WO2024044548A1 - Teclistamab pour le traitement du myélome multiple - Google Patents

Teclistamab pour le traitement du myélome multiple Download PDF

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WO2024044548A1
WO2024044548A1 PCT/US2023/072584 US2023072584W WO2024044548A1 WO 2024044548 A1 WO2024044548 A1 WO 2024044548A1 US 2023072584 W US2023072584 W US 2023072584W WO 2024044548 A1 WO2024044548 A1 WO 2024044548A1
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product
approved
approved product
dose
teclistamab
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Jenna GOLDBERG
Arnob BANERJEE
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Janssen Biotech Inc
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Janssen Biotech Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific

Definitions

  • MM multiple myeloma
  • kits comprising the disclosed approved products or pharmaceutical products are also provided.
  • kits for treating relapsed and refractory multiple myeloma in a patient comprising administering the disclosed approved products to the patient in an amount and manner that is described in a drug product label for the approved product.
  • methods for treating relapsed and refractory multiple myeloma in a patient comprising administering a corticosteroid, an antihistamine, an antipyretic, and the disclosed approved products to the patient in an amount and manner that is described in a drug product label for the approved product.
  • Also provided are methods of selling an approved product comprising selling such approved product, wherein an approved product label for a reference product for such approved product includes instructions for treating adult patients with relapsed and refractory multiple myeloma after three or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
  • kits for offering for sale an approved product comprising offering for sale such approved product, wherein an approved product label for a reference product for such approved product includes instructions for treating adult patients with relapsed and refractory multiple myeloma after three or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti- CD38 monoclonal antibody.
  • an approved product label for a reference product for such approved product includes instructions for treating adult patients with relapsed and refractory multiple myeloma after three or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti- CD38 monoclonal antibody.
  • the number of significant figures used for a particular value may be one non-limiting method of determining the extent of the word “about.”
  • the gradations used in a series of values may be used to determine the intended range available to the term “about” for each value.
  • the term “about” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of up to ⁇ 10% from the specified value.
  • approved product means: a pharmaceutical product that i) has been approved for introduction into commerce by a regulatory agency for use in treating humans with relapsed and refractory multiple myeloma; ii) includes a biological product having at least the amino acid sequences of SEQ ID NOs: 1, 2, 3, and 4; iii) is formulated for delivery by injection in either a 10 mg/ml or 90 mg/ml concentration; and iv) induces an overall response
  • biosimilar means a product approved by a regulatory agency comprising a biological product that is highly similar to and does not cause any clinically meaningful differences when administered to patients relative to a pioneer company’s reference product approved product.
  • a biosimilar can be shown to be highly similar to the reference product by extensively analyzing (i.e., characterizing) the structure and function of both the reference product and the proposed biosimilar and comparing characteristics of the products, such as purity, chemical identity, and bioactivity.
  • oligosaccharide profiles may exist between products produced using different cell lines or manufacturing techniques and that a biosimilar may behave differently in patients if manufactured using a different cell line or a different methodology.
  • the manufacturer of a proposed biosimilar product generates data comparing the proposed product to the approved reference product in order to demonstrate biosimilarity.
  • a biosimilar product application must include data demonstrating biosimilarity to the reference product, which includes data from: - Analytical studies demonstrating that the biological product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components; - Animal studies, including an assessment of toxicity; and - A clinical study or studies sufficient to demonstrate safety, purity, and potency of the proposed biosimilar product in one or more of the indications for which the reference product is licensed, which typically includes assessing immunogenicity, pharmacokinetics (PK), and, in some cases, pharmacodynamics (PD) and may also include a comparative clinical study.
  • PK pharmacokinetics
  • PD pharmacodynamics
  • a biosimilar manufacturer may not need to conduct as many clinical trials and can simply rely on the innovative research, development, and clinical work of the pioneer company to bring its biosimilar forward into commerce.
  • the term “reference product” refers to a product that is approved by a regulatory agency (e.g. the approved product) against which a proposed biosimilar product is compared.
  • a reference product is approved based on, among other things, a full complement of safety and effectiveness data.
  • a proposed biosimilar product is compared to, and evaluated against, a reference product to ensure that the product is highly similar and has no clinically meaningful differences.
  • ORR all response rate
  • PR partial response
  • VGPR very good partial response
  • CR complete response
  • sCR stringent complete response
  • Label or “approved product label” refers to information provided to a patient which provides relevant information regarding the approved product. Such information includes, without limitation, one or more of: the description of the approved product, clinical pharmacology, indications (uses for the approved product), contraindication (who should not take the approved product), warnings, precautions, adverse events (side effects), drug abuse and dependence, dosage and administration, use in pregnancy, use in nursing mothers, use in children and older patients, how the approved product is supplied, safety information for the patient, or any combination thereof.
  • the label or approved product label identifies teclistamab and provides instructions for its use in a patient.
  • Antibody refers to all isotypes of immunoglobulins (IgG, IgA, IgE, IgM, IgD, and IgY) including various monomeric, polymeric, and chimeric forms, unless otherwise specified. Specifically encompassed by the term “antibody” are polyclonal antibodies, monoclonal antibodies (mAbs), and antibody-like polypeptides, such as chimeric antibodies and humanized antibodies.
  • mAbs monoclonal antibodies
  • BCMA refers to human B cell maturation antigen, also known as CD269 and TNFRSF17 (UniProt Q02223), which is a member of the tumor necrosis receptor superfamily that is preferentially expressed in differentiated plasma cells.
  • CD3 refers to the human CD3 protein multi-subunit complex.
  • the CD3 protein multi-subunit complex is composed to six distinctive polypeptide chains. These include a CD3 ⁇ chain (SwissProt P09693), a CD3 ⁇ chain (SwissProt P04234), two CD3 ⁇ chains (SwissProt P07766), and one CD3 ⁇ chain homodimer (SwissProt 20963), and which is associated with the T cell receptor ⁇ and ⁇ chain.
  • CD3 includes any CD3 variant, isoform and species homolog which is naturally expressed by cells (including T cells).
  • Teclistamab is a humanized immunoglobulin G4 (IgG4) bispecific antibody against B-cell maturation antigen (BCMA) and cluster of differentiation 3 (CD3) receptors with a molecular mass of 146,261 Da for the predominant G0F/G0F glycoform.
  • Teclistamab has 2 heavy chains (HC) and 2 light chains (LC), joined by disulfide bonds. It is prepared by controlled reduction and oxidation of the anti-BCMA mAb and the anti- CD3 mAb resulting in an exchange of the Fab arms.
  • Teclistamab utilizes an IgG4 PAA scaffold containing Pro mutations (S229P in the anti-BCMA mAb and S233P in the anti-CD3 mAb, according to sequential numbering of amino acids) that stabilize the hinge region and Ala/Ala mutations (F235A, L236A in the anti-BCMA mAb and F239A, L240A in anti-CD3 mAb, according to sequential numbering of amino acids) that suppress Fc ⁇ R binding.
  • the resulting teclistamab bispecific antibody comprises Fc substitutions, with the BMCA-binding arm and CD3-binding arm each comprising Pro/Ala/Ala substitutions at amino acid positions 228/234/235, respectively (according to EU index numbering); and the CD3-binding arm also comprising F405L and R409K substitutions (according to EU index numbering).
  • the term “patient” refers to a human. Subject and patient can be used interchangeably throughout this disclosure.
  • the term “refractory” refers to disease which becomes non-responsive or progressive on therapy.
  • compositions described herein refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a human.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
  • placebo means administration of a pharmaceutical composition that does not include teclistamab.
  • Treatment includes reducing the severity and/or frequency of symptoms, eliminating symptoms and/or the underlying cause of the symptoms, reducing the frequency or likelihood of symptoms and/or their underlying cause, and improving or remediating damage caused, directly or indirectly, by the relapsed and/or refractory multiple myeloma. “Treatment” can also mean delaying or slowing of disease progression and/or prolonging survival as compared to expected survival if a subject was not receiving the treatment. Treatment includes, for example, achieving desired clinical results, such as the efficacy results provided in Example 1 or in Example 2.
  • Approved Product Disclosed herein are approved products comprising: 10 mg/mL of teclistamab in solution for injection; and/or 90 mg/mL of teclistamab in solution for injection.
  • the approved product comprises 10 mg/mL of teclistamab in solution for injection.
  • the approved product comprises 90 mg/mL of teclistamab in solution for injection.
  • the approved product comprises 10 mg/mL of teclistamab in solution for injection and 90 mg/mL of teclistamab in solution for injection.
  • the approved product can be formulated for delivery to a human in a dosing schedule comprising: a 0.06 mg/kg single dose administered as a first step-up dose on Day 1; a 0.3 mg/kg single dose administered as a second step-up dose 2 to 7 days after the first step-up dose; a 1.5 mg/kg single dose administered as a first maintenance dose 2 to 7 days after the second step-up dose; and a 1.5 mg/kg once weekly dose administered as a subsequent maintenance dose one week after the first maintenance dose, and weekly thereafter.
  • An exemplary dosing schedule is provided below: a Dose is based on actual body weight and should be administered subcutaneously. b Step-up dose 2 may be given between 2 to 7 days after Step-up dose 1.
  • First maintenance dose may be given between 2 to 7 days after Step-up dose 2. This is the first full treatment dose (1.5 mg/kg).
  • d Maintain a minimum of five days between weekly maintenance doses.
  • the first step-up dose of 0.06 mg/kg is administered using the 10 mg/mL of teclistamab in solution for injection
  • the second step- up dose of 0.3 mg/kg is administered using the 10 mg/mL of teclistamab in solution for injection
  • each maintenance dose of 1.5 mg/kg is administered using the 90 mg/mL of teclistamab in solution for injection.
  • An alternative dosing schedule permits a reduction in the frequency of treatment doses if the subject exhibits a complete response for a minimum of 6 months.
  • the approved product can be formulated for delivery to a human according to a dosing schedule comprising: a 0.06 mg/kg single dose administered as a first step-up dose on Day 1; a 0.3 mg/kg single dose administered as a second step-up dose 2 to 7 days after the first step-up dose; a 1.5 mg/kg single dose administered as a first maintenance dose 2 to 7 days after the second step-up dose; a 1.5 mg/kg once weekly dose administered as a subsequent maintenance dose one week after the first maintenance dose, and weekly thereafter; and if the subject has a complete response or better for a minimum of 6 months, a 1.5 mg/kg bi-weekly dose administered as a subsequent maintenance dose bi- weekly.
  • a Dose is based on actual body weight and should be administered subcutaneously. b See Table 2 for recommendations on restarting TECVAYLI® after dose delays. c Step-up dose 2 may be given between two to seven days after Step-up dose 1. d First maintenance dose may be given between two to seven days after Step-up dose 2. This is the first full maintenance dose (1.5 mg/kg). e Maintain a minimum of five days between weekly maintenance doses.
  • step-up dosing refers to ascending concentrations of doses of the approved product administered prior to the weekly dosing schedule.
  • first step-up dose refers to Step-up dose 1 in the above table.
  • second step-up dose refers to Step-up dose 2 in the above table.
  • the “subsequent maintenance dose” can be administered one week after the first maintenance dose and weekly thereafter.
  • One or more subsequent maintenance doses can be administered (e.g. once weekly on weeks 1, 2, 3, 4, 5, 6, 7, 8, or for more than 8 weeks after the first maintenance dose).
  • the frequency of dosing can be reduced to 1.5 mg/kg every two weeks.
  • the second step-up dose is administered on Day 3, Day 4, Day 5, Day 6, Day 7, or Day 8. In some embodiments, the second step-up dose is administered on Day 3. [0052] In some embodiments, the first maintenance dose is administered 2 to 7 days after the second step-up dose. In some embodiments, the first maintenance dose is administered on Day 5.
  • the approved product can be formulated for delivery to a human in a dosing schedule comprising: a 0.06 mg/kg single dose administered as a first step-up dose on Day 1; a 0.3 mg/kg single dose administered as a second step-up dose on Day 3; a 1.5 mg/kg single dose administered as a first maintenance dose on Day 5; and a 1.5 mg/kg once weekly dose administered as a subsequent maintenance dose one week after the first maintenance dose, and weekly thereafter.
  • the approved product can be formulated for delivery to a human in a dosing schedule comprising: a 0.06 mg/kg single dose administered as a first step-up dose on Day 1; a 0.3 mg/kg single dose administered as a second step-up dose on Day 3; a 1.5 mg/kg single dose administered as a first maintenance dose on Day 5; a 1.5 mg/kg once weekly dose administered as a subsequent maintenance dose one week after the first maintenance dose, and weekly thereafter; and, if the subject has a complete response or better for a minimum of 6 months, a 1.5 mg/kg bi- weekly dose administered as a subsequent maintenance dose bi-weekly.
  • the approved product is a biosimilar of teclistamab.
  • the approved product can include the following excipients: EDTA disodium salt dihydrate; glacial acetic acid; Polysorbate 20 (E432); sodium acetate trihydrate; sucrose; and water for injections.
  • the approved product can be in a 3 ml vial comprising 30 mg of teclistamab, 0.054 mg EDTA disodium salt dihydrate, 0.72 mg glacial acetic acid, 1.2 mg polysorbate 20 (E432), 2.7 mg sodium acetate trihydrate, 240 mg sucrose, and water for injections.
  • the approved product can be in a 1.7 ml vial comprising 153 mg of teclistamab, 0.031 mg EDTA disodium salt dihydrate, 0.41 mg glacial acetic acid, 0.68 mg polysorbate 20 (E432), 1.5 mg sodium acetate trihydrate, 140 mg sucrose, and water for injection.
  • the approved products can be administered to the patient in combination with a corticosteroid, an antihistamine, and an antipyretic.
  • a corticosteroid, an antihistamine, an antipyretic Provided herein is a combination of a corticosteroid, an antihistamine, an antipyretic, and an approved product.
  • the corticosteroid, the antihistamine, and the antipyretic can be administered prior to the first step-up dose, prior to the second step-up dose, prior to the first maintenance dose, and/or prior to each subsequent maintenance dose.
  • the combination can comprise a corticosteroid comprising oral or intravenous dexamethasone, an antihistamine comprising oral or intravenous diphenhydramine, and an antipyretic comprising oral or intravenous acetaminophen.
  • the combination comprises 16 mg of oral or intravenous dexamethasone, 50 mg or equivalent of oral or intravenous diphenhydramine, and 650 mg to 1000 mg, or equivalent, of oral or intravenous acetaminophen.
  • the approved product comprises a first heavy chain (HC) (SEQ ID NO: 1) and a first light chain (LC) (SEQ ID NO: 2) that pair to form a first antigen-binding site that immunospecifically binds BCMA, and a second heavy chain (HC) (SEQ ID NO: 3) and a second light chain (LC) (SEQ ID NO: 4) that pair to form a second antigen-binding site that immunospecifically binds CD3.
  • HC first heavy chain
  • LC first light chain
  • SEQ ID NO: 3 second heavy chain
  • LC second light chain
  • a biosimilar can comprise, for example, a first HC having 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 1, a first LC having 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 2, a second HC having 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 3, and a second LC having 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 4.
  • the antigen-binding site that binds BCMA comprises a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 5, HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 7, and light chain CDR1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 8, LCDR2 comprising the amino acid sequence of SEQ ID NO: 9, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 10.
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 comprising the amino acid sequence of SEQ ID NO: 6
  • HCDR3 comprising the amino acid sequence of SEQ ID NO: 7
  • LCDR1 light chain CDR1
  • LCDR2 comprising the amino acid sequence of SEQ ID NO: 9
  • LCDR3 comprising the amino acid sequence of SEQ ID NO: 10.
  • the antigen-binding site that binds CD3 comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 11, HCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 13, and LCDR1 comprising the amino acid sequence of SEQ ID NO: 14, LCDR2 comprising the amino acid sequence of SEQ ID NO: 15, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
  • Antibody sequences are provided in the below table: [0062] Also provided herein are pharmaceutical products comprising teclistamab in a solution for injection, wherein the pharmaceutical product is packaged, and wherein the package includes a label that identifies the pharmaceutical product as indicated as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrated disease progression on the last therapy. [0063] Also provided herein is an approved drug product with at least one approved indication, wherein said approved drug product comprises teclistamab.
  • a drug product comprising teclistamab, wherein the drug product is approved for treating relapsed and refractory multiple myeloma.
  • an approved drug product comprises teclistamab, wherein such approved drug product improves anti-cancer cell activity as measured by overall response rate, duration of response, time to first response, minimal residual disease negativity, or overall survival relative to a patient with multiple myeloma who is not receiving treatment with a bispecific antibody.
  • an approved drug product comprises teclistamab and is reference listed on the basis of data demonstrating an improvement in anti-cancer cell activity as measured by overall response rate, duration of response, time to first response, minimal residual disease negativity, or overall survival relative to a patient with multiple myeloma who is not receiving treatment with a bispecific antibody.
  • Methods of Treatment with Approved Product [0067] Disclosed herein are methods for treating relapsed and refractory multiple myeloma in a patient, the method comprising administering the disclosed approved products to the patient in an amount and manner that is described in a drug product label for the approved product.
  • the approved product is teclistamab.
  • the method of treatment embodiments described herein encompass the use of an approved product for the manufacture of a medicament and the approved product for use in treatment.
  • the methods Prior to the administering of the approved product, the methods comprise administering a corticosteroid, an antihistamine, and an antipyretic to the patient.
  • the corticosteroid is dexamethasone
  • the antihistamine is diphenhydramine
  • the antipyretic is acetaminophen.
  • a corticosteroid can comprise oral or intravenous dexamethasone
  • the antihistamine can comprise oral or intravenous diphenhydramine
  • the antipyretic can comprise oral or intravenous acetaminophen.
  • the methods comprise administering 16 mg of oral or intravenous dexamethasone, 50 mg or equivalent of oral or intravenous diphenhydramine, 650 mg to 1000 mg, or equivalent, of oral or intravenous acetaminophen, and the disclosed approved products to the patient in an amount and manner that is described in a drug product label for the approved product.
  • the corticosteroid, the antihistamine, and the antipyretic are administered to the patient prior to a step-up dose or a maintenance dose.
  • the patient has not had a stroke or a seizure within 6 months of receiving the approved product.
  • the patient has no active, or history of, autoimmune disease, excluding vitiligo, type 1 diabetes, and thyroiditis.
  • the administration of the approved product can provide improved anti- cancer cell activity as measured by overall response rate, duration of response, time to first response, minimal residual disease negativity, or overall survival relative to a patient with multiple myeloma who is not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity as measured by overall response rate, duration of response, or time to first response relative to a patient with multiple myeloma who is not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity as measured by overall response rate relative to a patient with multiple myeloma who is not receiving treatment with a bispecific antibody. [0074] The administration of the approved product can provide improved anti- cancer cell activity as measured by stringent complete response data relative to a patient with multiple myeloma who is not receiving treatment with a bispecific antibody. [0075] The administration of the approved product can provide improved anti- cancer cell activity as measured by complete response data relative to a patient with multiple myeloma who is not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity as measured by very good partial response data relative to a patient with multiple myeloma who is not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity as measured by partial response data relative to a patient with multiple myeloma who is not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity as measured by stringent complete response data, complete response data, very good partial response data, and partial response data relative to a patient with multiple myeloma who is not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity as measured by progression-free survival relative to a patient with multiple myeloma who is not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity as measured by duration of response relative to a patient with multiple myeloma who is not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity as measured by time to first response relative to a patient with multiple myeloma who is not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity as measured by minimal residual disease negativity rate relative to a patient with multiple myeloma who is not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity as measured by overall survival relative to a patient with multiple myeloma who is not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity in a patient population as measured by overall response rate relative to a patient population with multiple myeloma who are not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity in a patient population as measured by complete response (CR) or better, including stringent complete response (sCR) and CR, data relative to a patient population with multiple myeloma who are not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity in a patient population as measured by very good partial response data relative to a patient population with multiple myeloma who are not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity in a patient population as measured by partial response data relative to a patient population with multiple myeloma who are not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity in a patient population as measured by stringent complete response data, complete response data, very good partial response data, and partial response data relative to a patient population with multiple myeloma who are not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity in a patient population as measured by duration of response relative to a patient population with multiple myeloma who are not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity in a patient population as measured by time to first response relative to a patient population with multiple myeloma who are not receiving treatment with a bispecific antibody.
  • the administration of the approved product can provide improved anti- cancer cell activity in a patient population as measured by duration of response rate relative to a patient population with multiple myeloma who are not receiving treatment with a bispecific antibody.
  • the improvement in anti-cancer cell activity can be relative to treatment with placebo.
  • the improvement in anti-cancer cell activity can be relative to no treatment.
  • the improvement in anti-cancer cell activity can be relative to standard of care.
  • the administration of the approved product can result in no more than a grade 2 adverse event.
  • the administration of an amount of the approved product can result in no more than a grade 3 adverse event.
  • the administration of an amount of the approved product can result in no more than a grade 4 adverse event.
  • Pharmaceutical Compositions and Routes of Administration [0098] In view of its useful pharmacological properties, the approved product described herein may be formulated into various pharmaceutical forms for administration purposes. [0099]
  • the pharmaceutical composition e.g., formulation
  • the approved product is teclistamab.
  • an effective amount of the approved product is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • the pharmaceutical compositions can comprise an effective amount of the approved product combined in intimate admixture with one or more pharmaceutically acceptable excipients.
  • suitable pharmaceutically acceptable excipients include EDTA disodium salt dihydrate, glacial acetic acid, polysorbate 20 (E432), sodium acetate trihydrate, sucrose, and water for injections.
  • the pharmaceutical compositions can be in any form suitable for oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration.
  • the pharmaceutical compositions preferably are suitable for parenteral administration.
  • parenteral includes intravenous, intramuscular, subcutaneous, rectal, vaginal, and intraperitoneal administration. More preferably, the pharmaceutical compositions suitable for peripheral systemic delivery by intravenous, intraperitoneal, or subcutaneous injection. Most preferably, the pharmaceutical composition of the approved product is administered by subcutaneous injection.
  • These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for parenteral injection.
  • the pharmaceutical compositions can be prepared by mixing the biological product included in the approved product with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions.
  • the pharmaceutical composition comprising the approved product can comprise one or more excipients selected from EDTA disodium salt dihydrate, glacial acetic acid, Polysorbate 20, sodium acetate trihydrate, sucrose, and water.
  • the pharmaceutical composition comprising the approved product can be essentially sodium free, i.e., the pharmaceutical composition contains less than 1 mmol (23 mg) sodium per dose.
  • the pharmaceutical compositions comprising the approved product are essentially sodium free, i.e., the pharmaceutical compositions contain less than 1 mmol (23 mg) sodium per dose.
  • Also provided herein are methods of preparing a pharmaceutical composition that comprises the approved product, in the form of an aqueous solution, characterized by combining the approved product with one or more excipients selected from the group consisting of EDTA disodium salt dihydrate, glacial acetic acid, Polysorbate 20, sodium acetate trihydrate, sucrose, and water.
  • the aqueous solution can comprise teclistamab, EDTA disodium salt dihydrate, glacial acetic acid, Polysorbate 20, sodium acetate trihydrate, sucrose, and water.
  • the approved product is formulated to provide patients with a dose of about 0.06 mg/kg, 0.3 mg/kg, or 1.5 mg/kg of teclistamab in accordance with the approved product label.
  • Methods of Dosing and Treatment Regimens [0105] The approved product is administered in an amount sufficient to exert its anti-cancer cell activity.
  • the recommended dosing amounts, regimens, and other key elements of uses of the approved product is provided in Table 1 of Example 1.
  • Other recommended dosing amounts, regimens, and other key elements of uses of the approved product is provided in Table 1 of Example 2.
  • a patient is provided with a step- up dose 1 of the approved product in the amount of 0.06 mg/kg on day 1, followed by a step-up dose 2 of the approved product in the amount of 0.3 mg/kg on day 3, followed by a first maintenance dose of the approved product in the amount of 1.5 mg/kg on day 7.
  • the patient is then provided with a weekly dosing schedule of the approved product in the amount of 1.5 mg/kg that begins one week after the first maintenance dose and is continued weekly thereafter.
  • dosing schedule of the approved product in the amount of 1.5 mg/kg that begins one week after the first maintenance dose and is continued weekly thereafter.
  • the patient may switch from the weekly dosing schedule to a bi-weekly dosing schedule of the approved product in the amount of 1.5 mg/kg bi- weekly.
  • the approved product is teclistamab.
  • the patient is a patient who has received at least three prior lines of therapy for the treatment of multiple myeloma including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, wherein the patient has demonstrated disease progression on the last therapy.
  • the patient can be a patient whose multiple myeloma progressed during or within 12 months following treatment with a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
  • the patient is pre-treated with one or more secondary medicinal products prior to receiving the approved product.
  • a patient may be administered one or more pre- treatment medicinal products about 10 minutes to 6 hours, more specifically 30 minutes to 4.5 hours, or more specifically 1 hour to 3 hours prior to administration of the approved product.
  • the one or more pre-treatment medicinal products include a corticosteroid, an antihistamine, an antipyretic, and/or an anti-viral prophylaxis.
  • the corticosteroid is oral or intravenous dexamethasone.
  • the antihistamine is oral or intravenous diphenhydramine.
  • the antipyretic is oral or intravenous acetaminophen.
  • the patient is administered about 16 mg of oral or intravenous dexamethasone, about 50 mg or equivalent of oral or intravenous diphenhydramine, and about 650 mg to 1000 mg, or equivalent, of oral or intravenous acetaminophen one to three hours prior to administration of a step-up dose or a maintenance dose of the approved product. Additional details regarding pre-treatment are provided in Example 1. Other details regarding pre-treatment are provided in Example 2.
  • kits and articles of manufacture comprising the disclosed approved products or the disclosed pharmaceutical products (“kits” shall be construed to include the elements of the approved product as defined herein).
  • kits include a package or container that is compartmentalized to receive one or more dosages of the approved product disclosed herein.
  • Suitable containers include, for example, bottles or vials.
  • the containers can be formed from a variety of materials such as glass or plastic.
  • the approved product is teclistamab.
  • the articles of manufacture provided herein contain packaging materials.
  • kits typically includes labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.
  • a label is on or associated with the container. In an embodiment, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • kits of the invention are kits comprising TECVAYLI®.
  • a further example is a kit comprising a biosimilar.
  • An example of an article of manufacture of the invention is an article of manufacture comprising TECVAYLI®.
  • a further example is an article of manufacture comprising a biosimilar.
  • a label is used to indicate that the contents of a kit or of an article of manufacture are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.
  • the kit or the article of manufacture can comprise the approved product label.
  • the kits may comprise one or more suitably aliquoted compositions or reagents to generate compositions of the disclosure.
  • kits may be packaged either in aqueous media or in lyophilized form.
  • the container means of the kits may include at least one vial, test tube, flask, bottle, syringe, or other container means, into which a component may he placed, and preferably, suitably aliquoted. Where there is more than one component in the kit, the kit also will generally contain a second, third, or other additional containers into which the additional components may be separately placed. However, various combinations of components may be comprised in a vial.
  • the kits of the present invention also will typically include a means for containing the approved product and any other reagent containers in close confinement for commercial sale. Such containers may include injection or blow molded plastic containers into which the desired vials are retained, for example.
  • the vial or dispenser device is accompanied by instructions for administration.
  • the vial or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • Such notice for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Methods of Selling and Methods of Offering For Sale an Approved Product are methods of selling an approved product, said method comprising selling such approved product, wherein an approved product label for a reference product for such approved product includes instructions for treating adult patients with relapsed and refractory multiple myeloma after three or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
  • the methods comprise selling teclistamab.
  • the methods of selling comprise selling the biosimilar, wherein an approved product label for a reference product for the biosimilar includes instructions for treating adult patients with relapsed and refractory multiple myeloma after three or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
  • Also provided herein are methods of offering for sale an approved product comprising offering for sale such approved product, wherein an approved product label for a reference product for such approved product includes instructions for treating adult patients with relapsed and refractory multiple myeloma after three or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
  • the methods comprise offering teclistamab for sale.
  • the methods of offering for sale comprise offering for sale the biosimilar, wherein an approved product label for a reference product for the biosimilar includes instructions for treating adult patients with relapsed and refractory multiple myeloma after three or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
  • the biosimilar is a biosimilar of Teclistamab.
  • the method comprising selling such kits, wherein an approved product label for a reference product for such approved product includes instructions for treating multiple myeloma such as those described in Example 2.
  • the method comprises selling the kit, wherein an approved product label for a reference product for the approved product includes instructions for treating a patient with relapsed and refractory multiple myeloma after three or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
  • the methods of selling comprise methods of selling a kit comprising a biosimilar, said method comprising selling the biosimilar, wherein an approved product label for a reference product for the biosimilar includes instructions for treating a patient with relapsed and refractory multiple myeloma, and in some embodiments, for treating a patient with relapsed and refractory multiple myeloma after three or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
  • the disclosure further provides methods of offering for sale a kit comprising teclistamab, said method comprising offering for sale such kit, wherein the approved product label for a reference product for teclistamab includes instructions for treating a patient with relapsed and refractory multiple myeloma, and in some embodiments, for treating a patient with relapsed and refractory multiple myeloma after three or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.
  • the biosimilar label that is similar to or the same as a reference product label comprises overall response rate data.
  • the overall response rate data is stringent complete response data.
  • the overall response rate data is complete response data.
  • the overall response rate data is very good partial response data.
  • the overall response rate data is partial response data.
  • An example of the overall response rate data is stringent complete response data, complete response data, very good partial response data, and partial response data.
  • the overall response rate data for a biosimilar or the approved product is at least 63%, in particular, wherein the patients have relapsed and refractory multiple myeloma. In some embodiments, the overall response rate data for a biosimilar or the approved product is at least 63%, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody and have demonstrated disease progression on the last therapy.
  • the stringent complete response data for a biosimilar or the approved product is at least 32.7%, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody and have demonstrated disease progression on the last therapy.
  • the complete response data for a biosimilar or the approved product is at least 6.7%, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody and have demonstrated disease progression on the last therapy.
  • the very good partial response data for a biosimilar or the approved product is at least 19.4%, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody and have demonstrated disease progression on the last therapy.
  • the partial response data for a biosimilar or the approved product is at least 4.2%, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody and have demonstrated disease progression on the last therapy.
  • the duration of response data for a biosimilar or the approved product is at least 14.9 months, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody and have demonstrated disease progression on the last therapy.
  • the time to first response data for a biosimilar or the approved product is at least 1.2 months, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody and have demonstrated disease progression on the last therapy.
  • the minimal residual disease negative rate for a biosimilar or the approved product is at least 26.7%, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody and have demonstrated disease progression on the last therapy.
  • the minimal residual disease negative rate for a biosimilar or the approved product is at least 46.2%, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody, and have demonstrated disease progression on the last therapy, and wherein the patient has achieved stringent complete response or complete response.
  • Still further provided herein are methods of improving overall response rate, duration of response, time to first response, and minimal residual disease negativity rate in patients with relapsed and refractory multiple myeloma, said methods comprising administering to said patients a biosimilar or the approved product.
  • the overall response rate data for a biosimilar or the approved product is at least 63%, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody and have demonstrated disease progression on the last therapy.
  • the stringent complete response data for a biosimilar or the approved product is at least 32.7%, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody and have demonstrated disease progression on the last therapy.
  • the complete response data for a biosimilar or the approved product is at least 6.7%, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody and have demonstrated disease progression on the last therapy.
  • the very good partial response data for a biosimilar or the approved product is at least 19.4%, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody and have demonstrated disease progression on the last therapy.
  • the partial response data for a biosimilar or the approved product is at least 4.2%, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody and have demonstrated disease progression on the last therapy.
  • the duration of response data for a biosimilar or approved product is at least 14.9 months, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody and have demonstrated disease progression on the last therapy.
  • the time to first response data for a biosimilar or the approved product is at least 1.2 months, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody and have demonstrated disease progression on the last therapy.
  • the minimal residual disease negative rate for a biosimilar or the approved product is at least 26.7%, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody and have demonstrated disease progression on the last therapy.
  • the minimal residual disease negative rate for a biosimilar or the approved product is at least 46.2%, in particular, wherein the patients have relapsed and refractory multiple myeloma, who have received at least three prior therapies, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody, and wherein the patient has achieved stringent complete response or complete response and have demonstrated disease progression on the last therapy.
  • EXAMPLES [0134] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
  • EXAMPLE 1 Approved Drug Product Label
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  • EXAMP PLLEE 2 Ap ppprroovveedd Dr ruugg Pr rod duuctct Labe ell
  • EXAMP PLLEE 2 Ap ppprroovveedd Dr ruugg Pro odduuctct La abbelel ANNE EXX I SUMMA ARRYY OF F PROD DUUCCTT CHAR RAACCTTEERRIISSTTIICS 1
  • This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1.
  • TECVAYLI 10 mg/mL solution for injection One 3 mL vial contains 30 mg of teclistamab (10 mg/mL).
  • TECVAYLI 90 mg/mL solution for injection One 1.7 mL vial contains 153 mg of teclistamab (90 mg/mL).
  • Teclistamab is a humanised immunoglobulin G4-proline, alanine, alanine (IgG4-PAA) bispecific antibody directed against the B cell maturation antigen (BCMA) and CD3 receptors, produced in a mammalian cell line (Chinese hamster ovary [CHO]) using recombinant DNA technology.
  • PHARMACEUTICAL FORM Solution for injection injection (injection). The solution is colourless to light yellow, with a pH of 5.2 and osmolarity of approximately 296 mOsm/L (10 mg/mL solution for injection), and approximately 357 mOsm/L (90 mg/mL solution for injection).
  • CLINICAL PARTICULARS 4.1 Therapeutic indications TECVAYLI is indicated as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrated disease progression on the last therapy.
  • TECVAYLI Posology and method of administration Treatment with TECVAYLI should be initiated and supervised by physicians experienced in the treatment of multiple myeloma. TECVAYLI should be administered by a healthcare professional with adequately trained medical personnel and appropriate medical equipment to manage severe reactions, including cytokine release syndrome (CRS) (see section 4.4). Posology Pre-treatment medicinal products should be administered prior to each dose of TECVAYLI in the step- up dosing schedule (see below).
  • TECVAYLI step-up dosing schedule should not be administered in patients with active infection (see Table 3 and section 4.4).
  • Recommended dosing schedule The recommended dosing schedule for TECVAYLI is provided in Table 1.
  • the recommended doses of TECVAYLI are 1.5 mg/kg by subcutaneous injection (SC) weekly, preceded by step-up doses of 0.06 mg/kg and 0.3 mg/kg. In patients who have a complete response or better for a minimum of 6 months, a reduced dosing frequency of 1.5 mg/kg SC every two weeks may be considered (see section 5.1).
  • Treatment with TECVAYLI should be initiated according to the step-up dosing schedule in Table 1 to reduce the incidence and severity of cytokine release syndrome.
  • TECVAYLI dosing schedule a Dose is based on actual body weight and should be administered subcutaneously. b See Table 2 for recommendations on restarting TECVAYLI after dose delays. c Step-up dose 2 may be given between two to seven days after Step-up dose 1.
  • First maintenance dose may be given between two to seven days after Step-up dose 2. This is the first full maintenance dose (1.5 mg/kg).
  • e Maintain a minimum of five days between weekly maintenance doses.
  • Duration of treatment Patients should be treated with TECVAYLI until disease progression or unacceptable toxicity.
  • Pre-treatment medicinal products The following pre-treatment medicinal products must be administered 1 to 3 hours before each dose of the TECVAYLI step-up dosing schedule (see Table 1) to reduce the risk of cytokine release syndrome (see sections 4.4 and 4.8).
  • Corticosteroid oral or intravenous dexamethasone 16 mg
  • Antihistamine oral or intravenous diphenhydramine 50 mg, or equivalent
  • Antipyretics oral or intravenous acetaminophen 650 to 1000 mg, or equivalent
  • Administration of pre-treatment medicinal products may also be required prior to administration of subsequent doses of TECVAYLI for the following patients: • Patients who repeat doses within the TECVAYLI step-up dosing schedule due to dose delays (Table 2), or • Patients who experienced CRS following the previous dose (Table 3).
  • Prevention of herpes zoster reactivation Prior to starting treatment with TECVAYLI, antiviral prophylaxis should be considered for the prevention of herpes zoster virus reactivation, per local institutional guidelines.
  • TECVAYLI Restarting TECVAYLI after dose delay If a dose of TECVAYLI is delayed, therapy should be restarted based on the recommendations listed in Table 2 and TECVAYLI resumed according to the dosing schedule (see Table 1). Pre-treatment medicinal products should be administered as indicated in Table 2. Patients should be monitored accordingly (see section 4.2). Table 2: Recommendations for restarting therapy with TECVAYLI after dose delay a Pre-treatment medicinal products should be administered prior to TECVAYLI dose and patients monitored accordingly. Dose modifications Treatment with TECVAYLI should be initiated according to the step-up dosing schedule in Table 1. Dose reductions of TECVAYLI are not recommended.
  • Dose delays may be required to manage toxicities related to TECVAYLI (see section 4.4). Recommendations on restarting TECVAYLI after a dose delay are provided in Table 2. Recommended actions after adverse reactions following administration of TECVAYLI are listed in Table 3.
  • ASTCT American Society for Transplantation and Cellular Therapy
  • Fever may not always be present concurrently with hypotension or hypoxia as it may be masked by interventions such as antipyretics or anticytokine therapy (e.g., tocilizumab or corticosteroids).
  • c Low-flow nasal cannula is ⁇ 6 L/min, and high-flow nasal cannula is >6 L/min.
  • NCI-CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events
  • TECVAYLI TECVAYLI
  • Elderly 65 years of age and older
  • Renal impairment No dosage adjustment is recommended for patients with mild or moderate renal impairment (see section 5.2).
  • Hepatic impairment No dosage adjustment is recommended for patients with mild hepatic impairment (see section 5.2).
  • Method of administration TECVAYLI is for subcutaneous injection only. For instructions on handling of the medicinal product before administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
  • Cytokine release syndrome Cytokine release syndrome
  • Clinical signs and symptoms of CRS may include but are not limited to fever, hypoxia, chills, hypotension, tachycardia, headache, and elevated liver enzymes.
  • Potentially life-threatening complications of CRS may include cardiac dysfunction, adult respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (DIC).
  • Treatment should be initiated with TECVAYLI according to the step-up dosing schedule to reduce risk of CRS.
  • Pre-treatment medicinal products corticosteroids, antihistamine and antipyretics
  • tocilizumab and/or corticosteroids should be instituted, based on severity as indicated in Table 4 below.
  • myeloid growth factors particularly granulocyte macrophage-colony stimulating factor (GM-CSF)
  • GM-CSF granulocyte macrophage-colony stimulating factor
  • Treatment with TECVAYLI should be withheld until CRS resolves as indicated in Table 3 (see section 4.2).
  • Management of cytokine release syndrome CRS should be identified based on clinical presentation. Patients should be evaluated and treated for other causes of fever, hypoxia, and hypotension. If CRS is suspected, TECVAYLI should be withheld until the adverse reaction resolves (see Table 3).
  • CRS should be managed according to the recommendations in Table 4.
  • CRS including but not limited to anti-pyretic agents, intravenous fluid support, vasopressors, supplemental oxygen, etc.
  • CRS cardiovascular disease
  • DIC disseminated intravascular coagulation
  • haematology parameters as well as pulmonary, cardiac, renal, and hepatic function should be considered.
  • Table 4 Recommendations for management of cytokine release syndrome with
  • Patients should be monitored for signs or symptoms of neurologic toxicities during treatment and treated promptly. Patients should be counselled to seek medical attention should signs or symptoms of neurologic toxicity occur. At the first sign of neurologic toxicity, including ICANS, patients should be immediately evaluated and treated based on severity. Patients who experience Grade 2 or higher ICANS or first occurrence of Grade 3 ICANS with the previous dose of TECVAYLI should be instructed to remain within proximity of a healthcare facility and monitored for signs and symptoms daily for 48 hours. For ICANS and other neurologic toxicities, treatment with TECVAYLI should be withheld as indicated in Table 3 (see section 4.2).
  • ICE Immune Effector Cell-Associated Encephalopathy
  • Hepatitis B virus reactivation can occur in patients treated with medicinal products directed against B cells, and in some cases, may result in fulminant hepatitis, hepatic failure, and death.
  • Patients with evidence of positive HBV serology should be monitored for clinical and laboratory signs of HBV reactivation while receiving TECVAYLI, and for at least six months following the end of TECVAYLI treatment.
  • treatment with TECVAYLI should be withheld as indicated in Table 3 and manage per local institutional guidelines (see section 4.2).
  • Hypogammaglobulinaemia Hypogammaglobulinaemia has been reported in patients receiving TECVAYLI (see section 4.8).
  • Immunoglobulin levels should be monitored during treatment with TECVAYLI. Intravenous or subcutaneous immunoglobulin therapy was used to treat hypogammaglobulinaemia in 39% of patients. Patients should be treated according to local institutional guidelines, including infection precautions, antibiotic or antiviral prophylaxis, and administration of immunoglobulin replacement. Vaccines Immune response to vaccines may be reduced when taking TECVAYLI. The safety of immunisation with live viral vaccines during or following TECVAYLI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 4 weeks prior to the start of treatment, during treatment and least 4 weeks after treatment. Neutropenia Neutropenia and febrile neutropenia have been reported in patients who received TECVAYLI (see section 4.8).
  • toxicity or medicinal product concentrations should be monitored in patients who are receiving concomitant CYP450 substrates with a narrow therapeutic index.
  • the dose of the concomitant medicinal product should be adjusted as needed.
  • 4.6 Fertility, pregnancy and lactation Women of child-bearing potential/Contraception in males and females Pregnancy status for females of child-bearing potential should be verified prior to starting treatment with TECVAYLI. Women of child-bearing potential should use effective contraception during treatment and for five months after the final dose of TECVAYLI.
  • male patients with a female partner of child-bearing potential used effective contraception during treatment and for three months after the last dose of teclistamab.
  • teclistamab is excreted in human or animal milk, affects breast-fed infants or affects milk production. Because of the potential for serious adverse reactions in breast-fed infants from TECVAYLI, patients should be advised not to breast-feed during treatment with TECVAYLI and for at least five months after the last dose. Fertility There are no data on the effect of teclistamab on fertility. Effects of teclistamab on male and female fertility have not been evaluated in animal studies.
  • TECVAYLI has major influence on the ability to drive and use machines. Due to the potential for ICANS, patients receiving TECVAYLI are at risk of depressed level of consciousness (see section 4.8). Patients should be instructed to avoid driving and operating heavy or potentially dangerous machinery during and for 48 hours after completion of TECVAYLI step-up dosing schedule and in the event of new onset of any neurological symptoms (Table 1) (see section 4.2 and section 4.4).
  • TECVAYLI Serious adverse reactions were reported in 65% patients who received TECVAYLI, including pneumonia (16%), COVID-19 (15%), cytokine release syndrome (8%), sepsis (7%), pyrexia (5%), musculoskeletal pain (5%), acute kidney injury (4.8%), diarrhoea (3.0%), cellulitis (2.4%), hypoxia (2.4%), febrile neutropenia (2.4%), and encephalopathy (2.4%).
  • TECVAYLI was evaluated in MajesTEC-1, which included 165 adult patients with multiple myeloma who received the recommended dosing regimen of TECVAYLI as monotherapy.
  • Adverse events are coded using MedDRA Version 24.0.
  • the output includes the diagnosis of CRS and ICANS; the symptoms of CRS or ICANS are excluded.
  • 1 Pneumonia includes Enterobacter pneumonia, lower respiratory tract infection, lower respiratory tract infection viral, Metapneumovirus pneumonia, Pneumocystis jirovecii pneumonia, pneumonia, Pneumonia adenoviral, Pneumonia bacterial, Pneumonia klebsiella, Pneumonia moraxella, Pneumonia pneumococcal, Pneumonia pseudomonal, Pneumonia respiratory syncytial viral, Pneumonia staphylococcal and Pneumonia viral.
  • 2 Sepsis includes bacteraemia, Meningococcal sepsis, neutropenic sepsis, Pseudomonal bacteraemia, Pseudomonal sepsis, sepsis and Staphylococcal bacteraemia.
  • 3 COVID-19 includes asymptomatic COVID-19 and COVID-19.
  • 4 Upper respiratory tract infection includes bronchitis, nasopharyngitis, pharyngitis, respiratory tract infection, respiratory tract infection bacterial, rhinitis, rhinovirus infection, sinusitis, tracheitis, upper respiratory tract infection and viral upper respiratory tract infection.
  • 5 Anaemia includes anaemia, iron deficiency and iron deficiency anaemia.
  • Hypogammaglobulinaemia includes patients with adverse events of hypogammaglobulinaemia, hypoglobulinaemia, immunoglobulins decreased, and/or patients with laboratory IgG levels below 500 mg/dL following treatment with teclistamab.
  • Encephalopathy includes confusional state, depressed level of consciousness, lethargy, memory impairment and somnolence.
  • Neuropathy peripheral includes dysaesthesia, hypoaesthesia, hypoaesthesia oral, neuralgia, paraesthesia, paraesthesia oral, peripheral sensory neuropathy and sciatica.
  • Haemorrhage includes conjunctival haemorrhage, epistaxis, haematoma, haematuria, haemoperitoneum, haemorrhoidal haemorrhage, lower gastrointestinal haemorrhage, melaena, mouth haemorrhage and subdural haematoma.
  • Hypertension includes essential hypertension and hypertension.
  • Dyspnoea includes acute respiratory failure, dyspnoea and dyspnoea exertional.
  • Cough includes allergic cough, cough, productive cough and upper-airway cough syndrome.
  • Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain and pain in extremity.
  • Injection site reaction includes injection site bruising, injection site cellulitis, injection site discomfort, injection site erythema, injection site haematoma, injection site induration, injection site inflammation, injection site oedema, injection site pruritus, injection site rash, injection site reaction and injection site swelling.
  • Pain includes ear pain, flank pain, groin pain, non-cardiac chest pain, oropharyngeal pain, pain, pain in jaw, toothache and tumour pain.
  • Oedema includes face oedema, fluid overload, oedema peripheral and peripheral swelling.
  • Fatigue includes asthenia, fatigue and malaise.
  • Transaminase elevation includes alanine aminotransferase increased and aspartate aminotransferase increased.
  • PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other monoclonal antibodies and antibody drug conjugates, ATC code: L01FX24 Mechanism of action Teclistamab is a full-size, IgG4-PAA bispecific antibody that targets the CD3 receptor expressed on the surface of T cells and B cell maturation antigen (BCMA), which is expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells.
  • BCMA B cell maturation antigen
  • teclistamab With its dual binding sites, teclistamab is able to draw CD3 + T cells in close proximity to BCMA + cells, resulting in T cell activation and subsequent lysis and death of BCMA + cells, which is mediated by secreted perforin and various granzymes stored in the secretory vesicles of cytotoxic T cells. This effect occurs without regard to T cell receptor specificity or reliance on major histocompatibility complex (MHC) Class 1 molecules on the surface of antigen presenting cells.
  • MHC major histocompatibility complex
  • TECVAYLI monotherapy was evaluated in patients with relapsed or refractory multiple myeloma in a single-arm, open-label, multi-centre, Phase 1/2 study (MajesTEC-1). The study included patients who had previously received at least three prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
  • Step-up Dose 1 and Step-up Dose 2 were eligible to reduce dosing frequency to 1.5 mg/kg subcutaneously every two weeks until disease progression or unacceptable toxicity (see section 4.2).
  • the median duration between Step-up Dose 1 and Step-up Dose 2 was 2.9 (Range: 2-7) days.
  • the median duration between Step-up Dose 2 and the initial maintenance dose was 3.1 (Range: 2-9) days.
  • Patients were hospitalised for monitoring for at least 48 hours after administration of each dose of the TECVAYLI Step-up dosing schedule.
  • the efficacy population included 165 patients.
  • the median age was 64 (Range: 33-84) years with 15% of subjects ⁇ 75 years of age; 58% were male; 81% were White, 13% were Black, 2% were Asian.
  • the International Staging System (ISS) at study entry was 52% in Stage I, 35% in Stage II and 12% in Stage III.
  • High-risk cytogenetics presence of del(17p), t(4;14) or t(14;16) were present in 26% of patients. Seventeen percent of patients had extramedullary plasmacytomas.
  • MRD-negativity rate is defined as the proportion of participants who achieved MRD negative status (at 10 -5 ) at any timepoint after initial dose, and prior to progressive disease (PD) or subsequent anti-myeloma therapy.
  • the median follow-up after schedule change was 12.6 (Range: 1.0 to 24.7) months in patients who switched to 1.5 mg/kg subcutaneously every two weeks.
  • Teclistamab exhibited approximately dose-proportional pharmacokinetics following subcutaneous administration across a dose range of 0.08 mg/kg to 3 mg/kg (0.05 to 2.0 times the recommended dose).
  • teclistamab exhibited approximately dose-proportional pharmacokinetics following subcutaneous administration across a dose range of 0.08 mg/kg to 3 mg/kg (0.05 to 2.0 times the recommended dose).
  • the mean accumulation ratio between the first and 13 th weekly maintenance dose of teclistamab 1.5 mg/kg was 4.2-fold for C max , 4.1-fold for C trough , and 5.3-fold for AUC tau .
  • the C max , C trough , and AUC tau of teclistamab are presented in Table 8.
  • Table 8 Pharmacokinetic parameters of teclistamab for the 13 th recommended weekly maintenance dose (1.5 mg/kg) in patients with relapsed or refractory multiple myeloma in MajesTEC-1 Absorption
  • the mean bioavailability of teclistamab was 72% when administered subcutaneously.
  • the median (range) T max of teclistamab after the first and 13 th weekly maintenance doses were 139 (19 to 168) hours and 72 (24 to 168) hours, respectively.
  • Distribution The mean volume of distribution was 5.63 L (29% coefficient of variation (CV)). Elimination Teclistamab clearance decreases over time, with a mean (CV%) maximal reduction from baseline to the 13 th weekly maintenance dose of 40.8% (56%).
  • the geometric mean (CV%) clearance is 0.472 L/day (64%) at the 13 th weekly maintenance dose.
  • Patients who discontinue teclistamab after the 13 th weekly maintenance dose are expected to have a 50% reduction from C max in teclistamab concentration at a median (5 th to 95 th percentile) time of 15 (7 to 33) days after T max and a 97% reduction from C max in teclistamab concentration at a median time of 69 (32 to 163) days after T max .
  • Population pharmacokinetic analysis (based on MajesTEC-1) showed that soluble BCMA did not impact teclistamab serum concentrations. Special populations The pharmacokinetics of TECVAYLI in paediatric patients aged 17 years and younger have not been investigated.
  • Results of population pharmacokinetic analyses indicate that age (24 to 84 years) and sex did not influence the pharmacokinetics of teclistamab. Renal impairment No formal studies of TECVAYLI in patients with renal impairment have been conducted. Results of population pharmacokinetic analyses indicate that mild renal impairment (60 mL/min/1.73 m 2 ⁇ estimated glomerular filtration rate (eGFR) ⁇ 90 mL/min/1.73 m 2 ) or moderate renal impairment (30 mL/min/1.73 m 2 ⁇ eGFR ⁇ 60 mL/min/1.73 m 2 ) did not significantly influence the pharmacokinetics of teclistamab. Limited data are available from patients with severe renal impairment.
  • in-use storage times of the prepared syringe should be no longer than 20 hours at 2 °C - 8 °C or ambient temperature (15 °C – 30 °C). Discard after 20 hours if not used.
  • Special precautions for storage Store in a refrigerator (2 °C - 8 °C). Do not freeze. Store in the original carton in order to protect from light.
  • TECVAYLI should be administered by a healthcare professional with adequately trained medical personnel and appropriate medical equipment to manage severe reactions, including cytokine release syndrome (see section 4.4).
  • TECVAYLI 10 mg/mL and TECVAYLI 90 mg/mL vials are for single use only.
  • TECVAYLI vials of different concentrations should not be combined to achieve maintenance dose.
  • Aseptic technique should be used to prepare and administer TECVAYLI. Any unused medicinal product or waste material should be disposed in accordance with local requirements.
  • Preparation of TECVAYLI • Verify the prescribed dose for each TECVAYLI injection. To minimise errors, use the following tables to prepare TECVAYLI injection.
  • Table 11 Injection volumes of TECVAYLI (90 mg/mL) for maintenance dose (1.5 mg/kg) • Remove the appropriate TECVAYLI vial from refrigerated storage (2 °C – 8 °C) and equilibrate to ambient temperature (15 °C – 30 °C), as needed, for at least 15 minutes. Do not warm TECVAYLI in any other way. • Once equilibrated, gently swirl the vial for approximately 10 seconds to mix. Do not shake. • Withdraw the required injection volume of TECVAYLI from the vial(s) into an appropriately sized syringe using a transfer needle. o Each injection volume should not exceed 2.0 mL. Divide doses requiring greater than 2.0 mL equally into multiple syringes. • TECVAYLI is compatible with stainless steel injection needles and polypropylene and polycarbonate syringe material. • Replace the transfer needle with an appropriately sized needle for injection.
  • TECVAYLI Visually inspect TECVAYLI for particulate matter and discolouration prior to administration. Do not use if the solution is discoloured, or cloudy, or if foreign particles are present. o TECVAYLI solution for injection is colourless to light yellow.
  • Administration of TECVAYLI • Inject the required volume of TECVAYLI into the subcutaneous tissue of the abdomen (preferred injection site). Alternatively, TECVAYLI may be injected into the subcutaneous tissue at other sites (e.g., thigh). If multiple injections are required, TECVAYLI injections should be at least 2 cm apart. • Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard or not intact. 7.
  • ANNEX II A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION
  • PSURs Periodic safety update reports
  • the requirements for submission of PSURs for this medicinal product are set out in Article 9 of Regulation (EC) No 507/2006 and, accordingly, the marketing authorisation holder (MAH) shall submit PSURs every 6 months.
  • the requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal.
  • the marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 months following authorisation. D.
  • RMP Risk management plan
  • the marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP.
  • An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.
  • the MAH shall ensure that in each Member State where TECVAYLI is marketed, all patients/carers who are expected to use teclistamab have access to/are provided with the Patient Card which will inform and explain to patients the risks of CRS.
  • the Patient Card also includes a warning message for healthcare professionals treating the patient that the patient is receiving teclistamab.
  • the Patient Card will contain the following key messages: • A description of the key signs and symptoms of CRS • A description of when to seek urgent attention from the healthcare provider or seek emergency help, should signs and symptoms of CRS present themselves • The prescribing physician’s contact details E.
  • A.. LABE ELLLLIINNGG 29 TECVAYLI 10 mg/mL solution for injection teclistamab One 3 mL vial contains 30 mg of teclistamab (10 mg/mL) 3.
  • METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For subcutaneous use only. Keep out of the sight and reach of children. Store in a refrigerator. Do not freeze.
  • TECVAYLI is and what it is used for 2. What you need to know before you are given TECVAYLI 3. How TECVAYLI is given 4. Possible side effects 5. How to store TECVAYLI 6. Contents of the pack and other information 1. What TECVAYLI is and what it is used for TECVAYLI is a cancer medicine that contains the active substance ‘teclistamab’ and is used to treat adults with a type of cancer of the bone marrow called multiple myeloma. It is used for patients who have had at least three other kinds of treatment that have not worked or have stopped working. How TECVAYLI works TECVAYLI is an antibody, a type of protein which has been designed to recognise and attach to specific targets in your body.
  • TECVAYLI targets B cell maturation antigen (BCMA), which is found on multiple myeloma cancer cells, and cluster of differentiation 3 (CD3), which is found on so-called T cells of your immune system.
  • BCMA B cell maturation antigen
  • CD3 cluster of differentiation 3
  • This medicine works by attaching to these cells and bringing them together, so that your immune system can destroy the multiple myeloma cancer cells. 2. What you need to know before you are given TECVAYLI You must not be given TECVAYLI if you are allergic to teclistamab, or any of the other ingredients of this medicine (listed in section 6). If you are not sure if you are allergic, talk to your doctor or nurse before you are given TECVAYLI.
  • Warnings and precautions Talk to your doctor or nurse before you are given TECVAYLI if you have had a stroke or seizure within the past 6 months.
  • TECVAYLI and vaccines Talk to your doctor or nurse before you are given TECVAYLI if you have had a recent vaccination or are going to have a vaccination.
  • Cytokine release syndrome is a serious immune reaction with symptoms such as fever, chills, nausea, headache, fast heartbeat, feeling dizzy, and difficulty breathing. • Effects on your nervous system. Symptoms include feeling confused, feeling less alert, or having difficulty writing. Some of these may be signs of a serious immune reaction called ‘immune effector cell-associated neurotoxicity syndrome’ (ICANS). • Signs and symptoms of an infection. Tell your doctor or nurse if you notice any signs of the above. Children and adolescents Do not give TECVAYLI to children or young people below 18 years of age, because it is not known how this medicine will affect them. Other medicines and TECVAYLI Tell your doctor or nurse if you are taking, have recently taken, or might take any other medicines.
  • ICANS immune effector cell-associated neurotoxicity syndrome
  • TECVAYLI affects an unborn baby or if it passes into breast milk.
  • Pregnancy-information for women Tell your doctor or nurse before you are given TECVAYLI if you are pregnant, think you might be pregnant or are planning to have a baby. If you become pregnant while being treated with this medicine, tell your doctor or nurse straight away.
  • Pregnancy-information for men If your partner becomes pregnant while you are taking this medicine, tell your doctor straight away.
  • Contraception information for men If your partner could become pregnant, you must use effective contraception during treatment and for 3 months after stopping treatment with TECVAYLI.
  • Breast-feeding You and your doctor will decide if the benefit of breast-feeding is greater than the risk to your baby. If you and your doctor decide to stop taking this medicine, you should not breast-feed for 5 months after stopping treatment.
  • TECVAYLI contains sodium TECVAYLI contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’. 3. How TECVAYLI is given How much is given Your doctor will determine your dose of TECVAYLI. The dose will depend on your body weight. The first two doses will be lower. TECVAYLI is given as follows: • You will receive 0.06 mg for each kilogram of bodyweight for your first dose.
  • TECVAYLI How the medicine is given TECVAYLI will be given to you by a doctor or nurse as an injection under your skin (‘subcutaneous’ injection). It is given in the stomach area (abdomen) or thigh.
  • Other medicines given during treatment with TECVAYLI You will be given medicines 1-3 hours before each of your first three doses of TECVAYLI, which help to lower the chance of side effects, such as cytokine release syndrome. These may include: • medicines to reduce the risk of an allergic reaction (antihistamines) • medicines to reduce the risk of inflammation (corticosteroids) • medicines to reduce the risk of fever (such as paracetamol) You may also be given these medicines for later doses of TECVAYLI based on any symptoms you have.
  • Some of the symptoms are: o feeling confused o feeling less alert o having difficulty writing Tell your doctor right away if you notice any of the above-listed serious side effects. Other side effects Other side effects are listed below. Tell your doctor or nurse if you get any of these side effects.
  • TECVAYLI contains •
  • the active substance is teclistamab.
  • TECVAYLI comes in two different strengths: o 10 mg/mL - one 3 mL vial contains 30 mg teclistamab o 90 mg/mL - one 1.7 mL vial contains 153 mg teclistamab •
  • the other ingredients are EDTA disodium salt dihydrate, glacial acetic acid, polysorbate 20, sodium acetate trihydrate, sucrose, water for injections (see “TECVAYLI contains sodium” in section 2).
  • TECVAYLI looks like and contents of the pack TECVAYLI is a solution for injection (injection) and is a colourless to light yellow liquid.
  • TECVAYLI is supplied as a carton pack containing 1 glass vial.
  • TECVAYLI should be administered via subcutaneous injection only. Do not administer TECVAYLI intravenously. TECVAYLI should be administered by a healthcare professional with adequately trained medical personnel and appropriate medical equipment to manage severe reactions, including cytokine release syndrome. TECVAYLI 10 mg/mL and TECVAYLI 90 mg/mL vials are for single use only. TECVAYLI vials of different strengths should not be combined to achieve maintenance dose. Aseptic technique should be used to prepare and administer TECVAYLI.
  • TECVAYLI Verify the prescribed dose for each TECVAYLI injection. To minimise errors, use the following tables to prepare TECVAYLI injection. o Use Table 1 to determine total dose, injection volume and number of vials required based on patient’s actual body weight for Step-up dose 1 using TECVAYLI 10 mg/mL vial. Table 1: Injection volumes of TECVAYLI (10 mg/mL) for Step-up dose 1 (0.06 mg/kg) o Use Table 2 to determine total dose, injection volume and number of vials required based on patient’s actual body weight for Step-up dose 2 using TECVAYLI 10 mg/mL vial.
  • Table 2 Injection volumes of TECVAYLI (10 mg/mL) for Step-up dose 2 (0.3 mg/kg) o Use Table 3 to determine total dose, injection volume and number of vials required based on patient’s actual body weight for the maintenance dose using TECVAYLI 90 mg/mL vial.
  • Table 3 Injection volumes of TECVAYLI (90 mg/mL) for maintenance dose (1.5 mg/kg) • Remove the appropriate strength TECVAYLI vial from refrigerated storage (2 °C–8 °C) and equilibrate to ambient temperature (15 °C – 30 °C), as needed, for at least 15 minutes. Do not warm TECVAYLI in any other way.
  • TECVAYLI is compatible with stainless steel needles, polypropylene and polycarbonate syringe material.
  • TECVAYLI Inject the required volume of TECVAYLI into the subcutaneous tissue of the abdomen (preferred injection site). Alternatively, TECVAYLI may be injected into the subcutaneous tissue of the thigh. If multiple injections are required, TECVAYLI injections should be at least 2 cm apart. • Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard or not intact. Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. EMBODIMENTS [0135] The following list of embodiments is intended to complement, rather than displace or supersede, the previous descriptions. Embodiment 1.
  • An approved product comprising: 10 mg/mL of teclistamab in solution for injection; or 90 mg/mL of teclistamab in solution for injection.
  • Embodiment 2. The approved product of embodiment 1, comprising 10 mg/mL of teclistamab in solution for injection.
  • Embodiment 3. The approved product of embodiment 1, comprising 90 mg/mL of teclistamab in solution for injection.
  • the approved product of any one of the previous embodiments wherein the approved product is formulated for delivery to a human in a dosing schedule comprising: a 0.06 mg/kg single dose administered as a first step-up dose on Day 1; a 0.3 mg/kg single dose administered as a second step-up dose 2 to 7 days after the first step-up dose; a 1.5 mg/kg single dose administered as a first maintenance dose 2 to 7 days after the second step-up dose; and a 1.5 mg/kg once weekly dose administered as a subsequent maintenance dose one week after the first maintenance dose, and weekly thereafter.
  • Embodiment 5 The approved product of embodiment 4, wherein the second step-up dose is administered on Day 3.
  • Embodiment 6. The approved produce of embodiment 4 or 5, wherein the first maintenance dose is administered on Day 5.
  • Embodiment 7. The approved product of any one of the previous embodiments, wherein the approved product is formulated for delivery to a human in a dosing schedule comprising: a 0.06 mg/kg single dose administered as a first step-up dose on Day 1; a 0.3 mg/kg single dose administered as a second step-up dose on Day 3; a 1.5 mg/kg single dose administered as a first maintenance dose on Day 5; and a 1.5 mg/kg once weekly dose administered as a subsequent maintenance dose one week after the first maintenance dose, and weekly thereafter.
  • Embodiment 9 The approved product of any one of the previous embodiments, wherein the approved product is a biosimilar.
  • Embodiment 9 The approved product of any one of the previous embodiments, in a 3 ml vial comprising 30 mg of teclistamab, EDTA disodium salt dihydrate, glacial acetic acid, polysorbate 20 (E432), sodium acetate trihydrate, sucrose, and water for injections.
  • Embodiment 13 The approved product of any one of embodiments 1-8, in a 1.7 ml vial comprising 153 mg of teclistamab, 0.031 mg EDTA disodium salt dihydrate, 0.41 mg glacial acetic acid, 0.68 mg polysorbate 20 (E432), 1.5 mg sodium acetate trihydrate, 140 mg sucrose, and water for injection.
  • Embodiment 13 The approved product of any of previous embodiments, in combination with a corticosteroid, an antihistamine, and an antipyretic.
  • Embodiment 14 The approved product of any of previous embodiments, in combination with a corticosteroid, an antihistamine, and an antipyretic.
  • Embodiment 15 The approved product of any one of embodiments 1-14, wherein, following administration, the median follow-up duration of response is 18.4 months.
  • Embodiment 16 A combination of a corticosteroid, an antihistamine, an antipyretic, and an approved product.
  • a pharmaceutical product comprising teclistamab in a solution for injection, wherein the pharmaceutical product is packaged, and wherein the package includes a label that identifies the pharmaceutical product as indicated as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrated disease progression on the last therapy.
  • Embodiment 20 A kit comprising the approved product of any one of embodiments 1- 15, the combination of any one of embodiments 16-18, or the pharmaceutical product of embodiment 19.
  • Embodiment 21 Embodiment 21.
  • a method for treating relapsed and refractory multiple myeloma in a patient comprising administering the approved product of any one of embodiments 1-15 or the combination of any one of embodiments 16-18 to the patient in an amount and manner that is described in a drug product label for the approved product.
  • Embodiment 22 The method of embodiment 21, further comprising, prior to the administering of the approved product, administering a corticosteroid, an antihistamine, and an antipyretic to the patient.
  • the method of embodiment 22, wherein the corticosteroid is dexamethasone, the antihistamine is diphenhydramine, and the antipyretic is acetaminophen.
  • Embodiment 24 wherein the corticosteroid is dexamethasone, the antihistamine is diphenhydramine, and the antipyretic is acetaminophen.
  • Embodiment 23 comprising administering 16 mg of oral or intravenous dexamethasone, 50 mg of oral or intravenous diphenhydramine, or equivalent, and 650 mg to 1000 mg oral or intravenous acetaminophen, or equivalent, prior to the administering of the approved product.
  • Embodiment 25 The method of any one of embodiments 22-24, wherein the corticosteroid, the antihistamine, and the antipyretic are administered to the patient prior to a step-up dose or a maintenance dose.
  • Embodiment 26 comprising administering 16 mg of oral or intravenous dexamethasone, 50 mg of oral or intravenous diphenhydramine, or equivalent, and 650 mg to 1000 mg oral or intravenous acetaminophen, or equivalent, prior to the administering of the approved product.
  • a method for treating relapsed and refractory multiple myeloma in a patient comprising administering a corticosteroid, an antihistamine, an antipyretic, and the approved product of any one of embodiments 1-15 to the patient in an amount and manner that is described in a drug product label for the approved product.
  • Embodiment 27. The method of embodiment 26, comprising administering 16 mg of oral or intravenous dexamethasone, 50 mg of oral or intravenous diphenhydramine, or equivalent, and 650 mg to 1000 mg oral or intravenous acetaminophen, or equivalent prior to administering the approved product.
  • Embodiment 28 comprising administering 16 mg of oral or intravenous dexamethasone, 50 mg of oral or intravenous diphenhydramine, or equivalent, and 650 mg to 1000 mg oral or intravenous acetaminophen, or equivalent prior to administering the approved product.
  • a method of selling an approved product comprising selling such approved product, wherein an approved product label for a reference product for such approved product includes instructions for treating adult patients with relapsed and refractory multiple myeloma after three or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
  • Embodiment 29 A method of offering for sale an approved product, said method comprising offering for sale such approved product, wherein an approved product label for a reference product for such approved product includes instructions for treating adult patients with relapsed and refractory multiple myeloma after three or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti- CD38 monoclonal antibody.
  • Embodiment 30 An approved drug product with at least one approved indication, wherein said approved drug product comprises teclistamab.
  • Embodiment 31 A drug product comprising teclistamab, wherein the drug product is approved for treating relapsed and refractory multiple myeloma.
  • Embodiment 32 An approved drug product comprising teclistamab, wherein such approved drug product improves anti-cancer cell activity as measured by overall response rate, duration of response, time to first response, minimal residual disease negativity, or overall survival relative to a patient with multiple myeloma who is not receiving treatment with a bispecific antibody.
  • Embodiment 33 Embodiment 33.

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Abstract

L'invention concerne des produits approuvés et des méthodes d'utilisation de produits approuvés pour traiter un myélome multiple récidivant et réfractaire chez un patient. L'invention concerne également des procédés de vente ou d'offre pour la vente d'un produit approuvé.
PCT/US2023/072584 2022-08-23 2023-08-21 Teclistamab pour le traitement du myélome multiple Ceased WO2024044548A1 (fr)

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