WO2021070885A1 - 後天性血友病aの予防および/または治療に用いられる医薬組成物、および当該医薬組成物を含む製品 - Google Patents
後天性血友病aの予防および/または治療に用いられる医薬組成物、および当該医薬組成物を含む製品 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
Definitions
- the present disclosure relates to pharmaceutical compositions used in the prevention and / or treatment of acquired hemophilia A in a novel dosing regimen, and products containing such pharmaceutical compositions. More specifically, the present disclosure describes a pharmaceutical composition, which comprises administering a pharmaceutical composition containing emicizumab for at least two consecutive days (daily load administration), and a document relating to the pharmaceutical composition and its administration. Regarding products including.
- Hemophilia is a bleeding disorder caused by a congenital deficiency or dysfunction of factor VIII (FVIII) or factor IX (FIX).
- the former is called hemophilia A and the latter is called hemophilia B.
- FVIII preparations are generally administered on-demand (on-demand therapy).
- FVIII preparations have also been administered prophylactically to prevent bleeding events (regular replacement therapy; Non-Patent Documents 1 and 2).
- the half-life in blood of FVIII preparations is approximately 8-19 hours. Therefore, for continuous prophylaxis, FVIII preparations are administered to patients 1-3 times a week (Non-Patent Documents 3 and 4).
- FVIII preparations are additionally administered at regular intervals as needed to prevent recurrence of bleeding.
- FVIII preparations are mainly administered at home, since they are administered intravenously, the difficulty of securing blood vessels becomes a problem. Therefore, there is a strong need for drugs that are less burdensome to administer than FVIII preparations.
- Emicizumab (trade name: Hemlibra, ACE910, RO5534262), which is a bispecific antibody that replaces the function of FVIII, and its use have been disclosed (Patent Documents 1, 2, and 3, 4, and 5, Non-Patent Documents 5, 6, 7, and 8).
- Emicizumab is a recombinant humanized bispecific antibody that binds (a) FIX and / or FIXa and (b) FX and / or activated blood coagulation factor FX (FXa), replacing the cofactor function of FVIII. To do.
- Emicizumab has recently been approved in the United States and Japan as a recombinant formulation that suppresses bleeding tendency in patients with congenital FVIII deficiency.
- This preparation is administered subcutaneously at 3 mg / kg (body weight) four times at weekly intervals, and then 1.5 mg / kg (body weight) at weekly intervals, at 3 mg / kg (body weight) once.
- It is a long-acting subcutaneous administration preparation that can be administered subcutaneously at intervals of 2 weeks or at a dose of 6 mg / kg (body weight) at intervals of 4 weeks. Efficacy has been confirmed with or without an inhibitor against.
- the median time from the start of treatment to the achievement of complete remission (CR) is several months, and the median time to achievement of partial remission (PR) is also about 1 month, during which the risk of bleeding and the susceptibility to immunotherapy At risk.
- many of the causes of death in acquired hemophilia A are severe bleeding and severe infections. Therefore, when immunotherapy is performed, treatment with a drug that complements the function of FVIII is required until the effect is obtained.
- continuous administration of a drug that complements the function of FVIII is required for patients who cannot use immunotherapy or who have not obtained a meaningful effect even after immunotherapy.
- the effective concentration of emicizumab in plasma is high in the early stage after the start of administration. It is required to be obtained and its effective concentration to be maintained. This requirement applies regardless of whether administration of emicizumab is performed under immunotherapy.
- the effect of immunotherapy such as measurement of FVIII activity and inhibitor titer of the patient is regularly evaluated, and if the effect is observed, the dose of the immunotherapeutic drug should be reduced or discontinued in a timely manner. If not, change or add drugs.
- Non-Patent Documents 7 and 12 research reports confirming the hemostatic effect of emicizumab in a model experiment of acquired hemophilia A and patients with acquired hemophilia A
- Non-Patent Documents 13 and 14 reports of administration of emicizumab
- This disclosure was made in view of this situation, and one of the purposes is to provide an optimal administration regimen of emicizumab for the treatment of acquired hemophilia A.
- the inventors of the present disclosure have conducted diligent research to achieve the above objectives, and found that more effective administration of a pharmaceutical composition containing emicizumab for the prevention and / or treatment of acquired hemophilia A.
- I succeeded in finding a regimen. More specifically, by administering emicizumab continuously for at least 2 days (daily loading administration), an effective plasma emicizumab concentration can be obtained early after the start of administration, and 1 emicizumab is administered about 1 week after the initial administration. It was found that the effective concentration can be maintained by administration at intervals of 4 weeks (maintenance administration at intervals of 1 to 4 weeks).
- the antibody dose of 3 mg / kg to 6 mg / kg was administered on the first day, the antibody dose of 3 mg / kg to 6 mg / kg was administered on the second day, and the antibody dose of 1.5 mg / kg to 3 mg / kg was administered every week from the 8th day.
- the pharmaceutical composition, wherein the administration of is repeated one or more times.
- [2] The pharmaceutical composition according to [1], wherein the administration on the first day, the administration on the second day, and the weekly administration from the eighth day are each administered once. [3] The pharmaceutical composition according to [1] or [2], wherein the administration on the first day, the administration on the second day, and the weekly administration from the eighth day are performed subcutaneously, respectively. [4] The pharmaceutical composition according to any one of [1] to [3], wherein emicizumab is administered at an antibody dose of 3 mg / kg on the second day. [5] The pharmaceutical composition according to any one of [1] to [4], wherein administration of emicizumab is repeated at least once every week from the 8th day at an antibody dose of 1.5 mg / kg to 2 mg / kg. ..
- [6] The pharmaceutical composition according to any one of [1] to [5], wherein administration of emicizumab is repeated at least once every week from the 8th day at a dose of an antibody of 1.5 mg / kg.
- the product of [9] or [10], in which the first day administration, the second day administration, and the weekly administration from the eighth day are administered subcutaneously, respectively.
- the antibody dose of 3 mg / kg to 6 mg / kg was administered on the first day, the antibody dose of 3 mg / kg to 6 mg / kg was administered on the second day, and the antibody dose of 3 mg / kg to 4 mg / kg was administered every two weeks from the 8th day.
- the pharmaceutical composition wherein the administration is repeated one or more times, or the administration is repeated one or more times every 4 weeks from the 8th day at a dose of 6 mg / kg antibody.
- a pharmaceutical composition comprising emicizumab for use in treating acquired hemophilia A and / or reducing the incidence of acquired hemophilia A, wherein emicizumab is 6 mg / kg.
- the antibody dose was administered on the first day, the antibody dose of 3 mg / kg to 6 mg / kg was administered on the second day, the antibody dose of 1.5 mg / kg to 3 mg / kg was administered on the eighth day, and The antibody dose of 3 mg / kg to 4 mg / kg is repeated at least once every 2 weeks from the 15th day, or the antibody dose of 6 mg / kg is administered once every 4 weeks from the 15th day.
- the pharmaceutical composition which is repeated as described above.
- Administration on the first day, administration on the second day, administration on the 8th day, and administration every 2 weeks or 4 weeks from the 15th day are performed in a single dose, respectively, [22] or [23].
- Pharmaceutical composition. [25] Administration on the first day, administration on the second day, administration on the 8th day, and administration every 2 weeks or 4 weeks from the 15th day are performed subcutaneously, respectively, [22] to [24]. Any pharmaceutical composition of.
- a pharmaceutical composition comprising emicizumab for use in treating acquired hemophilia A and / or reducing the incidence of acquired hemophilia A, wherein emicizumab is 6 mg / kg.
- the antibody dose was administered on the first day, the antibody dose of 3 mg / kg to 6 mg / kg was administered on the second day, the antibody dose of 1.5 mg / kg to 6 mg / kg was administered on the third day, and The antibody dose of 1.5 mg / kg to 3 mg / kg is repeated once or more every week from the 8th day, and the antibody dose of 3 mg / kg is administered once every 2 weeks from the 8th day.
- the pharmaceutical composition which is repeated above or once or more every 4 weeks from the 8th day at a dose of 6 mg / kg antibody.
- Administration on the first day, administration on the second day, administration on the third day, and administration from the eighth day every week, every two weeks, or every four weeks are performed in one dose, respectively, [30] ] Pharmaceutical composition.
- Administration on the first day, administration on the second day, administration on the third day, and administration from the eighth day every week, every two weeks, or every four weeks are performed subcutaneously, respectively [30].
- the pharmaceutical composition of [31] [33] The pharmaceutical composition of any of [30]-[32], wherein emicizumab is administered at a dose of 3 mg / kg antibody on day 2.
- [38] A method of treating acquired hemophilia A and / or reducing the incidence of acquired hemophilia A, in which emicizumab is administered on the first day at an antibody dose of 6 mg / kg, 3 mg. Administer at an antibody dose of / kg to 6 mg / kg on day 2 and repeat administration at a dose of 1.5 mg / kg to 3 mg / kg from day 8 to weekly at least once. Included, said method. [39] The method of [38], wherein the first day administration, the second day administration, and the weekly administration from the eighth day are each administered once. [40] The method of [38] or [39], wherein the administration on the first day, the administration on the second day, and the weekly administration from the eighth day are performed subcutaneously, respectively.
- emicizumab for the production of therapeutic agents for acquired hemophilia A and / or agents for reducing the incidence of acquired hemophilia A, where emicizumab was used on day 1 at an antibody dose of 6 mg / kg. Is administered at a dose of 3 mg / kg to 6 mg / kg antibody on the second day, and at a dose of 1.5 mg / kg to 3 mg / kg antibody is administered at least once every week from the 8th day. Repeated, said use. [47] Use of [46], in which the first day administration, the second day administration, and the weekly administration from the eighth day are each administered once.
- [48] Use of [46] or [47], where the first day administration, the second day administration, and the weekly administration from the eighth day are administered subcutaneously, respectively.
- [49] Use of any of [46] to [48] in which emicizumab is administered on day 2 at a dose of antibody of 3 mg / kg.
- [50] Use of any of [46] to [49], in which emicizumab is administered at an antibody dose of 1.5 mg / kg to 2 mg / kg at least once weekly from day 8.
- [51] Use of any of [46] to [50], in which emicizumab is administered at a dose of 1.5 mg / kg antibody at least once weekly from day 8.
- Emicizumab for use in the treatment of acquired hemophilia A and / or in reducing the incidence of acquired hemophilia A, administered at an antibody dose of 6 mg / kg on the first day, 3 mg / kg.
- Emicizumab administered at a dose of ⁇ 6 mg / kg antibody on day 2 and repeated weekly administration from day 8 at a dose of 1.5 mg / kg ⁇ 3 mg / kg antibody.
- Emicizumab of [54] in which the first day administration, the second day administration, and the weekly administration from the eighth day are each administered once.
- Emicizumab according to any of [54] to [58] in which administration at a dose of 1.5 mg / kg antibody is repeated at least once every week from the 8th day.
- Emicizumab according to any one of [54] to [59] used under immunosuppressive drug administration.
- Emicizumab whose immunosuppressive drug is a steroid drug, [60].
- Administer at an antibody dose of / kg-6 mg / kg on day 2, administer at an antibody dose of 1.5 mg / kg-3 mg / kg on day 8, and administer 3 mg / kg-4 mg / kg antibody The method comprising: repeating administration every 2 weeks from day 15 at a dose of 1 or more, or once or more every 4 weeks from day 15 at a dose of 6 mg / kg antibody. .. [64] A method of treating acquired hemophilia A and / or reducing the incidence of acquired hemophilia A, in which emicizumab is administered on the first day at an antibody dose of 6 mg / kg, 3 mg.
- said method comprising repeating administration at a dose of 6 mg / kg antibody every 4 weeks from day 8 at least once.
- emicizumab for the production of therapeutic agents for acquired hemophilia A and / or agents for reducing the incidence of acquired hemophilia A, where emicizumab was administered at an antibody dose of 6 mg / kg on the first day.
- emicizumab was administered at an antibody dose of 6 mg / kg on the first day.
- emicizumab for the production of therapeutic agents for acquired hemophilia A and / or agents for reducing the incidence of acquired hemophilia A, where emicizumab was used on day 1 at an antibody dose of 6 mg / kg.
- emicizumab was used on day 1 at an antibody dose of 6 mg / kg.
- emicizumab for the production of therapeutic agents for acquired hemophilia A and / or agents for reducing the incidence of acquired hemophilia A, where emicizumab was used on day 1 at an antibody dose of 6 mg / kg.
- emicizumab was used on day 1 at an antibody dose of 6 mg / kg.
- Emicizumab for use in the treatment of acquired hemophilia A and / or in reducing the incidence of acquired hemophilia A, administered at an antibody dose of 6 mg / kg on the first day, 3 mg / kg.
- Emicizumab for use in the treatment of acquired hemophilia A and / or in reducing the incidence of acquired hemophilia A, administered at an antibody dose of 6 mg / kg on the first day, 3 mg / kg.
- Emicizumab Administered at a dose of ⁇ 6 mg / kg antibody on day 2, administered at a dose of 1.5 mg / kg ⁇ 3 mg / kg antibody on day 8, and at a dose of 3 mg / kg ⁇ 4 mg / kg antibody 15
- Emicizumab which is administered at least once every two weeks from day 1 or at a dose of 6 mg / kg antibody every 4 weeks from day 15.
- Figure 1 shows the change over time in plasma emicizumab concentration determined by simulation (approved weekly regimen).
- the X-axis shows the number of days elapsed when the first day of administration of emicizumab is Day 1 (1st day, 1st day).
- the Y-axis indicates plasma emicizumab concentration ( ⁇ g / mL).
- the circles and solid lines are the predicted median transitions that plot the trough values, the peripheral range is the 5th to 95th percentile range, and the vertical solid lines are Day 29, which is expected to be the last trough point before PR achievement in about half of the patients, and the horizontal dashed line is.
- the assumed effective concentration of 30 ⁇ g / mL is shown.
- the dosage and administration was 3 mg / kg, which was repeatedly subcutaneously administered (load administration) for 4 weeks at 1-week intervals, and then 1.5 mg / kg was repeatedly subcutaneously administered (maintenance administration) at 1-week intervals.
- Figure 2 shows the temporal changes in plasma emicizumab concentration obtained by simulation (daily loading administration + weekly maintenance administration regimen).
- the X-axis shows the number of days elapsed when the first day of administration of emicizumab is Day 1 (day 1).
- the Y-axis indicates plasma emicizumab concentration ( ⁇ g / mL).
- the circles and solid lines are the predicted median transitions that plot the trough values, the peripheral range is the 5th to 95th percentile range, and the vertical solid lines are Day 29, which is expected to be the last trough point before PR achievement in about half of the patients, and the horizontal dashed line is.
- the assumed effective concentration of 30 ⁇ g / mL is shown.
- the dosage and administration were 6 mg / kg on Day 1 and 3 mg / kg on Day 2 subcutaneously (load administration), and from Day 8 to 1.5 mg / kg repeated subcutaneous administration (maintenance administration) at weekly intervals.
- Emicizumab (ACE910, RO5534262) has (a) blood coagulation factor IX (FIX) and / or activated blood coagulation factor IX (FIXa) and (b) blood coagulation factor X (FX) and / or It is a bispecific antigen-binding molecule that recognizes activated blood coagulation factor X (FXa) and has an activity to replace the function of coagulation factor VIII (FVIII).
- the phrase "substitutes the function of FVIII” means that (a) FIX and / or FIXa and (b) FX and / or FXa are recognized and the activation of FX by FIXa is promoted (by FIXa). FXa generation is promoted).
- FXa production promoting activity can be evaluated using, for example, a measurement system containing FIXa, FX, synthetic substrate S-2222 (synthetic substrate of FXa), and phospholipids. Such a measurement system shows a correlation between disease severity and clinical symptoms in hemophilia A cases (Rosen S, Andersson M, Blomback M et al. Clinical applications of a chromogenic substrate method for determination of FVIII). activity. Thromb Haemost 1985; 54: 811-23).
- antigen-binding molecules such as antibodies
- Such antigen-binding molecules that recognize (a) FIX and / or FIXa and (b) FX and / or FXa are described, for example, in WO2005 / 035756, WO2006 / 109592, and WO2012 / 067176. Can be obtained according to.
- antibodies can be produced using genetic recombination techniques known to those of skill in the art based on the sequences of antibodies to FIX and / or FIXa and antibodies to FX and / or FXa.
- a polynucleotide encoding the antibody can be constructed, inserted into an expression vector and then expressed in a suitable host cell.
- a suitable host cell For example, Co, M. S. et al., J. Immunol. (1994) 152, 2968-2976; Better, M. and Horwitz, A. H., Methods Enzymol. (1989) 178, 476-496; Pluckthun, A. and Skerra, A., Methods Enzymol. (1989) 178, 497-515; Lamoyi, E., Methods Enzymol. (1986) 121, 652-663; Rousseaux, J. et al. , Methods Enzymol. (1986) 121, 663-669; and Bird, R. E. and Walker, B. W., Trends Biotechnol. (1991) 9, 132-137).
- Emicizumab is a bispecific antibody in which the first polypeptide and the third polypeptide are associated, and the second polypeptide and the fourth polypeptide are associated, and has the following structure.
- bispecific antibodies including; (B) The first polypeptide, which is an H chain containing the H chain variable region amino acid sequence of SEQ ID NO: 4, and the H chain containing the H chain variable region amino acid sequence of SEQ ID NO: 9.
- a bispecific antibody that comprises a second polypeptide; and third and fourth polypeptides that are shared L chains containing the L chain variable region amino acid sequence of SEQ ID NO: 14; or ( c) First polypeptide that is an H chain containing the amino acid sequence of SEQ ID NO: 5; second polypeptide that is an H chain containing the amino acid sequence of SEQ ID NO: 10; and SEQ A bispecific antibody (Q499-z121 / J327-z119 / L404-k) containing third and fourth polypeptides that are shared L chains containing the amino acid sequence of ID NO: 15.
- compositions of the invention used for therapeutic or prophylactic purposes can be prepared by mixing emicizumab, if desired, with a suitable pharmaceutically acceptable carrier, vehicle, etc. It can be a lyophilized formulation or a solution formulation.
- suitable pharmaceutically acceptable carriers and vehicles include sterile water, physiological saline, stabilizers, excipients, antioxidants (such as ascorbic acid), buffers (phosphate, citric acid, histidine, etc.) And other organic acids such as), preservatives, surfactants (such as PEG and Tween), chelating agents (such as EDTA), and binders. They include other low molecular weight polypeptides, proteins such as serum albumin, gelatin, and immunoglobulins, amino acids such as glycine, glutamine, asparagine, glutamic acid, aspartic acid, methionine, arginine, and lysine, and sugars such as polysaccharides and monosaccharides.
- saline and isotonic solutions containing, for example, saline and glucose and other adjuvants such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride are used.
- Suitable solubilizers such as alcohols (eg, ethanol), polyhydric alcohols (such as propylene glycol and PEG), and nonionic surfactants (such as polysorbate 80, polysorbate 20, poroxamer 188, and HCO-50).
- alcohols eg, ethanol
- polyhydric alcohols such as propylene glycol and PEG
- nonionic surfactants such as polysorbate 80, polysorbate 20, poroxamer 188, and HCO-50
- the pharmaceutical composition of the present invention may be pre-loaded in a syringe.
- the solution preparation can be prepared according to the method described in WO2011 / 090088.
- emicizumab can be encapsulated in microcapsules (eg, made of hydroxymethyl cellulose, gelatin, and poly (methyl methacrylate)), or colloidal drug delivery systems (eg, liposomes, albumin microspheres). , Microemulsion, nanoparticles, and nanocapsules) (see, eg, "Remington's Pharmaceutical Science 16th edition", Oslo Ed. (1980)).
- microcapsules eg, made of hydroxymethyl cellulose, gelatin, and poly (methyl methacrylate)
- colloidal drug delivery systems eg, liposomes, albumin microspheres
- Microemulsion, nanoparticles, and nanocapsules see, eg, "Remington's Pharmaceutical Science 16th edition", Oslo Ed. (1980)
- Methods of preparing drugs as release control agents are also well known and such methods can be applied to emicizumab (Langer et al., J. Biomed. Mater. Res. 15: 267-2
- Preferred liquid formulations are as follows. 20 mg / ml-180 mg / ml emicizumab, 0.2mg / ml-1mg / ml poloxamer 188, 10 mM-40 mM histidine-aspartate buffer, 100 mM to 300 mM arginine (pH about 4.5 to 6.5).
- the dose of emicizumab in one vial can be 30 mg, 60 mg, 90 mg, 105 mg or 150 mg.
- administration refers to administration performed once or in multiple times. Administration is via any suitable route, eg, intravenously, intramuscularly, intraperitoneally, intracephaly, percutaneously, subcutaneously, intra-articularly by bolus injection or continuous infusion over a predetermined period of time. Can be administered to the patient, sublingually, intrasynovial sac, orally, by inhalation, topically, or by topical application. Intravenous administration (IV) or subcutaneous administration (SC) is preferred.
- IV intravenous administration
- SC subcutaneous administration
- the dose of emicizumab is expressed by the dose of antibody, for example, "6 mg / kg (body weight)".
- First day administration refers to the first administration of emicizumab to a patient for the prevention and / or treatment of acquired hemophilia A.
- administration on the second day refers to the next day with the administration on the first day as the first day
- administration on the eighth day refers to the eighth day with the administration on the first day as the first day. The same applies to other dates.
- Every 1 week used in this specification can be read as “weekly” or “weekly interval”, and the same applies to 2 weeks, 4 weeks, etc. Is. Also, “4 weeks” is used interchangeably with “1 month”.
- administration is repeated one or more times
- administration interval refers to the interval between the nth dose (n is an integer of 1 or more) and the (n + 1) dose.
- Emicizumab is administered subcutaneously at a dose of 3 mg / kg (body weight) at weekly intervals for 4 weeks (loading at weekly intervals), and thereafter at a dose of 1.5 mg / kg at weekly intervals of 3 mg / kg.
- plasma effective early after the start of administration by administering emicizumab for at least 2 consecutive days (daily loading administration).
- a medium plasmab concentration is obtained, and the effective concentration can be maintained by administering emicizumab at intervals of 1 to 4 weeks (maintenance administration at intervals of 1 to 4 weeks) about 1 week after the initial administration.
- loading administration generally refers to administration to a patient performed in the early stage after the start of administration, and then maintenance administration at various doses and administration intervals is performed.
- the loading administration can be performed 0 to 24 times, preferably at least 1 time, at least 2 times, at least 3 times, at least 4 times, or more, preferably 2 or 3 times. ..
- dosing is performed at intervals of several days, such as approximately every 2 to 6 days, or 1 to 4 weeks, such as approximately weekly, approximately every 2 weeks, approximately every 3 weeks, or approximately every 4 weeks.
- the administration regimen of the present disclosure is performed daily, that is, the administration interval of loading administration is It is characterized by one day.
- loading is performed at an antibody dose of 1.5 mg / kg to 6 mg / kg, preferably 3 mg / kg or 6 mg / kg.
- the dose administration is to bring the plasma concentration of the therapeutic agent to the effective concentration range as soon as possible and to stabilize it as soon as possible (to reach a steady state).
- a dose of 6 mg / kg antibody is subcutaneously administered once on the first day, followed by a dose of 3-6 mg / kg antibody once on the second day, optionally an additional 1.5-6 mg.
- a dose of / kg of antibody is administered subcutaneously once every 3 days.
- maintenance administration refers to administration to a patient performed over a treatment period after the plasma concentration of the therapeutic agent reaches the effective concentration range by load administration. In maintenance administration, different doses and different dosing intervals can be combined.
- maintenance doses are doses of 1.5-6 mg / kg (body weight) antibody (emicizumab), eg, 1.5 mg / kg, 1.75 mg / kg, 1.8 mg / kg, 2 mg / kg, 2.1 mg / kg.
- the dosing interval for maintenance is 1 to 4 weeks or 1 month, eg, 1 week (QW), 2 week (Q2W), or 4 week (Q4W).
- the maintenance dose is a 4-week interval dosing (Q4W) at a dose of 6 mg / kg, which can be referred to as a 6 mg / kg antibody maintenance dosing regimen every 4 weeks.
- the maintenance dose is 3 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 4 mg / kg, 4.2 mg / kg, 4.5 mg / kg, 4.8 mg / kg, 5 mg / kg, 5.4 mg / kg. , 5.5 mg / kg, or 6 mg / kg antibody dose at 2-week intervals (Q2W).
- maintenance doses are 1.5 mg / kg, 1.75 mg / kg, 1.8 mg / kg, 2 mg / kg, 2.1 mg / kg, 2.25 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.7.
- different or alternative doses and dosing intervals may be applicable after the first dose and dosing interval described above.
- the aforementioned 6 mg / kg antibody maintenance dosing regimen can be modified every 4 weeks to apply different, alternative, or modified doses and dosing intervals.
- the dose of maintenance administration and the number of times the administration interval can be changed are not particularly limited.
- the maintenance dose and interval may be changed several times, eg, 1 to 4 times. In other words, one to several different doses and dosing intervals, eg, 1 to 5 different doses and dosing intervals, (0) dosing at a certain dose and dosing interval, (1) discontinuing dosing at that dose and dosing interval and first.
- the modified dose may be applied from the beginning without using the 6 mg / kg antibody maintenance dosing regimen described above every 4 weeks.
- the number of times the dose is administered in maintenance administration is not particularly limited, and the number of times is, for example, at least once, at least two times, at least three times, at least four times, at least five times, at least six times, at least seven times, at least eight times. Times, at least 9, at least 10, at least 15, at least 20, at least 25, at least 35, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, At least 100 times, at least 500 times, at least 1000 times, at least 10000 times, or more.
- the antibody is administered as follows. (1) Administer subcutaneously once at a dose of 6 mg / kg antibody on the first day; (2) On day 2, administer once subcutaneously at a dose of 3 mg / kg, 4.5 mg / kg, or 6 mg / kg antibody; and (3) from day 8 at a dose of 1.5 mg / kg antibody. Repeat subcutaneous administration once a week, once every two weeks at a dose of 3 mg / kg antibody, or once every four weeks at a dose of 6 mg / kg antibody.
- the antibody is administered as follows. (1) Administer subcutaneously once at a dose of 6 mg / kg antibody on the first day; (2) On the second day, administer once subcutaneously at a dose of 6 mg / kg of antibody; (3) Administer once subcutaneously at doses of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, or 6 mg / kg antibody on day 3; and (4) 1.5 mg / kg from day 8.
- Antibody dose once weekly, 3 mg / kg antibody dose every 2 weeks, or 6 mg / kg antibody dose once every 4 weeks. To do.
- the antibody is administered as follows. (1) One subcutaneous dose of 6 mg / kg antibody on the first day; and (2) one subcutaneous dose of 4.5 mg / kg antibody on the second day, 1.75 mg / kg from day 8. Repeat subcutaneous administration once weekly at a dose of kg antibody or once every two weeks at a dose of 3.5 mg / kg antibody; A single subcutaneous dose of 4.8 mg / kg antibody on day 2 and a weekly subcutaneous dose of 1.8 mg / kg antibody or a dose of 3.6 mg / kg antibody from day 8.
- the antibody is administered as follows. (1) Administer subcutaneously once at a dose of 6 mg / kg antibody on the first day; (2) On the second day, administer once subcutaneously at a dose of 6 mg / kg of antibody; (3) On the 3rd day, a dose of 1.5 mg / kg antibody is subcutaneously administered once, and from the 8th day, a dose of 2.25 mg / kg antibody is subcutaneously administered once a week or 4.5 mg / kg.
- the regimen of the present invention may be applicable for patients at risk of bleeding or excessive bleeding.
- the regimens of the invention are applicable in methods of preventing and / or treating bleeding in such patients, increasing blood coagulation activity in such patients, or reducing excess bleeding in such patients.
- "prevention" of bleeding refers to reducing the incidence of bleeding in a patient (reducing the frequency of bleeding episodes) or reducing the likelihood of bleeding.
- hyperbleeding in such patients is caused by diminished or deficient activity of FVIII and / or FVIIIa.
- the patient at risk of bleeding has hemophilia, which can be hemophilia A or severe hemophilia A.
- the regimen of the present invention comprises patients with hemophilia A, preferably patients with hemophilia A with FVIII inhibitors and / or hemophilia A without FVIII inhibitors, especially acquired. It may be applicable for patients with hemophilia A.
- inhibitor patient refers to a patient with hemophilia A carrying an FVIII inhibitor.
- non-inhibitor patient refers to a patient with hemophilia A who does not carry an FVIII inhibitor.
- the regimen of the present invention may be applicable for patients with severe hemophilia A.
- the pharmaceutical composition according to the dosing regimen of the present invention is used under immunosuppressive drug administration.
- immunosuppressive drugs include steroid drugs such as prednisolone and methylprednisolone, cyclophosphamide, rituximab, and cyclosporin A.
- "Used under immunosuppressive drug administration” means that the administration of emicizumab is performed at the same time as the administration of the immunosuppressive drug, in parallel with the administration of the immunosuppressive drug, before the administration of the immunosuppressive drug, or the immunosuppressive drug. It means that it is performed after the administration of.
- the effect of the immunosuppressive drug is determined by measuring FVIII activity, inhibitor titer, and / or activated partial thromboplastin time (APTT).
- APTT activated partial thromboplastin time
- the pharmaceutical composition containing emicizumab is administered in parallel with the administration of an immunosuppressive drug, the activity of emicizumab is neutralized with an anti-emicizumab antibody (neutralizing antibody against emicizumab) or the like.
- an anti-emicizumab antibody neutralizing antibody against emicizumab
- the effect of immunosuppressive drugs will be determined by measuring FVIII activity and the like by a synthetic substrate method or the like using a blood coagulation factor of an animal species that does not show reactivity.
- the administration of emicizumab will be discontinued.
- the pharmaceutical composition according to the administration regimen of the present invention has undesired complications in performing immunotherapy, has hemophilia A resistant to immunotherapy, or has clinically problematic side effects due to immunotherapy. It can also be applied to patients who cannot receive immunotherapy due to reasons such as expression. It can also be applied to patients who have not been able to obtain a significant therapeutic effect by immunotherapy.
- the regimen of the present invention may be applicable for adult and / or pediatric patients and / or for such special patient populations where exposure is expected to be lower.
- the medication regimen is determined, for example, by considering efficacy and safety.
- the dosing regimen is determined by considering patient convenience, as long as it does not compromise efficacy and safety.
- a dosing regimen for a patient with hemophilia A can be determined by considering its effectiveness in preventing bleeding in the patient and clinically acceptable safety.
- the present invention provides a product comprising (i) a container, (ii) a pharmaceutical composition in said container comprising emicizumab, and (iii) at least a document instructing administration of emicizumab by any of the above dosing regimens. ..
- labels, syringes, needles, pharmaceutically acceptable media, alcohol-impregnated cotton, gauze bandages and the like may be packaged within the product.
- the container may be, for example, a bottle, a glass bottle, or a syringe and may be made of various materials such as glass or plastic.
- a device to assist administration may be included with the product.
- the pharmaceutical composition is stored in a container, and the mouth of the container is sealed with a rubber stopper or the like.
- a label is attached to the container indicating that the pharmaceutical composition is to be used to prevent or treat the selected medical condition.
- the document (iii) may include instructions defining the dose, frequency or interval of loading and maintenance administration by the dosing regimen described above. Examples of documents include package inserts, package inserts, prescribing information, etc. attached to medical drugs.
- Treatment of bleeding is, for example, stopping bleeding by administering the composition to a bleeding patient who is actually showing bleeding symptoms (treatment of bleeding) and / or pre-existing bleeding symptoms.
- treatment of bleeding refers to, but is not limited to, reducing the frequency of bleeding (prevention of bleeding) by administering the composition to a patient who has shown bleeding.
- Treatment and prevention of bleeding may be understood to have the same meaning in certain cases, and such treatment and prevention of bleeding is also referred to as prophylaxis or routine therapy of emicizumab.
- Prevention of hemophilia refers to, for example, reducing the incidence of hemophilia or reducing the likelihood of hemophilia.
- the bleeding investigated and counted as the number of bleeding events in a patient is, for example, bleeding requiring hemostatic treatment with a coagulation factor preparation.
- the coagulation factor preparation refers to, for example, an FVIII preparation and a bypass preparation (active prothrombin complex preparation, recombinant FVIIa preparation, etc.).
- the number of bleeding per year (annual bleeding rate (ABR)) is calculated as, for example, (number of bleeding events x 365.25) / number of observation days.
- Example 1 Optimal application method / dose in patients with acquired hemophilia A (1) Assumed effective concentration in patients with acquired hemophilia A Since the molecular structure of emicizumab is different from that of FVIII, the FVIII inhibitor is the FVIII function of emicizumab. It does not affect the substitution activity, and it is considered that the same degree of bleeding suppression effect can be obtained by regular administration of emicizumab regardless of the presence or absence of FVIII inhibitor. In patients with congenital hemophilia A, the FVIII-substituting activity and bleeding-suppressing effect of emicizumab were similar in patients with and without inhibitors.
- a model in which anti-FVIII antibody is administered to crab monkeys to cause acquired hemophilia A pathology and then intramuscular puncture is performed to induce bleeding.
- Neutralized hemophilia A / puncture bleeding model and a model that induces bleeding by daily activities and operations under the condition that FVIII activity is reduced by the same method (Kanikuisaru FVIII neutralized hemophilia A / spontaneous bleeding model) , The bleeding-suppressing effect and hemostatic effect of emicizumab were suggested.
- the length of this period corresponds to the period of overdose of the approved dosage and administration of emicizumab in congenital hemophilia A (4 weeks), and the plasma emicizumab concentration trough value in the approved weekly regimen. Is also the period during which the steady state is reached. Therefore, as an example of the future treatment system for acquired hemophilia A, assuming that regular administration of emicizumab is started at the same time as the start of IST, the approved dosage and administration have a high risk of bleeding before PR is achieved. Is in the process of increasing plasma emicizumab concentration, while about half of the patients have already achieved PR 4 weeks after the start of administration (Day 29) when the plasma emicizumab concentration has finished increasing.
- the dosage and administration considered are expected to reach the expected effective concentration of 30 ⁇ g / mL earlier and stabilize earlier.
- 6 mg / kg on Day 1 and 3 mg / kg on Day 2 load administration
- Day 8 to 1.5 mg / kg repeated subcutaneous administration at weekly intervals (daily)
- Load administration + 1-week interval maintenance administration regimen The dose of 6 mg / kg given on Day 1 is the highest dose considered through a clinical development program in congenital hemophilia A and the highest approved dose per dose.
- Simulations of changes in plasma emicizumab concentration when the approved 1-week interval regimen and the disclosed daily load administration + 1-week interval maintenance administration regimen are administered to patients with acquired hemophilia A are shown in FIGS.
- plasma emicizumab concentration exceeded 30 ⁇ g / mL in many patients by 1 week after the start of administration (Day 8), and 2 weeks after the start of administration (Day 15). Since it is predicted that the plasma emicizumab concentration trough value will reach a steady state by then, the effect of regular administration of emicizumab for the purpose of preventing bleeding in acquired hemophilia A may be obtained promptly and stably. ..
- the daily load administration + weekly maintenance administration regimen of the present disclosure assumed in patients with acquired hemophilia A is considered to be sufficiently higher than the NOAEL exposure in these cynomolgus monkeys. Be done.
- the assumed daily dose + weekly maintenance regimen of the present disclosure ( Figure 2) is the highest dose tolerated through a clinical development program in congenital hemophilia A. It is below the mean plasma concentration trough value (120 ⁇ g / mL) in the steady state at 3 mg / kg weekly administration.
- the daily loading interval of the present disclosure + 1-week interval maintenance administration regimen which is the administration interval of loading administration, is a short administration interval that has not been experienced in previous non-clinical studies and clinical studies, but plasma is rapidly administered immediately after administration.
- the mean initial plasma concentration of NOAEL in a 4-week intravenous administration study using cynomolgus monkeys was 2160 to 2270 ⁇ g / mL, which was the daily load administration of the present disclosure + the load administration in the 1-week interval maintenance administration regimen. It is considered that the plasma emicizumab concentration (Fig. 2) is sufficiently covered. From these results, it was considered that a safe margin was secured for the daily load administration + 1-week interval maintenance administration regimen of the present disclosure.
- Example 2 In order to investigate the safety, efficacy, pharmacokinetics and pharmacodynamics of subcutaneous administration of emicizumab to patients with acquired hemophilia A by the daily load administration + 1-week interval maintenance administration regimen disclosed in the present disclosure, a multicenter, blind Conduct a screening, non-randomized, phase III clinical trial (hereinafter referred to as the "main clinical trial").
- emicizumab was subcutaneously administered at 6 mg / kg on Day 1 and 3 mg / kg on Day 2 (load administration), and from Day 8 to 1.5 mg / kg was repeatedly subcutaneously administered (maintenance administration) at weekly intervals. ..
- Subjects enrolled in this study will continue to receive emicizumab until they meet the criteria for termination / discontinuation of emicizumab or discontinue the study. Subjects who have completed / discontinued emicizumab will be followed up for safety 24 weeks after the end / discontinuation of emicizumab.
- the criteria for termination of administration of emicizumab are FVIII activity (emicizumab non-reactivity; one-step coagulation method under neutralization of emicizumab) of more than 50 IU / dL and 72 hours after administration of the last blood coagulation factor preparation for bleeding requiring the latest treatment It is that the super has passed.
- the criteria for discontinuing emicizumab are pregnancy and the development of unacceptable adverse events.
- the study consists of two cohorts, a cohort 1 that receives emicizumab with immunosuppressive therapy (with immunosuppressive drugs) and a cohort 2 with emicizumab without immunosuppressive therapy.
- a cohort 1 that receives emicizumab with immunosuppressive therapy (with immunosuppressive drugs)
- a cohort 2 with emicizumab without immunosuppressive therapy are two cohorts.
- the primary analysis should be performed when all of the following conditions are met: If it is determined that the dosage and administration need to be changed, the clinical trial will be conducted when all of the following conditions are met in the subjects who started the clinical trial with the changed dosage and administration. ⁇ At least 10 cases are registered in Cohort 1. ⁇ After 3 or more patients in Cohort 1 met the criteria for termination of administration of emicizumab, safety follow-up (24 weeks after termination of administration of emicizumab) was completed or the study was discontinued during the safety follow-up period. ⁇ All subjects in Cohort 1 have reached either end / discontinuation of emicizumab, continued emicizumab for at least 24 weeks, or discontinuation of the trial.
- Safety includes adverse events, physical laboratory findings, vital signs, 12-lead electrocardiogram, laboratory test values, blood coagulation factor VIII (FVIII) inhibitor (emicizumab non-reactivity; emicizumab neutralized coagulation one-step Bethesda method), anti-emicizumab Evaluate by antibody or the like. Efficacy is evaluated based on the number of bleedings required for treatment with a blood coagulation factor preparation, the actual use of the blood coagulation factor preparation, the actual blood transfusion, and the transition of hemoglobin level. Pharmacokinetics is assessed by plasma emicizumab concentration.
- Pharmaceutical dynamics include FVIII activity (emicizumab non-reactivity; one-step coagulation method under emicizumab neutralization), FVIII activity (emicizumab non-reactivity; synthetic substrate method using bovine coagulation factor), FVIII activity (emicizumab reactivity; human). It is evaluated by synthetic substrate method using coagulation factor), activated partial thromboplastin time (APTT), etc. From the results of this study, the usefulness of emicizumab in patients with acquired hemophilia A by the daily load administration + 1-week interval maintenance administration regimen disclosed in the present disclosure can be confirmed.
- the present invention provides an administration regimen of a pharmaceutical composition containing emicizumab, which can effectively prevent and / or treat acquired hemophilia A.
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Abstract
Description
エミシズマブは、(a)FIXおよび/またはFIXaならびに(b)FXおよび/または活性化血液凝固因子FX(FXa)と結合する組換えヒト化二重特異性抗体であり、FVIIIの補因子機能を代替する。エミシズマブは、先天性FVIII欠乏患者における出血傾向を抑制する遺伝子組換え製剤として、最近、米国や日本で承認された。この製剤は、1回3mg/kg(体重)を1週間の間隔で4回皮下投与し、以降は1回1.5 mg/kg(体重)を1週間の間隔、1回3mg/kg(体重)を2週間の間隔、または1回6mg/kg(体重)を4週間の間隔のいずれかの用法・用量で皮下投与する、という低頻度の投与が可能な長期作用型の皮下投与製剤であり、FVIIIに対するインヒビターの有無によらず有効性が確認されている。
後天性血友病Aを発症した患者は、通常、各種の免疫抑制療法による治療(以下、「免疫治療」)を受けることにより、70~80%は完全寛解(CR)を達成すると報告されている。しかし、治療開始から完全寛解(CR)達成までの期間中央値は数ヶ月、部分寛解(PR)達成までの中央値も約1ヶ月であり、その間、出血のリスク及び免疫治療による易感染性のリスクにさらされる。実際、後天性血友病Aの死因の多くは重篤な出血と重症感染症である。したがって、免疫治療を行う際に、その効果が得られるまでの間、FVIIIの機能を補完する薬剤による治療が必要となる。また、免疫治療を用いることのできない患者や、免疫治療を施しても有意義な効果を得られなかった患者については、FVIIIの機能を補完する薬剤の継続的な投与が必要となる。後天性血友病A患者に生じているインヒビターにより、FVIII製剤では治療効果を期待できないことから、FVIII製剤と比較して出血抑制効果が十分ではないバイパス製剤が用いられている。したがって、インヒビター存在下でも効果を発揮する、エミシズマブの後天性血友病Aへの適用が期待される。
一般に、後天性血友病Aの出血症状は先天性血友病患者に比べて重篤なものが多く、出血死のリスクが高い。また、発症早期の出血リスクが高く、免疫療法により出血リスクが低下していくことから、後天性血友病Aの治療剤としてエミシズマブを用いる場合、投与開始後早期に有効な血漿中エミシズマブ濃度が得られ、かつその有効濃度が維持されることが求められる。
この要請は、エミシズマブの投与が免疫治療下で行われるか否かに依らず適用される。免疫治療下では、患者のFVIII活性やインヒビター力価の測定などの免疫治療の効果判定を定期的に行い、効果が認められる場合は適時免疫治療薬剤の用量の減量および中止を、効果が認められない場合は薬剤の変更や追加を行う。免疫治療剤の投与と並行してエミシズマブの投与が行われる場合、この効果判定の結果により、エミシズマブの投与継続・中止も決定することが想定される。したがって、このようなモニタリングと治療継続・中止の決定の体制を早期にエミシズマブの使用と併せて適用することが望ましい。
エミシズマブの後天性血友病A用途については、後天性血友病Aのモデル実験でエミシズマブによる止血効果を確認した研究報告(非特許文献7、12)や、後天性血友病A患者へのエミシズマブ投与の報告(非特許文献13、14)が知られている。しかし、これらの報告では、後天性血友病Aにおけるエミシズマブの治療効果を得るまでの期間を短縮するという課題および解決手段についての記載はない。
[1] 後天性血友病Aを治療するおよび/または後天性血友病Aの発症率を低下させるために使用するための、エミシズマブを含む医薬組成物であって、エミシズマブが、6mg/kgの抗体の用量で初日に投与され、3mg/kg~6mg/kgの抗体の用量で2日目に投与され、かつ1.5mg/kg~3mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復される、前記医薬組成物。
[2] 初日の投与、2日目の投与、および8日目からの1週間毎の投与が、それぞれ1回投与で行われる、[1]の医薬組成物。
[3] 初日の投与、2日目の投与、および8日目からの1週間毎の投与が、それぞれ皮下投与で行われる、[1]または[2]の医薬組成物。
[4] エミシズマブが、3mg/kgの抗体の用量で2日目に投与される、[1]~[3]のいずれかの医薬組成物。
[5] エミシズマブが、1.5mg/kg~2mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復される、[1]~[4]のいずれかの医薬組成物。
[6] エミシズマブが、1.5mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復される、[1]~[5]のいずれかの医薬組成物。
[7] 免疫抑制薬投与下で使用される、[1]~[6]のいずれかの医薬組成物。
[8] 免疫抑制薬がステロイド薬である、[7]の医薬組成物。
[9] (i)容器;(ii)エミシズマブを含む、前記容器内の医薬組成物、ならびに(iii)エミシズマブを6mg/kgの抗体の用量で初日に投与し、3mg/kg~6mg/kgの抗体の用量で2日目に投与し、かつ1.5mg/kg~3mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復されることを指示する文書を含む、製品。
[10] 初日の投与、2日目の投与、および8日目からの1週間毎の投与が、それぞれ1回投与で行われる、[9]の製品。
[11] 初日の投与、2日目の投与、および8日目からの1週間毎の投与が、それぞれ皮下投与で行われる、[9]または[10]の製品。
[12] エミシズマブが、3mg/kgの抗体の用量で2日目に投与される、[9]~[11]のいずれかの製品。
[13] エミシズマブが、1.5mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復される、[9]~[12]のいずれかの製品。
[14] エミシズマブは免疫抑制薬と併用して使用することを指示する前記文書を含む、[9]~[13]のいずれかの製品。
[15] 後天性血友病Aを治療するおよび/または後天性血友病Aの発症率を低下させるために使用するための、エミシズマブを含む医薬組成物であって、エミシズマブが、6mg/kgの抗体の用量で初日に投与され、3mg/kg~6mg/kgの抗体の用量で2日目に投与され、かつ3mg/kg~4mg/kgの抗体の用量で8日目から2週間毎の投与が1回以上反復される、または6mg/kgの抗体の用量で8日目から4週間毎の投与が1回以上反復される、前記医薬組成物。
[16] エミシズマブが、3mg/kgの抗体の用量で8日目から2週間毎の投与が1回以上反復される、[15]の医薬組成物。
[17] 初日の投与、2日目の投与、および8日目からの2週間毎または4週間毎の投与が、それぞれ1回投与で行われる、[15]または[16]の医薬組成物。
[18] 初日の投与、2日目の投与、および8日目からの2週間毎または4週間毎の投与が、それぞれ皮下投与で行われる、[15]~[17]のいずれかの医薬組成物。
[19] エミシズマブが、3mg/kgの抗体の用量で2日目に投与される、[15]~[18]のいずれかの医薬組成物。
[20] 免疫抑制薬投与下で使用される、[15]~[19]のいずれかの医薬組成物。
[21] 免疫抑制薬がステロイド薬である、[20]の医薬組成物。
[22] 後天性血友病Aを治療するおよび/または後天性血友病Aの発症率を低下させるために使用するための、エミシズマブを含む医薬組成物であって、エミシズマブが、6mg/kgの抗体の用量で初日に投与され、3mg/kg~6mg/kgの抗体の用量で2日目に投与され、1.5mg/kg~3mg/kgの抗体の用量で8日目に投与され、かつ3mg/kg~4mg/kgの抗体の用量で15日目から2週間毎の投与が1回以上反復される、または6mg/kgの抗体の用量で15日目から4週間毎の投与が1回以上反復される、前記医薬組成物。
[23] エミシズマブが、3mg/kgの抗体の用量で15日目から2週間毎の投与が1回以上反復される、[22]の医薬組成物。
[24] 初日の投与、2日目の投与、8日目の投与、および15日目からの2週間毎または4週間毎の投与が、それぞれ1回投与で行われる、[22]または[23]の医薬組成物。
[25] 初日の投与、2日目の投与、8日目の投与、および15日目からの2週間毎または4週間毎の投与が、それぞれ皮下投与で行われる、[22]~[24]のいずれかの医薬組成物。
[26] エミシズマブが、3mg/kgの抗体の用量で2日目に投与される、[22]~[25]のいずれかの医薬組成物。
[27] エミシズマブが、1.5mg/kgの抗体の用量で8日目に投与される、[22]~[26]のいずれかの医薬組成物。
[28] 免疫抑制薬投与下で使用される、[22]~[27]のいずれかの医薬組成物。
[29] 免疫抑制薬がステロイド薬である、[28]の医薬組成物。
[30] 後天性血友病Aを治療するおよび/または後天性血友病Aの発症率を低下させるために使用するための、エミシズマブを含む医薬組成物であって、エミシズマブが、6mg/kgの抗体の用量で初日に投与され、3mg/kg~6mg/kgの抗体の用量で2日目に投与され、1.5mg/kg~6mg/kgの抗体の用量で3日目に投与され、かつ1.5mg/kg~3mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復される、3mg/kgの抗体の用量で8日目から2週間毎の投与が1回以上反復される、または6mg/kgの抗体の用量で8日目から4週間毎の投与が1回以上反復される、前記医薬組成物。
[31] 初日の投与、2日目の投与、3日目の投与、および8日目からの1週間毎、2週間毎または4週間毎の投与が、それぞれ1回投与で行われる、[30]の医薬組成物。
[32] 初日の投与、2日目の投与、3日目の投与、および8日目からの1週間毎、2週間毎または4週間毎の投与が、それぞれ皮下投与で行われる、[30]または[31]の医薬組成物。
[33] エミシズマブが、3mg/kgの抗体の用量で2日目に投与される、[30]~[32]のいずれかの医薬組成物。
[34] エミシズマブが、1.5mg/kgの抗体の用量で3日目に投与される、[30]~[33]のいずれかの医薬組成物。
[35] エミシズマブが、1.5mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復される、[30]~[34]のいずれかの医薬組成物。
[36] 免疫抑制薬投与下で使用される、[30]~[35]のいずれかの医薬組成物。
[37] 免疫抑制薬がステロイド薬である、[36]の医薬組成物。
[38] 後天性血友病Aを治療するおよび/または後天性血友病Aの発症率を低下させる方法であって、エミシズマブを、6mg/kgの抗体の用量で初日に投与すること、3mg/kg~6mg/kgの抗体の用量で2日目に投与すること、および1.5mg/kg~3mg/kgの抗体の用量で8日目から1週間毎の投与を1回以上反復することを含む、前記方法。
[39] 初日の投与、2日目の投与、および8日目からの1週間毎の投与が、それぞれ1回投与で行われる、[38]の方法。
[40] 初日の投与、2日目の投与、および8日目からの1週間毎の投与が、それぞれ皮下投与で行われる、[38]または[39]の方法。
[41] エミシズマブが、3mg/kgの抗体の用量で2日目に投与される、[38]~[40]のいずれかの方法。
[42] エミシズマブが、1.5mg/kg~2mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復される、[38]~[41]のいずれかの方法。
[43] エミシズマブが、1.5mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復される、[38]~[42]のいずれかの方法。
[44] 免疫抑制薬投与下で使用される、[38]~[43]のいずれかの方法。
[45] 免疫抑制薬がステロイド薬である、[44]の方法。
[46] 後天性血友病Aの治療剤および/または後天性血友病Aの発症率低下剤の製造のためのエミシズマブの使用であって、エミシズマブが、6mg/kgの抗体の用量で初日に投与され、3mg/kg~6mg/kgの抗体の用量で2日目に投与され、かつ1.5mg/kg~3mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復される、前記使用。
[47] 初日の投与、2日目の投与、および8日目からの1週間毎の投与が、それぞれ1回投与で行われる、[46]の使用。
[48] 初日の投与、2日目の投与、および8日目からの1週間毎の投与が、それぞれ皮下投与で行われる、[46]または[47]の使用。
[49] エミシズマブが、3mg/kgの抗体の用量で2日目に投与される、[46]~[48]のいずれかの使用。
[50] エミシズマブが、1.5mg/kg~2mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復される、[46]~[49]のいずれかの使用。
[51] エミシズマブが、1.5mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復される、[46]~[50]のいずれかの使用。
[52] 免疫抑制薬投与下で使用される、[46]~[51]のいずれかの使用。
[53] 免疫抑制薬がステロイド薬である、[52]の使用。
[54] 後天性血友病Aの治療および/または後天性血友病Aの発症率の低下に用いるためのエミシズマブであって、6mg/kgの抗体の用量で初日に投与され、3mg/kg~6mg/kgの抗体の用量で2日目に投与され、かつ1.5mg/kg~3mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復される、エミシズマブ。
[55] 初日の投与、2日目の投与、および8日目からの1週間毎の投与が、それぞれ1回投与で行われる、[54]のエミシズマブ。
[56] 初日の投与、2日目の投与、および8日目からの1週間毎の投与が、それぞれ皮下投与で行われる、[54]または[55]のエミシズマブ。
[57] 3mg/kgの抗体の用量で2日目に投与される、[54]~[56]のいずれかのエミシズマブ。
[58] 1.5mg/kg~2mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復される、[54]~[57]のいずれかのエミシズマブ。
[59] 1.5mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復される、[54]~[58]のいずれかのエミシズマブ。
[60] 免疫抑制薬投与下で使用される、[54]~[59]のいずれかのエミシズマブ。
[61] 免疫抑制薬がステロイド薬である、[60]のエミシズマブ。
[62] 後天性血友病Aを治療するおよび/または後天性血友病Aの発症率を低下させる方法であって、エミシズマブを、6mg/kgの抗体の用量で初日に投与すること、3mg/kg~6mg/kgの抗体の用量で2日目に投与すること、および3mg/kg~4mg/kgの抗体の用量で8日目から2週間毎の投与を1回以上反復するか、または6mg/kgの抗体の用量で8日目から4週間毎の投与を1回以上反復することを含む、前記方法。
[63] 後天性血友病Aを治療するおよび/または後天性血友病Aの発症率を低下させる方法であって、エミシズマブを、6mg/kgの抗体の用量で初日に投与すること、3mg/kg~6mg/kgの抗体の用量で2日目に投与すること、1.5mg/kg~3mg/kgの抗体の用量で8日目に投与すること、および3mg/kg~4mg/kgの抗体の用量で15日目から2週間毎の投与を1回以上反復するか、または6mg/kgの抗体の用量で15日目から4週間毎の投与を1回以上反復することを含む、前記方法。
[64] 後天性血友病Aを治療するおよび/または後天性血友病Aの発症率を低下させる方法であって、エミシズマブを、6mg/kgの抗体の用量で初日に投与すること、3mg/kg~6mg/kgの抗体の用量で2日目に投与すること、1.5mg/kg~6mg/kgの抗体の用量で3日目に投与すること、および1.5mg/kg~3mg/kgの抗体の用量で8日目から1週間毎の投与を1回以上反復するか、3mg/kg~4mg/kgの抗体の用量で8日目から2週間毎の投与を1回以上反復するか、または6mg/kgの抗体の用量で8日目から4週間毎の投与を1回以上反復することを含む、前記方法。
[65] 後天性血友病Aの治療剤および/または後天性血友病Aの発症率低下剤の製造のためのエミシズマブの使用であって、エミシズマブが、6mg/kgの抗体の用量で初日に投与され、3mg/kg~6mg/kgの抗体の用量で2日目に投与され、かつ3mg/kg~4mg/kgの抗体の用量で8日目から2週間毎の投与が1回以上反復されるか、または6mg/kgの抗体の用量で8日目から4週間毎の投与が1回以上反復される、前記使用。
[66] 後天性血友病Aの治療剤および/または後天性血友病Aの発症率低下剤の製造のためのエミシズマブの使用であって、エミシズマブが、6mg/kgの抗体の用量で初日に投与され、3mg/kg~6mg/kgの抗体の用量で2日目に投与され、1.5mg/kg~3mg/kgの抗体の用量で8日目に投与され、かつ3mg/kg~4mg/kgの抗体の用量で15日目から2週間毎の投与が1回以上反復されるか、または6mg/kgの抗体の用量で15日目から4週間毎の投与が1回以上反復される、前記使用。
[67] 後天性血友病Aの治療剤および/または後天性血友病Aの発症率低下剤の製造のためのエミシズマブの使用であって、エミシズマブが、6mg/kgの抗体の用量で初日に投与され、3mg/kg~6mg/kgの抗体の用量で2日目に投与され、1.5mg/kg~6mg/kgの抗体の用量で3日目に投与され、かつ1.5mg/kg~3mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復されるか、3mg/kg~4mg/kgの抗体の用量で8日目から2週間毎の投与が1回以上反復されるか、または6mg/kgの抗体の用量で8日目から4週間毎の投与が1回以上反復される、前記使用。
[68] 後天性血友病Aの治療および/または後天性血友病Aの発症率の低下に用いるためのエミシズマブであって、6mg/kgの抗体の用量で初日に投与され、3mg/kg~6mg/kgの抗体の用量で2日目に投与され、かつ3mg/kg~4mg/kgの抗体の用量で8日目から2週間毎の投与が1回以上反復されるか、または6mg/kgの抗体の用量で8日目から4週間毎の投与が1回以上反復される、エミシズマブ。
[69] 後天性血友病Aの治療および/または後天性血友病Aの発症率の低下に用いるためのエミシズマブであって、6mg/kgの抗体の用量で初日に投与され、3mg/kg~6mg/kgの抗体の用量で2日目に投与され、1.5mg/kg~3mg/kgの抗体の用量で8日目に投与され、かつ3mg/kg~4mg/kgの抗体の用量で15日目から2週間毎の投与が1回以上反復されるか、または6mg/kgの抗体の用量で15日目から4週間毎の投与が1回以上反復される、エミシズマブ。
[70] 後天性血友病Aの治療および/または後天性血友病Aの発症率の低下に用いるためのエミシズマブであって、6mg/kgの抗体の用量で初日に投与され、3mg/kg~6mg/kgの抗体の用量で2日目に投与され、1.5mg/kg~6mg/kgの抗体の用量で3日目に投与され、かつ1.5mg/kg~3mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復されるか、3mg/kg~4mg/kgの抗体の用量で8日目から2週間毎の投与が1回以上反復されるか、または6mg/kgの抗体の用量で8日目から4週間毎の投与が1回以上反復される、エミシズマブ。
エミシズマブ(ACE910、RO5534262)は、(a)血液凝固第IX因子(FIX)および/または活性化血液凝固第IX因子(FIXa)ならびに(b)血液凝固第X因子(FX)および/または活性化血液凝固第X因子(FXa)を認識する二重特異性抗原結合分子であり、凝固第VIII因子(FVIII)の機能を代替する活性を有する。
(a)それぞれ、SEQ ID NO:1、2、および3のCDR 1、2、および3のアミノ酸配列を含有しているH鎖可変領域を含有しているH鎖である第1のポリペプチド;それぞれ、SEQ ID NO:6、7、および8のCDR 1、2、および3のアミノ酸配列を含有しているH鎖可変領域を含有しているH鎖である第2のポリペプチド;ならびに、それぞれ、SEQ ID NO:11、12、および13のCDR 1、2、および3のアミノ酸配列を含有しているL鎖可変領域を含有している共有のL鎖である第3および第4のポリペプチドを含む、二重特異性抗体;
(b)SEQ ID NO:4のH鎖可変領域アミノ酸配列を含有しているH鎖である第1のポリペプチド;SEQ ID NO:9のH鎖可変領域アミノ酸配列を含有しているH鎖である第2のポリペプチド;ならびにSEQ ID NO:14のL鎖可変領域アミノ酸配列を含有している共有のL鎖である第3および第4のポリペプチドを含む、二重特異性抗体;または
(c)SEQ ID NO:5のアミノ酸配列を含有しているH鎖である第1のポリペプチド;SEQ ID NO:10のアミノ酸配列を含有しているH鎖である第2のポリペプチド;ならびにSEQ ID NO:15のアミノ酸配列を含有している共有のL鎖である第3および第4のポリペプチドを含む、二重特異性抗体(Q499-z121/J327-z119/L404-k)。
20mg/ml~180mg/mlのエミシズマブ、
0.2mg/ml~1mg/mlのポロキサマー188、
10mM~40mMのヒスチジン-アスパラギン酸緩衝液、
100mM~300mMのアルギニン(約4.5~6.5のpH)。
また、1バイアル中のエミシズマブの用量は30mg, 60mg, 90mg, 105mgまたは150mgとすることができる。
「初日の投与」とは、後天性血友病Aの予防および/または治療のための、患者へのエミシズマブの最初の投与を指す。また、「2日目の投与」とは、初日の投与を1日目として翌日を指し、「8日目の投与」とは、初日の投与を1日目として8日目を指す。その他の日付についても同様である。
それに対して、本開示の投与レジメン(連日負荷投与+1~4週間隔維持投与レジメン)においては、エミシズマブを少なくとも2日続けて投与すること(連日負荷投与)によって、投与開始後早期に有効な血漿中エミシズマブ濃度が得られ、初回投与から約1週間後以降はエミシズマブを1~4週間隔で投与すること(1~4週間隔維持投与)によって前記有効濃度が維持されうる。
(1)初日に6mg/kgの抗体の用量で1回皮下投与する;
(2)2日目に、3mg/kg、4.5mg/kg、または6mg/kgの抗体の用量で1回皮下投与する;ならびに
(3)8日目から、1.5mg/kgの抗体の用量で1週間毎の1回皮下投与、3mg/kgの抗体の用量で2週間毎の1回皮下投与、または6mg/kgの抗体の用量で4週間毎の1回皮下投与を反復する。
(1)初日に6mg/kgの抗体の用量で1回皮下投与する;
(2)2日目に6mg/kgの抗体の用量で1回皮下投与する;
(3)3日目に、1.5mg/kg、3mg/kg、4.5mg/kg、または6mg/kgの抗体の用量で1回皮下投与する;ならびに
(4)8日目から、1.5mg/kgの抗体の用量で1週間毎の1回皮下投与、3mg/kgの抗体の用量で2週間毎の1回皮下投与、または6mg/kgの抗体の用量で4週間毎の1回皮下投与を反復する。
(1)初日に6mg/kgの抗体の用量で1回皮下投与する;ならびに
(2)2日目に4.5mg/kgの抗体の用量で1回皮下投与し、8日目から、1.75mg/kgの抗体の用量で1週間毎の1回皮下投与または3.5mg/kgの抗体の用量で2週間毎の1回皮下投与を反復する;
2日目に4.8mg/kgの抗体の用量で1回皮下投与し、8日目から、1.8mg/kgの抗体の用量で1週間毎の1回皮下投与または3.6mg/kgの抗体の用量で2週間毎の1回皮下投与を反復する;
2日目に6mg/kgの抗体の用量で1回皮下投与し、8日目から、2mg/kgの抗体の用量で1週間毎の1回皮下投与または4mg/kgの抗体の用量で2週間毎の1回皮下投与を反復する;あるいは
2日目に3.3mg/kgの抗体の用量で1回皮下投与し、3日目に3.3mg/kgの抗体の用量で1回皮下投与し、8日目から、2.1mg/kgの抗体の用量で1週間毎の1回皮下投与または4.2mg/kgの抗体の用量で2週間毎の1回皮下投与を反復する。
(1)初日に6mg/kgの抗体の用量で1回皮下投与する;
(2)2日目に6mg/kgの抗体の用量で1回皮下投与する;
(3)3日目に1.5mg/kgの抗体の用量で1回皮下投与し、8日目から、2.25mg/kgの抗体の用量で1週間毎の1回皮下投与または4.5mg/kgの抗体の用量で2週間毎の1回皮下投与を反復する;
3日目に2.4mg/kgの抗体の用量で1回皮下投与し、8日目から、2.4mg/kgの抗体の用量で1週間毎の1回皮下投与または4.8mg/kgの抗体の用量で2週間毎の1回皮下投与を反復する;
3日目に3mg/kgの抗体の用量で1回皮下投与し、8日目から、2.5mg/kgの抗体の用量で1週間毎の1回皮下投与または5mg/kgの抗体の用量で2週間毎の1回皮下投与を反復する;
3日目に4.2mg/kgの抗体の用量で1回皮下投与し、8日目から、2.7mg/kgの抗体の用量で1週間毎の1回皮下投与または5.4mg/kgの抗体の用量で2週間毎の1回皮下投与を反復する;
3日目に4.5mg/kgの抗体の用量で1回皮下投与し、8日目から、2.75mg/kgの抗体の用量で1週間毎の1回皮下投与または5.5mg/kgの抗体の用量で2週間毎の1回皮下投与を反復する;あるいは
3日目に6mg/kgの抗体の用量で1回皮下投与し、8日目から、3mg/kgの抗体の用量で1週間毎の1回皮下投与または6mg/kgの抗体の用量で2週間毎の1回皮下投与を反復する。
<維持投与が1週間隔の場合>
<維持投与が2週間隔の場合>
<維持投与が4週間隔の場合>
「免疫抑制薬投与下で使用される」とは、エミシズマブの投与が、免疫抑制薬の投与と同時に、免疫抑制薬の投与と並行して、免疫抑制薬の投与の前に、または免疫抑制薬の投与の後に行われることをいう。
先天性血友病Aにおけるエミシズマブの臨床開発プログラムを通じて、後天性血友病Aにおいて標準的な止血治療薬として用いられているバイパス製剤に対し、出血抑制効果に関する既承認のエミシズマブ1週間隔レジメンの優越性がインヒビター保有先天性血友病A患者において示されている。
インヒビター保有先天性血友病A成人/青年患者を対象とした国際共同第III相臨床試験(BH29884試験)において、試験参加前にバイパス製剤による出血時止血療法を受けていた患者を対象に、エミシズマブを既承認の1週間隔レジメンにて定期投与した際(A群)、エミシズマブ定期投与非実施群(Bcontrol群)と比較して、治療を要した出血の年間出血率について統計学的に有意で臨床的に意味のある低下が認められた。また、同試験において、試験参加前に非介入試験(BH29768試験)に参加してバイパス製剤による出血時止血療法又は定期輸注を受けていた患者(それぞれANIS群又はCNIS群)を対象に、エミシズマブを同用法・用量にて定期投与した際、バイパス製剤による出血時止血療法実施時又は定期輸注時と比較して、いずれも治療を要した出血の年間出血率の低下が認められた。インヒビター保有先天性血友病A小児患者を対象とした国際共同第III相臨床試験(BH29992試験)においても、試験参加前にBH29768試験に参加してバイパス製剤による出血時止血療法又は定期輸注を受けていた患者を対象に、エミシズマブを同用法・用量にて定期投与した際、バイパス製剤による出血時止血療法実施時又は定期輸注時と比較して、治療を要した出血の年間出血率の低下が認められた。
インヒビター保有先天性血友病A患者において示されたバイパス製剤に対する既承認のエミシズマブ1週間隔レジメンの優越性は、多くの患者で血漿中エミシズマブ濃度が30 μg/mLを上回る用法・用量間で一般化が可能であると考えられる。
BH29884試験、BH29992試験、インヒビター非保有先天性血友病A成人/青年患者を対象とした国際共同第III相臨床試験(BH30071試験)、並びにインヒビター保有及び非保有先天性血友病A成人/青年患者を対象とした国際共同第III相臨床試験(BO39182試験)を通じて、エミシズマブを既承認の1週、2週又は4週間隔レジメンにて定期投与した際の出血抑制効果は、FVIIIインヒビターの有無及び用法・用量に依らず同程度であった。既承認の1週、2週又は4週間隔レジメンを投与した際、有効性解析期間全体におけるエミシズマブの平均血漿中濃度と治療を要した出血に基づく年間出血率との間に顕著な関連性は認められなかったことから、用法・用量に依らず多くの患者においてエミシズマブが有する最大又は最大に近い出血抑制効果が得られていることが示唆された。また、母集団曝露量-有効性解析により、およそ30 μg/mL超の血漿中エミシズマブ濃度存在下で治療を要する出血に基づく年間出血率の低下効果が最大に達すると予測され、多くの患者で血漿中エミシズマブ濃度が30 μg/mLを上回ると推定される既承認の1週、2週及び4週間隔レジメン間の血漿中エミシズマブ濃度推移の違いは、有効性に影響を与えないと考えられた。
(1)後天性血友病A患者における想定有効濃度
エミシズマブの分子構造はFVIIIと異なることから、FVIIIインヒビターはエミシズマブのFVIII機能代替活性に影響を与えず、FVIIIインヒビターの有無に依らずエミシズマブ定期投与により同程度の出血抑制効果が得られると考えられる。先天性血友病A患者において、エミシズマブのFVIII機能代替活性及び出血抑制効果は、インヒビター保有患者と非保有患者で類似していた。
エミシズマブの効力を裏付ける薬効薬理試験(in vivo)として、カニクイザルに抗FVIII抗体を投与して後天的な血友病A病態にした上で筋肉内穿刺等を施して出血を惹起させるモデル(カニクイザルFVIII中和血友病A/穿刺出血モデル)、及び同方法でFVIII活性を低下させた状況下で日常行動・操作により出血を惹起させるモデル(カニクイザルFVIII中和血友病A/自然出血モデル)において、エミシズマブの出血抑制効果及び止血効果が示唆された。また、後天性血友病A患者から得られた血漿検体にex vivoで複数濃度のエミシズマブを添加して包括的凝固能検査を実施した結果、血漿中エミシズマブ濃度依存的な凝固能の改善が認められたことが報告されている(Blood 126(23), 3565 (2015))。
これらの結果から、後天性血友病A患者においてもエミシズマブ定期投与により出血抑制効果が得られ、先天性血友病A患者と同様の曝露量-有効性関係を示すことが期待される。そのため、後天性血友病Aにおいて標準的な止血治療薬として用いられているバイパス製剤に対する優越性の一般化が可能になると考えられる30 μg/mLを、後天性血友病A患者における想定有効濃度に設定することとした。
FVIIIの先天的欠損又は機能不全に起因し、生涯にわたり止血及び出血予防を目的とした治療が必要とされる先天性血友病Aとは異なり、後天性血友病Aに起因して出血リスクに晒される期間は、FVIIIインヒビターが存在してFVIII活性が低下している期間に限定的であると考えられる。免疫抑制療法(IST)によりFVIII活性が回復し、出血リスクが最小化されるまでに要する期間の指標として、ISTを開始してから部分寛解(PR)を達成するまでの期間が中央値で31日という報告がある(Blood 125(7), 1091-1097 (2015))。この期間の長さは、先天性血友病Aにおけるエミシズマブの既承認用法・用量の負荷投与の期間(4週間)に相当しており、既承認の1週間隔レジメンにおいて血漿中エミシズマブ濃度トラフ値が定常状態に到達する期間でもある。したがって、将来的な後天性血友病Aの治療体系の一例として、ISTの開始と同時にエミシズマブ定期投与が開始されることを仮定した場合、既承認用法・用量では、出血リスクが高いPR達成前は血漿中エミシズマブ濃度が上昇している最中である一方、血漿中エミシズマブ濃度が上昇し終わった投与開始4週後(Day 29)の時点では、およそ半数の患者が既にPRを達成しており、それ以上のエミシズマブの投与が必要とされなくなっていることが想定される。そのため、既承認用法・用量では、後天性血友病Aにおける出血予防を目的としたエミシズマブ定期投与のポテンシャルを最大化できない可能性がある。
これらの想定に基づき、後天性血友病Aの治療体系及び臨床経過に適合するエミシズマブの用法・用量を検討した。先天性血友病A患者の血漿中エミシズマブ濃度データを用いて構築した母集団薬物動態モデルを用い、後天性血友病A患者における血漿中エミシズマブ濃度推移をシミュレーションした。母集団薬物動態モデルの構造モデルには、一次吸収過程及び一次消失過程を伴う1-コンパートメントモデルが選択された。個体間変動モデル及び残差変動モデルには、それぞれ指数誤差モデル及び混合誤差モデルが選択された。母集団薬物動態モデルのパラメータ推定値を表1に、組み込まれた共変量の効果を表2に示す。シミュレーション時の共変量の分布(平均値±標準偏差)又は内訳として、年齢は74.9±10.5歳、体重は69±13.3 kg、アルブミンは45.0±4.13 g/L、及び人種は非黒人/非アフリカ系アメリカ人とした。77歳超の患者におけるバイオアベイラビリティは、一貫して77歳の患者と等しいと仮定した。解析はNONMEM version 7.2.0又は7.4.3(ICON Development Solutions, Ellicott City, MD, USA)を用いて実施した。
a 分散に対して算出されたRSE。
b 共分散に対して算出されたRSE。
既承認の1週間隔レジメン及び本開示の連日負荷投与+1週間隔維持投与レジメンを後天性血友病A患者に投与した際の血漿中エミシズマブ濃度推移のシミュレーションを、それぞれ図1及び図2に示す。既承認の1週間隔レジメンでは、投与開始1週後(Day 8)及び4週後(Day 29)における血漿中エミシズマブ濃度トラフ値の中央値は、それぞれ11.6及び37.8 μg/mLと予測される。一方、本開示の連日負荷投与+1週間隔維持投与レジメンでは、投与開始1週後(Day 8)及び4週後(Day 29)における血漿中エミシズマブ濃度トラフ値の中央値は、それぞれ34.6及び36.9 μg/mLと予測される。本開示の連日負荷投与+1週間隔維持投与レジメンでは、投与開始1週後(Day 8)までに多くの患者で血漿中エミシズマブ濃度が30 μg/mLを上回り、投与開始2週後(Day 15)までに血漿中エミシズマブ濃度トラフ値が定常状態に到達すると予測されることから、後天性血友病Aにおける出血予防を目的としたエミシズマブ定期投与の効果が速やか且つ安定的に得られる可能性がある。
エミシズマブの毒性評価プログラムとして、カニクイザルを用いた13週間及び26週間皮下投与試験、並びに4週間静脈内投与試験が実施された。無毒性量(NOAEL)はそれぞれ1週間隔投与量として30、30及び100 mg/kgと判断され、NOAELにおける最終投与時の平均最高血漿中濃度(静脈内投与試験では平均初期血漿中濃度)は、それぞれ1070~1200、1340~1370及び3550~3560 μg/mLであった。後天性血友病A患者で想定される本開示の連日負荷投与+1週間隔維持投与レジメンにおける血漿中エミシズマブ濃度(図2)は、これらのカニクイザルでのNOAELにおける曝露量よりも十分に高いと考えられる。ヒトにおいては、本開示の連日負荷投与+1週間隔維持投与レジメンで想定される曝露量(図2)は、先天性血友病Aにおける臨床開発プログラムを通じて忍容性が確認された最高用量である3 mg/kg 1週間隔投与での定常状態における血漿中濃度トラフ値の平均値(120 μg/mL)を下回っている。
本開示の連日負荷投与+1週間隔維持投与レジメンにおける負荷投与の投与間隔である1日は、これまでの非臨床試験及び臨床試験において経験のない短い投与間隔であるが、投与直後に急速に血漿中エミシズマブ濃度が上昇する静脈内投与での毒性試験成績に基づき、急性毒性に関する安全域は確保されていると考えられる。カニクイザルを用いた4週間静脈内投与試験でのNOAELにおける初回投与時の平均初期血漿中濃度は2160~2270 μg/mLであり、本開示の連日負荷投与+1週間隔維持投与レジメンにおける負荷投与時の血漿中エミシズマブ濃度(図2)を十分にカバーできていると考えられる。
これらの結果から、本開示の連日負荷投与+1週間隔維持投与レジメンには安全域が確保されていると考えられた。
本開示の連日負荷投与+1週間隔維持投与レジメンにより後天性血友病A患者にエミシズマブを皮下投与した際の安全性、有効性、薬物動態及び薬力学を検討するため、多施設共同、非盲検、非ランダム化、第III相臨床試験(以下、「本治験」)を実施する。
本治験では、エミシズマブをDay 1に6 mg/kg及びDay 2に3 mg/kgを皮下投与(負荷投与)し、Day 8から1.5 mg/kgを1週間隔で反復皮下投与(維持投与)する。本治験に登録された被験者は、エミシズマブ投与終了/中止基準に該当する又は治験の中止までエミシズマブ投与を継続する。エミシズマブ投与終了/中止した被験者は、エミシズマブ投与終了/中止後24週間の安全性フォローアップを実施する。エミシズマブ投与終了基準は、FVIII活性(エミシズマブ非反応性;エミシズマブ中和下での凝固一段法)が50 IU/dL超、かつ直近の治療を要した出血に対する最後の血液凝固因子製剤投与後72時間超が経過していることである。エミシズマブ投与中止基準は、妊娠及び許容できない有害事象の発現である。
後天性血友病A患者におけるエミシズマブの至適用法・用量を確認するため、後天性血友病A患者における当該用法・用量の適切性を中間データレビューにて評価する。治験依頼者は、コホート1に登録された最初の6例がエミシズマブ投与開始4週後に至った時点、又は必要に応じてそれ以前に、それまでの安全性、有効性、薬物動態及び薬力学を、医学専門家と協議の上、総合的に評価し、用法・用量の適切性を判断する。用法・用量の変更が必要と判断された場合は、コホート1に追加で症例を登録し、新たな用法・用量を検討する可能性がある。
用法・用量が適切であると判断された後に、治験登録時点で治験責任(分担)医師により免疫抑制療法の実施が困難な容態と判断された18歳以上の後天性血友病A患者のコホート2への登録を開始し、1例以上登録する。
● コホート1に最低10例が登録されている。
● コホート1の3例以上がエミシズマブ投与終了基準に該当後、安全性フォローアップ(エミシズマブ投与終了後24週間)を完了又は安全性フォローアップ期間中に治験を中止している。
● コホート1のすべての被験者がエミシズマブ投与終了/中止、エミシズマブ投与を24週間以上継続、又は治験中止のいずれかに到達している。
本治験の結果から、本開示の連日負荷投与+1週間隔維持投与レジメンによる後天性血友病A患者におけるエミシズマブの有用性を確認することができる。
Claims (15)
- 後天性血友病Aを治療するおよび/または後天性血友病Aの発症率を低下させるために使用するための、エミシズマブを含む医薬組成物であって、エミシズマブが、6mg/kgの抗体の用量で初日に投与され、3mg/kg~6mg/kgの抗体の用量で2日目に投与され、かつ1.5mg/kg~3mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復される、前記医薬組成物。
- 初日の投与、2日目の投与、および8日目からの1週間毎の投与が、それぞれ1回投与で行われる、請求項1に記載の医薬組成物。
- 初日の投与、2日目の投与、および8日目からの1週間毎の投与が、それぞれ皮下投与で行われる、請求項1または2に記載の医薬組成物。
- エミシズマブが、3mg/kgの抗体の用量で2日目に投与される、請求項1~3のいずれかに記載の医薬組成物。
- エミシズマブが、1.5mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復される、請求項1~4のいずれかに記載の医薬組成物。
- 免疫抑制薬投与下で使用される、請求項1~5のいずれかに記載の医学的組成物。
- 免疫抑制薬がステロイド薬である、請求項6に記載の医学的組成物。
- (i)容器;(ii)エミシズマブを含む、前記容器内の医学的組成物、ならびに(iii)エミシズマブを6mg/kgの抗体の用量で初日に投与し、3mg/kg~6mg/kgの抗体の用量で2日目に投与し、かつ1.5mg/kg~3mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復されることを指示する文書を含む、製品。
- 初日の投与、2日目の投与、および8日目からの1週間毎の投与が、それぞれ1回投与で行われる、請求項8に記載の製品。
- 初日の投与、2日目の投与、および8日目からの1週間毎の投与が、それぞれ皮下投与で行われる、請求項8または9に記載の製品。
- エミシズマブが、3mg/kgの抗体の用量で2日目に投与される、請求項8~10のいずれかに記載の製品。
- エミシズマブが、1.5mg/kgの抗体の用量で8日目から1週間毎の投与が1回以上反復される、請求項8~11のいずれかに記載の製品。
- エミシズマブは免疫抑制薬と併用して使用することを指示する前記文書を含む、請求項8~12のいずれかに記載の製品。
- 後天性血友病Aを治療するおよび/または後天性血友病Aの発症率を低下させるために使用するための、エミシズマブを含む医薬組成物であって、エミシズマブが、6mg/kgの抗体の用量で初日に投与され、3mg/kg~6mg/kgの抗体の用量で2日目に投与され、かつ3mg/kg~4mg/kgの抗体の用量で8日目から2週間毎の投与が1回以上反復される、または6mg/kgの抗体の用量で8日目から4週間毎の投与が1回以上反復される、前記医薬組成物。
- 後天性血友病Aを治療するおよび/または後天性血友病Aの発症率を低下させるために使用するための、エミシズマブを含む医薬組成物であって、エミシズマブが、6mg/kgの抗体の用量で初日に投与され、3mg/kg~6mg/kgの抗体の用量で2日目に投与され、1.5mg/kg~3mg/kgの抗体の用量で8日目に投与され、かつ3mg/kg~4mg/kgの抗体の用量で15日目から2週間毎の投与が1回以上反復される、または6mg/kgの抗体の用量で15日目から4週間毎の投与が1回以上反復される、前記医薬組成物。
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CN202080070494.4A CN114599391A (zh) | 2019-10-11 | 2020-10-08 | 可用于预防和/或治疗获得性血友病a的药物组合物,以及包含所述药物组合物的产品 |
CR20220198A CR20220198A (es) | 2019-10-11 | 2020-10-08 | Composición farmacéutica que puede usarse para la prevención y/o el tratamiento de la hemofilia a adquirida, y producto que comprende la composición farmacéutica |
CA3152701A CA3152701A1 (en) | 2019-10-11 | 2020-10-08 | Pharmaceutical composition which can be used for prevention and/or treatment of acquired hemophilia a, and product comprising said pharmaceutical composition |
KR1020227014361A KR20220082000A (ko) | 2019-10-11 | 2020-10-08 | 후천성 혈우병 a의 예방 및/또는 치료에 이용되는 의약 조성물, 및 당해 의약 조성물을 포함하는 제품 |
AU2020364698A AU2020364698A1 (en) | 2019-10-11 | 2020-10-08 | Pharmaceutical composition which can be used for prevention and/or treatment of acquired hemophilia A, and product comprising said pharmaceutical composition |
EP20873831.0A EP4043033A4 (en) | 2019-10-11 | 2020-10-08 | PHARMACEUTICAL COMPOSITION THAT MAY BE USED FOR THE PREVENTION AND/OR TREATMENT OF ACQUIRED HEMOPHILIA A AND PRODUCT CONTAINING THE PHARMACEUTICAL COMPOSITION |
JP2020555930A JP6836696B1 (ja) | 2019-10-11 | 2020-10-08 | 後天性血友病aの予防および/または治療に用いられる医薬組成物、および当該医薬組成物を含む製品 |
US17/763,948 US20220305122A1 (en) | 2019-10-11 | 2020-10-08 | Pharmaceutical composition which can be used for prevention and/or treatment of acquired hemophilia a, and product comprising said pharmaceutical composition |
MX2022003912A MX2022003912A (es) | 2019-10-11 | 2020-10-08 | Composicion farmaceutica que puede usarse para la prevencion y/o el tratamiento de la hemofilia a adquirida, y producto que comprende la composicion farmaceutica. |
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US11352438B2 (en) | 2016-09-06 | 2022-06-07 | Chugai Seiyaku Kabushiki Kaisha | Methods of using a bispecific antibody that recognizes coagulation factor IX and/or activated coagulation factor IX and coagulation factor X and/or activated coagulation factor X |
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Cited By (1)
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US11352438B2 (en) | 2016-09-06 | 2022-06-07 | Chugai Seiyaku Kabushiki Kaisha | Methods of using a bispecific antibody that recognizes coagulation factor IX and/or activated coagulation factor IX and coagulation factor X and/or activated coagulation factor X |
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