as described herein in case of experiencing or expecting to experience (based on reasonable predictions) at least one adverse reaction after treatment discontinuation.
  • the drug prescriber including, if needed, the drug supplier and the drug distributor
  • the counseling described herein is preferably delivered to the patient, or the patient's legal guardian(s) or representative(s), prior to both a new prescription and any future refill prescription.
  • Any drug prescriber, distributor, packer, or authorized dispenser is preferably required to provide such counseling in one or both of verbal and written formats (e.g., in the patient labeling) to the patient, or the legal guardian(s) or representative(s) of the patient, when a new prescription or refill prescription is dispensed.
  • Any drug manufacturer or supplier is preferably further required to: 1) obtain approval from the drug regulatory agency (e.g., the U.S.
  • the counseling information or warning described herein including, for example, the potential risk of adverse effects after discontinuing the complement inhibitor treatment, may be provided by any drug manufacturer, supplier, distributor, prescriber, authorized dispenser, or supervising practitioner (e.g., a licensed doctor or nurse or other practitioner) to any drug manufacturer, supplier, distributor, prescriber, authorized dispenser, supervising professional personnel, or patient who is taking or has a potential to take such drug.
  • any drug manufacturer, supplier, distributor, prescriber, authorized dispenser, or supervising practitioner e.g., a licensed doctor or nurse or other practitioner
  • the term "prescriber” refers to any individual who is capable of prescribing drugs, including, for example medical doctors or physicians or pharmacies.
  • authorized dispenser used herein is intended to mean an individual, a facility, or an organization which is licensed, registered, or otherwise permitted by the jurisdiction in which the individual, facility, or organization practices to provide drug products on prescription in the course of professional practice.
  • Authorized dispensers have the ability to authorized distribution of the complement inhibitor once the relevant regulatory agencies approve marketing of the complement inhibitor.
  • dispense to patients or “prescription is dispensed,” or similar terms used herein are intended to mean the act of delivering a prescription drug to a patient, or the patient's legal guardian(s) or representative(s), either: i) by a licensed practitioner or an agent of a licensed practitioner, either directly or indirectly, for self-administration by the patient, or the patient's legal guardian(s) or representative(s), or outside the licensed practitioner's direct supervision; or ii) by an authorized dispenser or an agent of an authorized dispenser under a lawful prescription of a licensed practitioner.
  • such counseling information or warning is provided in the drug label information of the complement inhibitor.
  • the prescription drug labeling information is also known as prescribing information, package insert, professional labeling, direction circular, package circular, etc.
  • label or similar terms used herein are intended to mean a display of written, printed, or graphic matter upon the immediate container of any article or meant to include a package insert; and a requirement made by or under authority of U.S. Code of Federal Regulations and the U.S.
  • labeling or similar terms used herein are intended to mean all labels and other written, printed, or graphic matters (1) upon any article or any of its containers or wrappers, or (2) accompanying such article, e.g., a package insert.
  • such counseling information or warning with or without patient information (e.g., bibliographic information, clinical record, personal and/or family disease and/or therapy record, the risk factors and/or laboratory parameters for disease diagnosing and/or monitoring, etc.) and/or the acknowledgement of the counseling or warning and agreement to the complement inhibitor treatment from the patient, are collected and stored, preferably in a database via a computer readable medium.
  • patient information e.g., bibliographic information, clinical record, personal and/or family disease and/or therapy record, the risk factors and/or laboratory parameters for disease diagnosing and/or monitoring, etc.
  • acknowledgement of the counseling or warning and agreement to the complement inhibitor treatment from the patient are collected and stored, preferably in a database via a computer readable medium.
  • such collected information is reported fully or partially to any drug manufacturer, supplier, distributor, prescriber, supervising professional personnel, patients who are taking or have a potential to take such drug, and/or any regulatory agencies (e.g., the U.S. FDA or the
  • such collected information is updated and/or modified (e.g. with updated patient information and/or any change in the acknowledgement and agreement from the patient, or with updated counseling information or warning based on postmarketing studies or research), preferably in a periodic manner, and reported as described herein.
  • the present disclosure also features a database prepared by the methods disclosed herein, preferably via a computer readable medium, containing registered patients' information.
  • patient information may include patient personal information (e.g., bibliographic information, personal or family disease and/or treatment record, and the fact or potential to have at least one of the adverse clinical events after discontinuing use of the complement-inhibiting drug) and the patient's acknowledgement the potential adverse reactions after drug discontinuation and agreement to drug treatment as described herein.
  • patient information may be updated, preferably periodically, and be provided to any relevant personnel, facility, organization, or authority as described herein.
  • the present disclosure also features a method to distribute the complement inhibitor disclosed herein to a physician or a pharmacy who will further distribute the inhibitor to a patient who has a complement-associated disorder disclosed herein for a treatment of said disorder.
  • the inhibitor will be authorized for distribution to the physician or pharmacy only upon certification from the physician or pharmacy that: i) the physician or pharmacy has received one or both of verbal and written warning as to the risk of adverse clinical events associated with discontinuing use of the complement inhibitor to treat the disorder; and ii) the physician or pharmacy will distribute the warning to the patient, or the legal guardian or representative of the patient.
  • the certification and the information of the physician or pharmacy will be registered via a computer readable medium into a database.
  • the physician or pharmacy may require a certification or acknowledgement of receiving and understanding of the warning disclosed herein and/or an agreement of the treatment from the patient, or the legal guardian or representative of the patient prior to or at the same time of distributing the complement- inhibiting drug disclosed herein to the patient, or the legal guardian or representative of the patient.
  • Such certification or acknowledgement and/or agreement may be further submitted to the drug distributor, manufacturer, and/or regulatory authorities, who may register such information into a database via a computer readable medium.
  • such information including the certification or acknowledgement and/or agreement from the physician (or pharmacy) or the patient (or the legal guardian or representative of the patient) or both, is to be received prior to or at the same time of or in a reasonable time frame after distributing the complement-inhibiting drug to the physician or pharmacy.
  • the certification is to be received after the distribution of the inhibitor to the physician or pharmacy but prior to the distribution of the inhibitor to the patient, or the legal guardian or representative of the patient.
  • the present disclosure also features a method of creating a database of physicians or pharmacies who will be allowed to distribute the complement inhibitor disclosed in this application for use in treating a complement-associated disorder.
  • the database is registered via a computer readable medium containing information that the physicians or pharmacies have received and acknowledged one or both of verbal and written warning as to the risk of adverse clinical events associated with discontinuing use of a complement inhibitor to treat the disorder and agreed to distributing the warning to the patient who has the disorder, or the legal guardian or representative of the patient.
  • the complement-associated disorder disclosed herein is selected from the group consisting of: a complement-associated inflammatory disorder, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), age-related macular degeneration (AMD), rheumatoid arthritis (RA), myasthenia gravis (MG), neuromyelitis optica (NMO), catastrophic anti-phospholipid syndrome (CAPS), anti- phospholipid syndrome (APS), sepsis, a complement-associated pulmonary disorder, asthma, and chronic obstructive pulmonary disease (COPD).
  • PNH paroxysmal nocturnal hemoglobinuria
  • aHUS atypical hemolytic uremic syndrome
  • AMD age-related macular degeneration
  • RA age-related macular degeneration
  • RA rheumatoid arthritis
  • MG myasthenia gravis
  • NMO neuromyelitis optica
  • CAS catastrophic anti-phospholipid syndrome
  • APS anti-
  • the present disclosure also features a database of physicians or pharmacies created by the methods disclosed herein.
  • the present disclosure also features a method to manufacture the complement inhibitor described herein.
  • the potential manufacturer should obtain an approval from a relevant government regulatory authority for manufacturing for sale the specific drug for the specific disease or indication.
  • the regulatory authority including, for example, the U.S. FDA and other corresponding agencies in the country or region where the drug will be manufactured and/or sold
  • the potential manufacturers may manufacture the complement-inhibiting drug in the approved country or region.
  • the manufacturer may be further required to produce or ensure the production of a document which provides a warning or caution comprising the whole or part of the information submitted to the regulatory authority, for example, the adverse clinical events after drug discontinuation.
  • the manufacturer may be further required to provide the manufactured drug together with the produced document to any relevant personnel, facility, organization, or authority, if necessary.
  • the present disclosure also features a method to distribute the complement inhibitor described herein.
  • the potential distributor should obtain an approval from a relevant government regulatory authority for distributing the specific drug for the specific disease or indication.
  • the regulatory authority including, for example, the U.S. FDA or other corresponding agencies in the country or region where the drug will be distributed
  • the potential distributor may distribute the complement-inhibiting drug in the approved country or region.
  • the distributor may be further required to produce or ensure the production of a document which provides a warning or caution comprising the whole or part of the information submitted to the regulatory authority, for example, the adverse clinical events after drug discontinuation.
  • the distributor may receive the document from the relevant manufacturer or the authority.
  • the distributor may be further required to provide the
  • a "memory” refers to the physical devices used to store programs or data on a temporary or permanent basis for use in a computer or other digital electronic device.
  • a “computer readable medium” refers to a medium capable of storing data in a format readable by a computer or a computer-related mechanical device. Examples of such computer readable media include magnetic media such as magnetic disks, cards, tapes, and drums, punched cards and paper tapes, optical disks (e.g., CD, CD-ROM, CD-R, CD-RW, DVD, etc.), and other media well known in the art.
  • the present disclosure also features a system for distributing the disclosed complement inhibitor (CIl) for use in treating a patient: (i) afflicted with, suspected of having, or at risk for developing a complement-associated disorder, and (ii) in need of treatment with the complement inhibitor.
  • the system comprises: a memory or a storage device for storing information about the patient and about whether an instruction to distribute the complement inhibitor is executed; and a processor configured to execute the instruction.
  • the instruction causes the processor to perform the steps comprising: i) searching the memory or storage device for certifications that:
  • the patient, or the legal guardian or representative of the patient is competent to comprehend and assess information and to make decisions;
  • the patient, or the legal guardian or representative of the patient has received one or both of verbal and written warning as to the risk of adverse clinical events associated with discontinuing use of the complement inhibitor to treat the disorder;
  • step i) the patient, or the legal guardian or representative of the patient, has expressed acknowledgment of the warning and agreement to the treatment; ii) upon the identification of certifications in step i), authorizing distribution of the complement inhibitor to treat the patient; and iii) registering via the memory or storage device the distribution of the complement inhibitor.
  • the systems and methods disclosed herein can be implemented on a computer system, server, or other electronic device, that is capable of storing information or processing
  • the system includes one or more computer systems, servers, or other electronic devices capable of storing information or processing information.
  • the systems store information on paper or on a computer readable medium.
  • the stored information may include, for example, the basic information and clinical record of the patient, the information about the manufacturer(s) who will manufacture the complement inhibitor, the information about the pharmacy(s) or the physician(s) who will distribute the complement inhibitor to the patient, the information about the distribution of the warning regarding the disclosed adverse clinical events to the patient, the legal guardian or representative of the patient, and/or the pharmacy(s) or the physician(s), and the acknowledgement of receiving of such information and/or agreeing to the treatment by the patient, its legal guardian or representative, and/or the pharmacy(s) or the physician(s).
  • the system disclosed herein may further store information including, for example, the information about the discontinuing use of the complement inhibitor by the patient, the information that the patient is monitored for adverse clinical events prior to, at the same time of, or after the discontinuation, and the information that the patient is treated by re-initiation of the complement inhibitor (CI1) treatment or with an alternative therapy to treat the adverse clinical events after the discontinuing use of the complement inhibitor (CI1).
  • information including, for example, the information about the discontinuing use of the complement inhibitor by the patient, the information that the patient is monitored for adverse clinical events prior to, at the same time of, or after the discontinuation, and the information that the patient is treated by re-initiation of the complement inhibitor (CI1) treatment or with an alternative therapy to treat the adverse clinical events after the discontinuing use of the complement inhibitor (CI1).
  • the information stored in the system disclosed herein can be collected in a voluntary or mandatory manner from the corresponding patient (or his or her legal guardian or representative), the manufacturer or distributor of the complement inhibitor, and/or the pharmacy or the physician who will distribute the complement inhibitor to the patient.
  • the information can be stored and created, for example, into a database.
  • the information can be reported to a government regulatory agency in a voluntary or mandatory manner. In some embodiments, a review of such reported information followed by an approval from the government regulatory agency is required prior to the distribution of the complement inhibitor.
  • the collection and/or the submission of the information disclosed herein can be executed by hand, mail, telephone, facsimile transmission, or on-line transmission.
  • FIGS. 1A and IB depict example network and database structures that may be used to implement the systems and methods disclosed herein.
  • FIG. 1 A is a block diagram of a computerized system 100 for authorizing the distribution of a drug to patients, according to an illustrative implementation.
  • the system 100 includes a server 104 and three user
  • processors 110A - 1 IOC (generally, user device 110) connected over a network 102 to the server 104.
  • the server 104 includes a processor 105 and an electronic database 106, and each user device 110 includes a processor 112 and a user interface 114.
  • processor or “computing device” refers to one or more computers, microprocessors, logic devices, servers, or other devices configured with hardware, firmware, and software to carry out one or more of the computerized techniques described herein.
  • Processors and processing devices may also include one or more memory devices for storing inputs, outputs, and data that is currently being processed.
  • user interface includes, without limitation, any suitable combination of one or more input devices (e.g., keypads, touch screens, trackballs, voice recognition systems, etc.) and/or one or more output devices (e.g., visual displays, speakers, tactile displays, printing devices, etc.).
  • user device includes, without limitation, any suitable combination of one or more devices configured with hardware, firmware, and software to carry out one or more of the computerized techniques described herein.
  • Examples of user devices include, without limitation, personal computers, laptops, and mobile devices (such as smartphones, blackberries, PDAs, tablet computers, etc.).
  • One server and three user devices are shown in FIG. 1 A.
  • the arrangement and number of components shown in FIG. 1A are merely illustrative, and the system 100 can support multiple servers and any number of user devices in any suitable configuration.
  • system 100 of FIG. 1A may be arranged, distributed, and combined in any of a number of ways.
  • the components of system 100 may be distributed over multiple processing and storage devices connected via the network 102.
  • Such an implementation may be appropriate for distributed computing over multiple communication systems including wireless and wired communication systems that share access to a common network resource.
  • system 100 is implemented in a cloud computing environment in which one or more of the components are provided by different processing and storage services connected via the Internet or other communications system.
  • the server 104 may be implemented as virtual servers instantiated in a cloud computing
  • the electronic database 106 may be a distributed system of databases that includes data regarding patient information such as a patient's demographic features (such as date of birth, gender, height, weight, or any other demographic feature), diagnosis, prognosis, administered medications, symptoms, physicians, pharmacists, geographical location, or any other suitable data related to a patient.
  • patient information such as a patient's demographic features (such as date of birth, gender, height, weight, or any other demographic feature), diagnosis, prognosis, administered medications, symptoms, physicians, pharmacists, geographical location, or any other suitable data related to a patient.
  • the improved availabililty associated with using distributed architecture advantageously facilitates continuous tracking and logging of inputs from various patients, physicians, pharmacists, or any other suitable representative of a patient.
  • FIG. 1A may be implemented as one or more components included with or local to a user device 110.
  • FIG. 1A depicts a user device 110 that includes a processor 112 and a user interface 114.
  • the processor 112 may be configured to perform any of the functions described herein for the user interface 114. Additionally, the functions performed by each of the components in system 100 may be rearranged. In some
  • the processor 112 may perform some or all of the functions of the processor 105 as described herein. Any suitable variation of this system may be used.
  • a user provides user input over the user interface 114.
  • the user may be the patient or a representative of the patient such as a legal guardian, physician, pharmacist, or nurse.
  • the user input may include any data related to a patient.
  • the user input includes data indicative of the patient's identity, such as the patient's name or an identification number associated with the patient such as a social security number, a healthcare insurance number.
  • the processor 112 transmits this data over the network 102 to the server 104, and the processor 105 parses the electronic database 106 for a previous registration of the patient.
  • an event may include an administration of a drug, a symptom expressed by the patient, a measurement of a level of physiological parameter related to the patient, or any other suitable event (e.g., an adverse clinical event) related to the care of the patient.
  • the event data is then transmitted over the network 102, received by the processor 105, and stored in the electronic database 106.
  • the user device 110 is configured to prompt the user to register the patient. Registration of a patient may require several electronic certifications over the user interface 114, including a certification that a representative of the patient is competent and can make decisions regarding the patient's treatment. In addition, the representative receives a warning regarding the risk of adverse clinical events associated with the use of a drug to treat the patient. Another possible required certification for registration of the patient is that the representative has acknowledged receipt of the warning. A third possible certification requires that the representative agrees to using the drug in treatment for the patient.
  • the processor 112 transmits the new patient's data over the network 102 to the server 104, where the data is stored in the electronic database 106 as a registered patient. Then, the processor 105 updates an electronic authorization variable associated with the registered patient, thereby authorizing distribution of the drug for use in treating the patient.
  • the same user device 110 may be used to register different patients. Similarly, data regarding a given patient may be provided over multiple user devices 110 over the course of the patient's treatment. In this way, system 100 provides a secure method of authorizing distribution of a drug to patients with representatives who acknowledge a risk of adverse clinical events associated with the drug.
  • FIG. IB The components of FIG. IB are similar to those of FIG. 1A, with the exception that FIG. IB additionally includes a healthcare service provider system 116 including a processor 118 and an electronic database 120.
  • the healthcare service provider system 116 is configured to share patient-related data stored on the electronic database 120 with the server 104.
  • the healthcare service provider system 116 may have additional data regarding a registered patient that have not been directly provided by a user device 110.
  • the user device 110 may have been used to register a patient for a particular disorder.
  • the same patient may be treated at a hospital for a different disorder, and the hospital may monitor patient treatments and symptoms.
  • the hospital staff may have provided data indicative of the patient's treatment and/or symptoms to the healthcare service provider system 116, which stores the data on the electronic database 120.
  • the data on the electronic database 120 is then shared with the server 104. By aggregating patient-related data across different sources, the server 104 is more likely to maintain an updated patient history and achieves a more accurate patient profile.
  • the patient data stored on the electronic databases 106 and 120 may include private and classified information, and it is desirable to maintain a degree of confidentiality.
  • the systems 100 and 130, and every system disclosed herein, are configured to comply with any privacy or confidentiality laws that may exist in the jurisdiction in which the system is installed.
  • all data in relation to all patients is processed using encryption and decryption algorithms to ensure secure data transmission over the network 102.
  • FIG. 2 depicts a data structure 200 for records in a patient database, which may be stored on the electronic database 106.
  • the data structure 200 includes a list of patient identification numbers, representative identification numbers, and patient-related data.
  • each patient may be labeled with a patient identification number, and in addition, the representative of each patient may also be labeled with a representative identification number.
  • the representatives of the patients 1254 and 574 may be legal guardians, physicians, pharmacists, or any other suitable representative.
  • a patient may be his/her own representative, as is the case with patient 1345.
  • the data structure 200 further includes the ages and genders of the patients, and a flag variable representative of whether the patient is registered. For registered patients, a date indicating the beginning of the administration of the drug and a date indicating the
  • discontinuation of the drug administration are also recorded, if applicable.
  • the patients 1254 and 1345 were administered the drug for an amount of time before
  • patient 576 still includes the use of the drug.
  • patient 687 has not yet been registered, and so there is no corresponding representative identification number or dates of beginning and discontinuation of drug administration.
  • the data structure 200 may also include further patient-related information, such as dates of actual administration of the drug, doses of the administered drug, patient symptoms, or any other suitable patient-related information.
  • the data structure 200 may be updated periodically with data generated from patient reports that may be prepared by the patient or a representative of the patient. In this way, the data structure 200 may track the progression of a patient throughout the patient's treatment.
  • the system 100 provides a method for monitoring a patient's progress during treatment and also provides a rich database with information that may provide insight for future decisions regarding the same patient or a patient with similar characteristics.
  • FIG. 3 is a flowchart of a method 300 that may be implemented by the server 104 to authorize distribution of a drug for use in treating a patient.
  • the method 300 includes the steps of receiving certification that a patient representative has received a warning of risks associated with use of a complement inhibitor (or a drug) and that the representative has agreed to use of the complement inhibitor for the patient (step 350), storing data indicative of the certification in an electronic database (step 352), and transmitting a signal indicative of an authorization for distribution of the complement inhibitor (step 354).
  • the server 104 receives certification from a user device 110 that a representative of a patient has received a warning regarding the risks associated with the use of a complement inhibitor. Furthermore, the server 104 also receives certification that the representative has agreed to the use of the complement inhibitor in treatment for the patient. In particular, the representative may be required to provide an acknowledgment of receipt of the warning as well as agreement to use of the complement inhibitor in the form of a signature or any other suitable form of certification. This certification may then be electronically
  • a signal representative of the certification may be transmitted over the network 102 and received by the server 104.
  • the server 104 After receiving the certification, at step 352, the server 104 stores data indicative of the certification in an electronic database 106.
  • a data structure such as data structure 200 or any other suitable data structure may be stored in the electronic database 106 to track the registration status of patients.
  • the server 104 authorizes the distribution of the complement inhibitor by transmitting a signal over the network 104 to the user device 110.
  • the signal is indicative of the authorization to use the complement inhibitor in treating the registered patient.
  • FIG. 4 is a flowchart of a method 400 that may be implemented by the server 104 to receive and store patient-related data.
  • the method 400 includes the steps of receiving registered and authorized patient data (step 450), receiving a report of patient treatment (step 452), storing the patient treatment in a database (step 454), receiving a report of patient symptoms (step 456), and storing the patient symptoms in the database (step 458).
  • the server 104 receives data related to a registered patient from a user device 110.
  • a user at the user device 110 may wish to enter patient-related data into the electronic database 106 and first provides some data identifying the patient.
  • the received data may include the patient's identification number such as depicted in the first column of data structure 200, or any other suitable data identifying a patient.
  • the server 104 receives an electronic report of features of a patient's treatment.
  • the report may include information such as a drug that was administered to the patient, the time and date of administration, and an amount of the administered drug.
  • the report may further include an identity of a person who administered the drug, where the administration took place, or any other information related to a treatment of the patient.
  • the server 104 stores data corresponding to the received report of patient treatment in the electronic database 106.
  • the processor 105 is configured to process the received report before storage. For example, the information in the received report may be sorted or categorized to facilitate efficient future retrieval of the data.
  • the server 104 receives a report of patient symptoms that are determined during one or more subsequent treatment sessions or evaluations of the patient at the same or different health care facility.
  • the report may include quantitative measures such as the patient's temperature, blood pressure, or any other suitable physiological metric used to monitor a patient's overall health.
  • the report may also include information such as such as aches, inflammation, irritation, discoloration, or any other suitable symptom identified during that subsequent session.
  • the symptom report may also include times or time intervals corresponding to each symptom.
  • the patient symptoms are stored in the electronic database 106.
  • the processor 105 is configured to process the received patient symptoms before storage.
  • the information in the received patient symptom report may be processed to facilitate efficient future retrieval of the data and to efficiently group a large number of patients together who exhibit similar symptoms.
  • a quantitative measure such as the patient's temperature may be categorized as very high, high, normal, low, or very low, for example.
  • FIG. 5 is a flowchart of a method 500 that may be implemented by the server 104 to compare a symptom expressed by a patient with an adverse clinical event, such as an adverse event corresponding to a risk certified previously by the patient or the patient's representative (e.g., FIG. 3).
  • the method 500 includes the steps of storing a first electronic variable indicative of an acknowledged adverse clinical event (step 550) and storing a second electronic variable indicative of a symptom expressed by the patient (step 552).
  • the first and second electronic variables are compared (step 554), and the processor 105 determines whether there is a match between the two variables (step 556).
  • step 558 data indicative of the match is stored in the electronic database 106 (step 558), and a warning or other indicator may be provided.
  • a counter variable may be incremented that tracks a number of patients expressing a symptom that is not included as an adverse clinical event (step 560).
  • the server 104 stores a first electronic variable indicative of an adverse clinical event acknowledged by the patient's representative during patient registration.
  • the first electronic variable may be an identification number corresponding to the clinical event, or may simply be a flag variable indicating that the adverse clinical event has been acknowledged by the patient's representative.
  • the server 104 stores a second electronic variable indicative of a symptom expressed by the patient.
  • the second electronic variable may be an identification number corresponding to the symptom and may have been received with the report of patient symptoms as described in relation to FIG. 4.
  • the report of patient symptoms may have been processed to determine a value for the second electronic variable.
  • the first and second electronic variables are compared.
  • the processor 105 may perform some processing on one or both of the electronic variables in order to get the variables into a form suitable for comparison.
  • the server 104 determines whether there is a match between the two electronic variables.
  • a match requires that the expressed symptom corresponds to the adverse clinical event in some way.
  • a match may be associated with a match strength value.
  • an adverse clinical event associated with a drug may be that the patient is susceptible to a rise in temperature by at least 5 degrees. If the patient exhibits an increase in temperature of 6 degrees after being administered the drug, the server 104 may associate one match strength value with the patient. If another patient exhibits an increase in temperature of 10 degrees after being administered the drug, the server 104 may associated a stronger match strength value with the other patient.
  • match strength values may be also be stored in the electronic database 106 when updating the patient's information.
  • the server 104 determines whether the drug was discontinued prior to the expression of the symptom by the patient. In particular, if the drug was discontinued prior to the expression of the symptom, at step 558, the server 104 provides an alert to a user.
  • the alert may include information indicating that a match between a risk of a side effect that was acknowledged by the patient's
  • the server 104 may store data indicative of the match, such as the match strength value, or a flag variable indicating the match, is stored in the electronic database 106 at step 558.
  • the server 104 may increment a counter variable.
  • the counter variable corresponds to the expressed symptom and represents a number of registered patients that have expressed the symptom during a predefined time interval after administration of the drug.
  • the time interval may be a minute, an hour, a day, a week, or any other suitable time interval corresponding to an expression of a symptom after drug administration.
  • the server 104 may store counter variables for a number of various symptoms not normally associated with the drug.
  • the server 104 may also store separate counter variables for categories of patients, sorted by their age, gender, or any other suitable category for a patient.
  • the server 104 keeps track of a number of patients expressing particular symptoms and can transmit an alert to an authorized user when the number of patients exceeds some threshold. In this way, the server 104 may detect symptoms that are often expressed by patients in a particular category, in which the symptoms were not previously associated with the drug.
  • steps 552-560 may be repeated for each symptom retrieved from a received symptom report for comparison to an adverse clinical event.
  • method 500 may be repeated for each adverse clinical event listed in the warning received by the patient's representative for comparison to each recorded symptom expressed by the patient.
  • FIG. 6 is a flowchart of a method 600 that may be implemented by the server 104 to determine whether to authorize a user access to a drug.
  • the method 600 includes the steps of receiving a user attempt to obtain access to a drug for a patient (step 650) and determining whether the patient is registered (step 652). If the patient is registered, the server 104 authorizes the user to obtain access to the drug (step 658). Otherwise, the user is prompted to register the patient in the database (step 656).
  • the patient may be registered by the method described in FIG. 7.
  • FIG. 7 is a flowchart of a method 700 that may be implemented by the server 104 to register a patient.
  • the method 700 includes the steps of confirming an identity and a competency of a representative of the patient (step 750), transmitting a warning to the patient representative of risks associated with the drug (step 752), receiving acknowledgment of the warning from the representative (step 754), receiving certification that the representative agrees to the use of the drug in treating the patient (step 756), storing the patient in the database (step 758), and authorizing the distribution of the drug for treating the patient (step 760).
  • FIG. 8 is a block diagram of a computing device, such as any of the components of the systems of FIGS. 1A-1B, for performing any of the processes described herein.
  • Each of the components of these systems may be implemented on one or more computing devices 800.
  • a plurality of the components of these systems may be included within one computing device 800.
  • a component and a storage device may be implemented across several computing devices 800.
  • the computing device 800 comprises at least one communications interface unit, an input/output controller 810, system memory, and one or more data storage devices.
  • the system memory includes at least one random access memory (RAM 802) and at least one read-only memory (ROM 804). All of these elements are in communication with a central processing unit (CPU 806) to facilitate the operation of the computing device 800.
  • the computing device 800 may be configured in many different ways. For example, the computing device 800 may be a conventional standalone computer or alternatively, the functions of computing device 800 may be distributed across multiple computer systems and architectures. In FIG. 8, the computing device 800 is linked, via network or local network, to other servers or systems.
  • the computing device 800 may be configured in a distributed architecture, wherein databases and processors are housed in separate units or locations. Some units perform primary processing functions and contain at a minimum a general controller or a processor and a system memory. In distributed architecture implementations, each of these units may be attached via the communications interface unit 808 to a communications hub or port (not shown) that serves as a primary communication link with other servers, client or user computers and other related devices.
  • the communications hub or port may have minimal processing capability itself, serving primarily as a communications router.
  • a variety of communications protocols may be part of the system, including, but not limited to: Ethernet, SAP, SASTM, ATP, BLUETOOTHTM, GSM and TCP/IP.
  • the CPU 806 comprises a processor, such as one or more conventional microprocessors and one or more supplementary co-processors such as math co-processors for offloading workload from the CPU 806.
  • the CPU 806 is in communication with the communications interface unit 808 and the input/output controller 810, through which the CPU 806
  • the communications interface unit 808 and the input/output controller 810 may include multiple communication channels for simultaneous communication with, for example, other processors, servers or client terminals.
  • the CPU 806 is also in communication with the data storage device.
  • the data storage device may comprise an appropriate combination of magnetic, optical or semiconductor memory, and may include, for example, RAM 802, ROM 804, flash drive, an optical disc such as a compact disc or a hard disk or drive.
  • the CPU 806 and the data storage device each may be, for example, located entirely within a single computer or other computing device; or connected to each other by a communication medium, such as a USB port, serial port cable, a coaxial cable, an Ethernet cable, a telephone line, a radio frequency transceiver or other similar wireless or wired medium or combination of the foregoing.
  • the CPU 806 may be connected to the data storage device via the communications interface unit 808.
  • the CPU 806 may be configured to perform one or more particular processing functions.
  • the data storage device may store, for example, (i) an operating system 812 for the computing device 800; (ii) one or more applications 814 (e.g., computer program code or a computer program product) adapted to direct the CPU 806 in accordance with the systems and methods described here, and particularly in accordance with the processes described in detail with regard to the CPU 806; or (iii) database(s) 816 adapted to store information that may be utilized to store information required by the program.
  • applications 814 e.g., computer program code or a computer program product
  • the operating system 812 and applications 814 may be stored, for example, in a compressed, an uncompiled and an encrypted format, and may include computer program code.
  • the instructions of the program may be read into a main memory of the processor from a computer-readable medium other than the data storage device, such as from the ROM 804 or from the RAM 802. While execution of sequences of instructions in the program causes the CPU 806 to perform the process steps described herein, hard-wired circuitry may be used in place of, or in combination with, software instructions for implementation of the processes of the present disclosure.
  • the systems and methods described are not limited to any specific combination of hardware and software.
  • Suitable computer program code may be provided for performing one or more functions in relation to aligning dietary behavior as described herein.
  • the program also may include program elements such as an operating system 812, a database management system and "device drivers" that allow the processor to interface with computer peripheral devices (e.g., a video display, a keyboard, a computer mouse, etc.) via the input/output controller 810.
  • computer peripheral devices e.g., a video display, a keyboard, a computer mouse, etc.
  • Nonvolatile media include, for example, optical, magnetic, or opto-magnetic disks, or integrated circuit memory, such as flash memory.
  • Volatile media include dynamic random access memory (DRAM), which typically constitutes the main memory.
  • Computer-readable media include, for example, a floppy disk, a flexible disk, hard disk, magnetic tape, any other magnetic medium, a CD-ROM, DVD, any other optical medium, punch cards, paper tape, any other physical medium with patterns of holes, a RAM, a PROM, an EPROM or EEPROM (electronically erasable programmable read-only memory), a FLASH-EEPROM, any other memory chip or cartridge, or any other non-transitory medium from which a computer can read.
  • a floppy disk a flexible disk, hard disk, magnetic tape, any other magnetic medium, a CD-ROM, DVD, any other optical medium, punch cards, paper tape, any other physical medium with patterns of holes, a RAM, a PROM, an EPROM or EEPROM (electronically erasable programmable read-only memory), a FLASH-EEPROM, any other memory chip or cartridge, or any other non-transitory medium from which a computer can read.
  • Various forms of computer readable media may be involved in carrying one or more sequences of one or more instructions to the CPU 806 (or any other processor of a device described herein) for execution.
  • the instructions may initially be borne on a magnetic disk of a remote computer (not shown).
  • the remote computer can load the instructions into its dynamic memory and send the instructions over an Ethernet connection, cable line, or even telephone line using a modem.
  • a communications device local to a computing device 800 e.g. , a server
  • the system bus carries the data to main memory, from which the processor retrieves and executes the instructions.
  • the instructions received by main memory may optionally be stored in memory either before or after execution by the processor.
  • instructions may be received via a communication port as electrical, electromagnetic or optical signals, which are exemplary forms of wireless communications or data streams that carry various types of information.

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Abstract

La présente invention se rapporte aux méthodes pour autoriser la distribution de médicaments inhibant le complément à des patients qui ont des troubles associés à un complément de manière à garantir que les patients sont conscients des dangers possibles d'interruption du traitement avec les médicaments. Une base de données est préparée comprenant les informations sur les patients y compris les événements cliniques défavorables connus après l'interruption du traitement médicamenteux. Les informations de la base de données sont recueillies et peuvent être signalées. Les patients reçoivent un avertissement relatif aux événements défavorables qui peuvent survenir si un traitement avec les médicaments inhibant le complément est interrompu.
PCT/US2012/029499 2012-03-16 2012-03-16 Méthodes de distribution de médicaments inhibant le complément aux patients recevant un inhibiteur de complément WO2013137912A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
PCT/US2012/029499 WO2013137912A2 (fr) 2012-03-16 2012-03-16 Méthodes de distribution de médicaments inhibant le complément aux patients recevant un inhibiteur de complément
CN201280071445.8A CN104205155A (zh) 2012-03-16 2012-03-16 给接受补体抑制剂的患者分配补体抑制药物的方法
EA201400950A EA201400950A1 (ru) 2012-03-16 2012-03-16 Способы распространения комплемент-ингибирующих лекарственных средств среди пациентов, получающих ингибитор комплемента
EP12870989.6A EP2825989A4 (fr) 2012-03-16 2012-03-16 Méthodes de distribution de médicaments inhibant le complément aux patients recevant un inhibiteur de complément
IL234680A IL234680A0 (en) 2012-03-16 2014-09-16 Methods for distributing complement inhibitor drugs to patients receiving a complement inhibitor
HK15105150.8A HK1204693A1 (en) 2012-03-16 2015-05-29 Methods of distributing complement-inhibiting drugs to patients receiving a complement inhibitor

Applications Claiming Priority (1)

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PCT/US2012/029499 WO2013137912A2 (fr) 2012-03-16 2012-03-16 Méthodes de distribution de médicaments inhibant le complément aux patients recevant un inhibiteur de complément

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WO2013137912A2 true WO2013137912A2 (fr) 2013-09-19
WO2013137912A3 WO2013137912A3 (fr) 2014-05-01

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WO (1) WO2013137912A2 (fr)

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CN105260974A (zh) * 2015-09-10 2016-01-20 济南市儿童医院 一种生成具有告签功能的电子病历方法及系统
CN115177291B (zh) * 2022-08-01 2023-11-10 首都医科大学附属北京朝阳医院 用于识别重症监护病房获得性肌无力的方法和装置

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HUE030105T2 (en) * 2006-03-15 2017-04-28 Alexion Pharma Inc Treatment of paroxysmal nocturnal hemoglobin uptake with complement inhibitor
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015073514A1 (fr) * 2013-11-13 2015-05-21 Viropharma Holdings Limited Compositions et méthodes utiles pour le traitement de troubles du spectre de la neuromyélite optique
JP2016540746A (ja) * 2013-11-13 2016-12-28 シャイア バイロファーマ インコーポレイテッド 視神経脊髄炎スペクトル障害の治療に有用な組成物及び方法
US10272142B2 (en) 2013-11-13 2019-04-30 Shire Viropharma Incorporated Compositions and methods useful for the treatment of neuromyelitis optica spectrum disorders
US11938174B2 (en) 2013-11-13 2024-03-26 Takeda Pharmaceutical Company Limited Compositions and methods useful for the treatment of neuromyelitis optica spectrum disorders

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EA201400950A1 (ru) 2014-12-30
CN104205155A (zh) 2014-12-10
EP2825989A4 (fr) 2016-01-06
HK1204693A1 (en) 2015-11-27
WO2013137912A3 (fr) 2014-05-01
EP2825989A2 (fr) 2015-01-21
IL234680A0 (en) 2014-11-30

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