Compositions and methods for treating immune thrombocytopenia

Abstract

This provides a treatment method for individuals diagnosed with immune thrombocytopenia (ITP). [Solution] The method involves administering a human neonatal type Fc receptor (hFcRn) antagonist to a human subject, optionally in combination with standard treatment for ITP. In certain embodiments, the hFcRn antagonist is fgultigimod (ARGX-113). Standard treatment for ITP may include administering a corticosteroid, an immunosuppressant, and / or a thrombopoietin receptor (TPO-R) agonist.

Description

[Technical Field]

[0001] (Related applications) This application is U.S. Patent Application No. 62 / 682,805, filed on June 8, 2018, and was approved on September 16, 2018. U.S. Patent Application No. 62 / 731,947 filed, and U.S. Patent Application filed on September 17, 2018. This application claims the benefit of priority under No. 62 / 732,414, and the entire content of these applications is cited. It is incorporated into this specification as needed.

[0002] (Sequence Listing) This application is submitted electronically in ASCII format and is cited in its entirety. This specification includes sequence listings. This ASCII copy was created on June 6, 2019. The file name is 613052_AGX5-045PC_ST25.txt and its size is 8,254 bytes. ru.

[0003] (Field of invention) This invention generally relates to the treatment of immune thrombocytopenia (ITP), and more specifically, optionally ITP Regarding treatment methods, including the administration of FcRn antagonists in combination with standard treatment procedures. . [Background technology]

[0004] (Background of the invention) Immunotoxic thrombocytopenia is sometimes called immunotoxic thrombocytopenic purpura or idiopathic thrombocytopenia. It is generally called ITP, but this is a healthy individual's 150 × 10 9 ~450×10 9 Compared to / L, 100 x 10 9 It is characterized by a decrease in peripheral blood platelet count to less than 1 / L. ITPs are glycoproteins This is an autoimmune disease in which autoantibodies are formed that interfere with platelet production. It is thought to contribute to both the suppression of platelet count and the promotion of platelet destruction. It can be transient or persistent and can stem from a variety of causes.

[0005] ITP in which the associated cause or disorder cannot be determined is called primary ITP, whereas other ITPs are referred to as primary ITP. ITP linked to autoimmune disorders or medical disorders is called secondary ITP. ITP typically develops latently without a preceding viral or other illness, and While ITP usually follows a chronic course, ITP in children is usually short-lived, with at least two-thirds of cases lasting six months. It will recover naturally within a few months.

[0006] ITP is platelet-type bleeding (e.g., petechiae; purpura; conjunctival hemorrhage or other types of skin bleeding). This can manifest itself. ITP can be associated with fatal complications such as intracranial hemorrhage. Even if serious consequences are not present, ITP patients are at risk of developing other chronic diseases such as diabetes and rheumatoid arthritis. Similar to sexually transmitted diseases, it can lead to a decline in quality of life.

[0007] In 2011, the American Society of Hematology (ASH) issued treatment guidelines for ITP. (References: Neunert C et al., Blood) , 117: 4190-4207 (2011). Overall, five different approaches were available to the treating physician. It is possible. Generally, treatment involves continuously reducing the platelet count to 30 × 10⁶. 9 This is necessary for patients with a blood alcohol content of less than / L. It is thought that...

[0008] One treatment approach is the use of immunosuppressants such as corticosteroids. The commonly used drugs are prednisone (oral or IV), methylprednisone (methylpred It is also known as nisolone, and dexamethasone.

[0009] The second approach involves administering intravenous immunoglobulin (IVIg) or anti-RhD immunoglobulin. Yes, the latter is also known as Rho(D) immunoglobulin (anti-D). The American Society of Hematology states that If a rapid increase in platelet count is required, a combination of corticosteroids and IV1 is recommended. IVIg or anti-D is recommended when corticosteroids are contraindicated.

[0010] Corticosteroids, IVIg, and anti-D are considered first-line treatment options. If other options fail, splenectomy is often considered because the spleen can disrupt platelet function. This is because it plays a major role in the breakdown. Another example of a second treatment option is Tro This involves the administration of a thrombopoietin receptor (TPO-R) agonist. Thrombopoietin (TPO) is administered to the liver. These are endogenous cytokines that are produced from megakaryocytes. They are involved in the growth and circulation of platelets. It plays a major role in transport. Megakaryocytes and platelets present TPO receptors. -R agonists are thought to promote platelet production and their release into the circulation.

[0011] Currently, the following three TPO-R agonists are approved for use in the treatment of ITP. It is: Romiplostim, Eltrombopag, and Abatrombopag. Romiplostim It is a fusion molecule containing a TPO-R binding domain and a human Fc domain. The purpose of the Fc domain is The goal is to increase the half-life of the drug. Eltrombopag is a small molecule TPO-R agonist. Abatrombopag is another small molecule TPO-R agonist. The drawback is that their long-term response rates are low (40-50%).

[0012] Another second treatment option for ITP is a small molecule inhibitor of spleen tyrosine kinase (Syk). It is fostamatinib.

[0013] Rituximab (anti-CD20 mAb) and alemtuzumab (anti-CD52 mAb) are third-line treatment options. It is used in regimens.

[0014] Neonatal Fc receptors (FcRn) were initially characterized as neonatal transport receptors related to maternal IgG. It was kicked. This also functions to protect IgG from degradation in adults. FcRn is It binds to IgG that has undergone pinocytosis and returns it to the extracellular compartment. This cycle protects IgG from transport to degradable lysosomes.

[0015] Rozanolixizumab is a humanized, high-affinity anti-human FcRn monoclonal antibody. Which FcRn antagonist has been suggested for use in ITP treatment regimens? By binding to the substance, these molecules block the FcRn antibody salvage mechanism, and as a result IgG antibodies, including pathogenic IgG antibodies, are cleared from circulation. Autoantibodies involved in ITP are I If the gG class is present, FcRn antagonists may have beneficial effects.

[0016] Aside from splenectomy, many of the treatment options currently available are generally blood-based in ITP patients. It produces only short-term and mild improvements in small numbers. Therefore, it is inferior to what is available today. There is a need for treatment regimens that lead to more robust improvements in platelet count. Standard treatment In ITP patients, including those receiving treatment, treatment regimens that improve long-term platelet response are, It is especially necessary. [Overview of the project]

[0017] (Summary of the invention) The present invention includes administering one or more doses of an FcRn antagonist to a subject, thereby improving immunity. By providing a method for treating human subjects diagnosed with intermittent thrombocytopenia (ITP), this These problems are addressed. In a particular embodiment, this method is a standard treatment for ITP ( This includes administering one or more doses of an FcRn antagonist to the subject in combination with SoC treatment. In certain embodiments, this method is approved with respect to SoC treatment for ITP. This further includes administering one or more doses of a single compound to the subject.

[0018] Preferably, the compound approved for standard therapeutic treatment is an FcRn antagonist with a mechanism of action. It acts through a mechanism different from the initial one. For example, it acts by weakening the immune system. Costeroids can be used in combination with FcRn antagonists. As another example, TPO-R agonists, which act by stimulating platelet production, and FcRn antagonists They can be used in combination.

[0019] One aspect of the present invention involves administering one or more doses of a human FcRn (hFcRn) antagonist to a subject. This is a method for treating human subjects diagnosed with immune thrombocytopenia (ITP), including the following: The above dosage of an hFcRn antagonist is administered to the subject, including immunotherapy in the subject. Human FcRn (hFcRn) antagonists for use in the treatment of intermittent thromboplasty (ITP) It is also provided. In certain embodiments, this method is approved for standard treatment of ITP. The further method includes administering one or more doses of at least one compound to the subject.

[0020] In a particular embodiment, the hFcRn antagonist is an antibody that specifically binds to hFcRn or This is an antibody fragment. In a particular embodiment, this antibody or antibody fragment is specifically effective against hFcRn. It contains one or more CDRs to bind to. In a particular embodiment, this antibody or antibody fragment is human Fc Includes a domain. In a particular embodiment, this human Fc domain is bound to hFcRn. It includes one or more mutations that modify M252. In certain embodiments, these one or more mutations are M252 Includes one or more of Y, S254T, T256E, H433K, and N434F (EU numbering). In a particular embodiment And one or more of these mutations are M252Y, S254T, T256E, H433K, and N434F (EU numbering) This includes the following. In a particular embodiment, the human Fc domain is the mutant M252Y, S254T, T256E, H43 Includes 3K and N434F (EU numbering).

[0021] In a particular embodiment, the hFcRn antagonist is an isolated FcRn antagonist. Yes, here the FcRn antagonist consists of two Fc domains that form a homodimer. It consists of a riant Fc region, where the amino acid sequence of each Fc domain is as follows: SEQ ID NO: 1 .

[0022] In a particular embodiment, the hFcRn antagonist is an isolated FcRn antagonist. Yes, here the FcRn antagonist consists of two Fc domains that form a homodimer. It consists of a riant Fc region, where the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 2. .

[0023] In a particular embodiment, the hFcRn antagonist is an isolated FcRn antagonist. Yes, here the FcRn antagonist consists of two Fc domains that form a homodimer. It consists of a riant Fc region, where the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 3. .

[0024] In a particular embodiment, the hFcRn antagonist is evgarchigimodo (ARGX-113) ru.

[0025] One aspect of the present invention involves administering one or more doses of a human FcRn (hFcRn) antagonist to a subject. A method for treating a human subject diagnosed with immune thrombocytopenia (ITP), including the following: Here, the hFcRn antagonist is a Varian consisting of two Fc domains that form a homodimer. It consists of an Fc region, and the amino acid sequence of each Fc domain is as follows: Sequence ID: 1. Human FcRn (hFcR) for use in methods of treating immune thrombocytopenia (ITP) n) Antagonists are also available, and this method targets one or more doses of hFcRn antagonists. This includes administering to a b, which consists of two Fc domains that form a homodimer. It consists of a riant Fc region, where the amino acid sequence of each Fc domain is as follows: SEQ ID NO: 1 .

[0026] One aspect of the present invention involves administering one or more doses of a human FcRn (hFcRn) antagonist to a subject. A method for treating a human subject diagnosed with immune thrombocytopenia (ITP), including the following: Here, the hFcRn antagonist is a Varian consisting of two Fc domains that form a homodimer. It consists of an Fc region, and the amino acid sequence of each Fc domain is as shown in Sequence ID No. 2. Human FcRn (hFcR) for use in methods of treating immune thrombocytopenia (ITP) n) Antagonists are also available, and this method targets one or more doses of hFcRn antagonists. This includes administering to a b, which consists of two Fc domains that form a homodimer. It consists of a riant Fc region, where the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 2. .

[0027] One aspect of the present invention involves administering one or more doses of a human FcRn (hFcRn) antagonist to a subject. A method for treating a human subject diagnosed with immune thrombocytopenia (ITP), including the following: Here, the hFcRn antagonist is a Varian consisting of two Fc domains that form a homodimer. It consists of an Fc region, and the amino acid sequence of each Fc domain is as follows: Sequence ID: 3. Human FcRn (hFcR) for use in methods of treating immune thrombocytopenia (ITP) n) Antagonists are also available, and this method targets one or more doses of hFcRn antagonists. This includes administering to a b, which consists of two Fc domains that form a homodimer. It consists of a riant Fc region, where the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 3. .

[0028] In a particular embodiment, the hFcRn antagonist is evgarchigimodo (ARGX-113) ru.

[0029] In certain embodiments, this method is approved for at least the standard treatment of ITP. This further includes administering one or more doses of one type of compound to a subject. Accordingly, in one embodiment, the present invention relates to one or more doses of a human FcRn (hFcRn) antagonist and And one or more doses of at least one compound approved for the standard treatment of ITP, For the treatment of human subjects diagnosed with immune thrombocytopenia (ITP), including administration to elephants. It is the law.

[0030] The following applies to each of the above embodiments and designs.

[0031] In a particular embodiment, the hFcRn antagonist is present in a concentration of approximately 10 nmol / kg to approximately 1000 nmol / kg. It will be administered at the above dosage.

[0032] In a particular embodiment, the dose of one or more hFcRn antagonists is approximately 50 nmol / kg to approximately 3 The range is 00 nmol / kg.

[0033] In a particular embodiment, the dose of one or more hFcRn antagonists is approximately 90 nmol / kg to approximately 2 The range is 00 nmol / kg.

[0034] In a particular embodiment, at least one compound approved for standard treatment of ITP The substance contains corticosteroids. In certain embodiments, corticosteroids are administered via From oral prednisone, intravenous prednisone, dexamethasone, and any combination thereof It is selected from the following group.

[0035] In a particular embodiment, at least one compound approved for standard treatment of ITP The substance contains rituximab.

[0036] In a particular embodiment, at least one compound approved for standard treatment of ITP The substance contains alemtuzumab.

[0037] In a particular embodiment, at least one compound approved for standard treatment of ITP The substance contains fostamatinib.

[0038] In a particular embodiment, at least one compound approved for standard treatment of ITP The substance is selected from the group consisting of cyclosporine, dapsone, and azathioprine.

[0039] In a particular embodiment, at least one compound approved for standard treatment of ITP The substance comprises a thrombopoietin receptor agonist. In certain embodiments, thrombopo The etin receptor agonist is eltrombopag. In certain embodiments, tron The vopoietin receptor agonist is abatrombopag. In certain embodiments, The rhombopoietin receptor agonist is romiplostim. In certain embodiments, The thrombopoietin receptor agonist is the non-Fc portion of romiplostim.

[0040] In a particular embodiment, human subjects were 30 × 10 before treatment. 9 Having a platelet count of less than / L

[0041] In certain embodiments, the subject is the standard treatment of ITP prior to treatment according to the method of the present invention. During standard treatment with at least one compound approved for placement, <100 × 10 9 / L has a platelet count. In certain embodiments, the subject has, prior to treatment according to the methods of the invention, at the time of standard treatment with at least one compound approved for standard treatment of ITP, ≦50×10 9 / L. In certain embodiments, the subject has, prior to treatment according to the methods of the invention, at the time of standard treatment with at least one compound approved for standard treatment of ITP, ≦30×10 9 / L. In certain embodiments, the subject has, prior to treatment according to the methods of the invention, at the time of standard treatment with at least one compound approved for standard treatment of ITP, ≦20×10 9 / L. In certain embodiments, the subject has, prior to treatment according to the methods of the invention, at the time of standard treatment with at least one compound approved for standard treatment of ITP, ≦10×10 9 / L.

[0042] In certain embodiments, the treatment results in an increase in platelet count above 50×10 9 / L. In certain embodiments, the increase in platelet count above 50×10 / L is maintained for at least 4 weeks 9 In certain embodiments, the treatment results in an increase in platelet count above 100×10 / L. In certain embodiments, the increase in platelet count above 100×10

[0043] / L is maintained for at least 4 weeks 9 In certain embodiments, the treatment results in an increase in platelet count above 100×10 / L. In certain embodiments, the increase in platelet count above 100×10 9 / L is maintained for at least 4 weeks In one aspect of the invention, a method of treating a human subject diagnosed with immune thrombocytopenia (ITP)

[0044] is provided. The law includes administering one or more doses of a human FcRn (hFcRn) antagonist to a target. Here, the hFcRn antagonist contains an affibody specific to human FcRn. In this embodiment, the hFcRn antagonist consists of an affibody specific to human FcRn. In a particular embodiment, an affibody specific to human FcRn is shown as Sequence ID: 4. It contains an amino acid sequence. In a particular embodiment, the hFcRn antagonist is human albumin A human FcRn-specific affibody linked to an albumin-specific albumin-binding domain It is a fusion protein containing a human FcRn-specific affibody. This includes the amino acid sequence shown as Sequence ID: 4. In a particular embodiment, this method , one or more doses of at least one compound approved for standard treatment of ITP, This further includes administering it to elephants. [Brief explanation of the drawing]

[0045] (Brief explanation of the drawing) [Figure 1] Figure 1 shows the design of the Phase II clinical trial described in Example 5. [Figure 2] Figure 2 shows the design of the open-label continuation portion of the clinical trial described in Example 6. [Figure 3] Figure 3 is a graph showing the percentage decrease in total IgG evaluated during the primary test described in Example 5. [Figure 4] Figures 4A-4D are graphs showing the percentage decrease of each IgG subtype as evaluated during the primary test described in Example 5. Figure 4A, IgG1; Figure 4B, IgG2; Figure 4C, IgG3; and Figure 4D, IgG4. [Figure 5]Figure 5 is a graph showing the mean platelet count and mean standard error per patient group during the primary trial described in Example 5. The arrows indicate the timing of efgaltigimod administration. [Figure 6] Figure 6 shows the percentage of patients who achieved the platelet count increase threshold evaluated in the primary trial described in Example 5. [Figure 7] Figure 7 illustrates the platelet count response in chronic ITP patients treated with 5 mg / kg efgaltigimod as described in Example 5. The platelet counts shown are expressed in units of ×10⁹ / L. [Figure 8] Figure 8 illustrates the platelet count response in chronic ITP patients treated with 10 mg / kg efgaltigimod as described in Example 5. The platelet counts shown are expressed in units of ×10⁹ / L. [Figure 9] Figure 9 illustrates the platelet count response in newly diagnosed ITP patients treated with 5 mg / kg efgaltigimod as described in Example 5. The platelet counts shown are expressed in units of ×10⁹ / L. [Figure 10] Figure 10 illustrates the platelet count response in newly diagnosed ITP patients treated with 5 mg / kg efgaltigimod as described in Example 5. The platelet counts shown are expressed in units of ×10⁹ / L. [Figure 11] Figure 11 illustrates the platelet count response in patients with persistent ITP who had not received treatment prior to enrollment in the Phase II trial (i.e., were in an approved wait-and-see approach with at least one compound approved for the treatment of ITP) and were treated with 10 mg / kg efgaltigimod as described in Example 5. The platelet counts shown are expressed in units of ×10⁹ / L. [Figure 12] Figure 12 is a graph showing the percentage of patients experiencing bleeding events, as assessed using the World Health Organization (WHO) scale. [Figure 13]Figure 13 shows a series of three graphs illustrating the proportion of patients with bleeding events as assessed using the ITP-Specific Bleeding Assessment Tool (ITP-BAT) scale. From left to right: skin score > 0, organ score > 0, and mucosal score > 0. [Figure 14] Figure 14 shows the design of the Phase III clinical trial described in Example 7. [Modes for carrying out the invention]

[0046] (Detailed description of the invention) The following is a detailed description of the invention.

[0047] (definition) As used herein, the term "ITP" refers to immune thrombocytopenia. ITP is a pathogenic disease. In this autoimmune disease, IgG antibodies destroy platelet-producing cells (megakaryocytes) and circulating blood platelets. It is a disease or disorder. Pathogenic IgG drives disease progression through a multifaceted approach: these It promotes platelet clearance, inhibits platelet production, directly induces platelet death, and also promotes blood It interferes with the ability of platelets to perform platelet coagulation. ITP is generally diagnosed as thrombocytopenia. Thrombocytopenia (circulating platelet count < 100 × 10) in the absence of other possible causes or disorders. 9 / This is a diagnostic method of exclusion that requires the presence of L). Patients affected generally have a platelet count <30 × 10 9 / L This carries a risk of spontaneous bleeding, which occurs when the platelet count is <10 × 10 9 Including fatal bleeding at / L. ITP is, It can be acute or chronic. In certain individual embodiments, ITP is a novel diagnosis of ITP. It can be classified as persistent ITP or chronic ITP. Newly diagnosed ITP refers to the initial diagnosis made at the first medical examination. ITP occurs within 3 months of diagnosis. Persistent ITP is ITP that lasts for 3 to 12 months from the diagnosis. Chronic ITP This refers to ITP that persists for more than 12 months from the diagnosis. (Reference: Rodeghiero F et al., Blood, 113(11):) 2386-2393 (2009).

[0048] In this specification, the term "standard-of-care treatment" is used in conjunction with ITP. "Treatment" refers to any treatment method that is generally recognized as effective in treating ITP. In certain embodiments, such standard treatment procedures may be national or equivalent standards, such as those of the American Society of Hematology. This follows guidelines published by international organizations. In specific embodiments, "standard treatment procedures" This involves taking a wait-and-see approach, i.e., when the target is a platelet count > 30 × 10⁻¹⁰ 9 / L has and / or While there is no evidence of bleeding, clinical parameters and clinical laboratory parameters are observed without therapeutic intervention. This inevitably involves monitoring the meter. In a particular embodiment, "standard treatment "Therapeutic treatment" refers to treatment by one or more compounds and / or splenectomy as discussed herein. It inevitably involves targeted intervention. Regarding standard treatment procedures involving intervention with one or more compounds, This one or more compound is administered on one or more occasions, and on multiple occasions In this case, each compound can be administered independently based on a schedule or as needed. Cut.

[0049] As used herein, the phrase "compound approved for standard therapeutic treatment" is generally understood to mean a compound approved for standard therapeutic treatment. This refers to any compound that has been recognized as effective in the treatment of ITP. In 2011, The American Society of Hematology has issued guidelines regarding the treatment of ITP. (Neunert C et al., Blood, 117: 4190) -4207 (2011). Any compound or compound class mentioned in these guidelines is a "standard." These fall within the definition of "compounds approved for quasi-therapeutic treatment." These are corticosteroids. This includes, but is not limited to, IVIg, anti-D, rituximab, and TPO-R agonists. No. Similarly, the International Conference on Research and Management of Primary Immunothrombocytopenia in 2010 The census report (Provan D et al., Blood, 115: 168-186 (2010)) falls within this definition. Examples of compounds that are considered to be approved in relation to standard treatment are provided. The compounds also include TPO-R agonists (e.g., romiplostim, eltrombopag, and argon). Batrombopag, cyclosporine, azathioprine, fostamatinib, rituximab It may contain one or more of the following: , and alemtuzumab. Novel compounds are a result of scientific advancements. As we progress, it will become clear that this definition will be expanded upon.

[0050] In certain embodiments, the term "approved with respect to standard treatment procedures" as used herein "Compounds that have been used" include, for example, corticosteroids, IVIg, anti-D, TPO-R agonists (for example, Romiplostim, eltrombopag, and abatrombopag), cyclosporine, azathi Oplin, fostamatinib, rituximab, and / or alemtuzumab (one of these) One of the aforementioned compounds, including those listed above, that are generally recognized as effective in treating ITP. exclude.

[0051] In specific embodiments, the approved compounds for standard treatment exclude IVIg. In certain embodiments, the approved compounds for standard treatment exclude anti-D. In specific embodiments, the approved compounds for standard therapeutic treatment are IVIg and anti-D. Exclude both.

[0052] The terms “to treat,” “treating,” and “treatment” as used herein are defined in this Specification. This refers to therapeutic or preventive measures described in the specification. Methods of "treatment" include prevention, cure, delay, and severe treatment. Relief of the degree of, or one or more symptoms of a disease or disability, or the disease or disability in the subject To improve recurrence, or beyond what would be expected if such treatment were not available. To prolong the subject's survival, an effective amount of the substance is administered to the subject.

[0053] As used herein, the term "subject" refers to mammals. The subject is human. In a particular embodiment, the human subject is at least 18 years of age. It is a person. In a particular embodiment, the human subject is at least 12 years old but under 18 years old. In certain embodiments, the human subjects are under 12 years of age. In certain embodiments, The subjects are non-human primates.

[0054] In this specification, the term "FcRn" refers to the neonatal type Fc receptor. In this context, FcRn refers to human FcRn (hFcRn). Human FcRn is well known, and this is its... Mino acid sequences, such as the FCGRT gene shown in GenBank deposit number NM-004017, are used to code This includes the GenBank deposit number NP_004098.

[0055] As used herein, the term "FcRn antagonist" refers to a substance that specifically binds to FcRn. Furthermore, it refers to any substance that inhibits the binding of immunoglobulins to FcRn. In a particular embodiment, Furthermore, FcRn antagonists are full-length IgG antibodies (e.g., rozanolixizumab). In a specific embodiment, the FcRn antagonist is a fragment of an IgG antibody. In this embodiment, the FcRn antagonist is the Fc fragment of the IgG antibody. In a particular embodiment, F The cRn antagonist is evgarchigimod (ARGX-113). Evgarchigimodo, also known as ARGX-113, is an isolated FcRn antagonist. Yes, and here this FcRn antagonist consists of two Fc domains that form a homodimer. It consists of variant Fc regions, where the amino acid sequence of each Fc domain is from SEQ ID NO: 1 In a particular embodiment, the FcRn antagonist is two Fc that form a homodimer. It consists of a variant Fc region comprising domains, where the amino acid sequence of each Fc domain is Column number: Consists of 2. In a particular embodiment, the FcRn antagonist forms a homodimer. It consists of a variant Fc region comprising two Fc domains, where each Fc domain is ami The no-acid sequence consists of SEQ ID NO:3. In a particular embodiment, the FcRn antagonist is A affibody specific to human FcRn, or this affibody and albumin-binding domain (ABD ) is a fusion protein containing. In a particular embodiment, a human FcRn-specific affibole D has the amino acid sequence shown as Sequence ID: 4.

[0056] As used herein, the term "antibody" refers to a compound that is mutually bound by disulfide bonds. An immunoglobulin molecule containing four polypeptide chains, two heavy (H) chains and two light (L) chains, and This refers to their polymers (e.g., IgM). Each heavy chain has a variable heavy chain region (abbreviated as VH) and a constant heavy chain region. The region includes the heavy chain constant region, which contains three domains: CH1, CH2, and CH3. Each light chain is It includes a variable light chain region (abbreviated as VL) and a constant light chain region. The constant light chain region consists of one domain (CL). This includes the VH and VL regions, which are further preserved in a region called the framework region (FR). It can be further subdivided into more scattered, hypervariable regions called complementarity-determining regions (CDRs).

[0057] As used herein, the term "Fc region" is formed by the Fc domains of its two heavy chains. This refers to the undenatured immunoglobulin, such as the IgG portion. The undenatured Fc region is homozygous. It is a dimer.

[0058] As used herein, the term "Fc domain" generally refers to the area immediately adjacent to the papain cleavage site. A segment of the immunoglobulin heavy chain that begins in the upstream hinge region and ends at the C-terminus of the antibody. It refers to the minute. In the context of efgalchigimod (ARGX-113), the Fc domain is sequence number 1 and It has the amino acid sequence shown.

[0059] The term "EU location" as used herein is derived from the literature of Edelman, GM et al., Proc. Natl. Acad. Sci USA, 63: 78-85 (1969) and the literature by Kabat et al., "Proteins of Immunological Interest" "Sequences of Proteins of Immunological Interest," US Dept. Health a EU numbering conventions for Fc areas, as described in nd Human Services, 5th edition, 1991. This refers to the position of an amino acid.

[0060] (Method of invention) In the most broad embodiment of the present invention, the present invention relates to a diagnosis of immune thrombocytopenia (ITP). A method for treating a human subject, comprising administering one or more doses of an FcRn antagonist to the subject. The method includes doing so. In a particular embodiment, the FcRn antagonist is Efga This invention relates to lutigimod (ARGX-113). The present invention also relates to one or more doses of an FcRn antagonist. In a method of treating immune thrombocytopenia (ITP) in a subject, including administration to elephants Provides an FcRn antagonist for use. In a particular embodiment, the FcRn antagonist The gonist is a human FcRn (hFcRn) antagonist.

[0061] Therefore, in certain embodiments, the present invention relates to a patient diagnosed with immune thrombocytopenia (ITP). A method of treating a target, comprising administering one or more doses of an FcRn antagonist to the target. Regarding methods that include the following, here the FcRn antagonist forms a homodimer with two FcRn The variant consists of a main Fc region, where the amino acid sequence of each Fc domain is: Number: Starting with 1.

[0062] In certain embodiments, the present invention relates to human subjects diagnosed with immune thrombocytopenia (ITP). A method of treating the condition, which involves administering one or more doses of an FcRn antagonist to the target. Regarding the method of inclusion, here the FcRn antagonist consists of two Fc domains that form a homodimer. It consists of a variant Fc region, where the amino acid sequence of each Fc domain is: Sequence ID: It consists of 2.

[0063] In certain embodiments, the present invention relates to human subjects diagnosed with immune thrombocytopenia (ITP). A method of treating the condition, which involves administering one or more doses of an FcRn antagonist to the target. Regarding the method of inclusion, here the FcRn antagonist consists of two Fc domains that form a homodimer. It consists of a variant Fc region, where the amino acid sequence of each Fc domain is: Sequence ID: It consists of 3.

[0064] In a particular embodiment, the method involves administering one or more doses of an FcRn antagonist to ITP. This includes administering the drug to the subject in conjunction with standard medical treatment. In this situation, specific In this embodiment, the standard treatment procedure for ITP is, specifically, an elective treatment for ITP. The approach involves at least one compound approved for standard treatment of ITP. Patients can be monitored without administering one or more doses of the substance to the target. In a particular embodiment, the FcRn antagonist is evgarchigimodo (ARGX-113).

[0065] In certain embodiments, the present invention relates to human subjects diagnosed with immune thrombocytopenia (ITP). A method for treating the condition, relating to one or more doses of an FcRn antagonist and standard treatment procedures. A method comprising administering to a subject one or more doses of at least one compound approved by law. Regarding this, in certain embodiments, the present invention relates to immune thrombocytopenia (ITP) in a subject. Regarding FcRn antagonists for use in therapeutic methods, here this method is IT In combination with at least one compound approved for standard treatment of P, the FcRn antagonist This includes administering one or more doses of the drug to the target. In certain embodiments, FcRn an The tagonist is Evgarchgimod (ARGX-113).

[0066] In some embodiments, the method of the present invention is approved for a small number of standard treatments for ITP. Without co-administration of one or more doses of a single compound, an FcRn antagonist was administered. This includes giving in to the agreement.

[0067] In some embodiments, the method of the present invention involves administering an FcRn antagonist, and For the standard treatment of ITP, at least one approved compound in a stable dose is available. This includes administering the drug regimen simultaneously.

[0068] In some embodiments, the method of the present invention involves administering an FcRn antagonist, and Gradual dose reduction of at least one compound approved for the standard treatment of ITP. This includes administering drug regimens simultaneously. In some embodiments, the method of the present invention is Fc The administration of Rn antagonists and the standard treatment of ITP have been approved by at least This also includes administering a tapering regimen of one compound simultaneously.

[0069] In some embodiments, the method of the present invention involves administering an FcRn antagonist, and For the standard treatment of ITP, at least one approved compound is administered in a dose of 1 or more. This includes simultaneously interrupting the jimen. In some embodiments, the method of the present invention involves FcRn The administration of an antagonist and at least one of the standard treatments approved for ITP. This includes simultaneously discontinuing the drug regimen of the compound.

[0070] In certain embodiments, the subject suffers from chronic ITP. In other embodiments, The subjects are those suffering from persistent ITP. In yet another embodiment, the subjects are those with ITP and newly It has been diagnosed. FcRn antagonists are small molecules that specifically bind to human FcRn (hFcRn). This may be an antibody, antibody fragment, affibody, or nanobody. In a particular embodiment, The FcRn antagonist is an antibody or antibody containing one or more CDRs that specifically bind to hFcRn. It is a fragment. An example is a full-length monoclonal antibody, such as rozanolixizumab (UCB-7 665; UCB), DX-2504 (Dyax / Shire), DX-2507 (Dyax / Shire), HL161 (HanAll Biopharm a) M281 (Momenta Pharmaceuticals), and SYNT001 (Syntimmune), etc.; and Fn Examples include monoclonal antibody fragments, including Ab-8 (Shanghai Jiao University). WO 2009 / 131702;WO 2014 / 019727;WO 2014 / 204280;WO 2016 / 123521;WO 2016 / 1833 See also 52 and WO 2017 / 121330. For affiliate bodies, see, for example, Seijsing J See the following document, Sci Rep 8: 5141 (2018). Regarding nanobodies, see, for example, An See the paper by dersen JT et al., Sci Rep 3: 1118 (2013).

[0071] In a preferred embodiment, the FcRn antagonist modifies its affinity for hFcRn. This is a human Fc region that has been manipulated to perform certain actions. An example is efgalchigimod (ARGX-113). This includes human IgG that has been modified to enhance hFcRn affinity through the following mutations. The isolated Fc regions of the antibody are: M252Y, S254T, T256E, H433K, and N434F (EU numbering). In summary, these mutations affect pH 6.0 (pH of acidified endosomes) and pH 7.4 (pH of cells). This is a so-called "Abdeg" mutation that produces enhanced Fc-FcRn binding at both external pH and external pH. The difference is that it blocks the binding of circulating IgG to FcRn and clears IgG through lysosomal degradation. To promote the initiative. See, for example, WO 2006 / 130834 and WO 2015 / 100289.

[0072] In a particular embodiment, the FcRn antagonist forms a homodimer with two Fc domes. It consists of a variant Fc region comprising the sequence number, where the amino acid sequence of each Fc domain is Number: Consists of 1.

[0073] In a particular embodiment, the FcRn antagonist forms a homodimer with two Fc domes. It consists of a variant Fc region comprising the sequence number, where the amino acid sequence of each Fc domain is It consists of two parts.

[0074] In a particular embodiment, the FcRn antagonist forms a homodimer with two Fc domes. It consists of a variant Fc region comprising the sequence number, where the amino acid sequence of each Fc domain is It consists of 3 parts.

[0075] Since the role of FcRn receptors in IgG homeostasis is essential, efgaltigimod To better achieve this, inhibiting this FcRn function is possible in IgG-driven autoimmune diseases. This is expected to lead to the rapid degradation of endogenous IgG, which is thought to contain autoantibodies. Along with pharmacokinetic / pharmacodynamic (PK / PD) studies in cynomolgus monkeys, various mouse disease models are used. It has been validated in [location]. See Challa DK et al., MAbs. 5(5): 655-9 (2013). See also S 2015 / 0218239.

[0076] In in vivo disease models of rheumatoid arthritis and multiple sclerosis in mice, the disease score was A clear improvement was observed after treatment with a molecule containing Abdeg. This improvement is related to autoantibody regression. This was achieved by a general decline in Bell's condition. (Patel DA et al., J Immunol. 187: 1015-22 (2) 011).

[0077] Pharmacokinetic and pharmacodynamic (PD) studies in cynomolgus monkeys are relevant to the study of pharmacokinetics and pharmacodynamics in related animal models. The antibody-clearing properties of efgultigimod were confirmed. A single injection of efgultigimod is Without changing serum albumin concentration, and the levels of IgM or IgA, the optimal level of endogenous IgG This resulted in a significant 55% reduction. This PD effect was due to both the depth of the PD effect and the speed of its onset. It has been proven to be more potent than IVIg, which is considered a SoC therapy in ITP. Medication can improve the effect of Parkinson's disease (PD) by up to 75% in reducing IgG levels.

[0078] As mentioned above, efgarchigimodo consists of two Fc domains that form a homodimer. This is the variant Fc region, where the amino acid sequence of each Fc domain is shown as Sequence ID:1. did.

[0079] [ka]

[0080] In a particular embodiment, the Fc domain of the variant Fc region of efgarchigimodo is Fc It has GlcNAc (N-acetylglucosamine) branching at the main EU position 297, and is N-linked It contains glycans.

[0081] The closely related variant Fc region consists of two Fc domains that form a homodimer. Here, the amino acid sequence of each Fc domain is shown as Sequence ID: 2.

[0082] [ka]

[0083] Another closely related variant, the Fc region, is formed from two Fc domains that form a homodimer. Here, the amino acid sequence of each Fc domain is shown as Sequence ID: 3.

[0084] [ka]

[0085] The dosage of pharmacoactive compounds is converted to the weight of the compound administered per kilogram of body weight in a human subject. Therefore, it is customary to report the dose in mg, for example. Available hFcRn antagonists are widely It ranges to a wide range of molecular weights. For example, the molecular weight of rozanolixizumab is approximately 150 kDa; Efgarch Gimodo's is approximately 54 kDa. The mechanism of action is at the molecular level, and it is nanometers per kg of body weight. Expressing medication dosage as mol / kg is considered more meaningful. In the case of elephants, if desired, those skilled in the art may use nmol / kg as used herein, or mg / kg It can be easily converted to [this format].

[0086] In a particular embodiment, the hFcRn antagonist is present in a concentration of approximately 10 nmol / kg to approximately 1000 nmol / kg. The above dosage is administered. Generally, clinicians may avoid overexposing patients to side effects. The goal is to select the highest possible dose. Rozanolixizumab is administered at approximately 20 nmol / kg to approximately 50 nmol / kg. It is preferable that the drug be administered in a dose range of l / kg (i.e., approximately 3 mg / kg to approximately 7.5 mg / kg). It is known that efugalgimod has a good safety profile. It contains approximately 50 nmol / kg to approximately 300 nmol / kg (i.e., approximately 2.7 mg / kg to approximately 16.2 mg / kg), and is preferable. The dosage ranges from approximately 90 nmol / kg to approximately 200 nmol / kg (i.e., approximately 4.9 mg / kg to approximately 10.8 mg / kg). It may be administered to human subjects.

[0087] In certain embodiments, the subject has a novel diagnostic ITP. In certain embodiments, The subject has persistent ITP. In certain embodiments, the subject has chronic ITP.

[0088] In a specific embodiment, the subject has a platelet count <100 × 10¹⁶ prior to treatment according to the method of the present invention. 9 It has / L. In a particular embodiment, the subject has platelet count before treatment according to the method of the present invention. ≤50×10 9 It has / L. In certain embodiments, the subject is before treatment according to the method of the present invention. Platelet count ≤ 30 × 10 9 It has / L. In a particular embodiment, the subject is according to the method of the present invention. Before treatment, platelet count ≤ 20 × 10 9 It has / L. In a particular embodiment, the subject is the present invention. Before treatment according to the method, platelet count ≤ 10 × 10 9 It has / L.

[0089] In certain embodiments, the subject is a standard treatment for ITP prior to treatment according to the method of the present invention. When standard treatment is administered with at least one approved compound, platelet count <100 × 10 9 It has / L. In certain embodiments, the subject is a pre-treatment of ITP according to the method of the present invention. During standard treatment with at least one compound approved for sub-therapeutic treatment, platelets Number ≤ 50 × 10 9 It has / L. In a particular embodiment, the subject is pre-treatment according to the method of the present invention. When standard treatment is performed with at least one compound approved for standard treatment of ITP. Platelet count ≤ 30 × 10 9 It has / L. In a particular embodiment, the subject is the method of the present invention. Standard treatment of ITP with at least one approved compound prior to treatment. At the time of treatment, platelet count ≤ 20 × 10 9 It has / L. In a particular embodiment, the subject is this At least one compound approved for standard treatment of ITP before treatment according to the method of Akashi During standard treatment, platelet count ≤ 10 × 10 9 It has / L.

[0090] In some embodiments, the subjects to be treated according to the method of the present invention are those exhibiting clinical signs of bleeding. It has ITP without a cause. In some embodiments, it is treated according to the method of the present invention. The subjects are those with ITP without clinical evidence of bleeding.

[0091] According to a specific embodiment of the present invention, an effective amount of hFcRn antagonist alone is administered to human subjects. Any one or more compounds that are administered, i.e., approved for standard treatment of ITP. It cannot be linked to administration. For example, platelet count > 30 × 10 9 Having / L and / or evidence of bleeding Patients with ITP without accompanying symptoms should receive an effective dose of an hFcRn antagonist to treat ITP. It may be administered. According to such embodiments, this method is an elective approved standard treatment for ITP. During treatment, administer one or more doses of a human FcRn (hFcRn) antagonist to the subject. Includes. In certain embodiments, the FcRn antagonist is efgarchigimodo (ARGX-113) be.

[0092] According to certain other embodiments of the present invention, in addition to an hFcRn antagonist, ITP is used in human subjects. At least one compound approved for standard treatment is administered. hFcRn Antagon At least one compound approved for use with stents and standard treatments may be used together or individually. They may be administered separately. These should be administered together in close proximity in time, or their administration should be separate. They may be staggered. When these are administered individually, in a particular embodiment, hF cRn antagonists are used before one or more compounds approved for standard treatment of ITP. They are administered. When these are administered individually, in certain embodiments, they are considered standard treatment for ITP. One or more compounds approved for the treatment are administered prior to the hFcRn antagonist. At least one compound approved as an hFcRn antagonist or for standard therapeutic treatment is the same It may be administered by the same or different route of administration.

[0093] In certain embodiments, the compounds approved for standard treatment of ITP are cortico Steroids, such as oral or intravenous prednisone, methylprednisolone, dexamethasone, etc., and combinations thereof are included. In certain embodiments, the compounds approved for the standard treatment of ITP can consist of corticosteroids, such as oral or intravenous prednisone, methylprednisolone, dexamethasone, etc., and combinations thereof. In certain embodiments, the compounds approved for the standard treatment of ITP can exclude corticosteroids, such as oral or intravenous prednisone, methylprednisolone, dexamethasone, etc., and combinations thereof. In certain embodiments, the compounds approved for the standard treatment of ITP can include IVIg or anti-D. In certain embodiments, the compounds approved for the standard treatment of ITP can consist of IVIg. In certain embodiments, the compounds approved for the standard treatment of ITP

[0094] can consist of anti-D. In certain embodiments, the compounds approved for the standard treatment of ITP can exclude IVIg. In certain embodiments, the compounds approved for the standard treatment of ITP can exclude anti-D. In certain embodiments, the compounds approved for the standard treatment of ITP can exclude both IVIg and anti-D. In certain embodiments, the compounds approved for the standard treatment of ITP can include cyclosporine. In certain embodiments, the compounds approved for the standard treatment of ITP can consist of cyclosporine. In certain embodiments, ITP can exclude both IVIg and anti-D.

[0095] In certain embodiments, the compounds approved for the standard treatment of ITP can include cyclosporine. In certain embodiments, the compounds approved for the standard treatment of ITP approved can consist of cyclosporine. In certain embodiments, ITP The compounds approved for standard treatment can exclude cyclosporine.

[0096] In certain embodiments, the compound approved for standard treatment of ITP is dapsone. This may include, in certain embodiments, approved standard treatments for ITP. The compound may consist of dapsone. In a particular embodiment, the standard treatment for ITP For compounds approved for use, dapsone may be excluded.

[0097] In certain embodiments, the compound approved for standard treatment of ITP is azathio It may contain purines. Approved for standard treatment of ITP in certain embodiments. The compound may consist of azathioprine. In a particular embodiment, ITP Azathioprine can be excluded from the list of approved compounds for standard treatment.

[0098] In certain embodiments, the compounds approved for standard treatment of ITP are rituxi It may contain mab. In certain embodiments, it is approved for standard treatment of ITP. The compound may consist of rituximab. In a particular embodiment, the ITP label For compounds approved for quasi-therapeutic treatment, rituximab can be excluded.

[0099] In certain embodiments, the compound approved for standard treatment of ITP is Alemz. It may contain zumab. Approved for standard treatment of ITP in certain embodiments. The compound may consist of alemtuzumab. In a particular embodiment, ITP For standard treatment, alemtuzumab can be excluded from the list of approved compounds.

[0100] In certain embodiments, the compounds approved for standard treatment of ITP are fosta It may contain matinib. In certain embodiments, the standard treatment for ITP may be approved. The approved compound may consist of fostamatinib. In a particular embodiment, The compounds approved for standard treatment of ITP can exclude fostamatinib. Cut.

[0101] In a particular embodiment, the compounds approved for standard treatment of ITP are one or more TPO-R agonists, such as romiplostim, eltrombopag, and avatrombopag It may include. In certain embodiments, approved formulations for standard treatment of ITP. The compound contains one or more TPO-R agonists, such as romiplostim, eltrombopag, and It may consist of batrombopag. In certain embodiments, it is used as a standard treatment for ITP. The compounds approved for this purpose are one or more TPO-R agonists, such as romiplostim, erto Rombopugs and Abatrombopugs can be excluded.

[0102] In a particular embodiment, at least one compound approved for standard treatment of ITP The substance consists of a single compound. In a particular embodiment, the standard treatment for ITP is approved. At least one recognized compound consists of two compounds from the same or different classes. In a particular embodiment, at least one compound approved for standard treatment of ITP The substance consists of three compounds from one, two, or three classes. In a particular embodiment, IT At least one compound approved for standard treatment of P is 1, 2, 3, or 4 or It consists of four or more compounds from more classes.

[0103] Exemplary classes of compounds approved for standard treatment of ITP are: (i) broad immunosuppressive drugs , such as corticosteroids, cyclosporine, and azathioprine; (ii) preparations of natural immune globulins , such as IVIg and anti-D; (iii) antigen-specific monoclonal antibodies , such as rituximab and alemtuzumab; (iv) TPO-R agonists, such as eltrombopag , romiplostim, and avatrombopag; and, (v) small molecule inhibitors of spleen tyrosine kinase (Syk), such as fostamatinib (Tavalisse). Rozanolixizumab is currently in clinical trials for ITP in adults.

[0104] For example, in certain embodiments, the method includes administering to a subject one or more doses of an hFcRn antagonist and one or more doses of a corticosteroid.

[0105] As another example, in certain embodiments, the method includes administering to a subject one or more doses of an hFcRn antagonist, one or more doses of a corticosteroid, and one or more doses of a TPO-R agonist.

[0106] In embodiments seeking more compounds than those approved for standard treatment of ITP alone, two or more compounds approved for standard treatment of ITP can be administered on the same or different schedules. Further, in embodiments seeking more compounds than those approved for standard treatment of ITP alone, two or more compounds approved for standard treatment of ITP can be administered on the same or different schedules. The compounds independently react with the same or different schedules as the FcRn antagonists. It can be administered as a single treatment, in addition to the standard treatment for ITP approved for use alone. In embodiments seeking compounds with a high concentration, two or more compounds approved for standard treatment of ITP are available. The compounds, in their original amounts or different amounts (e.g., reduced amounts), and FcRn ant It can be administered independently, either on the same or a different schedule as the gonist. Cut.

[0107] Some of these combinations can be expected to be more effective than others. This is how it will be understood. For example, corticosteroids remove autoantibodies from the patient's body. It is thought to complement the action of the hFcRn antagonist and reduce the production of autoantibodies. In accordance with the present invention, the combination of a corticosteroid and an hFcRn antagonist is actually It is known to be beneficial.

[0108] On the other hand, the mechanism of IVIg and hFcRn antagonists is that both bind to FcRn and F Similar insofar as it acts as a competitive inhibitor of cRn-mediated IgG recycling. It is thought that the effect of IVIg is impaired by the hFcRn antagonist. There are two approaches, and the latter is more efficient.

[0109] The combination administration method according to the present invention can employ any of the following various forms. In one embodiment, a human subject diagnosed with ITP is approved for standard treatment of ITP. The patient first receives standard treatment, which includes the administration of at least one compound. If the patient's platelet count does not increase, or does not increase sufficiently, administer an hFcRn antagonist. This is initiated. At this point, at least one compound approved for standard treatment of ITP is used. The administration of the substance may be interrupted. Alternatively, at this point, the standard treatment for ITP may be approved. The administration of at least one of the compounds is continued, but at a reduced administration rate (i.e., reduced It can be continued (in a reduced amount and / or frequency). In another embodiment, at this point, If the administration of at least one compound approved for standard treatment of TP is continued without change However, this patient may receive an hFcRn antagonist.

[0110] In a particular embodiment, the FcRn antagonist is administered periodically in an ongoing manner. For example, a dose of 1 or more is administered every 2, 3, 4, 5, 6, 7, or 8 weeks or more. This may be due to the schedule or the presence of bleeding. The time between such repeated administrations depends on the schedule or the presence of bleeding. Or non-existence and / or a specific threshold level, e.g., 10 × 10 9 / L, 15×10 9 / L, 20×10 9 / L, 25×10 9 / L, or 30×10 9 A decrease in platelet count of / L or below, etc. By monitoring the parameters of the bed and / or clinical laboratory, it can be set. can.

[0111] In a particular embodiment, one or more doses of the FcRn antagonist are administered every two weeks. In a particular embodiment, one or more doses of the FcRn antagonist are administered every three weeks. In a particular embodiment, one or more doses of the FcRn antagonist are administered every four weeks. In a particular embodiment, one or more doses of an FcRn antagonist are administered every five weeks. In a particular embodiment, one or more doses of an FcRn antagonist are administered every six weeks. It is administered. In a particular embodiment, one or more doses of an FcRn antagonist are administered every 7 weeks. It is administered to the following: In a particular embodiment, one or more doses of an FcRn antagonist are administered for 8 weeks. It is administered every or more doses.

[0112] In a particular embodiment, one or more doses of an FcRn antagonist are administered over a 3-week period. After completing the initial treatment period, which includes four doses of the antagonist, it is administered every two weeks. In this embodiment, one or more doses of the FcRn antagonist are administered over a 3-week period. After the completion of the initial treatment period, which includes four doses of Nist, it is administered every three weeks. (Specific Embodiments) In this context, a dose of 1 or more FcRn antagonists over a 3-week period of FcRn antagonist treatment After the completion of the initial treatment period, which includes four doses, it is administered every four weeks. In a specific embodiment... A dose of 1 or more of an FcRn antagonist is equivalent to four doses of an FcRn antagonist administered over a three-week period. It is administered every 5 weeks after the completion of the initial treatment period, including [specific example]. In certain embodiments, FcRn One or more doses of the antagonist include four doses of the FcRn antagonist over a three-week period. It is administered every 6 weeks after the completion of the initial treatment period. In certain embodiments, FcRn Antah A gonist dose of 1 or more is the first dose of an FcRn antagonist, including four doses over a 3-week period. After the completion of the treatment period, it is administered every 7 weeks. In certain embodiments, FcRn antagonist A dose of 1 or more of the FcRn antagonist is part of the initial treatment phase, which includes four doses over three weeks. After completion of the intervening period, it is administered every 8 weeks or more.

[0113] In certain embodiments, hFcRn antagonists and standard treatments for ITP have been approved. The administration of at least one of the compounds may occur simultaneously or staggered. In other words, the administration of at least one compound approved for standard treatment of ITP is hFcRn The agonist can be gradually reduced after administration has been initiated. Other permutations are obvious to those skilled in the art. Generally, the patient's platelet count is monitored, and the treatment regimen is tailored to the individual. It is possible.

[0114] The combination of an hFcRn antagonist and a TPO-R agonist, according to the present invention, is used to diagnose ITP. It was found to be effective in increasing platelet counts in human subjects. The theory Although we do not intend to link them, the inventors believe this is the way these substances work. I believe the formula is a result of the fact that it is completely different.

[0115] FcRn antagonists can be administered by any preferred one or more routes of administration. In certain embodiments, the FcRn antagonist is administered intravenously. In this embodiment, the FcRn antagonist is administered intraperitoneally. In a specific embodiment, FcRn antagonists are administered subcutaneously.

[0116] For example, efgaltigimod (ARGX-113) is administered via any preferred one or more routes of administration. It can be done. In certain embodiments, the FcRn antagonist is administered intravenously. In certain embodiments, the FcRn antagonist is administered intraperitoneally. In this embodiment, the FcRn antagonist is administered subcutaneously.

[0117] With regard to subcutaneous administration, in a particular embodiment, the FcRn antagonist is 20 mM histidine. / Histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.02%~0.04% (w / v) polysorbate 20 Alternatively, polysorbate 80, pH 6.0, containing approximately 100-200 mg / mL of efgartigimod (ARGX-113). It is an aqueous formulation in which ARGX-113 is an isolated FcRn variant consisting of the Fc region. It is an antagonist, and here the variant Fc region forms two Fc domains that form a homodimer. It consists of in, and the amino acid sequence of each Fc domain is as follows: Sequence ID: 1

[0118] With regard to subcutaneous administration, in a particular embodiment, the FcRn antagonist is 20 mM histidine. Histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.04% (w / v) polysorbate 20, pH 6.0 This is an aqueous formulation containing 150 mg / mL of efgartigimod (ARGX-113).

[0119] With regard to subcutaneous administration, in a particular embodiment, the FcRn antagonist is 20 mM histidine. Histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.04% (w / v) polysorbate 20, pH 6.0 This is an aqueous formulation containing 175 mg / mL of efgartigimod (ARGX-113).

[0120] With regard to subcutaneous administration, in a particular embodiment, the FcRn antagonist is 20 mM histidine. Histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.04% (w / v) polysorbate 20, pH 6.0 This is an aqueous formulation containing water and 200 mg / mL of fgartigimod (ARGX-113).

[0121] With regard to subcutaneous administration, in a particular embodiment, the FcRn antagonist is 20 mM histidine. / Histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.02%~0.04% (w / v) Approximately 100-200 mg / mL of Evgarchigi in polysorbate 20 or polysorbate 80, pH 6.0 This is an aqueous formulation containing mod (ARGX-113).

[0122] With regard to subcutaneous administration, in a particular embodiment, the FcRn antagonist is 20 mM histidine. / histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.04% (w / v) poly This aqueous formulation contains 165 mg / mL of efgartigimod (ARGX-113) in Sorbate 20, pH 6.0. be.

[0123] With regard to subcutaneous administration, in a particular embodiment, the FcRn antagonist is 20 mM histidine. / histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.03% (w / v) poly This aqueous formulation contains 175 mg / mL of efgartigimod (ARGX-113) in Sorbate 20, pH 6.0. be.

[0124] With regard to subcutaneous administration, in a particular embodiment, the FcRn antagonist is 20 mM histidine. / histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.03% (w / v) poly This aqueous formulation contains 200 mg / mL of efgartigimod (ARGX-113) in Sorbate 20, pH 6.0. be.

[0125] With regard to subcutaneous administration, in certain embodiments, the FcRn antagonist is 50 mM histidine. / histidine HCl, 60 mM sucrose, 100 mM arginine HCl, and 0.02%~0.04% (w / v) polysol Approximately 100-200 mg / mL of efgartigimod (ARGX-11) is contained in Bate 20 or Polysorbate 80, pH 6.0. It is an aqueous formulation containing 3).

[0126] With regard to subcutaneous administration, in a particular embodiment, the FcRn antagonist is 20 mM histidine. / Histidine HCl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine, and 0.02%~ Approximately 100-200 mg / mL of polysorbate in 0.04% (w / v) polysorbate 20 or polysorbate 80, pH 6.0. This is an aqueous formulation containing gultigimod (ARGX-113).

[0127] With regard to subcutaneous administration, in a particular embodiment, the FcRn antagonist is 20 mM histidine. / histidine HCl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine, and 0.03% (w / v) Aqueous solution containing 175 mg / mL of f-gultigimod (ARGX-113) in polysorbate 20, pH 6.0. It is a pharmaceutical product.

[0128] With regard to subcutaneous administration, in a particular embodiment, the FcRn antagonist is 20 mM histidine. / histidine HCl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine, and 0.03% (w / v) Aqueous solution containing 200 mg / mL of f-gultigimod (ARGX-113) in polysorbate 20, pH 6.0. It is a pharmaceutical product.

[0129] Antiplatelet autoantibodies are thought to negatively affect platelet counts in at least two ways. This can be seen in the literature of Houwerzijl EJ, Blood, 103: 500-506 (2004); and the literature of Kuter DJ et al., Hemat ol Oncol Clin North Am 23: 1193-1211 (2009). Such antibodies bind to megakaryocytes, This is thought to lead to apoptosis. As a result, platelets are produced. Fewer megakaryocytes are capable of this. In the second mode of action, such autoantibodies exist. The body binds to newly formed platelets. These blood cells are marked with autoantibodies. The plates are removed by the spleen. Plasma levels of TPO are controlled by the binding of TPO to circulating platelets. This leads to its removal from circulation and subsequent decomposition. (Stasi R et al., B) lood Rev 24(4-5): 179-90 (2010). As a result, this autoantibody causes TPO deficiency.

[0130] By removing autoantibodies from circulation, hFcRn antagonists increase the available TPO. This TPO-R agonist makes the available TPOs more effective. Therefore, hFcRn agonist The administration of a agonist reinforces or amplifies the effects of a TPO-R agonist, and vice versa.

[0131] Therefore, in certain embodiments, this treatment method involves a TPO-R agonist and an hFcRn antagonist. This includes administering the agonist. At this point, the preferred TPO-R agonist is Eltrombo. These are Pugs, Romiplostim, and Abatrombo Pugs.

[0132] Eltrombopag (e.g., PROMACTA®, Novartis) is a low-molecular-weight substance (MW approximately 442 Da) Therefore, its pharmacokinetics are not thought to be affected by co-administration of an hFcRn antagonist. It can be done.

[0133] Similar to eltrombopag, abatrombopag (e.g., DOPTELET®, Dova Pharma) Ceuticals is a small molecule (MW approximately 650 Da), and its pharmacokinetics are those of an hFcRn antagonist. It is thought that co-administration will not have any effect.

[0134] Romiplostim (e.g., NPLATE®, Amgen Inc.) is an Fc-type compound used to improve half-life. This is a fusion molecule containing the main component. The effect of this Fc domain is counteracted by the hFcRn antagonist. It acts in pairs. Regarding co-administration with hFcRn antagonists, the romiplostim molecule is, for example, For example, it can be modified by omitting the Fc domain portion and retaining the TPO-R binding portion. This results in molecules with lower molecular weights that are easier to manufacture and administer. [Examples]

[0135] (Examples) (Example 1: Single-dose toxicity study of ARGX-113 in cynomolgus monkeys) ARGX-113 is available in four dose levels (10, 30, 50, and 100 mg / kg body weight [bw]) and a control group. The drug was administered via 2-hour intravenous infusion to cynomolgus monkeys. This was associated with local intolerance of ARGX-113. No signs were observed at any of the tested dose levels. The purpose is to measure the behavior, weight, food consumption, and electrocardiogram parameters of any animal at any dosage level. Circulatory function, hematological parameters, lymphocyte typing, urinary parameters, ophthalmic and auditory parameters No findings were observed regarding function or organ weight. In addition, macroscopic or microscopic whole-body measurements were not obtained. No organ changes were observed in any of the tested animals, and in particular, no histopathological changes were observed in any of the tested animals. No adverse reactions were observed in the monkey liver at the tested dose levels.

[0136] Administration of ARGX-113 produces significant changes in biochemical parameters, which are not considered harmful. It was thought that a decrease in serum γ-globulin concentration was observed in all ARGX-113-treated groups. It was found that ARGX-113 enhances antibody clearance by binding to the FcRn receptor. The decrease in overall immunoglobulins (gamma-globulin fraction) is not considered an adverse effect. Furthermore, it should be considered to be related to the mechanism of action of ARGX-113. Therefore, γ-globulin The decrease in globulin is due to a general decrease in IgG isotypes and albumin / globulin. This resulted in an increase in the ratio. However, such a decrease was observed in IgM, IgA, or alpha compared to the control group. Bumin levels were not detected.

[0137] Based on these findings, the no-adverse-effect level (NOAEL) of ARGX-113 was determined to be 100 mg / kg bw.

[0138] (Example 2: Repeated-dose toxicity study of ARGX-113 in cynomolgus monkeys) In a 1-month repeated-dose toxicity study in cynomolgus monkeys, ARGX-113 was administered in three different doses. The drug was administered at levels (3, 30, and 100 mg / kg) to 10 cynomolgus macaques (5 males and 5 females). The animals were treated at each dose level and received IV ARGX-113 every 48 hours for a total of 15 infusions. I received the infusion. ARGX-113 is used in clinical signs, weight, macroscopic examination, histopathology, food consumption, Furthermore, when determined by hematological and serum biochemical parameters, all animals The drug was well-tolerated at the given dosage. No macroscopic changes related to ARGX-113 were observed. Histopathological examination revealed liver changes at an ARGX-113 dose of 100 mg / kg. The changes included cytoplasmic alterations and degeneration, as well as diffuse mixed-type inflammatory cell infiltration. 10 In animals receiving a 0 mg / kg dose, no liver pathology was observed at the final stage of the untreated recovery phase. No significant ARGX-113-related changes were observed in the 3 mg / kg or 30 mg / kg dose groups. It was.

[0139] Therefore, the NOAEL in this study was considered to be 30 mg / kg.

[0140] In a 26-week chronic toxicity study in cynomolgus monkeys, ARGX-113 was effective against 24 male and 24 female monkeys. It was administered to female cynomolgus monkeys by repeated IV infusions over 30 minutes. At least 8 weeks The reversibility of any effect after the recovery period was evaluated. ARGX-113 or vehicle was 0 (vehicle). The drug was administered once a week for 26 weeks at doses of 10, 30, and 100 mg / kg.

[0141] At any test dose level, clinical signs, body weight, food consumption, ECG, circulatory function, coagulation, and urinary condition are monitored. Condition, ophthalmic and auditory function, relative and absolute organ weight, and the ratio of bone marrow to red blood cells. However, no effect of ARGX-113 was observed. No animals died prematurely during the study period. Ta.

[0142] Local intolerance associated with ARGX-113 was reported in all treated animals. I couldn't do it.

[0143] Administration of ARGX-113 resulted in significant changes in biochemical parameters, which were observed in previous toxicity studies. If the same theoretical basis as that explained was followed, it was considered virtually harmless.

[0144] Lymphocyte typing involves examining a subset of cells (NK cells, helper T cells, activated lymphocytes). ruper T cells, cytotoxic T cells, activated cytotoxic T cells, immature T cells, and B cells). No changes related to ARGX-113 in composition or activation grade were identified. Hematological No changes related to ARGX-113 were observed in the parameters.

[0145] Changes related to macroscopic or microscopic toxicity test items are considered for all animals tested. It was not reported either.

[0146] Based on these findings, the NOAEL of ARGX-113 was determined to be 100 mg / week administered via 30-minute IV infusion. It was in kg.

[0147] (Example 3: Repeated-dose toxicity study of ARGX-113 in rats) In a 1-month repeated-dose toxicity study in rats, ARGX-113 showed three different dose levels. They were administered with Bell (10, 30, and 100 mg / kg). 20 animals, 10 males and 10 females, Treatment is administered at each dosage level, with a total of 15 infusions of ARGX-113 administered via IV injection every 48 hours. ARGX-113 was used to measure clinical signs, body weight, macroscopic examination, histopathology, food consumption, and hematology. Based on serum biochemical parameters, all animals tolerated all doses well. No macroscopic changes related to ARGX-113 were observed. Histopathological examination revealed that At a dose of 100 mg / kg of ARGX-113, in some animals, the following were observed in relation to the test items in the liver. The pathological lesion was identified. This lesion consisted of Kupffer cell hypertrophy / hyperplasia, This was observed in both sexes in the group treated with ARGX-113 at 100 mg / kg. In the case of the substance, no liver pathology was present at the end of the untreated recovery phase. Clear ARGX-113-related No sequential changes were observed in the 10 mg / kg or 30 mg / kg dose groups.

[0148] Therefore, in this study, the NOAEL is considered to be 30 mg / kg.

[0149] (Example 4: Phase I dose-escalation clinical trial of efgaltigimod in healthy humans) In a Phase I dose escalation study in healthy humans, administration of fgaltigimod (ARGX-113) After a single IV dose of 0.2, 2.0, 10, 25, and 50 mg / kg, efgaltigimod C max The dosage is 0.2-10 mg Between / kg, the increase was greater than proportional to the dose (for a 50-fold increase in dose, it increased by 115 times). (Increases), and thereafter increases in proportion to the dose over the range of 10-50 mg / kg (administration) For a five-fold increase in quantity, the AUC of Efgarchigimodo is 5.6 times higher. 0-96h The dosage is 0.2-2.0 mg / Between kg, the increase was greater than proportional to the dose (for a 10-fold increase in dose, 16.6%). (AUC doubles). 0-96h and AUC 0-∞ Both are generally administered in doses ranging from 2.0 to 50 mg / kg. The increase was proportional to the increase in dosage (for every 25-fold increase in dosage, the increase was 23.5 times and 25.1 times, respectively).

[0150] In all cohorts, C max The median time to reach this point was 2.0 hours (i.e., note (At the end of administration). The half-life of efgaltigimod is approximately 85.1 hours across the 2.0 to 50 mg / kg dose groups. It was approximately 104 hours, and in the 0.2 mg / kg dose group, it was about 140 hours (however, probably (The end times have likely not yet been reached.)

[0151] Efgaltigimod is administered as a single IV dose at doses of 0.2 and 2.0 mg / kg, followed by 0- It was not possible to quantify it in urine over a 72-hour period. At higher tested dose levels, The excretion of efgartigimod in urine was very low (<0.1%) and rapid (first 12 hours) Within 55-100%.

[0152] In the multiple dose-escalation phases of this study, Efgar after the initial dose in all treatment groups The pharmacokinetics (PK) of tigimod were consistent with those observed in the single dose escalation phase of this study. Ta.

[0153] Overall, efgultigimod accumulation occurred after 21 days of q4d administration and after 22 days of q7d administration. It was not observed, and the accumulation ratio (R ac The geometric mean of ) ranged from 0.814 to 1.26. Last day of medication The subsequent PK profile (i.e., after multiple doses) was more similar than the profile after the initial dose.

[0154] After a single dose of efgultigimod, a decrease in total serum IgG levels was observed compared to receiving a placebo. Compared to the control group, this was observed in all dose groups except the lowest dose (0.2 mg / kg). Great decrease (E max ) When efgaltigimod is administered in doses ranging from 10 to 50 mg / kg, The highest percentage was (53.1-62.8%). The dose / response ratio was determined only by the level of the observed reduction. However, for a dose of 2.0 mg / kg, the period from 96 to 336 hours after administration, and for doses of 10 to 50 mg / kg, The study covers the dosage from 48 hours after administration until the final sample collection time (i.e., 672 hours after administration). This also occurred during the period of the reduction effect. Therefore, higher doses resulted in a more sustained increase in total IgG in the serum. This resulted in a decrease.

[0155] In general, different IgG subtypes (1, 2, 3, and 4) are reduced to a similar degree. While the serum levels were generally present, the levels of subtype 4 were only slightly lower.

[0156] A reduction in total IgG levels was observed after a single dose of efgaltigimod compared to placebo. At both dose levels (10 and 25 mg / kg), this inhibition was multiple for efgaltigimod. Enhancement was observed after the first dose.

[0157] After multiple administrations of efgartigimod at 10 mg / kg q4d, 10 mg / kg q7d, or 25 mg / kg q7d , each E max The average range was 69.4-77.5%. In general, different IgG subtypes (1, 2, 3, and 4) had similarly reduced serum levels, but sub As for Type 4, the number was only slightly less than average.

[0158] The degree of decrease in total serum IgG levels differed significantly between the tested doses or regimens. This means that the maximum reduction in total IgG levels with efgaltigimod is at a dose of 10 mg / kg. This suggests that it has already been achieved by q7d. This also implies that other than IgG subtype 2, IgG subtype This was reflected at the type level.

[0159] Overall, the effects of systemic exposure to efgaltigimod and the drug on the reduction of total IgG serum levels A correlation was observed between mechanical (PD) action (area under the action curve (AUEC)). Similar results were obtained for Ig It was observed in subtypes G (1, 2, 3, and 4).

[0160] Administration of efgartigimod has been associated with a reduction in serum levels of IgA, IgD, IgE, and IgM. It did not induce a small number.

[0161] After a single dose of efgartigimod at doses of 0.2, 2.0, 10, 25, and 50 mg / kg or placebo The most frequently reported adverse events (TEAEs) during administration of the investigational drug were abnormal differences and increases in white blood cell (WBC) counts. The symptoms included elevated C-reactive protein (CRP), headache, dizziness, and chills.

[0162] The event of increased CRP was of moderate severity in the 25 mg / kg efgaltigimod dose group. Furthermore, the severity was considered mild in the 50 mg / kg efgaltigimod dose group. TEAE Chills were reported as moderate in one subject (50 mg / kg efgaltigimod). Other reports All reported TEAEs were considered to be of mild severity.

[0163] All of the following events—abnormal WBC count differences, increased CRP, headache, dizziness, and chills—should be reported to the principal investigator. Therefore, the study drug was associated only with the highest dose groups (i.e., 25 and 50 mg / kg). It was considered that the reported abnormal WBC count discrepancies were due to a decrease in CD8, CD3, CD56, CD4 and CD 19. It was associated with abnormalities in immunological clinical laboratory values ​​at the lymphocyte level.

[0164] After multiple doses of 10 mg / kg q4d, the most frequently reported TEAEs were diarrhea and nasopharyngitis. The most important thing was to find out about the subjects who received either 10 or 25 mg / kg of efgaltigimod on q7d. Frequently reported TEAEs include headache, chills, shivering, fatigue, drowsiness, nasopharyngitis, lower back pain, and catheterization. This included pain in the affected area. Chills, lower back pain, shivering, fatigue, and drowsiness associated with TEAE were reported at the maximum dose (25 mg / kg). Headaches, reported only on q7d, were observed by the principal investigator in three subjects (all receiving 25 mg / kg on q7d). In this case, the headache was thought to be related to the investigational drug, and in one of these subjects, The severity was moderate. All symptoms of chills, shivering, and fatigue were mild, and the clinical trial was not conducted. The physician suspected that it was related to the investigational drug. In the multiple dose group, lymphocytes No significant changes were reported in the subset. One serious adverse event (SAE) of hyperventilation was reported. This was observed in the 25 mg / kg q7d group, and it is thought that this is probably not related to the investigational drug therapy. However, all TEAEs in this Phase I trial were not confirmed by the principal investigator to be effective against the investigational drug. It should be noted that this was deemed unrelated.

[0165] Transient, out-of-range CRP and some lymphocyte subsets reported as TEAEs Furthermore, the clinical laboratory results did not show any clinically relevant changes. No abnormalities were observed in the electrocardiogram (ECG).

[0166] (Example 5: Phase II clinical trial of efgaltigimod in humans with primary ITP) This example demonstrates the safety of efgaltigimod in patients with primary immune thrombocytopenia. A fully randomized, double-blind, placebo-controlled comparative study to evaluate efficacy, pharmacokinetics, and pharmacodynamics. Phase II trial (primary trial), followed by any period of open-label continued treatment (explained in Example 6) This explains the following. Figure 1 shows the overall design of this study. Figure 2 shows the open-label study. Show the design.

[0167] (Experimental design) In short, this main trial consists of a 2-week screening period, a 3-week treatment period, and Involved in a randomized, double-blind, placebo-controlled phase II trial including an 8-week follow-up (FU) period. After this protocol was modified, platelet count ≥ 30 × 10 9 Complete the first 8-week FU period with / L Furthermore, patients with at least twice the baseline platelet count are eligible for continued FU for up to 13 weeks. Registered patients, as well as patients who have relapsed (platelet count of 30 × 10 9 (defined as less than / L) 1 year open label Retreatment is possible during the OLE (Open Lesion) treatment period.

[0168] This study included patients aged 18-85 years with confirmed primary ITP and a mean platelet count at screening. <30×10 9 / L (average of 2 counts, no measurement was >35 × 10) 9 Patients with (not L) It included: oral corticosteroids, oral immunosuppressants, and / or TPO-RA during the study period. It is permitted, and the dosage for at least 4 weeks prior to screening and during the study period. The frequency had to be stable. In addition, the total IgG level at the time of screening. Patients with a dose of <6g / L were excluded. Patients were either newly diagnosed (within 3 months of diagnosis) or had persistent symptoms (3-1 months from diagnosis). It was described as lasting 2 months, and chronic (continuing for more than 12 months).

[0169] (therapeutic intervention) The patient will receive either placebo or efgaltigimod at a dose of 5 mg / kg or 10 mg / kg body weight. Participants will be randomly assigned in a 1:1:1 ratio to receive intravenous infusion once a week for four weeks (on days 1, 8, 15, and 22). Patients enrolled during the OLE period received weekly infusions of efgaltigimod 10 mg / kg for 4 weeks. I received Ikul (multiple possible). Salvage therapy (initiation of a new ITP therapy or dosage of concomitant ITP therapy) (or an increase in the frequency of medication) may be deemed medically necessary, if the clinical trial is conducted by the competent officer. At the discretion of the physician, permission was granted during the trial period. Patients receiving salvage therapy were given the investigational drug (invested). The tigational medicinal product was discontinued, and the patient was monitored until the end of the safety test.

[0170] (Patient characteristics, demographic features, and baseline features) 62 patients were screened, and 38 of them were given either placebo (N=12) or Efgal. Tigimodo is administered once a week for 4 weeks at a dose of either 5 mg / kg (N=13) or 10 mg / kg body weight (N=13). Participants were randomized in a 1:1:1 ratio to receive a total of the intravenous infusions. Overall, 35 participants (92.1%) Of the patients, 32 (84.2%) completed this treatment period, and 14 (36) completed the 8-week FU. 0.8% of patients were enrolled in continuing FU (6 patients in the efgaltigimod 5 mg / kg group, 6 in the efgaltigimod group). (Lutigimod 10 mg / kg group, and 2 patients in the placebo group). Finally, 12 patients (31.6%) had an OLE duration. Register and receive one or more cycles of weekly infusions of efgaltigimod 10 mg / kg for 4 weeks. Of these 12 patients, 2 (15.4%) underwent EfGART during the randomization period. Six patients (46.2%) received gimod 5 mg / kg, and four patients (33.3%) received efgaltigimod 10 mg / kg. ) received a placebo.

[0171] The demographic and baseline characteristics of the trials are generally the same across these trial groups. (Table 1) 28 patients (73.7%) were classified as having chronic ITP, and 2 patients (5.3%) were classified as having chronic ITP. The patient was diagnosed with ITP (for a period of ≤3 months). The median duration of ITP was 4.8 years (0.1–47). (In the range of 0.8). 20 patients (52.6%) had a baseline platelet count <15 × 10⁶. 9 / L, ITP treatment The previous median was 2.0 (1-10). Nine patients (23.7%) had previously received rituximab. Of these, 14 (36.8%) received TPO-RA, and 10 (26.3%) of them had TP at baseline. Of those receiving O-RA treatment, 6 (15.8%) had previously undergone splenectomy. 27 (71.1%) The patient was receiving at least one combination ITP therapy at baseline.

[0172] Table 1: Summary of demographic and baseline features (full analysis set) [Table 1] TIFF2026113657000005.tif191170

[0173] Ig: Immunoglobulin, ITP: Primary immune thrombocytopenia, IV: Intravenous, N: Analysis Number of patients in the group, n: number of observed patients in each treatment group, TPO-RA: thrombopoietin receptor Agonist. Note: Percentages are based on N.

[0174] The primary endpoints were changes in vital signs, electrocardiogram parameters, and clinical laboratory assessments. The incidence and severity of adverse events (TEAEs) during administration of the investigational drug were also considered. The test includes pharmacodynamic (PD) markers (total IgG, subtypes IgG1, IgG2, IgG3, and IgG4) and pharmacokinetic (PK) markers. This included the assessment of the presence of anti-drug antibodies (ADAs) of IgG bound to platelets. Sex determination was performed at Sanquin Diagnostic Laboratory using commercially available solid-phase ELISA (P Using the akAuto® assay (Immucor GTI Diagnostics, USA), the manufacturer... I followed the instructions.

[0175] Efficacy evaluation is also assessed as a secondary endpoint, and the platelet count at any given time point is also evaluated. ≥ 50 × 10 9 / L and ≥100 × 10 9 The frequency and percentage of patients whose platelet count increased to / L, the mean platelet count change, and The definition of "response" in the International Working Group is "a short distance of more than 7 days". Platelet counts ≥ 30 and < 100 × 10⁻¹⁰ confirmed at least in two separate consecutive opportunities. 9 / L , as well as an increase of more than two times from baseline, and the absence of bleeding), and “complete response” (Platelet count ≥ 100 confirmed on at least two separate consecutive occasions separated by ≥ 7 days) ×10 9 / L, and absence of bleeding), and the World Health Organization (WHO) bleeding scale and ITP-specific The study included bleeding assessment using the ITP-BAT (Integrated Trauma-Breaking Analysis Tool). Post-hoc analyses were performed at least twice. In this instance, platelet count ≥ 50 × 10 9 The percentage of patients with / L, and the percentage of patients who have reached this threshold. Platelet count ≥ 50 × 10 9 Includes the period of / L. In addition, at least 10 cumulative days Platelet count ≥ 50 × 10 (AYS) 9 The percentage of patients with / L was calculated. Evaluation schedule The details are shown in Table 2.

[0176] Table 2: Evaluation Schedule: Primary Trial Including Follow-up Period [Table 2] TIFF2026113657000007.tif235170

[0177] Abbreviations: AE = Adverse Event; DNA = Deoxyribonucleic Acid; ECG = Electrocardiogram; ED = Early Withdrawal; EoFU = End of Life End of over-observation; EoS = End of trial; EoT = End of treatment; FACT-Th6 = Questions for functional assessment of cancer treatment Vote - Th6; HBcAb = Hepatitis B core antibody; HBsAg = Hepatitis B surface antigen; HIV = Human immunodeficiency virus S; ICF = Informed Consent Form; IgG = Immunoglobulin G; IMP = Investigational Drug (IMP) );SMOG / ITP-BAT=Immune Thrombocytopenia-Bleeding Assessment Tool;SAE=Serious Adverse Event;SF-36=S Shortform-36; TB = Tuberculosis; US = Scheduled Outpatient Clinic; WHO = World Health Organization. • The possible window period between visits during the treatment and follow-up periods is two consecutive visits. The interval is ±1 day, provided that the visit dates are at least 3 days apart. As explained in the previous "Evaluation Schedule," each visit date should be the exact date (base Every effort is made to schedule appointments for online visits or [Day 1 visits]. It should be done. a This procedure is performed 1 to 14 days before the first IMP administration on the first day of hospital visit. b The assessment related to the test must be performed before signing the informed consent form. It was not done. Evaluation of inclusion and exclusion criteria for further confirmation of eligibility will be conducted using other testing tools. This was performed on day 1 of hospital visits, prior to the initiation of the physical procedure / randomization. c Height was measured at the time of screening (and the body mass index was calculated accordingly). Weight was recorded at screening and before each dose of IMP (IMP is administered according to the patient's weight). (I'll decide on the spot.) d Patients reporting outcome assessments were asked to do so before any other assessments during their visit. e Hematology and blood chemistry are clinical chemistry subjects (sodium, potassium, chloride, glucose, carbonate). Raw salt, creatinine, blood urea nitrogen, alanine transaminase, AST, total bilirubin (γ-GT, CRP, AP, lactate dehydrogenase, uric acid, total protein, and albumin), blood Hypophysics (hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin content, average) (Equal hemoglobin concentration, red blood cell count, platelet count, white blood cell differential), and urine test (on a test strip) This included all of the abnormal blood samples. The patient had a low blood glucose level before the blood glucose assessment at the time of screening. Both patients fasted for 8 hours. At all other hospital visits (including the pre-medication sample collection on the first day), blood levels were measured. The glucose test was performed by measuring HbA1c, so the patient did not need to fast. f Evaluations were completed before drug administration on all investigational drug infusion days. gTo determine patient eligibility, platelet counts are measured at two separate visits during the screening period. The tests were conducted with at least one day's interval between them. The first count was taken during the screening. The first count was performed by the central clinical laboratory based on the sample. The second count was performed by the regional clinical laboratory. The results were based on and were collected within 3 days prior to the start of the trial treatment. Samples for the central clinical laboratory were: This information was collected during this visit. h Antinuclear antibody, prothrombin time, international normalized ratio, activated partial thromboplastin time, Thyroglobulin, thyroid-stimulating hormone. i Menopause in women who have had amenorrhea for 12 months or more and in women who are not receiving hormone replacement therapy. We evaluated it to check its condition later. j Total IgG, IgG subtypes (IgG1, IgG2, IgG3, and IgG4), anti-platelet antibodies. Pharmacodynamic samples are total Data was collected before administration on each medication day. In addition, IgA, IgD, IgE, and IgM were evaluated. Antiplatelet The antibody was tested using two different assays (PakAuto assay (on day 1 before hospital visit and before medication, on day 8 [or day 9])). [Visit to the hospital] and visit on day 16), and unvalidated assays [Visit to the hospital from day 1 to day 16] Measured by ]). k Serum pregnancy tests are performed at screening, and urine pregnancy tests are performed at randomization and other relevant times. I did this at every single visit to the hospital. l HBsAg, HBcAb, anti-HBs and anti-HCV, HIV-1 and 2 antibodies, and TB serological diagnosis (QuantiFERON (Registered) Contains (registered trademark)-TB Gold). m Randomization was completed before IMP administration. nBlood sample (for future correlation studies of FcRn genotype based on obtained PK and safety characteristics) This information is collected at any point after signing an individual pharmacogenetic ICF and before the first dose (day 1 visit). If blood collection at baseline fails, the sample will be collected at the next visit during the main study. The sample was taken before administering the medication. o The investigational drug or placebo will be administered as an intravenous infusion over 2 hours on visits on days 1, 3, 5, and 7. The patient was monitored at the facility for at least two hours after the injection. p Adverse events, concomitant medication use (multiple medications are possible), and new procedures should be recorded in the final trial after signing the ICF. Related activities were continuously monitored. In cases of early withdrawal, the "early withdrawal" period was 30 minutes after the patient's first visit to the hospital. All AE / SAE were evaluated over several days, or until satisfactory resolution or stabilization was achieved. q PK evaluation is performed before and after administration on all IMP injection days (for pre-injection samples, 30 minutes from the start of injection). The tests were conducted both within minutes and, for post-administration samples, within 30 minutes after the completion of the injection. r During these visits, platelet counts were obtained as part of hematological tests. Central and regional clinical The values ​​from the laboratory are used as the "baseline" for all subsequent platelet count measurements. Ta. s On the 7th day, the patient visited the clinic, and an ECG was obtained after the injection. t During screening: Total immunoglobulin G (IgG) levels at the time of screening are determined by the local clinical Determined by the floor testing laboratory (excl. crit. 10.g.). u During screening: The principal investigator determined the abnormality in the screening laboratory. In this case, the result was confirmed by a local clinical laboratory. vEither TSH or thyroglobulin was measured at the time of "screening". If these results from the trial are not available at the time of randomization, alternative trials (TSH or thyrog) may be used. Robulin was measured. w Continuing FU period: Platelet count and rescue drug therapy from the local clinical laboratory are performed as part of the patient's medical care. Collected from Ill, both backward and forward. x If available in the patient's medical file, only the WHO bleeding scale will be reported. y The revised ICF for the main trial must be signed by all patients. z The end of follow-up visits for the continuous FU period is determined by the presence of a recurrence and the completion of salvage treatment. If you come in for a follow-up visit, or if no recurrence occurs, come in as soon as possible before the end of the 13-week continuous FU period. It was thought to be a hospital.

[0178] (Clinical Pharmacology) Efgaltigimod at doses of 5 and 10 mg / kg induced a rapid decrease in total IgG (Figure 3), compared to the placebo group. Compared to the indistinguishable change from baseline, on day 25, the maximum average change was Evgarchig Mod 5 mg / kg showed a 60.4% increase (from baseline of 9.9 g / L [SD=3.2] to 4.0 g / L [SD=0.8]), and 10 The percentage reached 63.7% at mg / kg (from 10.6 g / L [SD=5.1] at baseline to 4.1 g / L [SD=2.0]). G reduction was observed in all IgG subtypes (Figure 4).

[0179] The mean percentage change from baseline in IgA, IgD, IgE, and IgM was compared between the placebo group and the Eff group. Similarity was observed among the gultigimod treatment groups, mostly within ±10–15% of baseline. Yes (data not shown), and the change was not considered clinically relevant. Positive Prior to medication, ADA was observed in one patient (7.7%) treated with efgaltigimod 5 mg / kg, and in one patient treated with efgaltigimod 1 It was detectable in 3 patients (23.1%) in the 0 mg / kg group and in 2 patients (16.7%) in the placebo group. Post-drug ADA titer was measured in 5 patients (38.5%) treated with efgaltigimod 5 mg / kg. It was detected in 4 patients (30.8%) treated with 10 mg / kg and 2 patients (16.7%) treated with placebo. ADA titers were typically low and did not show any clear effect on PK / PD. Analysis of platelet antibody eluate revealed that platelet-related autoantibodies were present in all randomized patients. The existence of (GPIIb / IIIa, GPIb / IX, GPIa / IIa) was revealed. It was cured with 5 mg / kg efgaltigimod. In 8 out of 12 patients (66.7%) who received treatment and 7 out of 10 patients (70.0%) in the 10 mg / kg group, autoantibodies were found. A greater than 40% reduction in platelet-associated autoantibody signals for at least one type of autoantibody However, this was observed at treatment on days 25 / 29 and / or 78. One patient (7.7%) in the 5 mg / kg group and In the 10 mg / kg group, three patients (23.1%) lost their baseline sample or did not recover any post-dosing samples. The presence of autoantibodies in serum could not be evaluated because the sample was either obtained after the treatment was completed or otherwise. It wasn't very widespread.

[0180] (Effectiveness) Both groups treated with efgultiquimod showed higher baseline levels compared to the placebo group. The large mean platelet count change was achieved (77.2 × 10⁶ on day 11 in the 5 mg / kg group). 9 / L, 10 mg / kg group 71.5 x 10 on day 78 9 / L and 31.1 × 10⁻¹⁰ days in placebo 9 / L) (Figure 5). At any time Platelet count at a given point ≥ 50 × 10 9 / L refers to 7 patients (53.8%) in both efgaltigimod treatment groups. This was achieved in 6 individuals (50.0%) in the patient group and the placebo group (Figure 6). Platelet count at any given time point. Number ≥ 100 × 10 9 / L refers to 6 patients (46.2%) in the efgaltigimod 5 mg / kg group, and efgaltigimod 1 This was achieved in 5 patients (38.5%) in the 0 mg / kg treatment group and in 1 patient (8.3%) in the placebo group. The International Working Group definition of "complete response" is 5 patients (38.5%) in the efgaltigimod 5 mg / kg group. ) Patients, 4 (30.8%) in the efgaltigimod 10 mg / kg treatment group and 2 (16.7%) in the placebo group This was achieved in [location]. On the other hand, two newly diagnosed ITP patients and one chronic ITP patient continued into the FU phase. The increased platelet count was maintained throughout the period (up to day 162).

[0181] A post-hoc analysis was performed (Figure 6). Platelet counts ≥ 50 × 10⁴ at least two occasions. 9 / L is both Six patients (46.2%) in the fugartigimod treatment group and three patients (25.0%) in the placebo group. This was achieved by the following criteria: For these patients, platelet count ≥ 50 × 10 9 The average cumulative period of / L is E In patients treated with fugartigimod, the period was 24.5 days (SD=20.70) within the range of 3 and 73 days, and In patients treated with placebo, the response time was 7.3 days (SD=2.89) in the range of 4 and 9 days. , 10 patients (38.5%) treated with efgaltigimod and 0 patients (0.0%) treated with placebo This refers to a cumulative period exceeding 10 days in which the platelet count is ≥ 50 × 10 9 / L was achieved. Platelet count ≥ 50 ×10 9 / L at the first time point of achievement (patients with platelet count ≥ 50 × 10 9 / L achieved on at least 2 occasions) was in the range of 8 to 43 days for patients treated with efgartigimod. (Regarding).

[0182] Four (30.8%) patients in the efgartigimod 5 mg / kg treatment group received rescue treatment during the randomization period, and 3 did not achieve a platelet count ≥ 50 × 10 9 / L. In the efgartigimod 10 mg / kg treatment group, 3 (23.1%) patients received rescue therapy during the randomization period, and 2 of them (15.4%) received only 3 doses. These patients did not achieve a platelet count ≥ 50 × 10 9 / L. One placebo patient received rescue therapy on day 53.

[0183] Among the 12 patients who were enrolled during the OLE period and received 4 - week once - weekly infusions of 10 mg / kg, 3 patients (25.0%) achieved a platelet count ≥ 50 × 1 0 9 / L at at least 2 occasions during the randomization period and were all treated with efgartigimod 10 mg / kg (Table 3). Among the 8 (66.7 %) of the 12 patients, they achieved a platelet count ≥ 50 ×10 9 / L at at least 2 occasions during the first cycle of the OLE period. Among these 8 patients, 2 from efgartigimod 5 mg / kg and 3 from placebo did not achieve this threshold during the randomization period, and 3 patients who achieved this threshold during the randomization period were retreated with efgartigimod 10 mg / kg and achieved it during both the randomization period and the OLE period. (Regarding).

[0184] Table 3: Patients achieving different platelet thresholds in the first cycle of open label duration ( N = 12) [Table 3] N: Number of patients in the analysis set, n: Number of patients observed within each treatment group. Note: Percentages are based on N.

[0185] Figures 7 and 8 show the results of 2 patients with chronic ITP treated with 5 mg / kg or 10 mg / kg of efgartigimod, respectively Patient 400 - 004 (Figure 7) is a 41-year-old female who was first diagnosed with ITP in 1984 and has been continuing with SoC treatment consisting of once-daily p.o. eltrombopag 75 mg since 2014 As shown in Figure 7, she had a baseline platelet count < 10 × 10 9 / L and by the time she received the 4th dose of efgartigimod 5 mg / kg, she had achieved a platelet count of ~200 × 10 9 / L. Patient 365 - 002 (Figure 8) is a 57-year-old male who was first diagnosed with ITP in 2005 and has been continuing with SoC treatment consisting of once-daily p.o. methylprednisolone 100 mg since 2017 As shown in Figure 8, he had a baseline platelet count of approximately 10 × 10 9 / L and after receiving his first dose of efgartigimod 10 mg / kg, he initiated a sustained response of > 100 × 10 / L approximately 60 days later 9 and had achieved it.

[0186] Figures 9 and 10 show the results of 2 newly diagnosed ITP patients treated with 5 mg / kg of efgartigimod Patient 363-007 (Figure 9) was diagnosed with ITP approximately one month prior to screening for this study. A 32-year-old woman was diagnosed with Solu-Melodol 12 mg once daily for a short period after her diagnosis. Treatment is continuing. As shown in Figure 9, her baseline platelet count was ~20 × 10⁶ 9 / L She had the condition, and at the time she received her fourth dose of efgaltigimod at a dosage of 5 mg / kg A sustained increase in platelet count starting around ~200 × 10⁻¹⁴ 9 / L was achieved. Patient 383-001 (Figure) 10) is a 50-year-old woman who was diagnosed with ITP approximately 2.5 months prior to screening for this study. Approximately two months after the woman's diagnosis, she was given a course of action consisting of prednisone 10mg once daily. As shown in Figure 10, her baseline platelet count was approximately 15 × 10⁶. 9 He has / L and he The woman began experiencing symptoms approximately three weeks after receiving her fourth dose of efugaltigimod at a dosage of 5 mg / kg. Sustained platelet count > 50 × 10⁻¹⁰ 9 / L was achieved.

[0187] Figure 11 shows the results for patients with persistent ITP treated with 10 mg / kg efgaltigimod. This patient (331-003) had been receiving "elective" treatment (observation without active intervention) prior to enrollment in this study. As shown in Figure 9, this patient had a baseline platelet count <10 × 10 9 / L In addition, symptoms began approximately one week after receiving the fourth dose of efgaltigimod 10 mg / kg. The platelet count increased over approximately 6 weeks, > approximately 100 x 10⁶ 9 / L was achieved.

[0188] (Bleeding-related events) At least one bleeding TEAE occurred in 5 patients (38.5%) in each treatment group, and in the placebo group. It was reported in 3 individuals (25.0%). The hemorrhagic TEAE was not considered to be related to the investigational drug. No severe bleeding events were reported. The incidence, location, and severity of any bleeding symptoms were also not reported. Furthermore, the WHO and ITP-BAT scales were used for reporting (Figures 12 and 13, respectively). Hemorrhage (total WHO > 0) The proportion of patients with this condition was 46.2% in both the efgaltigimod 5 mg / kg and 10 mg / kg groups, respectively. The percentage decreased to 7.7% on day 64, and also decreased from 38.5% to 7.7% on day 29.

[0189] (Consideration) This randomized, double-blind, placebo-controlled phase II trial investigated the response to prior ITP therapy. Patients with insufficient ITP, primarily those with long-term ITP (median disease duration 4.82 [0.1–47.8] years). In this study, the safety and efficacy of efgaltigimod were evaluated. In more than half of the patient population (2 0 patients [52.6%]) had a baseline platelet count <15 × 10⁻⁶ 9 It had / L.

[0190] Efgaltigimod was well-tolerated, and there were no dose-related safety findings. Sex profiles were consistent with previous findings in healthy volunteers and patients with myasthenia gravis. No increase in the incidence of the disease was observed in these efgaltigimod treatment groups. (1 case) A case of pneumonia was reported during the OLE period, which occurred 8 weeks after the final dose of efgaltigimod. At this time, total IgG levels approached baseline, and in patients with a history of splenectomy... there were.

[0191] Targeting FcRn with efgaltigimod is selective for IgG reduction and also selective for other immunosuppressants. It did not affect the levels of epidemic globulin isotypes. In addition, the decrease in total IgG was Infections in diseases that do not reach very low levels and cause hypogammaglobulinemia It was found to be associated with an increased risk. In particular, efugaltigimod administration was found to be associated with an increased risk. The anti-FcRn monoclonal antibody in this area does not cause a decrease in albumin levels. This suggests that the mechanisms of these two types of FcRn antagonists are different.

[0192] Short-cycle treatment with efgaltigimod showed that total IgG and in all treated patients were observed to be positive for all patients. A rapid and significant decrease occurred in all IgG subtypes, and in the efgaltigimod 10 mg / kg group. A larger decrease was observed. This was common in 60% to 70% of ITP patients and is generally the most abundant. This includes targeting platelet surface GP, GPIIb / IIIa, GPIb / IX, and GPIa / IIa, for detectable platelets. Although related autoantibodies were present, these were identified in all patients in this study, and The number of cases decreased after treatment with efgaltigimod.

[0193] The mean platelet count increased in both groups treated with efgaltigimod. (efgaltigimod 5 mg / kg) The early and substantial increase in the group can be explained by one patient. This patient The patient is receiving eltrombopag as concomitant ITP therapy, and their platelet count is... 500 x 10 by day 15 9 It increased above / L. IgG-depletion due to efgarchigimod and TP Further research is needed to determine whether there are synergistic effects between other ITP treatments with different mechanisms of action, such as O-RA. The test would be interesting.

[0194] A surprisingly high number of patients receiving placebo had a single platelet count of ≥ 50 × 10 during the study period. 9 Achieved / L (6% compared to 14% across two 24-week fostamatinib Phase III trials, for example). (50%). However, platelet count ≥ 50 × 10 9 / L at a greater frequency or duration, or increased Platelet count ≥ 100 × 10 9 Post-hoc analyses requiring / L will reveal the efficacy of efgarchigimodo. Six patients (46%) treated in both efgartigimod groups had at least two occasions. Increased platelet count > 50 × 10 9 It showed / L. In addition, statistically significant more aggressive treatment In patients who underwent this treatment, platelet counts were ≥ 50 × 10 for cumulative days exceeding 10 days, compared to the placebo group. 9 / L Achieved (10 people [38%] vs. 0 people [0%]).

[0195] Autoantibodies in ITP opsonize platelets, leading to cleavage by macrophages in the spleen. This can produce platelets, which inhibit the proliferation and differentiation of megakaryocytes and weaken platelets. It can generate and induce platelet apoptosis or complement-dependent lysis. Recently, some anti-GP antibodies inhibit platelet aggregation and thrombus formation, or reduce blood volume. Either desialylation of the platelets or Fc-dependent liver clearance is induced, thereby altering the platelet mechanism. It has been reported that it can interfere with function. More precisely, in three different patient profiles... Il was observed in this study. More precisely, after short-term exposure to efgalchigimod, High variability was observed in the onset and duration of the reaction. As shown in Figure 7, blood A rapid increase in the number of platelets was observed in some patients treated with efgartigimodo (efgartigimodo). (3 patients in the lutigimod 5 mg / kg group and 2 patients in the 10 mg / kg group), this is due to anti-CD16 antibody, IVIg and splenectomy. This is similar to the response time reported for this treatment / procedure. Since it is thought to interfere with the mechanism of disease onset, the limited level of autoantibodies in some patients The resulting decrease inhibits Fcγ receptor-mediated phagocytosis of antibody-coated platelets. This suggests that it may be sufficient to do so. In another patient, the response time was as shown in Figure 11. It was delayed as illustrated in the example. In these patients, the platelet elevation was observed after the 4th infusion ( Observed on day 22, this indicates that a more significant reduction in autoantibodies is needed, and / Alternatively, autoantibodies primarily affect platelet production by megakaryocytes in the bone marrow, and their removal is It can be pointed out that this has a longer-term effect on the platelet count throughout the body. In addition, F Very few patients showed a twofold increase in platelet count after gultigimod treatment (as illustrated in Figure 11). As shown above, this suggests two distinct pathogenic autoantibody mechanisms with different kinetics. Interestingly, this phenomenon also occurs in acute cases treated with plasmapheresis. This can also be explained in ITP patients. The majority of patients who responded to ephaltigimod had platelet counts. There was a transient increase, and the number returned to baseline levels during the treatment-free FU period. Two newly diagnosed ITP patients and one chronic ITP patient increased throughout the continuous FU period (up to day 162). The platelet count was maintained. Similar findings were observed in "acute" ITP patients after plasmapheresis. While this was obtained, the response in chronic patients was reported to be merely transient.

[0196] ITP classification (new diagnosis, persistent or chronic ITP), sub-based on concomitant ITP treatment or use of TPO-RA Encouragingly, as expected in group analysis, a clear efficacy based on an increase in platelet count was observed. There were cases of patients treated with ephgartigimod accompanied by [unclear]. Nevertheless, it was limited. As expected in this study involving a number of patients, in each of these subcategories, There were no significant differences.

[0197] During the OLE period, 12 patients received efgaltigimod 10 mg / kg, which was randomized. The study included four patients from the placebo group of the trial. These results were obtained during the randomization period. Platelet count ≥ 50 × 10⁴ on at least two occasions. 9 / L was achieved, and this again during the OLE period. Like the three patients in the efgaltigimod 10 mg / kg group who achieved the threshold, efgaltigimod- The reproducibility of the induced platelets was revealed to be increased. Interestingly, these two The patient was initially treated with efgaltigimod 5 mg / kg and did not show an increase in platelet count, OLE An increase was observed when treated with efgaltigimod 10 mg / kg during the period, which is due to efgaltigimod This suggests that higher doses or longer exposure to mod are necessary (Table 3).

[0198] Efgaltigimod is used primarily in patients with ITP who are refractory to a series of prior ITP therapies. The finding that it induces an increased platelet count is in contrast to the use of prior ITP therapies (e.g., steroids). Regardless of rituximab, TPO-RA, or splenectomy, the central role of pathogenic IgG in ITP and This supports the potential usefulness of IgG depletion. Patients benefited from both doses tested. This further supports the hypothesis of IgG reduction. The 10 mg / kg dosage is superior in several ways. The signal is present, which means that there are no newly diagnosed patients in this group, and the primary trial Two patients did not receive all four 10 mg / kg doses, and in the primary trial, efgaltigimod 5 Two patients whose platelet count did not increase with mg / kg were given efgaltigimod 10 mg / during the OLE period. This includes the fact that it increased during treatment with kg (Table 3). In addition, both efgartigimod-treatment In the treatment group, bleeding measured using a bleeding scale (sum of WHO and ITP-BAT scores > 0) A decrease in incidence was observed, with a numerically greater decrease in the efgaltigimod 10 mg / kg group. Ta.

[0199] (Example 6: Open label duration) During participation in the primary testing described in Example 5, the recurrence of the issue in its ongoing SoC occurred. For patients whose intent can be evaluated, the safety and tolerability, efficacy, and PK / PD of efugaltigimod should be assessed. Participants were given the option to enroll in the open-label continuation period of this study to further investigate the matter. During the follow-up period of this main trial (i.e., an 8-week follow-up period plus a 13-week continuous follow-up period) Observation period), recurrence occurred in 30 × 10 cm in the absence of bleeding. 9 Platelet count in patients whose platelet count has decreased to below / L, or Bloodless 30x10 9 Patients whose platelet counts did not reach / L were characterized as such. Figure 2 shows The design of the open-label continuing study is shown in Tables 4 and 5. Endpoint evaluations are shown in Tables 4 and 5. As detailed below, the evaluation was conducted according to the "evaluation schedule".

[0200] Table 4: Evaluation Schedule: Open-Label Treatment Period - First Treatment Cycle [Table 4] TIFF2026113657000010.tif235170

[0201] Abbreviations: AE = Adverse Event; ED = Early Withdrawal; EoC = End of Cycle; EoS = End of Trial; EoT = Completion of treatment; FACT-Th6 = Functional Assessment Questionnaire for Cancer Treatment - Th6; ICF = Informed Consensus Toform; IgG = Immunoglobulin G; IMP = Investigational drug; SMOG / ITP-BAT = Immunothrombocytopenia Bleeding assessment tool; SAE = serious adverse event; SF-36 = short form-36; US = scheduled outpatient visit; W HO = World Health Organization. * The possible window period between hospital visits during the treatment and follow-up periods is two consecutive visits. The condition is that visits are separated by at least 3 days, with a tolerance of ±1 day. As explained in the "Evaluation Schedule" above, please specify the exact date for each visit (17th day onwards). Every effort should be made to schedule it (for the hospital). a The procedures listed in Table 2 for EoS visits (visits on day 16) are applicable in the open-label treatment phase. If performed within one week prior to the first dose of ARGX-113 at 10 mg / kg, these procedures are considered "treatment evaluation." The patient did not repeat the procedure in the "visit to the hospital" section. ARGX-113 was an open-label treatment in this study. It can only be administered if the patient agrees to participate in the program and has signed the ICF. b Evaluation of inclusion and exclusion criteria to determine patient eligibility for open-label treatment periods. Before evaluation, a specific ICF regarding the open-label treatment duration must be signed. cHeight was measured during the "treatment evaluation visit" (and the body mass index was calculated accordingly). (Calculated). Body weight was recorded at the "treatment evaluation visit" and before each administration of IMP (IMP is the patient's body weight). (It will be decided accordingly.) d Patients reporting outcome assessments were asked to do so before any other assessments during their visit. e Evaluations were completed before drug administration on all investigational drug infusion days. f To determine patient eligibility, platelet counts are performed during the "treatment evaluation visit" or during End of Service (EoS). (Visited on day 16) It was done during the visit. g Hematology and blood chemistry are clinical chemistry subjects (sodium, potassium, chloride, glucose, carbonate). Raw salt, creatinine, blood urea nitrogen, alanine transaminase, AST, total bilirubin (γ-GT, CRP, AP, lactate dehydrogenase, uric acid, total protein, and albumin), blood Hypophysics (hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin content, average) (Equal hemoglobin concentration, red blood cell count, platelet count, white blood cell differential), and urine test (on a test strip) It included all of the abnormal blood. h Total IgG, anti-platelet antibodies. Pharmacodynamic samples were collected pre-administration on all administration days. Anti-platelet Antibodies were measured by a validated assay (on visits on days 17, 25, and 28). i The investigational drug was administered as an intravenous infusion over two hours on visits on days 17, 19, 21, and 23. The individuals were monitored within the facility for at least two hours after the injection. j Adverse events, concomitant medication use (multiple medications are possible), and new procedures should be recorded in the final trial after signing the ICF. Related activities were continuously monitored. In cases of early withdrawal, the "early withdrawal" period was 30 minutes after the patient's first visit to the hospital. All AE / SAE were evaluated over several days, or until satisfactory resolution or stabilization was achieved. k PK evaluation is performed before and after administration on all IMP injection days (for pre-injection samples, 30 minutes from the start of injection). The tests were conducted both within minutes and, for post-administration samples, within 30 minutes after the completion of the injection. l During these visits, platelet counts were obtained as part of hematological tests. m If the patient experiences a relapse between the visit on day 26 and the visit on day 28, these visits are considered EoC visits and / Alternatively, it was considered a follow-up visit for treatment evaluation in the next cycle. n Continuing FU period: Platelet count from local clinical laboratories, WHO bleeding scale, and salvage drug therapy are performed. These are collected retrospectively / prospectively from the patient's medical files. o If available in the patient's medical file, only the WHO bleeding scale will be reported. p On the 23rd day, an ECG was obtained after the infusion was administered. q At the end of the cycle visit for the first open-label treatment cycle, a relapse was observed. It was considered a visit to the hospital for the purpose of providing relief treatment. r If the patient experiences a relapse between the visit on day 26 and the visit on day 28, these visits are considered EoC visits and / Alternatively, it was considered a follow-up visit for treatment evaluation in the next cycle.

[0202] Table 5: Evaluation Schedule: Open-label treatment period - Subsequent treatment cycles (multiple) [Table 5]

[0203] Abbreviations: AE = Adverse Event; ED = Early Withdrawal; EoC = End of Cycle; EoS = End of Trial; EoT = Completion of treatment; FACT-Th6 = Questionnaire for Functional Assessment of Cancer Treatment - Th6; IMP = Investigational drug; SMOG / ITP-BAT = Immune-mediated thrombocytopenia - Bleeding Assessment Tool; SAE = Serious Adverse Event; SF-36 = Short Form-36 US = Scheduled outpatient clinic; WHO = World Health Organization. * The time window between two consecutive (re)treatment cycles was at least 4 weeks of FU. If the patient experiences a relapse between V34 and V36, these visits will be considered an EoC visit and / or the next visit. This visit was considered to be for treatment evaluation of Kuru. In the case of retreatment, during the continuous follow-up period from the cycle... End-of-Clinic (EoC) visits can be scheduled together with subsequent treatment evaluation visits. ** The final retreatment cycle is due at the first half of the 10th month of the open-label treatment period. It was initiated. The duration of the open-label treatment period is as follows: The period was set at a maximum of 12 months from the time of signing the ICF. *** The possible window period between visits during the treatment and follow-up periods is ±1 day. As explained in the previous "evaluation schedule" without a window, each visit day Every effort will be made to schedule it to the exact date (for the 29th day visit). It should. a Height was measured at the "re-treatment evaluation visit" (and the body mass index was calculated accordingly). (Calculated). Body weight was recorded before each IMP administration (because the IMP dosage is determined according to the patient's weight). b On day 29, an ECG was obtained before the injection. On day 32, an ECG was obtained after the injection. c Patients reporting outcome assessments were asked to do so before any other assessments during their visit. dEvaluations were completed before drug administration on all investigational drug infusion days. e Hematology and blood chemistry are clinical chemistry subjects (sodium, potassium, chloride, glucose, carbonate). Raw salt, creatinine, blood urea nitrogen, alanine transaminase, AST, total bilirubin (γ-GT, CRP, AP, lactate dehydrogenase, uric acid, total protein, and albumin), blood Hypophysics (hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin content, average) (Equal hemoglobin concentration, red blood cell count, platelet count, white blood cell differential), and urine test (on a test strip) It included all of the abnormal blood. f Total IgG, anti-platelet antibodies. Pharmacodynamic samples were collected on the day of administration, before administration. Anti-platelet antibodies were Measured by validated assays (visits on days 29 and 36). g During these visits, platelet counts were obtained as part of hematological tests. h The investigational drug was administered as an intravenous infusion over two hours on visits on days 29, 30, 31, and 32. The individuals were monitored within the facility for at least two hours after the injection. i Adverse events, concomitant medication use (multiple medications are possible), and new procedures should be recorded in the final trial after signing the ICF. Related activities were continuously monitored. In cases of early withdrawal, the "early withdrawal" period was 30 minutes after the patient's first visit to the hospital. All AE / SAE were evaluated over several days, or until satisfactory resolution or stabilization was achieved. j Continuing FU period: Platelet count and rescue drug therapy from the local clinical laboratory are performed as part of the patient's medical care. Collected from Ill, both backward and forward. k If available in the patient's medical file, only the WHO bleeding scale will be reported. lThe end of cycle visits for the open-label treatment period is determined by the visits in which a relapse is observed. It was thought that the patient had received salvage treatment. If a recurrence occurs within 4 weeks after this treatment period, The patient was unable to consider the next treatment cycle. If there is no relapse, The final visit before the end of the 12-month open-label treatment period is considered a "final test" visit. Ta.

[0204] As shown in Figure 2, the open-label period for the Phase II trial was extended for a maximum of one year. Each patient undergoes a 4-week cycle of weekly IV infusions, with individual treatment cycles spaced at least 4 weeks apart. In other words, in addition to SoC, in four doses over three weeks, a dose of 10 mg / kg bw was administered to Evgalchig. Received mod. During open-label treatment, administered doses of efgaltigimod or SoC. And changes in frequency were not permitted. However, during the observation period, if medically necessary Only in patients who have achieved a conceivable and complete response, the investigator may, at their discretion, administer a 25% level reduction. Only the SoC weight reduction was permitted.

[0205] The initial open-label continuation cycle involves a treatment evaluation visit in week 1 and open-label treatment in week 3. The period (from the visit on day 17 to the visit on day 23), and the minimum follow-up period for week 4 (from the visit on day 24 to day 28) This included visits up to the first treatment visit. Short-term safety evaluation visits were scheduled between the two treatment visits. Possible window periods between visits during the initial open-label treatment period and follow-up period. This is conditional on these two consecutive visits being separated by at least 3 days, with a difference of ±1 day. As explained in Table 4, each hospital visit was scheduled on the same day (relative to the visit on day 17). Therefore, every effort should be made.

[0206] Each subsequent retreatment cycle includes a follow-up visit for retreatment evaluation in week 1, and an open-label treatment period in week 3 (for example). (For example, from the visit on day 29 to the visit on day 32), and the minimum follow-up period of 4 weeks (for example, the visit on day 33) This includes visits during each open-label treatment period and follow-up period. The possible window period between hospital visits was ±1 day. As explained in Table 5, each visit was on the same day. Every effort should be made to schedule (for example, a visit on day 29). That is the case.

[0207] The time window between consecutive (re)treatment cycles was a minimum of 4 weeks. Regarding Ikuru, the 4-week observation period can be extended according to the flexible observation period. It is possible. Information gathered from daily practice can be used to manage relapses and / or the next course of treatment for ITP, for example. This included platelet count, salvage treatment, bleeding events, and any serious adverse events.

[0208] (result) A total of 12 patients from the three treatment arms of the main trial were treated during the open-label period. Low platelet count (for example, 15 × 10) 9 Several patients with a blood count less than / L are continuing to be open-label. In response to the treatment, 50 x 10 9 / L or 100×10 9 A platelet count exceeding / L was achieved. This is noteworthy. In particular, one patient from the 5 mg / kg efgaltigimod treatment arm survived the entire duration of the primary trial. Throughout, never 30x10 9 Although we never achieved a platelet count exceeding / L, this open lab During the continuation of the treatment, the platelet count was approximately 80 x 10 9 / L achieved.

[0209] (Example 7: Phase III clinical trial of efgaltigimod in humans with primary ITP) This example shows the use of efgaltigimod in adult patients with primary immune thrombocytopenia (ITP). A Phase III multicenter study to evaluate the efficacy and safety of ARGX-113) 10 mg / kg intravenously. This describes a double-blind, placebo-controlled, comparative clinical trial lasting up to 30 weeks. The primary objective of this trial is to At least 50 during at least 4 of the 6 visits between the 19th and 24th visits of the clinical trial. ×10 9 A sustained platelet count response, defined as a platelet count of / L, is observed in patients with chronic primary ITP. The efficacy of efgartigimod in achieving a sustained platelet count response in plastic The objective is to evaluate it in comparison to sebum. A secondary objective is to evaluate the overall platelet count response. Evaluation of the efficacy of efgartigimod compared to vo; administered intravenously (IV) once weekly or every other week. Evaluation of the safety and tolerability of efgultigimod; efgultigimod compared to placebo Evaluation of the incidence and severity of bleeding events during treatment with [unclear]; compared to placebo. Changes in the use of salvage therapy and concomitant ITP therapy during treatment with gultigimod Evaluation of the treatment; measurement of quality of life (QoL) compared to placebo and patient-reported outcomes (PRO). Evaluation of the effects of efgartigimod therapy; evaluation of the immunogenicity of efgartigimod; efgartigimod This includes evaluation of the pharmacokinetics (PK) of gimodo, as well as evaluation of the pharmacodynamic (PD) effects of efgaltigimod. .

[0210] The target population has a mean platelet count <30 × 10⁻¹⁰. 9 Patients with / L and who have previously undergone at least one ITP therapy. The patient is an adult with persistent or chronic primary ITP who is receiving treatment. If receiving combination ITP therapy, these therapies will stabilize the patient over the four weeks prior to randomization. The dosage and frequency of administration will be maintained as specified. Starting from week 12, the dosage may be increased and / or permitted. The approved combination ITP therapy schedule was deemed insufficient for a "sufficient" response (i.e., during the last four weeks). Platelet count ≥ 30 × 10 at any given visit 9 This is possible for patients who have (not / L). These patients are considered "refractory" to the primary endpoint analysis.

[0211] After eligibility is confirmed, the patient will be enrolled in a 24-week treatment period and will receive IV ephaltigimod 10 mg / kg. Alternatively, a placebo may be administered once a week from the first to the fourth visit, and then from the fifth to the sixteenth visit. You will receive it either weekly or bi-weekly, adjusted according to your platelet count. Patients will be randomized. From the 17th to the 24th visit, patients will receive the medication they received at the 16th visit. It will be fixed to a schedule (i.e., once a week or every other week).

[0212] Patients who complete the 24-week randomized trial period will receive at the end of the primary trial. The patient received IV doses of efgaltigimod 10 mg / kg according to the frequency (i.e., once a week or every other week). Therefore, they are eligible to enroll in an open-label continuing clinical trial.

[0213] Approximately 117 patients with chronic ITP and up to 39 patients with persistent ITP were each given efgaltigimod. Alternatively, patients will be randomized in a 2:1 ratio to receive either a placebo or a placebo. All eligible patients will be considered for this trial. Then, receive an IV infusion of efgaltigimod 10 mg / kg body weight or a matching placebo. Patients will be randomized. All patients will initially receive weekly IV infusions during their first 1-4 visits. Based on the platelet count at the second visit, the frequency of medication will be determined according to the following rules, from the 5th to the 16th visit. The hospital can be changed (the change in medication frequency will likely be made at the time of the most recent visit): (i ) Platelet count ≥ 100 × 10 9 Patients who achieve / L (4th visit is the latest (This is a visit to the hospital), and at the end of these four visits, or at the end of three consecutive visits, the platelet count is ≥ 100 × 10 9 / L In patients having the following conditions, the frequency of treatment decreases from once a week to once every two weeks; or (ii) platelet count is two consecutive Regarding your visit 100 x 10 9 / L or below, or <30x10 at the first visit 9 In patients with / L For patients receiving salvage therapy, the frequency may be increased from once every two weeks to once a week.

[0214] The dosage and schedule were changed for the last four weeks prior to randomization (i.e., the first visit). If not, patients receiving approved combination ITP therapy are eligible for this trial. The approved combination ITP drug therapies include oral corticosteroids, oral immunosuppressants, and dapsone / dana. Contains zole and / or eltrombopag. Approved combination ITP therapy dosage and frequency. This will remain unchanged during this clinical trial. The only exception is the thrombopoietin receptor agonist. This patient is receiving combination therapy with Streptococcus positivity (TPO-RA) and eltrombopag, and in this patient... The dose reduction of eltrombopag is possible at the platelet threshold specified on the label.

[0215] Patients who are not receiving combination ITP therapy are also eligible for this trial.

[0216] Patients randomized to receive efgultigimod will receive 10 mg efgultigimod / kg. The dose is administered via IV infusion over one hour during each infusion visit. Maximum total dose per infusion. The dosage is 1,200 mg for patients whose body weight is ≥ 120 kg as measured at the time of infusion. Patients randomized to receive the same excipients as Efgartigimod, but Efgarti A matching placebo, which does not contain gimodo, is administered via IV injection over one hour during the patient's visit for injection. It can be done.

[0217] Figure 14 shows the overall design of this examination.

[0218] The results of this study showed that efgaltigimod administered at 10 mg / kg body weight was associated with chronic primary ITP. In achieving a sustained platelet count response in patients, it is more effective than placebo. We confirmed that this sustained platelet count response was observed at the 19th and 24th visits of this clinical trial. At least 50 × 10 for at least 4 of the 6 visits in between. 9 The platelet count is specified as / L. ru.

[0219] (Example 8: Comparison with rozanolixizumab) The results of the Phase II trial of the anti-FcRn monoclonal antibody rozanolixizumab (UCB7665) have recently been released. This was reported in Robak T et al., Blood 130: 15 (2017). In that study, 30 patients with chronic illnesses... Adult patients with sexually transmitted or persistent ITP receive a subcutaneous dose of 4 mg / kg once weekly for 5 weeks. Alternatively, multiple doses of rozanolixizumab, either 7 mg / kg sc once weekly for three weeks. Treatment was administered according to the dosage. This differs from the Phase II trial of efgaltigimod (ARGX-113) described herein. In this rozanolixizumab trial, the mean decrease in total IgG was measured. High variability in pharmacodynamic effects was observed. For example, 4 and 7 mg / kg rozanolixizumab The maximum IgG reduction ranges were 29.9-65% and 29.5-65.5%, respectively, for 5 and 10 mg / kg. The maximum IgG reduction ranges with fugalchigimod were 48–81% and 46–72%, respectively. In one trial, the response in many patients was lost within one month of the final dose. Unlike the rozanolixizumab trial, the Phase II efgartigimod trial described herein The patients included those whose response lasted longer than 30 days, and some of them had long-term responses. Considering the short treatment duration and the results reported in the rozanolixizumab trial, Efga This extended response observed with lutigimod was surprising.

[0220] (Example 9: Treatment of ITP using affibody or affibody derivative) Human FcRn-specific affibodies can be found alone (MW approximately 6.5 kDa) or in albumin-bound form. Main (ABD; fusion protein MW approximately 19kDa, Seijsing et al., (2014) Proc Natl Acad Sci USA 111(48): 17110-17115; Seijsing et al., (2018) Sci Rep. 8(1):5141; WO 2014 / A fusion protein with either 140366) or human albumin (fusion protein MW approximately 73kDa). It is expressed as. In this embodiment, the affibody (and any of the fusion proteins) It exhibits high affinity for FcRn at pH 6.0 and low affinity for FcRn at pH 7.4. In this case, the affibody (and any fusion protein) is present at both pH 6.0 and pH 7.4. It has a high affinity for FcRn. ABD interacts with serum albumin in the blood with high affinity. ABD is a manipulated, independently folding domain that can be operated. It does not affect the interaction of serum albumin with its binding site on cRn, and this is the next step. This differs from the binding site of gG and the affibody interaction with FcRn.

[0221] Affibody, affibody fusion protein(s), or unrelated control is introduced into mice. The drug was administered intravenously once daily for 7-14 days, starting on day 1. Serum total IgG was measured before the initial dose, and Then, every other day starting from the 4th day (for example, the 4th, 6th, 8th, 10th, 12th, 14th, 16th, 18th, and 20th day) (Measured after administration.) Considering that MWs are different, each dose of afibody alone is The dose is approximately three times larger (mass / kg body weight) than that of the Fibody-ABD fusion protein. Or, in addition, each dose of the afibody-ABD fusion protein is afibody-al The dosage of albumin is approximately four times larger (mass / kg body weight) than that of bumin fusion protein. At least approximately 3.5 times larger than the administered dose, or an Fc fragment variant, such as Efgulch This is at least approximately 2.5 times the dosage of gimodo.

[0222] In this embodiment, the affibody-ABD fusion protein is shown as SEQ ID NO: 4. Contains a amino acid sequence:

[0223] [ka]

[0224] Here, the 58 amino acids at the C-terminus correspond to the affibody, and ABD and affibody The molecule is linked by a glycerin linker consisting of five amino acids.

[0225] Affibody alone, Affibody-ABD fusion protein, or Affibody-album Treatment with fusion proteins effectively reduces serum total IgG, and this is because these substances The quality suggests that it can be used to treat ITP in humans.

[0226] (Inclusion of references) All patent and non-patent documents cited herein are provided in their entirety by reference. It is included in the specification.

[0227] (Equivalents) Without departing from the spirit and scope of the present invention, many modifications in addition to those described herein are possible. The structures and techniques described herein may be carried out. Therefore, although specific embodiments are described, These are merely illustrative examples and do not limit the scope of the present invention. This application provides the invention in the following embodiments. (Aspect 1) A method for treating human subjects diagnosed with immune thrombocytopenia (ITP), wherein human FcRn(hF Approved for at least one dose of cRn) antagonists and standard treatment for ITP. The method further includes administering one or more doses of one type of compound to a subject. (Aspect 2) The aforementioned hFcRn antagonist is administered in doses of 1 or more, ranging from approximately 10 nmol / kg to approximately 1000 nmol / kg. The method described in Embodiment 1. (Aspect 3) The above-mentioned dose of the hFcRn antagonist is in the range of approximately 50 nmol / kg to approximately 300 nmol / kg. The method described in Embodiment 2. (Aspect 4) The above-mentioned dose of the hFcRn antagonist is in the range of approximately 90 nmol / kg to approximately 200 nmol / kg. The method described in Embodiment 2. (Aspect 5) The embodiment in which the hFcRn antagonist is an antibody or antibody fragment that specifically binds to hFcRn. The method described in any one of items 1 to 4. (Aspect 6) The antibody or antibody fragment comprises one or more CDRs that specifically bind to hFcRn, according to embodiment 5. Law. (Aspect 7) The antibody or antibody fragment comprises or consists of a human Fc domain, as described in embodiment 5 or 6. The method. (Pattern 8) The human Fc domain comprises one or more mutations that alter its binding to hFcRn, as described in Embodiment 7. The method. (Aspect 9) The one or more mutations mentioned above result in one or more of M252Y, S254T, T256E, H433K, and N434F (EU numbering). Including the method described in embodiment 8. (Aspect 10) The aforementioned hFcRn antagonist is a Varian consisting of two Fc domains that form a homodimer. It consists of an Fc region, where the amino acid sequence of each Fc domain is as follows, in aspect 5 Method of description. (Aspect 11) The method according to embodiment 5, wherein the hFcRn antagonist is efgarchigimodo (ARGX-113). (Aspect 12) The method according to embodiment 11, wherein the aforementioned efgaltigimod (ARGX-113) is administered at a dose of approximately 5 mg / kg. . (Aspect 13) The method described in Embodiment 11, in which the aforementioned efgaltigimod (ARGX-113) is administered at a dose of approximately 10 mg / kg. Law. (Aspect 14) At least one compound approved for the standard treatment of ITP is corticosteroid A method according to any one of embodiments 1 to 13, including an id. (Aspect 15) The corticosteroids mentioned above include oral prednisone, intravenous prednisone, and dexamethasone. The method according to embodiment 14, selected from the group consisting of, and any combination thereof. (Aspect 16) At least one compound approved for the standard treatment of ITP is rituximab or The method according to any one of embodiments 1 to 15, comprising alemtuzumab. (Aspect 17) At least one compound approved for the standard treatment of ITP is fostamatin A method according to any one of the embodiments 1 to 16, including B. (Aspect 18) At least one compound approved for the standard treatment of ITP is cyclosporine A method according to any one of embodiments 1 to 17, comprising dapsone or azathioprine. (Aspect 19) At least one compound approved for the standard treatment of ITP is thrombopoietic A method according to any one of embodiments 1 to 18, comprising an ion receptor agonist. (Aspect 20) The method according to embodiment 19, wherein the thrombopoietin receptor agonist is eltrombopag. Law. (Aspect 21) The method according to embodiment 19, wherein the thrombopoietin receptor agonist is abatrombopag. Law. (Aspect 22) The method according to embodiment 19, wherein the thrombopoietin receptor agonist is romiplostim. . (Aspect 23) Embodiment 1: The thrombopoietin receptor agonist is the non-Fc portion of romiplostim. The method described in section 9. (Aspect 24) The aforementioned human subjects were 30 × 10 before treatment. 9 Having a platelet count of less than / L, any one of embodiments 1 to 23 The method described in the section. (Aspect 25) The standard treatment of ITP in the aforementioned human subjects before administration of one or more doses of an hFcRn antagonist. During standard treatment with at least one compound approved for therapeutic purposes, <100 × 10 9 / The method according to any one of embodiments 1 to 24, having a platelet count of L. (Aspect 26) The standard treatment of ITP in the aforementioned human subjects before administration of one or more doses of an hFcRn antagonist. During standard treatment with at least one compound approved for therapeutic purposes, ≤ 50 × 10 9 / L A method according to any one of embodiments 1 to 25, having a platelet count. (Aspect 27) The standard treatment of ITP in the aforementioned human subjects before administration of one or more doses of an hFcRn antagonist. When standard treatment is performed with at least one compound approved for therapeutic purposes, ≤30 × 10 9 / L A method according to any one of embodiments 1 to 26, having a platelet count. (Aspect 28) The standard treatment of ITP in the aforementioned human subjects before administration of one or more doses of an hFcRn antagonist. When standard treatment is performed with at least one compound approved for the treatment, ≤20 × 10 9 / L A method according to any one of embodiments 1 to 27, having a platelet count. (Aspect 29) The standard treatment of ITP in the aforementioned human subjects before administration of one or more doses of an hFcRn antagonist. When standard treatment is performed with at least one compound approved for the treatment, ≤10 × 10 9 / L A method according to any one of embodiments 1 to 28, having a platelet count. (Aspect 30) The method according to any one of embodiments 1 to 29, wherein the human subject has a novel diagnosed ITP. (Aspect 31) The method according to any one of embodiments 1 to 30, wherein the human subject has persistent ITP. (Aspect 32) The method according to any one of embodiments 1 to 31, wherein the human subject has chronic ITP. (Aspect 33) The aforementioned treatment is 50 × 10 9 One of embodiments 1 to 32, which results in an increase in platelet count exceeding / L. Method of description. (Aspect 34) The aforementioned treatment is 100 × 10 9 The method according to embodiment 33, which produces an increase in platelet count exceeding / L. (Aspect 35) The method according to embodiment 33, wherein the increase in platelet count is sustained for at least one month. (Aspect 36) The method according to embodiment 33, wherein the increase in platelet count is sustained for at least two months. (Aspect 37) The method according to embodiment 33, wherein the increase in platelet count is sustained for at least three months. (Aspect 38) A treatment method for humans diagnosed with immune thrombocytopenia (ITP), which involves human FcRn (hFcRn) This includes administering one or more doses of an antagonist to the target, where hFcRn antagonist The to consists of a variant Fc region comprising two Fc domains that form a homodimer, and here The amino acid sequence of each Fc domain is the sequence number 1, according to the method. (Aspect 39) The method according to embodiment 38, wherein the hFcRn antagonist is efgarchigimodo (ARGX-113). . (Approach 40) The aforementioned hFcRn antagonist is administered in doses of 1 or more, ranging from approximately 10 nmol / kg to approximately 1000 nmol / kg. The method described in aspect 39. (Aspect 41) The above-mentioned dose of the hFcRn antagonist is in the range of approximately 50 nmol / kg to approximately 300 nmol / kg. The method described in aspect 39. (Aspect 42) The above-mentioned dose of the hFcRn antagonist is in the range of approximately 90 nmol / kg to approximately 200 nmol / kg. The method described in aspect 39. (Aspect 43) The method according to embodiment 39, wherein the hFcRn antagonist is administered at a dose of 5 mg / kg. (Aspect 44) The method according to embodiment 39, wherein the hFcRn antagonist is administered at a dose of 10 mg / kg. (Aspect 45) Targeting at least one approved compound dose for standard treatment of ITP. The method according to any one of embodiments 39 to 44, further comprising administering to [a specific body]. (Aspect 46) At least one compound approved for the standard treatment of ITP is corticosteroid The method according to embodiment 45, including the id. (Aspect 47) The corticosteroids mentioned above include oral prednisone, intravenous prednisone, and dexamethasone. The method according to embodiment 46, selected from the group consisting of the following and any combination thereof. (Aspect 48) At least one compound approved for the standard treatment of ITP is rituximab or The method according to embodiment 45, comprising alemtuzumab. (Aspect 49) At least one compound approved for the standard treatment of ITP is fostamatin The method according to embodiment 45, including b. (Appearance 50) At least one compound approved for the standard treatment of ITP is cyclosporine The method according to embodiment 45, selected from the group consisting of dapsone and azathioprine. (Aspect 51) At least one compound approved for the standard treatment of ITP is thrombopoietic The method according to embodiment 45, comprising a receptor agonist. (Appearance 52) The method according to embodiment 51, wherein the thrombopoietin receptor agonist is eltrombopag. Law. (Aspect 53) The method according to embodiment 51, wherein the thrombopoietin receptor agonist is abatrombopag. Law. (Aspect 54) The method according to embodiment 51, wherein the thrombopoietin receptor agonist is romiplostim. . (Aspect 55) The thrombopoietin receptor agonist is the non-Fc portion of romiplostim, in embodiment 5. Method described in 1. (Aspect 56) The aforementioned human subjects were 30 × 10 before treatment. 9 Any of embodiments 39 to 55, having a platelet count of less than / L The method described in item 1. (Aspect 57) The standard treatment of ITP in the aforementioned human subjects before administration of one or more doses of an hFcRn antagonist. During standard treatment with at least one compound approved for therapeutic purposes, <100 × 10 9 / The method according to any one of embodiments 39 to 56, having a platelet count of L. (Pattern 58) The standard treatment of ITP in the aforementioned human subjects before administration of one or more doses of an hFcRn antagonist. During standard treatment with at least one compound approved for therapeutic purposes, ≤ 50 × 10 9 / L A method according to any one of embodiments 39 to 56, having a platelet count. (Aspect 59) The standard treatment of ITP in the aforementioned human subjects before administration of one or more doses of an hFcRn antagonist. When standard treatment is performed with at least one compound approved for therapeutic purposes, ≤30 × 10 9 / L A method according to any one of embodiments 39 to 56, having a platelet count. (Appendix 60) The standard treatment of ITP in the aforementioned human subjects before administration of one or more doses of an hFcRn antagonist. When standard treatment is performed with at least one compound approved for the treatment, ≤20 × 10 9 / L A method according to any one of embodiments 39 to 56, having a platelet count. (Aspect 61) The standard treatment of ITP in the aforementioned human subjects before administration of one or more doses of an hFcRn antagonist. When standard treatment is performed with at least one compound approved for the treatment, ≤10 × 10 9 / L A method according to any one of embodiments 39 to 56, having a platelet count. (Aspect 62) The method according to any one of embodiments 39 to 61, wherein the human subject has a novel diagnosed ITP. (Aspect 63) The method according to any one of embodiments 39 to 61, wherein the human subject has persistent ITP. (Personal aspect 64) The method according to any one of embodiments 39 to 61, wherein the human subject has chronic ITP. (Patent 65) The aforementioned treatment is 50 × 10 9Any one of embodiments 39 to 61, which results in an increase in platelet count exceeding / L Method of description. (Aspect 66) The aforementioned platelet count 50 × 10 9 An increase exceeding / L is maintained for at least four weeks, as described in Embodiment 65. The method. (Patent 67) The aforementioned platelet count 50 × 10 9 An increase exceeding / L is maintained for at least two months, as described in aspect 65. Method of loading. (Pattern 68) The aforementioned platelet count 50 × 10 9 An increase exceeding / L is maintained for at least three months, as described in aspect 65. Method of loading. (Patent 69) The aforementioned treatment is 100 × 10 9 One of embodiments 39 to 64 that results in an increase in platelet count exceeding / L The method described in the section. (Aspect 70) 100 × 10 of the aforementioned platelet count 9 An increase exceeding / L is maintained for at least four weeks, as described in Embodiment 69. The method. (Aspect 71) The aforementioned platelet count 50 × 10 9 An increase exceeding / L is maintained for at least two months, as described in aspect 69. Method of loading. (Aspect 72) The aforementioned platelet count 50 × 10 9 An increase exceeding / L is maintained for at least three months, as described in aspect 69. Method of loading. (Aspect 73) A treatment method for humans diagnosed with immune thrombocytopenia (ITP), which involves human FcRn (hFcRn) This includes administering one or more doses of an antagonist to the target, where hFcRn antagonist The method wherein the affibody includes an affibody specific to human FcRn. (Aspect 74) The affibody specific to human FcRn contains the amino acid sequence shown in SEQ ID NO: 4, The method described in aspect 73. (Aspect 75) The aforementioned hFcRn antagonist binds to an albumin-binding domain specific to human albumin. The fusion protein containing an affibody specific to the fused human FcRn, as described in Embodiment 73. Law. (Aspect 76) The affibody specific to human FcRn contains the amino acid sequence shown in SEQ ID NO: 4, The method described in aspect 75. (Aspect 77) Targeting at least one approved compound dose for standard treatment of ITP. The method according to any one of embodiments 73 to 76, further comprising administering to [a specific body].

Claims

1. Used in methods of treating human subjects diagnosed with persistent or chronic immune thrombocytopenia (ITP). A pharmaceutical composition comprising a human FcRn (hFcRn) antagonist for the purpose of, The method involves intravenously administering the hFcRn antagonist to the subject at a dose of approximately 10 mg / kg. The hFcRn antagonist comprises two Fc domains that form a homodimer. It consists of a riant Fc region, and the amino acid sequence of each Fc domain is either SEQ ID NO: 1 or SEQ ID NO: 2 The pharmaceutical composition comprising the amino acid sequence described above.

2. The pharmaceutical combination according to claim 1, wherein the hFcRn antagonist is administered once a week or once every two weeks. A finished product.

3. One or more doses of the aforementioned hFcRn antagonist over a period of three weeks After completion of the initial treatment period, which includes four doses, the medical device according to claim 1 or 2 is administered once every two weeks. A pharmaceutical composition.

4. Claim 1, wherein the amino acid sequence of each Fc domain consists of the amino acid sequence described in Sequence ID No.

1. A pharmaceutical composition according to any one of the following three items.

5. Claim 1, wherein the amino acid sequence of each Fc domain consists of the amino acid sequence described in Sequence ID No.

2. A pharmaceutical composition according to any one of the following three items.

6. The hFcRn antagonist is efgarchigimodo, as described in any one of claims 1 to 3. A listed pharmaceutical composition.

7. The method involves one or more compounds approved for standard treatment of ITP. A pharmaceutical compound according to any one of claims 1 to 6, further comprising administering the dose to the subject. A finished product.

8. At least one compound approved for the standard treatment of ITP is corticosteroid Ido, rituximab, alemtuzumab, fostamatinib, cyclosporine, dapsone, Danazol, intravenous immunoglobulin (IVIg), Rho(D) immunoglobulin (anti-D), azathioprine Claim 7, comprising a thrombopoietin receptor agonist, or any combination thereof. The pharmaceutical composition described.

9. The corticosteroids mentioned above include oral prednisone, intravenous prednisone, and dexamethasone. The pharmaceutical composition according to claim 8, selected from the group consisting of the and any combination thereof.

10. The aforementioned thrombopoietin receptor agonists include eltrombopag, abatrombopag, and ro A group consisting of miprostim, the non-Fc portion of romiprostim, and any combination thereof. A pharmaceutical composition according to claim 8, selected from the above.

11. The aforementioned human subjects had <30 × 10 before administration of the hFcRn antagonist. 9 Platelet count / L or the pharmaceutical composition according to any one of claims 1 to 10.

12. Regarding the standard treatment procedures for ITP in the aforementioned human subjects prior to administration of the hFcRn antagonist: During standard treatment with at least one approved compound, <100 × 10 9 / L, ≤50×10 9 / L, ≤30×10 9 / L, ≤20×10 9 / L, or ≤10 × 10 9 Having a platelet count of / L, according to claims 1 to 10 Any of the pharmaceutical compositions described in item one.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the human subject has persistent ITP.

14. The pharmaceutical composition according to any one of claims 1 to 12, wherein the human subject has chronic ITP.

15. The aforementioned treatment results in a platelet count of ≥ 50 × 10 9 This results in an increase to / L, and optionally, the platelet count is ≥50 × 10 9 The increase to / L is: (i) at least 4 weeks; (ii) at least two months; or (iii) at least 3 months A pharmaceutical composition according to any one of claims 1 to 14, which is maintained for a certain period of time.

16. the treatment results in an increase in the platelet count to ≧ 100 × 10 9 / L, and optionally, the platelet count is ≧ 100 × 1 0 9 The increase to / L is: (i) at least 4 weeks; (ii) at least two months; or (iii) at least 3 months A pharmaceutical composition according to any one of claims 1 to 15, which is maintained for a certain period of time.

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