EP4619026A1 - Treatment of immune thrombocytopenia - Google Patents

Abstract

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

Description

PAT059387 TREATMENT OF IMMUNE THROMBOCYTOPENIA FIELD OF THE INVENTION [0001] The present invention relates to a method of treatment of immune thrombocytopenia (ITP), especially in a patient in need thereof, comprising administering (especially in a therapeutically effective amount) a molecule that inhibits B-cell activating factor receptor (BAFF-R), e.g. an anti-BAFF-R antibody or a binding fragment thereof, especially ianalumab (collectively called Drug of the Invention, which is interchangeably used throughout this application) ,and related invention embodiments as mentioned herein. SEQUENCE LISTING [0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION [0003] Immune Thrombocytopenia (ITP) is a rare, acquired immune-mediated disease of adults and children, characterized by transient or persistent decrease of the platelet count and, depending upon the degree of thrombocytopenia, increased risk of bleeding. [0004] The clinical course of ITP may be different depending on whether it is primary ITP (not associated with any other conditions), or is associated with an underlying autoimmune condition, caused by infection or by chemotherapy treatment in cancer patients (secondary ITP) (Rodeghiero et al 2009). [0005] The goal of therapy in ITP is to achieve platelet counts that ensure adequate hemostasis and minimize the risk of clinically significant bleeding while avoiding, as much as possible, treatment-related toxicities and burden for patients. [0006] Corticosteroids are the recommended standard first-line treatment for patients with ITP. While initial response rates to corticosteroids are generally high (>75% of adult patients), around 20-25% of ITP patients do not respond (refractory ITP). [0007] The duration of corticosteroid treatment should be limited to 6-8 weeks to avoid the risk of adverse events and likely trivial benefit of continuing steroids beyond 6-8 weeks. PAT059387 While most patients initially respond to corticosteroids therapy, only 20-30% of will maintain adequate platelet counts (sustained remission) after the treatment is stopped. Consequently, the majority of ITP patients will need subsequent lines of therapy (Ghanima et al 2021). [0008] The addition of intravenous immunoglobulins (IVIg) or intravenous (i.v.) anti-Rho(D) to corticosteroids treatment is recommended in ITP patients who require a rapid increase in the platelet count (e.g. in patients with bleeding, high risk of bleeding, or prior to surgery). IVIg are also used as monotherapy when corticosteroids are contraindicated (Neunert et al 2019, Provan et al 2019). However, while the effect of IVIg/anti-D is rapid, it is typically not durable, lasting only a few weeks (Arnold 2005). [0009] In second-line treatment of primary ITP, TPO-RAs are a preferred treatment option for patients who relapse or have an inadequate response to initial corticosteroids therapy (second-line) or after immunoglobulins 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-RAs typically require a chronic treatment approach since cessation of treatment leads to return of thrombocytopenia in most cases. [0010] In addition, approximately one-third of patients discontinue a TPO-RA due to lack of response and need to be switched to another TPO-RA or an alternative therapy. Switching to an alternative therapy may also be needed in case of severe platelet count fluctuations or side effects (Ghanima et al 2019). [0011] There is still an unmet medical need to establish a longer time period for patients spent in remission (TFR), that is, a longer time period without a need of treatment and with improved ease and quality of life. BRIEF DESCRIPTION OF THE FIGURES [0012] Fig.1: Simulations for the ianalumab PK (top panel) and B cell count (middle panel) were obtained from the data-driven PK/PD model, and for the bottom panels from the hypothesis-driven tissue RO model. Shaded area is the 90% prediction interval (5^th to 95^th percentile), and thick line is the predicted median. Black dotted lines in the top panel represent trough concentration of 1.8 µg/mL for 300 mg q4w sc as identified in study CVAY736A2201 in patients with primary Sjögren’s Syndrome. Gray dashed lines represent LLOQ at 0.025 µg/mL, B cell depletion threshold at 10 cells/µL and 90% tissue receptor occupation (RO). PAT059387 [0013] Fig.2: Auto-antibodies reduction at week 12 and week 24 from baseline (expressed as geometric mean ratio to baseline) in patients participating primary Sjögren’s syndrome trial: SSAro52 (Fig.2A), SSAro60 (Fig.2B) and SSB autoantibodies (Fig.2C). [0014] Fig.3: Auto-antibodies reduction at week 12 and week 24 from baseline (expressed as geometric mean ratio to baseline) in patients participating Systemic Lupus erythematosus (SLE) trial: C1q (Fig.3A) and anti-dSDNA (Fig.3B). DETAILED DESCRIPTION OF THE INVENTION [0015] The present invention provides potentially disease–modifying therapies for ITP, especially in the early stages of ITP, that are well tolerated, require shorter course of treatment that is more convenient for patients, and induce a high rate of response, which is also maintained after end of the treatment period. Furthermore the present invention extends the period of treatment free remission (TFR) and the period of time to treatment failure (TTF). The present invention addresses the unmet medical needs in first-line (e.g. with concomitant corticosteroid, such as predniso(lo)ne or dexamethasone administration) and second-line (e.g. with concomitant administration of a TPO-RA, such as eltrombopag) settings based on a strong scientific rationale and chronicity early on in the course of the disease. The term “early stages of ITP), as used herein and hereunder, refers to the stage of ITP, where the subject is freshly diagnosed, or is still being treated by the first line (initial treatment after diagnosed with ITP) or the second line (the second treatment, which is immediately after the first line) ITP treatment. [0016] In one aspect, the present invention provides a method of treating immune thrombocytopenia (ITP), especially in a subject in need thereof, comprising administering, especially in a therapeutically effective amount, a molecule that inhibits the B-cell activating factor receptor (BAFF-R). In one embodiment, the molecule that inhibits the BAFF-R is an antibody against BAFF-R (anti-BAFF-R antibody) or a binding fragment thereof. In one further embodiment such anti-BAFF-R antibody is afucosylated. It has been shown that enhanced antibody-dependent cellular cytotoxicity (ADCC), as a result of using afucosylated antibodies, can improve clinical outcomes in autoimmune diseases such as lupus nephritis (LN) (Furie et al 2022). [0017] In one aspect, the present invention provides a molecule that inhibits the B-cell activating factor receptor (BAFF-R), especially the anti-BAFF-R antibody, or a binding PAT059387 fragment thereof, especially ianalumab, for use, as monotherapy or in combination with other ITP treatment, typically with the first line or the second line ITP treatment, for the treatment of ITP. [0018] 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, 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. [0019] In one embodiment, the anti-BAFF-R antibody or a binding fragment thereof comprises VH having the amino acid sequences of SEQ ID NO: 3 and VL having the amino acid sequences of SEQ ID NO: 4, respectively. [0020] In one embodiment, the anti-BAFF-R antibody comprises a heave chain having the amino acid sequences of SEQ ID NO:1 and a light chain having the amino acid sequences of SEQ ID NO:2, respectively. [0021] In one embodiment, the anti-BAFF-R antibody or a fragment thereof is ianalumab or a binding fragment thereof. [0022] The pathophysiology of ITP is characterized by both an increased peripheral destruction of platelets together with an inappropriate platelet production in the bone marrow. Although the factors triggering primary ITP remain unknown, autoreactive splenic B-cells differentiating into antiplatelet antibody-producing plasma cells have a key role (Audia et al 2021). These autoantibodies directed against different glycoproteins on the surface of platelets mediate cellular 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 major 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 further antiplatelet antibodies (Audia et al 2021). [0023] Recent publications described different resistance mechanisms to rituximab that may explain the low rate of patients maintaining long-term responses. These include splenic autoreactive residual memory B-cells, which actively contribute to disease relapses, and may survive rituximab-mediated B-cell depletion due to phenotype modifications, including decreased or lack of CD20 expression (Mahevas et al 2013, Crickx et al 2021). Plasma cells also downregulate CD20 expression and are therefore not targeted by rituximab. It was PAT059387 further observed that B-cell activating factor (BAFF) is reactively elevated in CD20-mediated B-cell depletion. BAFF signaling and CD4+T cell interaction are major factors for B-cell activation as well as transformation into and survival of long-lived splenic plasma cells. Long-lived plasma cells could subsequently maintain the production of platelet-targeting auto-antibodies for years, independently from the B-cell pool (Mahevas et al 2013; Markmann et al 2021). Moreover, there is evidence that BAFF-receptor (BAFF-R) and other pathways including can impair rituximab-induced antibody-dependent cellular cytotoxicity (ADCC) (Wild et al 2015). [0024] The immune response is also directed against megakaryocytes that express surface glycoproteins like those on platelets. The deficient production of platelets in ITP can consequently be attributed to the humoral and cytotoxic immune responses directed against megakaryocytes in the bone marrow (Audia et al 2021, Audia and Bonnotte 2021). [0025] 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) 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). [0026] BAFF overexpression results in disruption of B-cell immune tolerance and consequently in autoimmune disorders (Mackay et al 2002). In ITP, high serum BAFF levels were seen in untreated (Emmerich et al 2006) and in rituximab-resistant patients (Mahevas et al 2013), and were further shown to impair rituximab-induced antibody-dependent cellular cytotoxicity (ADCC) (Wild et al 2015). These mechanisms of resistance to rituximab are reasonably expected to be amenable to alternative treatment approaches including BAFF-R pathway inhibition and provide advantages over CD-20 targeting agents such as rituximab. The antigen specificity of ianalumab 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. Pro- and pre-B cells that express CD20 but not BAFF-R are therefore not expected to be affected by ianalumab. Hence, compared to the existing B cell depleting anti- PAT059387 CD20 antibody therapies, ianalumab targets a narrower spectrum of more differentiated B cells. [0027] Thus in one embodiment, the subject did not respond to rituximab treatment, e.g. the platelet counts cannot be brought to 30 x 10⁹/L or above, or has relapsed after rituximab treatment, e.g. the platelet counts drops below 30 x 10⁹/L. In one embodiment the subject does not receive rituximab treatment during time being treated with ianalumab. [0028] In one embodiment, the subject according to the present invention is never treated with rituximab or at least one year or at least six months before receiving Drug of the Invention. [0029] Recent evidence from a phase 2 clinical study (Mahevas et al 2020) further confirms the importance of targeting the BAFF-R signaling pathway to achieve long-term response in ITP. [0030] Ianalumab is a glycoengineered (afucosylated), fully human IgG1 monoclonal antibody directed against BAFF-R which is expressed on the surface of B-cells, thereby targeting B-cells and their function with two modes of action: a. Direct lysis and depletion of BAFF-R-expressing B-cells by enhanced ADCC thanks to its fucose-deficient Fc (fragment crystallizable) region; and b. BAFF receptor blockade that interrupts BAFF-mediated signaling for B-cell maturation, proliferation, and survival (Bowman et al 2022). [0031] In preclinical studies, ianalumab significantly enhanced ADCC against B-cells and cytokine production by NK cells, and was more potent in depleting B-cells when compared to approved anti-CD20 antibodies, including rituximab, obinutuzumab, and ofatumumab (McWilliams et al 2019). [0032] Due to its dual activity, ianalumab is capable of preventing pathogenic BAFF-driven rebound mechanisms by combining rapid and potent B-cell depletion and continuous BAFF- R blockade (Genovese et al 2010, Furie et al 2011, Mariette 2012). Ianalumab demonstrated efficacy in primary Sjögren’s syndrome (pSS) in a phase II study (Bowman SJ, et al (2021). [0033] Ianalumab has not been studied in ITP yet. However, the use of ianalumab in ITP is supported by the following: ^ B-cell depletion is a therapeutic measure in the treatment of ITP PAT059387 ^ BAFF-R pathway inhibition has been demonstrated to be effective and safe in non- hematologic autoimmune diseases (BENLYSTA® Prescribing Information) ^ BAFF-R blockade combined with B-cell depletion has been demonstrated to be effective and safe in ITP ^ Clinical studies with ianalumab have demonstrated its efficacy in other autoimmune diseases [0034] Thus through its dual mechanism of action, in combination with existing data and data disclosed in this application, ianalumab is expected to demonstrate efficacy and safety in treating ITP, especially address the above-described limitations of B-cell depleting therapy by potent B-cell depletion and BAFF-R blockade, thereby preventing the BAFF-driven pathogenic rebound and resistance mechanisms. [0035] • In one embodiment, the ITP is primary ITP. In one embodiment, the ITP is secondary ITP. Preferably the ITP is primary ITP. [0036] In one embodiment, the anti-BAFF-R antibody or a fragment thereof, especially ianalumab, is administered to a subject, especially in need thereof, at a dose from about 1 to about 27 mg/kg, from about 1 to about 21 mg/kg, from about 1 to about 18 mg/kg, from about 1 to about 15 mg/kg, from about 1 to about 9 mg/kg, from 3 to about 27 mg/kg, from about 3 to about 21 mg/kg, from about 3 to about 18 mg/kg, from about 3 to about 15 mg/kg, from about 3 to about 9 mg/kg. Preferably the dose is between about 3 to about 18 mg/kg. More preferably the dose is between about 3 to about 9 mg/kg. In one embodiment, ianalumab is administered to a subject, especially in need thereof, at a dose of about 3 mg/kg.

PAT059387 ianalumab is administered to a subject, especially in need thereof, at a dose of about 9 mg/kg. In one embodiment the antibody is administered intravenously. [0037] In one embodiment, the antibody, especially ianalumab, or a binding fragment thereof, is administered to a subject, especially in need thereof, once every 4 weeks (monthly, +/- 3 days). [0038] In one embodiment, the antibody is ianalumab, wherein ianalumab is administered to a subject, especially in need thereof, at a dose of 3 mg/kg, intravenously, once every four weeks (monthly, +/- 3 days). [0039] In one embodiment, the antibody is ianalumab, wherein ianalumab is administered to a subject, especially in need thereof, at a dose of 9 mg/kg, intravenously, once every four weeks (monthly, +/- 3 days). [0040] In one embodiment, the molecule that inhibits the B-cell activating factor receptor (BAFF-R), especially the anti-BAFF-R antibody or a binding fragment thereof, especially ianalumab, is administered to a subject, especially in need thereof, as a monotherapy. The subject does not receive any other treatment of ITP during the time period of being treated with the Drug of the Invention. Normally the ITP is primary ITP. The term “time being treated with the Drug of the Invention”, is understood as a period of time, during which the Drug of the Invention, is administered to the subject. Typically the period extends to one interval between the two administrations, during which time the subject normally still has detectable concentration of the Drug of the Invention in blood. By way of example, in the situation when ianalumab is to be administered in a total of 4 doses with 4 weeks interval, the time period of being treated with ianalumab includes from week 1, day1 to week 13, day 1when the fourth and last dose is administered, plus the additional 4 weeks. Thus the time period of being treated with ianalumab is a total of 16 weeks. [0041] The term “in combination with” is understood as the two or more drugs are administered subsequently or simultaneously, which is either in separate dose or in a fixed dose. Alternatively, the term “in combination with” is understood that two or more drugs are administered in the manner that the effective therapeutical concentration of the drugs are expected to be overlapping for a majority of the period of time within the patient’s body. The two or more drugs may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect. The terms “co-administration” or “combined PAT059387 administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The drug administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient and the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein. [0042] In one embodiment, ianalumab is administered to a subject as a monotherapy, wherein the subject is naive ITP patient (did not receive any other ITP treatment). [0043] In one embodiment, ianalumab is administered to a subject as a monotherapy, wherein the subject had an insufficient response or relapsed after the initial treatment, typically the initial treatment refers to the first line steroid treatment, as standard of care. [0044] In one embodiment, the molecule that inhibits the B-cell activating factor receptor (BAFF-R), especially the anti-BAFF-R antibody, or a binding fragment thereof, especially ianalumab, is administered to a subject, wherein subject receives the initial treatment, or at the same time when the initial treatment is started, after diagnosed with ITP, especially diagnosed with primary ITP. [0045] In one embodiment, the molecule that inhibits the B-cell activating factor receptor (BAFF-R), especially the anti-BAFF-R antibody, or a binding fragment thereof, especially ianalumab, is administered to a subject, in combination with the initial treatment, for the treatment of ITP. [0046] In one embodiment, the present invention provides a B-cell activating factor receptor (BAFF-R), especially the anti-BAFF-R antibody, or a binding fragment thereof, especially ianalumab, for use in the combination with the initial treatment for the treatment of ITP. [0047] In these cases, the anti-BAFF-R antibody, or a binding fragment thereof, especially ianalumab, is added on top of the initial treatment. Typically the subject is responsive to the initial treatment, e.g. the platelet counts is brought above to 30 x 10⁹/L with corticosteroid and then ianalumab is added on top. [0048] The initial treatment is normally the standard of care, normally first line, treatment for ITP, especially primary ITP. Initial treatment includes but not limited to corticosteroids, PAT059387 immunoglobulins (e.g. IVIG or anti-D- immunoglobulin), thrombopoietin receptor agonists (TPO-RAs) or rituxamab. [0049] In one embodiment, the initial treatment is corticosteroids, preferably glucocorticoid, preferably dexamethasone, preferably prednisone or prednisolone. [0050] The initial treatment is administered according to the approved doses. For example, First-line of corticosteroid therapy will be defined as: prednisone/prednisolone approximately 0.5-2 mg/kg/day for a minimum of 2 weeks, or minimum of 1 course of high-dose dexamethasone 20-40 mg/day for consecutive 4 days ±IVIG (used as rescue therapy). [0051] Maximum exposure to corticosteroids treatment must not be longer than 3 months overall, including period of dose tapering, or 3 courses of high-dose dexamethasone. Thus in one embodiment, corticosteroid is tapered out to discontinuation during or after treatment with the molecule that inhibits BAFF-R, especially the anti-BAFF-R antibody, or a binding fragment thereof, especially ianalumab. [0052] In one embodiment, the initial treatment is or includes treatment with a thrombopoietin receptor agonist. The term “thrombopoietin receptor agonist” used herein and hereunder, includes but not limited to romiplostim, oprelvekin, lusutrombopag, avatrombopag, betrombopag and eltrombopag; or a pharmaceutically acceptable salt thereof, respectively. [0053] In one alternative embodiment, the initial treatment does not include rituximab. The subject never receives rituximab or least one year or at least 6 months before being treated with the Drug of the Invention. [0054] Generally, the term “insufficient response” refers to platelets count not reaching 30 G/L despite of any ITP treatment. The term “relapse” refers to platelet counts drop below 30 G/L at any time after platelet counts having reached 30 G/L or above due to any ITP treatment. [0055] In one embodiment, the molecule that inhibits BAFF-R, especially the anti-BAFF-R antibody, or a binding fragment thereof, especially ianalumab, is administered to a subject who had an insufficient response or relapsed after the initial treatment, typically the first line steroid treatment. Subject treated with corticosteroids not reaching platelets count ≥30 G/L or requiring corticosteroids for longer than 8 weeks to keep the response, are considered having PAT059387 an insufficient response. Relapse after a first-line treatment with corticosteroids is defined when platelet counts drop <30 G/L at any time after having achieved an initial response. [0056] In one embodiment, the Drug of the Invention is administered to a subject who had an insufficient response or relapsed after the initial treatment, typically the first line steroid treatment, (and typically the initial treatment has been discontinued), in combination with a second treatment, which is normally the standard of care as the second line treatment. [0057] In one embodiment, the present invention provides a molecule that inhibits BAFF-R, especially the anti-BAFF-R antibody, or a binding fragment thereof, especially ianalumab, for use, as monotherapy or in combination with another ITP treatment, typically a second line ITP treatment, for the treatment of ITP, typically primary ITP, in a subject, wherein the subject had an insufficient response or relapsed after the initial treatment. [0058] In this case, the anti-BAFF-R antibody, or a binding fragment thereof, especially ianalumab, is added on top of the second treatment. The second treatment, typically, includes or is the treatment with a thrombopoietin receptor agonist. Typically or preferably, the thrombopoietin receptor agonist is eltrombopag, or a pharmaceutically acceptable salt thereof, typically eltrombopag olamine. In one embodiment, the subject will start the treatment with the Drug of the Invention and the second treatment at the same time. At the same time, as used herein, is understood as the start of the treatment with the Drug of the Invention and the start of the second treatment is not more than 3 days apart, likely not more than 2 days apart and typically on the same day. [0059] In one embodiment, the subject has started the second treatment, for at most about 1 month, at most about 2 weeks or at most about 1 week before the start the treatment with the Drug of the Invention. [0060] The second treatment is administered according to the approved dose. For example, romiplostim is suggested to be from 0.2 to 1 mcg/kg, likely from 0.5 to 1 mcg/kg, likely 1 mcg/kg, once per week. Avatrombopag, typically the initial dose is 10mg to 30mg, which can up-titrated or down-titrated according to platelet count in the course of the treatment. The dose of eltrombopag will be adjusted to have patients using the minimal efficacious dosage in order to achieve platelet counts ≥50 G/L. Eltrombopag is suggested to be 25mg or 12.5mg PAT059387 (for Asian) and 50mg (or non-Asian), once per day. Typically the initial dose can be up- titrated or down-titrated according to platelet count in the course of the treatment. [0061] It is envisaged that the second treatment is tapered out to discontinuation during or after treatment with the molecule that inhibits BAFF-R, especially the anti-BAFF-R antibody, or a binding fragment thereof, especially ianalumab. In one embodiment, etrombopag is taped to discontinuation after the completion of treatment of ianalumab. Typically after 4 doses of ianalumab or typically after 16 weeks from the start of ianalumab administration. Typically the subject has platelet counts at about 30 x 10⁹/L or above, preferably at 50 x 10⁹/L or above at time when tapering begins. [0062] The duration of tapering of eltrombopag will be individualized and depends on the dose and the response of the participant: normally the tapering period lasts not more than 8 weeks. [0063] In participants receiving a dose ≥50 mg, decreases in the daily dose will be performed by 25 mg every other week. After the dose of 25 mg is reached for 2 weeks, if platelets are ≥ 30 G/L, a daily dose of 12.5 mg (or 25 mg every other day) for 2 weeks should be given until treatment is totally discontinued. [0064] In participants receiving a dose ≤25 mg (including participants of East-/Southeast- Asian ancestry), decreases in the daily dose will be performed by 12.5 mg every other week until treatment is totally discontinued. [0065] In one embodiment, the present invention provides a molecule that inhibits BAFF-R, especially the anti-BAFF-R antibody, or a binding fragment thereof, especially ianalumab, for use, in the treatment of ITP, typically primary ITP, in a subject, wherein the subject has been previously treated with at least a corticosteroid and with at least a thrombopoietin receptor agonist (TPO-RA). Typically, at the time of initiation of the treatment with a molecule that inhibits BAFF-R, especially the anti-BAFF-R antibody, or a binding fragment thereof, especially ianalumab, the subject showed loss of response, insufficient response, no response or intolerance. Typically the platelet counts is less than 30 x 10⁹/L. The subject can also have received other ITP treatment, e.g. Intravenous Immunoglobulin [IVIG], and the corticosteroid and TPO-RA do not need to be the last treatment. [0066] In one further embodiment, the molecule that inhibits the B-cell activating factor receptor (BAFF-R), especially the anti-BAFF-R antibody, or a binding fragment thereof, especially ianalumab, is administered, as monotherapy or in combination with other ITP treatment, typically with the first line or the second line ITP treatment. In one embodiment, PAT059387 the subject after the initiation of the treatment with a molecule that inhibits BAFF-R, especially the anti-BAFF-R antibody, or a binding fragment thereof, especially ianalumab, achieves complete response, i.e. the platelet counts reaches 50 x 10⁹/L or more, preferably at two consecutive measurements, typically the two consecutive measurements are 7 days, 14 days, 21 days or 28 days apart. In one still further embodiment, ianalumab is administered at a dose of 9mg/kg. In one still further embodiment, ianalumab is administered monthly. In one still further embodiment, ianalumab is administered in a total of 4 doses. [0067] In one embodiment, the molecule that inhibits the BAFF-R, such as an anti-BAFF-R antibody or a binding fragment thereof, especially ianalumab, is administered (especially to a subject in need thereof) in not more than 8 doses, or not more than 5 doses, or not more than 4 doses. [0068] In one embodiment, the molecule that inhibits the BAFF-R, such as an anti-BAFF-R antibody or a binding fragment thereof, especially ianalumab, is administered (especially to a subject in need thereof) in at least 4 doses. [0069] In one embodiment, the molecule that inhibits the BAFF-R, such as an anti-BAFF-R antibody or a binding fragment thereof, especially ianalumab, is administered (especially to a subject in need thereof) in a total of about 4, about 6 or about 8 doses, typically or preferably in a total of about 4 doses. [0070] Due to its dual function, ianalumab is expected to have a quick and lasting treatment effect. Thus in one embodiment, ianalumab is administered to a subject having ITP, especially primary ITP, (especially to a subject in need thereof) in a total of about 4, about 6 or about 8 doses, typically or preferably in a total of about 4 doses. Normally ianalumab, is administered every four weeks, typically and preferably at the dose of 3-9mg/kg, preferably intravenously. [0071] In one embodiment, the subject achieves complete response. The term “complete response” as used herein and hereunder, refers to the platelet counts of the subject reaches above about 100 x 10⁹/L. The absolute value could vary, in about ±10%, in about ±5%, in view of a subject’s conditions, such as age, comorbidities, risk of bleeding, etc. The treating physician should be able to decide whether the subject has reached complete response. - [0072] In one embodiment, the subject maintains durable response for a longer period of time, than without Drug of the Invention, particularly without ianalumab added on top of the initial or the second treatment. The average time period when patients maintain durable PAT059387 response with the initial treatment, e.g. first line treatment with corticosteroid, or with the second treatment, e.g. the second line treatment with eltrombopag can be calculated based on real world large dataset. The term “durable response” as used herein and hereunder, is understood as that the patient remains responsive over time during the treatment, and patient’s platelet counts does not drop below 30 x 10⁹/L and/or patient does not need additional treatment to stop or reduce the risk of bleeding. According to IWG criteria, patient remains responsive when platelet counts are maintained ≥30 x 10⁹/L. [0073] The time from first administration of the Drug of the Invention till the time when platelet count drops below 30 G/L, the start of a new ITP treatment due to any reasons, the use of rescue treatment (e.g., corticosteroids, IVIG, or platelet transfusion), the ineligibility to taper or inability to discontinue the treatment as prescribed or the death (whatever the cause) defines the Time to Treatment Failure (TTF). Patient treated according to the present invention, especially patient treated with ianalumab, is expected to have the TTF for a period of about 30 months, about 24 months, about 20 months, about 18 months, about 16 months, about 12 months, or about 9 months. [0074] In one embodiment, the subject maintains treatment free remission for a longer period of time, than without Drug of the Invention, particularly without ianalumab added on top of the initial or the second treatment. The term “treatment free remission (TFR)”, as used herein, refers to a platelet count ≥30 x 10⁹/L in the absence of treatment (Provan et al, 2019). This period of time ends if patient relapses. [0075] Patient treated according to the present invention, especially patient treated with ianalumab, is expected to have the TFR for a period 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. [0076] The term “relapse”, as used herein, refers to, in most cases, a drop of platelet counts below about 30 x 10⁹/L or the need to receive additional treatments for ITP. [0077] – The present invention provides advantages in maintaining TFR such that (1) patients maintains remission and no longer need any ITP treatment at least for an extended time; (2) the period of TFR is longer than without the present invention added; (3) once platelet count drops below 30 x 10⁹/L, it can be quickly brought back to remission by any ITP treatment options, including but not limited to the treatment options of the present invention. PAT059387 [0078] - A sustained increase in the platelet count that is considered hemostatic for the individual patient: one of the goals for the present invention is to reach platelet counts of at least 30 x 10⁹/L, 50 x 10⁹/L 100 x 10⁹/L or higher, respectively, especially of more than 30 x 10⁹/L. [0079] In one embodiment, the invention relates to ianalumab for use in the treatment of ITP, especially primary ITP, or relates to a method of treating ITP, especially primary ITP, comprising administering ianalumab, typically in a therapeutically effective amount, in a subject, especially in need thereof, wherein the subject has relapsed after TFR . In one embodiment, the subject has received ianalumab treatment prior to TFR (re-treatment). In one further embodiment, the subject receives the same dosing regimen as he received prior to TFR, e.g. 3mg/Kg or 9mg/Kg every 4 weeks. In one embodiment, the subject receives less doses than the doses he had received prior to TFR. In one embodiment, the subject receives more doses than the doses he had received prior to TFR. Typically and preferably the subject receives less doses. For example, the subject receives in total of 4 doses of ianalumab prior to TFR and during the re-treatment schedule, the subject receives less than 4 doses, e.g.3 doses, 2 doses or 1 dose, which is sufficient to boost the platelet counts above 30 x 10⁹/L. [0080] In one aspect, the present invention provides the method of treating ITP, particularly primary ITP, in a subject, especially in the need thereof, comprising administering, typically or preferably a therapeutically effective amount of, molecule that inhibits BAFF-R, especially the anti-BAFF-R antibody, or a binding fragment thereof, especially ianalumab, in the subject, in combination with a BTK inhibitor. [0081] In one aspect, the present invention provides a molecule that inhibits BAFF-R, especially the anti-BAFF-R antibody, or a binding fragment thereof, especially ianalumab, for use in the treatment of ITP, particularly primary ITP, in combination with with a BTK inhibitor. [0082] In one embodiment, the BTK inhibitor binds reversibly BTK. In another embodiment, BTK inhibitor binds covalently BTK. [0083] In one embodiment, the BTK inhibitor is rilzabrutinib and/or a pharmaceutical acceptable salt thereof. Rilzabrutinib is an exception to the general rule. It covalently binds to its receptor but the binding is reversible. In one embodiment rilzabrutinib is in the form of H2SO4 salt, HCl salt or mesylate salt. An ongoing phase III trial tests rilzabrutinib 400mg orally twice daily for up to 24 weeks in ITP patients. PAT059387 [0084] The following definitions, in addition to others already provided, serve to define particular, preferred meanings of features and language used in the present invention description and claims, where any one or more or all of more general terms can be replaced with the particular meaning(s), leading to special invention embodiments. [0085] The term "binding fragment" as used herein refers to a portion of an anti-BAFF-R antibody capable of binding a BAFF-R epitope, especially an epitope involved in the binding of BAFF to BAFF-R and/or negatively, e.g. by allosterically binding, affecting the activation of BAFF-R by BAFF. The binding of the antibody (or a binding fragment thereof) to BAFF- R reduces the formation of BAFF/BAFF-R complexes, and/or reduces the activation of BAFF-R. [0086] Ianalumab Heavy chain: SEQ ID NO: 1 QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWGWIRQSPGRGLEWLGRIYYRS KWYNSYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARYDWVPKIGVFDS WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK [0087] Ianalumab Light chain: SEQ ID NO: 2 DIVLTQSPATLSLSPGERATLSCRASQFISSSYLSWYQQKPGQAPRLLIYGSSSRATGV PARFSGSGSGTDFTLTISSLEPEDFAVYYCQQLYSSPMTFGQGTKVEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC [0088] Ianalumab Variable Domain of Heavy Chain (VH): SEQ ID NO: 3 QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWGWIRQSPGRGLEWLGRIYYRS [0089] Ianalumab Variable Domain of Light Chain (VL): SEQ ID NO: 4 PAT059387 DIVLTQSPATLSLSPGERATLSCRASQFISSSYLSWYQQKPGQAPRLLIYGSSSRATGV PARFSGSGSGTDFTLTISSLEPEDFAVYYCQQLYSSPMTFGQGTKVEIKRT [0090] Ianalumab comprises the following Complementarity Determining Regions (CDRs): Heavy Chain: HCDR1: GDSVSSNSAAWG SEQ ID NO: 5 [0091] The term "a therapeutically effective amount", refers to an amount of the molecule that inhibits BAFF-R, especially the anti-BAFF-R antibody, or a binding fragment thereof, especially ianalumab, and/or the combination partner according to the present invention that will elicit the biological or medical response of a subject, in particular ameliorating, inhibiting, removing or otherwise beneficially influencing one or more symptoms of ITP, slowing or delaying disease progression, or preventing ITP. [0092] As used herein, the term “subject” and its interchangeably used term “patient”, refers to a human, especially an ITP patient with 18 or more years; however, younger children may also be treated according to the invention. [0093] As used herein, the term “inhibit”, "inhibition" or “inhibiting” refers to the reduction or suppression of a given pathway or condition or symptom found in a subject suffering from ITP. [0094] As used herein, the term “treat”, “treating" or "treatment" of ITP refers in one embodiment, to ameliorating this disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat”, "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter of ITP including those which may not be discernible by the patient. In yet PAT059387 another embodiment, “treat”, "treating" or "treatment" refers to modulating ITP, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. Particularly, there are three main reasons for treating ITP: 1) preventing bleeding; 2) remission induction (which may be defined as normalization of platelet count, “complete remission”, or a sustained elevation of platelet count to a hemostatic level (“treatment free partial remission”); and 3) improving of life and alleviating ITP related symptoms (including fatigue). [0095] As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment. [0096] As used herein, the term "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 plural unless otherwise indicated herein or clearly contradicted by the context. [0097] As used herein, the term "about”, unless otherwise defined, includes a variation of ±10%, or ±5% from the value given. [0098] 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 intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. However, it may relate to preferable features. [0099] Invention embodiments and their hierarchical relationship to each other are also defined in the claims which are to be regarded as included here. EXAMPLES [0100] The Examples below are set forth to aid in the understanding of the invention and, though also being specific invention embodiments, are not intended to, and should not be construed to, limit its scope in any way. Example 1: A phase III, randomized, double-blind study of ianalumab (VAY736) versus placebo in addition to first-line corticosteroids in primary immune thrombocytopenia (VAYHIT1) PAT059387 Objective, Endpoints and Estimands are mentioned in the following table: Objectives Endpoints PAT059387 Objectives Endpoints [0101] Trial Design: This is a multicenter, randomized, double-blinded Phase 3 study to assess the efficacy and safety of two different doses of ianalumab (3 and 9 mg/kg) compared to placebo in adult participants with primary ITP. [0102] During the screening period (up to 28 days) participants will receive corticosteroids (predniso(lo)ne or dexamethasone) as per standard of care. Corticosteroids may be initiated up to 14 days prior to screening, however, the maximum allowed duration of corticosteroids prior to randomization is 28 days. IVIG will be allowed if clinically indicated. After completion of the screening period, participants who responded to first-line corticosteroids (platelets count ≥50 G/L any time prior to randomization) will enter the 16-week randomized treatment period in one of the following three arms: Arm A (ianalumab 3 mg/kg IV every 4 PAT059387 weeks), Arm B (ianalumab 9 mg/kg IV every 4 weeks), or Arm C (placebo IV every 4 weeks). Standard-of-care corticosteroids regimen initiated prior to randomization will continue to be given during treatment period as per guidelines for a total time of 6 weeks (maximum of 8 weeks) including tapering in case of predniso(lo)ne , or for up to a total of three 4-day cycles given every 2 weeks in case of dexamethasone. [0103] After the treatment period, all participants will enter a follow-up period to be monitored for efficacy and safety or safety only, depending on how the participant responded to the study treatment. Efficacy and safety follow-up period will last until treatment failure or up to 39 months after randomization of the last participant, whichever occurs first. Safety follow-up period will be performed for at least 20 weeks (Short-term safety follow-up) and up to 2 years after the last ianalumab/placebo dose (Long-term safety follow-up). [0104] Study population: Adult (≥18 years of age) patients with primary ITP diagnosed within 3 months before corticosteroids initiation who require first-line corticosteroid treatment and responded to corticosteroids (+/-IVIG) prior to randomization. [0105] Brief Summary: Study treatment will be administered in a double-blinded manner for 16 weeks (in total 4 doses of ianalumab 3 mg/kg or 9 mg/kg or placebo together with corticosteroids). ^ During the treatment period, visit frequency will be once a week (qw) up to W9D1 visit, and every other week (q2w) thereafter. Participants who complete the study treatment or discontinue the treatment prematurely will complete EOT disposition and will enter the follow-up period. ^ Participants who did not meet treatment failure criteria by the end of treatment period will enter in safety and efficacy follow-up, whereas participants who met treatment failure criteria during treatment period will enter in safety follow-up. ^ For efficacy and safety follow-up, visits occur every 4 weeks until treatment failure or up to 2 years; after that, visits will occur every 12 weeks until treatment failure or up to 39 months after randomization of the last participant, whichever occurs first. For safety follow-up, visits will occur every 4 weeks for 20 weeks and then every 12 weeks up to 2 years after the last dose. ^ The estimated study duration is 39 months post-randomization of the last participant. Number of Participants: [0106] 225 participants will be randomly assigned to one of the 2 active arms or placebo in a 1:1:1 ratio. PAT059387 [0107] Key Inclusion criteria 1a. Signed informed consent prior to participation in the study. 2a. Male or female participants aged 18 years and older on the day of signing informed consent 3a. Primary ITP diagnosed within 3 months before initiating first-line ITP therapy (corticosteroids, IVIG) 4. Platelet count below 30 G/L before starting any first-line ITP therapy (corticosteroids, IVIG) 5. Response (platelet count >=50 G/L) to corticosteroids (+/- IVIG) at any time prior to randomization. Note: Platelet count measured within 7 days of platelet transfusion will not be considered as response. Key Exclusion criteria ^ Evans syndrome or any other cytopenia ^ Current life-threatening bleeding 3a. Previous ITP treatment, including splenectomy, except for corticosteroids and/or IVIG for up to 28 days before randomization. ^ Prior use of B-cell depleting therapy (e.g., rituximab). 6a. Absolute neutrophil count below 1.0 G/L at randomization 7a. Participants with concurrent coagulation disorders and/or receiving anti-platelet or anticoagulant medication with an exemption of low dose of acetylsalicylic acid. Example 2: Phase III randomized, double blind study of ianalumab versus placebo in addition to eltrombopag with primary immune thrombocytopenia (ITP) who had an insufficient response or relapsed after first line steroid treatment (second line treatment) (VAYHIT2) Objectives Endpoints PAT059387 eltrombopag alone in participants with randomization, start of a new ITP PAT059387 Number of severe infections and PAT059387 [0108] This is a multicenter, randomized, double-blinded phase 3 study to assess the efficacy and safety of two different doses of ianalumab (3 and 9 milligram (mg)/ kilogram (kg)) compared to placebo in adult participants with primary ITP (platelets count < 30 G/L) treated with eltrombopag. [0109] Key Inclusion criteria 1. Male or female patients aged 18 years and older 2. A diagnosis of primary ITP, with insufficient response to, or relapse after a first-line steroid therapy ± IVIG. 3. Platelet count <30 G/L. [0110] Key Exclusion criteria 1. ITP patients who received second-line ITP treatments (other than corticosteroid therapy ± IVIG) including splenectomy. However, patients exposed to thrombopoietin receptor agonists (TPO-RAs) for a limited time (max. one week) before screening are eligible. 2. Patients with key lab abnormalities and patients with Evans syndrome or any other cytopenia 3. Patients with history of clinically significant hematological disorders, or with marked altered hematologic parameters 4. Patients with current or history of life-threatening bleeding 5. Patient that are Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), Hepatitis B surface Antigen (HBsAg)/ Hepatitis B core antibody (HBcAB)-positive 6. Patients with known active or uncontrolled infection requiring systemic treatment during screening period 7. Patients with hepatic impairment 8. Patients with concurrent coagulation disorders and/or receiving anti-platelet or anticoagulant medication Treatment Groups: [0111] At the end of up to 2 weeks screening period, eligible participants (N=150) will be randomized in a 1:1:1 ratio to one of the three following treatment arms: [0112] Eltrombopag once daily orally + 4 cycles of ianalumab 3 mg/kg intravenously given every 4 weeks (4 doses in total) PAT059387 [0113] Eltrombopag once daily orally + 4 cycles of ianalumab 9 mg/kg intravenously given every 4 weeks (4 doses in total) [0114] Eltrombopag once daily orally + 4 cycles of placebo intravenously given every 4 weeks (4 doses in total) [0115] After this 16-week randomized combination treatment period, participants in all the groups will start tapering eltrombopag depending on the platelet counts: [0116] Participants who will have at least two consecutive assessments with a platelet count ≥50 G/L at the end of the combination treatment period (W15D1 and W17D1), will start tapering eltrombopag for a maximum of 8 weeks until discontinuation if platelet counts remain ≥30 G/L; [0117] Participants who will not have at least two consecutive assessments with a platelet count ≥50 G/L at the end of the combination treatment period (W15D1 and W17D1), will not be considered eligible to start eltrombopag tapering and will continue the same visit schedule until W25D1 and then enter in the safety follow-up. These participants can continue receiving eltrombopag, but the treatment will not be considered as part of the study treatment after W25D1. [0118] Time to treatment failure (TTF) is defined as the time from randomization until any one of the below events: (1) platelet count below 30 G/L later than 8 weeks from randomization, (2) start of a new ITP treatment due to any reasons, (3) rescue treatment (e.g., corticosteroids, IVIG, or platelet transfusion) later than 8 weeks from randomization, (4) ineligibility to taper or inability to discontinue eltrombopag (5) death (whatever the cause) [0119] In this study eltrombopag will be administered according to the locally approved ITP starting dose, e.g., 50 mg QD (25 mg or 12.5 mg in East/Southeast-Asian patients in countries where lower starting dose is approved) in all treatment arms. The dose of eltrombopag will be adjusted to have patients using the minimal efficacious dosage in order to achieve platelet counts ≥50 G/L. [0120] The duration of tapering (maximum 8 weeks) will be individualized and depends on the dose at W17D1 and the response of the participant: [0121] In participants receiving a dose ≥50 mg, decreases in the daily dose will be performed by 25 mg every other week. After the dose of 25 mg is reached for 2 weeks, if platelets are ≥ PAT059387 30 G/L, a daily dose of 12.5 mg (or 25 mg every other day) for 2 weeks should be given until treatment is totally discontinued. [0122] In participants receiving a dose ≤25 mg (including participants of East-/Southeast- Asian ancestry), decreases in the daily dose will be performed by 12.5 mg every other week until treatment is totally discontinued. [0123] Participants who fail to discontinue eltrombopag by Week 24 (tapering period stopped due to platelet counts below <30 G/L and/or need for rescue treatment) will resume the last eltrombopag dose able to keep platelet counts ≥30 G/L. These participants can continue receiving eltrombopag treatment or start a new ITP treatment on Investigator`s discretion. [0124] Permitted concomitant therapy [0125] To avoid fast deterioration of platelet level and to prevent participants from experiencing bleeding events before study treatment is efficacious, corticosteroids (+/- IVIG) bridging therapy is allowed in the following conditions: ^ High dose of dexamethasone or predniso(lo)ne (>15 mg/day) is allowed until randomization (e.g., if clinically needed during screening). ^ Predniso(lo)ne ≤15 mg/day is allowed after randomization with tapering period and discontinuation expected no later than W2D7 ^ Dexamethasone is not allowed after randomization ^ IVIG 1-2 g/kg as per locally approved schedule are allowed until W2D7. [0126] Possible rescue therapies until the end of Week 8 are platelet transfusion, corticosteroids and IVIG. Example 3 Pharmacokinetics-Pharmacodynamic modelling [0127] A population PK/PD model was built using a sequential PK/PD (Zhang, J Pharmacokinet Pharmacodyn;30(6):387-404.2003) approach to describe ianalumab concentrations and CD19+ B-cell count of from various auto-immune diseases. Population PK/PD model [0128] A two-compartment population PK model with linear clearance was fitted to i.v. and s.c. data derived from studies in RA patients and in pSS patients. The PK/PD model, was parameterized in terms of B-cell counts at baseline (Base), death rate of B cells (kout), PAT059387 volume of peripheral compartment for B cells (Vb), intercompartment transition rate of B cells (Qb), maximum stimulating effect of ianalumab on the death rate of B cells (Emax) and the ianalumab concentration for which VAY736 effect is half-maximal (EC50). PK-tissue receptor occupancy (RO) structural model [0129] As circulating B-cell dynamics as described by the population PK/PD model are not necessarily expected to be predictive of clinical efficacy, a hypothesis-driven tissue receptor occupancy (RO) model was also developed and used to consider the competitive binding between ianalumab and soluble BAFF (sBAFF) on BAFF-R under a quasi-steady state assumption. The following equation links the PK (Cianalumab(t), nM) to the BAFF-R engagement by ianalumab (ROVAY(t), %): ^^{^୧ୟ୬ୟ୪^ ^ ^^^/ ^^ ^^ ^^ ^^} _{୧ୟ୬ୟ୪^୫ୟୠ} ^{^ ^^^ ൌ ୫ୟୠ ୧ୟ୬ୟ୪^୫ୟୠ} 1 _{^ ^^୧ୟ୬ୟ୪^୫ୟୠ^ ^^^/ ^^ ^^୧ୟ୬ୟ୪^୫ୟୠ ^ ^^^^^ிி/ ^^ ^^^^^ிி} ^{ൈ 100} where CsBAFF is the soluble BAFF concentration in tissues (nM), Kdianalumab and KdsBAFF are respectively the dissociation constants of ianalumab to BAFF-R and of sBAFF to BAFF-R. The above equation assumes a reasonable excess of ligands compared to receptors. It is further assumed that sBAFF concentrations are approximately constant, whereas ianalumab concentrations vary with time. [0130] To determine the BAFF-R occupancy in a fictive disease-related tissue, the following assumptions, supported by in-house experiments, were made: Tissue: Serum concentration ratio ianalumab: 1:5 ^ Tissue: Serum concentration ratio sBAFF: 4:1 Table 1 lists all parameters used for tissue receptor occupancy predictions. Table 1 Tissue receptor occupancy model parameters Parameter Definition Value Source Kd_ianalumab Dissociation constant 0.046 nM In vitro experiments for ianalumab PAT059387 Parameter Definition Value Source Kd_sBAFF Dissociation constant 0.73 nM In vitro experiments for sBAFF m_ianalumab Molecular weight of 150 kDa Measured ianalumab msBAFF Molecular weight of 17 kDa Measured sBAFF CsBAFF in serum Soluble BAFF 2.7 ng/mL Median at week of concentration CVAY736X2201 data Rianalumab Tissue:serum 1/5 AIN457 (skin) concentration ratio of (Shah and Betts ianalumab 2013) R_sBAFF Tissue:serum 4/1 ”Arbitrary” concentration ratio of assumption sBAFF Dose selection simulations for the proposed phase 3 study in wAIHA [0131] It was assumed that the PK of ianalumab would be comparable in the target wAIHA patient populations as observed in other autoimmune diseases. In addition, based on available literature, baseline B cell in ITP patients is comparable to those previously measured in ianalumab studies in pSS (Toffoletti et al 2008). Given the similarity in pathophysiology between ITP and wAIHA, similar levels of B cells in wAIHA have been used as baseline. Therefore, the final population PK/PD model was used to support the dose and regimen selection in the proposed phase 3 study in wAIHA patients. [0132] In addition, the same hypothesis-driven tissue RO model was also assumed to be appropriate in both autoimmune diseases and wAIHA, therefore the PK-RO model as described in Table 1 was used. Only the level of soluble BAFF concentration in serum was fixed at a lower level of 1.817 ng/mL for wAIHA patients instead of 2.7 ng/mL as in the autoimmune diseases. Of note, serum BAFF concentrations reported in patients with AIHA is 1358.7 ± 141.0 pg/mL (Xu et al 2015), the fixed level at 1.817 ng/mL is chosen for a conservative tissue RO prediction at approximately 3 standard deviation away from the mean. [0133] PKPD simulations were conducted to support selection of the 4-week dose interval using the following criteria: ^ B cell depletion within the dosing window (<10 cells/µL); PAT059387 ^ Tissue RO based on a hypothetical model as described in Table 1 (90% threshold); ^ Ianalumab PK assessed by Ctrough >1.8 µg/mL, which is the steady-state trough concentration for 300 mg q4w s.c., a dose that resulted in the highest clinical response in the multiple-dose, dose-range finding study CVAY736A2201, in pSS patients (week 52 CSR A2201). [0134] The PKPD simulations Fig 1 suggest that ianalumab doses and dose regimen at 3 mg/kg and 9 mg/kg, administered every 4 weeks (q4w) i.v., for the treatment period of 16 weeks (4 doses in total) can be considered for the phase 3 study in wAIHA patients. The lower dose at 3 mg/kg iv q4w leads to half of the simulated patients with a trough higher than 1.8 ug/mL, and >95% patients had predicted tissue RO >90% (Table 2). The higher dose at 9 mg/kg i.v. q4w can increase the patients’ coverage for PK and tissue RO. Table 2 Characteristics of PK, B-cell and tissue RO for the proposed dosing regimens 3 mg/kg q4w i.v. 9 mg/kg q4w i.v. _{PK dynamics} % pts with Ctrough >1.8 µg/mL at the last _{ianalumab dose} ^{50% 92%} Median (90% PI) of Ctrough (µg/mL) at the _{last ianalumab dose} ^{1.8 [0.5-5.9] 5.5 [1.5-15.7]} Median (90% PI) of Cmax (µg/mL) after the _{last ianalumab dose} ^{62 [36.7-100] 182.9 [110.3-301.2]} Median (90% PI) of AUC0-28d 880.5 [470.2- _{(day*µg/mL) after the last ianalumab dose} 1543.3] Time since last dose for >95% pts with _{ianalumab concentration <LLOQ} ^{22 week} B cell dynamics Median (90% PI) of total B cell count at the _{last ianalumab dose} ^{2.1 [0.4-14.8] 2 [0.4-14.9]} % pts with total B cell count <10 cells/µL at _{the last ianalumab dose} ^{91% 90%} Time since last dose for B cell recovery* % pts with B cell recovery* 61% 60% Median (90% PI) of total B cell count at end _{of follow-up**} ^{68.5 [11.8-384.8] 62.9 [11-412.7]} % pts with total B cell count >50 cells/µL at _{end of follow-up**} ^60% % pts with total B cell count >80 cells/µL at _{end of follow-up**} ^{44% 43%} Tissue RO dynamics Median (90% PI) of predicted RO*** at the _{last ianalumab dose} ^{97.1 [90.9-99.1] 99 [96.4-99.7]} PAT059387 3 mg/kg q4w i.v. 9 mg/kg q4w i.v. % pts with predicted RO*** >90% at the last _{ianalumab dose} ^{96% 100%} LLOQ = 0.025 µg/mL *B-cell recovery is defined as ≥80% of baseline or ≥50 cells/µL. **End of follow-up is defined as 1 year after stopping of ianalumab treatment. ***Predicted tissue RO is calculated based on the trough concentration before the last ianalumab dose. [0135] Mean simulated exposures after the ianalumab 9 mg/kg i.v. dose after last dose (Cmax 192 µg/mL and AUC0-28d 931 day*µg/mL) are within those previously observed at the highest tested i.v. doses, in study in pSS patients after a single i.v. dose of 10 mg/kg (Mean Cmax 213 µg/mL and AUCinf 1140 day*µg/mL, n=12) and study in CLL patients i.v. doses of 9 mg/kg q2w (cycle 3 mean Cmax 262 µg/mL and AUC0-28d,ss 3730 day*µg/mL, 2 doses over 4 weeks, q2w, n=4). [0136] The comparative exposure between the pre-clinical species and mean simulated exposures after ianalumab monthly i.v. doses of 9 mg/kg demonstrates a 14- to 15-fold and 4.3- to 5.6-fold safety margin is observed for Cmax and AUC, respectively, for the monthly 9 mg/kg i.v. dose, indicating the highest ianalumab dose of 9 mg/kg i.v. q4w 9 is safe. Example 4 Reduction of auto-antibodies in patients participating primary Sjögren's syndrome (pSS) trial. [0137] In primary Sjögren's syndrome (pSS) trial, 190 patients with pSS were treated with subcutaneous ianalumab (5, 50, 150 or 300 mg q4w for 24 weeks) or placebo (Bowman SJ, Fox R, Dörner 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. Lancet; 399(10320):161-171). The study showed a significant dose-response effect of ianalumab on the ESSDAI, and an increase in stimulated salivary flow, with the greatest effect observed at the highest dose. [0138] For quantitative data interpretation for VAY736 effect on autoantibodies in this trial, SSA Ro52kd/TRIM21, SSRo60kd and SSB autoantibodies have been analyzed at same dilution for baseline and post-treatment samples using kit FIDIS™ Connective Profile. [0139] Data below represents data obtained in VAY736 treated arms for SSAro52 (Fig.2A), SSAro60 (Fig.2B) and SSB autoantibodies (Fig.2C) at baseline, week 12 and week 24 using optimal dilution. Data are expressed in % change from baseline. Results clearly shows that decrease of the three autoantibodies upon VAY736 was dose dependent between 5mg, 50 and PAT059387 300 mg doses and this decrease of autoantibodies in placebo reached a maximum at week 24 of 4% decrease versus 12 to 16% for 50 and 300mg VAY736 treated arms. Example 5: Reductions of auto-antibodies in patients participating systemic lupus erythematosus (SLE) trial [0140] This is a double-blind, randomized, placebo-controlled, multi-center two-arm study, evaluating a dose of 300 mg ianalumab administered s.c. once monthly against placebo, in patients with SLE receiving standard-of-care treatment. The dose regimen for this study is 300 mg s.c. ianalumab once monthly for the treatment period of 18 months. Key Inclusion Criteria Fulfill ≥4 of the 11 American College of Rheumatology 1997 classification criteria for SLE at screening Patient diagnosed with SLE for at least 6 months prior to screening Elevated serum titers at screening of ANA (≥1:80) in a pattern consistent with an SLE diagnosis, including at a minimum 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) Currently receiving corticosteroids and/or anti-malarial and/or thalidomide treatment and/or another DMARD according to the following: Where corticosteroids are the single standard-of-care medication: an oral dose of ≤30 mg/d for a minimum of 8 weeks prior to randomization and at a stable dose for ≥2 weeks prior to randomization Where oral corticosteroids are not as a single standard-of-care medication: a stable oral dose of ≤30 mg/d of prednisone or equivalent for a minimum of 8 weeks prior to randomization and at a stable dose for ≥2 weeks prior to randomization An anti-malarial and/or thalidomide treatment and/or one of the following DMARDs: methotrexate or an imidazole derivative (e.g., azathioprine, mizoribine) or mycophenolic acid derivatives (e.g., mycophenolate mofetil) for a minimum of 12 weeks prior to screening and at a stable dose for ≥8 weeks prior to randomization. Combination of other DMARDs is not permitted SLEDAI-2K score of ≥6 at screening BILAG-2004 score at screening of: - At least one “A” in either the mucocutaneous domain or in the musculoskeletal domain, PAT059387 OR - one “B” in either the mucocutaneous or musculoskeletal domain AND at least one “A” or “B” in a second domain Weigh at least 40 kg at screening Key Exclusion criteria History of receiving prior to screening: - Within 12 weeks: i.v. high dose corticosteroids, calcineurin inhibitors or other oral DMARD except as listed in inclusion criterion 6 - Within 24 weeks: cyclophosphamide, or biologics such as intravenous Ig, plasmapheresis, anti-TNF-α mAb, CTLA4-Fc Ig (abatacept) or BAFF targeting agents (e.g., belimumab) - Any B-cell depleting therapies (e.g., anti-CD20 mAb, anti-CD22 mAb, anti-CD52 mAb) or TACI-Ig (atacicept) administered within 52 weeks prior to screening and B-cell count <50 cells/μL at the time of screening [0141] Presence of severe lupus kidney disease as defined by proteinuria above 6 g / day or equivalent using spot urine protein to creatinine ratio, or serum creatinine greater than 2.5 mg/dL(221.05 µmol/L), or requiring immune suppressive induction or maintenance treatment exceeding protocol- defined limits. Efficacy assessments: ^ SRI-4 (SLE responder index) ^ Physician Global Assessment Visual Analogue Scale (PhGA-VAS) ^ Patient Global Assessment (VAS) ^ Flare Rate by BILAG-2004 score ^ Lupus Low Disease Activity State (LLDAS) Results: [0142] The proportion of study patients who achieved the composite primary endpoint at Week 28 of SRI-4 under sustained prednisolone reduction ≤5 mg/d was 42% greater for ianalumab than for placebo. Ianalumab also was better than placebo for the incidence of moderate or severe flares (45% vs 73%, respectively) and time-to-first flare (median not reached vs 11.9 weeks, respectively). At Week 28 the differences between ianalumab and PAT059387 placebo were 50% for proportion of patients achieving SRI-4 response, 34% for reduced corticosteroid use, 43% for the primary combined endpoint of these two outcomes, 20% for Lupus Low Disease Activity State (LLDAS) and 31% for BILAG-based Combined Lupus Assessment (BICLA). Ianalumab was well tolerated without any new safety signals detected during the blinded 28-week treatment period as well as during the open-label treatment period (Week 28 to Week 52) and subsequent safety follow up period. [0143] VAY736 effect on C1q autoantibodies was determined using EnzymeImmunoassay (EIA) provided by BÜHLMANN LABORATORIES, product reference number EK- AC1QA-U. [0144] Data below represents data obtained at baseline, week 12 and week 24. Data are expressed as geometric mean ratio to baseline. Results clearly shows that decrease of antiC1q autoantibodies upon VAY736 reaching almost 40 % versus 18% in the placebo at week 29 ratio to baseline (Fig.3A). [0145] VAY736 effect on anti-dSDNA autoantibodies was determined with INOVA QUANTA Lite SC ELISA. [0146] Data obtained at baseline, week 12 and week 24 are expressed as geometric mean ratio to baseline (Fig.3B). Results clearly shows that decrease of anti-dSDNA autoantibodies upon VAY736 reaching almost 40 % versus 10% in the placebo at week 29 ratio to baseline. [0147] Conclusion : All these data shows that VAY736 decrease autoantibodies in pSS or SLE patients. This effect is VAY736 dose and time dependent. Elevated autoantibodies play important role in the development and progression of ITP, which are to be reduced by the treatment with VAY736. Example 6 Preclinical study of the effects of ianalumab [0148] The most frequently used murine model of immune thrombocytopenia is a short term passive model that measures the platelet levels following the injection of anti-platelet antibodies, which are inducing platelet elimination through phagocytic cells (Crow A.R et al, Br J Haematology, 2001, 115(3), 679-86). However, this model is not suitable to study chronic ITP and in particular the role of immune cells in the establishment of the disease. A more recently developed active model of ITP (Chow L. et al. Blood (2010) 115 (6): 1247– 1253) presents similarity to the clinical features of human severe ITP and represents more accurately the immune defects of chronic ITP. It has indeed been described to be dependent on the presence of both B cells and T cells to induce a sustained reduction in platelet levels . PAT059387 In this model, CD61-deficient mice are injected with wild-type platelets in order to generated an immune response against anti Splenocytes from the mice are then transferred into severe combined immunodeficiency (SCID) mice, which induces a strong reduction of platelet levels within a week. Both CD19- and CD8- positive populations are required to induce a sustained decreased level of circulating platelets. [0149] Since ianalumab is depleting mouse B cells, we are therefore expecting to see effect on chronic ITP in this mouse model. Splenocytes from mice immune against platelet CD61 are transferred into SCID mice. The mice are treated with 2 to 4 injections of 1) PBS, 2) ianalumab at 10mg/kg or 3) ianalumab at 100mg/kg. The mice are bled every week for 4 weeks to evaluate their platelet counts. It is expected to see an increase in platelet counts over time, confirming the efficacy of ianalumab in chronic ITP. Example 7 A phase 2 study to evaluate the efficacy and safety of ianalumab (VAY736) in patients with primary immune thrombocytopenia (ITP) previously treated with at least a corticosteroid and a thrombopoietin receptor agonist (TPO-RA) [0150] Objective, Endpoints and Estimands are mentioned in the following table: Objectives Endpoints PAT059387 Objectives Endpoints [0151] This is a phase 2, open-label, single-arm study. [0152] The study will consist of three periods: Screening period (up to 14 days prior to first ianalumab dose). ^ Primary endpoint assessment period (until Week 25 Day 1 visit). The participants will receive ianalumab 9 mg/kg dose, administered intravenously (i.v.), every 4 weeks, for a total of 4 doses, over a period of 16 weeks. All participants will be assessed for efficacy and safety from Week 1 Day 1 visit until the final day of the primary endpoint assessment period (Week 25 Day 1 visit). Visit frequency will be weekly up to Week 9 Day 1 visit, and every 2 weeks thereafter until Week 25 Day 1 visit. ^ Efficacy and safety follow-up (FU) period beyond Week 25 Day 1 visit: The study will end once all participants have completed 24 months of safety follow-up since their last dose of ianalumab or discontinued the study earlier. PAT059387 Key inclusion criteria: 1. Confirmed diagnosis of primary ITP. 2. Prior treatment with at least a corticosteroid (±Intravenous Immunoglobulin [IVIG]) and a TPO-RA: ^ Prior additional therapies are allowed; the corticosteroid and TPO-RA do not need to be the last treatment. ^ Documented response to IVIG/anti-D or a corticosteroid that was not maintained. 3. At last ITP treatment, loss of response, insufficient response, no response or intolerance. 4. Platelet count <30 G/L and assessed as needing treatment (per physician’s discretion). If concomitant ITP medication is clinically indicated, the platelet assessment showing a value <30 G/L must be performed after at least 14 days on a stable dose of a corticosteroid or/and a TPO-RA (less than 10% variation from current dose) and continue stable thereafter. Key Exclusion criteria: 1. Diagnosis of secondary thrombocytopenia. 2. Platelet or whole blood transfusion, plasmapheresis, or use of any other rescue medications within 14 days before first ianalumab infusion. 3. Neutrophils <1000/mm³. 4. Treatment with a B-cell depleting therapy (e.g., rituximab) or anti-B-cell Activating Factor of the Tumor Necrosis Factor Family (BAFF) (e.g., belimumab) within 12 weeks prior to the first administration of ianalumab. 5. Immunosuppressant drugs other than corticosteroids within 5 times the elimination half- life of the drug or 14 days before first ianalumab infusion, whichever is longer. 6. Prior splenectomy. [0153] While various specific embodiments have been illustrated and described, it will be appreciated that various changes can be made without departing from the spirit and scope of the disclosure(s). [0154] All publications, patents, patent applications and other documents cited in this application are hereby incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent, patent application or other document PAT059387 were individually indicated to be incorporated by reference for all purposes. In the event that there are any inconsistencies between the teachings of one or more of the references incorporated herein and the present disclosure, the teachings of the present specification are intended.

Claims

PAT059387 What is claimed is: 1. A method of treating immune thrombocytopenia (ITP) in a subject 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 the 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 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, 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 sequences of SEQ ID NO: 3 and VL having the amino acid sequences of SEQ ID NO: 4, respectively. 6. The method according to any one of the preceding claims, wherein the anti-BAFF-R antibody comprises a heave chain having the amino acid sequences of SEQ ID NO:1 and a light chain having the amino acid sequences of SEQ ID NO:2, respectively. 7. The method according to any one of the preceding claims, wherein the anti-BAFF-R antibody or a fragment thereof is ianalumab 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, especially ianalumab, is administered to a subject at a dose from about 1 to about 27 mg/kg. 10. The method according to any one of the preceding claims, wherein the anti-BAFF-R antibody a binding fragment thereof, especially ianalumab, is administered to a 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 ianalumab is administered to a subject at a dose of about 3 mg/kg. 12. The method according to any one of the preceding claims, wherein ianalumab is administered to a subject at a dose of about 9 mg/kg. PAT059387 13. The method according to any one of the preceding claims, wherein the anti-BAFF-R antibody or a binding fragment thereof, especially ianalumab, is administered to a 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, especially ianalumab, is administered to a 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 ianalumab, wherein ianalumab is administered to a subject at a dose of 3 mg/kg, intravenously, once every four weeks (monthly, +/- 3 days). 16. The method according to any one of the preceding claims, wherein the antibody is ianalumab, wherein ianalumab is administered to a subject at a dose of 9 mg/kg, intravenously, 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), especially the anti-BAFF-R antibody or a binding fragment thereof, especially ianalumab, is administered to a subject, wherein the subject receives the initial treatment after diagnosed with ITP (1L combination). 18. The method of claim 17, wherein the platelet counts is above 30 x 10⁹/L due to the initial treatment or due to the 1L combination. 19. The method according to claim 17 or 18, wherein the initial treatment includes one or more treatment selected from corticosteroids, immunoglobulins (e.g. IVIG or anti-D- immunoglobulin), thrombopoietin receptor agonists (TPO-RAs) or rituxamab. 20. The method according to any one of the claims 17 to 19, wherein the initial treatment is corticosteroids, preferably glucocorticoid, preferably dexamethasone, preferably prednisone or prednisolone. 21. The method according to any one of the claims 17 to 20, wherein the initial treatment includes 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), especially the anti-BAFF-R antibody or a binding fragment thereof, especially ianalumab, is administered to a subject, wherein the subject has insufficient response to or relapse after the initial treatment, preferably the initial treatment is corticosteroid treatment ± IVIG. 23. The method according to claim 22, wherein the subject receives a second treatment (2L combination), which is different from the initial treatment. PAT059387 24. The method according to claim 23, wherein the second treatment includes the treatment with a 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, respectively. 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 comprising administering ianalumab, wherein the subject has primary ITP and had an insufficient response or relapsed 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 ianalumab or a fragment thereof is administered to the subject not more than 8 doses, or not more than 5 doses, or not more than 4 doses. 29. The method according to any one of the preceding claims, wherein ianalumab or a fragment thereof is administered in a total of about 8 doses, about 6 doses, or about 4 doses. 30. The method according to any one of the preceding claims, wherein ianalumab or a fragment thereof is administered in a total of 4 doses. 31. The method according to any one of the preceding claims, wherein the initial treatment is tapered out to discontinuation during or after the treatment with the molecule that inhibits BAFF-R, especially ianalumab. 32. The method according to any one of the preceding claims, wherein the second treatment is tapered out to discontinuation during or after the treatment with the molecule that inhibits BAFF-R, especially ianalumab. 33. The method according to any one of the preceding claims, wherein the platelet counts of the subject is above 100 x 10⁹/L during or after treatment with the molecule that inhibits BAFF-R, especially ianalumab. 34. The method according to any one of the preceding claims, wherein the platelet counts of the subject is equal or above 30 x 10⁹/L and/or is not in the risk of bleeding after discontinuation of any ITP treatment (treatment free remission, TFR). 35. The method according to any one of the preceding claims, wherein the period of treatment free remission (TFR), especially for subject treated with ianalumab, is about 30 months, about 24 months, about 20 months, about 18 months, about 16 months, about 12 PAT059387 months, about 9 months or about 6 months, wherein the period of TFR is calculated from the time of discontinuation of the last ITP treatment till the platelet counts drops below 30 x 10⁹/L or subject resumes ITP treatment. 36. The method according to any one of the preceding claims, wherein the 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 period of TTF is calculated from the start of the treatment with ianalumab until any one of the below events: (i) platelet count below 30 G/L; (ii) the start of a new ITP treatment due to any reasons, especially after 8 weeks from Ianalumab treatment; (iii) the use of rescue treatment (e.g., corticosteroids, IVIG, or platelet transfusion); (iv) optionally the ineligibility to taper or inability to discontinue the treatment as prescribed; or (v) the death (whatever the cause). 37. The method according to any one of the preceding claims, wherein the subject to be treated has relapsed after TFR (re-treatment). 38. A molecule that inhibits the B-cell activating receptor (BAFF-R) for use in the treatment of immune thrombocytopenia (ITP) in a subject. 39. A molecule for use according to claim 38, wherein the molecule that inhibits the BAFF- R is an antibody against BAFF-R (anti-BAFF-R antibody) or a binding fragment thereof. 40. A molecule for use according to claim 39, wherein the anti-BAFF-R- antibody is afucosylated. 41. A molecule for use according to any one of claims 38 to 40, wherein the BAFF-R- antibody of 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, 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 a binding fragment thereof comprises VH having the amino acid sequences of SEQ ID NO: 3 and VL having the amino acid sequences of SEQ ID NO: 4, respectively. PAT059387 43. A molecule for use according to any one of claims 38 to 42, wherein the anti-BAFF-R antibody comprises a heave chain having the amino acid sequences of SEQ ID NO:1 and a light chain having the amino acid sequences 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 a fragment thereof is ianalumab 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 a binding fragment thereof, especially ianalumab, is administered to the subject at a dose from 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 a binding fragment thereof, especially ianalumab, 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 ianalumab 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 ianalumab 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 a binding fragment thereof, especially ianalumab, 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 a binding fragment thereof, especially ianalumab, 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 ianalumab, wherein ianalumab is administered to the subject at a dose of 3 mg/kg, intravenously, 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 ianalumab, wherein ianalumab is administered to the subject at a dose of 9 mg/kg, intravenously, 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), especially the anti-BAFF-R antibody or a binding fragment thereof, especially ianalumab, is administered to the subject, wherein the subject receives the initial treatment after diagnosed with ITP (1L combination). PAT059387 55. A molecule for use according to claim 54, wherein the platelet counts is above 30 x 10⁹/L due to the initial treatment or due to the 1L combination. 56. A molecule for use according to claim 54 or 55, wherein the initial treatment includes one or more treatment selected from corticosteroids, immunoglobulins (e.g. IVIG or anti-D- immunoglobulin), thrombopoietin receptor agonists (TPO-RAs) or rituxamab. 57. A molecule for use according to any one of the claims 54 to 56, wherein the initial treatment is corticosteroids, preferably glucocorticoid, preferably dexamethasone, preferably prednisone or prednisolone. 58. A molecule for use according to any one of the claims 54 to 57, wherein the initial treatment includes treatment with a thrombopoietin receptor agonist. 59. A molecule for use according to any one of the claims 38 to 58, wherein the molecule that inhibits the B-cell activating factor receptor (BAFF-R), especially the anti-BAFF-R antibody or a binding fragment thereof, especially ianalumab, is administered to the subject, wherein the subject has insufficient response to or relapse after the initial treatment, preferably the initial treatment is corticosteroid treatment ± IVIG. 60. A molecule for use according to claim 59, wherein the subject receives a second treatment (2L combination), which is different from the initial treatment. 61. A molecule for use according to claim 60, wherein the second treatment includes the treatment with a 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, respectively. 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. Ianalumab for use in treating immune thrombocytopenia (ITP) in a subject, the method comprises administering ianalumab, wherein the subject has primary ITP and had an insufficient response or relapsed 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 ianalumab or a fragment thereof is administered to the subject not more than 8 doses, or not more than 5 doses, or not more than 4 doses. 66. A molecule for use according to any one of claims 38 to 65, wherein ianalumab or a fragment thereof is administered in a total of about 8 doses, about 6 doses, or about 4 doses. PAT059387 67. A molecule for use according to any one of claims 38 to 66, wherein ianalumab or a fragment thereof is administered in a total of 4 doses. 68. A molecule for use according to any one of claims 38 to 67, wherein the initial treatment is tapered out to discontinuation during or after treatment with the molecule that inhibits BAFF- R, especially ianalumab. 69. A molecule for use according to any one of claims 38 to 68, wherein the second treatment is tapered out to discontinuation during or after treatment with the molecule that inhibits BAFF-R, especially ianalumab. 70. A molecule for use according to any one of claims 38 to 69, wherein the platelet counts of the subject is above 100 x 10⁹/L during or after treatment with the molecule that inhibits BAFF-R, especially ianalumab. 71. A molecule for use according to any one of claims 38 to 70, wherein the platelet counts of the subject is equal or above 30 x 10⁹/L and/or is not in the risk of bleeding after discontinuation of any ITP treatment (treatment free remission, TFR). 72. A molecule for use according to any one of claims 38 to 71, wherein the period of treatment free remission (TFR), especially for subject treated with ianalumab, 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 TFR is calculated from the time of discontinuation of the last ITP treatment till the platelet counts drops below 30 x 10⁹/L or subject resumes ITP treatment. 73. A molecule for use according to any one of claims 38 to 72, wherein the 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 period of TTF is calculated from the start of the treatment with ianalumab until any one of the below events: (i) platelet count below 30 G/L; (ii) the start of a new ITP treatment due to any reasons, especially after 8 weeks from Ianalumab treatment; (iii) the use of rescue treatment, especially after 8 weeks from Ianalumab treatment; or (iv) death (whatever cause) 74. A molecule for use according to any one of the claims 38 to 73, wherein the subject to be treated has relapsed after TFR (re-treatment).