Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
• • 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
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/75—Agonist effect on antigen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
  • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

• T1D type 1 diabetes
• BACKGROUND [0004] Type 1 diabetes (T1D) is caused by the autoimmune destruction of insulin producing beta cells in the islets of Langerhans leading to dependence on exogeneous insulin injections for survival. Approximately 1.6 million Americans have Type 1 diabetes, and after asthma, it remains one of the most common diseases of childhood. Despite improvements in care, most affected individuals with T1D are not able to consistently achieve desired glycemic targets. For individuals with type 1 diabetes, there are persisting concerns for increased risk of both morbidity and mortality.
• T1D clinical type 1 diabetes
• Some aspects relate to teplizumab for use in a method of treating clinical type 1 diabetes (T1D), comprising administering to a subject in need thereof a 12-day course of the teplizumab at a total dose of more than about 9000 ⁇ g/m 2 .
• the total dose is between about 9000 and about 9500 ⁇ g/m 2 .
• the total dose is between about 9000 and about 14000 ⁇ g/m 2 .
• a method of treating type 1 diabetes comprising administering to a subject in need thereof a 12-day course of teplizumab at a total dose of from about 9000 to about 9500 ⁇ g/m 2 .
• a method of treating type 1 diabetes is provided comprising administering to a subject in need thereof a 12-day course of teplizumab at a total dose of from about 9000 to about 14000 ⁇ g/m 2 .
• the 12-day course comprises a first dose of 106 ⁇ g/m 2 teplizumab on day 1, a second dose of 425 ⁇ g/m 2 teplizumab on day 2, and one dose of 850 ⁇ g/m 2 on each of days 3–12, and wherein the total dose is approximately 9031 ⁇ g/m 2 .
• the 12-day course comprises a first dose of 211 ⁇ g/m 2 teplizumab on day 1, a second dose of 423 ⁇ g/m 2 teplizumab on day 2, and one dose of 840 ⁇ g/m 2 on each of days 3–12, and wherein the total dose is approximately 9034 ⁇ g/m 2 .
• the method can include administering a first and a second 12-day courses of teplizumab.
• the first and the second 12-day courses are administered at about 1-6 months, about 2-5 months or about 3 months interval.
• the method can include administering to the subject in need thereof a third or more 12-day course of teplizumab, each course at a total dose of more than about 9000 ⁇ g/m 2 .
• the third or more 12-day course of teplizumab comprises a first dose of 106 ⁇ g/m 2 teplizumab on day 1, a second dose of 425 ⁇ g/m 2 teplizumab on day 2, and one dose of 850 ⁇ g/m 2 on each of days 3–12, and wherein the total dose of each course is approximately 9031 ⁇ g/m 2 .
• the third or more 12-day course of teplizumab comprises a first dose of 211 ⁇ g/m 2 teplizumab on day 1, a second dose of 423 ⁇ g/m 2 teplizumab on day 2, and one dose of 840 ⁇ g/m 2 on each of days 3–12, and wherein the total dose of each course is approximately 9034 ⁇ g/m 2 .
• the third or more 12-day course of teplizumab is administered at about a 12 month to about a 24-month interval.
• the method can further include determining, after the administration of each 12-day course, a baseline of a level of TIGIT+KLRG1+CD8+ cells with respect to all CD3+ T cells, monitoring the level of the TIGIT+KLRG1+CD8+CD3+ T-cells and administering an additional 12-day course of teplizumab when the level of the TIGIT+KLRG1+CD8+CD3+ T-cells returns to the baseline level.
• the determining of TIGIT+KLRG1+CD8+CD3+ T-cells is by flow cytometry.
• the monitoring of TIGIT+KLRG1+CD8+CD3+ T-cells is by flow cytometry.
• the determining of TIGIT+KLRG1+CD8+CD3+ T-cells is about 1-6 months, about 2-5 months, or about 3 months after the administration of each 12-day course.
• subsequent monitoring is annual.
• subsequent monitoring is every about 3-6 months.
• the subject in need thereof has been diagnosed with T1D within 6 weeks prior to the administrating step.
• the administrating step results in reduction by at least 10% of insulin use, HbA1c levels, hypoglycemic episodes, or combinations thereof as compared to pre- treatment levels.
• each dose is administered parenterally.
• each dose is administered by intravenous infusion.
• the subject in need thereof is about 8 to 17 years old.
• the subject in need thereof have a peak C-peptide level of ⁇ 0.2 pmol/mL during a mixed meal tolerance test (MMTT).
• the subject receiving teplizumab has a higher mean C-peptide value compared with a control receiving placebo.
• the method further includes assessing the area under the time- concentration curve (AUC) of C-peptide following a mixed meal tolerance test (MMTT), at 78 weeks.
• AUC area under the time- concentration curve
• MMTT mixed meal tolerance test
• the subject in need thereof has at least 20% of beta-cell function prior the administration of the first dose.
• the reduction of insulin use, HbA1c levels, hypoglycemic episodes, or combinations thereof is over a period of 12 months or more.
• Figure 25 shows a diagram of the study design according to one embodiment.
• Figure 26 Predicted Mean Difference Between Teplizumab and Control in the Change from Baseline in C-Peptide AUC (nmol/L) at 1 Year follow-up in Supportive Study Meta- Analysis.
• Figure 27 Predicted Mean Difference Between Teplizumab and Control in the Change from Baseline in C-peptide AUC (nmol/L) at 2 Year follow-up in Supportive Study Meta- Analysis.
• Figure 28 TN-10: C-Peptide AUCs (nmol/L) in Patients with T1D.
• Figures 29a-29e Average Insulin Use at Each Visit for Protégé regimen (Figure 29a), Encore regimen (Figure 29b), Study 1 regimen (Figure 29c), AbATE regimen (Figure 29d) and Delay regimen (Figure 29e) .
• Figure 30 Predicted Mean Teplizumab Serum Concentration Versus Time Profile Following 14-Day Regimen Across Different Body Weights.
• Figure 31 Plot Emax model: precited C-peptide change vs AUC, Year 2.
• Type 1 diabetes usually develops in childhood and adolescence; however, it can also present in adulthood as late as the 5th and 6th decades of life, although much less frequently (Atkinson 2014, Bluestone 2010, Streisand 2014).
• T1D type 1 diabetes
• the method comprises diagnosing patients 8 to 17 years of age with T1D, administering to the patients within 6 weeks of diagnosis a first course of daily doses of teplizumab for 12 days, and a second course of daily doses of teplizumab for 12 days, wherein the first and second courses are separated with a 6-month interval.
• the method further comprises assessing the area under the time-concentration curve (AUC) of C-peptide following a mixed meal tolerance test (MMTT), at 78 weeks (18 months or 1.5 years), and/or evaluating clinical endpoints such insulin use, HbA1c levels, and hypoglycemic episodes.
• AUC time-concentration curve
• the articles “a” and “an” refer to one or more than one, e.g., to at least one, of the grammatical object of the article.
• the use of the words “a” or “an” when used in conjunction with the term “comprising” herein may mean “one,” but it is also consistent with the meaning of "one or more,” “at least one,” and “one or more than one.”
• “about” and “approximately” generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given range of values.
• substantially means more than 50%, preferably more than 80%, and most preferably more than 90% or 95%.
• the term “comprising” or “comprises” is used in reference to compositions, methods, and respective component(s) thereof, that are present in a given embodiment, yet open to the inclusion of unspecified elements.
• the term “consisting essentially of” refers to those elements required for a given embodiment. The term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment of the disclosure.
• the term “consisting of” refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment.
• the term “antibody” herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.
• An “antibody fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds.
• antibody fragments include but are not limited to Fv, Fab, Fab', Fab'-SH, F(ab') 2 ; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); and multispecific antibodies formed from antibody fragments.
• onset of disease with reference to Type-1 diabetes refers to a patient meeting the criteria established for diagnosis of Type-1 diabetes by the American Diabetes Association (see, Mayfield et al., 2006, Am. Fam. Physician 58:1355-1362).
• a "protocol” includes dosing schedules and dosing regimens. The protocols herein are methods of use and include therapeutic protocols.
• a “dosing regimen”, “dosage regimen” or “course of treatment” may include administration of several doses of a therapeutic agent over 1 to 20 days.
• the terms “subject” and “patient” are used interchangeably.
• the terms “subject” and “subjects” refer to an animal, preferably a mammal including a non-primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey or a human), and more preferably a human.
• the patient population comprises children.
• the patient population comprises children newly diagnosed with T1D.
• the patient population is treated within 6 weeks of the T1D diagnosis.
• the patient population comprises children who are positive for at least one T1D-associated autoantibody and have a peak stimulated C-peptide of ⁇ 0.2 pmol/mL at screening.
• children includes those being around 8 to 17 years of age.
• effective amount refers to that amount of teplizumab sufficient to result in the delay or prevention of the development, recurrence or onset of one or more symptoms of T1D.
• the terms “treat”, “treatment” and “treating” refer to the amelioration of one or more symptoms associated with T1D that results from the administration of one or more CD3 binding molecules. In some embodiments, such terms refer to a reduction in a human's average number of hypoglycemic episodes. In other embodiments, such terms refer to the maintenance of a reference level of C-peptide in the peripheral blood.
• the effective amount reduces one or more T1D symptoms by at least 5%, by at least 10%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, by at least 50%, by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, by at least 80%, by at least 85%, by at least 90%, by at least 95%.
• Various aspects of the disclosure are described in further detail below. Additional definitions are set out throughout the specification.
• anti-CD3 antibody and “an antibody that binds to CD3” refer to an antibody or antibody fragment that is capable of binding cluster of differentiation 3 (CD3) with sufficient affinity such that the antibody is useful as a prophylactic, diagnostic and/or therapeutic agent in targeting CD3.
• the extent of binding of an anti-CD3 antibody to an unrelated, non-CD3 protein is less than about 10% of the binding of the antibody to CD3 as measured, e.g., by a radioimmunoassay (RIA).
• RIA radioimmunoassay
• an antibody that binds to CD3 has a dissociation constant (Kd) of ⁇ 1 ⁇ , ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM (e.g. 10 -8 M or less, e.g. from 10 -8 M to 10 -13 M, e.g., from 10 -9 M to 10 -13 M).
• an anti-CD3 antibody binds to an epitope of CD3 that is conserved among CD3 from different species.
• the anti-CD3 antibody can be ChAglyCD3 (otelixizumab).
• Otelixizumab is a humanized Fc nonbinding anti-CD3, which was evaluated initially in phase 2 studies by the Belgian Diabetes Registry (BDR) and then developed by Tolerx, which then partnered with GSK to conduct the phase 3 DEFEND new onset T1D trials (NCT00678886, NCT01123083, NCT00763451). Otelixizumab is administered IV with infusions over 8 days. See, e.g., Wiczling et al., J. Clin. Pharmacol.
• the anti-CD3 antibody can be visilizumab (also called HuM291; Nuvion).
• Visilizumab is a humanized anti-CD3 monoclonal antibody characterized by a mutated IgG2 isotype, lack of binding to Fc ⁇ receptors, and the ability to induce apoptosis selectively in activated T cells. It was evaluated in patients in graft-versus-host disease (NCT00720629; NCT00032279) and in ulcerative colitis (NCT00267306) and Crohn’s Disease (NCT00267709). See, e.g., Sandborn et al., Gut 59 (11) (Nov 2010) 1485–1492, incorporated herein by reference.
• the anti-CD3 antibody can be teplizumab.
• Teplizumab also known as hOKT3yl(Ala-Ala) (containing an alanine at positions 234 and 235) is an anti-CD3 antibody that had been engineered to alter the function of the T lymphocytes that mediate the destruction of the insulin-producing beta cells of the islets of the pancreas.
• Teplizumab binds to an epitope of the CD3 ⁇ chain expressed on mature T cells and by doing so changes their function.
• Circulating T cells are transiently reduced following teplizumab treatment, in a process that may include margination and depletion (Long 2017, Sherry 2011).
• teplizumab appears to both increase the number and function of regulatory T cells (Tregs) (Ablamunits 2010, Bisikirska 2005, Long 2017, Waldron-Lynch 2012). More recent studies indicate that teplizumab induces immunologic “exhaustion” in a subset of effector CD8+ T cells, perhaps making them more susceptible to regulation or deletion (Long 2016, Long 2017).
• teplizumab not only exerts a “suppressive” effect on ⁇ cell immune destructive processes but rather is an immune “modulator” favoring a rebalancing of effector and regulatory arms involved with T1D autoimmunity and supporting the notion that teplizumab may have the ability to contribute to the re-introduction of ⁇ cell self-tolerance (Lebastchi 2013).
• Sequences and compositions of teplizumab are disclosed in U.S. Patent Nos.6,491,916; 8,663,634; and 9,056,906, each incorporated herein by reference in its entirety.
• the molecular weight of teplizumab is approximately 150 KD.
• Teplizumab Light Chain (SEQ ID NO: 1): DIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLASGVP SRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLQITRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Teplizumab Heavy Chain (SEQ ID NO: 2): QVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKGLEWIGYINPSRG YTNYNQKVKDRFTISRDNSKNTAFLQMDSLRPEDTGVYFCARYYDDHYCLDYWGQ GTP
• compositions comprise an effective amount of an anti-CD3 antibody, and a pharmaceutically acceptable carrier.
• 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 animals, and more particularly in humans.
• carrier refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered.
• Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
• Water is a preferred carrier when the pharmaceutical composition is administered intravenously.
• Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
• Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like (See, for example, Handbook of Pharmaceutical Excipients, Arthur H. Kibbe (ed., 2000, which is incorporated by reference herein in its entirety), Am. Pharmaceutical Association, Washington, D.C.
• compositions can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
• These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained release formulations and the like.
• Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin.
• Such compositions contain a therapeutically effective amount of a therapeutic agent preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
• the formulation should suit the mode of administration.
• the pharmaceutical compositions are sterile and in suitable form for administration to a subject, preferably an animal subject, more preferably a mammalian subject, and most preferably a human subject.
• a subject preferably an animal subject, more preferably a mammalian subject, and most preferably a human subject.
• care must be taken to use materials to which the anti-CD3 antibody does not absorb.
• the composition can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353- 365 (1989); Lopez-Berestein, ibid., pp.317-327; see generally ibid.).
• the composition can be delivered in a controlled release or sustained release system.
• a pump may be used to achieve controlled or sustained release (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed.
• polymeric materials can be used to achieve controlled or sustained release of the antibodies of the disclosure or fragments thereof (see e.g., Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J., Macromol. Sci. Rev. Macromol. Chem.
• polymers used in sustained release formulations include, but are not limited to, poly(2-hydroxy ethyl methacrylate), poly(methyl methacrylate), poly(acrylic acid), poly(ethylene-co-vinyl acetate), poly(methacrylic acid), polyglycolides (PLG), polyanhydrides, poly(N-vinyl pyrrolidone), poly(vinyl alcohol), polyacrylamide, poly(ethylene glycol), polylactides (PLA), poly(lactide-co-glycolides) (PLGA), and polyorthoesters.
• the polymer used in a sustained release formulation is inert, free of leachable impurities, stable on storage, sterile, and biodegradable.
• a controlled or sustained release system can be placed in proximity of the therapeutic target, i.e., the lungs, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol.2, pp.115-138 (1984)).
• Controlled release systems are discussed in the review by Langer (1990, Science 249:1527-1533). Any technique known to one of skill in the art can be used to produce sustained release formulations comprising one or more antibodies of the disclosure or fragments thereof. See, e.g., U.S. Pat. No. 4,526,938; PCT Publication No. WO 91/05548; PCT Publication No.
• a pharmaceutical composition can be formulated to be compatible with its intended route of administration.
• routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, oral, intranasal (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.
• the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to human beings.
• a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings.
• compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
• compositions may also include a solubilizing agent and a local anesthetic such as lignocamne to ease pain at the site of the injection.
• a solubilizing agent such as lignocamne to ease pain at the site of the injection.
• the compositions may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
• the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
• the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
• a suitable vehicle e.g., sterile pyrogen-free water
• the disclosure provides dosage forms that permit administration of the anti-CD3 antibody continuously over a period of hours or days (e.g., associated with a pump or other device for such delivery), for example, over a period of 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours, 30 hours, 36 hours, 4 days, 5 days, 7 days, 10 days or 12 days.
• the disclosure provides dosage forms that permit administration of a continuously increasing dose, for example, increasing from 106 ug/m 2 /day to 850 ug/m 2 /day or 211 ug/m 2 /day to 840 ug/m 2 /day over a period of 24 hours, 30 hours, 36 hours, 4 days, 5 days, 7 days, 10 days or 12 days.
• the compositions can be formulated as neutral or salt forms.
• compositions disclosed herein are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
• composition is to be administered by infusion
• it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
• an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
• the disclosure provides that the anti-CD3 antibodies, or pharmaceutical compositions thereof, can be packaged in a hermetically sealed container such as an ampoule or sachette indicating the quantity of the agent.
• the anti-CD3 antibody, or pharmaceutical compositions thereof is supplied as a dry sterilized lyophilized powder or water free concentrate in a hermetically sealed container and can be reconstituted, e.g., with water or saline to the appropriate concentration for administration to a subject.
• the anti-CD3 antibody, or pharmaceutical compositions thereof is supplied as a dry sterile lyophilized powder in a hermetically sealed container at a unit dosage of at least 5 mg, more preferably at least 10 mg, at least 15 mg, at least 25 mg, at least 35 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg.
• the lyophilized agents, or pharmaceutical compositions herein should be stored at between 2 oC and 8 oC in its original container and the therapeutic agents, or pharmaceutical compositions of the disclosure should be administered within 1 week, preferably within 5 days, within 72 hours, within 48 hours, within 24 hours, within 12 hours, within 6 hours, within 5 hours, within 3 hours, or within 1 hour after being reconstituted.
• the pharmaceutical composition is supplied in liquid form in a hermetically sealed container indicating the quantity and concentration of the agent.
• the liquid form of the administered composition is supplied in a hermetically sealed container at least 0.25 mg/ml, more preferably at least 0.5 mg/ml, at least 1 mg/ml, at least 2.5 mg/ml, at least 5 mg/ml, at least 8 mg/ml, at least 10 mg/ml, at least 15 mg/ml, at least 25 mg/ml, at least 50 mg/ml, at least 75 mg/ml or at least 100 mg/ml.
• the liquid form should be stored at between 2 oC and 8 oC in its original container.
• the disclosure provides that the composition of the disclosure is packaged in a hermetically sealed container such as an ampoule or sachette indicating the quantity of the anti-CD3 antibody.
• the compositions may, if desired, be presented in a pack or dispenser device that may contain one or more unit dosage forms containing the active ingredient.
• the pack may, for example, comprise metal or plastic foil, such as a blister pack.
• the amount of the composition of the disclosure which is effective in the treatment of one or more symptoms associated with T1D can be determined by standard clinical techniques. The precise dose to be employed in the formulation can also depend on the route of administration and the seriousness of the condition, and should be decided according to the judgment of the practitioner and each patient's circumstances.
• Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
• Methods and Use encompasses administration of anti-human CD3 antibodies such as teplizumab to patients 8 through 17 years old 6 weeks from T1D diagnosis having a peak C-peptide level of ⁇ 0.2 pmol/mL during a mixed meal tolerance test (MMTT).
• MMTT mixed meal tolerance test
• the peak C-peptide level at screening rages from 0.2 pmol/mL (inclusive) to 0.7 pmol/mL (inclusive).
• T1D diagnosis is according to the American Diabetes Association (ADA) criteria.
• the test should be performed in a laboratory using a method that is National Glycohemoglobin Standardization Program (NGSP) certified and standardized to the Diabetes Control and Complications Trial (DCCT) assay.
• NGSP National Glycohemoglobin Standardization Program
• DCCT Diabetes Control and Complications Trial
• ADA a patient with classic symptoms, measurement of plasma glucose is sufficient to diagnose clinical diabetes (symptoms of hyperglycemia or hyperglycemic crisis plus a random plasma glucose ⁇ 200 mg/dL [11.1 mmol/L]). In these cases, knowing the plasma glucose level is critical because, in addition to confirming that symptoms are due to diabetes, it will inform management decisions. Some providers may also want to know the HbA1C to determine how long a patient has had hyperglycemia. In addition, T1D, previously called “insulin-dependent diabetes” or "juvenile-onset diabetes,” accounts for 5-10% of diabetes and is due to cellular-mediated autoimmune destruction of the pancreatic ⁇ -cells.
• Autoimmune markers include islet cell autoantibodies and autoantibodies to GAD (GAD65), insulin, the tyrosine phosphatases IA-2 and IA-2 ⁇ , and ZnT8.
• T1D is defined by the presence of one or more of these autoimmune markers.
• CGM continuous glucose monitoring system
• the patient diagnosed with clinical T1D has a positive result on testing for at least one of the following T1D-related autoantibodies: Glutamic acid decarboxylase 65 (GAD65) autoantibodies, Islet antigen 2 (IA-2) autoantibodies, Zinc transporter 8 (ZnT8) autoantibodies Islet cell cytoplasmic autoantibodies (ICA) or Insulin autoantibodies (if testing obtained within the first 14 days of insulin treatment).
• Glutamic acid decarboxylase 65 Glutamic acid decarboxylase 65 (GAD65) autoantibodies, Islet antigen 2 (IA-2) autoantibodies, Zinc transporter 8 (ZnT8) autoantibodies Islet cell cytoplasmic autoantibodies (ICA) or Insulin autoantibodies (if testing obtained within the first 14 days of insulin treatment).
• Glutamic acid decarboxylase 65 Glutamic acid decarboxylase 65 (GAD65) autoantibodies
• Islet antigen 2 IA-2
• ⁇ cells continue to be lost following T1D diagnosis.
• the patients to be treated are within 6 weeks from T1D diagnosis and have a peak C-peptide level of ⁇ 0.2 pmol/mL during a mixed meal tolerance test (MMTT).
• MMTT mixed meal tolerance test
• ⁇ -cell function prior to, during, and after therapy may be assessed by methods described herein or by any method known to one of ordinary skill in the art.
• DCCT Diabetes Control and Complications Trial
• HA1 and HA1c percentage glycosylated hemoglobin
• characterization of daily insulin needs, C-peptide levels/response, hypoglycemic episodes, and/or FPIR may be used as markers of ⁇ -cell function or to establish a therapeutic index (See Keymeulen et al., 2005, N. Engl. J.
• FPIR is calculated as the sum of insulin values at 1 and 3 minutes post IGTT, which are performed according to Islet Cell Antibody Register User's Study protocols (see, e.g., Bingley et al., 1996, Diabetes 45:1720-1728 and McCulloch et al., 1993, Diabetes Care 16:911-915).
• the effective amount comprises a 12-day course of subcutaneous intravenous (IV) infusion of the anti-CD3 antibody such as teplizumab at 106-850 micrograms/meter squared ( ⁇ g/m 2 ).
• IV subcutaneous intravenous
• the total dosage over the duration of the regimen is about 14000 ug/m 2 , 13500 ug/m 2 , 13000 ug/m 2 , 12500 ug/m 2 , 12000 ug/m 2 , 11500 ug/m 2 , 11000 ug/m 2 , 10500 ug/m 2 , 10000 ug/m 2 , 9500 ug/m 2 , 9000 ug/m 2 , 8000 ug/m 2 , 7000 ug/m 2 , 6000 ug/m 2 , and may be less than 5000 ug/m 2 , 4000 ug/m 2 , 3000 ug/m 2 , 2000 ug/m 2 , or 1000 ug/m 2 .
• the total dosage over the duration of the regimen is from about 9030 ⁇ g/m 2 to about 14000 ⁇ g/m 2 , about 9030 ⁇ g/m 2 to about 13500 ⁇ g/m 2 , about 9000 ⁇ g/m 2 to about 13000 ⁇ g/m 2 , about 9000 ⁇ g/m 2 to about 12500 ⁇ g/m 2 , about 9000 ⁇ g/m 2 to about 12000 ⁇ g/m 2 , about 9000 ⁇ g/m 2 to about 11500 ⁇ g/m 2 , about 9000 ⁇ g/m 2 to about 11000 ⁇ g/m 2 , about 9000 ⁇ g/m 2 to about 10500 ⁇ g/m 2 , about 9000 ⁇ g/m 2 to about 10000 ⁇ g/m 2 , about 9000 ⁇ g/m 2 to about 9500 ⁇ g/m 2 .
• the total dosage over the duration of the regimen is from about 9030 ⁇ g/m 2 to about 14000 ⁇ g/m 2 , about 9030 ⁇ g/m 2 to about 13500 ⁇ g/m 2 , about 9030 ⁇ g/m 2 to about 13000 ⁇ g/m 2 , about 9030 ⁇ g/m 2 to about 12500 ⁇ g/m 2 , about 9030 ⁇ g/m 2 to about 12000 ⁇ g/m 2 , about 9030 ⁇ g/m 2 to about 11500 ⁇ g/m 2 , from about 9030 ⁇ g/m 2 to about 11000 ⁇ g/m 2 , about 9030 ⁇ g/m 2 to about 10500 ⁇ g/m 2 , about 9030 ⁇ g/m 2 to about 10000 ⁇ g/m 2 , about 9030 ⁇ g/m 2 to about 9500 ⁇ g/m 2 .
• the effective amount comprises a 12-day course IV infusion of teplizumab at a first dose of 106 ⁇ g/m 2 teplizumab on day 1, a second dose of 425 ⁇ g/m 2 teplizumab on day 2, and one dose of 850 ⁇ g/m 2 on each of days 3–12.
• the effective amount comprises a 12-day course IV infusion of teplizumab at a first dose of 211 ⁇ g/m 2 teplizumab on day 1, a second dose of 423 ⁇ g/m 2 teplizumab on day 2, and one dose of 840 ⁇ g/m 2 on each of days 3–12.
• the effective amount comprises a 12- day course IV infusion of teplizumab at a first dose of approximately 100 ⁇ g/m 2 teplizumab on day 1, a second dose of approximately 400 ⁇ g/m 2 teplizumab on day 2, a third dose of approximately 850 ⁇ g/m 2 on day 3, and approximately 1,200 ⁇ g/m 2 on each of days 4–12.
• the effective amount comprises a 12-day course IV infusion of teplizumab at a first dose of approximately 100 ⁇ g/m 2 teplizumab on day 1, a second dose of approximately 400 ⁇ g/m 2 teplizumab on day 2, a third dose of approximately 850 ⁇ g/m 2 on day 3, and approximately 1,300 ⁇ g/m 2 on each of days 4–12.
• the effective amount comprises a 12-day course IV infusion of teplizumab at a first dose of approximately 100 ⁇ g/m 2 teplizumab on day 1, a second dose of approximately 400 ⁇ g/m 2 teplizumab on day 2, a third dose of approximately 850 ⁇ g/m 2 on day 3, and approximately 1,400 ⁇ g/m 2 on each of days 4– 12.
• the effective amount comprises a 12-day course IV infusion of teplizumab at a first dose of approximately 200 ⁇ g/m 2 teplizumab on day 1, a second dose of approximately 400 ⁇ g/m 2 teplizumab on day 2, a third dose of approximately 850 ⁇ g/m 2 on day 3, and approximately 1,200 ⁇ g/m 2 on each of days 4–12.
• the effective amount comprises a 12-day course IV infusion of teplizumab at a first dose of approximately 200 ⁇ g/m 2 teplizumab on day 1, a second dose of approximately 400 ⁇ g/m 2 teplizumab on day 2, a third dose of approximately 850 ⁇ g/m 2 on day 3, and approximately 1,300 ⁇ g/m 2 on each of days 4–12.
• the effective amount comprises a 12-day course IV infusion of teplizumab at a first dose of approximately 200 ⁇ g/m 2 teplizumab on day 1, a second dose of approximately 400 ⁇ g/m 2 teplizumab on day 2, a third dose of approximately 850 ⁇ g/m 2 on day 3, and approximately 1,400 ⁇ g/m 2 on each of days 4–12.
• a dosing regimen comprising two or more courses of dosing with an anti-CD3 antibody such as teplizumab comprising a first course of dosing at week 1 and second course of dosing at week 26.
• teplizumab is administered via IV infusion in two courses, with the first course starting on Day 1 (Week 1) and the second course on approximately Day 182 (Week 26), each course of treatment including daily infusions for 12 days, with a cumulative teplizumab dose of 9000 ug/m 2 for each course of treatment.
• teplizumab is administered via IV infusion in two courses, with the first course starting on Day 1 (Week 1) and the second course on approximately Day 182 (Week 26), each course of treatment including daily infusions for 12 days, with a cumulative teplizumab dose of 9500 ug/m 2 for each course of treatment.
• teplizumab is administered via IV infusion in two courses, with the first course starting on Day 1 (Week 1) and the second course on approximately Day 182 (Week 26), each course of treatment including daily infusions for 12 days, with a cumulative teplizumab dose of 10000 ug/m 2 for each course of treatment.
• teplizumab is administered via IV infusion in two courses, with the first course starting on Day 1 (Week 1) and the second course on approximately Day 182 (Week 26), each course of treatment including daily infusions for 12 days, with a cumulative teplizumab dose of 10500 ug/m 2 for each course of treatment.
• teplizumab is administered via IV infusion in two courses, with the first course starting on Day 1 (Week 1) and the second course on approximately Day 182 (Week 26), each course of treatment including daily infusions for 12 days, with a cumulative teplizumab dose of 11000 ug/m 2 for each course.
• teplizumab is administered via IV infusion in two courses, with the first course starting on Day 1 (Week 1) and the second course on approximately Day 182 (Week 26), each course of treatment including daily infusions for 12 days, with a cumulative teplizumab dose of 11500 ug/m 2 for each course of treatment. of treatment.
• teplizumab is administered via IV infusion in two courses, with the first course starting on Day 1 (Week 1) and the second course on approximately Day 182 (Week 26), each course of treatment including daily infusions for 12 days, with a cumulative teplizumab dose of 12000 ug/m 2 for each course of treatment.
• teplizumab is administered via IV infusion in two courses, with the first course starting on Day 1 (Week 1) and the second course on approximately Day 182 (Week 26), each course of treatment including daily infusions for 12 days, with a cumulative teplizumab dose of 12500 ug/m 2 for each course of treatment.
• teplizumab is administered via IV infusion in two courses, with the first course starting on Day 1 (Week 1) and the second course on approximately Day 182 (Week 26), each course of treatment including daily infusions for 12 days, with a cumulative teplizumab dose of 13000 ug/m 2 for each course of treatment.
• teplizumab is administered via IV infusion in two courses, with the first course starting on Day 1 (Week 1) and the second course on approximately Day 182 (Week 26), each course of treatment including daily infusions for 12 days, with a cumulative teplizumab dose of 13500 ug/m 2 for each course of treatment.
• teplizumab is administered via IV infusion in two courses, with the first course starting on Day 1 (Week 1) and the second course on approximately Day 182 (Week 26), each course of treatment including daily infusions for 12 days, with a cumulative teplizumab dose of 14000 ug/m 2 for each course of treatment.
• the 12 days course has a 2-day ramp-up phase and a 10-day fixed-, maximal dosing period.
• 106 ⁇ g/m 2 teplizumab is administered on day 1
• 425 ⁇ g/m 2 teplizumab teplizumab is administered on day 2
• 850 ⁇ g/m 2 teplizumab is administered on each of days 3–12 [00116]
• the course of dosing can be repeated at 2 month, 4 month, 5 month, 6 month, 8 month, 9 month, 10 month, 12 month, 15 month, 18 month, 24 month, 30 month, or 36 month intervals.
• efficacy of the treatment with the anti-CD3 antibody such as teplizumab is determined as described herein, or as is known in the art, at 2 months, 4 months, 5 month, 6 months, 9 months, 12 months, 15 months, 18 months, 24 months, 30 months, or 36 months subsequent to the previous treatment.
• a subject is administered one or more doses, preferably 12 daily doses, of the anti-CD3 antibody such as teplizumab at about 5-1200 ug/m 2 , preferably, 106-850 ug/m 2 to treat, or slow the progression of or ameliorate one or more symptoms of T1D.
• the subject is administered a treatment regimen comprising two courses of daily doses of an effective amount of the anti-CD3 antibody such as teplizumab, wherein the course of treatment is administered over 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days or 12 days.
• the treatment regimen comprises administering doses of the effective amount every day, every 2nd day, every 3rd day or every 4th day.
• a subject is administered a treatment regimen comprising one or more doses of a prophylactically effective amount of the anti-CD3 antibody such as teplizumab, wherein the prophylactically effective amount is 200 ug/kg/day, 175 ug/kg/day, 150 ug/kg/day, 125 ug/kg/day, 100 ug/kg/day, 95 ug/kg/day, 90 ug/kg/day, 85 ug/kg/day, 80 ug/kg/day, 75 ug/kg/day, 70 ug/kg/day, 65 ug/kg/day, 60 ug/kg/day, 55 ug/kg/day, 50 ug/kg/day, 45 ug/kg/day, 40 ug/kg/day, 35 ug/kg/day, 30 ug/kg/day, 26 ug/kg/day, 25 ug/kg/day, 20 u
• the total dosage over the duration of the regimen is preferably a total of less than about 14000 ug/m 2 , 13500 ug/m 2 , 13000 ug/m 2 , 12500 ug/m 2 , 12000 ug/m 2 , 11500 ug/m 2 , 11000 ug/m 2 , 10500 ug/m 2 , 10000 ug/m 2 , 9500 ug/m 2 , 9000 ug/m 2 , 8000 ug/m 2 , 7000 ug/m 2 , 6000 ug/m 2 , and may be less than 5000 ug/m 2 , 4000 ug/m 2 , 3000 ug/m 2 , 2000 ug/m 2 , or 1000 ug/m 2 .
• the daily dosage administered in the regimen is from about 100 ug/m 2 to about 200 ug/m 2 , about 100 ug/m 2 to about 500 ug/m 2 , about 100 ug/m 2 to about 1000 ug/m 2 , or about 500 ug/m 2 to about 1000 ug/m 2 .
• the dose escalates over the first three, first 1/4 of the doses (e.g., over the first 3 days of a 12-day regimen of one dose per day) of the treatment regimen until the daily effective amount of the anti-CD3 antibody such as teplizumab is achieved.
• a subject is administered a treatment regimen comprising one or more doses of an effective amount of the anti-CD3 antibody such as teplizumab, wherein the effective amount is increased by, e.g., 0.01 ug/kg, 0.02 ug/kg, 0.04 ug/kg, 0.05 ug/kg, 0.06 ug/kg, 0.08 ug/kg, 0.1 ug/kg, 0.2 ug/kg, 0.25 ug/kg, 0.5 ug/kg, 0.75 ug/kg, 1 ug/kg, 1.5 ug/kg, 2 ug/kg, 4 ug/kg, 5 ug/kg, 10 ug/kg, 15 ug/kg, 20 ug/kg, 25 ug/kg, 30 ug/kg, 35 ug/kg, 40 ug/kg, 45 ug/kg, 50 ug/kg, 55 ug/kg, 60 ug/kg, 0.01
• a subject is administered a treatment regimen comprising one or more doses of an effective amount of the anti-CD3 antibody such as teplizumab, wherein the effective amount is increased by a factor of 1.25, a factor of 1.5, a factor of 2, a factor of 2.25, a factor of 2.5, or a factor of 5 until the daily effective amount of the anti- CD3 antibody such as teplizumab is achieved.
• a subject is intramuscularly administered one or more doses of a 200 ug/kg or less, preferably 175 ug/kg or less, 150 ug/kg or less, 125 ug/kg or less, 100 ug/kg or less, 95 ug/kg or less, 90 ug/kg or less, 85 ug/kg or less, 80 ug/kg or less, 75 ug/kg or less, 70 ug/kg or less, 65 ug/kg or less, 60 ug/kg or less, 55 ug/kg or less, 50 ug/kg or less, 45 ug/kg or less, 40 ug/kg or less, 35 ug/kg or less, 30 ug/kg or less, 25 ug/kg or less, 20 ug/kg or less, 15 ug/kg or less, 10 ug/kg or less, 5 ug/kg or less, 2.5 ug/kg or less,
• a subject is subcutaneously administered one or more doses of a 200 ug/kg or less, preferably 175 ug/kg or less, 150 ug/kg or less, 125 ug/kg or less, 100 ug/kg or less, 95 ug/kg or less, 90 ug/kg or less, 85 ug/kg or less, 80 ug/kg or less, 75 ug/kg or less, 70 ug/kg or less, 65 ug/kg or less, 60 ug/kg or less, 55 ug/kg or less, 50 ug/kg or less, 45 ug/kg or less, 40 ug/kg or less, 35 ug/kg or less, 30 ug/kg or less, 25 ug/kg or less, 20 ug/kg or less, 15 ug/kg or less, 10 ug/kg or less, 5 ug/kg or less, 2.5 ug/kg or less, 2
• a subject is intravenously administered one or more doses of a 100 ug/kg or less, preferably 95 ug/kg or less, 90 ug/kg or less, 85 ug/kg or less, 80 ug/kg or less, 75 ug/kg or less, 70 ug/kg or less, 65 ug/kg or less, 60 ug/kg or less, 55 ug/kg or less, 50 ug/kg or less, 45 ug/kg or less, 40 ug/kg or less, 35 ug/kg or less, 30 ug/kg or less, 25 ug/kg or less, 20 ug/kg or less, 15 ug/kg or less, 10 ug/kg or less, 5 ug/kg or less, 2.5 ug/kg or less, 2 ug/kg or less, 1.5 ug/kg or less, 1 ug/kg or less, 0.5 ug/kg or less, or
• the intravenous dose of 100 ug/kg or less, 95 ug/kg or less, 90 ug/kg or less, 85 ug/kg or less, 80 ug/kg or less, 75 ug/kg or less, 70 ug/kg or less, 65 ug/kg or less, 60 ug/kg or less, 55 ug/kg or less, 50 ug/kg or less, 45 ug/kg or less, 40 ug/kg or less, 35 ug/kg or less, 30 ug/kg or less, 25 ug/kg or less, 20 ug/kg or less, 15 ug/kg or less, 10 ug/kg or less, 5 ug/kg or less, 2.5 ug/kg or less, 2 ug/kg or less, 1.5 ug/kg or less, 1 ug/kg or less, 0.5 ug/kg or less, or 0.2 ug/kg or less of the anti-CD3 antibody such
• a subject is orally administered one or more doses of a 100 ug/kg or less, preferably 95 ug/kg or less, 90 ug/kg or less, 85 ug/kg or less, 80 ug/kg or less, 75 ug/kg or less, 70 ug/kg or less, 65 ug/kg or less, 60 ug/kg or less, 55 ug/kg or less, 50 ug/kg or less, 45 ug/kg or less, 40 ug/kg or less, 35 ug/kg or less, 30 ug/kg or less, 25 ug/kg or less, 20 ug/kg or less, 15 ug/kg or less, 10 ug/kg or less, 5 ug/kg or less, 2.5 ug/kg or less, 2 ug/kg or less, 1.5 ug/kg or less, 1 ug/kg or less, 0.5 ug/kg or less, or 0.2
• the dose on day 1 of the regimen is 100-250 ug/m2/day, preferably 106 ug/m2/day and escalates to the daily dose as recited immediately above by day 2, and 3.
• the subject is administered a dose of approximately 106 ug/m 2 /day, on day 2 approximately 425 ug/m 2 /day, and on subsequent days of the regimen (e.g., days 3-12) 850 ug/m 2 /day.
• the subject on day 1, is administered a dose of approximately 211 ug/m 2 /day, on day 2 approximately 423 ug/m 2 /day, on day 3 and subsequent days of the regimen (e.g., days 3-12) approximately 840 ug/m 2 /day.
• the first 1, 2, or 3 doses or all the doses in the regimen are administered more slowly by intravenous administration.
• a dose of 106 ug/m 2 /day may be administered over about 5 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, and about 22 hours.
• the dose is administered by slow infusion over a period of, e.g., 20 to 24 hours.
• the dose is infused in a pump, preferably increasing the concentration of antibody administered as the infusion progresses.
• a set fraction of the doses for the 106 ug/m 2 /day to 850 ug/m 2 /day regimen described above is administered in escalating doses.
• the anti-CD3 antibody such as teplizumab is not administered by daily doses over a number of days, but is rather administered by infusion in an uninterrupted manner over 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 24 hours, 30 hours or 36 hours.
• the infusion may be constant or may start out at a lower dosage for, for example, the first 1, 2, 3, 5, 6, or 8 hours of the infusion and then increase to a higher dosage thereafter.
• the speed and duration of the infusion is designed to minimize the level of free anti-CD3 antibody such as teplizumab in the subject after administration.
• the level of free anti-CD3 antibody such as teplizumab should not exceed 200 ng/ml free antibody.
• the infusion is designed to achieve a combined T cell receptor coating and modulation of at least 50%, 60%, 70%, 80%, 90%, 95% or of 100%.
• the anti-CD3 antibody such as teplizumab is administered chronically to treat, or slow the progression, or ameliorate one or more symptoms of type 1 diabetes.
• a low dose of the anti-CD3 antibody such as teplizumab is administered once a month, twice a month, three times per month, once a week or even more frequently either as an alternative to the 6 to 14-day dosage regimen discussed above or after administration of such a regimen to enhance or maintain its effect.
• Such a low dose may be anywhere from 1 ug/m 2 to 100 ug/m 2 , such as approximately 5 ug/m 2 , 10 ug/m 2 , 15 ug/m 2 , 20 ug/m 2 , 25 ug/m 2 , 30 ug/m 2 , 35 ug/m 2 , 40 ug/m 2 , 45 ug/m 2 , or 50 ug/m 2 .
• the subject may be re-dosed at some time subsequent to administration of the two course anti-CD3 antibody such as teplizumab dosing regimen, for example, based upon one or more physiological or biomarker parameters or may be done as a matter of course.
• Such redosing may be administered and/or the need for such redosing evaluated 2 months, 4 months, 6 months, 8 months, 9 months, 1 year, 15 months, 18 months, 2 years, 30 months or 3 years after administration of a dosing regimen and may include administering a course of treatment every 6 months, 9 months, 1 year, 15 months, 18 months, 2 years, 30 months or 3 years indefinitely.
• the level (or relative amounts) of phenotypically exhausted T cells such as TIGIT+KLRG1+CD8+CD3+ cells with respect to all CD3+ T cells is determined, for example by flow cytometry.
• the level of the TIGIT+KLRG1+CD8+CD3+ T-cells can be monitored for example by flow cytometry.
• an additional 12-day course of anti-CD3 antibody such as teplizumab, is administered when the level of the TIGIT+KLRG1+CD8+CD3+ T-cells corresponds to (e.g., returns to) the baseline level.
• the determining of TIGIT+KLRG1+CD8+CD3+ T-cells is about 3 months (or about 1-6 months) after the administration of the second 12-day course.
• the monitoring can be annual.
• the monitoring can be every about 3-6 months.
• the re-dosing comprises administering additional (e.g., second, third, or beyond) 12-day course(s) of teplizumab each at a total dose of more than about 9000 ⁇ g/m 2 as described herein.
• the additional 12-day course of teplizumab comprises a first dose of 106 ⁇ g/m 2 teplizumab on day 1, a second dose of 425 ⁇ g/m 2 teplizumab on day 2, and one dose of 850 ⁇ g/m 2 on each of days 3–12, and wherein the total dose is approximately 9031 ⁇ g/m 2 .
• the additional 12-day course of teplizumab comprises a first dose of 211 ⁇ g/m 2 teplizumab on day 1, a second dose of 423 ⁇ g/m 2 teplizumab on day 2, and one dose of 840 ⁇ g/m 2 on each of days 3–12, and wherein the total dose is approximately 9034 ⁇ g/m 2 .
• the additional (e.g., second, third, or beyond) 12-day course of anti-CD3 antibody, such as teplizumab can be administered about 12 month to about a 24 month after the administering of the prior 12-day course, for example 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23 or 24 months.
• the anti-CD3 antibody such as teplizumab is administered to achieve, or maintain a level of glycosylated hemoglobin (HA1 or HA1c) less than 8%, less than 7.5%, less than 7%, less than 6.5%, less than 6%, less than 5.5% or 5% or less.
• HA1 or HA1c glycosylated hemoglobin
• patients have a HA1 or HA1c level of less than 8%, less than 7.5%, less than 7%, less than 6.5%, less than 6%, or, more preferably, from 4%-6% (preferably measured in the absence of other treatment for diabetes, such as administration of exogenous insulin).
• Such patients preferably have retained at least 95%, 90%, 80%, 70%, 60%, 50%, 40% 30% or 20% of beta-cell function prior to initiation of treatment.
• the administration of the anti-CD3 antibodies prevents damage, thereby slowing progression of the disease and reducing the need for insulin administration.
• the methods of treatment provided herein result in a level of HA1 or HA1c is 7% or less, 6.5% or less, 6% or less, 5.5% or less, or 5% or less 6 months, 9 months, 12 months, 15 months, 18 months, or 24 months after the previous treatment.
• the administration of the anti-CD3 antibodies according to the methods provided herein decreases the average level of HA1 or HA1c in the patient by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65% or about 70% as compared to pre-treatment levels at 6 months, 9 months, 12 months, 15 months, 18 months, or 24 months after the previous treatment.
• the administration of the anti- CD3 antibodies according to the methods provided herein results in an average level of HA1 or HA1c in the patient that only increases by about 0.5%, about 1%, about 2.5%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% as compared to pre-treatment levels at 6 months, 9 months, 12 months, 15 months, 18 months, or 24 months after the previous treatment.
• administration of the anti-CD3 antibodies, in particular teplizumab according to the methods provided herein slows the loss of ⁇ cells and/or preserves ⁇ cell function (as evidenced by e.g., C-peptide levels, episodes of hypo- or hyper- glycemia, time in range (of glycemia), insulin use, or other assessment method known in the art) over 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 2 months, 24 month or more in children and adolescents 8-17 years old who have been diagnosed with T1D in the previous 6 weeks.
• administering slows the loss of ⁇ cells and/or preserves ⁇ cell function over 18 months (78 weeks) in children and adolescents 8-17 years old who have been diagnosed with T1D in the previous 6 weeks.
• Teplizumab for use in a method of treating clinical type 1 diabetes (T1D), comprising administering to a subject in need thereof a 12-day course of the teplizumab at a total dose of more than about 9000 ⁇ g/m 2 .
• the total dose is between about 9000 and about 9500 ⁇ g/m 2 .
• the total dose is between about 9000 and about 14000 ⁇ g/m 2 .
• the 12-day course comprises a first dose of 106 ⁇ g/m 2 teplizumab on day 1, a second dose of 425 ⁇ g/m 2 teplizumab on day 2, and one dose of 850 ⁇ g/m 2 on each of days 3–12, and wherein the total dose is approximately 9031 ⁇ g/m 2 .
• the 12-day course comprises a first dose of 211 ⁇ g/m 2 teplizumab on day 1, a second dose of 423 ⁇ g/m 2 teplizumab on day 2, and one dose of 840 ⁇ g/m 2 on each of days 3–12, and wherein the total dose is approximately 9034 ⁇ g/m 2 .
• the method can include administering a first and a second 12- day courses of teplizumab.
• the first and the second 12-day courses are administered at about 1-6 months, about 2-5 months or about 3 months interval.
• the method can include administering to the subject in need thereof a third or more 12-day course of teplizumab, each course at a total dose of more than about 9000 ⁇ g/m 2 .
• the third or more 12-day course of teplizumab comprises a first dose of 106 ⁇ g/m 2 teplizumab on day 1, a second dose of 425 ⁇ g/m 2 teplizumab on day 2, and one dose of 850 ⁇ g/m 2 on each of days 3–12, and wherein the total dose of each course is approximately 9031 ⁇ g/m 2 .
• the third or more 12-day course of teplizumab comprises a first dose of 211 ⁇ g/m 2 teplizumab on day 1, a second dose of 423 ⁇ g/m 2 teplizumab on day 2, and one dose of 840 ⁇ g/m 2 on each of days 3–12, and wherein the total dose of each course is approximately 9034 ⁇ g/m 2 .
• the third or more 12-day course of teplizumab is administered at about a 12 month to about a 24-month interval.
• the method can further include determining, after the administration of each 12-day course, a baseline of a level of TIGIT+KLRG1+CD8+ cells with respect to all CD3+ T cells, monitoring the level of the TIGIT+KLRG1+CD8+CD3+ T-cells and administering an additional 12-day course of teplizumab when the level of the TIGIT+KLRG1+CD8+CD3+ T-cells returns to the baseline level.
• the determining of TIGIT+KLRG1+CD8+CD3+ T-cells is by flow cytometry.
• the monitoring of TIGIT+KLRG1+CD8+CD3+ T-cells is by flow cytometry.
• the determining of TIGIT+KLRG1+CD8+CD3+ T-cells is about 1-6 months, about 2-5 months, or about 3 months after the administration of each 12-day course.
• subsequent monitoring is annual.
• subsequent monitoring is every about 3-6 months.
• the subject in need thereof has been diagnosed with T1D within 6 weeks prior to the administrating step.
• the administrating step results in reduction by at least 10% of insulin use, HbA1c levels, hypoglycemic episodes, or combinations thereof as compared to pre- treatment levels.
• each dose is administered parenterally.
• each dose is administered by intravenous infusion.
• the subject in need thereof is about 8 to 17 years old.
• the subject in need thereof have a peak C-peptide level of ⁇ 0.2 pmol/mL during a mixed meal tolerance test (MMTT).
• the subject receiving teplizumab has a higher mean C-peptide value compared with a control receiving placebo.
• the method further includes assessing the area under the time- concentration curve (AUC) of C-peptide following a mixed meal tolerance test (MMTT), at 78 weeks.
• AUC area under the time- concentration curve
• MMTT mixed meal tolerance test
• the subject in need thereof has at least 20% of beta-cell function prior the administration of the first dose.
• the reduction of insulin use, HbA1c levels, hypoglycemic episodes, or combinations thereof is over a period of 12 months or more.
• Some aspects relate to a method of treating clinical type 1 diabetes (T1D), comprising administering to a subject in need thereof a 12-day course of teplizumab at a total dose of more than about 9000 ⁇ g/m 2 . Some aspects relate to teplizumab for use in a method of treating clinical type 1 diabetes (T1D), comprising administering to a subject in need thereof a 12-day course of the teplizumab at a total dose of more than about 9000 ⁇ g/m 2 .
• a method of treating clinical type 1 diabetes comprising administering to a subject in need thereof a 12-day course of teplizumab at a total dose of from about 9000 to about 9500 ⁇ g/m 2 .
• a method of treating clinical type 1 diabetes is provided comprising administering to a subject in need thereof a 12-day course of teplizumab at a total dose of from about 9000 to about 14000 ⁇ g/m 2 .
• Teplizumab Population Pharmacokinetic Simulations Introduction
• Teplizumab is a 150 kD monoclonal antibody that binds the CD3- ⁇ epitope of the T cell receptor (TCR) complex. The primary mechanism of action of the antibody involves binding the CD3 antigen target on T cells.
• a population pharmacokinetic (PK) model that describes teplizumab concentrations following IV administration was developed. Teplizumab PK was described by a Quasi-Steady-State (QSS) approximation of the Target-Mediated Drug Disposition (TMDD) model. The aim of this investigation was to use the model to simulate and compare concentration-time profiles of teplizumab following several dosing regimens of interest.
• QSS Quasi-Steady-State
• the objectives of the analysis were: ⁇ To apply the previously developed population PK model to simulate the following three dosing regimens: ⁇ "Herold Dosing Regimen": Day 1: 51 ⁇ g/m 2 ; Day 2: 103 ⁇ g/m 2 ; Day 3: 207 ⁇ g/m 2 ; Day 4: 413 ⁇ g/m 2 ; Days 5-14: 826 ⁇ g/m 2 ; ⁇ Regimen 1: Day 1: 211 ⁇ g/m 2 ; Day 2: 423 ⁇ g/m 2 ; Days 3-12: 840 ⁇ g/m 2 ; ⁇ Regimen 2: Day 1: 106 ⁇ g/m2; Day 2: 425 ⁇ g/m 2 ; Day 3-12: 850 ⁇ g/m 2 .
• the Herold regimen is a 14-day course of teplizumab consisting of daily intravenous (IV) infusions (over at least 30 minutes) of 51 ⁇ g/m 2 , 103 ⁇ g/m 2 , 207 ⁇ g/m 2 , and 413 ⁇ g/m 2 on Study Days 1–4, respectively, and an infusion of 826 ⁇ g/m 2 on each of Study Days 5–14.
• the total dose for a 14-day course is approximately 9034 ⁇ g/m 2 .
• the new Regimen 1 is a 12-day course of teplizumab consisting of daily IV infusion (over at least 30 minutes) of 211 ⁇ g/m 2 and 423 ⁇ g/m 2 on Study Days 1 and 2, respectively, and an infusion of 840 ⁇ g/m 2 on each of Study Days 3–12.
• the total dose for a 12-day course is approximately 9034 ⁇ g/m 2 .
• the new Regimen 2 is a 12-day course of teplizumab consisting of daily IV infusion (over at least 30 minutes) of 106 ⁇ g/m 2 and 425 ⁇ g/m 2 on Study Days 1 and 2, respectively, and an infusion of 850 ⁇ g/m 2 on each of Study Days 3–12.
• the total dose for a 12-day course is approximately 9031 ⁇ g/m 2 .
• the same total dose is to be delivered by all three regimens, but in Regimens 1 and 2, delivery is over 12 days rather than 14 days of the original Herold regimen. Simulations [00165] The final model of the previous analysis was used for simulations.
• Concentration-time courses were simulated for 40 days (Day 0 to Day 40), with 10 time points each day.
• the model included the study effect as patients from Protégé Encore study were found to have higher clearance and central volume than patients from Protégé study. Therefore, the simulations were conducted separately for these 2 studies.
• Table 1 illustrates mean and standard deviation of predicted concentrations (ng/mL) over 1000 simulated subjects from Protégé study Table 1. Teplizumab Concentration Predictions: C trough 1 day After the Last Dose [00169] The results of the simulations for typical adult patients with high level of detected ADAs are shown in Figures 5-8. As expected, overall teplizumab levels are much lower for subjects with very high immunogenic response, but the conclusions about differences between the three investigated dosing regimens still hold. [00170] The results of the simulations for typical pediatric patients are shown in Figures 9-16.
• Figures 17-24 show concentration profiles comparing Herold Regimen and Regimen 2 for a longer time period and Table 2- Table 3 summarized Cmax and AUC from 0 to 42 days in the simulations. Figures show that by day 42 concentrations are very low, so values for AUC0- 42 are essentially the same as for AUCinfinity.
• Table 2 illustrates mean and standard deviation of predicted maximum concentrations (ng/mL) over 1000 simulated subjects using Protégé Model 205.
• Table 3 illustrates mean and standard deviation of predicted AUC from 0 to 42 days (ng/mL*day) over 1000 simulated subjects using Protégé Model 205 Table 2.
• Teplizumab Concentration Predictions C max Table 3. Teplizumab Concentration Predictions: AUC 0-42 Conclusions [00172] The simulations indicated that: ⁇ Predicted concentrations of teplizumab are nearly identical for 2 suggested dosing regimens (Regimen 1 and Regimen 2) except for the first day of dosing; ⁇ Predicted concentrations of teplizumab increase faster during dosing for Regimens 1 and 2 compared to Herold regimen, but they are nearly identical for all regimens at the last day of dosing; ⁇ Predicted concentrations of teplizumab at 1 day after the last dose are nearly identical for all 3 regimens; ⁇ BSA-proportional dosing provides homogeneous exposure levels for adult and pediatric subjects with different body size measures.
• Teplizumab (PRV-031), a Humanized, FcR Non- Binding, anti-CD3 Monoclonal Antibody, in Children and Adolescents with Newly Diagnosed Type 1 Diabetes (T1D) [00173]
• Teplizumab (also known as PRV-031, hOKT3 ⁇ 1 [Ala-Ala], and MGA031) is a humanized 150-kilodalton monoclonal antibody (mAb) that binds to the CD3- ⁇ epitope of the T cell receptor.
• Teplizumab was developed when preclinical studies demonstrated that targeting T cells (the cells that are instrumental in initiating and coordinating the autoimmune process responsible for type 1 diabetes [T1D] mellitus) via this mechanism altered diabetes immunopathogenesis and prevented and reversed disease in relevant animal models. The goal of this study is to evaluate teplizumab in children and adolescents very recently diagnosed with T1D. Teplizumab holds the promise to be the first disease modifying therapy available to improve both the medical management and overall outlook in those who suffer the most devastating short- and long-term consequences of this disease.
• teplizumab is safe, well-tolerated, and effective in slowing the loss of ⁇ cells and maintaining a clinically relevant level of ⁇ cell function in children and adolescents newly diagnosed with T1D while improving key aspects of T1D clinical management over an 18-month period.
• the secondary objectives are: ⁇ To evaluate participant improvements in key clinical parameters of diabetes management, including insulin use, glycemic control (including hemoglobin A1c [HbA1c] and time in glycemic target range [TIR]), and clinically important hypoglycemic episodes ⁇ To determine the safety and tolerability of two courses of teplizumab, administered intravenously (IV) 6 months apart ⁇ To evaluate the pharmacokinetics (PK) and immunogenicity of two courses of IV teplizumab [00177] The exploratory objectives are: ⁇ To assess ⁇ cell function and T1D-focused clinical parameters ⁇ To evaluate immunologic, endocrinologic, molecular, and genetic markers Endpoints 1.
• the primary endpoint is: ⁇ The area under the time-concentration curve (AUC) of C-peptide after a 4-hour (4h) mixed meal tolerance test (MMTT), a measure of endogenous insulin production and ⁇ cell function, at Week 78. 2.
• the secondary endpoints are as follows: A.
• Exogenous insulin use defined as a daily average in units per kilogram per day (U/kg/d), at Week 78 ⁇ HbA1c levels: expressed in % and mmol/mol, at Week 78 ⁇ TIR: expressed as a daily average of the percentage of time in a 24-hour day a participant’s blood glucose (BG) is >70 but ⁇ 180 mg/dL (>3.9 to ⁇ 10.0 mmol/L), assessed using continuous glucose monitoring (CGM), at Week 78 ⁇ Clinically important hypoglycemic episodes: defined as the total number of episodes of a BG reading of ⁇ 54 mg/dL (3.0 mmol/L) and/or episodes of severe cognitive impairment requiring external assistance for recovery, from randomization through Week 78 B.
• TEAEs Treatment-emergent adverse events
• AESIs adverse events of special interest
• SAEs serious adverse events
• TEAEs Treatment-emergent adverse events
• AESIs adverse events of special interest
• SAEs serious adverse events
• TEAEs Treatment-emergent adverse events
• EBV Epstein-Barr virus
• CMV cytomegalovirus
• significant viremia ie, DNA-based polymerase chain reaction viral load >10,000 copies per mL or 10 6 cells
• herpes zoster ⁇ Incidence and severity of immediate or delayed study drug infusion-related reactions, such as hypersensitivity reactions, pain requiring interruption or discontinuation of infusions, cytokine release syndrome, and serum sickness C.
• PK and Immunogenicity Endpoints ⁇ Teplizumab serum concentrations ⁇ Incidence and titers of anti-teplizumab antibodies after treatment courses 3.
• the exploratory endpoints are as follows: A. Assessments of ⁇ cell function and health throughout the study: ⁇ 4h MMTT C-peptide AUC ⁇ Participants with the recognized clinically significant stimulated peak C-peptide of ⁇ 0.2 pmol/mL during 4h and 2-hour (2h) MMTTs ⁇ Proinsulin-to-C-peptide ratios, a measure of ⁇ cell endoplasmic reticulum stress and dysfunction B.
• participant is randomized at a 2:1 ratio using randomly permuted blocks and stratification based on the following criteria: ⁇ Peak C-peptide level at screening: within the range of 0.2 (inclusion criterion) to 0.7 pmol/mL (inclusive) versus >0.7 pmol/mL ⁇ Age at randomization: within the range of 8 to 12 years (inclusive) versus >12 to 17 years [00180] Teplizumab or matching placebo are administered via IV infusion in two courses, with the first course starting on Day 1 (Week 1) and the second course approximately 6 months later at Day 182 (Week 26). Each course of treatment include daily infusions for 12 days.
• the total study duration for each participant is up to 84 weeks. This includes a screening period of up to 6 weeks and a post-randomization period of 78 weeks. The treatment period includes two 12-day treatment courses separated by 6 months and a post-treatment observation period of approximately 52 weeks.
• Study Population [00182] This study enrolls male and female participants 8 to 17 years of age with new-onset T1D who are able to be randomized and initiate study treatment within 6 weeks of their diagnosis. To be eligible for randomization, participants must be positive for at least one T1D- associated autoantibody and have a peak stimulated C-peptide of ⁇ 0.2 pmol/mL at screening. They must also meet all of the specific inclusion criteria and none of the exclusion criteria.
• each participant receives the first dose of the study drug in the first 12-day treatment course, as shown in the table below.
• the study drugs (teplizumab or placebo) are administered via IV infusion at the study site or other qualified facility by study-approved personnel.
• the doses of study drug is calculated based on the participant’s body surface area (BSA) measured on the first day of each treatment course. No dose adjustment is permitted.
• BSA body surface area
• HbA1c This is the percent of red blood cells (measured as hemoglobin) that has become non-enzymatic glycated proportional to blood glucose levels. This indicates, on average, approximately a 3-month average of blood glucose values. It is a key clinical target in the management of T1D.
• Insulin use As an average over 7 days of data collected before each specified visit to quantify exogenously injected insulin.
• hypoglycemia Clinically important and potentially life-threating hypoglycemia is the result of insulin therapy and more likely to occur in patients who are attempting to achieve glycemic control goals. This study ask participants to record information regarding BG levels of ⁇ 70mg/dL (3.9 mmol/L) and/or events that are consistent with hypoglycemia. A particular focus is on clinically significant hypoglycemic events that are defined as a reliable glucose reading of ⁇ 54 mg/dL (3.0 mmol/L) and/or severe cognitive impairment and/or physical status requiring external assistance for recovery.
• Glucose Monitoring Intermittent glucose monitoring (e.g, spot-check or fingerstick) performed by participants or caregivers multiple times a day as a necessary part of glycemic management to gauge insulin dosing and assist in diet and activity. All participants are to bring in their glucometers at all visits for review. In addition to data regarding glycemic control, at specified times during the study, participants report their daily before-meal and before-bedtime BG readings and have glucose levels assessed for 2-week intervals using CGM.
• this study recruits participants within 6 weeks from T1D diagnosis and a peak C-peptide level of ⁇ 0.2 pmol/mL during a mixed meal tolerance test (MMTT).
• MMTT mixed meal tolerance test
• the value of 0.2 pmol/mL was chosen as it is a key and accepted threshold of C-peptide correlated with clinically important lower rates of T1D-associated short- and long-term complications (Lachin 2014, Palmer 2001, Palmer 2009).
• the total study duration for each participant is up to 84 weeks. This includes a screening period of up to 6 weeks and a post-randomization period of 78 weeks.
• the post- randomization period includes two 12-day treatment courses separated by 6 months and a post- treatment observation period of approximately 52 weeks. The final visit takes place at Week 78.
• the overall study length and timepoints for key assessments were chosen due to the natural course of remaining ⁇ cell loss following the diagnosis of T1D and study goals to demonstrate durability of effect and to confirm post-treatment safety profiles of teplizumab.
• At the time of diagnosis there can be substantial ⁇ cell reserves, often estimated at 10-20% but in some cases over 40% of normal ⁇ cell mass (Matveyenko 2008, Campbell-Thompson 2016).
• T1D diagnosis the majority of this reserve appears to be functionally impaired due to metabolic or immunologic (i.e, cytokine induced) stress.
• the 18-month time point for the primary and key secondary clinical endpoints provide key data needed for the acceptance of teplizumab as a T1D disease modifying therapy into regular medical practice and is consistent with existing guidelines for endpoints recommended by the EMA and FDA.
• Data from T1D natural history studies and interventional trials show that ⁇ cell loss in those with T1D can be quite variable, especially within the weeks to months following diagnosis.
• This study is enrolling participants in close proximity to T1D diagnosis (i.e. within 6 weeks) who are younger, there may be the added complexity of the consideration of the Honeymoon phenomenon (or spontaneous, transient partial remission) - that may last up to ⁇ 1 year in the study population (Abdul-Rasoul 2006).
• the 18-month timing of the primary and key secondary clinical endpoints allows for a substantial amount of the inherent, natural metabolic variability due to different trajectories of ⁇ cell loss and/or transiently enhanced ⁇ cell function due to the Honeymoon phenomenon to be minimized - so that the true effect on teplizumab on ⁇ cell function and clinical parameters can be differentiated from chance.
• Other key assessments are done at randomization, Week 26 (6 months) and Week 52 (12 months) to better understand natural history of ⁇ cell decline and the effect of teplizumab in this specific study population.
• the primary and key clinical endpoints are assessed approximately 1 year after the last dose of study drug administration.
• the length of effect is recognized as an important property of an intermittent disease modifying therapy for T1D.
• a 12-month off-therapy period whilst maintaining positive metabolic and clinical effects can, at this time, be considered a reasonable time frame to substantiate an assertion of a metabolically and clinically relevant durable benefit.
• participants are assessed regularly via in-person interviews and physical exams, self-reports, and laboratory examinations. Assessments occur daily during the two 12-day treatment courses and regularly during the 6-month interval between courses and the 12 months following the second treatment course.
• the on- and off-therapy observation times in this study are well within, if not significantly beyond, the periods traditionally used to assess for safety and side effects for immune therapies approved for other autoimmune conditions, including those for pediatric indications.
• T1D diagnosis is according to ADA criteria.
• the patient diagnosed with T1D has a positive result on testing for at least one of the following T1D-related autoantibodies: Glutamic acid decarboxylase 65 (GAD65) autoantibodies, Islet antigen 2 (IA-2) autoantibodies, Zinc transporter 8 (ZnT8) autoantibodies Islet cell cytoplasmic autoantibodies (ICA) or Insulin autoantibodies (if testing obtained within the first 14 days of insulin treatment).
• Glutamic acid decarboxylase 65 Glutamic acid decarboxylase 65 (GAD65) autoantibodies, Islet antigen 2 (IA-2) autoantibodies, Zinc transporter 8 (ZnT8) autoantibodies Islet cell cytoplasmic autoantibodies (ICA) or Insulin autoantibodies (if testing obtained within the first 14 days of insulin treatment).
• BSA square root [height (cm) x weight (kg) / 3600], using the height and weight of the obtained on that day.
• Teplizumab and placebo are prepared according to the Pharmacy Manual provided to the site.
• Polyvinyl chloride (PVC) infusion bags and tubing and normal saline should be used for study agent preparation and administration.
• Two (2) mL of study drug should be drawn from the study drug vial and slowly reconstituted in 18 mL of 0.9% sodium chloride solution for injection by gentle mixing.
• the resulting 20 mL of 1:10 dilution is used as the initial study drug solution, which contains either placebo or teplizumab at a concentration of 100 ⁇ g/mL.
• This initial drug solution should then be added to a PVC infusion bag containing 25 mL 0.9% sodium chloride solution. Finally, this resulting preparation should be gently mixed before administration to the participant.
• This study requires two courses of intravenous infusions and blood draws over 12 days. It is recognized that intravenous access (for infusions and blood draws for laboratory sampling) in the pediatric population that is the focus of this study may pose a challenge.
• ADA American Diabetes Association
• the glycemic targets by the ADA are focused at management strategies to achieve a HbA1c level of ⁇ 7.5% (58 mmol/mol) for individuals 17 years old and younger, and ⁇ 7.0% (53 mmol/mol) 18 years and older while minimizing severe or frequent hypoglycemic events.
• the glycemic goal should be attempted through proper glycemic monitoring, administration of exogenous insulin, and monitoring of activity level and diet.
• Exogenous insulin may include rapid, intermediate, and/or long-acting insulins, administered intermittently or via the use of a personal insulin pump. Blood glucose levels should be measured at least 4 times a day, including before meals and before bedtime.
• Insulin use including the type of products, dosages, and dosing schedules, is expected to change during the course of the study. As part of routine T1D clinical care, if the caring physician judges it to be clinically appropriate, a participant’s insulin dose may be increased, reduced, or even discontinued.
• the study team should contact the participant’s primary clinical care team about possible adjustments in the insulin regimen, referral to a registered dietitian, or other approaches that may improve the glucose control.
• Insulin Discontinuation If a participant has achieved a HbA1c level of ⁇ 6.5% with insulin use of ⁇ 0.25 U/kg/day, insulin therapy can be discontinued. The participant’s blood glucose and HbA1c levels should continue to be monitored per protocol, and urine ketones should be monitored once a day.
• Study Visit Week 1 Patient receives premedication of an NSAID (eg, ibuprofen) (acetaminophen if NSAID is contraindicated) and an antihistamine (eg, diphenhydramine) for at least the first 5 days of the treatment course, unless contraindicated by drug allergy or sensitivity. After at least 30 minutes following the premedication administration, the infusion of study drug can begin.
• an NSAID eg, ibuprofen
• an antihistamine eg, diphenhydramine
• study drug should begin as soon as possible after preparation and no later than 2 hours after preparation.
• Study drug should be planned to be administered intravenously over 30 minutes according to standard practices, but it may be slowed if there are signs or symptoms of intolerance.
• an additional volume of saline equal to the volume contained in the infusion tubing, at the same constant rate is to be infused to ensure that all study drug has been cleared from the infusion tubing. The starting and ending times for the infusion are to be recorded.
• Day 2-12 Continued Treatment Course 1 Infusions [0213] If there are no clinical or laboratory concerns, the patient can proceed with the next infusion as described above at least 30 minutes following administration of prophylactic NSAID (acetaminophen if NSAID is contraindicated) and antihistamine. Close monitoring is to occur during the infusions and for 60 minutes following the infusions for any signs or symptoms of intolerability or infusion reactions. Day 2-11 [0214] On Days 2-11, the patient is then able to leave the facility and return the following day for the next study drug infusion.
• prophylactic NSAID acetaminophen if NSAID is contraindicated
• Study Visit Week 26 4h MMTT and Treatment Course 2
• the visit window for these study visits are ⁇ 3 days from the target visit day. Days 182-193 [0219] Day 182 clinical and laboratory assessments (including a 4h MMTT) and for initiation of the second course of study drug administration. [0220] Of specific note, height and weight are to be obtained at this visit and used for the BSA based dosing calculation for course 2.
• the patient is to be premedicated with an oral NSAID (acetaminophen if NSAID is contraindicated) and antihistamine at least 30 minutes before the first 5 study drug infusions is started (and on an as needed basis with subsequent infusions), administration of study drug should begin as soon as possible after preparation and no later than 2 hours after preparation, and an additional volume of saline equal to the volume contained in the infusion tubing is to be infused.
• an additional volume of saline equal to the volume contained in the infusion tubing is to be infused.
• participants are to be monitored for signs or symptoms of infusion reactions.
• two blood draws are obtained for teplizumab serum levels.
• Days 183-192 (Day 2-11 of Course 2 dosing) [0222] On Days 183-192, the participant may leave the facility and return the following day for the next study drug infusion.
• Day 193 (Day 12 of Course 2 dosing) [0223] Following the completion of the final infusion for this course and at least a 30-minute observation, a CGM sensor is applied and the patient is to be given instructions on CGM monitoring care and use.
• Study Visits Week 30, 34, 39, 52 and 65 [0224] The visit window for these study visits are ⁇ 4 days from the target visit day. At the Week 52 visit, a 4h MMTT is conducted.
• Study Visits Week 39 and Week 65 [0226] Give patient instructions for Week 52 and Week 78, respectively, 4h MMTT including overnight fast and pre-MMTT insulin dosing.
• Week 65 visit dispense to patient CGM equipment for home application to start around Week 76.
• Study Visit Week 78 [0227] The visit window for this study visit is ⁇ 7 days from the target visit day. During this visit the 4h MMTT is conducted.
• Mixed Meal Tolerance Tests [0228] A 2h MMTT is performed at screening to determine study eligibility (based on peak C-peptide level).
• a 4h MMTTs is performed at randomization and at Weeks 26, 52, and 78 to obtain 4h C-peptide AUCs and other data.
• a 4h MMTT is used at and post-randomization as it has been shown to be more precise and reliable in assessing the MMTT-induced C-peptide AUC than the 2h MMTT (Boyle 2015, Rigby 2013, Rigby 2016).
• the 2h-MMTT is used at screening as it is sufficient to capture the peak C-peptide level needed for study entry. Samples from these assessments are assessed for C-peptide, serum glucose, and insulin. Samples are stored for potential future evaluations including but not limited to proinsulin levels. The measurements of C-peptide and glucose in serum samples are done.
• HbA1c is assessed as a blood test at select study visits Insulin Use [0230] Patient’s daily insulin use is documented by the participant in an eDiary at select times for 7 days prior to randomization and at about Weeks 12, 26, 39, 52, 65 and 78 visits. The patient records all short-, intermediate- and long-acting insulin administered as intermittent injections or use with an “insulin pump” during this time.
• Insulin use data are not recorded on the day before or the day of the study visit. If a patient forgets to record insulin use on one or more days before a visit, they should continue to record insulin use for up to 72 hours post-dose to obtain up to 7 days of data. Every effort should be made to collect a total of 7 days of insulin use data for all the aforementioned visits except Week 78 (final visit), as patients return the eDiary at the final visit.
• Episodes of Hypoglycemia Clinically important and other non-severe and non-serious hypoglycemic episodes are recorded throughout the study by participants and through evaluation of glucometer readings.
• Glucose Monitoring (1) Intermittent Glucose Monitoring (Fingerstick) [0232] Blood glucose levels outside of MMTT and CGM are recorded and analyzed as an endpoint at various times. As part of routine care, BG levels are usually measured by a fingerstick glucometer at least 4 times a day, including before each meal and at bedtime. At screening, participants are offered a study-supplied glucometer and glucometer strips, but participants are permitted to use their own glucometers if they choose, in which case glucose monitoring strips are not be supplied. Each participant is instructed to bring their glucometer (or glucometers if they use more than one, eg, at home and in school) to each visit for review.
• Continuous glucose monitors record interstitial glucose levels (which closely approximate blood glucose values) at regular intervals, eg every 5-15 minutes depending on device. Increasingly clinical studies are supporting that such measurements and their assessments provides valuable and unique insights to glycemic control in diabetes. In this study, CGM assessments are conducted to provide key secondary clinical and exploratory endpoint data to address if and how teplizumab affects glycemic control, such as glucose excursions, time in select glucose ranges, and average daily glucose values (Steck 2014, Helminen 2016, Danne 2017).
• CGM are used to assess glycemic control approximately 7 times throughout the study: after the completion of treatment courses at randomization and Week 26; after the visit at Weeks 12, 39, 52, and 65; and before the visit at Week 78.
• CGM sensors are placed by qualified study staff, and education and training on CGM use and care are given. Sensors remain in place for up to 2 weeks. If during that 2-week period a sensor comes off, it can be replaced by the participant, a knowledgeable family member/guardian, or a qualified medical professional.
• CGM sensors are placed on participants after the study drug administration has completed for Course 1 and Course 2 and other clinical and laboratory assessments have been made on the days specified in the Schedule of Events tables. At the Weeks 12, 39, 52, and 65 visits, the sensor is placed on participants after all clinical and laboratory assessments and the MMTT have completed.
• Study CGM readings are not intended for medical management of participant’s diabetes but can be under the supervision of a participant’s health care team. Of note, routine use of the personal CGM under guidance of a participant’s regular healthcare provider is permitted.
• Example 3 Meta-Analysis of C-peptide in Five Stage 3 T1D Studies Summary
• Confirmatory evidence in the form of a meta-analysis was conducted using pooled C- peptide data from 5 supportive studies, all of which were randomized clinical studies: Protégé, Encore, Study 1, AbATE, and Delay. These 5 studies compared teplizumab to either placebo or standard of care in newly diagnosed patients with Stage 3 clinical T1D and had similar designs that allowed for cross-study comparisons (Table 5).
• the meta-analysis evaluated the change from baseline in C-peptide AUC in a 4-hour mixed meal tolerance test (MMTT).
• the Protégé and Encore studies enrolled newly diagnosed patients with Stage 3 T1D in 4 treatment arms: placebo and 3 teplizumab dosing regimens (full-dose 14 days [9.0 mg/m2 cumulative dose], one-third dose 14 days [ ⁇ 3.0 mg/m2 cumulative dose] and truncated 6-days [ ⁇ 2.5 mg/m2 cumulative dose]).
• C-peptide data from the full-dose 14-day regimen was used.
• Study 1, AbATE, and Delay studies all used the full-dose 14-day regimen (9.0 mg/m2 cumulative dose).
• Teplizumab is a humanized monoclonal antibody that targets the cluster of differentiation 3 (CD3) antigen, which is co-expressed with the T-cell receptor (TCR) on the surface of T lymphocytes.
• CD3 cluster of differentiation 3
• TCR T-cell receptor
• Figure 30 shows plots of predicted mean teplizumab concentrations over time using a 14-day intravenous (IV) dosing regimen with a 4-day ramp-up followed by repeated doses of 826 ⁇ g/m2 on Days 5 to 14.
• the left panel represents a typical 60 kg male subject and the right panel represents a typical 40 kg and 90 kg male subject.
• Body surface area (BSA)-based dosing normalizes the exposure across body size.
• the repeated IV infusions resulted in increasing serum teplizumab levels, although steady-state PK was not achieved at the end of dosing (Day 14 with this dosing regimen).
• the average accumulation ratio for area under the curve (AUC) between Day 5 and Day 14 was 3.4.
• the predicted mean ( ⁇ SD) total AUC for the 14-day dosing regimen was 6421 ⁇ 1940 ng•day/mL with Cmax and Cmin of 826 ⁇ 391 and 418 ⁇ 225 ng/mL, respectively, on Day 14.
• Distribution The central and peripheral volume of distribution from population PK analysis was 3.4 L and 6.9 L, respectively.
• Elimination Teplizumab clearance is not dose-proportional, likely driven by its saturable binding to CD3 receptors on the T-cell surface. Teplizumab is expected to be degraded into smaller peptide fragments by catabolic pathways.
• the clearance of teplizumab following the 14- day dosing regimen was estimated from population PK analysis to be 2.3 L/day, with a terminal half-life of approximately 4 days.
• the planned commercial drug product is manufactured in a different facility from the clinical trial product and was not used in the clinical studies submitted to support efficacy and safety.
• a single-dose PK bridging study was conducted in healthy volunteers that evaluated the biocomparability of the commercial drug product with the clinical trial drug product.
• the mean AUC0-inf for the commercial product was less than half (48.5%, 90% CI: 43.6 to 54.1) of the AUC0-inf for the product used in the primary efficacy study.
• Adverse events associated with teplizumab administration are also being studied. Notably, while teplizumab does not have an overall infection safety signal to date, patients receiving the 12-day dosing regimen (1 or 2 courses) instead of 14-day regimen appear to report fewer numeric adverse events of infection, based on the data from completed studies (Table 7).
• Standardizing clinically meaningful outcome measures beyond HbA1c for type 1 diabetes a consensus report of the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange. Diabetes Care. 2017;40(12):1622-1630. Akirav EM, Kushner JA, Herold KC. ⁇ cell mass and type 1 diabetes: Going, going, gone? Diabetes.2008;57:2883-2888. American Diabetes Association. 12. Children and Adolescents: Standards of medical Care in Diabetes-2018. Diabetes Care.2018;41(Suppl.1):S126-S136.
• Teplizumab preserves C- peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo- controlled Protégé trial. Diabetes.2013;62(11):3901-8. doi: 10.2337/db13-0236. Epub 2013 Jun 25. Helminen O, Pokka T, Tossavainen P, et al. Continuous glucose monitoring and HbA1c in the evaluation of glucose metabolism in children at high risk for type 1 diabetes mellitus. Diabetes Res Clin Pract.2016;120:89-96. Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, Bluestone JA.
• Teplizumab (anti-CD3 mAb) treatment preserves C- peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders. Diabetes. 2013(a);62(11):3766-3774.
• Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial. Diabetologia.2013(b);56(2):391-400.
• Diabetes.2014;63(2):739-748 Laitinen OH, Honkanen H, Pakkanen O, et al. Coxsackievirus B1 is associated with induction of ⁇ -cell autoimmunity that portends type 1 diabetes. Diabetes.2014;63(2):446-455. Lebastchi J, Deng S, Lebastchi AH, et al. Immune therapy and ⁇ -cell death in type 1 diabetes. Diabetes.2013;62(5):1676-1680. Lin A, Northam EA, Werther GA, Cameron FJ. Risk factors for decline in IQ in youth with type 1 diabetes over the 12 years from diagnosis/illness onset. Diabetes Care.2015;38:236-242.
• Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo- controlled trial. Lancet.2011;378(9790):487-97. Sorensen JS, Johannesen J, Pociot F, et al. Residual ⁇ -cell function 3–6 years after onset of type 1 diabetes reduces risk of severe hypoglycemia in children and adolescents. Diabetes Care. 2013;36:3454–3459. Sosenko JM, Skyler JS, Herold KC, et al. The metabolic progression to type 1 diabetes as indicated by serial oral glucose tolerance testing in the Diabetes Prevention Trial-type 1. Diabetes.2012;61(6):1331-7. Steck AK, Dong F, Taki I, et al.

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