Treatment of immune thrombocytopenia

Abstract

The present invention relates to a method of treating immune thrombocytopenia (ITP), in particular immune thrombocytopenia (ITP) in a subject in need thereof, comprising administering, in particular in a therapeutically effective amount, a molecule that inhibits BAFF-R, in particular an anti-BAFF-R antibody or fragment thereof, in particular Iliumeumab, as first or second line therapy.

Description

Technical Field

[0001] The present invention relates to methods for treating immune thrombocytopenia (ITP), particularly in patients in need thereof, which methods comprise administering (particularly in a therapeutically effective amount) a molecule that inhibits B cell-activating factor receptor (BAFF-R), such as an anti-BAFF-R antibody or a binding fragment thereof, particularly epratuzumab (collectively referred to as the medicaments of the present invention and used interchangeably throughout the present application), and related inventive embodiments as mentioned herein.

[0002] Sequence Listing

[0003] This application contains a Sequence Listing that has been electronically submitted in XML format and is hereby incorporated by reference in its entirety. Background Art

[0004] Immune thrombocytopenia (ITP) is a rare acquired immune-mediated disease in adults and children, characterized by a transient or persistent decrease in platelet count and an increased risk of bleeding depending on the degree of thrombocytopenia.

[0005] The clinical course of ITP can be variable, depending on whether it is primary ITP (unrelated to any other condition) or associated with a potential autoimmune condition (secondary ITP) caused by infection or chemotherapy treatment in cancer patients (Rodeghiero et al. 2009).

[0006] The goal of ITP therapy is to obtain a platelet count that ensures adequate hemostasis and minimizes the risk of clinically significant bleeding, while avoiding treatment-related toxicities and patient burden as much as possible.

[0007] For ITP patients, corticosteroids are the recommended standard first-line treatment. Although the initial remission rate for corticosteroids is usually high (>75% of adult patients), approximately 20%-25% of ITP patients are non-responsive (refractory ITP).

[0008] The duration of corticosteroid treatment should be limited to 6-8 weeks to avoid the risk of adverse events and the minimal benefits that may result from continued use of steroids beyond 6-8 weeks. Although most patients initially respond to corticosteroid therapy, only 20%-30% of patients are able to maintain an adequate platelet count (sustained remission) after treatment is stopped. Thus, most ITP patients will require subsequent therapy (Ghanima et al. 2021).

[0009] For ITP patients who need to rapidly increase platelet counts (e.g., bleeding patients, patients at high risk of bleeding, or pre-operative patients), adding intravenous immunoglobulin (IVIg) or intravenous (i.v.) anti-Rho(D) to corticosteroid therapy is recommended. When corticosteroids are contraindicated, IVIg is also used as monotherapy (Neunert et al. 2019, Provan et al. 2019). However, although the effects of IVIg / anti-D are rapid, they are typically not durable and only last for a few weeks (Arnold, 2005).

[0010] In second-line treatment of primary ITP, TPO-RA is the preferred treatment option for relapsed patients or those who are insufficiently responsive to initial corticosteroid therapy (second-line) or after immunoglobulin or splenectomy. According to international guidelines, other second-line options include off-label use of rituximab or splenectomy (Neunert et al. 2019, Provan et al. 2019). TPO-RA typically requires long-term treatment regimens because in most cases, discontinuation of treatment leads to recurrence of thrombocytopenia.

[0011] In addition, approximately one-third of patients discontinue TPO-RA due to lack of remission and need to switch to another TPO-RA or alternative therapy. Switching to alternative therapy may also be necessary in cases of severe platelet count fluctuations or side effects (Ghanima et al. 2019).

[0012] The medical need to establish longer treatment-free remission periods (TFR) (i.e., longer periods without treatment and with improved comfort and quality of life) for patients has not been met. Description of the Drawings

[0013] Figure 1 : Simulations of ixekizumab PK (upper inset) and B cell counts (middle inset) obtained from a data-driven PK / PD model, and simulations of the lower inset obtained from a hypothesis-driven tissue RO model. The shaded area is the 90% prediction interval (5th to 95th percentile), and the thick line is the predicted median. The black dashed line in the upper inset represents the trough concentration of 1.8 μg / mL at 300 mg q4w sc as determined in patients with primary Sjögren's syndrome in study CVAY736A2201. The grey dashed line represents the LLOQ of 0.025 μg / mL, the B cell depletion threshold of 10 cells / μL, and 90% tissue receptor occupancy (RO).

[0014] Figure 2: Reduction in autoantibodies from baseline at week 12 and week 24 in patients participating in the primary Sjögren's syndrome trial (expressed as geometric mean ratio relative to baseline): SSAro52( Figure 2A )、SSAro60 ( Figure 2B )and SSB autoantibodies ( Figure 2C ) 。

[0015] Figure 3: Autoantibody reduction from baseline at weeks 12 and 24 in patients participating in the systemic lupus erythematosus (SLE) trial (expressed as geometric mean ratio relative to baseline): C1q( Figure 3A ) and anti-dSDNA( Figure 3B ). DETAILED DESCRIPTION

[0016] The present invention provides potentially disease-modifying therapies for ITP (particularly in the early stages of ITP) that are well-tolerated, require shorter treatment courses (more convenient for patients), and induce high remission rates (maintained even after the end of the treatment period). In addition, the present invention extends the duration of treatment-free remission (TFR) and the time to treatment failure (TTF). The present invention addresses unmet medical needs in the first-line (e.g., concomitant administration of corticosteroids such as prednisone (or prednisolone) or dexamethasone) and second-line (e.g., concomitant administration of TPO-RA such as eltrombopag) settings, based on strong scientific principles and chronicity in the early stages of the disease process. As used herein and hereinafter, the term "early stage of ITP" refers to the stage of ITP in which a subject is newly diagnosed with ITP or is still receiving first-line (initial treatment after diagnosis of ITP) or second-line (second treatment, following first-line treatment) ITP treatment.

[0017] In one aspect, the present invention provides a method of treating immune thrombocytopenia (ITP) (particularly in a subject in need thereof), the method comprising administering (particularly in a therapeutically effective amount) a molecule that inhibits B cell activating factor receptor (BAFF-R). In one embodiment, the molecule that inhibits BAFF-R is an antibody against BAFF-R (anti-BAFF-R antibody) or a binding fragment thereof. In a further embodiment, such anti-BAFF-R antibody is afucosylated. It has been shown that enhanced antibody-dependent cell cytotoxicity (ADCC) can improve the clinical outcome of autoimmune diseases such as lupus nephritis (LN) due to the use of afucosylated antibodies (Furie et al. 2022).

[0018] In one aspect, the present invention provides a molecule that inhibits B cell activating factor receptor (BAFF-R), particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly eculizumab, for use as a monotherapy or in combination with other ITP treatments (typically in combination with first-line or second-line ITP treatments) to treat ITP.

[0019] In one embodiment, the anti-BAFF-R antibody or a binding fragment thereof comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, respectively, and CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:10, respectively.

[0020] In one embodiment, the anti-BAFF-R antibody or a binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO:3 and a VL having the amino acid sequence of SEQ ID NO:4.

[0021] In one embodiment, the anti-BAFF-R antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:1 and a light chain having the amino acid sequence of SEQ ID NO:2.

[0022] In one embodiment, the anti-BAFF-R antibody or a fragment thereof is eculizumab or a binding fragment thereof.

[0023] The pathophysiology of ITP is characterized by increased peripheral platelet destruction accompanied by inappropriate platelet production in the bone marrow. Although the factors triggering primary ITP are unclear, the differentiation of autoreactive splenic B cells into plasma cells that produce antiplatelet antibodies plays a key role (Audia et al. 2021). These autoantibodies against different glycoproteins on the platelet surface mediate antibody-dependent cell cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Opsonized platelets are further phagocytosed by monocytes and splenic macrophages in an Fcγ receptor (FcγR)-dependent mechanism. Splenic macrophages are the main antigen-presenting cells that stimulate autoreactive T cells in ITP. These autoreactive T cells interact with autoreactive B cells and induce their proliferation, differentiation into plasma cells, and production of additional antiplatelet antibodies (Audia et al. 2021).

[0024] Recent publications have described different mechanisms of resistance to rituximab, which can explain the low rate of patients maintaining long-term remission. These include splenic autoreactive residual memory B cells, which actively contribute to disease relapse and may survive rituximab-mediated B cell depletion due to phenotypic modifications, including reduced or absent CD20 expression (Mahevas et al. 2013, Crickx et al. 2021). Plasma cells also downregulate CD20 expression and are thus not targets of rituximab. Increased reactivity of B cell activating factor (BAFF) has further been observed in CD20-mediated B cell depletion. BAFF signaling and CD4+ T cell interactions are major factors in B cell activation and conversion to long-lived splenic plasma cells and survival. Long-lived plasma cells can then produce autoantibodies targeting platelets independently of the B cell repertoire for many years (Mahevas et al. 2013, Markmann et al. 2021). In addition, there is evidence that BAFF receptor (BAFF-R) and other pathways involved can impair rituximab-induced antibody-dependent cell cytotoxicity (ADCC) (Wild et al. 2015).

[0025] The immune response is also directed against megakaryocytes expressing surface glycoproteins such as those on platelets. Thus, insufficient platelet production in ITP can be attributed to humoral and cytotoxic immune responses against megakaryocytes in the bone marrow (Audia et al. 2021, Audia and Bonnotte 2021).

[0026] B cell activating factor (BAFF) is a member of the tumor necrosis factor (TNF) family and is produced by many cell types, including antigen-presenting cells (B cells, monocytes / macrophages, dendritic cells), neutrophils, epithelial cells, and activated T cells. BAFF acts via its receptor (BAFF-R), which is expressed on most B cells. The BAFF-R signaling pathway is critically involved in the activation of B cell effector functions, such as antibody production, isotype class switching, B cell proliferation, maturation, and survival (Mackay et al. 2009).

[0027] BAFF overexpression leads to the disruption of B cell immune tolerance, thereby causing autoimmune disorders (Mackay et al. 2002). In ITP, high serum BAFF levels are seen in untreated patients (Emmerich et al. 2006) and rituximab-resistant patients (Mahevas et al. 2013), and further shown to impair rituximab-induced antibody-dependent cell cytotoxicity (ADCC) (Wild et al. 2015). It is reasonably expected that these mechanisms of resistance to rituximab are suitable for alternative treatment methods (including BAFF-R pathway inhibition) and provide advantages over CD-20 targeting agents such as rituximab. The antigen specificity of epratuzumab is directed against the BAFF receptor BAFF-R (Syn: BR3), which is expressed on the surface of immature and mature B cells up to the lymphoblast stage. Therefore, pro-B cells and pre-B cells that express CD20 but not BAFF-R are not expected to be affected by epratuzumab. Thus, compared to existing anti-CD20 antibody therapies that deplete B cells, epratuzumab targets a narrower spectrum of more differentiated B cells.

[0028] Thus, in one embodiment, the subject is non-responsive to rituximab treatment, e.g., the platelet count fails to reach 30 x 10 9 / L or above, or relapses after rituximab treatment, e.g., the platelet count drops below 30 x 10 9 / L. In one embodiment, the subject does not receive rituximab treatment during treatment with epratuzumab.

[0029] In one embodiment, the subject according to the present invention has never been treated with rituximab or has not been treated with rituximab for at least one year or at least six months prior to receiving the medicament of the present invention.

[0030] Latest evidence from a phase 2 clinical study (Mahevas et al. 2020) further confirms the importance of targeting the BAFF-R signaling pathway for long-term remission in ITP.

[0031] Epratuzumab is a glycoengineered (afucosylated), fully human IgG1 monoclonal antibody directed against BAFF-R expressed on the surface of B cells, thereby targeting B cells and their functions in two modes of action:

[0032] a. Direct lysis and depletion of BAFF-R expressing B cells by enhanced ADCC due to its fucose-deficient Fc (fragment crystallizable) region; and

[0033] b. BAFF receptor blockade, which interrupts the signaling of BAFF-mediated B cell maturation, proliferation, and survival (Bowman et al. 2022).

[0034] In preclinical studies, epratuzumab significantly enhanced ADCC against B cells and cytokine production by NK cells and was more effective in depleting B cells compared to approved anti-CD20 antibodies, including rituximab, obinutuzumab, and ofatumumab (McWilliams et al. 2019).

[0035] Due to its dual activity, epratuzumab is able to combine rapid and efficient B cell depletion with sustained BAFF-R blockade to prevent pathogenic BAFF-driven rebound mechanisms (Genovese et al. 2010, Furie et al. 2011, Mariette 2012). The efficacy of epratuzumab in primary Sjögren's syndrome (pSS) was demonstrated in a phase II study (Bowman SJ et al. 2021).

[0036] No studies of epratuzumab in ITP have been conducted. However, the use of epratuzumab in ITP is supported by the following:

[0037] · B cell depletion is a therapeutic measure for treating ITP

[0038] · Inhibition of the BAFF-R pathway has been shown to be effective and safe in non-hematologic autoimmune diseases ( prescribing information)

[0039] · The combination of BAFF-R blockade and B cell depletion has been shown to be effective and safe in ITP

[0040] · Clinical studies of epratuzumab have demonstrated its efficacy in other autoimmune diseases

[0041] Therefore, through its dual mechanism of action, and in combination with the existing data and the data disclosed in this application, it is expected to demonstrate the efficacy and safety of epratuzumab in treating ITP, particularly by effectively depleting B cells and blocking BAFF-R to address the above limitations of B cell depletion therapies and thereby prevent BAFF-driven pathogenic rebound and resistance mechanisms.

[0042] · In one embodiment, the ITP is primary ITP. In one embodiment, the ITP is secondary ITP. Preferably, the ITP is primary ITP.

[0043] In one embodiment, an anti-BAFF-R antibody or fragment thereof, particularly eculizumab, is administered to a subject, particularly a subject in need thereof, at a dose of about 1 to about 27 mg / kg, about 1 to about 21 mg / kg, about 1 to about 18 mg / kg, about 1 to about 15 mg / kg, about 1 to about 9 mg / kg, 3 to about 27 mg / kg, about 3 to about 21 mg / kg, about 3 to about 18 mg / kg, about 3 to about 15 mg / kg, about 3 to about 9 mg / kg. Preferably, the dose is between about 3 and about 18 mg / kg. More preferably, the dose is between about 3 and about 9 mg / kg. In one embodiment, eculizumab is administered to a subject, particularly a subject in need thereof, at a dose of about 3 mg / kg and at a dose of about 9 mg / kg. In one embodiment, the antibody is administered intravenously.

[0044] In one embodiment, an antibody (particularly eculizumab) or binding fragment thereof is administered to a subject, particularly a subject in need thereof, once every 4 weeks (monthly, + / - 3 days).

[0045] In one embodiment, the antibody is eculizumab, wherein eculizumab is administered intravenously to a subject, particularly a subject in need thereof, at a dose of 3 mg / kg once every four weeks (monthly, + / - 3 days).

[0046] In one embodiment, the antibody is eculizumab, wherein eculizumab is administered intravenously to a subject, particularly a subject in need thereof, at a dose of 9 mg / kg once every four weeks (monthly, + / - 3 days).

[0047] In one embodiment, a molecule that inhibits B cell activating factor receptor (BAFF-R), particularly an anti-BAFF-R antibody or binding fragment thereof, particularly eculizumab, is administered to a subject, particularly a subject in need thereof, as a single therapy. During the period of treatment with the medicament of the present invention, the subject does not receive any other ITP treatment. Generally, ITP is primary ITP. The term "period of treatment with the medicament of the present invention" should be understood as the time period during which the medicament of the present invention is administered to the subject. Typically, this time period extends to an interval between two administrations, during which the medicament of the present invention is usually still present in detectable concentration in the subject's blood. For example, in the case of administering a total of 4 doses of eculizumab at 4-week intervals, the period of treatment with eculizumab includes from day 1 of week 1 to day 1 of week 13 (when the fourth and last dose is administered), plus an additional 4 weeks. Thus, the total period of treatment with eculizumab is 16 weeks.

[0048] The term "in combination with" should be understood to mean administering two or more drugs subsequently or simultaneously, either in separate doses or in a fixed dose. Alternatively, the term "in combination with" should be understood to mean administering two or more drugs in such a way that the effective therapeutic concentrations of the drugs overlap for most of the time period in the patient. The two or more drugs can be administered independently at the same time or separately at time intervals, especially when these time intervals allow the combination partners to exhibit a cooperative (e.g., synergistic) effect. As used herein, the terms "co-administer" or "administer in combination" etc. are meant to encompass administering the selected combination partners to a single subject (e.g., a patient) in need, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or simultaneously. Without a specific time limit, the drugs are administered to the patient as separate entities simultaneously, in parallel or sequentially, where such administration provides a therapeutically effective level of the two compounds in the patient, and the treatment regimen will provide the beneficial effect of the drug combination in treating the disorders or conditions described herein.

[0049] In one embodiment, ixekizumab is administered to a subject as a monotherapy, wherein the subject is a treatment-naive ITP patient (has not received any other ITP treatment).

[0050] In one embodiment, ixekizumab is administered to a subject as a monotherapy, wherein the subject has an inadequate remission or recurrence after initial treatment, typically the initial treatment refers to first-line steroid treatment (as standard of care).

[0051] In one embodiment, a molecule that inhibits the B-cell activating factor receptor (BAFF-R), particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly ixekizumab, is administered to a subject, wherein the subject receives initial treatment after being diagnosed with ITP (particularly primary ITP), or receives it simultaneously with the start of initial treatment.

[0052] In one embodiment, a molecule that inhibits the B-cell activating factor receptor (BAFF-R), particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly ixekizumab, is co-administered with initial treatment to a subject for the treatment of ITP.

[0053] In one embodiment, the present invention provides a B-cell activating factor receptor (BAFF-R), particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly ixekizumab, for use in combination with initial treatment to treat ITP.

[0054] In these cases, an anti-BAFF-R antibody or a binding fragment thereof, particularly ixekizumab, is added on top of the initial treatment. Typically, the subject responds to the initial treatment, for example, the platelet count is higher than 30x109 / L, and then add ixekizumab on this basis.

[0055] Initial treatment is usually the standard of care for ITP (especially primary ITP) and is usually the first-line treatment. Initial treatment includes, but is not limited to, corticosteroids, immunoglobulins (such as IVIG or anti-D immunoglobulin), thrombopoietin receptor agonists (TPO-RA), or rituximab.

[0056] In one embodiment, the initial treatment is a corticosteroid, preferably a glucocorticoid, preferably dexamethasone, preferably prednisone or prednisolone.

[0057] The initial treatment is administered according to the approved dose. For example, the first-line corticosteroid therapy is defined as: prednisone / prednisolone (about 0.5 - 2 mg / kg / day) for at least 2 weeks, or at least 1 course of high-dose dexamethasone 20 - 40 mg / day for 4 consecutive days ± IVIG (used as a rescue therapy).

[0058] The total maximum exposure to corticosteroid treatment shall not exceed 3 months, including the dose tapering period or 3 courses of high-dose dexamethasone. Thus, in one embodiment, during or after treatment with a molecule that inhibits BAFF-R, especially an anti-BAFF-R antibody or its binding fragment, especially ixekizumab, the corticosteroid is gradually tapered to discontinuation.

[0059] In one embodiment, the initial treatment is or includes treatment with a thrombopoietin receptor agonist. The term "thrombopoietin receptor agonist" as used herein and hereinafter includes, but is not limited to, romiplostim, oprelvekin, lusutrombopag, avatrombopag, betrombopag, and eltrombopag; or a pharmaceutically acceptable salt thereof.

[0060] In an alternative embodiment, the initial treatment does not include rituximab. The subject has never received rituximab or has not received rituximab for at least one year or at least 6 months prior to treatment with the drug of the present invention.

[0061] Generally, the term "inadequate remission" means that the platelet count has not reached 30 G / L despite any ITP treatment. The term "relapse" means that the platelet count drops below 30 G / L at any time after the platelet count has reached 30 G / L or above due to any ITP treatment.

[0062] In one embodiment, a molecule that inhibits BAFF-R, particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly eculizumab, is administered to a subject who has inadequate remission or has relapsed after initial treatment (typically first-line corticosteroid treatment). A subject treated with corticosteroids is considered to have inadequate remission if the platelet count does not reach ≥ 30 G / L or if corticosteroids are required for more than 8 weeks to maintain remission. Relapse after first-line treatment with corticosteroids is defined as a platelet count dropping to < 30 G / L at any time after achieving initial remission.

[0063] In one embodiment, the medicament of the present invention is administered in combination with a second treatment (typically standard of care as second-line treatment) to a subject who has inadequate remission or has relapsed after initial treatment (typically first-line corticosteroid treatment) (and typically has stopped the initial treatment).

[0064] In one embodiment, the present invention provides a molecule that inhibits BAFF-R, particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly eculizumab, for use as a monotherapy or in combination with another ITP treatment (typically second-line ITP treatment) to treat ITP (typically primary ITP) in a subject, wherein the subject has inadequate remission or has relapsed after initial treatment.

[0065] In such a case, an anti-BAFF-R antibody or a binding fragment thereof, particularly eculizumab, is added on top of the second treatment. The second treatment typically comprises or is treatment with a thrombopoietin receptor agonist. Typically or preferably, the thrombopoietin receptor agonist is eltrombopag or a pharmaceutically acceptable salt thereof, typically eltrombopag ethanolamine. In one embodiment, the subject will start treatment with the medicament of the present invention and the second treatment simultaneously. As used herein, "simultaneously" should be understood to mean that the start of treatment with the medicament of the present invention and the start of the second treatment are separated by no more than 3 days, possibly no more than 2 days, and typically on the same day.

[0066] In one embodiment, the subject has started the second treatment up to about 1 month, up to about 2 weeks, or up to about 1 week before starting treatment with the medicament of the present invention.

[0067] Administer the second treatment according to the approved dose. For example, it is recommended that romiplostim be 0.2 to 1 mcg / kg, possibly 0.5 to 1 mcg / kg, possibly 1 mcg / kg, once a week. For avatrombopag, the typical initial dose is 10 mg to 30 mg, and the dose can be gradually increased or decreased during the treatment according to the platelet count. In order to make the platelet count ≥ 50 G / L, adjust the dose of eltrombopag so that the patient uses the minimum effective dose. It is recommended that eltrombopag be 25 mg or 12.5 mg (for Asians) and 50 mg (for non-Asians), once a day. Typically, the initial dose can be gradually increased or decreased during the treatment according to the platelet count.

[0068] It is envisioned that during or after treatment with a molecule that inhibits BAFF-R, particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly eculizumab, the second treatment is gradually tapered to discontinuation. In one embodiment, after treatment with eculizumab is completed, the dose of etrombopag is gradually reduced to discontinuation. Typically, after 4 doses of eculizumab or typically 16 weeks after starting the administration of eculizumab. Typically, at the start of the gradual taper, the platelet count of the subject is about 30x10 9 / L or above, preferably 50x10 9 / L or above.

[0069] The duration of the gradual taper of eltrombopag is individualized and depends on the dose and the remission of the participant: generally, the gradual taper period does not exceed 8 weeks.

[0070] In participants receiving a dose ≥ 50 mg, the daily dose is reduced by 25 mg every other week. After reaching a 25 mg dose for 2 weeks, if the platelets are ≥ 30 G / L, continue to administer at a daily dose of 12.5 mg (or 25 mg every other day) for 2 weeks until the treatment is completely stopped.

[0071] In participants receiving a dose ≤ 25 mg (including participants of East Asian / Southeast Asian descent), the daily dose is reduced by 12.5 mg every other week until the treatment is completely stopped.

[0072] In one embodiment, the present invention provides a molecule that inhibits BAFF-R, particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly eculizumab, for treating ITP (typically primary ITP) in a subject, wherein the subject has previously received treatment with at least one corticosteroid and at least one thrombopoietin receptor agonist (TPO-RA). Typically, when starting treatment with a molecule that inhibits BAFF-R, particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly eculizumab, the subject exhibits loss of remission, inadequate remission, no remission, or intolerance. Typically, the platelet count is less than 30x10 9 / L. Subjects may also receive other ITP treatments, such as intravenous immunoglobulin [IVIG], and corticosteroids and TPO-RA are not necessarily the last resort.

[0073] In another embodiment, a molecule that inhibits the B-cell activating factor receptor (BAFF-R), particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly epratuzumab, is administered as a single therapy or in combination with other ITP treatments, typically in combination with first-line or second-line ITP treatments. In one embodiment, after initiating treatment with a molecule that inhibits BAFF-R, particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly epratuzumab, the subject achieves a complete remission, i.e., the platelet count reaches 50 x 10 9 / L or higher, preferably at two consecutive measurements, typically these two consecutive measurements being separated by 7 days, 14 days, 21 days, or 28 days. In yet another embodiment, epratuzumab is administered at a dose of 9 mg / kg. In yet another embodiment, epratuzumab is administered monthly. In yet another embodiment, a total of 4 doses of epratuzumab are administered.

[0074] In one embodiment, no more than 8 doses, or no more than 5 doses, or no more than 4 doses of a molecule that inhibits BAFF-R, such as an anti-BAFF-R antibody or a binding fragment thereof, particularly epratuzumab, are administered (particularly to a subject in need).

[0075] In one embodiment, at least 4 doses of a molecule that inhibits BAFF-R, such as an anti-BAFF-R antibody or a binding fragment thereof, particularly epratuzumab, are administered (particularly to a subject in need).

[0076] In one embodiment, a total of approximately 4 doses, approximately 6 doses, or approximately 8 doses, typically or preferably a total of approximately 4 doses of a molecule that inhibits BAFF-R, such as an anti-BAFF-R antibody or a binding fragment thereof, particularly epratuzumab, are administered (particularly to a subject in need).

[0077] Due to the dual function of epratuzumab, it is expected to have a rapid and durable therapeutic effect. Thus, in one embodiment, a total of approximately 4 doses, approximately 6 doses, or approximately 8 doses, typically or preferably a total of approximately 4 doses of epratuzumab are administered to a subject (particularly a subject in need) suffering from ITP (particularly primary ITP). Generally, it is administered once every four weeks, typically and preferably at a dose of 3 - 9 mg / kg, preferably by intravenous administration of epratuzumab.

[0078] In one embodiment, the subject achieves a complete response. As used herein and hereinafter, the term "complete response" means that the platelet count of the subject reaches above about 100 x 10 9 / L. Considering the subject's condition, such as age, comorbidities, bleeding risk, etc., the absolute value may vary within about ±10%, about ±5%. The treating physician should be able to determine whether the subject has achieved a complete response. -

[0079] In one embodiment, compared with the absence of the drug of the present invention, especially without adding ixekizumab on the basis of initial treatment or second treatment, the subject maintains a durable response for a longer period. The average duration of durable response of patients to initial treatment (e.g., first-line treatment with corticosteroids) or second treatment (e.g., second-line treatment with eltrombopag) can be calculated based on real-world large datasets. As used herein and hereinafter, the term "durable response" should be understood as the patient maintaining a response over time during treatment, and the patient's platelet count does not drop below 30 x 10 9 / L and / or the patient does not require additional treatment to stop or reduce the bleeding risk. According to the IWG criteria, when the platelet count is maintained ≥ 30 x 10 9 / L, the patient is still responsive.

[0080] The time to treatment failure (TTF) is defined as the time from the first administration of the drug of the present invention to the following events: the platelet count drops below 30 G / L, starting a new ITP treatment for any reason, using rescue treatment (e.g., corticosteroids, IVIG, or platelet transfusion), not meeting the tapering criteria or being unable to discontinue treatment as prescribed, or death (regardless of the cause). Patients treated according to the present invention, especially those treated with ixekizumab, are expected to have a TTF duration of about 30 months, about 24 months, about 20 months, about 18 months, about 16 months, about 12 months, or about 9 months.

[0081] In one embodiment, compared with the absence of the drug of the present invention, especially without adding ixekizumab on the basis of initial treatment or second treatment, the subject maintains a treatment-free remission for a longer period. As used herein, the term "treatment-free remission (TFR)" means that the platelet count ≥ 30 x 10 9 / L in the absence of treatment (Provan et al. 2019). If the patient relapses, the period ends.

[0082] Patients treated according to the present invention, especially those treated with ixekizumab, are expected to have a TFR duration of about 24 months, about 20 months, about 18 months, about 16 months, about 12 months, or about 9 months, or about 8 months, 7 months, or 6 months.

[0083] As used herein, the term "relapse" refers to, in most cases, a platelet count dropping to below about 30 x 10 9 / L or the need to receive additional treatment for ITP.

[0084] – The present invention provides the advantage of maintaining TFR, such that (1) the patient maintains remission and no longer requires any ITP treatment for at least an extended period of time; (2) the TFR period is longer than without the use of the drug of the present invention; (3) once the platelet count drops to below 30 x 10 9 / L, remission can be rapidly restored through any ITP treatment option (including but not limited to the treatment options of the present invention).

[0085] - The platelet count continuously increases, which is considered to have a hemostatic effect on an individual patient: One of the objectives of the present invention is for the platelet count to reach at least 30 x 10 9 / L, 50 x 10 9 / L, 100 x 10 9 / L or higher, particularly greater than 30 x 10 9 / L.

[0086] In one embodiment, the present invention relates to epratuzumab for treating ITP (particularly primary ITP), or to a method of treating ITP (particularly primary ITP) in a subject (particularly a subject in need), the method comprising administering (typically in a therapeutically effective amount) epratuzumab, wherein the subject relapses after TFR. In one embodiment, the subject receives treatment with epratuzumab prior to TFR (reattachment). In a further embodiment, the subject receives the same dosing regimen as that received prior to TFR, such as 3 mg / Kg or 9 mg / Kg once every 4 weeks. In one embodiment, the subject receives fewer doses than those received prior to TFR. In one embodiment, the subject receives more doses than those received prior to TFR. Typically and preferably, the subject receives a smaller number of doses. For example, prior to TFR, the subject receives a total of 4 doses of epratuzumab, and during the re-treatment schedule, the subject receives fewer than 4 doses, such as 3 doses, 2 doses, or 1 dose, sufficient to increase the platelet count to above 30 x 10 9 / L.

[0087] On the one hand, the present invention provides a method of treating ITP (particularly primary ITP) in a subject (particularly a subject in need), the method comprising co-administering a molecule that inhibits BAFF-R, particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly epratuzumab, with a BTK inhibitor, typically or preferably in a therapeutically effective amount to the subject.

[0088] On the one hand, the present invention provides molecules that inhibit BAFF-R, in particular anti-BAFF-R antibodies or binding fragments thereof, in particular eculizumab, for use in combination with a BTK inhibitor to treat ITP (especially primary ITP).

[0089] In one embodiment, the BTK inhibitor binds BTK reversibly. In another embodiment, the BTK inhibitor binds BTK covalently.

[0090] In one embodiment, the BTK inhibitor is rilzabrutinib and / or a pharmaceutically acceptable salt thereof. Rilzabrutinib is an exception to the general rule. It binds covalently to its receptor, but the binding is reversible. In one embodiment, rilzabrutinib is in the form of the H2SO4 salt, the HCl salt or the mesylate salt. An ongoing Phase III trial tested ITP patients who orally received 400 mg of rilzabrutinib twice daily for up to 24 weeks.

[0091] In addition to the other definitions already provided, the following definitions are used to define the specific, preferred meanings of features and language used in the specification and claims of the present invention, where any one or more or all of the more general terms may be replaced by a specific meaning, thereby generating a specific embodiment of the invention.

[0092] As used herein, the term "binding fragment" refers to a portion of an anti-BAFF-R antibody that is capable of binding to a BAFF-R epitope, in particular an epitope that is involved in the binding of BAFF to BAFF-R and / or that negatively (e.g., by allosteric binding) affects the activation of BAFF-R by BAFF. The binding of the antibody (or its binding fragment) to BAFF-R reduces the formation of the BAFF / BAFF-R complex and / or reduces the activation of BAFF-R.

[0093] Ixekizumab heavy chain : SEQ ID NO:1

[0094] QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWGWIRQSPGRGLEWLGRIYYRSKWYNSYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARYDWVPKIGVFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0095] Ixekizumab light chain: SEQ ID NO:2

[0096] DIVLTQSPATLSLSPGERATLSCRASQFISSSYLSWYQQKPGQAPRLLIYGSSSRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQLYSSPMTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0097] Ixekizumab heavy chain variable domain (VH) : SEQ ID NO:3

[0098] QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWGWIRQSPGRGLEWLGRIYYRSKWYNSYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARYDWVPKIGVFDSWGQGTLVTVSS

[0099] Ixekizumab light chain variable domain (VL) : SEQ ID NO:4

[0100] DIVLTQSPATLSLSPGERATLSCRASQFISSSYLSWYQQKPGQAPRLLIYGSSSRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQLYSSPMTFGQGTKVEIKRT

[0101] Ixekizumab comprises the following Complementary Determining Regions (CDRs):

[0102] Heavy chain:

[0103] HCDR1: GDSVSSNSAAWG SEQ ID NO:5

[0104] HCDR2: RIYYRSKWYNSYAVSVKS SEQ ID NO:6

[0105] HCDR3: YDWVPKIGVFDS SEQ ID NO:7

[0106] Light chain:

[0107] LCDR1: RASQFISSSYLS SEQ ID NO:8

[0108] LCDR2: GSSSRAT SEQ ID NO:9

[0109] LCDR3: QQLYSSPMT SEQ ID NO:10

[0110] The term "therapeutically effective amount" refers to the amount of a molecule that inhibits BAFF-R, in particular an anti-BAFF-R antibody or a binding fragment thereof, in particular ixekizumab and / or a combination partner according to the invention, which amount will elicit a biological or medical response in a subject, in particular to ameliorate, inhibit, eliminate or otherwise beneficially affect one or more symptoms of ITP, slow or delay disease progression, or prevent ITP.

[0111] As used herein, the terms "subject" and its interchangeable term "patient" refer to a human, in particular an ITP patient 18 years of age or older; however, younger children can also be treated according to the invention.

[0112] As used herein, the term "inhibit (inhibit, inhibition or inhibiting)" refers to reducing or suppressing a given pathway or condition or symptom found in a subject with ITP.

[0113] As used herein, the term "treat", "treating", or "treatment" of ITP, in one embodiment, refers to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treat", "treating", or "treatment" refers to alleviating or ameliorating at least one physical parameter of ITP, including those physical parameters not discernible by the patient. In yet another embodiment, "treat", "treating", or "treatment" refers to modulating ITP physically (e.g., stabilization of discernible symptoms) or physiologically (e.g., stabilization of physical parameters) or both. In particular, there are three main reasons for treating ITP: 1) preventing bleeding; 2) inducing remission (which may be defined as normalization of platelet count, "complete remission", or sustained elevation of platelet count to a hemostatic level ("partial remission without treatment")); and 3) improving life and alleviating ITP-related symptoms (including fatigue).

[0114] As used herein, a subject is "in need of" treatment if the subject would benefit biologically, medically, or in terms of quality of life from the treatment.

[0115] As used herein, unless otherwise indicated herein or clearly contradicted by context, the terms "a / an", "the", and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and the plural.

[0116] As used herein, unless otherwise defined, the term "about" includes variations of ±10% or ±5% of a given value.

[0117] All methods described herein can be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is merely intended to better illustrate the invention and does not limit the scope of the invention otherwise claimed. However, it may relate to preferred features.

[0118] The invention embodiments and their hierarchical relationships to each other are also defined in the claims and are considered to be included herein.

[0119] Examples

[0120] The following examples are used to assist in understanding the invention (although they are also specific invention embodiments), but are not intended and should not be construed to limit its scope in any way.

[0121] Example 1: A Phase 3, randomized, double-blind study comparing ixekizumab (VAY736) with placebo in combination with first-line corticosteroids in primary immune thrombocytopenia (VAYHIT1)

[0122] The following table lists the objectives, endpoints, and estimators:

[0123]

[0124]

[0125] Study design: This is a multicenter, randomized, double-blind, phase 3 study to evaluate the efficacy and safety of two different doses of ixekizumab (3 and 9 mg / kg) compared to placebo in adult participants with primary ITP.

[0126] During the screening period (up to 28 days), participants will receive corticosteroids (prednisone (or prednisolone) or dexamethasone) according to standard of care. Corticosteroids can be started up to 14 days before screening; however, the maximum duration of corticosteroids allowed before randomization is 28 days. IVIG is permitted if there are clinical indications. After the screening period, participants who respond to first-line corticosteroids (platelet count ≥ 50 G / L at any time before randomization) will enter a 16-week randomized treatment period in one of the following three groups: Group A (ixekizumab, 3 mg / kg, IV, every 4 weeks), Group B (ixekizumab, 9 mg / kg, IV, every 4 weeks), or Group C (placebo, IV, every 4 weeks). The standard-of-care corticosteroid regimen started before randomization will be continued during treatment according to the guidelines, for a total of 6 weeks (up to 8 weeks) in the case of prednisone (or prednisolone) (including tapering), or every 2 weeks for up to a total of three 4-day cycles in the case of dexamethasone.

[0127] After the treatment period, all participants will enter a follow-up period to monitor efficacy and safety or only safety, depending on the participant's response to the study treatment. The efficacy and safety follow-up period will continue until treatment failure or up to 39 months after the last participant is randomized, whichever occurs first. The safety follow-up period will be at least 20 weeks (short-term safety follow-up) and up to 2 years (long-term safety follow-up) after the last ixekizumab / placebo administration.

[0128] Study population: Adult (≥ 18 years) patients diagnosed with primary ITP within 3 months before starting corticosteroids, who require first-line corticosteroid treatment and respond to corticosteroids (+ / - IVIG) before randomization.

[0129] Brief overview:

[0130] Study treatment will be administered in a double-blind manner for 16 weeks (a total of 4 doses of 3 mg / kg or 9 mg / kg of ixekizumab or placebo in combination with corticosteroids).

[0131] · During the treatment period, the visit frequency is once a week (qw) until the visit at W9D1, and then every other week (q2w). Participants who complete the study treatment or discontinue treatment prematurely will complete the EOT disposition and enter the follow-up period.

[0132] · Participants who do not meet the treatment failure criteria at the end of the treatment period will enter the safety and efficacy follow-up, while those who meet the treatment failure criteria during the treatment period will enter the safety follow-up.

[0133] · For the efficacy and safety follow-up, visits are conducted every 4 weeks until treatment failure or up to 2 years; thereafter, visits are conducted every 12 weeks until treatment failure or up to 39 months after randomization of the last participant, whichever occurs first. For the safety follow-up, visits are conducted every 4 weeks for 20 weeks and then every 12 weeks within 2 years after the last dose.

[0134] · The estimated study duration is 39 months after randomization of the last participant.

[0135] Number of participants:

[0136] 225 participants will be randomly assigned in a 1:1:1 ratio to one of the 2 active groups or the placebo group.

[0137] Key inclusion criteria

[0138] 1a. Sign the informed consent form before participating in the study.

[0139] 2a. Male or female participants aged 18 years and older on the day of signing the informed consent form

[0140] 3a. Diagnosed with primary ITP within 3 months before starting first-line ITP therapy (corticosteroids, IVIG)

[0141] 4. Platelet count below 30G / L before starting any first-line ITP therapy (corticosteroids, IVIG)

[0142] 5. Achieved remission (platelet count >= 50G / L) with corticosteroids (+ / - IVIG) at any time before randomization. Note: Platelet counts measured within 7 days after platelet transfusion are not considered remission.

[0143] Key exclusion criteria

[0144] · Evans syndrome or any other cytopenia

[0145] · Current life-threatening bleeding

[0146] 3a. Previous ITP treatment, including splenectomy, except for corticosteroids and / or IVIG up to 28 days before randomization.

[0147] · Have previously received B-cell depletion therapy (e.g., rituximab).

[0148] 6a. Absolute neutrophil count less than 1.0 G / L at randomization

[0149] 7a. Participants with concurrent coagulopathy and / or receiving antiplatelet or anticoagulant medications (excluding low-dose acetylsalicylic acid).

[0150] Example 2: A Phase 3, randomized, double-blind study comparing ixekizumab with placebo in combination with eltrombopag in primary immune thrombocytopenia (ITP) with inadequate response or relapse after first-line steroid therapy (second-line therapy) (VAYHIT2)

[0151]

[0152]

[0153]

[0154] This is a multicenter, randomized, double-blind, phase 3 study to evaluate the efficacy and safety of two different doses of ixekizumab (3 and 9 milligrams (mg) / kilogram (kg)) compared to placebo in adult participants with primary ITP (platelet count < 30 G / L) treated with eltrombopag.

[0155] Key inclusion criteria

[0156] 1. Male or female patients 18 years of age and older

[0157] 2. Diagnosed with primary ITP and with inadequate remission or recurrence after first-line steroid therapy ± IVIG.

[0158] 3. Platelet count < 30 G / L.

[0159] Key exclusion criteria

[0160] 1. ITP patients receiving second-line ITP treatment including splenectomy (except for corticosteroid therapy ± IVIG). However, patients with limited exposure (up to one week) to thrombopoietin receptor agonists (TPO-RAs) prior to screening are eligible to participate in the study.

[0161] 2. Patients with abnormal key laboratory test results and patients with Evans syndrome or any other cytopenia

[0162] 3. Patients with a history of clinically significant hematological diseases or patients with significantly altered hematological parameters

[0163] 4. Patients with current or previous life-threatening bleeding

[0164] 5. Patients positive for human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B surface antigen (HBsAg) / hepatitis B core antibody (HBcAB)

[0165] 6. Patients known to have active or uncontrolled infections requiring systemic treatment during the screening period

[0166] 7. Patients with liver function impairment

[0167] 8. Patients with concurrent coagulation disorders and / or receiving antiplatelet or anticoagulant therapy

[0168] Treatment groups:

[0169] At the end of a screening period of up to 2 weeks, eligible participants (N = 150) will be randomized in a 1:1:1 ratio to one of the following three treatment groups:

[0170] Elrombopag (oral administration, once daily) + 4 cycles of ixekizumab (3 mg / kg intravenous administration, once every 4 weeks for a total of 4 doses)

[0171] Elrombopag (oral administration, once daily) + 4 cycles of ixekizumab (9 mg / kg intravenous administration, once every 4 weeks for a total of 4 doses)

[0172] Elrombopag (oral administration, once daily) + 4 cycles of placebo (intravenous administration, once every 4 weeks for a total of 4 doses)

[0173] After this 16-week randomized combination treatment period, participants in all groups will start tapering elrombopag according to platelet counts:

[0174] At the end of the combination treatment period (W15D1 and W17D1), participants with platelet counts ≥ 50 G / L in at least two consecutive assessments will start tapering elrombopag, continuing for up to 8 weeks until the platelet count remains ≥ 30 G / L and then stopping;

[0175] At the end of the combination treatment period (W15D1 and W17D1), participants who do not achieve platelet counts ≥ 50 G / L in at least two consecutive assessments will be considered ineligible to start tapering elrombopag and will continue according to the same visit schedule until W25D1, then enter safety follow-up. These participants may continue to receive elrombopag, but after W25D1, this treatment will not be considered part of the study treatment.

[0176] Time to treatment failure (TTF) is defined as the time from randomization to any of the following events:

[0177] (1) Platelet count below 30 G / L 8 weeks after randomization,

[0178] (2) Starting new ITP treatment for any reason,

[0179] (3) rescue therapy (e.g., corticosteroids, IVIG, or platelet transfusion) 8 weeks after randomization,

[0180] (4) Not able to gradually reduce or stop eltrombopag

[0181] (5) Death (regardless of the cause)

[0182] In this study, eltrombopag was administered in all treatment groups according to the locally approved starting dose for ITP, e.g., 50 mg QD (25 mg or 12.5 mg for East / Southeast Asian patients in countries where lower starting doses were approved). The dose of eltrombopag was adjusted to allow patients to receive the minimum effective dose in order to achieve a platelet count ≥50 G / L.

[0183] The duration of tapering (up to 8 weeks) was individualized and depended on the dose at W17D1 and the participant's response:

[0184] In participants who received a dose of ≥50 mg, the daily dose was reduced by 25 mg every other week. After reaching the 25 mg dose for 2 weeks, if platelets were ≥30 G / L, the daily dose of 12.5 mg (or 25 mg every other day) was continued for 2 weeks until treatment was completely stopped.

[0185] In participants who received doses ≤25 mg (including participants of East / Southeast Asian ancestry), the daily dose was reduced by 12.5 mg every other week until treatment was completely discontinued.

[0186] Participants who failed to discontinue eltrombopag by week 24 (discontinuation of the taper period due to platelet counts falling below <30 G / L and / or need for rescue therapy) will continue to receive the last dose of eltrombopag that was able to maintain a platelet count ≥30 G / L. These participants may continue to receive eltrombopag or start a new ITP treatment at the discretion of the investigator.

[0187] Permitted concomitant therapy

[0188] To avoid rapid deterioration in platelet levels and prevent participants from experiencing a bleeding event before study treatment has taken effect, bridging therapy with corticosteroids (+ / - IVIG) is permitted in the following circumstances:

[0189] - High-dose dexamethasone or prednisolone (>15 mg / day) was permitted until randomization (eg, if clinically indicated during screening).

[0190] · After randomization, prednisone (prednisolone) ≤ 15 mg / d is allowed, and the expected tapering period and discontinuation are not later than W2D7.

[0191] · Dexamethasone is not allowed after randomization.

[0192] · Use of IVIG at 1 - 2 g / kg according to the locally approved schedule is allowed until W2D7.

[0193] Before the end of week 8, feasible rescue therapies are platelet transfusions, corticosteroids, and IVIG.

[0194] Example 3 Pharmacokinetics - Pharmacodynamics Modeling

[0195] A population PK / PD model was developed using the sequential PK / PD (Zhang, J Pharmacokinet Pharmacodyn [Journal of Pharmacokinetics and Pharmacodynamics]; 30(6):387 - 404. 2003) method to describe the concentration of ixekizumab and CD19 + B cell counts in patients with various autoimmune diseases.

[0196] Population PK / PD Model

[0197] A two - compartment population PK model with linear clearance was fitted to i.v. and s.c. data from studies in RA patients and pSS patients. The PK / PD model was parameterized according to the B cell count at baseline (baseline), B cell death rate (kout), peripheral compartment volume of B cells (Vb), inter - compartment transfer rate of B cells (Qb), maximum stimulatory effect of ixekizumab on B cell death rate (Emax), and the concentration of ixekizumab at which the VAY736 effect is half - maximal (EC50).

[0198] PK Tissue Receptor Occupancy (RO) Structural Model

[0199] Since the circulating B cell kinetics described by the population PK / PD model may not necessarily predict clinical efficacy, a hypothesis - driven tissue receptor occupancy (RO) model was also developed and used to consider the competitive binding of ixekizumab and soluble BAFF (sBAFF) to BAFF - R under the quasi - steady - state assumption. The following equation relates PK (C 伊利尤单抗 (t), nM) to the BAFF - R binding of ixekizumab (ROVAY(t), %).

[0200]

[0201] where C sBAFF is the concentration of soluble BAFF in tissue (nM), Kd 伊利尤单抗 and Kd sBAFFThey are the dissociation constants of ixekizumab with BAFF-R and sBAFF with BAFF-R, respectively. The above equations assume a reasonable excess of ligand compared to the receptor. It is further assumed that the sBAFF concentration is approximately constant, while the ixekizumab concentration varies over time.

[0202] To determine the occupancy of BAFF-R in fictional disease-related tissues, the following assumptions were made with the support of in-house experiments:

[0203] Tissue:serum concentration ratio of ixekizumab: 1:5

[0204] · Tissue:serum concentration ratio of sBAFF: 4:1

[0205] Table 1 lists all the parameters used for predicting tissue receptor occupancy.

[0206] Table 1 Tissue receptor occupancy model parameters

[0207]

[0208] Dose selection simulation for the proposed Phase 3 study in wAIHA

[0209] It is assumed that the PK of ixekizumab in the target wAIHA patient population is comparable to that observed in other autoimmune diseases. In addition, based on the existing literature, the baseline B cells in ITP patients are comparable to those measured in previous ixekizumab studies in pSS ( Toffoletti et al. 2008 ). Given the pathophysiological similarities between ITP and wAIHA, similar levels of B cells in wAIHA were used as the baseline. Therefore, in the proposed Phase 3 study in wAIHA patients, a final population PK / PD model was used to support dose and regimen selection.

[0210] In addition, the same assumption-driven tissue RO model was also assumed to be applicable to autoimmune diseases and wAIHA, so the PK-RO model described in Table 1 was used. For wAIHA patients, only the soluble BAFF concentration level in serum was fixed at a lower level of 1.817 ng / mL, rather than 2.7 ng / mL in autoimmune diseases. It should be noted that the reported serum BAFF concentration in AIHA patients was 1358.7 ± 141.0 pg / mL ( Xu et al. 2015 ), and a fixed level of 1.817 ng / mL was selected for conservative tissue RO prediction, which is about 3 standard deviations from the mean.

[0211] The following criteria were used for PKPD simulation to support the selection of a 4-week dosing interval:

[0212] · B cell depletion within the dosing window (<10 cells / μL);

[0213] · Tissue RO (90% threshold) based on the hypothetical model described in Table 1;

[0214] · Irituximab PK was evaluated by C trough > 1.8 μg / mL, which is the steady-state trough concentration of 300 mg q4ws.c., and this dose led to the highest clinical remission in the multiple-dose, dose-ranging discovery study CVAY736A2201 in pSS patients (CSR A2201 at week 52).

[0215] PKPD simulation Figure 1 indicated that for the phase 3 study in wAIHA patients, i.v. administration of 3 mg / kg and 9 mg / kg of rituximab doses and dosing regimens every 4 weeks (q4w) could be considered, with a treatment period of 16 weeks (a total of 4 doses). The lower dose of 3 mg / kg iv q4w resulted in trough values above 1.8 μg / mL in half of the simulated patients, and > 95% of the patients had predicted tissue RO > 90% (Table 2). The higher dose of 9 mg / kg i.v. q4w could increase the coverage of patients for PK and tissue RO.

[0216] Table 2 Characteristics of PK, B cells, and tissue RO of the proposed dosing regimens

[0217]

[0218]

[0219] LLOQ = 0.025 μg / mL

[0220] * B cell recovery was defined as ≥ 80% of baseline or ≥ 50 cells / μL.

[0221] ** End of follow-up was defined as 1 year after discontinuation of rituximab treatment.

[0222] *** Predicted tissue RO was calculated based on the trough concentration before the last dose of rituximab.

[0223] In the study after a single i.v. dose of 10 mg / kg in pSS patients (mean Cmax 213 μg / mL and AUCinf 1140 day*μg / mL, n = 12) and in the study after an i.v. dose of 9 mg / kg q2w in CLL patients (cycle 3 mean Cmax 262 μg / mL and AUC0-28d,ss 3730 day*μg / mL, 2 doses within 4 weeks, q2w, n = 4), the mean simulated exposure after the last dose of 9 mg / kg i.v. rituximab (Cmax 192 μg / mL and AUC0-28d 931 day*μg / mL) was within the range observed previously at the highest tested i.v. dose.

[0224] Comparison of exposure between preclinical species and mean simulated exposure after monthly i.v. doses of 9 mg / kg of ixekizumab showed safety margins of 14- to 15-fold and 4.3- to 5.6-fold for Cmax and AUC, respectively, for the monthly 9 mg / kg i.v. dose, indicating that the highest ixekizumab dose of 9 mg / kg i.v. q4w9 is safe.

[0225] Example 4 Reduction of autoantibodies in patients participating in the primary Sjögren's syndrome (pSS) trial.

[0226] In the primary Sjögren's syndrome (pSS) trial, 190 pSS patients were treated with subcutaneous ixekizumab (5, 50, 150, or 300 mg q4w for 24 weeks) or placebo (Bowman SJ, Fox R, T et al. (2021) Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial. [Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial] Lancet [The Lancet]; 399(10320):161-171). The study showed a significant dose-response effect of ixekizumab on ESSDAI, increased stimulated salivary flow, and the greatest effect was observed at the highest dose.

[0227] For the quantitative data interpretation of the effect of VAY736 on autoantibodies in this trial, the kit FIDIS TM Connective Profile was used to analyze SSA Ro52kd / TRIM21, SSA Ro60kd, and SSB autoantibodies in baseline and post-treatment samples at the same dilution.

[0228] The following data represent SSAro52 ( Figure 2A ), SSAro60 ( Figure 2B ), and SSB autoantibodies ( Figure 2C ) The data. The data is expressed as the percentage change compared to the baseline. The results clearly show that the reduction of the three autoantibodies in VAY736 is dose-dependent between the doses of 5 mg, 50 mg, and 300 mg. This reduction of autoantibodies in the placebo reaches its maximum at week 24, with a 4% decrease, while it is 12% to 16% in the 50 mg and 300 mg VAY736 treatment groups.

[0229] Example 5: Reduction of autoantibodies in patients participating in a systemic lupus erythematosus (SLE) trial

[0230] This study is a double-blind, randomized, placebo-controlled, multi-center, two-arm study conducted in SLE patients receiving standard care treatment to evaluate 300 mg of infliximab administered s.c. once a month (compared to placebo). The dose regimen of this study is 300 mg s.c. infliximab once a month for a treatment period of 18 months.

[0231] Key inclusion criteria

[0232] Meet ≥ 4 of the 11 American College of Rheumatology 1997 SLE classification criteria at screening

[0233] The patient has been diagnosed with SLE for at least 6 months before screening

[0234] In a pattern consistent with the SLE diagnosis, the serum titer is elevated during ANA screening (≥ 1:80), including at least anti-double-stranded DNA (anti-ds DNA) or anti-Ro (SSA) or anti-La (SSB) or anti-nuclear ribonucleoprotein (anti-RNP) or anti-Smith (anti-Sm)

[0235] Currently receiving corticosteroids and / or antimalarial treatment and / or thalidomide treatment and / or another DMARD, specifically as follows:

[0236] In the case where corticosteroids are the single standard care drug treatment: oral dose ≤ 30 mg / d for at least 8 weeks before randomization, and at a stable dose ≥ 2 weeks before randomization

[0237] In the case where oral corticosteroids are not the single standard care drug treatment: stable oral dose of prednisone or equivalent drug ≤ 30 mg / d for at least 8 weeks before randomization, and at a stable dose ≥ 2 weeks before randomization

[0238] Antimalarial treatment and / or thalidomide treatment and / or one of the following DMARDs: methotrexate or imidazole derivatives (such as azathioprine, mizoribine) or mycophenolic acid derivatives (such as mycophenolate mofetil) for at least 12 weeks before screening, and at a stable dose ≥ 8 weeks before randomization.

[0239] At screening, an SLEDAI-2K score of ≥6, in combination with other DMARDs, is not allowed. At screening, the BILAG-2004 scores are as follows:

[0240] - At least one "A" in either the mucocutaneous or the musculoskeletal region, or

[0241] - One "B" in either the mucocutaneous or the musculoskeletal region and at least one "A" or "B" in the second region

[0242] At screening, body weight is at least 40 kg

[0243] Key exclusion criteria

[0244] History of receiving the following medications prior to screening:

[0245] - Within 12 weeks: i.v. high-dose corticosteroids, calcineurin inhibitors, or other oral DMARDs, except as listed in inclusion criterion 6

[0246] - Within 24 weeks: cyclophosphamide or biologics such as i.v. Ig, plasmapheresis, anti-TNF-α mAb, CTLA4-Fc Ig (abatacept), or BAFF-targeting agents (e.g., belimumab)

[0247] - Within 52 weeks prior to screening, administration of any B-cell depletion therapy (e.g., anti-CD20 mAb, anti-CD22 mAb, anti-CD52 mAb) or TACI-Ig (atacicept), and at screening, B-cell count <50 cells / μL

[0248] Presence of severe lupus nephritis, defined as proteinuria >6 g / day or equivalent value using random urine protein-to-creatinine ratio, or serum creatinine >2.5 mg / dL (221.05 μmol / L), or requiring immunosuppressive induction or maintenance therapy beyond protocol-specified limits.

[0249] Efficacy assessment:

[0250] · SRI-4 (SLE Responder Index)

[0251] · Physician's Global Assessment Visual Analogue Scale (PhGA-VAS)

[0252] · Patient's Global Assessment (VAS)

[0253] · Rate of flare by BILAG-2004 score

[0254] · Lupus low disease activity state (LLDAS)

[0255] Results:

[0256] Among patients on a continuing prednisone taper ≤5 mg / d, the proportion of patients achieving the composite primary endpoint of SRI-4 at Week 28 was 42% higher in the ixekizumab group than in the placebo group. Ixekizumab was also superior to placebo for the incidence of moderate or severe flares (45% vs 73%, respectively) and time to first flare (not reached median vs 11.9 weeks, respectively). At Week 28, the differences between ixekizumab and placebo were: proportion of patients achieving an SRI-4 response 50%, reduction in corticosteroid use 34%, the primary combined endpoint for these two outcomes 43%, lupus low disease activity state (LLDAS) 20%, and BILAG-based comprehensive lupus assessment (BICLA) 31%. Ixekizumab was well tolerated during the 28-week blinded treatment period, the open-label treatment period (Weeks 28 to 52), and subsequent safety follow-up, and no new safety signals were detected.

[0257] The effect of VAY736 on C1q autoantibodies was measured using the enzyme immunoassay (EIA) provided by the laboratory, product reference number EK-AC1QA-U.

[0258] The following data represent data obtained at baseline, Week 12, and Week 24. The data are presented as geometric mean ratios relative to baseline. The results clearly show that at Week 29, the ratio of anti-C1q autoantibodies to VAY736 was reduced by nearly 40% relative to baseline, while that of the placebo was 18% ( Figure 3A ).

[0259] The effect of VAY736 on anti-dsDNA autoantibodies was measured by the INOVA QUANTA Lite SC ELISA.

[0260] The data obtained at baseline, Week 12, and Week 24 are presented as geometric mean ratios relative to baseline ( Figure 3B ). The results clearly show that at Week 29, the ratio of anti-dsDNA autoantibodies to VAY736 was reduced by nearly 40% relative to baseline, while that of the placebo was 10%.

[0261] Conclusion: All of these data indicate that VAY736 reduces autoantibodies in patients with pSS or SLE. This effect is dose- and time-dependent for VAY736. Elevated autoantibodies play an important role in the occurrence and progression of ITP, and autoantibodies are reduced by treatment with VAY736.

[0262] Example 6 Preclinical study of the effect of ixekizumab

[0263] The most commonly used murine model of immune thrombocytopenia is the short-term passive model, which measures platelet levels after injection of anti-platelet antibodies that induce platelet elimination by phagocytes (Crow A.R et al., Br J Haematology, 2001, 115(3), 679 - 86). However, this model is not suitable for studying chronic ITP, especially the role of immune cells in disease establishment. The recently developed ITP-active model (Chow L. et al., Blood (2010) 115(6):1247 - 1253) is similar to the clinical features of severe ITP in humans and more accurately represents the immune defects of chronic ITP. In fact, the presence of B cells and T cells has been described to be dependent on the induction of a sustained decrease in platelet levels. In this model, wild-type platelets are injected into CD61-deficient mice to generate an immune response, and then splenocytes from the mice are transferred into severe combined immunodeficient (SCID) mice, which induces a strong decrease in platelet levels within a week. CD19 and CD8 positive populations are required to induce a sustained decrease in circulating platelet levels.

[0264] Since eculizumab depletes murine B cells, we expect to see an effect on chronic ITP in this murine model. Splenocytes from mice immunized against platelet CD61 were transferred into SCID mice. Mice were treated with 2 to 4 injections of 1) PBS, 2) 10 mg / kg eculizumab, or 3) 100 mg / kg eculizumab. Mice were bled weekly for 4 weeks to assess their platelet counts. An increase in platelet counts over time was expected, confirming the efficacy of eculizumab in chronic ITP.

[0265] Example 7 A Phase 2 study to evaluate the efficacy and safety of eculizumab (VAY736) in patients with primary immune thrombocytopenia (ITP) who have previously received at least one corticosteroid and a thrombopoietin receptor agonist (TPO-RA)

[0266] The following table lists the objectives, endpoints, and estimators:

[0267]

[0268]

[0269]

[0270] This is a Phase 2, open-label, single-arm study.

[0271] This study consists of three periods:

[0272] Screening period (up to 14 days before the first dose of eculizumab).

[0273] · Primary endpoint assessment period (up to the visit on Day 1 of Week 25). Participants received ixekizumab at a dose of 9 mg / kg, administered intravenously (i.v.), once every 4 weeks for a total of 4 doses over 16 weeks. Efficacy and safety were evaluated in all participants from the visit on Day 1 of Week 1 to the last day of the primary endpoint assessment period (the visit on Day 1 of Week 25). The visit frequency was once a week until the visit on Day 1 of Week 9, and then once every 2 weeks until the visit on Day 1 of Week 25.

[0274] · Efficacy and safety follow-up (FU) period after the visit on Day 1 of Week 25:

[0275] The study ended once all participants had completed 24 months of safety follow-up after the last dose of ixekizumab or had stopped the study prematurely.

[0276] Key inclusion criteria:

[0277] 1. Diagnosed with primary ITP.

[0278] 2. Previously received at least one corticosteroid (± intravenous immunoglobulin (IVIG)) and TPO-RA treatment:

[0279] · Other previous therapies were permitted; corticosteroids and TPO-RA did not necessarily have to be the last treatment.

[0280] · There was no record of maintaining remission with IVIG / anti-D or corticosteroids.

[0281] 3. At the time of the last ITP treatment, remission was lost, remission was insufficient, there was no remission, or there was intolerance.

[0282] 4. Platelet count < 30 G / L and was evaluated as in need of treatment (at the physician's discretion). If concomitant ITP drug treatment was clinically required, platelet assessment must be performed at least 14 days after using a stable dose of corticosteroid or / and TPO-RA (with a change in the current dose of less than 10%) and showed a value < 30 G / L, and remained stable thereafter.

[0283] Key exclusion criteria:

[0284] 1. Diagnosed with secondary thrombocytopenia.

[0285] 2. Received platelet transfusions or whole blood transfusions, plasmapheresis, or any other rescue drug treatment within 14 days before the first ixekizumab infusion.

[0286] 3. Neutrophils < 1000 / mm 3 .

[0287] 4. Received B-cell depletion therapy (such as rituximab) or anti-B cell activating factor (BAFF) of the tumor necrosis factor family (such as belimumab) within 12 weeks before the first administration of ixekizumab.

[0288] 5. Received immunosuppressants other than corticosteroids within 5 times the drug elimination half-life or within 14 days before the first ixekizumab infusion (whichever is longer).

[0289] 6. History of splenectomy.

[0290] Although a number of specific embodiments have been illustrated and described, it should be understood that various changes may be made without departing from the spirit and scope of one or more of this disclosure.

[0291] All publications, patents, patent applications, and other documents cited in this application are hereby incorporated by reference in their entirety for all purposes to the extent that each individual publication, patent, patent application, or other document is specifically indicated to be incorporated by reference for all purposes. In the event of any inconsistency between one or more of the references incorporated herein and the teachings of this disclosure, the teachings of this specification are intended.

Claims

1. A method of treating a subject with immune thrombocytopenia (ITP), the method comprising administering a molecule that inhibits the B-cell activating factor receptor (BAFF-R).

2. The method according to claim 1, wherein the molecule that inhibits BAFF-R is an antibody against BAFF-R (anti-BAFF-R antibody) or a binding fragment thereof.

3. The method according to claim 2, wherein the anti-BAFF-R antibody is afucosylated.

4. The method according to any one of the preceding claims, wherein the anti-BAFF-R antibody or a binding fragment thereof comprises CDR-H1, CDR-H2 and CDR-H3 having the amino acid sequences of SEQ ID NO:5, SEQ ID NO:6 and SEQ ID NO:7, respectively, and CDR-L1, CDR-L2 and CDR-L3 having the amino acid sequences of SEQ ID NO:8, SEQ ID NO:9 and SEQ ID NO:10, respectively.

5. The method according to any one of the preceding claims, wherein the anti-BAFF-R antibody or a binding fragment thereof comprises VH having the amino acid sequence of SEQ ID NO:3 and VL having the amino acid sequence of SEQ ID NO:

4.

6. The method according to any one of the preceding claims, wherein the anti-BAFF-R antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:1 and a light chain having the amino acid sequence of SEQ ID NO:

2.

7. The method according to any one of the preceding claims, wherein the anti-BAFF-R antibody or a fragment thereof is epratuzumab or a binding fragment thereof.

8. The method according to any one of the preceding claims, wherein the ITP is primary ITP.

9. The method according to any one of the preceding claims, wherein the anti-BAFF-R antibody or a binding fragment thereof, particularly epratuzumab, is administered to the subject at a dose of about 1 to about 27 mg / kg.

10. The method according to any one of the preceding claims, wherein the anti-BAFF-R antibody or a binding fragment thereof, particularly epratuzumab, is administered to the subject at a dose of about 1 mg / kg to about 10 mg / kg.

11. The method according to any one of the preceding claims, wherein epratuzumab is administered to the subject at a dose of about 3 mg / kg.

12. The method according to any one of the preceding claims, wherein epratuzumab is administered to the subject at a dose of about 9 mg / kg.

13. The method according to any one of the preceding claims, wherein the anti-BAFF-R antibody or a binding fragment thereof, particularly epratuzumab, is administered to the subject intravenously (i.v.).

14. The method according to any one of the preceding claims, wherein the anti-BAFF-R antibody or a binding fragment thereof, particularly epratuzumab, is administered to the subject once every 4 weeks (monthly, + / - 3 days).

15. The method according to any one of the preceding claims, wherein the anti-BAFF-R antibody is eculizumab, and wherein eculizumab is intravenously administered to the subject at a dose of 3 mg / kg once every four weeks (monthly, + / - 3 days).

16. The method according to any one of the preceding claims, wherein the antibody is eculizumab, and wherein eculizumab is intravenously administered to the subject at a dose of 9 mg / kg once every four weeks (monthly, + / - 3 days).

17. The method according to any one of the preceding claims, wherein the molecule that inhibits the B-cell activating factor receptor (BAFF-R), in particular the anti-BAFF-R antibody or its binding fragment, in particular eculizumab, is administered to the subject, and wherein the subject receives an initial treatment (1L combination) after being diagnosed with ITP.

18. The method according to claim 17, wherein due to the initial treatment or due to the 1L combination, the platelet count is higher than 30 x 10 9 / L.

19. The method according to claim 17 or 18, wherein the initial treatment comprises one or more treatments selected from corticosteroids, immunoglobulins (such as IVIG or anti-D immunoglobulin), thrombopoietin receptor agonists (TPO-RA), or rituxamab.

20. The method according to any one of claims 17 to 19, wherein the initial treatment is a corticosteroid, preferably a glucocorticoid, preferably dexamethasone, preferably prednisone or prednisolone.

21. The method according to any one of claims 17 to 20, wherein the initial treatment comprises treatment with a thrombopoietin receptor agonist.

22. The method according to any one of the preceding claims, wherein the molecule that inhibits the B-cell activating factor receptor (BAFF-R), in particular the anti-BAFF-R antibody or its binding fragment, in particular eculizumab, is administered to the subject, and wherein the subject has an inadequate remission or recurrence after the initial treatment, preferably the initial treatment is corticosteroid ± IVIG.

23. The method according to claim 22, wherein the subject receives a second treatment (2L combination) different from the initial treatment.

24. The method according to claim 23, wherein the second treatment comprises treatment with the thrombopoietin receptor agonist.

25. The method according to claim 21, 23 or 24, wherein the thrombopoietin receptor agonist is selected from the group consisting of romiplostim, oprelvekin, lusutrombopag, avatrombopag, betrombopag and eltrombopag; or a pharmaceutically acceptable salt thereof.

26. The method according to any one of the preceding claims, wherein the thrombopoietin receptor agonist is eltrombopag or a pharmaceutically acceptable salt thereof.

27. A method of treating immune thrombocytopenia (ITP) in a subject, the method comprising administering eculizumab, wherein the subject has primary ITP, has an inadequate remission or recurrence after first-line corticosteroid treatment, and receives treatment with eltrombopag or a pharmaceutically acceptable salt thereof.

28. The method according to any one of the preceding claims, wherein up to 8 doses, or up to 5 doses, or up to 4 doses of eculizumab or a fragment thereof are administered to the subject.

29. The method according to any one of the preceding claims, wherein a total of about 8 doses, about 6 doses or about 4 doses of eculizumab or a fragment thereof are administered.

30. The method according to any one of the preceding claims, wherein a total of 4 doses of eculizumab or a fragment thereof are administered.

31. The method according to any one of the preceding claims, wherein during or after treatment with the molecule that inhibits BAFF-R, particularly eculizumab, the initial treatment is tapered off to discontinuation.

32. The method according to any one of the preceding claims, wherein during or after treatment with the molecule that inhibits BAFF-R, particularly eculizumab, the second treatment is tapered off to discontinuation.

33. The method according to any one of the preceding claims, wherein during or after treatment with the molecule that inhibits BAFF-R, in particular, eculizumab, the platelet count of the subject is higher than 100 x 10 9 / L.

34. The method according to any one of the preceding claims, wherein the platelet count of the subject is equal to or higher than 30 x 10 9 / L and / or there is no bleeding risk after discontinuation of any ITP treatment (treatment-free remission, TFR).

35. The method according to any one of the preceding claims, wherein, particularly for a subject treated with ixekizumab, the time period of treatment-free remission (TFR) is about 30 months, about 24 months, about 20 months, about 18 months, about 16 months, about 12 months, about 9 months or about 6 months, wherein the time period of the TFR is calculated from the time of stopping the last ITP treatment until the platelet count drops below 30 x 10 9 / L or the subject resumes ITP treatment.

36. The method according to any one of the preceding claims, wherein the time period of time to treatment failure (TTF) is about 35 months, about 30 months, about 24 months, about 18 months, about 12 months or about 9 months, wherein the time period of TTF is calculated from the start of treatment with eculizumab to any one of the following events: (i) Platelet count is less than 30 G / L; (ii) Initiation of a new ITP treatment for any reason, particularly after 8 weeks of eculizumab treatment; (iii) Use of rescue treatment (such as corticosteroids, IVIG or platelet transfusion); (iv) Optionally, failure to taper off or inability to discontinue treatment as prescribed; or (v) Death (regardless of the cause).

37. The method according to any one of the preceding claims, wherein the subject to be treated relapses after TFR (retreatment).

38. A molecule that inhibits the B cell activation receptor (BAFF-R) for use in the treatment of immune thrombocytopenia (ITP) in a subject.

39. The molecule for use according to claim 38, wherein the molecule that inhibits BAFF-R is an antibody against BAFF-R (anti-BAFF-R antibody) or a binding fragment thereof.

40. The molecule for use according to claim 39, wherein the anti-BAFF-R antibody is afucosylated.

41. The molecule for use according to any one of claims 38 to 40, wherein the BAFF-R antibody or a binding fragment thereof comprises CDR-H1, CDR-H2 and CDR-H3 having the amino acid sequences of SEQ ID NO:5, SEQ ID NO:6 and SEQ ID NO:7 respectively, and CDR-L1, CDR-L2 and CDR-L3 having the amino acid sequences of SEQ ID NO:8, SEQ ID NO:9 and SEQ ID NO:10 respectively.

42. A molecule for use according to any one of claims 38 to 41, wherein the anti-BAFF-R antibody or binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO:3 and a VL having the amino acid sequence of SEQ ID NO:4, respectively.

43. A molecule for use according to any one of claims 38 to 42, wherein the anti-BAFF-R antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:1 and a light chain having the amino acid sequence of SEQ ID NO:2, respectively.

44. A molecule for use according to any one of claims 38 to 43, wherein the anti-BAFF-R antibody or fragment thereof is eculizumab or a binding fragment thereof.

45. A molecule for use according to any one of claims 38 to 44, wherein the ITP is primary ITP.

46. A molecule for use according to any one of claims 38 to 45, wherein the anti-BAFF-R antibody or binding fragment thereof, particularly eculizumab, is administered to the subject at a dose of about 1 to about 27 mg / kg.

47. A molecule for use according to any one of claims 38 to 46, wherein the anti-BAFF-R antibody or binding fragment thereof, particularly eculizumab, is administered to the subject at a dose of about 1 mg / kg to about 10 mg / kg.

48. A molecule for use according to any one of claims 38 to 47, wherein eculizumab is administered to the subject at a dose of about 3 mg / kg.

49. A molecule for use according to any one of claims 38 to 48, wherein eculizumab is administered to the subject at a dose of about 9 mg / kg.

50. A molecule for use according to any one of claims 38 to 49, wherein the anti-BAFF-R antibody or binding fragment thereof, particularly eculizumab, is administered to the subject intravenously (i.v.).

51. A molecule for use according to any one of claims 38 to 50, wherein the anti-BAFF-R antibody or binding fragment thereof, particularly eculizumab, is administered to the subject once every 4 weeks (monthly, + / - 3 days).

52. A molecule for use according to any one of claims 38 to 51, wherein the anti-BAFF-R antibody is eculizumab, and eculizumab is administered to the subject intravenously at a dose of 3 mg / kg once every four weeks (monthly, + / - 3 days).

53. A molecule for use according to any one of claims 38 to 52, wherein the antibody is eculizumab, and eculizumab is administered to the subject intravenously at a dose of 9 mg / kg once every four weeks (monthly, + / - 3 days).

54. A molecule for use according to any one of claims 38 to 53, wherein the molecule that inhibits the B-cell activating factor receptor (BAFF-R), in particular the anti-BAFF-R antibody or a binding fragment thereof, in particular eculizumab, is administered to the subject, and the subject receives an initial treatment (1L combination) after being diagnosed with ITP.

55. The molecule for use according to claim 54, wherein the platelet count is higher than 30 x 10 9 / L as a result of the initial treatment or as a result of the 1L combination.

56. A molecule for use according to claim 54 or 55, wherein the initial treatment comprises one or more treatments selected from corticosteroids, immunoglobulins (such as IVIG or anti-D immunoglobulin), thrombopoietin receptor agonists (TPO-RAs), or rituximab.

57. A molecule for use according to any one of claims 54 to 56, wherein the initial treatment is a corticosteroid, preferably a glucocorticoid, preferably dexamethasone, preferably prednisone or prednisolone.

58. A molecule for use according to any one of claims 54 to 57, wherein the initial treatment comprises treatment with a thrombopoietin receptor agonist.

59. A molecule for use according to any one of claims 38 to 58, wherein the molecule that inhibits the B-cell activating factor receptor (BAFF-R), in particular the anti-BAFF-R antibody or a binding fragment thereof, in particular eculizumab, is administered to the subject, and the subject has inadequate remission or recurrence after the initial treatment, preferably the initial treatment is corticosteroid ± IVIG.

60. A molecule for use according to claim 59, wherein the subject receives a second treatment (2L combination) different from the initial treatment.

61. A molecule for use according to claim 60, wherein the second treatment comprises treatment with the thrombopoietin receptor agonist.

62. A molecule for use according to claim 58, 60 or 61, wherein the thrombopoietin receptor agonist is selected from the group consisting of romiplostim, oprelvekin, lusutrombopag, avatrombopag, betrombopag and eltrombopag; or a pharmaceutically acceptable salt thereof.

63. A molecule for use according to any one of claims 38 to 62, wherein the thrombopoietin receptor agonist is eltrombopag or a pharmaceutically acceptable salt thereof.

64. Eculizumab for use in the treatment of immune thrombocytopenia (ITP) in a subject, the method comprising administering eculizumab, wherein the subject has primary ITP, has inadequate remission or recurrence after first-line corticosteroid treatment, and receives treatment with eltrombopag or a pharmaceutically acceptable salt thereof.

65. A molecule for use according to any one of claims 38 to 64, wherein no more than 8 doses, or no more than 5 doses, or no more than 4 doses of eculizumab or a fragment thereof are administered to the subject.

66. A molecule for use according to any one of claims 38 to 65, wherein a total of about 8 doses, about 6 doses or about 4 doses of eculizumab or a fragment thereof are administered.

67. A molecule for use according to any one of claims 38 to 66, wherein a total of 4 doses of eculizumab or a fragment thereof are administered.

68. A molecule for use according to any one of claims 38 to 67, wherein during or after treatment with the molecule that inhibits BAFF-R, particularly eculizumab, the initial treatment is tapered off to discontinuation.

69. A molecule for use according to any one of claims 38 to 68, wherein during or after treatment with the molecule that inhibits BAFF-R, particularly eculizumab, the second treatment is tapered off to discontinuation.

70. A molecule for use according to any one of claims 38 to 69, wherein during or after treatment with the molecule that inhibits BAFF-R, in particular eculizumab, the platelet count of the subject is higher than 100 x 10 9 / L.

71. A molecule for use according to any one of claims 38 to 70, wherein the platelet count of the subject is equal to or higher than 30 x 10 9 / L and / or there is no bleeding risk after stopping any ITP treatment (treatment-free remission, TFR).

72. The molecule for use according to any one of claims 38 to 71, wherein, particularly for a subject treated with ixekizumab, the period of treatment-free remission (TFR) is about 30 months, about 24 months, about 20 months, about 18 months, about 16 months, about 12 months, about 9 months or about 6 months, wherein the period of the TFR is calculated from the time of cessation of the last ITP treatment until the platelet count drops below 30 x 10 9 / L or the subject resumes ITP treatment.

73. A molecule for use according to any one of claims 38 to 72, wherein the time period of time to treatment failure (TTF) is about 35 months, about 30 months, about 24 months, about 18 months, about 12 months or about 9 months, wherein the time period of TTF is calculated from the start of treatment with eculizumab to any one of the following events: (i) Platelet count is less than 30 G / L; (ii) Initiation of a new ITP treatment for any reason, particularly after 8 weeks of eculizumab treatment; (iii) Use of salvage treatment, particularly after 8 weeks of eculizumab treatment; or (iv) Death (regardless of cause).

74. A molecule for use according to any one of claims 38 to 73, wherein the subject to be treated relapses after TFR (retreatment).

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