EP3528845A2 - Methods, compositions and dosing regimens for treating or preventing interferon-gamma related indications - Google Patents

Methods, compositions and dosing regimens for treating or preventing interferon-gamma related indications

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Publication number
EP3528845A2
EP3528845A2 EP17829009.4A EP17829009A EP3528845A2 EP 3528845 A2 EP3528845 A2 EP 3528845A2 EP 17829009 A EP17829009 A EP 17829009A EP 3528845 A2 EP3528845 A2 EP 3528845A2
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EP
European Patent Office
Prior art keywords
dose
amino acid
acid sequence
seq
antibody
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EP17829009.4A
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German (de)
English (en)
French (fr)
Inventor
Cristina De Min
Walter Ferlin
Fabrizio DE BENEDETTI
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Swedish Orphan Biovitrum AB
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Novimmune SA
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Publication of EP3528845A2 publication Critical patent/EP3528845A2/en
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/249—Interferons
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the disclosure relates generally to methods and compositions for treating, preventing and/or delaying the onset or progression of, or alleviating a symptom associated with elevated levels interferon gamma (IFNy, IFN-gamma) such as for example, hemophagocytic lymphohistiocytosis (HLH), hemoragic fever, CAR-T cell therapy, transplant failure, transplant rejection, Graft-versus-host disease (GvHD), and/or an inflammatory disorder associated with transplant rejection.
  • IFNy interferon gamma
  • Human interferon gamma (IFNy, IFN-gamma) is a lymphokine produced by activated T-lymphocytes and natural killer cells. It manifests anti-proliferative and
  • IFNy-R immunomodulatory binds to IFNy-R, a heterodimeric receptor on most primary cells of the immune system, and triggers a cascade of events leading to inflammation.
  • IFNy-activity is known to have deleterious effects.
  • autoimmune diseases are associated with high levels of IFNy in the blood and diseased tissue from autoimmune patients.
  • IFNy-activity has also been linked to such disease states as cachexia and septic shock.
  • IFNy has been implicated in a number of disorders; and anti-IFNy agents are being developed as therapeutic agents..
  • the invention provides multiple variable dose treatment regimen for the treatement of diseases, disorder or conditions associated with elevated IFN-g levels.
  • the invention provides a method for the treatment of primary hemophagocytic lymphohistiocytosis (HLH) in a human by intravenously administering to a subject a first dose and second dose of an antibody that binds interferon gamma (IFNy).
  • the subject is an adult subject or a pediatric subject.
  • the first dose is 1.0 or 3.0 mg/kg of the subject's body weight and the second dose is 3.0, 6.0 or 10.0 mg/kg of the subject's body weight.
  • a third dose of 1.0 mg/kg of the subject's body weight is administered.
  • the invention provides a method for the treatment of secondary hemophagocytic lymphohistiocytosis (HLH) in a human pediatric subject by intravenously administering to a subject a first dose and second dose of an antibody that binds interferon gamma (IFNy).
  • the first dose is 6.0 mg/kg of the subject's body weight and the second dose is 3.0 mg/kg of the subject's body weight.
  • a third dose of 6.0 mg/kg of the subject's body weight is administered.
  • the invention provides a method for the treatment of secondary hemophagocytic lymphohistiocytosis (HLH) in a human adult subject by intravenously administering to a subject a first dose and second dose of an antibody that binds interferon gamma (IFNy).
  • the first dose is 3.0 mg/kg or 6.0 mg/kg of the subject's body weight and the second dose is no more than 10 mg/kg of the subject's body weight.
  • the second dose is 1.0, 3.0, 6.0 or 10.0 mg/kg.
  • a third dose of less than 10.0 mg/kg of the subject's body weight is administered.
  • the third dose is 1.0, 3.0, or 6.0 mg/kg of the subject's body weight.
  • the invention provides a method for the treatment of a condition in a human subject by intravenously administering to a subject a first dose and second dose of an antibody that binds interferon gamma (IFNy).
  • the subject is an adult subject or a pediatric subject.
  • the condition is transplant rejection such as solid organ transplant disorder or bone marrow acute graft rejection.
  • the condition is graft vs. host disease, paraneoplastic cerebellar degeneration, hemorrhagic fever, sarcoidosis, or adult onset Still's disease.
  • the method is administered to a subject after receiving CART cell therapy.
  • the first dose is between 1.0 to 10 mg/kg of the subject's body weight and the second dose is between 1.0 to 10 mg/kg of the subject's body weight e subject's body weight.
  • the second dose is 1.0, 3.0, 6.0 or 10.0 mg/kg.
  • the second dose is higher or lower than the first dose.
  • a third dose of between 1.0 to 10 mg/kg of the subject's body weight is administered.
  • the first, second, or third dose is 1.0, 3.0, 6.0 or 10.0 mg/kg of the subject's body weight.
  • the antibody that binds interferon gamma includes: a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SYAMS (SEQ ID NO: 1); a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of AISGSGGSTYYADSVKG (SEQ ID NO: 2); and a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of DGSSGWYVPHWFDP (SEQ ID NO: 3); a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of TRSSGSIASNYVQ (SEQ ID NO: 4); a variable light chain complementarity determining region 2 (VL CDR2) region comprising the amino acid sequence of EDNQRPS (SEQ ID NO: 5); and a variable light chain complementarity determining region 3 (VL CDR3) region comprising the amino acid sequence of QS
  • VH CDR1 compris
  • the dose of the antibody is administered within 1, hr, 6 hrs or 12 hrs.
  • the second dose is administered for a first treatment period of every three days after the first dose. Additionally, the second dose is administered for a second treatment period after completion of the first treatment period.
  • the the second treatment period is for example twice weekly.
  • the antibody dose is administered as a single injection.
  • the antibody is administered as a monotherapy or a co-therapy.
  • the methods of the invention further includes administering dexamethasone immediately prior to the dosing of the antibody, the dexamethasone is
  • the method further includes comprises administering at least a second agent to the subject.
  • the second agent is a therapeutic agent, an anti-inflammatory agent, and/or an immunosuppressive agent.
  • an injectable pharmaceutical formulation comprising per mL: 5 mg or 25 mg of a fully human anti-interferon gamma (IFND) monoclonal antibody; 1.55 mg L-histidine, 3.14 mg L-histidine monohydrochloride, monohydrate, 7.31 mg sodium chloride (NaCl), and 0.05 mg Polysorbate 80, where the pH is between 5.8 and 6.2.
  • the invention provides a unit dose vial containing 20 ml of a fully human anti-interferon gamma (IFND) monoclonal antibody solution suitable for injection where the concentration of antibody is 5 mg/ml or 25 mg/ml and the pH of the solution is between 5.8 and 6.2.
  • the antibody is solubilized in the solution such that the solution is clear, colorless, and without precipitate.
  • the invention provides a unit dose vial containing 10 ml or 20 ml of a fully human anti-interferon gamma (IFND) monoclonal antibody solution suitable for injection where the concentration of antibody is at 25 mg/ml, and he pH of the solution is between 5.8 and 6.2.
  • the antibody is solubilized in the solution such that the solution is clear, colorless, and without precipitate.
  • the invention provides a unit dose vial containing 2 ml or 10 ml of a fully human anti-interferon gamma (IFND) monoclonal antibody solution suitable for injection where the concentration of antibody is 5 mg/ml and the pH of the solution is between 5.8 and 6.2.
  • the antibody is solubilized in the solution such that the solution is clear, colorless, and without precipitate
  • the antibody that binds interferon gamma includes: a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SYAMS (SEQ ID NO: 1); a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of AISGSGGSTYYADSVKG (SEQ ID NO: 2); and a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of DGSSGWYVPHWFDP (SEQ ID NO: 3); a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of TRSSGSIASNYVQ (SEQ ID NO: 4); a variable light chain complementarity determining region 2 (VL CDR2) region comprising the amino acid sequence of EDNQRPS (SEQ ID NO: 5); and a variable light chain complementarity determining region 3 (VL CDR3) region comprising the amino acid sequence of QS
  • VH CDR1 compris
  • Figure 1 is a graph depicting correlations between predose serum CXCL9 levels and total IFNy levels at 24 h post infusion with the NI-0501 antibody in an ongoing phase 2 pilot study in primary HLH patients.
  • Figure 2 is a graph depicting correlations between serum CXCL9 levels and total
  • Figures 3A and 3B are a series of graphs depicting correlations between serum
  • Figures 4A-1, 4A-2, 4B-1, 4B-2, 4C-1, 4C-2, 4D-1, and 4D-2 are a series of graphs depicting correlations between IFNy and serum CXCL9 levels and clinical parameters in patients with active sJIA and MAS secondary to sJIA.
  • Figure 5 is a graph depicting that IFNy was fully neutralized as shown by undetectable levels of IFNy- inducible chemokines.
  • Figure 6 is a graph depicting improvement of HLH disease activity during NI-
  • Figures 7A and 7B are a series of graphs depicting the correlation between predose CXCL9 and total IFNy levels at 24h after NI-0501 infusion.
  • the insert shown in Figure 7B depicts an example of individual IFNy and CXCL9 profile during NI-0501 treatment.
  • Figures 8A, 8B, 8C, and 8D are a series of graphs depicting serum levels of IFNy and of CXCL9, CXCL10 and CXCL11 in individual patients from whom paired samples were available during active MAS and during active sJIA without MAS at sampling (ActsJIA).
  • Figures 9A and 9B are a series of graphs depicting Changes in white blood cell
  • WBC platelet
  • PHT platelet
  • Figures 10A, 10B, IOC, 10D, 10E, 10F, 10G, 10H, 101, and 10J are a series of graphs depicting correlation of levels of IFNy and CXCL9 with ferritin levels, neutrophil and platelet count and with LDH and ALT levels in patients with active MAS at sampling (red circles) and in patients with active sJIA without MAS at sampling (black triangles). Spearman correlation coefficient (Rs) and significance level (p) of each correlation are shown in Table 3.
  • Figures 11 A, 1 IB, 11C, 1 ID, 1 IE, and 1 IF are a series of graphs depicting the relation of IFNy with CXCL9 and CXCLIO production in MAS.
  • Panel A Correlations of the levels of IFNy with the levels of CXCL9 and CXCLIO in patients with MAS at sampling Spearman correlation coefficient (Rs) and significance level (p) of each correlation are shown in Table 3.
  • Figure 12 is a schematic representation of the screening, treatment, and follow-up portions of the studies presented in Example 7.
  • Figures 13A and 13B are graphs depicting the effect of NI-0501 administration on body temperature in two patients having body temperature > 37.5 °C at initiation of NI-0501 treatment.
  • Figure 14 is a series of graphs and a table depicting the effect of NI-0501 administration on neutrophil count in patients.
  • Figure 15 is a series of graphs and a table depicting the effect of NI-0501 administration on platelet count in patients.
  • Figure 16 is a series of graphs and a table depicting the effect of NI-0501 administration on serum levels of ferritin in patients.
  • Figure 17 is a series of graphs and a table depicting the effect of NI-0501 administration on glucocorticoid tapering in patients.
  • Figure 18 is a graph depicting that administration of NI-0510 maintained IFNy neutralization until the time of HSCT. HLH response to NI-0501 treatment also persisted until transplantation.
  • Figure 19 is a schematic representation of the screening, treatment, and follow-up portions of the studies presented in Example 8.
  • compositions and methods provided herein use a fully human IgGl anti- interferon gamma (IFNy) monoclonal antibody (mAb) referred to herein as NI-0501, which binds and neutralizes IFNy.
  • IFNy interferon gamma
  • NI-0501 binds to soluble and receptor (IFNyRl)-bound forms oflFNy.
  • IFNy is one of the most potent and pleiotropic cytokines of the immune system. It is critical for innate and adaptive immunity against viral and intracellular bacterial infections. After binding to its receptor, IFNy acts to produce a variety of physiological and cellular responses. Numerous studies over the last 20 years have associated IFNy with the pathogenesis and the maintenance of inflammatory diseases (see e.g., Billiau A. "Interferon-gamma: biology and role in pathogenesis.” Adv.
  • IFNy is produced predominantly by natural killer (NK) and natural killer T (NKT) cells, as part of the innate immune response, and by CD4 Thl and CD8 cytotoxic T lymphocyte (CTL) effector T cells, once antigen-specific immunity develops.
  • NK natural killer
  • NKT natural killer T
  • CTL cytotoxic T lymphocyte
  • compositions and methods provided herein are useful in the treatment of diseases, disorders and conditions associated with elevated IFNy.
  • Diseases, disorders and conditions amenable to treatment or prevention using the compositions and methods of the invention include for example, hemophagocytic lymphohistiocytosis (HLH), graft vs. host disease, paraneoplastic cerebellar degeneration, hemorrhagic fever, sarcoidosis, adult onset Still's disease, transplant failure, transplant rejection, and/or an inflammatory disorder associated with transplant rejection.
  • Transplant rejection included solid organ transplant disorder, bone marrow, acute graft rejection.
  • the composition and methods are also useful in the treatment or alleviation of a side effect of CAR-T cell therapy.
  • HLH is a syndrome characterized by a severe impairment or absence of cytotoxic function by NK and CD8+ T cells with striking activation of the immune system.
  • HLH comprises primary (genetic/familial) HLH and secondary HLH, both clinically described by a dysregulation of the immune system leading to a profound hypercytokinemia with deleterious consequences on various tissues and organs (Henter JI, Elinder G, Soder O et al. "Hypercytokinemia in familial hemophagocytic lymphohistiocytosis.” Blood 1991; 78:2918-2922).
  • HLH Classification is shown below in Table 9. HLH occurs in both adults and pediatric patients
  • Primary HLH is a heterogeneous autosomal recessive disorder. Primary HLH is mostly seen in infancy and early childhood with an estimated prevalence in Europe of
  • Typical symptoms of HLH include, for example, prolonged fever,
  • hypofibrinogenemia hemophagocytosis, hypercytokinmemia, and/or lymphohistiocytic infiltrate, bone marrow hypoplasia, meningeal infiltrate.
  • cytokines elevated in HLH patients are: IFNy, interleukin 6 (IL-6),
  • IL- 10 tumor necrosis factor (TNF) a
  • TNF tumor necrosis factor
  • IL-8 macrophage colony stimulating factor
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • HLH can also occur during the course of an infection, a rheumatic or a neoplastic disease, and in this case, it is referred to as secondary HLH.
  • Secondary HLH presents with the same signs and symptoms of primary forms and can be equally severe.
  • the current treatment of secondary HLH is aimed at addressing the cause of the underlying disease. This is certainly the case for HLH caused by infections such as Leishmaniasis.
  • infections such as Leishmaniasis.
  • the presence of certain infections, in particular viral infections such as those due to CMV or EBV is very often the trigger for the manifestation of primary forms of HLH. This observation is also supported by the evidence that in animal models of primary HLH, infection with lymphocytic
  • LCMV choriomeningitis virus
  • Jordan MB Hildeman D, Kappler J, Marrack P.
  • hematologicalmalignancy often the severity of the patient condition requires the immediate treatment of HLH, prior to specifically addressing the underlying disease.
  • sJIA systemic Juvenile Idiopathic Arthritis
  • SLE Systemic Lupus Erythematosus
  • MAS Macrophage Activation Syndrome
  • HLH While primary HLH is recognized as predominantly a childhood disease, HLH is a condition that can be found in adults, and increased awareness indicates this may happen more often than recognized in the past. In the majority of adult patients the disease develops during malignancies (mainly non-Hodgkin lymphomas), infections, auto- inflammatory or autoimmune diseases and iatrogenic immune deficiencies.
  • the management of primary HLH patients currently comprises of the following steps (Henter et al, Blood Cancer 2007): (i) induction therapy of 8 weeks with a combination of corticosteroids and immunosuppressive drugs (e.g. etoposide, CsA, alemtuzumab, anti- thymocyte globulin); (ii) maintenance therapy up to transplantation; and (iii) transplantation for all patients with an identified genetic deficiency and eventually in very severe HLH cases with no disease-associated mutations.
  • corticosteroids e.g. etoposide, CsA, alemtuzumab, anti- thymocyte globulin
  • the main goal of induction therapy is to suppress the life-threatening
  • HLH remains around 40 to 50% (Henter et al, Blood 2002; Trottestam H, Home A, Arico M et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood 2011; 118:4577-4584).
  • compositions and methods provided herein were developed as a targeted treatment ensuring efficacy with less toxicity.
  • Perforin knocked out mice are considered a relevant model for the human disease. In fact, these mice, once infected with LCMV, develop all the diagnostic and many of the clinical and laboratory characteristic features of the human disease, and they die if untreated. For these reasons, perforin KO mice have been used to study the pathophysiology of HLH. The HLH- like pathology that they develop is dependent on CD8+ T cells and IFNy produced in response to antigen stimulation.
  • mice Toll Like Receptor (TLR) ligands, these mice die with many of the features of the human disease (Strippolli R, Carvallo F, Scianaro R et al. Amplification of the response to Toll-like receptor ligands by prolonged exposure to interleukin-6 in mice: Implication for the pathogenesis of macrophage activation syndrome.
  • TLR Toll Like Receptor
  • IFNy levels were above the upper limit of normal (17.3 pg/mL) in all patients, and in particular 53.5% had levels above 1000 pg/mL. It was also reported that IFNy levels rise early and quickly, and can fall from > 5000 pg/mL to normal in 48 hours upon effective treatment of HLH.
  • IFNy high levels of IFNy were demonstrated both in patients with HLH secondary to infections and in patients with HLH occurring in the context of sJIA.
  • the disclosure also provides compositions and methods that are useful in identifying or otherwise refining a patient population suffering from a disorder, where the patient has an elevated level of CXCL9, alone or in combination with one or more additional interferony (IFNy) related biomarkers.
  • IFNy interferony
  • the disclosure provides compositions and methods for detecting CXCL9 levels as a biomarker for IFNy production in hemophagocytic
  • lymphohistiocytosis in second HLH, and/or in macrophage activation syndrome (MAS).
  • MAS macrophage activation syndrome
  • a body of evidence in animal models points to a pivotal pathogenic role of IFNy, in primary hemophagocytic lymphohistiocytosis (HLH). High levels of IFNy are also found in humans with HLH. It has been previously reported that high levels of IFNy and of the three IFNy- related chemokine, CXCL9, CXCL10 and CXCL11, are observed in patients with active MAS, a form of secondary HLH that occurs in the context of systemic Juvenile Idiopathic Arthritis (sJIA) (See e.g., Bracaglia C, Caiello I, De Graaf K., et al. Pediatric Rheumatology 2014,12(Suppl 1):03). Indirect evidence in mice suggests that IFNy is mostly produced in peripheral tissues and blood concentrations may be relatively low.
  • sJIA Juvenile Idiopathic Arthritis
  • MAS macrophage activation syndrome
  • sJIA systemic juvenile idiopathic arthritis
  • MAS occurs typically during active disease phases, including at disease onset.
  • An infectious trigger can be identified in a high proportion of patients.
  • Typical features of MAS include fever, splenomegaly, hemorrhages, and signs of liver, central nervous system and kidney involvement that may lead to multiple organ failure.
  • Laboratory abnormalities include decrease in white blood cells, platelet and hemoglobin, hypertransaminasemia, marked increase in ferritin, and evidence for intravascular activation of the coagulation system (Ravelli, A., et al,
  • Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis diagnosis, genetics, pathophysiology and treatment. Genes Immun. 13(4): p. 289-98).
  • MAS causes significant morbidity and mortality accounting for a relevant portion of the deaths due to sJIA (Minoia, F., et al., Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients.
  • MAS shares the majority of the clinical features and laboratory abnormalities of haemophagocytic lymphohistiocytoses (HLH), and it is indeed currently classified among secondary or reactive HLH (sec-HLH) (Jordan, M.B., et al., How I treat hemophagocytic lymphohistiocytosis. Blood, 2011. 118(15): p. 4041-52).
  • HHL haemophagocytic lymphohistiocytoses
  • HLH Primary forms of HLH (p-HLH) are caused by mutations of genes coding for proteins involved in granule exocytosis, including PRF1, UNCI 3D, STXBP2, STXI L RAB27A and XXAP, typically leading to defective cytotoxic activity of CD8+ lymphocytes and NK cells. According to the current classification, in the absence of an identifiable genetic cause and/or of familial inheritance, HLH is defined as secondary or reactive. Sec-HLH can occur in the absence of a demonstrable trigger or in the context of infections, malignancies or rheumatic diseases, the latter being commonly referred to as MAS.
  • FHL familial hemophagocytic lymphohistiocytosis
  • MAS macrophage activation syndrome
  • sJIA systemic juvenile idiopathic arthritis
  • lymphohistiocytosis CD8+ T cells and interferon gamma are essential for the disorder. Blood, 2004. 104(3): p. 735-43; Pachlopnik Schmid, J., et al, Neutralization oflFNgamma defeats haemophagocytosis in LCMV-infected perforin- and Rab27 a-deficient mice. EMBO Mol Med, 2009. 1(2): p. 112-24). In Rab27 deficient mice, in which the disease does not lead to death, neutralization of IFNy causes a marked improvement of the involvement of peripheral organs, including the central nervous system (Pachlopnik 2009).
  • the studies provided herein were designed to evaluate the correlation between serum levels of IFNy and of the three IFNy related chemokines with themselves and with laboratory parameters of disease activity in patients with active MAS in order to search for a biomarker of IFNy in vivo production.
  • circulating levels of IFNy, CXCL9, CXCL10, CXCL11 and IL-6 were measured in patients with sJIA where about 37% (20 outof 54) of the patients had MAS at time of sampling.
  • the relation of the circulating levels to disease activity parameters was also evaluated, as were the correlations of the levels of IFNy with those of CXCL9, CXCL10 and CXCL11.
  • the biomarker is total IFNy level, which is useful as a pharmacodynamic biomarker.
  • levels of IFNy and of the 3 IFNy- related chemokines CXCL9, CXCL10, and CXCL11 were significantly elevated in active MAS as compared to active sJIA without MAS at sampling.
  • active MAS laboratory parameters of disease severity such as ferritin, neutrophils, platelets, alanine aminotransferase and lactate dehydrogenase, were significantly correlated with IFNy and CXCL9, and to a lesser extent with CXCL10 and CXCL11 ; no correlation with IL-6 levels was found.
  • active MAS I IFNy levels were significantly correlated with levels of CXCL9, to a lesser extent with levels of CXCL10, and not with levels of CXCL11.
  • CXCL9 Chemokine (C-X-C Motif) Ligand 9
  • CXL10 Chemokine Ligand 9
  • CXCL11 three chemokines that are known to be induced by IFNy
  • levels of IFNy, CXCL9, CXCL10 and CXCL11 were correlated with laboratory parameters of disease severity.
  • the disclosure provides compositions and methods using a neutralizing anti-IFNy antibody or antigen-binding fragment thereof to treat, prevent and/or delay the onset or progression of, or alleviate a symptom associated with transplant failure, transplant rejection, and/or an inflammatory disorder associated with transplant rejection such as solid organ transplant disorder, bone marrow acute graft rejection.
  • the disclosure provides compositions and methods using a neutralizing anti- IFNy antibody or antigen-binding fragment thereof to treat, inhibit, delay the progression of, or otherwise ameliorate a symptom of Graft- versus-host disease (GvHD) in a subject who has received or is receiving a transplant comprising biological material or a series of transplants comprising biological material.
  • GvHD Graft- versus-host disease
  • compositions and methods using a neutralizing anti-IFNy antibody or antigen-binding fragment thereof to prolong survival of transplanted biological material The disclosure provides compositions and methods using a neutralizing anti-IFNy antibody or antigen-binding fragment thereof to treat, prevent and/or delay the onset or progression of, or alleviate a symptom associated paraneoplastic cerebellar degeneration, hemorrhagic fever, sarcoidosis, adult onset Still's disease or CART-T cell therapy.
  • compositions and methods provided herein are useful in transplanting any biological material, including, for example, cells, tissue(s), bone marrow, and/or organ(s), including, by way of non-limiting example, heart, kidney, pancreas, liver, and/or intestine.
  • the biological material to be transplanted is allogeneic biological material.
  • the transplanted biological material is bone marrow.
  • the transplanted biological material is a population of hematopoietic stem cells.
  • the biological material to be transplanted is or is derived from one or more hepatocytes.
  • NI-0501 is administered to a subject in need thereof for treating, preventing and/or delaying the onset or progression of, or alleviating a symptom associated with transplant failure, transplant rejection, and/or an inflammatory disorder associated with transplant rejection.
  • transplant rejection also referred to herein as transplant failure
  • the transplant rejection is acute.
  • the transplant rejection is hyperacute.
  • Neutralizing anti-IFNy antibodies of the invention include, for example, the heavy chain complementarity determining regions (CDRs) shown below in Table 1A, the light chain CDRs shown in Table IB, and combinations thereof.
  • CDRs heavy chain complementarity determining regions
  • CDR complementarity determining regions
  • Exemplary antibodies of the invention include, for example, the anti-IFNy antibodies described in PCT Publication No. WO 2006/109191, the contents of which are hereby incorporated by reference in their entirety.
  • Exemplary antibodies of the invention include, for example, the antibody referred to herein as NI-0501, which binds the human IFNy.
  • the heavy chain, light chain, variable heavy (VH) chain, and variable light (VL) chain sequences of the NI-0501 antibody are shown below, with the CDR sequences underlined in the VH and VL amino acid sequences:
  • Suitable anti-IFNy antibodies include the antibodies described in U.S. Patent
  • ARC1.2R3P2 A6 (“A6")
  • ARC1.2R3P2 B4 (“B4")
  • ARC1.2R3P2 B9 ARC1.2R3P2 B9
  • C9 ARC1.2R3P2 C10
  • CIO ARC1.2R3P2 C10
  • ARC1.2R3P2 E1 (“El")
  • ARC1.2R3P2 F8 (“F8")
  • ARC1.2R3P2 F9 ARC1.2R3P2 G7
  • the IFNy antibodies are formatted in an IgG isotype.
  • the IFNy antibodies are formatted in an IgGl isotype.
  • IFNy antibodies of the invention specifically bind human and/or cynomolgus IFNy, wherein the antibody binds to the same epitope as the NI- 0501 antibody, the A6 antibody, the B4 antibody, the B9 antibody, the C9 antibody, the CIO antibody, the D3 antibody, the D6 antibody, the D8 antibody, the El antibody, the F8
  • the F9 antibody the F9 antibody, the G7 antibody, the G9 antibody, and/or the G10 antibody.
  • compositions and methods are useful in the treatment of any of a variety of disorders associated with interferon-gamma (IFNy) expression and/or activity, including aberrant IFNy expression and/or activity.
  • IFNy interferon-gamma
  • the compositions and methods of the disclosure are useful in the treatment of hemophagocytic lymphohistiocytosis (HLH).
  • HHL hemophagocytic lymphohistiocytosis
  • HLH is a rare, serious and life threatening disease of pathologic immune activation, characterized by clinical signs and symptoms of extreme inflammation (fever, splenomegaly, cytopenias, coagulopathy), leading to the development of abnormal immune-mediated pathologies which, through tissue damage, ultimately may cause multi-organ failure and death (Henter JI, Elinder G, Soder O, Hansson M, et al: Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood 1991, 78:2918- 2922).
  • HLH comprises primary (genetic/familial) HLH and secondary HLH.
  • Primary HLH is a heterogeneous autosomal recessive disorder, mostly seen in infancy and early childhood with an estimated prevalence in Europe of 1/50,000 live births (Janka GE:
  • the impaired cytotoxic function characterizing the HLH syndrome is due to mutations in the gene encoding perforin (PRF1), a cytolytic protein of cytotoxic granules which is a key regulator for T-cell- and natural killer-cell-mediated cyto lysis 10.
  • PRF1 perforin
  • the disease is caused by mutations in the UNCI 3D gene, encoding a protein which is involved in the release of perforin into the target cell.
  • Griscelli syndrome type 2 (GS-2) and Chediak-Higashi syndrome (CHS)
  • HLH Chediak-Higashi syndrome
  • compositions and methods of the disclosure are useful in the treatment of secondary HLH.
  • compositions and methods of the disclosure are useful in the treatment of
  • MAS macrophage activation syndrome
  • MAS is a severe, potentially life-threatening complication of rheumatic diseases which is caused by excessive activation and expansion of T lymphocytes and macrophages.
  • the uncontrolled expansion of these immune cells results in a marked hypercytokinemia and a hyperinflammatory state associated with fever, cytopenias, hepatosplenomegaly, liver dysfunction, coagulation abnormalities and hyperferritinemia, and may progress to multiple organ failure and death (Schulert GS, Grom AA: Pathogenesis of macrophage activation syndrome and potential for cytokine- directed therapies.
  • Annu. Rev. Med. 2015, 66: 145-159 are organ failure and death.
  • MAS occurs most frequently in patients with sJIA and, more rarely with systemic lupus erythematosus (SLE), but is also described, though more rarely, in patients with vasculitis, particularly with Kawasaki disease.
  • SJIA systemic lupus erythematosus
  • MAS is potentially fatal, a timely diagnosis and immediate therapeutic intervention are essential for appropriate management of the disease.
  • the reported mortality rates in MAS reach 20-30%, and it remains the major source of mortality in pediatric rheumatology (Grom AA, Home A, De Benedetti F: Macrophage activation syndrome in the era of biologic therapy. Nat Rev Rheumatol. 2016 Mar 24. doi: 10.1038/nrrheum.2015.179).
  • Hemophagocytosis may not be present in a significant proportion of patients with MAS at presentation (Minoia F, Davi S, Home A, Demirkaya E, et al: Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients. Arthritis & rheumatology (Hoboken, N.J.) 2014, 66:3160-3169). Moreover, hemophagocytosis, NK cell activity and sCD25 are not routinely assessed in the context of MAS.
  • HScore diagnostic score
  • CsA Cyclosporine A
  • first line HLH treatments include dexamethasone.
  • treatments such as etoposide and/or dexamethasone are myelosuppressive and/or broadly immune suppressive.
  • second line HLH treatment treatments such as alemtuzumab/ATG are profoundly immunosuppressive, and survival is thought to be very poor with these treatments.
  • Ramanan AV Schneider R: Macrophage activation syndrome following initiation of etanercept in a child with systemic onset juvenile rheumatoid arthritis. J. Rheumatol. 2003, 30:401-403; De Benedetti F, Brunner HI, Ruperto N, Kenwright A, et al:
  • TNFa TNFa pathway
  • compositions including NI-0501 compositions, and methods of the disclosure are advantageous over current therapies for primary and secondary HLH.
  • MAS and HLH are characterized by sustained immune cell activation and an associated cytokine storm of proinflammatory cytokines with overproduction of IFNy, TNFa, IL- 1 and IL-6 (Henter JI, Elinder G, Soder O, Hansson M, et al: Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood 1991, 78:2918-2922; Imashuku S, Hibi S, Fujiwara F, Todo S: Hyper- interleukin (IL)-6-naemia in haemophagocytic lymphohistiocytosis. Br. J. Haematol.
  • mice For primary HLH, perforin knock-out mice are considered a relevant model as these mice, once infected with LCMV, develop all the diagnostic and many of the clinical and laboratory characteristic features of the human disease.
  • the HLH-like disease that they develop is dependent on CD8+ T cells and IFNy produced in response to antigen stimulation (Imashuku S, Hibi S, Fujiwara F, Todo S: Hyper-interleukin (IL)-6-naemia in haemophagocytic lymphohistiocytosis. Br. J. Haematol. 1996, 93:803-807).
  • IL Hyper-interleukin
  • the two IFNy-inducible chemokines (CXCL9 and CXCL10) were upregulated after TLR9 stimulation both in blood and in liver, and a significantly correlation was observed between serum levels of IFNy with CXCL9 and CXCL10 serum concentrations.
  • mice showed a drop in platelet and neutrophil counts, increased sCD25, ferritin and LDH levels, resembling many of the features typically present in patients with MAS (Strippoli R, Carvello F, Scianaro R, De Pasquale L, et al: Amplification of the response to Toll-like receptor ligands by prolonged exposure to interleukin-6 in mice: implication for the pathogenesis of macrophage activation syndrome. Arthritis Rheum. 2012, 64: 1680-1688).
  • IFNy is neutralized with the administration of an anti- IFNy antibody
  • survival is markedly improved and laboratory parameters reverted (Prencipe G et al, manuscript in preparation).
  • IFNy and chemokines in particular CXCL9 correlated significantly with parameters of disease severity, such as neutrophil and platelet counts, ferritin and ALT, further supporting the pathogenic role of IFNy in secondary HLH and the potential use of chemokines as relevant biomarkers of the disease (Buatois V, Chatel L, Cons L, Lory S, et al: IFNy drives disease in the TLR9-mediated secondary HLH in mice: rationale for a new therapeutic target in secondary HLH).
  • compositions, including NI-0501 compositions, and methods of the disclosure are advantageous over current therapies for sJIA.
  • the compositions, including NI-0501 compositions, and methods of the disclosure are useful in treating
  • NI-0501 represents an innovative and effective therapeutic approach in the management of this severe, life-threatening complication of rheumatic diseases, potentially limiting side effects from long-term high dose glucocorticoid treatment.
  • formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LipofectinTM), DNA conjugates, anhydrous absorption pastes, oil-in- water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. Any of the foregoing mixtures may be appropriate in treatments and therapies in accordance with the present invention, provided that the active ingredient in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration.
  • Efficaciousness of treatment is determined in association with any known method for diagnosing or treating the particular immune-related disorder. Alleviation of one or more symptoms of the immune-related disorder indicates that the antibody confers a clinical benefit.
  • Antibodies of the invention may be used as therapeutic agents. Such agents will generally be employed to treat or prevent a disease or pathology associated with aberrant expression or activation of a given target in a subject.
  • An antibody preparation preferably one having high specificity and high affinity for its target antigen, is administered to the subject and will generally have an effect due to its binding with the target.
  • Administration of the antibody mayabrogate or inhibit or interfere with the signaling function of the target.
  • Administration of the antibody may abrogate or inhibit or interfere with the binding of the target with an endogenous ligand to which it naturally binds.
  • a therapeutically effective amount of an antibody of the invention relates generally to the amount needed to achieve a therapeutic objective. As noted above, this may be a binding interaction between the antibody and its target antigen that, in certain cases, interferes with the functioning of the target.
  • the amount required to be administered will furthermore depend on the binding affinity of the antibody for its specific antigen, and will also depend on the rate at which an administered antibody is depleted from the free volume other subject to which it is administered.
  • Common ranges for therapeutically effective dosing of an antibody or antibody fragment of the invention may be, by way of nonlimiting example, from about 0.1 mg/kg body weight to about 50 mg/kg body weight. Prefered doses include 1, 3, 6, 10 mg/kg body weight.
  • Common dosing frequencies may range, for example, from once daily to twice a week. Treatment may last 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks.
  • Antibodies or a fragment thereof of the invention can be administered for the treatment of a variety of diseases and disorders in the form of pharmaceutical compositions. Principles and considerations involved in preparing such compositions, as well as guidance in the choice of components are provided, for example, in Remington: The Science And Practice Of Pharmacy 19th ed. (Alfonso R. Gennaro, et al., editors) Mack Pub. Co., Easton, Pa.: 1995; Drug Absorption Enhancement: Concepts, Possibilities, Limitations, And Trends, Harwood Academic Publishers, Langhorne, Pa., 1994; and Peptide And Protein Drug Delivery
  • the formulation can also contain more than one active compound, e.g., anti-
  • the composition can comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent.
  • an agent that enhances its function such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent.
  • Such molecules are suitably present in combination in amounts that are effective for the purpose intended.
  • the active compound e.g., an anti-IFNy antagonist
  • combination therapy i.e., combined with one or more additional agents that are useful for treating pathological conditions or disorders.
  • additional agents that are useful for treating pathological conditions or disorders.
  • the term "in combination" in this context means that the agents are given substantially contemporaneously, either simultaneously or sequentially. If given sequentially, at the onset of administration of the second compound, the first of the two compounds is preferably still detectable at effective concentrations at the site of treatment.
  • the combination therapy can include one or more neutralizing anti-IFNy antibodies of the invention coformulated with, and/or coadministered with, one or more additional therapeutic agents, e.g., one or more cytokine and growth factor inhibitors, immunosuppressants, anti-inflammatory agents, metabolic inhibitors, enzyme inhibitors, and/or cytotoxic or cytostatic agents, as described in more detail below.
  • additional therapeutic agents e.g., one or more cytokine and growth factor inhibitors, immunosuppressants, anti-inflammatory agents, metabolic inhibitors, enzyme inhibitors, and/or cytotoxic or cytostatic agents, as described in more detail below.
  • Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding possible toxicities or complications associated with the various monotherapies.
  • the additional agent is an immunosuppressive agent.
  • the immunosuppressive agent is Cyclosporin A (CsA).
  • CsA Cyclosporin A
  • the subject has been receiving CsA prior to administration of NI-0501.
  • the additional agent includes at least etoposide.
  • the subject has been receiving etoposide prior to administration of NI- 0501.
  • the additional agent is intrathecal methotrexate and/or
  • the subject has been receiving intrathecal
  • methotrexate and/or glucocorticoids prior to administration of NI-0501.
  • the additional agent is IV immunoglobulins (IVIG).
  • IVIG IV immunoglobulins
  • the IVIG is administered as replacement treatment in a subject with a documented immunoglobulin deficiency.
  • IVIG is administered given at a dose of 0.5 g/kg, every 4 weeks or more frequently in order to maintain adequate IgG levels.
  • the one or more additional agents is analgesic treatment, transfusion of blood products, electrolyte and glucose infusions, antibiotics, anti-fungal and anti- viral treatment and/or general supportive care.
  • the smallest inhibitory fragment that specifically binds to the binding domain of the target protein and/or the smallest inhibitory fragment that interferes with or otherwise antagonizes IFNy signaling is preferred.
  • peptide molecules can be designed that retain the ability to bind the target protein sequence.
  • Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. (See, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA, 90: 7889-7893 (1993)).
  • the formulation can also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other.
  • the composition can comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent.
  • cytotoxic agent such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent.
  • Such molecules are suitably present in combination in amounts that are effective for the purpose intended.
  • the invention further provides dosing regimen for treating, preventing and/or delaying the onset or progression of, or alleviating a symptom associated with elevated IFN- ⁇ .
  • the dosing regimens are multiple variable dose regimens.
  • the dose between 1.0 to 10 mg/kg of the subject's body weight of an antibody that binds interferon gamma (IFNy).
  • the dose is administered in at least a first and second dose.
  • the second dose is lower or higher than the first dose.
  • hemophagocytic lymphohistiocytosis (HLH) in a human subject includes an induction or a first dose and a treatment or second dose of an anti- IFN-g monoclonal antibody.
  • the subject is an adult subject or a pediatric subject.
  • the first dose is 1.0 or 3.0, mg/kg body weight.
  • the second dose is 3.0, 6.0 or
  • the first dose is 1.0 mg/kg body weight an antibody and the second does is 3.0, 6.0 or 10.0 mg/kg body weight.
  • the first dose is 3.0 mg/kg body weight an antibody and the second does is 6.0 or 10.0 mg/kg body weight.
  • the first dose is administered once as a single dose.
  • the first dose is administer more than once for an induction treatment period.
  • the second dose is administered for one or more treatment periods.
  • the second dose is administered for a first treatment period.
  • the second dose is administered every three days after the first dose.
  • the first treatment period last about 1, 2, 3, 4, 5, 6 or more weeks.
  • Preferably the first treatment period is 2 weeks.
  • the second dose is administered for a second treatment period after completion of the first treatment period.
  • the second dose is administered twice a week.
  • the second treatment period lasts about 1-20 weeks, 2-20 weeks, 3- 20 weeks, 4-20 weeks, 5-20 weeks, 6- 20 weeks, 1-10 weeks, 2-10 weeks, 3- 10 weeks, 4-10 weeks, 5-10 weeks, 6- 10 weeks.
  • the second treatment period is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12 or more weeks.
  • the second dose is increased or decreased during the course of the first or second treatment period.
  • the increased or decreased dose is referred to as a third dose.
  • the third dose may 1.0, 3.0 or 6.0 mg/kg body weight.
  • the third dose is administered for the remainder of the first and second treatment period.
  • the third dose is administered for a third treatment period.
  • the third dose is referred to as a maintenance dose and the third treatment period is referred to as a maintenance period.
  • hemophagocytic lymphohistiocytosis in a human pediatric includes an induction or a first dose and a treatment or second dose of an anti- IFN-g monoclonal antibody .
  • the first dose is 6.0, mg/kg body weight.
  • the second dose is 3.0, mg/kg body weight. 10.0 mg/kg body weight.
  • the first dose is administered once as a single dose. Alternatively, the first dose is administered more than once for a induction treatment period.
  • the second dose is administered for one or more treatment periods.
  • the second dose is administered for a first treatment period.
  • the second dose is administered every three days after the first dose.
  • the first treatment period last about 1, 2, 3, 4, 5, 6 or more weeks.
  • Preferably the first treatment period is 2 weeks.
  • the second dose is administered for a second treatment period after completion of the first treatment period.
  • the second dose is administered twice a week.
  • the second treatment period lasts about 1-20 weeks, 2-20 weeks, 3- 20 weeks, 4-20 weeks, 5-20 weeks, 6- 20 weeks, 1-10 weeks, 2-10 weeks, 3- 10 weeks, 4-10 weeks, 5-10 weeks, 6- 10 weeks.
  • the second treatment period is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12 or more weeks.
  • the second dose is increased or decreased during the course of the first or second treatment period.
  • the increased or decreased dose is referred to as a third dose.
  • the third dose is 6.0 mg/kg body weight.
  • the third dose is administered for the remainder of the first and second treatment period.
  • the third dose is administered for a third treatment period.
  • the third dose is referred to as a maintenance dose and the third treatment period is referred to as a maintenance period.
  • the first dose is 3.0 or 6.0 mg/kg body weight.
  • the first dose is 6.0 mg/kg body weight.
  • the second dose is 6.0 or 10.0 mg/kg body weight.
  • the second dose is 10.0 mg/kg body weight.
  • the first dose is 6.0 mg/kg body weight an antibody and the second does is 10.0 mg/kg body weight.
  • the first dose is administered once as a single dose. Alternatively the first dose is administer more than once for an induction treatment period.
  • the second dose is administered for one or more treatment periods.
  • the second dose is administered for a first treatment period.
  • the second dose is administered every three days after the first dose.
  • the first treatment period last about 1, 2, 3, 4, 5, 6 or more weeks.
  • Preferably the first treatment period is 2 weeks.
  • the second dose is administered for a second treatment period after completion of the first treatment period.
  • the second dose is administered twice a week.
  • the second treatment period lasts about 1-20 weeks, 2-20 weeks, 3- 20 weeks, 4-20 weeks, 5-20 weeks, 6- 20 weeks, 1-10 weeks, 2-10 weeks, 3- 10 weeks, 4-10 weeks, 5-10 weeks, 6- 10 weeks.
  • the second treatment period is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12 or more weeks.
  • the second dose is increased or decreased during the course of the first or second treatment period.
  • the increased or decreased dose is referred to as a third dose.
  • the third dose may 1.0, 3.0 or 6.0 mg/kg body weight.
  • the third dose is administered for the remainder of the first and second treatment period.
  • the third dose is administered for a third treatment period.
  • the third dose is referred to as a maintenance dose and the third treatment period is referred to as a maintenance period.
  • a multiple variable dose regimen for the treatment of a condition in a human subject includes an induction or a first dose and a treatment or second dose of an anti- IFN-g monoclonal antibody.
  • the subject is an adult subject or a pediatric subject.
  • the condition is associated with elevated IFNg levels.
  • the condition is transplant rejection such as solid organ transplant disorder or bone marrow acute graft rejection graft vs. host disease, paraneoplastic cerebellar degeneration, hemorrhagic fever, sarcoidosis, adult onset Still's disease.
  • dosing regimen is administered to a subject after receiving CAR-T cell therapy.
  • the first dose is between 1.0- 10 mg/kg body weight.
  • first dose is 1.0, 3.0, 6.0, or 10 mg/kg body weight an antibody.
  • the second dose is higher or lower that the first doses.
  • the second dose is between 1.0- 10 mg/kg body weight.
  • second dose is 1.0, 3.0, 6.0 or 10, mg/kg body weight an antibody.
  • the first dose is 1.0 mg/kg body weight and the second does is 3.0, 6.0 or 10.0 mg/kg body weight.
  • the first dose is 3.0 mg/kg body weight an antibody and the second does is 6.0 or 10.0 mg/kg body weight.
  • the first dose is 6.0 mg/kg body weight an antibody and the second does is 10.0 mg/kg body weight.
  • the first dose is administered once as a single dose.
  • the first dose is administer more than once for an induction treatment period.
  • the second dose is administered for one or more treatment periods.
  • the second dose is administered for a first treatment period.
  • the second dose is administered every three days after the first dose.
  • the first treatment period last about 1, 2, 3, 4, 5, 6 or more weeks.
  • Preferably the first treatment period is 2 weeks.
  • the second dose is administered for a second treatment period after completion of the first treatment period.
  • the second dose is administered twice a week.
  • the second treatment period lasts about 1-20 weeks, 2-20 weeks, 3- 20 weeks, 4-20 weeks, 5-20 weeks, 6- 20 weeks, 1-10 weeks, 2-10 weeks, 3- 10 weeks, 4-10 weeks, 5-10 weeks, 6- 10 weeks.
  • the second treatment period is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12 or more weeks.
  • the second dose is increased or decreased during the course of the first or second treatment period.
  • the increased or decreased dose is referred to as a third dose.
  • the third dose may 1.0, 3.0, 6.0 or 10.0 mg/kg body weight.
  • the third dose is administered for the remainder of the first and second treatment period.
  • the third dose is administered for a third treatment period.
  • the third dose is referred to as a maintenance dose and the third treatment period is referred to as a maintenance period
  • the first and second time period for the second dose may be adjusted from time to time based upon for example, the subject's heath status.
  • adjustments to the time between doses may be adjusted ⁇ 1, 2, 3, or 4 days. Preferably + 2 days.
  • the dose is administered with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hrs.
  • the doses is administered with an hour.
  • the time period for infusion of the dose is based upon a number of factors know in the art, for example, age, weight, physical condition or adverse reaction to the therapeutic.
  • the time period for the infusion of the dose is typically the fasted infusion rate that is tolerated (i.e., without causing an adverse reaction) by the subject.
  • the dose is administered as a single injection.
  • the antibody is administered as a monotherapy or a co-therapy for the disease or condition being treated.
  • the subject is administered a second agent.
  • the second agent is for example an anti-inflammatory agent, and/or an immunosuppressive agent
  • the subject has been administered dexamethasone immediately prior to the dosing of the antibody.
  • the dexamethasone is administered at a dose of at least 10 mg/m2.
  • the dexamethasone is administered at a dose of at least 5 mg/m2.
  • subject has not previously been treated for HLH.
  • compositions suitable for administration can be incorporated into pharmaceutical compositions suitable for administration.
  • Such compositions typically comprise the antibody or soluble chimeric polypeptide and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's
  • compositions a standard reference text in the field, which is incorporated herein by reference.
  • Preferred examples of such carriers or diluents include, but are not limited to, water, saline, ringer's solutions, dextrose solution, and 5% human serum albumin. Liposomes and nonaqueous vehicles such as fixed oils may also be used.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • the preferred route of administration is by injection such as intravenous injection.
  • the intravenous injection can be rapid or slow infusion.
  • the infusions is over about a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hour period.
  • the time period for infusion is based upon a number of factors know in the art, for example, age, weight, physical condition or adverse reaction to the therapeutic.
  • the time period for the infusion is typically the fasted infusion rate that is tolerated (i.e., without causing an adverse reaction) by the subject.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Preferred injectable pharmaceutical compositions include excipients such g L- histidine, 3 L-histidine monohydrochloride, monohydrate, sodium chloride (NaCl),
  • the pH of the injectable pharmaceutical composition is between about 5.8 and 6.2.
  • the pH of the injectable pharmaceutical composition is pH 6.0.
  • the anti- IFN- ⁇ antibody such as NI-0501 is formulated (per ml) as follows: 5 mg of NI-051, 1.55 mg L-histidine, 3.14 mg L-histidine
  • the pharmaceutical composition is packaged in a unit dose.
  • the unit dose is packaged in a container.
  • the container is a glass or plastic container.
  • the container is a syringe, vial, infusion bottle, ampoule or carpoule.
  • the container can hold a volume of 1- 25 ml.
  • the container can hold a volume of 2, 5, 10 or 20 ml.
  • the unit dose of a fully human anti-interferon gamma (IFNy) monoclonal antibody is between 5- 25 mg/ ml. Preferably the unit dose is 5 mg/ml or 25 mg/ml.
  • the antibody is in a solution (e.g., water for injection) having per ml: 1.55 mg L-histidine, 3.14 mg L-histidine monohydrochloride, monohydrate, 7.31 mg sodium chloride (NaCl), and 0.05 mg Polysorbate 80.
  • the invention provides a unit dose container having 20 ml of a fully human anti-interferon gamma (IFNy) monoclonal antibody solution at a concentration of 5 mg/ml or 25 mg/ml antibody, wherein the pH of the solution is between 5.8 and 6.2.
  • the antibody is solubilized in the solution such that the solution is clear, colorless, and without precipitate.
  • the antibody is in a solution (e.g., water for injection) having per ml: 1.55 mg L- histidine, 3.14 mg L-histidine monohydrochloride, monohydrate, 7.31 mg sodium chloride (NaCl), and 0.05 mg Polysorbate 80.
  • a solution e.g., water for injection
  • NaCl sodium chloride
  • the invention provides a unit dose container having 10 ml or 20 ml of a fully human anti-interferon gamma (IFNy) monoclonal antibody solution at a concentration of 25 mg/ml antibody, wherein the pH of the solution is between 5.8 and 6.2.
  • the antibody is solubilized in the solution such that the solution is clear, colorless, and without precipitate.
  • the antibody is in a solution (e.g., water for injection) having per ml: 1.55 mg L-histidine, 3.14 mg L-histidine monohydrochloride, monohydrate, 7.31 mg sodium chloride (NaCl), and 0.05 mg Polysorbate 80.
  • the invention provides a unit dose container having 2 ml or
  • the antibody is solubilized in the solution such that the solution is clear, colorless, and without precipitate.
  • the antibody is in a solution (e.g., water for injection) having per ml: 1.55 mg L-histidine, 3.14 mg L-histidine monohydrochloride, monohydrate, 7.31 mg sodium chloride (NaCl), and 0.05 mg Polysorbate 80.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the compounds can also be prepared in the form of suppositories (e.g., with
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled
  • release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate,
  • polyanhydrides polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
  • the materials can also be obtained commercially from Alza Corporation and Nova
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U. S. Patent No. 4,522,811.
  • Dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound
  • compositions can be included in a container, pack, or
  • Detection agents can be used for detecting the presence of a given target (or a protein fragment thereof) in a sample.
  • the detection agent contains a detectable label.
  • the detection agent is an antibody (or fragment thereof) or a probe.
  • the agent or probe is labeled.
  • the term "labeled", with regard to the probe or antibody is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin.
  • biological sample is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. Included within the usage of the term “biological sample”, therefore, is blood and a fraction or component of blood including blood serum, blood plasma, or lymph.
  • the bodily fluids can be fluids isolated from anywhere in the body of the subject, preferably a peripheral location, including but not limited to, for example, blood, plasma, serum, synovial fluid, urine, sputum, spinal fluid, cerebrospinal fluid, pleural fluid, fluid of the respiratory, intestinal, and genitourinary tracts, saliva, intra-organ system fluid, ascitic fluid, tumor cyst fluid, amniotic fluid and combinations thereof.
  • the biological sample also includes experimentally separated fractions of all of the preceding fluids.
  • Biological samples also include solutions or mixtures containing homogenized solid material, such as feces, tissues, and biopsy samples.
  • the detection method of the invention can be used to detect an analyte mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo.
  • in vitro techniques for detection of an analyte mRNA include Northern hybridizations and in situ hybridizations.
  • In vitro techniques for detection of an analyte protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence.
  • In vitro techniques for detection of an analyte genomic DNA include Southern hybridizations.
  • dose refers to an amount of an anti- IFN-gamma antibody which is administered to a subject.
  • multiple-variable dose includes different doses of an anti- IFN-gamma antibody which are administered to a subject for therapeutic treatment.
  • Multiple-variable dose regimen or “multiple-variable dose therapy” describe a treatment schedule which is based on administering different amounts of an anti- IFN-gamma antibody at various time points throughout the course of treatment.
  • the invention describes a multiple- variable dose method of treatment comprising an induction phase and a treatment phase, wherein an anti- FN-gamma antibody is administered at a higher or lower dose during the induction phase than the treatment phase.
  • the invention describes a multiple-variable dose method of treatment comprising an induction phase, a first a treatment phase, and a second treatment phase wherein an anti- IFN-gamma antibody is administered at a higher or lower dose during the induction phase than the treatment phase.
  • the anti- IFN- gamma antibody may be administered at a higher or lower dose during the first treatment phase than the second treatment phase.
  • the dose is the same in the first treatment phases and the second treatment phase. .
  • induction phase or “loading phase”, as used herein, refers to a period of treatment comprising administration of an IFN-gamma antibody to a subject in order to attain a threshold level.
  • at least one induction dose of IFN-gamma is administered to a subject suffering from a disorder in which IFN-gamma is detrimental.
  • threshold level refers to a therapeutically effective level of an IFN-gamma antibody in a subject.
  • a threshold level is achieved by administering at least one induction dose during the induction phase of treatment. Any number of induction doses may be administered to achieve a threshold level of IFN-gamma. Once a threshold level is achieved, the treatment phase is initiated.
  • induction dose refers to the first dose of an anti- IFN-gamma antibody, which is either larger or smaller in comparison to the maintenance or treatment dose.
  • the induction dose can be a single dose or, alternatively, a set of doses.
  • the induction dose is often used to bring the drug in the body to a steady state amount, and may be used to which to achieve maintenance drug levels quickly.
  • An induction dose is subsequently followed by administration of smaller or larger doses of an anti- IFN- gamma antibody, i.e., the treatment dose.
  • the induction dose is administered during the induction phase of therapy.
  • treatment phase refers to a period of treatment comprising administration of an anti- IFN-gamma antibody to a subject in order to maintain a desired therapeutic effect.
  • the treatment phase follows the induction phase, and, therefore, is initiated once a threshold level is achieved.
  • Treatment phase may be Preferably, the substance is administered every 3, days following the induction dose. (e.g. initial dose) days. Alternatively, the substance is administered once or twice a week.
  • treatment dose or "maintenance dose” is the amount of an anti- IFN- gamma antibody taken by a subject to maintain or continue a desired therapeutic effect.
  • a treatment dose is administered subsequent to the induction dose.
  • a treatment dose can be a single dose or, alternatively, a set of doses.
  • a treatment dose is administered during the treatment phase of therapy.
  • Treatment doses are smaller or larger than the induction dose and can be equal to each other when administered in succession. When there is more than one treatment phases there may also be more than one treatment doses.
  • a "dosage regimen” or “dosing regimen” includes a treatment regimen based on a determined set of doses.
  • dosing refers to the administration of a substance (e.g., an an anti- IFN-gamma antibody) to achieve a therapeutic objective (e.g., the treatment of a IFN-gamma-associated disorder).
  • a substance e.g., an an anti- IFN-gamma antibody
  • a therapeutic objective e.g., the treatment of a IFN-gamma-associated disorder
  • biweekly dosing regimen refers to the time course of administering a substance (e.g., an anti- IFN-gamma antibody) to a subject to achieve a therapeutic objective (e.g., the treatment of a IFN-gamma-associated disorder).
  • a substance e.g., an anti- IFN-gamma antibody
  • the biweekly dosing regimen is not intended to include a weekly dosing regimen.
  • a first agent in combination with a second agent includes co administration of a first agent and a second agent, which for example may be dissolved or intermixed in the same pharmaceutically acceptable carrier, or administration of a first agent, followed by the second agent, or administration of the second agent, followed by the first agent.
  • the present invention therefore, includes methods of combination therapeutic treatment and combination pharmaceutical compositions.
  • concomitant as in the phrase “concomitant therapeutic treatment” includes administering an agent in the presence of a second agent.
  • a concomitant therapeutic treatment method includes methods in which the first, second, third, or additional agents are co-administered.
  • a concomitant therapeutic treatment method also includes methods in which the first or additional agents are administered in the presence of a second or additional agents, wherein the second or additional agents, for example, may have been previously administered.
  • a concomitant therapeutic treatment method may be executed step-wise by different actors.
  • one actor may administer to a subject a first agent and a second actor may to administer to the subject a second agent, and the administering steps may be executed at the same time, or nearly the same time, or at distant times, so long as the first agent (and additional agents) are after administration in the presence of the second agent (and additional agents).
  • the actor and the subject may be the same entity (e.g., human).
  • combination therapy refers to the administration of two or more therapeutic substances, e.g., an anti- IFN-gamma antibody and another drug, such as a DMARD or NSAID.
  • the other drug(s) may be administered concomitant with, prior to, or following the administration of an anti- IFN-gamma antibody.
  • NI-0501 is formulated as a sterile concentrate for infusion (per mL).
  • NI-0501 is formulated as follows: 5 mg of NI-051, 1.55 mg L-histidine, 3.14 mg L-histidine monohydrochloride, monohydrate, 7.31 mg sodium chloride (NaCl), and 0.05 mg Polysorbate 80, where the pH is between 5.8 and 6.2.
  • NI-0501 is formulated as follows: 5 mg of NI-051, 1.55 mg L-histidine, 3.14 mg L-histidine monohydrochloride, monohydrate, 7.31 mg sodium chloride (NaCl), and 0.05 mg Polysorbate 80, where the pH is 6.0.
  • NI-0501 is administered to a subject in need thereof for treating, preventing and/or delaying the onset or progression of, or alleviating a symptom associated with HLH.
  • NI-0501 is administered to a subject in need thereof by IV infusion over a period of one hour at an initial dose of 1 mg/kg.
  • thelVinfusion may last more than one hour, for example, at least 90 minutes, at least 2 hours, or at least 3 hours or greater.
  • NI-0501 is administered to a subject in need thereof by at least one additional IV infusion after the initial IV infusion over a period of one hour at an initial dose of 1 mg/kg.
  • the at least one additional IV infusion is at a dose that is higher than the initial dose of 1 mg/kg.
  • the at least one additional IV infusion dosage is 3 mg/kg.
  • the at least one additional IV infusion is administered at least three days after the initial IV infusion.
  • the at least one additional IV infusion is administered at a time selected from the group consisting of at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion. In some embodiments, the at least one additional IV infusion is administered at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion.
  • NI-0501 is administered to a subject in need thereof by at least one series additional IV infusions after the initial IV infusion over a period of one hour at an initial dose of 1 mg/kg, where the series of additional IV infusions includes at least one series of twice weekly IV infusions.
  • the at least one series of twice weekly IV infusions is administered at a dose higher than the initial dose of 1 mg/kg.
  • the at least one series of twice weekly IV infusions is administered at a dose of 3 mg/kg.
  • the at least one additional IV infusion is administered at least three weeks after the initial IV infusion.
  • additional IV infusion is administered at a time selected from the group consisting of at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion.
  • the at least one additional IV infusion is administered at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion.
  • NI-0501 is administered to a subject in need thereof by at least two additional IV infusions after the initial IV infusion.
  • the at least two additional IV infusions are at a dose that is higher than the initial dose of 1 mg/kg.
  • the first additional IV infusion and the second additional IV infusion are administered at the same dosage.
  • the first additional IV infusion and the second additional IV infusion are administered at the same dosage that is higher than the initial dose.
  • at least one of the first and second additional IV infusions is administered at a dosage of 3mg/kg.
  • the first additional IV infusion is administered at least three days after the initial IV infusion.
  • the first additional IV infusion is administered at a time selected from the group consisting of at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion. In some embodiments, the first additional IV infusion is administered at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion.
  • the second additional IV infusion is administered at a time selected from the group consisting of at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion. In some embodiments, the second additional IV infusion is administered at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion.
  • the first additional IV infusion is administered at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion
  • the second additional IV infusion is administered at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion.
  • the first additional IV infusion and the second additional IV infusion are administered at different dosages. In some embodiments, the first additional IV infusion and the second additional IV infusion are administered at different dosages, where the second additional IV infusion dosage is higher than the first additional IV infusion. In some embodiments, the first additional IV infusion and the second additional IV infusion are administered at different dosages, where the second additional IV infusion dosage is higher than the first additional IV infusion, and where both the first and the second additional IV infusion dosages are higher than the initial dosage. In some embodiments, at least one of the first and second additional IV infusions is administered at a dosage of 3mg/kg.
  • the first additional IV infusion is administered at a dosage of 3 mg/kg, and the second additional IV infusion is administered at a dosage of 6 mg/kg. In some embodiments, the first additional IV infusion is administered at least three days after the initial IV infusion. In some embodiments, the first additional IV infusion is administered at a time selected from the group consisting of at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion.
  • the first additional IV infusion is administered at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion.
  • the second additional IV infusion is administered at a time selected from the group consisting of at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion.
  • the second additional IV infusion is administered at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion.
  • the first additional IV infusion is administered at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion
  • the second additional IV infusion is administered at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion.
  • the first additional IV infusion includes at least a first series of twice weekly IV infusions and the second additional IV infusion includes at least a second series of twice weekly IV infusions.
  • the first series of twice weekly IV infusions and the second series of twice weekly IV infusions are administered at a dose higher than the initial dose of 1 mg/kg.
  • the first series of twice weekly IV infusions is administered at a dose of 3 mg/kg, and the second series of twice weekly IV infusions is administered at a dose of 6 mg/kg.
  • the first series of additional IV infusion is administered at least three days after the initial IV infusion.
  • the first series of additional IV infusions is administered at a time selected from the group consisting of at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion. In some embodiments, the first series of additional IV infusions is administered at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion.
  • the second series of additional IV infusions is administered at a time selected from the group consisting of at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion. In some embodiments, the second series of additional IV infusions is administered at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion. In some
  • the first series of additional IV infusions is administered at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion
  • the second series of additional IV infusions is administered at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion.
  • infusions are performed every 3 days after the initial dose for up to 15 days after the initial dose. In some embodiments, infusions are performed every 3 days after the initial dose for up to 15 days after the initial dose, followed by infusions twice per week starting at least 15 days after the initial dose. In some embodiments, the infusion dosage is increased to 3 mg/kg at any point after the initial dose. In some embodiments, after a minimum of two infusions at 3 mg/kg, the dose of NI-0501 is increased to 6 mg/kg for up to four infusions.
  • NI-0501 is administered to a subject in need thereof for treating, preventing and/or delaying the onset or progression of, or alleviating a symptom associated with HLH.
  • NI-0501 is administered to a subject in need thereof by IV infusion over a period of one hour at an initial dose of 1 mg/kg.
  • infusions are performed every 3 days after the initial dose for up to 15 days after the initial dose.
  • infusions are performed every 3 days after the initial dose for up to 15 days after the initial dose, followed by infusions twice per week starting at least 15 days after the initial dose.
  • the infusion dosage is increased to 3 mg/kg at any point after the initial dose. In some embodiments, after a minimum of two infusions at 3 mg/kg, the dose of NI-0501 is increased to 6 mg/kg for up to four infusions.
  • NI-0501 is administered to a subject in need thereof for treating, preventing and/or delaying the onset or progression of, or alleviating a symptom associated with HLH.
  • NI-0501 is administered to a subject in need thereof by IV infusion for a dosage of greater than 6 mg/kg.
  • NI-0501 is administered to a subject in need thereof by IV infusion, after an initial dosage, for a second dosage of greater than 6 mg/kg.
  • the second dosage is at least 10 mg/kg.
  • the second dosage is 10 mg/kg.
  • the second dosage is 10 mg/kg, repeated daily.
  • the second dosage is 10 mg/kg, repeated daily for 1 week.
  • the second dosage is 10 mg/kg, repeated daily for 2 weeks.
  • the second dosage is 10 mg/kg, repeated daily for more than 2 weeks.
  • NI-0501 is administered to a subject in need thereof for treating, preventing and/or delaying the onset or progression of, or alleviating a symptom associated with secondary HLH. In some embodiments, NI-0501 is administered to a subject in need thereof for treating, preventing and/or delaying the onset or progression of, or alleviating a symptom associated with secondary HLH on a background of sJIA. In some embodiments, NI- 0501 is administered to a subject in need thereof as an initial dose of 6 mg/kg. In some embodiments, the NI-0501 treatment is continued with a subsequent NI-0501 dose. In some embodiments, the NI- 0501 treatment is continued with a subsequent NI-0501 dose of 3 mg/kg every 3 days for at least 4 weeks (i.e., up to SD27).
  • NI-0501 treatment is reduced, stopped, or otherwise shortened upon achievement of a desired clinical outcome. In some embodiments, NI-0501 treatment is shortened upon evidence of complete clinical response, i.e., MAS remission.
  • NI-0501 treatment is continued for up to an additional 4 weeks (i.e., up to SD56) as maintenance as needed until MAS remission is achieved.
  • NI-0501 treatment is continued for up to an additional 4 weeks (i.e., up to SD56) as maintenance as needed until MAS remission is achieved, with the possibility of decreasing the dose to 1 mg/kg and elongating the interval between infusion to weekly administration.
  • NI-0501 is administered to a subject in need thereof for treating, preventing and/or delaying the onset or progression of, or alleviating a symptom associated with HLH, where the subject has been
  • the subject is a
  • treatment-naive patient i.e., has not previously been treated for HLH
  • dexamethasone is administered at a dose of at least 10 mg/m 2 .
  • the subject is receiving NI-0501 as a second line HLH treatment, and the dexamethasone is administered at a dose of in the range of 10 mg/m 2 to 5 mg/m 2 .
  • the subject is receiving NI-0501 as a second line HLH treatment, and the dexamethasone is administered at a dose of at least 5 mg/m 2 .
  • the subject is receiving NI-0501 as a second line HLH treatment, and the dexamethasone is administered at a dose of less than 5 mg/m .
  • NI-0501 is administered before and/or during and/or after treatment in combination with one or more additional agents such as, by way of non- limiting example, a therapeutic agent, an anti-inflammatory agent, and/or an
  • the second agent is an agent known to be used in the treatment of HLH.
  • the additional agent includes at least etoposide.
  • NI-0501 and the additional agent are formulated into a single therapeutic composition, and NI- 050 land additional agent are
  • NI-0501 and additional agent are separate from each other, e.g., each is formulated into a separate therapeutic composition, and NI-0501and the additional agent are administered simultaneously, or NI- 0501and the additional agent are administered at different times during a treatment regimen.
  • NI-0501 is administered prior to the administration of the additional agent
  • NI- 0501 is administered subsequent to the administration of the additional agent
  • NI- 0501 and the additional agent are administered in an alternating fashion.
  • NI-0501 and additional agent are administered in single doses or in multiple doses.
  • NI-0501 and the additional agent(s) are administered simultaneously.
  • NI-0501 and the additional agent(s) can be formulated in a single composition or administered as two or more separate compositions.
  • NI- 0501 and the additional agent(s) are administered sequentially, or NI- 0501 and the additional agent are administered at different times during a treatment regimen.
  • the additional agent is an immunosuppressive agent.
  • the immunosuppressive agent is Cyclosporin A (CsA).
  • CsA Cyclosporin A
  • the subject has been receiving CsA prior to administration of NI-0501.
  • the additional agent includes at least etoposide.
  • the subject has been receiving etoposide prior to administration of NI- 0501.
  • the additional agent is intrathecal methotrexate and/or glucocorticoids.
  • the subject has been receiving intrathecal methotrexate and/or glucocorticoids prior to administration of NI-0501.
  • the additional agent is IV immunoglobulins (IVIG).
  • IVIG IV immunoglobulins
  • the IVIG is administered as replacement treatment in a subject with a documented immunoglobulin deficiency.
  • IVIG is administered given at a dose of 0.5 g/kg, every 4 weeks or more frequently in order to maintain adequate IgG levels.
  • the one or more additional agents is analgesic treatment, transfusion of blood products, electrolyte and glucose infusions, antibiotics, anti-fungal and anti- viral treatment and/or general supportive care.
  • compositions and methods provided herein are useful in treating, preventing and/or delaying the onset or progression of, or alleviating a symptom associated with
  • compositions and methods provided herein are useful in
  • Graft- versus-host disease in a subject who has received or is receiving a
  • compositions and methods provided herein are useful in prolonging
  • compositions and methods provided herein are useful in transplanting any biological material, including, for example, cells, tissue(s), bone marrow, and/or organ(s) or at least a portion of an organ, including, by way of non-limiting example, heart, kidney, pancreas, liver, and/or intestine.
  • the biological material to be transplanted is allogeneic biological material.
  • the transplanted biological material is bone marrow.
  • the transplanted biological material is a population of hematopoietic stem cells.
  • the biological material to be transplanted is or is derived from one or more hepatocytes.
  • NI-0501 is administered to a subject in need thereof for treating, preventing and/or delaying the onset or progression of, or alleviating a symptom associated with transplant failure, transplant rejection, and/or an inflammatory disorder associated with transplant rejection.
  • transplant rejection also referred to herein as transplant failure
  • the transplant rejection is acute.
  • the transplant rejection is hyperacute.
  • NI-0501 is formulated as a sterile concentrate for infusion (per mL).
  • NI-0501 is formulated as follows: 5 mg of NI-051, 1.55 mg L-histidine, 3.14 mg L-histidine monohydrochloride, monohydrate, 7.31 mg sodium chloride (NaCl), and 0.05 mg Polysorbate 80, where the pH is between 5.8 and 6.2.
  • NI-0501 is formulated as follows: 5 mg of NI-051, 1.55 mg L-histidine, 3.14 mg L-histidine monohydrochloride, monohydrate, 7.31 mg sodium chloride (NaCl), and 0.05 mg Polysorbate 80, where the pH is 6.0.
  • the transplant rejection is chronic.
  • NI- 0501 is administered to a subject in need thereof by IV infusion over a period of one hour at an initial dose of 1 mg/kg.
  • the IV infusion may last more than one hour, for example, at least 90 minutes, at least 2 hours, or at least 3 hours or greater.
  • NI-0501 is administered to a subject in need thereof by at least one additional IV infusion after the initial IV infusion over a period of one hour at an initial dose of 1 mg/kg.
  • the at least one additional IV infusion is at a dose that is higher than the initial dose of 1 mg/kg.
  • the at least one additional IV infusion dosage is 3 mg/kg.
  • the at least one additional IV infusion is administered at least three days after the initial IV infusion.
  • the at least one additional IV infusion is administered at a time selected from the group consisting of at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion. In some embodiments, the at least one additional IV infusion is administered at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion.
  • NI-0501 is administered to a subject in need thereof by at least one series additional IV infusions after the initial IV infusion over a period of one hour at an initial dose of 1 mg/kg, where the series of additional IV infusions includes at least one series of twice weekly IV infusions.
  • the at least one series of twice weekly IV infusions is administered at a dose higher than the initial dose of 1 mg/kg.
  • the at least one series of twice weekly IV infusions is administered at a dose of 3 mg/kg.
  • the at least one additional IV infusion is administered at least three weeks after the initial IV infusion.
  • the at least one additional IV infusion is administered at a time selected from the group consisting of at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion. In some embodiments, the at least one additional IV infusion is administered at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion.
  • NI-0501 is administered to a subject in need thereof by at least two additional IV infusions after the initial IV infusion.
  • the at least two additional IV infusions are at a dose that is higher than the initial dose of 1 mg/kg.
  • the first additional IV infusion and the second additional IV infusion are administered at the same dosage.
  • the first additional IV infusion and the second additional IV infusion are administered at the same dosage that is higher than the initial dose.
  • at least one of the first and second additional IV infusions is administered at a dosage of 3mg/kg.
  • the first additional IV infusion is administered at least three days after the initial IV infusion.
  • the first additional IV infusion is administered at a time selected from the group consisting of at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion. In some embodiments, the first additional IV infusion is administered at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion.
  • the second additional IV infusion is administered at a time selected from the group consisting of at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion. In some embodiments, the second additional IV infusion is administered at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion.
  • the first additional IV infusion is administered at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion
  • the second additional IV infusion is administered at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion.
  • the first additional IV infusion and the second additional IV infusion are administered at different dosages. In some embodiments, the first additional IV infusion and the second additional IV infusion are administered at different dosages, where the second additional IV infusion dosage is higher than the first additional IV infusion. In some embodiments, the first additional IV infusion and the second additional IV infusion are administered at different dosages, where the second additional IV infusion dosage is higher than the first additional IV infusion, and where both the first and the second additional IV infusion dosages are higher than the initial dosage. In some embodiments, at least one of the first and second additional IV infusions is administered at a dosage of 3mg/kg.
  • the first additional IV infusion is administered at a dosage of 3 mg/kg, and the second additional IV infusion is administered at a dosage of 6 mg/kg. In some embodiments, the first additional IV infusion is administered at least three days after the initial IV infusion. In some embodiments, the first additional IV infusion is administered at a time selected from the group consisting of at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion.
  • the first additional IV infusion is administered at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion.
  • the second additional IV infusion is administered at a time selected from the group consisting of at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion.
  • the second additional IV infusion is administered at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion.
  • the first additional IV infusion is administered at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion
  • the second additional IV infusion is administered at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion.
  • the first additional IV infusion includes at least a first series of twice weekly IV infusions and the second additional IV infusion includes at least a second series of twice weekly IV infusions.
  • the first series of twice weekly IV infusions and the second series of twice weekly IV infusions are administered at a dose higher than the initial dose of 1 mg/kg.
  • the first series of twice weekly IV infusions is administered at a dose of 3 mg/kg, and the second series of twice weekly IV infusions is administered at a dose of 6 mg/kg.
  • the first series of additional IV infusion is administered at least three days after the initial IV infusion.
  • the first series of additional IV infusions is administered at a time selected from the group consisting of at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion. In some embodiments, the first series of additional IV infusions is administered at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion.
  • the second series of additional IV infusions is administered at a time selected from the group consisting of at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion. In some embodiments, the second series of additional IV infusions is administered at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion.
  • the first series of additional IV infusions is administered at 3 days after the initial IV infusion, at 6 days after the initial IV infusion, at 9 days after the initial IV infusion, at 12 days after the initial infusion, and at 15 days after the initial infusion
  • the second series of additional IV infusions is administered at 3 weeks after the initial IV infusion, at 4 weeks after the initial IV infusion, at 5 weeks after the initial IV infusion, at 6 weeks after the initial infusion, at 7 weeks after the initial infusion, and at 8 weeks after the initial infusion.
  • infusions are performed every 3 days after the initial dose for up to 15 days after the initial dose. In some embodiments, infusions are performed every 3 days after the initial dose for up to 15 days after the initial dose, followed by infusions twice per week starting at least 15 days after the initial dose. In some embodiments, the infusion dosage is increased to 3 mg/kg at any point after the initial dose. In some embodiments, after a minimum of two infusions at 3 mg/kg, the dose of NI-0501 is increased to 6 mg/kg for up to four infusions.
  • the disclosure also provides compositions and methods that are useful in identifying or otherwise refining a patient population suffering from a disorder, where the patient has an elevated level of CXCL9, alone or in combination with one or more additional interferon ⁇ (IFNy) related biomarkers.
  • IFNy interferon ⁇
  • the disclosure provides compositions and methods for detecting CXCL9 levels as a biomarker for IFNy production in patients suffering from or suspected of suffering from hemophagocytic lymphohistiocytosis (HLH).
  • HHLH hemophagocytic lymphohistiocytosis
  • the disclosure provides compositions and methods for detecting CXCL9 levels as a biomarker for IFNy production in patients suffering from or suspected of suffering from secondary
  • the compositions and methods are used to detect CXCL9 levels as a biomarker for IFNy production in patients suffering from or suspected of suffering from macrophage activation syndrome (MAS). In some embodiments, the compositions and methods are used to detect CXCL9 levels as a biomarker for IFNy production in patients suffering from or suspected of suffering from MAS in the context of an autoimmune disease or inflammatory disorder. In some embodiments, the compositions and methods are used to detect CXCL9 levels as a biomarker for IFNy production in patients suffering from or suspected of suffering from MAS in the context of a systemic autoimmune disease or inflammatory disorder.
  • MAS macrophage activation syndrome
  • the compositions and methods are used to detect CXCL9 levels as a biomarker for IFNy production in patients suffering from or suspected of suffering from MAS in the context of an autoimmune disease or inflammatory disorder.
  • compositions and methods are used to detect CXCL9 levels as a biomarker for IFNy production in patients suffering from or suspected of suffering from MAS in the context of systemic Juvenile Idiopathic Arthritis (sJIA). In some embodiments, the compositions and methods are used to detect CXCL9 levels as a biomarker for IFNy production in patients suffering from or suspected of suffering from MAS in the context of Systemic Lupus Erythematosus (SLE).
  • SLE Systemic Lupus Erythematosus
  • Patients identified as having elevated levels of CXCL9 are identified as suitable candidates for treatment with an agent (e.g., antibodies or other polypeptide-based therapeutics, peptide-based therapeutics, small molecule inhibitors, nucleic acid-based therapeutics and derivatives thereof) that interferes with or otherwise antagonizes one or more biological activities of IFNy such as, for example, IFNysignaling, and neutralizes at least one biological activity of IFNy.
  • an agent e.g., antibodies or other polypeptide-based therapeutics, peptide-based therapeutics, small molecule inhibitors, nucleic acid-based therapeutics and derivatives thereof.
  • fluids and other biological samples contain elevated levels of CXCL9, alone or in combination with other IFNy-related biomarkers such as, for example, CXCL10 and/or CXCL11.
  • CXCL9 and these other biomarkers are indicators of in vivo IFNy production.
  • an anti-IFNy antagonist that interferes with, inhibits, reduces or otherwise antagonizes IFNy signaling, e.g., a neutralizing anti-IFNy antibody or other polypepti de-based therapeutic, a peptide-based therapeutic, a small molecule inhibitor, a nucleic acid-based therapeutic and derivatives thereof, blocks or otherwise inhibits IFNy activity.
  • compositions and methods are useful in treating, delaying the progression of or otherwise ameliorating a symptom of a disorder that is dependent on, driven by, associated with, or otherwise impacted by aberrant, e.g., elevated, IFNy expression and/or activity, aberrant pro- inflammatory cytokine production and/or combinations thereof, by administering an anti-IFNy antagonist, e.g., a neutralizing anti- IFNy antibody or other polypeptide-based therapeutic, a peptide-based therapeutic, a small molecule inhibitor, a nucleic acid-based therapeutic and derivatives thereof, to patients exhibiting an elevated level of expression CXCL9 and/or other biomarkers.
  • an anti-IFNy antagonist e.g., a neutralizing anti- IFNy antibody or other polypeptide-based therapeutic, a peptide-based therapeutic, a small molecule inhibitor, a nucleic acid-based therapeutic and derivatives thereof.
  • Patients that are likely suitable candidates for treatment with the anti-IFNy antagonist e.g., neutralizing anti-IFNy antibody such as those described herein, are identified by detecting the level of CXCL9, alone or in combination with one or more IFNy-related ligands or other biomarkers.
  • the anti-IFNy antagonist e.g., neutralizing anti-IFNy antibody such as those described herein.
  • patients that do not have elevated levels of CXCL9, alone or in combination with other IFNy-related biomarkers may still be treated with an anti- IFNy antagonist, including any of the neutralizing anti-IFNy antibodies described herein or other polypeptide-based therapeutic, a peptide-based therapeutic, a small molecule inhibitor, a nucleic acid-based therapeutic and derivatives thereof.
  • an anti- IFNy antagonist including any of the neutralizing anti-IFNy antibodies described herein or other polypeptide-based therapeutic, a peptide-based therapeutic, a small molecule inhibitor, a nucleic acid-based therapeutic and derivatives thereof.
  • Patients with elevated levels of CXCL9, alone or in combination with one or more additional IFNy-related biomarkers are identified as suitable candidates for therapy with one or more anti-IFNy antagonists, e.g., a neutralizing anti-IFNy antibody described herein.
  • the phrase "elevated level of expression” refers to a level of expression that is greater than a baseline level of expression of CXCL9, alone or in combination with one or more additional biomarkers, in a sample from a patient that is not suffering from or suspected of suffering from primary or secondary HLH or HLH-related disorder, or from another control sample.
  • the elevated level of expression of CXCL9 and/or other biomarker is a significant level of elevation.
  • the detected level of CXCL9 is useful to refine or otherwise stratify a patient population.
  • the detected level is used to determine the dosage of anti-IFNy antagonist that should be administered to a given patient.
  • the detected level is used to categorize or otherwise stratify a patient population. For example, patients can be classified as having "severe" or high grade MAS, or conversely, not severe or low grade MAS, based on the detected level of CXCL9.
  • the sample is, for example, blood or a blood component, e.g., serum, plasma.
  • the sample is another bodily fluid such as, by way of non-limiting example, urine, synovial fluid, bronchial alveolar fluid, cerebrospinal fluid, broncho-alveolar lavage (BAL), and/or saliva.
  • the biological sample is CSF.
  • the biological sample is CSF from an HLH patient.
  • suitable patients for treatment with an anti-IFNy antagonist can also be identified by evaluating any of a number of additional biological and clinical parameters that will improve the sensitivity and specificity of the biomarker for identifying or otherwise refining the patient population.
  • these additional biological and clinical parameters can be used alone as a means for identifying patients that are suitable candidates for treatment with an anti-IFNy antagonist or other suitable therapy.
  • These biological and clinical parameters include, by way of non-limiting example, any of the following: ferritin levels, neutrophil count, platelet count, alanine aminotransferase levels, and/or lactate dehydrogenase levels.
  • Disorders that are useful with the compositions and methods of the invention include any disorder where aberrant, e.g., elevated, IFNy expression and/or activity, particularly HLH, including secondary HLH, MAS, and/or sJIA.
  • Suitable autoimmune and/or inflammatory disorders include, by way of non-limiting example, primary and/or secondary HLH disorders associated with aberrant IFNyactivity and/or expression.
  • the anti-IFNy antagonist is a neutralizing anti-IFNy antibody or an immunologically active (e.g., antigen binding) fragment thereof.
  • Suitable neutralizing anti-IFNy antibodies include any of the anti-IFNy antibodies described herein.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises a variable heavy chain complementarity determining region 1 (VH CDR1) comprising an amino acid sequence at least 90%, 92%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SYAMS (SEQ ID NO: 1); a variable heavy chain complementarity determining region 2 (VH CDR2) comprising an amino acid sequence at least 90%, 92%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of
  • AISGSGGSTYYADSVKG (SEQ ID NO: 2); and a variable heavy chain complementarity determining region 3 (VH CDR3) comprising an amino acid sequence at least 90%, 92%, 95%,96%, 97% 98%,99% or more identical to the amino acid sequence of
  • VL CDR1 variable light chain complementarity determining region 1
  • variable light chain complementarity determining region 2 comprising an amino acid sequence at least 90%, 92%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of EDNQRPS (SEQ ID NO: 5); and a variable light chain complementarity determining region 3 (VL CDR3) comprising an amino acid sequence at least 90%, 92%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of QSYDGSNRWM (SEQ ID NO: 6).
  • the anti-IFNy antibody or immunologically active fragment thereof comprises a VH CDR1 comprising the amino acid sequence of SYAMS (SEQ ID NO: 1); a VH CDR2 region comprising the amino acid sequence of AISGSGGSTYYADSVKG (SEQ ID NO: 2); and a VH CDR3 region comprising the amino acid sequence of
  • VL CDR1 variable light chain complementarity determining region 1
  • VL CDR2 variable light chain complementarity determining region 1
  • VL CDR3 region comprising the amino acid sequence of QSYDGSNRWM (SEQ ID NO: 6).
  • the anti-IFNy antibody or immunologically active fragment thereof comprises a heavy chain that comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, and a VH CDR3 sequence, wherein the combination is a combination of the three heavy chain CDR sequences (VH CDR1, VH CDR2, VH CDR3) shown in a single row in Table 1A.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises a light chain that comprises a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination is a combination of the three light chain CDR sequences (VL CDR1, VL CDR2, VL CDR3) shown in a single row in Table IB.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises a heavy chain that comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, and a VH CDR3 sequence, wherein the combination is a combination of the three heavy chain CDR sequences (VH CDR1, VH CDR2, VH CDR3) shown in a single row in Table 1 A, and a light chain that comprises a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination is a combination of the three light chain CDR sequences (VL CDR1, VL CDR2, VL CDR3) shown in a single row in Table IB.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises an amino acid sequence at least 90%, 92%, 95%, 96%, 97% 98%, 99% or more identical to the heavy chain variable amino acid sequence to the amino acid sequence of SEQ ID NO: 47.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises an amino acid sequence at least 90%, 92%, 95%, 96%, 97% 98%, 99% or more identical to the light chain variable amino acid sequence to the amino acid sequence of SEQ ID NO: 48.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises an amino acid sequence at least 90%, 92%, 95%, 96%, 97% 98%, 99% or more identical to the heavy chain variable amino acid sequence to the amino acid sequence of SEQ ID NO: 47, and an amino acid sequence at least 90%, 92%, 95%, 96%, 97% 98%, 99% or more identical to the light chain variable amino acid sequence to the amino acid sequence of SEQ ID NO: 48.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises the heavy chain variable amino acid sequence to the amino acid sequence of SEQ ID NO: 47.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises the light chain variable amino acid sequence to the amino acid sequence of SEQ ID NO: 48.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises the heavy chain variable amino acid sequence to the amino acid sequence of SEQ ID NO: 47, and the light chain variable amino acid sequence to the amino acid sequence of SEQ ID NO: 48.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises an amino acid sequence at least 90%, 92%, 95%, 96%, 97% 98%, 99% or more identical to the heavy chain amino acid sequence to the amino acid sequence of SEQ ID NO: 44.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises an amino acid sequence at least 90%, 92%, 95%, 96%, 97% 98%, 99% or more identical to the light chain amino acid sequence to the amino acid sequence of SEQ ID NO: 46.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises an amino acid sequence at least 90%, 92%, 95%, 96%, 97% 98%, 99% or more identical to the heavy chain amino acid sequence to the amino acid sequence of SEQ ID NO: 44, and an amino acid sequence at least 90%, 92%, 95%, 96%, 97% 98%, 99% or more identical to the light chain amino acid sequence to the amino acid sequence of SEQ ID NO: 46.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises the heavy chain amino acid sequence to the amino acid sequence of SEQ ID NO: 44.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises the light chain amino acid sequence to the amino acid sequence of SEQ ID NO: 46.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises the heavy chain amino acid sequence to the amino acid sequence of SEQ ID NO: 44, and the light chain amino acid sequence to the amino acid sequence of SEQ ID NO: 46.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises an amino acid sequence at least 90%, 92%, 95%, 96%, 97% 98%, 99% or more identical to a heavy chain variable amino acid sequence selected from the group consisting of SEQ ID NOs: 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98, and 102.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises an amino acid sequence at least 90%, 92%, 95%, 96%, 97% 98%, 99% or more identical to a light chain variable amino acid sequence selected from the group consisting of SEQ ID NOs: 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, and 104.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises an amino acid sequence at least 90%, 92%, 95%, 96%, 97% 98%, 99% or more identical to a heavy chain variable amino acid sequence selected from the group consisting of SEQ ID NOs: 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98, and 102, and an amino acid sequence at least 90%, 92%, 95%, 96%, 97% 98%, 99% or more identical to a light chain variable amino acid sequence selected from the group consisting of SEQ ID NOs: 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, and 104.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises a heavy chain variable amino acid sequence selected from the group consisting of SEQ ID NOs: 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98, and 102.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises a light chain variable amino acid sequence selected from the group consisting of SEQ ID NOs: 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, and 104.
  • the anti-IFNy antibody or immunologically active fragment thereof comprises a heavy chain variable amino acid sequence selected from the group consisting of SEQ ID NOs: 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98, and 102, and a light chain variable amino acid sequence selected from the group consisting of SEQ ID NOs: 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, and 104.
  • the anti-IFNy antibody or immunologically active fragment thereof is administered in a therapeutically effective amount.
  • a therapeutically effective amount of an antibody of the invention relates generally to the amount needed to achieve a therapeutic objective.
  • This therapeutic objective may be a binding interaction between the antibody and its target antigen that, in certain cases, interferes with the functioning of the target.
  • Common ranges for therapeutically effective dosing of an antibody or antibody fragment of the invention may be, by way of nonlimiting example, from about 0.1 mg/kg body weight to about 50 mg/kg body weight. Common dosing frequencies may range, for example, from twice daily to once a week.
  • the anti-IFNy antibody or immunologically active fragment thereof is administered at an initial dose, i.e., load dose, in the range from about 0.5 mg/kg to about 2 mg/kg, for example, in a range from about 0.5 mg/kg to about 1.5 mg/kg, and/or from about 0.5 mg/kg to about 1.0 mg/kg. In some embodiments, the anti-IFNy antibody or immunologically active fragment thereof is administered at an initial dose of about 1.0 mg/kg.
  • the anti-IFNy antibody or immunologically active fragment thereof is administered as an initial load dose followed by one or more maintenance doses.
  • the one or more maintenance dose(s) is a dosage that is substantially similar to the initial load dose.
  • the one or more maintenance dose(s) is a dosage that is less than the initial load dose.
  • the one or more maintenance dose(s) is a dosage that is greater than the initial load dose.
  • the one or more maintenance dose(s) comprises at least two or more dosages, wherein each maintenance dosage is the same dosage. In some embodiments, the two or more maintenance dosages are substantially similar to the initial load dose. In some embodiments, the two or more maintenance dosages are greater than the initial load dose. In some embodiments, the two or more maintenance dosages are less than the initial load dose.
  • the one or more maintenance dose(s) comprises at least two or more dosages, wherein each maintenance dosage is not the same dosage. In some embodiments, the two or more maintenance dosages are administered in an increasing dosage amount. In some embodiments, the two or more maintenance dosages are administered in a decreasing dosage amount.
  • the one or more maintenance dose(s) comprises at least two or more dosages, wherein each maintenance dosage is administered at a periodic time interval. In some embodiments, two or more dosages are administered at increasing time intervals. In some embodiments, two or more dosages are administered at decreasing time intervals.
  • the anti-IFNy antibody or immunologically active fragment thereof is administered at an initial load dose in the range from about 0.5 mg/kg to about 2 mg/kg, for example, in a range from about 0.5 mg/kg to about 1.5 mg/kg, and/or from about 0.5 mg/kg to about 1.0 mg/kg, followed by at least one, e.g., two or more, three or more, four or more, or five or more maintenance doses.
  • the anti-IFNy antibody or immunologically active fragment thereof is administered at an initial load dose of about 1.0 mg/kg, followed by at least one, e.g., two or more, three or more, four or more, or five or more maintenance doses.
  • Pharmaceutical compositions according to the invention can include an anti- IFNy antibody of the invention and a carrier. These pharmaceutical compositions can be included in kits, such as, for example, diagnostic kits.
  • kits for practicing any of the methods provided herein.
  • the kits include a detection reagent specific for CXCL9, alone or in combination with one or more IFNy-related biomarkers and a means for detecting the detection reagent.
  • CXCL11 were significantly elevated in active MAS compared to active sJIA without MAS at sampling (all p-values ⁇ 0.005).
  • active MAS laboratory parameters of disease severity (ferritin, neutrophils, platelets, alanine aminotransferase and lactate dehydrogenase) were significantly correlated with IFNy and CXCL9, and to a lesser extent with CXCL10 and CXCL11 ; no correlation with IL-6 levels was found.
  • patients with active sJIA without MAS there was no significant correlation between laboratory parameters and cytokine levels as shown in Table 7 below.
  • sJIA Macrophage Activation Syndrome
  • MAS Macrophage Activation Syndrome
  • the patient in this study had the following characteristics: Onset at 20 days of age with fever, rash, marked hepatosplenomegaly, pancytopenia, hypofibrinogenemia, hypertriglyceridemia, marked ferritin and sCD25 increase. Followinged by multiorgan failure, required ICU admission. HLH diagnosis was based on 6 out of the 8 HLH-2004 criteria. Gene causing pnmary-HLH (PRF1, UNCI 3D, STXBP2, STX11, RAB27A, XIAP) and functional tests (perforin expression, degranulation and cytotoxicity) were negative. High-dose i.v.
  • glucocorticoids and i.v. cyclosporine-A with progressive improvement of general conditions and laboratory abnormalities.
  • HLH reactivation triggered by infections Candida Albicans and Klebsiella Pneumoniae sepsis
  • rapid worsening of general conditions and a new ICU admission.
  • Treatment with etoposide and/or ATG was not considered because of the presence of active infections in an already immunocompromised subject.
  • NI-0501 Compassionate use treatment with NI-0501 was started on a background of dexamethasone (13.6 mg/m ) and i.v. cyclosporine-A.
  • NI-0501 was administered every 3 and subsequently every 7 days according to pharmacokinetics. No infusion reaction was observed.
  • NI0501 was well tolerated.
  • HLH clinical features and laboratory abnormalities progressively improved. Active ongoing infections were rapidly cleared. After 5 months of treatment, the patient remained in excellent conditions. The patient continued to receive oral cyclosporine-A (6 mg/kg) and prednisone (0.3 mg/kg equivalent to 0.9 mg/m2 of dexamethasone). All HLH parameters have normalized.
  • NLRC4 showed a de novo missense mutation (T337N). Elevated serum IL-18 was documented, confirming the relevance of the NLRC4 mutation. High production of IFNy was demonstrated by high levels IFNy complexed with NI-0501. IFNy was fully neutralized as shown by undetectable levels of IFNy- inducible chemokines ( Figure 5 and Table 8). Circulating levels of were IL-18 persistently elevated.
  • HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) WITH NI-0501
  • HLH Primary HLH
  • pHLH Primary HLH
  • sHLH primary and secondary HLH
  • Immune-chemotherapy primarily etoposide-based regimens, are at present the only pharmacological approaches to control HLH and bring patients to curative allogeneic hematopoietic stem cell transplant (allo- HSCT). In spite of recent attempts to further intensify treatment regimens, mortality and morbidity remain high, in part due to drug-related toxicities.
  • NI-0501 is a fully human, high affinity, anti-IFNy mAb that binds to and neutralizes human IFNy, offering a novel and targeted approach for the control of HLH.
  • NI-0501 An open-label Phase 2 study has been conducted in United States and Europe to evaluate the safety and efficacy of NI-0501 in children with confirmed or suspected pHLH.
  • NI- 0501 was administered at the initial dose of 1 mg/kg every 3 days, with possible dose increase guided by PK data and/or clinical response in each patient, on initial background dexamethasone 5-10 mg/m 2 .
  • Treatment duration ranged from 4 to 8 weeks.
  • Ability to moveto allo-HSCT, relevant HLH disease parameters, and 8-week survival were assessed.
  • Study Population A total of 13 patients were enrolled: 8F/5M, median age l .Oy (range 2.5mo-13y). Twelve pts received NI-0501 as a second line treatment after having received conventional therapy and either reactivating, obtaining an unsatisfactory response, or being intolerant to therapy. One patient was treated with NI-0501 in 1 st line. Nine patients carried a known HLH genetic defect (3 FHL2, 2 FHL3, 2 GS-2, 1 XLP1, 1 XLP2). The majority of patients were at the severe end of HLH spectrum, in compromised general condition, carrying significant toxicities from previous HLH treatments.
  • NI-0501 was well tolerated and no safety concern was identified. None of the infections known to be favored by IFNy neutralization was reported, and no infections occurred in patients who did not receive previous chemotherapy. Seven patients reported at least one SAE, all assessed by the DMC as not related to NI-0501 administration. No unexpected events attributable to "off target" effects of NI-0501 (e.g. myelotoxicity, hemodynamic effects) were observed.
  • NI-0501 Targeted neutralization of IFNy by NI-0501 offers an innovative and potentially less toxic approach to HLH management.
  • the results of this study show that NI- 0501 is a safe and effective therapeutic option in patients with primary HLH who have unsatisfactorily responded to conventional therapy or shown intolerance to it.
  • therapy with NI-0501 was not associated with any of the typical short or long-term toxicities associated with etoposide- based regimens.
  • Assessment of NI-0501 as 1 st line treatment in patients with pHLH is ongoing, anticipating that similar significant clinical benefit can be achieved.
  • Interferon gamma is the pivotal mediator in murine models of primary haemophagocytic lymphohistiocytosis (HLH). Given the similarities between primary and secondary HLH (sec-HLH), including macrophage activation syndrome (MAS), IFNy levels and its biologic activity in patients with systemic juvenile idiopathic arthritis (sJIA) and MAS were analyzed.
  • IFNy-induced chemokines CXCL9 and CXCL10 mRNA levels in liver and spleen
  • their correlation with serum ferritin levels were assessed in an IL-6 transgenic mouse model in which MAS features are induced by TLR4 stimulation with LPS.
  • IFNy and of IFN- induced chemokines were markedly elevated during MAS, also referred to herein as active MAS, and sec-HLH.
  • Levels of IFNy and IFN induced chemokines were markedly higher in patients with MAS compared to those with active sJIA without MAS. In this latter group, IFNy and IFNy induced chemokines were comparable to those of patients with clinically inactive sJIA.
  • the laboratory abnormalities characterizing this syndrome including ferritin and alanine transferase levels and neutrophil and platelet count, were significantly correlated with levels of IFNy and CXCL9.
  • serum levels of ferritin were significantly correlated with mRNA levels of CXCL9 in liver and spleen.
  • IFN-induced chemokines and their correlation particularly for CXCL9 with the severity of laboratory abnormalities of MAS suggest that IFNy plays a pivotal role in MAS. Elevated circulating levels of interferon-y and interferon- induced chemokines characterize patients with macrophage activation syndrome complicating systemic JIA.
  • the plate was measured on the Luminex 200® system (Luminex Corp.). Raw data were acquired using x PONENT software version 3.1 (Luminex Corp.), and data were analyzed using Milliplex Analyst software version 3.5.5.0 (Millipore). Raw data obtained in Milliplex Analyst software were then further analyzed in dedicated macro for Luminex analysis (NI-Sc-ESM-MAC- 012-vOl and Sc-ESM-MAC-013-v01).
  • mice [0299] Animal Experiments. The generation and the phenotype of the IL-6 transgenic mice, as well as the features of the MAS-like syndrome induced by administration of TLR ligands, have been described previously (Strippoli, R, et al., Amplification of the response to Toll-like receptor ligands by prolonged exposure to interleukin-6 in mice: implication for the pathogenesis of macrophage activation syndrome. Arthritis Rheum, 2012. 64(5): p. 1680-8). Mice were maintained under specific pathogen-free conditions and handled in accordance with the national polices. The study protocol was approved by the local ethics committee. All experiments have been performed on mice between 10 and 14 weeks of age.
  • Spearman rank correlation was used to assess the relation with laboratory parameters. A p value ⁇ 0.05 was considered statistically significant.
  • Results Increased levels of IFNyand IFNy-induced chemokines in patients with MAS.
  • patients with active sJIA without MAS at sampling were compared with patients sampled during clinically inactive disease, it was found, as expected (de Benedetti, F., et al., Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis. Arthritis Rheum, 1991. 34(9): p. 1158-63), that IL-6 levels were significantly higher in patients with active sJIA (p ⁇ 0.01) compared to those of patients with clinically inactive disease.
  • the levels of the three IFNy related chemokines CXCL9, CXCL10 and CXCL11 were also markedly higher in patients with active MAS compared to patients with active sJIA without MAS at sampling. This difference was particularly evident for CXCL9 of which median levels were approximately 15 fold higher in patients with MAS compared to patients with active sJIA without MAS.
  • CXCL9 of which median levels were approximately 15 fold higher in patients with MAS compared to patients with active sJIA without MAS.
  • levels of IFNy as well as levels of the three IFNy- related chemokines were markedly increased.
  • the levels of IFNy and of the IFNy-related chemokines were largely indistinguishable from those of patients with MAS and the differences were not statistically significant.
  • levels of IFNy and of the three IFNy-induced chemokines were comparable in patients receiving no treatment and in patients already receiving treatment.
  • Levels of IFNy and of CXCL9, CXCL10 and CXCL11 are related to the presence of MAS in individual patients.
  • Figures 8A-8D show the levels of IFNy and of CXCL9, CXCLIO and CXCL11 in individual patients from whom paired samples were available during active MAS and during active sJIA without MAS.
  • the levels of IFNy and of the three IFNy- induced chemokines were significantly higher in samples obtained during MAS by paired sample analysis. Additionally, in several patients samples were available both prior to and after MAS episodes, and demonstrated that IFNy and IFNy- induced chemokine levels return to normal upon resolution of MAS clinical symptoms.
  • one patient in this study experienced three episodes of MAS, with serum samples obtained during these episodes as well as during disease phases without MAS at sampling. Further confirming the relation between increased production of IFNy and of the three IFNy- induced chemokines with active MAS, in this patient elevated levels of IFNy and of the three IFNy-related chemokines were found only at time of the MAS episodes ( Figures 9A-9B).
  • Levels of IFNy and of the IFNy related chemokines correlate with laboratory abnormalities of MAS.
  • the correlation of the levels of IFNy and of the three IFNy-induced chemokines with laboratory parameters of MAS at time of sampling was then examined.
  • levels of IFNy and of the three IFNy- induced chemokines were not associated with laboratory parameters of MAS with one exception: levels of CXCL9, CXCLIO and CXCLl l were weakly correlated with ALT levels with r 2 ranging from 0.17 to 0.25 (Table 2).
  • the significance of this association is unclear; however it should be noted that ALT levels were within normal range in all patients with active sJIA without MAS.
  • CXCL9 appears to be primarily and specifically induced by IFNy, while CXCL10 and CXCL11 are also induced by type I interferons.
  • IFNy-induced chemokines correlate with disease activity in mouse model of MAS.
  • MAS clinical and laboratory features are induced by mimicking acute infection with the TLR4 agonist lipopolysaccharide (LPS) on a background of high levels of IL-6 in IL-6 transgenic mice (Strippoli et al., Arthritis Rheum 2012).
  • LPS lipopolysaccharide
  • Shimizu et al reported that levels of neopterin, a catabolite of guanosine triphosphate synthesized by human macrophages upon stimulation with IFNy, were higher in patients with MAS during sJIA compared with patients with active sJIA without MAS (Shimizu, M., et al., Distinct cytokine profiles of systemic-onset juvenile idiopathic arthritis-associated macrophage activation syndrome with particular emphasis on the role of interleukin-18 in its pathogenesis. Rheumatology (Oxford), 2010. 49(9): p. 1645-53).
  • haemophagocytic lymphohistiocytosis tipping the balance between interleukin-18 and interferon- gamma. Rheumatology (Oxford), 2015). Consistently with these results, 5 patients with active sJIA without MAS at sampling had markedly lower levels of IFNy and CXCL10 (Put et al,
  • CXCL9 In patients with MAS, of the three IFNy-induced chemokines, CXCL9 was found to have the strongest correlation with IFNy levels. This observation is consistent with the established notion that CXCL9 production appears to be induced specifically and only by IFNy in contrast to the production of CXCL10 and CXCL11 that can also be induced by type I interferons (Groom, J.R and A.D. Luster, CXCR3 ligands: redundant, collaborative and antagonistic functions. Immunol Cell Biol, 2011. 89(2): p. 207-15). This suggests that CXCL9 levels could serve as a sensitive and specific biomarker for MAS activity.
  • NI-0501 intravenous
  • NI-0501 efficacy and benefit/risk profile in HLH patients
  • PK pharmacokinetics
  • NI-0501 shows similar binding affinity and blocking activity for IFNy from non-human primate species, including rhesus and cynomolgus monkeys, but not from dogs, cats, pigs, rabbits, rats or mice.
  • Toxicology and safety studies in cynomolgus monkeys demonstrated that there was no off-target toxicity attributed to administration of NI-0501, weekly administrations of NI-0501 were well tolerated and did not require the need for antibiotic prophylaxis, and no abnormal histopathological or behavioral findings were observed during these prior studies.
  • Phase I Clinical Studies A Phase 1 randomized double-blinded placebo- controlled single ascending dose study in 20 healthy adult volunteers investigating the safety, tolerability and pharmacokinetic profiles of single intravenous (IV) administrations of NI-0501. During this study, 6 subjects received placebo, while 3, 3, 4, and 4 subjects (in total 14 subjects)
  • NI-0501 received NI-0501 doses of 0.01, 0.1, 1, and 3 mg/kg, respectively.
  • NI-0501 The PK analysis of NI-0501 revealed the expected profile for an IgGl with a long half-life (around 22 days), a slow clearance ( ⁇ 0.007 L/h) and a low volume of distribution ( ⁇ 6 L on average).
  • Phase 2/3 Clinical Study Materials and Methods are performed on primary HLH patients. The studies are divided into three parts: screening, treatment, and follow- up. An overview is presented in Figure 12.
  • suitable patients include patients naive to HLH treatment (also referred to herein as "first line patients”), or patients who may have already received conventional HLH therapy (also referred to herein as “second line patients”) without having obtained a satisfactory response, e.g., according to the treating physician, or having shown signs of intolerance to it.
  • Patients who receive NI-0501 after having failed conventional HLH therapy or having shown intolerance to it represent the pivotal cohort of the study, to demonstrate the efficacy of NI-0501 as second line treatment of primary HLH.
  • Treatment-naive patients are enrolled for collection of efficacy and safety data in the first line setting.
  • patients who have had a diagnosis of secondary HLH consequent to a proven rheumatic or neoplastic disease patients who are previously treated with any T-cell depleting agents (such as, for example, anti- thymocyte globulin (ATG), anti- CD52 therapy) during the previous 2 weeks prior to screening or treated with any other biologic drug within 5 times their defined half-life period (with the exception for rituximab in case of documented B-cell EBV infection); patients having active mycobacteria, Histoplasma Capsulatum, Shigella, Salmonella, Campylobacter and Leishmania infections; patients with evidence of past history of tuberculosis or latent tuberculosis; patients with positive serology for HIV antibodies, hepatitis B surface antigen or hepatitis C antibodies; patients with presence of malignancy; patients with patients who have another concomitant disease or malformation severely affecting the cardiovascular, pulmonary, liver or renal function;
  • T-cell depleting agents such as, for
  • NI-0501 a fully human IgGl monoclonal antibody (mAb) directed against human IFNy.
  • mAb monoclonal antibody
  • NI-0501 is administered by IV infusion over a period of one hour at an initial dose of 1 mg/kg. This dose is predicted to inhibit for 3 days at least 99% of IFNy effect in patients with baseline IFNy concentrations lower or equal to 3400 pg/mL.
  • NI-0501 dose increase to 3 mg/kg is possible according to pre-defined criteria guided by clinical and laboratory response in each patient (as described in Table 5 below) at any time during the study. After a minimum of two infusions at 3 mg/kg if, upon re-assessment, the same clinical and laboratory criteria qualifying the patient to receive 3 mg/kg of NI-0501 are found to still apply, the dose of NI-0501 may be increased to 6 mg/kg for up to four infusions, with a regular monitoring of the clinical and laboratory FILH parameters.
  • the dose of NI-0501 may either i) be decreased back to 3 mg/kg, or ii) remain at 6 mg/kg for additional IV infusions (or be increased above 6 mg/kg), if PK and PD evidence indicates excessively high IFNy production and, consequently, fast NI-0501 elimination. Dose increase may occur any time during the study, if the clinical and laboratory criteria set forth herein are met. Table 5. Clinical and laboratory criteria to guide dose increase
  • NI-0501 is administered for 8 weeks, and the treatment period will be divided in 2 separate periods: Treatment Period 1 and 2 as shown in Figure 12.
  • NI-0501 After NI-0501 is administered for 8 weeks, the conditioning regimen in preparation for Hematopoietic Stem Cell Transplantation (HSCT) may be initiated.
  • the anticipated duration of treatment can be shortened, although not to less than 4 weeks, if the patient's condition and donor availability allow the performance of a transplant.
  • NI- 0501 treatment can be continued in the context of a long-term follow-up study, provided that a favorable benefit/risk has been established for the patient.
  • NI-0501 is administered on a background of dexamethasone, which can be tapered depending on patient condition.
  • NI-0501 will be administered on a background of 10 mg/m 2 of dexamethasone.
  • dexamethasone has to be administered at the dose of at least
  • Dexamethasone can be tapered depending on patient condition, according to the
  • the tapering scheme can be selected by the treating physician.
  • dexamethasone dose, at each step, is not more than halved and frequency of change is not more than weekly.
  • dexamethasone can be increased and maintained until a satisfactory response is achieved
  • patients receive prophylactic treatment for Pneumocystis jiroveci, fungal and Herpes Zoster virus infection from the day before initiation of NI- 0501 treatment until the end of the study.
  • Patients receive prophylactic treatments starting from the day prior to initiation of NI-0501 treatment (i.e. SD-1) until the end of the study.
  • prophylactic treatments starting from the day prior to initiation of NI-0501 treatment (i.e. SD-1) until the end of the study.
  • patients may receive, e.g. 750 mg/m /day sulfamethoxazole with 150 mg/m /day trimethoprim given orally in equally divided doses twice a day, on 3 consecutive days per week.
  • patients may receive, e.g. Fluconazole 12 mg/kg daily with a maximum of 400 mg daily dose.
  • patients may receive, e.g. Acyclovir 200 mg four times daily for children over two years, for children under two years 100 mg four times daily. These treatments will be given orally, whenever possible, otherwise intravenously.
  • Patients can also receive any of a variety of concomitant therapies, such as, for example, Cyclosporin A, intrathecal methotrexate and glucocorticosteroids, and others.
  • Cyclosporin A CsA
  • CsA can be continued if already being administered to the patient prior to screening.
  • CsA can be withdrawn at any time.
  • CsA is not to be introduced de novo during the course of the study once NI- 0501 administration has started.
  • IV immunoglobulins are only allowed as replacement treatment in case of a documented immunoglobulin deficiency.
  • IVIG can be given at a dose of 0.5 g/kg, every 4 weeks or more frequently in order to maintain adequate IgG levels. Any infusion within the previous 4 weeks prior to screening, as well as any infusion during NI-0501 treatment is acceptable.
  • Analgesic treatment, transfusion of blood products, electrolyte and glucose infusions, antibiotics, anti-fungal and anti-viral treatment and general supportive care are allowed. Additional HLH treatments may be allowed in case of unsustained or limited HLH improvement once the maximum NI-0501 dose level is achieved.
  • unsustained HLH improvement refers to patients who are unable to maintain at least 50% improvement from baseline for 3 HLH parameters (see Table 6 below). At least two consecutive measurements must document the loss of HLH improvement.
  • limited HLH improvement refers to less than 50% change from baseline in a minimum of 3 HLH clinical and laboratory criteria. Etoposide should be administered as additional HLH treatment, unless clear evidence of lack of response or intolerance to the drug is derived from previous medical history.
  • etoposide, T-cell depleting agents, or any other biologic drug is generally not allowed, except for the following: G-CSF, in case of prolonged neutropenia; Rituximab, in case of documented B-cell EBV infection; and additional HLH treatments, in case of unsustained or limited HLH improvement (as defined herein) at the maximum NI-0501 dose level.
  • Etoposide should be administered, unless a clear evidence of lack of response or intolerance to the drug is derived from previous medical history.
  • Vaccination with a live or attenuated (including BCG) vaccine must be avoided during the whole study including the 4 week follow-up period. In the event that NI-0501 concentrations remain at therapeutic levels after the end of the study, the period with no vaccinations should be extended until measurable concentration of NI-0501 are no longer detectable.
  • the secondary efficacy endpoints include time to response any time during the study; durability of response, i.e., maintenance of response achieved any time during the study until EoT and beyond (including data collected in any long-term follow-up study); number of patients able to reduce glucocorticoids by 50% or more of baseline dose; number of patients able to proceed to HSCT, when deemed indicated; survival at Week 8 (or EoT) and at the end of the study; serum concentration of NI-0501 to determine NI-0501 pharmacokinetic (PK) profile; determination of pharmacodynamic (PD) effects, including levels of circulating total IFNy and markers of its neutralization, namely CXCL9 and CXCL10; and determination of other biomarkers, e.g. sCD25, IL-10.
  • PK pharmacokinetic
  • PD pharmacodynamic
  • Safety parameters to be collected and assessed include incidence, severity, causality and outcomes of Adverse Events (AEs) (serious and non-serious), with particular attention being paid to infections; evolution of laboratory parameters such as complete blood cell count (CBC), with a focus on red cells (hemoglobin), neutrophils and platelets, liver tests, renal function tests and coagulation; number of patients withdrawn for safety reasons; and other parameters, such as the level (if any) of circulating antibodies against NI-0501 to determine immunogenicity (ADA).
  • AEs Adverse Events
  • the primary endpoint (Overall Response Rate) is evaluated using the exact binomial test at the one-sided 0.025 level. Time to Response, durability of Response and
  • FIG. 13A and 13B depict the effect of NI-0501 infusion on body temperature in two patients having body temperature > 37.5 °C at initiation of NI-0501 treatment.
  • Figure 14 is a series of graphs and a table depicting the effect of NI-0501 administration on neutrophil count in patients.
  • Figure 15 is a series of graphs and a table depicting the effect of NI-0501 administration on platelet count in patients.
  • Figure 16 is a series of graphs and a table depicting the effect of NI-0501 administration on serum levels of ferritin in patients.
  • Figure 17 is a series of graphs and a table depicting the effect of NI-0501 administration on glucocorticoid tapering in patients.
  • Figure 18 is a graph depicting that administration of NI- 0510 maintained IFNy neutralization until the time of HSCT. HLH response to NI-0501 treatment also persisted until transplantation. Patients were also evaluated for any CNS involvement following NI-0501 administration. A summary of the baseline CNS involvement and the status by the end of treatment (EOT) is shown below in Table 11.
  • EOT end of treatment
  • NI-0501 treatment improves and/or can resolve relevant clinical and laboratory abnormalities of HLH, including CNS signs and symptoms.
  • Response to NI-0501 is independent of the presence and the type of causative mutations and/or the presence and the type of an infectious trigger.
  • NI-0501 was well tolerated. No safety concerns emerged to date (e.g., no myelotoxicity, no broad immunosuppression). No infections caused by pathogens known to be promoted by IFNy neutralization have been observed. The neutralization of IFNy by NI-0501 can offer an innovative and targeted approach to the management of HLH.
  • MAS/sHLH Activation Syndrome/secondary HLH
  • NI-0501 for the treatment of MAS/sHLH in patients with sJIA, divided in two parts (i) a pilot study to evaluate the PK profile of NI-0501 and the dosing strategy, and to preliminarily assess the NI-0501 benefit/risk in this patient population; and (ii) a pivotal study to demonstrate the efficacy and safety of NI-0501 (study to be continued upon confirmation of the dosing regimen and the positive benefit/risk profile of NI-0501). An overview of this study design is shown in Figure 19.
  • the main objectives of the pilot study are: (i) to define an appropriate NI-0501 therapeutic dose regimen for sJIA patients with MAS/sHLH; (ii) to assess the benefit/risk profile of NI-0501 in sJIA patients with MAS/sHLH; and (iii) to describe the pharmacokinetics (PK) profile of NI-0501 in sJIA patients with MAS/sHLH.
  • the main objectives of the pivotal study are: (i) to determine NI-0501 efficacy in sJIA patients with MAS/sHLH; (ii) to evaluate the safety and tolerability profile of short-term intravenous (i.v.) administrations of NI-0501 in sJIA patients with MAS/sHLH; (iii) to confirm the positive benefit/risk profile of NI-0501 in sJIA patients with MAS/sHLH; (iv) to perform an exploratory evaluation of chemokines CXCL9 and CXCL10 as MAS/sHLH diagnostic biomarkers and as predictors of response to NI-0501 treatment; and (v) to assess the immunogenicity of NI-0501 in sJIA patients with MAS/sHLH.
  • the study population includes sJIA patients with MAS/sHLH having shown inadequate response to high dose glucocorticoid treatment.
  • the inclusion criteria include the following: (i) gender: male and female; (ii) age: ⁇ 16 years at the time of sJIA diagnosis; (iii) diagnosis of active MAS/sHLH confirmed by the treating rheumatologist, in the presence of at least 2 of the following laboratory and clinical criteria 1 : (a) laboratory criteria: platelet count ⁇ 262 xl0 9 /L, WBC count ⁇ 4.0 xl0 9 /L, AST levels > 59 U/L, and/or fibrinogen levels ⁇ 2.5 g/L; (b) clinical criterial: hepatomegaly, haemorrhagic manifestations, and/or CNS dysfunction; (iv) patient presenting an inadequate response to high dose i.v.
  • glucocorticoid treatment for at least 3 days (including but not limited to pulses of 30 mg/kg mPDN on 3 consecutive days), as per local standard of care;
  • high dose i.v. glucocorticoid should not be lower than 2 mg/Kg/day of mPDN equivalent in 2 separate daily doses up to 60 mg/day.
  • inclusion may occur within less than 3 days from starting high dose i.v. glucocorticoids;
  • patient consent or consent of legally authorized representative(s)); and
  • Exclusion criteria include: (i) diagnosis of suspected or confirmed primary HLH or HLH consequent to a neoplastic disease; (ii) patients treated with: Anakinra, Tocilizumab,
  • active mycobacteria typically and a
  • NI-0501 is used in the formulation shown in Example 7.
  • NI-0501 is administered at the initial dose of 6 mg/kg by infusion over a period of one hour on SD0.
  • NI- 0501 treatment is continued at the dose of 3 mg/kg every 3 days for 4 weeks (i.e. up to SD27).
  • NI-0501 treatment may be shortened upon achievement of complete clinical response (i.e. MAS remission).
  • NI-0501 treatment may be continued for up to additional 4 weeks (i.e.
  • TMDD TMDD-thus signaling an exceptionally high IFNy production
  • the dose of NI-0501 may be increased to 10 mg/kg guided by clinical and PK evidence. This dose increase is approved only upon careful assessment of the benefit/risk profile in that individual patient.
  • NI-0501 is administered on a background of at least 2 mg/kg of methylprednisolone (mPDN) equivalent up to 60 mg/day (in patients of 30 kg or more), which can be tapered during the treatment depending on patient conditions.
  • Patients receive prophylactic treatment for Herpes Zoster infections starting preferably the day before (and in any case prior to initiation of NI-0501 treatment) until serum NI-0501 levels are no longer detectable.
  • Cyclosporine A (CsA) can be continued if started at least 3 days prior to initiation of NI-0501 treatment. CsA dose adjustments are allowed in order to maintain therapeutic levels. CsA can be withdrawn at any time during the study, upon judgment of the Investigator.
  • CsA cannot be introduced de novo once NI-0501 administration has started. If the patient is receiving intrathecal methotrexate and glucocorticoids at the time of NI-0501 treatment initiation, this treatment may be continued as required. Vaccination with a live or attenuated (including BCG) vaccine must be avoided during the whole study and, in any case, until serum NI-0501 levels are no longer detectable. Analgesic treatment, transfusion of blood products, electrolyte and glucose infusions, antibiotics, anti-fungal and anti-viral treatments, and general supportive care are allowed.
  • Sample size In Part 1, at least 5 evaluable patients will be enrolled. In Part 2, upon continuation of the study, at least 10 evaluable patients will be enrolled to achieve a total of 15 evaluable patients. The sample size of 15 has not been formally justified given the rare orphan nature of the disease and the lack of any approved treatment. Nonetheless, based on the assumption that at least 50% of patients inadequately respond to systemic glucocorticoids alone, i.e. 50% of patients on glucocorticoids achieve MAS remission by Week 8 after start of treatment, this study will have 70% power to detect an improvement from 50% to 77% using a one-sided significance level of 5%.
  • Study Duration and Study End Definition The duration of the study will be 8 weeks for each patient (plus up to 1 week screening period). End of the study is defined as last patient last visit. All patients who have received at least one dose of NI-0501 will be asked to enter the NI- 0501 -05 study for a long-term follow-up.
  • the efficacy study endpoints are as follows: (a): primary efficacy endpoint: number of patients achieving MAS remission by Week 8 after initiation of NI-0501 treatment; and (b) secondary efficacy endpoints: time to MAS remission; time to initial response, according to the Investigator's assessment; number of patients for whom at any time during the study glucocorticoids can be tapered to the same (or lower) dose being administered before the occurrence of MAS; time to achievement of glucocorticoids tapering; survival at the end of the study; and number of patients withdrawn from the study due to lack of efficacy.
  • the safety study endpoints are as follows: (a) incidence, severity, causality and outcomes of AEs (serious and non-serious), with particular attention being paid to infections; evolution of laboratory parameters, in particular CBC (with a focus on hemoglobin, neutrophils and platelets), LFTs, and coagulation
  • ADA immunogenicity
  • chemokines known to be induced by IFNy e.g., CXCL9, CXCLIO, CXCLl l
  • correlation of chemokine and total IFNy levels, and laboratory parameters of MAS severity e.g.

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EP17829009.4A 2016-10-24 2017-10-24 Methods, compositions and dosing regimens for treating or preventing interferon-gamma related indications Pending EP3528845A2 (en)

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CA3041434A1 (en) 2018-05-03
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CN110167593A (zh) 2019-08-23
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BR112019008156A2 (pt) 2019-07-02
JP2022187025A (ja) 2022-12-15

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