Methods of Treatment with S1P Receptor Modulators

Abstract

The present invention relates to an S1P receptor modulator, preferably mocravimod, for use in treating patients suffering from acute myeloid leukemia (AML) and undergoing allogeneic hematopoietic stem cell transplantation (HSCT).The present invention particularly relates to a method of treating AML in a subject undergoing HSCT, comprising administering an effective amount of an S1P receptor modulator, preferably mocravimod, daily to said subject in need thereof for at least 6 months, preferably at least 12 months.

Description

[Technical field]

[0001] The present invention relates to an S1P receptor modulator, preferably moclavimod, for use in the treatment of patients suffering from acute myeloid leukemia and who have undergone an allogeneic hematopoietic stem cell transplant. [Background technology]

[0002] Acute myeloid leukemia (AML) is an aggressive, rapidly progressing disease in which there are too many myeloblasts (immature white blood cells that are not lymphoblasts) in the bone marrow and blood. It is also called acute myeloblastic leukemia, acute myeloid leukemia, acute nonlymphocytic leukemia, AML and ANLL. AML occurs when the bone marrow starts making blasts instead of mature white blood cells. The immature blasts are unable to fight infection. AML is the most common acute leukemia and progresses quickly. If left untreated, AML can lead to death within weeks or months.

[0003] Current treatments for AML include chemotherapy, including targeted chemotherapy, radiation therapy, and autologous or allogeneic hematopoietic stem cell transplantation. The side effects of each of these treatments are well documented. Typically, newly diagnosed AML patients are treated with induction chemotherapy regimens that attempt to put the cancer into remission. However, remission is most often a temporary measure, as most AML patients in remission eventually relapse. Post-remission therapy includes consolidation chemotherapy, allogeneic or autologous hematopoietic stem cell transplantation.

[0004] To date, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only treatment option for a possible cure. However, major complications of HSCT include graft-versus-host disease (GVHD) and other life-threatening complications. Even with the use of immunosuppressive prophylaxis, 30-60% of patients develop some level of acute GVHD (Abo-Zena and Horwitz, Curr Opin Pharmacol. 2002 Aug;2(4):452-7; Jagasia et al., Blood 2012 Jan 5;119(1):296-307; Ruggeri et al., J Hematol Oncol. 2016 Sep 17;9(1):89).

[0005] Immunosuppressive GVHD prophylaxis is based, for example, on the calcineurin inhibitors (CNIs) cyclosporine A (CsA) and methotrexate (MTX) as well-established immunosuppressive regimens. Criteria for deciding to proceed to allo-HSCT in patients in first complete remission (CR) include risk group classification based on prognostic factors and the presence or absence of a donor at the time of induction. Several criteria are added at the time of consolidation, such as the quality of remission and the persistence of measurable residual disease (MRD), comorbidities (HCT-CI as an index of comorbidities), and recipient-donor profile (Gratwohl score).

[0006] The European Leukemia Network (ELN) has proposed guidelines for the prognostic stratification of AML into three groups: favorable, intermediate, and adverse (Dohner et al., Blood 2017 Jan 26;129(4):424-447).

[0007] Based on the stratification, the ELN has suggested guidelines for allo-HSCT eligibility in patients with intermediate / adverse risk, and additional stratification for evaluating post-remission therapy: low, intermediate, and high risk of relapse (Dohner et al., Blood 2017 Jan 26;129(4):424-447). For example, HSCT is indicated for patients in first CR with adverse cytogenetics / molecular features and / or high MRD, as long as HCT-CI is good enough and as long as a donor is available in a timely manner.

[0008] While acute GVHD is an inflammatory disease, chronic GVHD resembles an autoimmune syndrome and typically develops 4-6 months after transplant due to antigen-specific donor immune cells causing autoimmune clinical signs. Chronic GVHD can occur independently of acute GVHD as a traditional form or as an overlap syndrome in the presence of acute features. The pathology of acute GVHD is characterized by T cell infiltration causing tissue inflammation and damage and is a risk factor for the later development of chronic GVHD, a fibrotic and sclerosing disease. However, it remains unclear whether acute and chronic GVHD are directly related and, if so, how they are mechanistically related.

[0009] Among them, one potential mechanism that may promote the transition from acute to chronic GVHD is the insufficient thymic function in acute GVHD. Indeed, preclinical data show that the weakening of tolerance induction during acute GVHD leads to the emergence of autoreactive T cells from the thymus to the periphery (Dertschnig S, et al. Blood. 2013;122(5):837-841;Dertschnig S, et al. Blood. 2015;125(17):2720-2723). When these autoreactive T cells are in the periphery, they may have the potential to cause the autoimmune syndrome typically observed during chronic GVHD.

[0010] Sphingosine-1-phosphate (S1P) is a metabolite of sphingolipids, which are components of biological membranes. S1P acts as a ligand for a family of five G-protein-coupled receptors named S1P receptor types 1-5 (S1PR1-5). In preclinical studies, FTY720 (fingolimod), a multi-S1PR inhibitor of S1PR1, 3-5, has been shown to attenuate acute GVHD after allogeneic hematopoietic stem cell transplantation (HSCT) by inhibiting donor T-cell infiltration into acute GVHD target organs and promoting rapid contraction of the donor T-cell pool associated with increased donor T-cell apoptosis (Kim et al. J Clin Invest. 2003; 111: 659-669, Hashimoto D, et al. Eur J Immunol. 2007; 37: 271-281).

[0011] In contrast to FTY720, which shows poor selectivity for S1PR1 over S1PR3-5, the compound KRP203 (moclavimod) acts specifically on S1PR1 with a potentially milder toxicity profile. Yokoyama et al. have shown that short-term administration of KRP203 alone induced apoptosis of donor T cells in secondary lymphoid organs and alleviated acute GVHD (Yokoyama E, et al. Bone Marrow Transplant. 2020; 55: 787-795). To our knowledge, the role of S1P receptor modulators in preventing or treating chronic GVHD, especially in human patients undergoing HSCT, has never been demonstrated.

[0012] Calcineurin inhibitors such as CsA and tacrolimus (TAC) suppress donor T cell activation and remain the most commonly used immunosuppressants for acute GVHD prophylaxis. WO2020 / 022507 discloses the results of a clinical study for treating patients with hematological malignancies, who undergo HSCT and are treated daily with KRP203 for a maximum duration of 110 days together with standard treatments for preventing acute GVHD with immunosuppressants such as CsA and MTX or MTX and TAC.

[0013] However, these immunosuppressants also inhibit leukemia-specific T cell responses and impair the graft-versus-leukemia (GVL) effect. Indeed, Yokoyama E et al. previously showed that long-term administration of CsA after mouse HSCT significantly impaired the GVL effect compared to KRP203 (Yokoyama E, et al. Bone Marrow Transplant. 2020; 55: 787-795).

[0014] WO 2020 / 022507 suggested that short-term administration of KRP203 significantly reduced the risk of acute GVHD and improved survival in patients with hematological malignancies.

[0015] However, there remains a need to improve survival for patients at high risk of relapse. In particular, relapse is the current leading cause of treatment failure after allogeneic HSCT, while transplant-related mortality and morbidity due to GVHD remains a problem despite some advances in GVHD therapy.

[0016] Also, there remains a need to find optimal stable formulations containing S1Pr drugs, and stability is an essential quality attribute for pharmaceutical formulations. Predictability of optimal formulations, especially for solid forms, remains a challenge in the industry (Curr Pharm Des. 2016;22(32):5019-5028).

[0017] Particularly in AML, there remains a need to provide treatments that can separate GVL and acute GVHD to improve relapse rates in patients while reducing the incidence and severity of chronic GVHD.

[0018] Without limiting the invention to any particular mechanism, the invention described herein meets this need, as the methods described provide a synergistic therapeutic effect that prevents acute and chronic GVHD effects while further ameliorating GVL effects and risk of relapse in high-risk AML patients. Summary of the Invention

[0019] Thus, a first object of the present invention relates to an S1P receptor modulator, preferably moclavimod, for use in the treatment of human subjects suffering from acute myeloid leukemia (AML) and undergoing allogeneic hematopoietic stem cell transplantation (HSCT).

[0020] Another object of the invention relates to an S1P receptor modulator, preferably moclavimod, for use in the treatment of chronic GVHD, typically in delaying the onset of chronic GVHD, in human subjects undergoing allogeneic hematopoietic stem cell transplantation (HSCT), preferably in human subjects in need of HSCT for treating acute myeloid leukemia.

[0021] Another object of the present invention is to provide an S1P receptor modulator of formula (II) or formula (IIa) or formula (IIb):

[0022] [ka] or a pharma- ceutically acceptable salt thereof; The present invention relates to a pharmaceutical composition comprising at least one filler selected from mannitol, microcrystalline cellulose and mixtures thereof, sodium starch glycolate as a disintegrant, magnesium stearate as a lubricant and colloidal silicon dioxide as a lubricant.

[0023] The present disclosure relates, inter alia, to various methods of treating acute myeloid leukemia in a subject undergoing allogeneic hematopoietic stem cell transplantation (HSCT), comprising: 1) administering to a subject an effective amount of an S1P receptor modulator; 2) conditioning the subject to substantially destroy the bone marrow and immune system, the conditioning comprising treating the subject with an effective amount of a chemotherapeutic agent and / or administering total body irradiation; 3) transplanting donor-derived allogeneic hematopoietic stem cells into the subject; 4) optionally co-administering an effective amount of one or more immunosuppressive agents to prevent acute GVHD; The present invention relates to a method comprising the steps of:

[0024] The present disclosure provides a method for preventing chronic GvHD in a subject undergoing allogeneic hematopoietic stem cell transplantation (HSCT), comprising: 1) administering to a subject an effective amount of an S1P receptor modulator; 2) conditioning the subject to substantially destroy bone marrow and immune system, comprising treating the subject with an effective amount of a chemotherapeutic agent and / or administering total body irradiation; 3) transplanting donor-derived allogeneic hematopoietic stem cells into the subject; 4) optionally co-administering an effective amount of one or more immunosuppressive agents to prevent acute GVHD; The present invention further relates to a method comprising the steps of:

[0025] The present disclosure further relates to the use of an S1P receptor modulator in the manufacture of a medicament for treating acute myeloid leukemia in a subject undergoing allogeneic hematopoietic stem cell transplantation.

[0026] The present disclosure also relates to the use of an S1P receptor modulator in the manufacture of a medicament for preventing, typically delaying the onset of, chronic GVHD in a patient undergoing allogeneic hematopoietic stem cell transplantation.

[0027] In some embodiments of the various methods and uses described herein, the S1P receptor modulator is selected from mocravimod, FTY720, siponimod, fingolimod, ozanimod, ponesimod, etrasimod, AKP-11, cenerimod, amiselimod, CBP-307, OPL-307, OPL-002, BMS-986166, SCD-044, BOS-173717, CP-1050, typically selected from mocravimod, FTY720 and siponimod, most preferably mocravimod.Preferably, the S1P receptor modulator is an S1P receptor agonist.More preferably, the S1P receptor modulator is of formula (I) or (II):

[0028] [ka] (In the formula, R 2 is H, halogen, trihalomethyl, C 1~4 Alkoxy, C 1~7 alkyl, phenethyl or benzyloxy; R 3 H, halogen, CF 3 , O.H., C. 1~7 Alkyl, C 1~4 Alkoxy, benzyloxy, phenyl or C 1~4 Alkoxymethyl; R 4 and R 5 each independently represents H or a residue of formula (a)

[0029] [ka] and R 8 and R 9 each independently represents C optionally substituted by H or a halogen 1~4 is alkyl; n is an integer from 1 to 4; R 6 is hydrogen, halogen, C 1~7 Alkyl, C 1~4 alkoxy or trifluoromethyl);

[0030] [ka] or a pharma- ceutically acceptable salt thereof, more preferably mocravimod or a pharma- ceutically acceptable salt thereof.

[0031] In some embodiments of the various methods and uses described herein, the S1P receptor modulator, such as mocrabimod or fingolimod, is selected to have a pharmacokinetic half-life of more than 40, 50, 60, 70, 90 hours, preferably more than 100 hours, thus maximizing the patient's drug exposure, thereby allowing for skipping doses of S1Pr administration for one or more days if the pretreatment procedure causes toxicity, such as bone marrow suppression, alopecia, nausea, vomiting, parotid swelling and erythema.In particular, since nausea and / or vomiting can prevent the patient from swallowing the treatment, such as oral doses of S1Pr drugs, it may be advantageous for the patient to use S1Pr drugs with long pharmacokinetic half-life.

[0032] In some embodiments, the S1P receptor modulator, preferably moclavimod, is initiated prior to allogeneic HSCT, preferably 7, 8, 9, 10, 11, 12, 13 or 14 days prior to HSCT, more preferably 11 days prior to HSCT.

[0033] In some embodiments, the S1P receptor modulator, preferably mocravimod, is administered daily for a period set at least 80 days, or at least 100 days or more following HSCT.

[0034] For preferred embodiments, the S1P receptor modulator, most preferably mocravimod, is administered daily for at least 6, 7, 8, 9, 10, 11, 12, 18 or 24 months or more, preferably for the life of the subject or until relapse, i.e., chronic daily treatment.

[0035] For example, the S1P receptor modulator, most preferably moclavimod, is administered daily from 1-14 days prior to HSCT, preferably 11 days prior to HSCT, for at least 6, 7, 8, 9, 10, 11, 12, 18 or 24 months or more following HSCT or until relapse.

[0036] In any of the methods and uses described herein, the amount of the S1P receptor modulator, most preferably moclavimod, can be administered in a fixed amount per day. Preferably, said fixed daily dosage is between 0.05 mg and 40 mg per day, preferably between 0.1 mg and 35 mg, more preferably between 0.5 mg and 30 mg, even more preferably between 1 mg and 15 mg per day, even more preferably between 1.5 mg and 7 mg, even more preferably between 2 mg and 5 mg, even more preferably about 3 mg per day or about 1 mg per day.

[0037] For example, the S1P receptor modulator can be mocravimod, and said mocravimod can be administered at a daily dose of about 1mg per day.Alternatively, mocravimod can be administered at a dose of about 3mg per day, preferably as three solid dosage forms of about 1mg or as one solid dosage form of about 3mg.Alternatively, mocravimod can be administered at a dose of about 2mg per day, preferably as two solid dosage forms of about 1mg or as one solid dosage form of about 2mg.

[0038] In a specific embodiment, the conditioning regimen in step 2) comprises chemotherapy with a chemotherapeutic agent selected from the group consisting of cyclophosphamide or thiotepa, cytarabine, etoposide, busulfan or melphalan, fludarabine and mixtures thereof, e.g., combined administration of fludarabine / busulfan, busulfan / cyclophosphamide or fludarabine / melphalan.

[0039] In a specific embodiment, the conditioning regimen is as follows: An effective amount of fludarabine administered intravenously; preferably 30 mg / m once daily 2 for 5 days from -8 to -4 (total 150 mg / m 2 ) An effective amount of thiotepa administered intravenously; preferably 5 mg / kg IV twice daily for 1 day on days -7 (total 10 mg / kg) Intravenous melphalan; preferably 60 mg / m once daily 2 IV for 2 days on days -2 and -1 (total 120 mg / m 2 ) Here, the day number is relative to the day of HSCT.

[0040] In other specific embodiments, the conditioning regimen of step 2) consists of: i. Administration of cyclophosphamide followed by total body irradiation, or ii. Administration of busulfan and cyclophosphamide, or iii. Administration of fludarabine and busulfan, and optionally, low-dose total body irradiation.

[0041] In a specific embodiment, hematopoietic stem cells are selected in step 3) from HLA-matched related or unrelated donors with an 8 / 8 or greater match at the HLA-A, -B, -C, -DRB1 and / or -DQB1 loci as determined by high-resolution HLA typing.

[0042] In a specific embodiment, in step 4) of the method, the one or more immunosuppressants are selected from the group consisting of cyclosporine A, sirolimus, tacrolimus, methotrexate and mycophenolate mofetil, preferably cyclosporine A, or a mixture and methotrexate or tacrolimus, or a mixture of tacrolimus and methotrexate. In a specific embodiment, the immunosuppressant is at least cyclosporine A. In another specific embodiment, the immunosuppressant is at least tacrolimus.

[0043] For example, cyclosporine A can be administered within the period between the start of administration of the S1P receptor modulator, preferably moclavimod, and the day of HSCT, preferably 3 days prior to HSCT. In a specific embodiment, cyclosporine A is administered intravenously or orally at an initial dosage of 2.5 mg / kg over 2 hours every 12 hours, and optionally adjusted to 150-400 mg / L.

[0044] For example, tacrolimus can be administered within the period between the start of administration of the S1P receptor modulator, preferably moclavimod, and the day of HSCT, preferably 3 days prior to HSCT. In a specific embodiment, tacrolimus is administered intravenously or orally at an initial dosage of 0.02-0.03 mg / kg / day, either as a continuous infusion or split into two bolus injections twice daily. In an embodiment, the injected dose should maintain a target blood concentration of 5-10 ng / mL.

[0045] In a specific embodiment, methotrexate is administered at a dosage of 10 mg / kg on the day of HSCT, and optionally at a dosage of 6 mg / kg on days 2 and 5 and 16 after the first administration, together with cyclosporine A or tacrolimus. In another embodiment, methotrexate is administered once at 15 mg / m on the day after HSCT. 2 IV dosage and then 10 mg / m once on days 3, 6, and 11 after HSCT. 2In the latter embodiment, the use of leucovorin rescue is permitted, which is recommended at the same dose as methotrexate, given in three doses every six hours, starting 24 hours after the methotrexate dose, and given orally or IV. Modifications to this regimen can be made to reduce clearance or meet methotrexate toxicity.

[0046] In a preferred embodiment, the one or more immunosuppressants used in step 4) do not include tacrolimus. In another preferred embodiment, the one or more immunosuppressants used in step 4) do not include cyclosporine A.

[0047] In a specific embodiment of the method and use, the S1P receptor modulator, preferably moclavimod, is administered for at least 6, 7, 8, 9, 10, 11, 12, 18, 24 months or more, preferably for the life of the subject or until remission, and said subject is further treated in step 4) with an effective amount of an immunosuppressant comprising at least cyclosporine A, said immunosuppressant treatment being reduced or stopped prior to 6 months following HSCT, preferably within a period of 3-6 months, or 3-5 months, or 3-4 months following HSCT. For example, said immunosuppressant treatment is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% compared to the starting dose of said immunosuppressant.

[0048] In specific embodiments of the methods and uses disclosed herein, said subject has refractory or relapsed AML after one or more AML treatments.

[0049] In a specific embodiment, the subject is selected from among patients suffering from acute myeloid leukemia and either in first morphological complete remission but in an adverse risk group called "CR1 high risk" or in second and subsequent complete morphological remission called "CR2", said CR1 high risk, CR2 patients being defined according to the disease classification corresponding to the ASBMT RFI 2017 - American Society for Blood and Marrow Transplantation CIBMTR classification, preferably the patients are classified as CR1 high risk and CR2.

[0050] In a specific embodiment, the subject is measurable residual disease (MRD) positive prior to being administered the method of the disclosure (e.g., HSCT with moclavimod). Thus, in a specific embodiment, prior to step (1), the method includes a step of detecting the subject's MRD status.

[0051] In a specific embodiment, said S1P receptor modulator is administered in an amount sufficient to treat AML and prevent acute GVHD.

[0052] In a specific embodiment, said S1P receptor modulator is administered in an amount sufficient to treat AML and prevent acute and chronic GVHD.

[0053] Preferably, the patient is GVHD-free and relapse free 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 months after HSCT.

[0054] In specific embodiments of the methods and uses, said subject does not exhibit one or more of the following at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months after HSCT: Grade III / IV acute graft-versus-host disease (GVHD) refractory to at least two lines of immunosuppressive treatment, - widespread chronic GVHD refractory to systemic immunosuppressive treatment, Disease recurrence, ·death.

[0055] In specific embodiments, the methods and uses described herein improve morbidity or mortality in a population of subjects, particularly through relapse-free survival (rGRFS) free of refractory GVHD, and both relapse-related and transplant-related mortality, at 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months after HSCT.

[0056] For example, the methods and uses reduce the incidence or severity of either GVHD, refractory GVHD, relapse or death in a population of subjects for 12, 18 or 24 months following HSCT.

[0057] Also disclosed herein are methods for improving overall survival in subjects, comprising, for each subject, treating the subject with any of the methods using an S1P receptor modulator disclosed herein.

[0058] In a specific embodiment, the method improves quality of life of a population of subjects at 3, 6, 12 or 24 months, preferably as measured by the Foundation for Accreditation of Cellular Therapy Bone Marrow Transplant (FACT-BMT) questionnaire and / or the MD Anderson Symptom Assessment Inventory (MDASI), compared to the same method of HSCT without administration of the S1PR modulator. The improvement can be significant, for example, quality of life can be increased by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more. [Brief description of the drawings]

[0059] [Figure 1]FIG. 1 shows the incidence of mild chronic GVHD in patients receiving KRP 203 1 mg+CsA, KRP203 3 mg+CsA and KRP203 3 mg+TAC. [Diagram 2] FIG. 1 shows the incidence of favorable relapse in patients receiving KRP 203 1 mg+CsA, KRP203 3 mg+CsA and KRP203 3 mg+TAC. [Diagram 3] 1 shows the incidence of moderate chronic GVHD in patients receiving KRP 203 1 mg + CsA, KRP203 3 mg + CsA, and KRP203 3 mg + TAC. [Figure 4A] KRP203 as a preventative treatment for chronic GVHD. Figure 1 shows the clinical scores of skin pathology in mice with GVHD that received either KRP203 (black) or vehicle (grey) as a preventative treatment. [Figure 4B] KRP203 as a prophylactic treatment for chronic GVHD. Schirmer test results measuring tear production at day 42 in mice with (black) or without (grey) prophylactic KRP203 treatment. [Figure 5A] KRP203 treatment in combination with CsA for short or long term. Overall survival of mice receiving either T cell depleted bone marrow (TCDBM) alone, or TCDBM+T cells and different treatment combinations. [Figure 5B] KRP203 treatment in combination with CsA for short or long term. Figure 1. Tumor numbers in mice receiving either TCDBM alone, or TCDBM+T cells and different treatment combinations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0060] Detailed Description The present disclosure relates to an S1P receptor modulator, preferably moclavimod, for use in the treatment of a human subject suffering from acute myeloid leukemia (AML) and undergoing allogeneic hematopoietic stem cell transplant (HSCT).

[0061] General definition As used herein, a "modulator" is a compound that, when administered to a subject, produces a desired interaction with a target receptor, either by a compound that acts directly on the receptor itself, or by a metabolite of a compound that acts on the receptor.When administered to a subject, an S1P receptor modulator, preferably moclavimod, interacts with the S1P receptor by either activating or inhibiting the signal transduction of the receptor.

[0062] As used herein, "S1P agonist" refers to a compound that initiates a physiological response when combined with an S1P receptor. Preferably, the initiated physiological response is agonist-induced internalization of the S1P receptor. The kinetics of agonist-induced internalization from the cell membrane and the recycling of the S1P receptor to the cell membrane after the compound is shed are compound-dependent. Such S1P receptor agonists may also be referred to as functional antagonists. The persistence of internalization regulates the "functional antagonism" properties of the agonist.

[0063] As used herein, HSC refers to hematopoietic stem cells.

[0064] As used herein, HSCT refers to allogeneic hematopoietic stem cell transplantation.

[0065] The term "a pharmaceutically acceptable salt thereof" includes both acid and base addition salts. Non-limiting examples of pharmaceutically acceptable acid addition salts include chloride, hydrochloride, bromide, sulfate, nitrate, phosphate, sulfonate, methanesulfonate, formate, tartrate, maleate, citrate, benzoate, salicylate and ascorbate. Non-limiting examples of pharmaceutically acceptable base addition salts include sodium, potassium, lithium, ammonium (substituted and unsubstituted), calcium, magnesium, iron, zinc, copper, manganese and aluminum salts. Pharmaceutically acceptable salts can be obtained, for example, using standard procedures well known in the pharmaceutical field. In the case of mocravimod, since mocravimod itself is a base, the pharmaceutically acceptable salt is typically considered to be an acid addition salt. Preferably, the pharmaceutically acceptable salt is the hydrochloride salt.

[0066] The term "excipient" as used herein refers to a non-active substance that is added together with a drug substance and is part of the formulation mixture. Pharmaceutically acceptable excipients are, for example, fillers, solvents, diluents, carriers, co-agents, dispersion and sensing agents, delivery agents, such as preservatives, disintegrants, wetting agents, emulsifiers, suspending agents, thickening agents, sweeteners, flavorings, fragrances, antibacterial agents, bactericides, lubricants and long-term delivery control agents, antioxidants, lubricants. Their selection and suitable ratios depend on the nature and method of administration, and dosage.

[0067] "Average particle size" refers here to D50, which means that 50% of the particles have a size equal to or less than the indicated value. For example, an average particle size equal to or less than 8 μm refers to a D50 of 8 μm, i.e., 50% of the particles have a size equal to or less than 8 μm. The term D90 means that 90% of the particles have a size equal to or less than the indicated value. For example, a D90 equal to or less than 25 μm means that 90% of the particles have a size equal to or less than 25 μm. D50 and D90 are determined by laser light diffraction using a liquid path, for example on a BECKMAN-COULTER laser diffraction particle size analyzer LS 230 equipped with its small volume dispersion module (liquid path), according to technical manuals and manufacturer's instructions.

[0068] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient, such as an S1P receptor modulator, preferably moclavimod, that is effective, alone or in combination with other active agents, to produce at least one therapeutic effect when administered to a subject either as a single dose or as part of a series of doses.

[0069] The term "about" is used herein to mean that the value which follows it can vary by ±20%, preferably ±10%, more preferably ±5%, even more preferably ±2%, and even more preferably ±1%.

[0070] The terms "patient," "subject," "individual," and the like are used interchangeably herein and refer to a human. In some embodiments, a patient, subject, or individual in need of treatment includes a patient, subject, or individual who already has a disease, condition, or disorder, i.e., acute myeloid leukemia.

[0071] "Combination" refers to either a fixed combination in one unit dosage form, or a combined administration where a compound of the disclosure and a combination partner (e.g., another drug, as described below, also referred to as a "therapeutic agent" or "co-agent") may be administered simultaneously and independently, or separately, within a time interval that allows the combination partners to exhibit a cooperative, e.g., synergistic, effect, among others. The single components may be packaged in a kit or packaged separately. One or both of the components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose prior to administration.

[0072] As used herein, terms such as "co-administration" or "administration in combination" are meant to encompass the administration of the selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens in which agents are not necessarily administered by the same route of administration or at the same time.

[0073] As used herein, unless otherwise specified, the term "treating" or "treatment" refers to reversing, alleviating, inhibiting the progression of or preventing the disorder or condition to which such term applies, or reversing, alleviating, inhibiting the progression of or preventing one or more symptoms of the disorder or condition to which such term applies.

[0074] As used herein, the term "AUClast" is defined as the concentration measured from time 0 to the last measurable concentration.

[0075] S1P receptor modulators for use as active principles in the treatment methods of the present disclosure S1P receptors are classified into five subtypes related to G-coupled protein receptors (i.e., S1P 1 , S1P 2 , S1P 3 , S1P 4 and S1P 5 ), which are expressed in a wide range of tissues and display different cell specificities.

[0076] In certain embodiments, modulators of S1P receptors for use in accordance with the methods of the present disclosure are capable of modulating the five S1P receptors types 1-5 (S1PRs) by activating or inhibiting signal transduction. 1~5 ) are compounds that modulate one or more of the S1P receptors. Such compounds are also referred to herein as "S1P agonists" and "S1P inhibitors," respectively.

[0077] In specific embodiments, the S1P receptor modulator for use in the treatment methods of the present disclosure is selected from KRP203 (moclavimod), FTY720 (fingolimod), siponimod (Mayzent®), fingolimod (Gilenya™), ozanimod (Zeposia®), ponesimod, etrasimod, AKP-11, cenerimod, amiselimod, CBP-307, OPL-307, OPL-002, BMS-986166, SCD-044, BOS-173717, CP-1050. Preferably, the S1P receptor modulator for use in the treatment methods of the present disclosure is selected from KRP203 (mocravimod), FTY720 (fingolimod) and Mayzent® (siponimod), most preferably mocravimod.

[0078] In one embodiment, the S1P receptor modulator for use in the treatment method of the present disclosure is an S1P agonist. Such S1P agonists include KRP203 (moclavimod), S1PR 1 Selective agonist or FTY720 (fingolimod), S1PR 1 , 3~5 Multi-S1PR agonist or siponimod, S1PR 3 agonists, or pharma- ceutically acceptable salts thereof. Preferably, in certain embodiments, the S1P agonist is an S1PR 1 The S1P agonist is selected from among S1P agonists that selectively activate

[0079] In a preferred embodiment, the S1P receptor modulator for use in accordance with the present disclosure is a compound of formula (I):

[0080] [ka] (In the formula, R 2 is H, halogen, trihalomethyl, C 1~4 Alkoxy, C 1~7 alkyl, phenethyl or benzyloxy; R 3 H, halogen, CF 3 , O.H., C. 1~7 Alkyl, C 1~4 Alkoxy, benzyloxy, phenyl or C 1~4 Alkoxymethyl; R 4 and R 5 each independently represents H or a residue of formula (a)

[0081] [ka] and R 8 and R 9 each independently represents C optionally substituted by H or a halogen 1~4 is alkyl; n is an integer from 1 to 4; R 6 is hydrogen, halogen, C 1~7 Alkyl, C 1~4 alkoxy or trifluoromethyl) It is.

[0082] In a specific embodiment, said compound of formula (I) is an S1P agonist, preferably an S1PR agonist. 1 Typically, in a preferred embodiment, R 3 is chlorine. More preferably, R 2 is H and R 3 is chlorine, R 6 is hydrogen. For example, R 2 is H and R 3 is chlorine, R 6 is hydrogen, and R 3 and R 5 Each of is independently H.

[0083] In a more preferred embodiment, an S1P receptor modulator, preferably an S1P agonist, preferably an S1PR 1The selective agonist is 2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-propane-1,3-diol (also called moclavimod or KRP203) of formula (II):

[0084] [ka] or a pharma- ceutically acceptable salt thereof.

[0085] Other S1P receptor modulators for use in accordance with the present disclosure, preferably S1PR 1 The selective agonist may be a phosphate derivative of the formula:

[0086] [ka] Includes.

[0087] In some embodiments of the various methods and uses described herein, the S1P receptor modulator, such as mocrabimod or fingolimod, is selected to have a pharmacokinetic half-life of more than 40, 50, 60, 70, 90 hours, preferably more than 100 hours, thus maximizing the patient's drug exposure, thereby allowing skipping S1Pr administration for one or more days if the pretreatment procedure causes toxicity, such as bone marrow suppression, alopecia, nausea, vomiting, parotid swelling and erythema.In particular, since nausea and / or vomiting can prevent the patient from swallowing the treatment, such as oral dosage of S1Pr drug, it may be advantageous for the patient to use an S1Pr drug with a long PK half-life.

[0088] The compounds and methods for their synthesis are also disclosed in WO 03 / 029205, WO 2004 / 074297, WO 2006 / 009092, WO 2006 / 041019 and WO 2014128611, the disclosures of which are incorporated herein by reference.

[0089] Mocravimod is particularly preferred. Indeed, the pharmacodynamic effects of different S1P regulators, such as mocravimod, FTY720 and BAF312, established in healthy volunteers reveal differences in the effectiveness of lymphocyte sequestration. The measurable parameter that determines the maintenance of the mode of action, i.e., lymphocyte sequestration in secondary lymphoid organs and bone marrow, is the reduction in peripheral lymphocyte count. After a single 1 mg dose of FTY720, multiple dose application of BAF312 over 28 days, or a single 3 mg dose of KRP203, the absolute lymphocyte count reaches recovery to 80% of normal count after more than 8, 7 and 10 days, respectively. Thus, the lymphocyte recovery time for KRP203 is significantly longer than for BAF312 and FTY720.

[0090] Particle size of S1P receptor modulator In the pharmaceutical industry, particle characterization of powder materials has become one of the important aspects of drug product development and quality control of solid oral dosage forms. The particle size distribution of drug substances can have a significant effect on the final drug product performance (e.g., dissolution, bioavailability, content uniformity, stability, etc.). In addition, the particle size distribution of drug substances can affect the manufacturability of drug products, e.g., flowability, blend uniformity, compactibility, and can have a significant impact on almost every step of the manufacturing process of solid oral dosage forms, including premixing / mixing, granulation, drying, milling, blending, coating, encapsulation, and compression. Thus, the particle size of drug substances can ultimately affect the safety, efficacy, and quality of drug products.

[0091] In an embodiment, the S1P receptor modulator of the present disclosure has a mean particle size (D50) of 8 μm or less, preferably 6 μm, more preferably 5 μm. In another embodiment, the S1P receptor modulator of the present disclosure has a D90 of 25 μm or less, preferably 22 μm, more preferably 19 μm. In fact, the inventors have found that a mean particle size (D50) of more than 8 μm, preferably more than 6 μm, more preferably more than 5 μm and / or a D90 of more than 25 μm, preferably more than 22 μm, more preferably more than 19 μm impairs drug dissolution by reducing surface contact with the solvent, resulting in reduced bioavailability and in vivo performance.

[0092] Pharmaceutical compositions comprising S1P receptor modulators The present disclosure also relates to pharmaceutical compositions of said S1P receptor modulators, preferably mocravimod, as described above, in particular for their use in the methods of treatment as disclosed.

[0093] In certain embodiments, the pharmaceutical compositions of the present disclosure comprise an S1P receptor modulator, preferably moclavimod, and one or more pharma- ceutically acceptable excipients.

[0094] Any suitable excipient known to those of ordinary skill in the art for use in pharmaceutical compositions may be used in the compositions described herein.

[0095] Pharmaceutical compositions may be administered in any manner suitable for the disease or disorder to be treated as determined by those skilled in the medical field.Appropriate dosage and suitable duration and frequency of administration are determined by factors as discussed herein, including the condition of the patient, the type and severity of the patient's disease, the specific form of active ingredient, and the method of administration.In general, appropriate dosage (or effective dosage) and treatment regimen provide a sufficient amount of pharmaceutical composition to produce therapeutic effect, for example, improved clinical outcome, for example, more frequent complete or partial remission, or longer disease-free survival and / or overall survival, or reduced symptom severity, or other benefits as described in detail herein.

[0096] The pharmaceutical compositions described herein may be administered to a subject in need thereof by any of several routes that can effectively deliver an effective amount of the compound.The pharmaceutical compositions may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically, bucally, or as an oral or nasal spray.In a preferred embodiment, the pharmaceutical composition is suitable for oral administration.

[0097] In another embodiment, the pharmaceutical composition may be in a solid dosage form suitable for oral administration.Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.In a preferred embodiment, the pharmaceutical composition is a capsule or tablet.The capsule may be a soft or hard gelatin capsule, preferably a hard gelatin capsule.For example, the capsule is a crushed HGC or crushed HPMC capsule.

[0098] In certain embodiments, the release of the capsule or tablet contents may be immediate or modified, such as delayed, targeted or extended, etc. In a preferred embodiment, the solid dosage form is an immediate release dosage form.

[0099] In one embodiment, the pharmaceutical composition comprises an S1P receptor modulator, preferably moclavimod, one or more pharma- ceutically acceptable excipients, in particular at least one filler and mixtures thereof, a disintegrant, a lubricant, and a glidant.

[0100] Filler A filler (also called a diluent, dilutant or solvent) is a substance added to a drug substance to make it suitable for oral administration (e.g., capsule, tablet). The filler itself should not produce any pharmacological effect in humans. Examples of fillers include mannitol, crystalline cellulose, lactose monohydrate, anhydrous lactose, corn starch, xylitol, sorbitol, sucrose, dicalcium phosphate, maltodextrin and gelatin. The pharmaceutical composition of the present disclosure comprises at least one filler selected from mannitol, crystalline cellulose and mixtures thereof. In a preferred embodiment, the pharmaceutical composition of the present disclosure comprises a mixture of mannitol and crystalline cellulose.

[0101] Disintegrants Disintegrants are added to oral solid dosage forms to aid in the disaggregation of the oral solid dosage form. Disintegrants are formulated to cause the rapid disintegration of the solid dosage form when it comes into contact with moisture. Disintegration is typically considered the first step of the dissolution process. Examples of disintegrants include modified starches such as sodium starch glycolate, sodium carboxymethyl starch and pregelatinized starch, cross-linked polymers such as cross-linked polyvinylpyrrolidone (crospovidone) or cross-linked sodium carboxymethyl starch (croscarmellose sodium), and calcium silicate. The pharmaceutical composition of the present disclosure includes sodium starch glycolate as a disintegrant.

[0102] lubricant Lubricants are substances used in tablet and capsule formulations to reduce friction. Lubricants can facilitate the extrusion of the tablet from the matrix and thus prevent the formation of scratches on the tablet surface. Lubricants can be divided into two groups according to their nature: a) fatty and fatty substances; b) powdery substances. Powdery substances are more applicable than fatty substances, since fatty substances affect the solubility and chemical stability of the tablet. Powdery lubricants are introduced by the powdering of granules. They feed the outflow mass for tableting from the hopper to the matrix at a constant rate and ensure the accuracy and consistency of the drug substance dosage.

[0103] Examples of lubricants include magnesium stearate, hydrogenated castor oil, glyceryl behenate, calcium stearate, zinc stearate, mineral oil, silicone fluid, sodium lauryl sulfate, L-leucine and sodium stearyl fumarate. The pharmaceutical composition of the present disclosure includes magnesium stearate as a lubricant.

[0104] Lubricants Lubricants are blended with the formulation to enhance the flow properties of the tablet core blend material. During the early stages of compression, lubricants are mixed into the particle arrangement of the tablet powder blend to improve flow and uniformity in the die cavity of the tablet press. Lubricants enhance the flow of tablet granulation by reducing friction between particles. The effect of lubricants on the flow of granules depends on the size and shape of the particles of the granules and the lubricant. Rather, above a certain concentration, lubricants act to inhibit flow. In tablet manufacturing, lubricants are usually added just before compression. Examples of lubricants include colloidal silicon dioxide, starch, magnesium stearate and talc. The pharmaceutical composition of the present disclosure includes colloidal silicon dioxide as a lubricant.

[0105] The pharmaceutical composition of the present disclosure comprises an S1P receptor modulator, at least one filler selected from mannitol, microcrystalline cellulose and mixtures thereof, sodium starch glycolate as a disintegrant, magnesium stearate as a lubricant, and colloidal silicon dioxide as a lubricant.

[0106] Any suitable excipient known to a person skilled in the art in pharmaceutical compositions may further be used in the compositions described herein.

[0107] In one embodiment, the dosage strength of the S1P receptor modulator, preferably the hydrochloride salt of formula (I), in the solid dosage form is from 0.05 mg to 15 mg / unit, preferably from 0.1 mg to 10 mg / unit, for example, about 0.1 mg / unit, or about 0.4 mg / unit, or about 1 mg / unit, or about 10 mg / unit, more preferably about 1 mg / unit.

[0108] More specifically, the pharmaceutical compositions of the present disclosure further comprise the following ingredients: mannitol, preferably with a content of 48 to 88 mg / unit, more preferably with a content of 58 to 78 mg / unit, even more preferably with a content of about 68 mg / unit; - microcrystalline cellulose, preferably with a content of 5 to 45 mg / unit, more preferably with a content of 15 to 35 mg / unit, even more preferably with a content of about 25 mg / unit; - sodium starch glycolate, preferably in a content of 1 to 8 mg / unit, more preferably in a content of 2 to 6 mg / unit, even more preferably in a content of about 4 mg / unit; - magnesium stearate, preferably in a content of 0.025 to 4 mg / unit, more preferably in a content of 0.5 to 2 mg / unit, and even more preferably in a content of about 1 mg / unit; and - colloidal silicon dioxide, preferably in a content of 0.125 to 2 mg / unit, more preferably in a content of 0.25 to 1 mg / unit, even more preferably in a content of about 0.5 mg / unit.

[0109] In another embodiment, the pharmaceutical composition of the present disclosure comprises the following ingredients: - an S1P receptor modulator, preferably moclavimod, in a content of 0.05% to 15%, more preferably 0.1% to 10% mg / unit, even more preferably about 0.1%, or 0.4%, or 1%, or 10%; mannitol, preferably with a content between 48% and 88%, more preferably between 58% and 78%, even more preferably with a content of about 68%; - microcrystalline cellulose, preferably with a content between 5% and 45%, more preferably between 15% and 35%, and even more preferably with a content of about 25%; - sodium starch glycolate, preferably with a content between 1% and 8%, more preferably between 2% and 6%, and even more preferably with a content of about 4%; - magnesium stearate, preferably with a content between 0.025% and 4%, more preferably with a content between 0.5% and 2%, and even more preferably with a content of about 1%; colloidal silicon dioxide, preferably in a content of 0.125-2 mg / unit, more preferably in a content of 0.25-1 mg / unit, and even more preferably in a content of about 0.5 mg / unit; (Percentages represent mg / mg by dry weight of total composition).

[0110] A preferred stable formulation of the present disclosure is as follows (derived from Blend 17 of Examples 4 and 5 and detailed in Example 6):

[0111] [Table 1]

[0112] Drug stability assessment can prevent toxicity and increase safety, efficacy and quality of the final drug product. This is especially important for treating patients in countries with fluctuating temperatures (hot and humid), since once the patient's condition stabilizes within a few weeks after HSCT therapy, the patient will be discharged from the hospital and will take capsules of the composition at home.

[0113] In certain embodiments, the pharmaceutical compositions of the present disclosure are stable at 50° C. for at least 1 month, preferably at 50° C. for 2 months.

[0114] In another embodiment, the pharmaceutical composition of the present disclosure is stable at 5° C. for at least 24 months.

[0115] In another embodiment, the pharmaceutical compositions of the present disclosure are stable at 25° C. / 60% relative humidity for at least 24 months.

[0116] As used herein, the stability of a composition is measured according to the following method: High Pressure Liquid Chromatography (HPLC), which is widely known in the art. A composition is stable if the sum of the impurities is equal to or less than 0.7% with a [98-102]% confidence interval.

[0117] Methods for preparing pharmaceutical compositions Another aspect of the present disclosure is a method for preparing the above-mentioned pharmaceutical composition, comprising the steps of: a. blending the S1P receptor modulator with microcrystalline cellulose, colloidal silicon dioxide, preferably at 22 rpm for 18 minutes; b. adding mannitol and blending the resulting mixture, preferably at 22 rpm, for 9 minutes; c. adding sodium starch glycolate and blending the resulting mixture, preferably at 22 rpm, for 5 minutes; d. adding magnesium stearate and blending the resulting pharmaceutical composition, preferably at 22 rpm, for 5 minutes; e. recovering the pharmaceutical composition of the present disclosure. The present invention relates to a method comprising the steps of:

[0118] In a preferred embodiment, the method comprises the steps of: f. filling the resulting pharmaceutical composition into a capsule; g. collecting the resulting capsules filled with the pharmaceutical composition; Further includes:

[0119] Patient populations that the treatment method preferably targets The treatment methods disclosed herein are suitable for patients with acute myeloid leukemia (AML) who, in accordance with standard medical practice, require myeloablative conditioning prior to allogeneic hematopoietic stem cell transplantation.

[0120] The treatment methods disclosed herein, particularly in patients at high risk of relapse as defined below, more particularly in combination with chronic administration of an S1P receptor modulator and / or tapering of immunosuppressant treatment as described in the next section, improve the GVL effect while reducing acute and chronic GVHD, and optionally the side effects of immunosuppressants, particularly calcineurin inhibitors, e.g., cyclosporin A.

[0121] Thus, the methods of the present disclosure are particularly suitable for subjects with refractory or relapsed AML following one or more AML therapies.

[0122] As used herein, the term "refractory" refers to a subject who has failed to achieve a complete remission (e.g., less than 5% of cells in the bone marrow are blasts, there are no blasts with Auer rods in the bone marrow, there is no extramedullary disease, and there is complete hematologic recovery (e.g., absolute neutrophil count (ANC) >1,000 / pL and platelet count >100,000 / pL)) and / or CRi after treatment of a disease, or who has achieved a CR and / or CRi where less than 5% of cells in the bone marrow are blasts, there are no blasts with Auer rods in the bone marrow, there is no extramedullary disease, and there is complete hematologic recovery (e.g., absolute neutrophil count (ANC) >1,000 / pL and platelet count >100,000 / pL), e.g., lasting less than 90 days after treatment of the disease.

[0123] As used herein, the terms "relapse" or "relapsed" have their ordinary meaning in the art and may refer to the resumption of AML or signs and symptoms of AML after a period of treatment-induced complete remission (e.g., initial complete remission).

[0124] In some embodiments, relapse may refer to a recurrence of disease after a complete remission that meets one or more of the following criteria: (i) >5% blasts in bone marrow or peripheral blood, and / or (ii) presence of extramedullary disease and / or disease as determined by a physician upon clinical evaluation. In some embodiments, "relapse" refers to a recurrence of disease after CR and / or CRi) that lasts for 90 days or more, e.g., less than 5% of cells in the bone marrow are blasts, there are no blasts with Auer rods in the bone marrow, there is no extramedullary disease, and there is complete hematological recovery (e.g., absolute neutrophil count (ANC) >1,000 / pL and platelet count >100,000 / pL).

[0125] As used herein, the term "remission" has its usual meaning in the art and may refer to the reduction or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission (CR), all signs and symptoms of cancer have disappeared, but cancer may still be present in the body.

[0126] As used herein, "complete remission" is measured by morphologic complete response (CMR), which is defined as leukemia clearance (<5% bone marrow blasts and no circulating peripheral blasts) along with normal absolute neutrophil and platelet counts, no signs of extramedullary leukemia, and no need for repeated transfusions, and includes CR, CRi, and CRh, as defined below.

[0127] In some embodiments, complete remission of AML means that the disease is treated and the following are true: (i) complete blood counts are normal; (ii) less than 5% of the cells in the bone marrow are blasts (leukemia cells); and (iii) there are no signs or symptoms of leukemia in the brain and spinal cord or elsewhere in the body. In some embodiments, complete remission of AML means that less than 5% of the cells in the bone marrow are blasts, there are no blasts with Auer's bands in the bone marrow, there is no extramedullary disease, and there is complete hematological recovery (e.g., absolute neutrophil count (ANC)>1,000 / pL and platelet count>100,000 / pL).

[0128] As used herein, CR is defined as leukemia clearance (<5% bone marrow blasts and no circulating peripheral blasts) along with morphologic complete response, normal absolute neutrophil and platelet counts, no signs of extramedullary leukemia, and no need for repeated transfusions.

[0129] As used herein, CRi is defined as meeting all CMR criteria except absolute neutrophil count <1,000 / μL or platelet count <100,000 / μL.

[0130] As used herein, CRh means that less than 5% of cells in the bone marrow are blasts, there are no blasts with Auer bands in the bone marrow, there is no extramedullary disease, and there is partial hematologic recovery of both peripheral blood cell types (e.g., ANC>500 / pL and platelet count>50,000 / pL).

[0131] As used herein, "partial remission" means that 5% to 25% of the cells in the bone marrow are blasts, and at least a 50% reduction in the percentage of blasts. In some embodiments, partial remission of AML means (i) 5% to 25% of the cells in the bone marrow are blasts, (ii) at least a 50% reduction in the percentage of blasts, and (iii) normal complete blood counts.

[0132] In certain embodiments, the patient population is selected among patients suffering from acute myeloid leukemia and classified as CR1 or CR2 according to the CIBMTR classification.

[0133] In a specific embodiment, the subject is selected from among patients suffering from acute myeloid leukemia who are either in first morphologic complete remission but in an adverse risk group termed "CR1 high risk" or in second and subsequent morphologic complete remission termed "CR2."

[0134] First complete remission or CR1 is defined as a patient having a treatment response, i.e., complete remission after the first treatment, according to the "ASBMT RFI 2017 - Disease Classifications Corresponding to CIBMTR Classifications of the American Society for Blood and Marrow Transplantation".

[0135] CR1 patients are classified into three groups: favorable, intermediate, and adverse. CR1 high-risk patients correspond to an adverse group defined according to the 2017 European Leukemia Network (ELN) genetic risk stratification (Dohner H, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017 Jan 26;129(4):424-447. doi: 10.1182 / blood-2016-08-733196. Epub 2016 Nov 28. PMID: 27895058; PMCID: PMC5291965), which includes t(6;9)(p23;q34.1), DEK-NUP214t(v;11q23.3), KMT2A rearrangement t(9;22)(q34.1;q11.2) and BCR-ABL1 inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2), GATA2, MECOM (EVI1-5 or del(5q);-7;-17 / abn(17p), complex karyotype, monosomic karyotype, wild-type NPM1 and FLT3-ITD high The present invention relates to a gene abnormality selected from the group consisting of mutant RUNX1, mutant ASXL1, and mutant TP53.

[0136] Second complete remission or CR2 is defined as patients in second and subsequent complete remission (CR) according to the "ASBMT RFI 2017 - Disease Classifications Corresponding to the American Society of Blood and Marrow Transplantation CIBMTR Classification" (https: / / higherlogicdownload.s3.amazonaws.com / ASBMT / 43a1f41f-55cb-4c97-9e78-c03e867db505 / UploadedImages / ASBMT_RFI_2018B_CIBMTR_Disease_Classifications.pdf). As defined above, CR2 patients have achieved CR, relapsed, and achieved one complete remission again. Final pre-HSCT status must be complete remission.

[0137] As used herein, CR2 includes patients in CR2+, i.e., third or subsequent complete remission (CR), as defined according to the "ASBMT RFI 2017 - Disease Classification Corresponding to the American Society of Blood and Marrow Transplantation CIBMTR Classification." As defined above, CR2+ patients have achieved CR twice, relapsed, and achieved complete remission again.

[0138] Because HSCT basal performance may vary depending on CR status, stratification between CR1 and CR2 requires interpretation of the results of S1P receptor modulator studies.

[0139] In one embodiment, the CR1 high risk, CR2 patient is a male or female subject between the ages of 18-70 with acute myeloid leukemia.

[0140] All CR1 high-risk and CR2 patients require hematopoietic stem cell transplantation (HSCT) and are at very high risk of relapse.

[0141] In a specific embodiment, a subject in need of the treatment methods or uses of the present disclosure is measurable residual disease (MRD) positive before the HSCT and S1P receptor modulator (preferably HSCT and moclavimod) treatment method described herein is administered.

[0142] In hematological cancers such as AML, measurable residual disease and minimal residual disease refer to the post-treatment persistence of leukemic cells at levels below morphological detection. Without wishing to be bound by any particular theory, MRD is believed to be a strong prognostic index of increased risk of recurrence or shorter survival in patients with hematological cancers such as AML. MRD testing for AML is preferably performed using one of three techniques: immunophenotypic detection by multiparameter flow cytometry (MFC), real-time quantitative PCR (RT-qPCR) and next-generation sequencing technology. MFC uses a panel of fluorochrome-labeled monoclonal antibodies to identify antigens that are abnormally exposed on leukemic cells. RT-qPCR can be used to amplify genetic abnormalities associated with leukemia. Next-generation sequencing technology can be used to evaluate a small number of genes or the entire genome. Together, RT-qPCR and next-generation sequencing technology represent a molecular approach to MRD testing. Each of the aforementioned methods of detecting a subject's MRD status are described in Ravandi, F., et al, Blood Advances 12 June 2018, vol. 2, no. 11 and Schuurhuis, GJ, et al., Blood 2018 March 22, 131(12): 1275-1291, the relevant contents of which are incorporated herein by reference in their entireties.

[0143] To guide the development of a standardized approach to MRD testing, the European LeukemiaNet (ELN) has proposed consensus recommendations for the measurement of MRD in AML. According to the ELN, a percentage of cancer (e.g., AML) cells relative to white blood cells in the subject's bone marrow measured by MFC according to the ELN recommendations for MRD testing by MFC of 0.1% or more indicates that the subject is MRD positive (MRD+) by MFC according to the ELN recommendations for MRD testing by MFC. A percentage of cancer cells relative to white blood cells in the subject's bone marrow measured by MFC according to the ELN recommendations for MRD testing by MFC of less than 0.1% indicates that the subject is MRD negative (MRD-) by MFC according to those of the ELN.

[0144] The ELN has also proposed guidelines for molecular MRD testing in AML. The ELN defines complete molecular remission as morphologic complete remission plus two consecutive MRD-negative samples obtained within a >4-week interval with a sensitivity level of at least 1 in 1,000, with samples collected and measured according to the ELN guidelines for molecular MRD testing. The ELN defines molecular persistence at low copy numbers, associated with a low risk of relapse, as low copy number MRD (<100–200 copies / 104 ABL copies corresponding to <1–2% of the target relative to the reference gene or allelic burden) in patients with morphologic CR, and a copy number or relative gain of <1 log between any two positive samples collected at the end of treatment, with samples collected and measured according to the ELN guidelines for molecular MRD testing. The ELN defines molecular progression in patients with molecular persistence as a MRD copy number gain of >1 log10 between any two positive samples collected and measured according to the ELN guidelines for molecular MRD testing. The ELN defines molecular relapse as an increase in MRD levels of >1 log10 between two positive samples in patients who previously tested negative, with samples collected and measured according to the ELN guidelines for molecular MRD testing. Both molecular persistence and molecular relapse are indicators of subjects who are MRD positive by RT-qPCR performed according to the ELN guidelines for MRD testing by RT-qPCR. Thus, patients in complete molecular remission and those labeled as having molecular persistence at low copy number are MRD negative by RT-qPCR performed according to the ELN guidelines for MRD testing by RT-qPCR. RT-qPCR is the recommended molecular method for MRD testing as discussed in Ravandi, F., el al. and Schuurhuis, GJ, el al.Specific recommendations for collecting and measuring samples (e.g., bone marrow samples) for MRD testing are described in Ravandi, F, et al, Blood Advances 12 June 2018, vol. 2, no. 11 and Schuurhuis, GJ, et al, Blood 2018 March 22, 131(12): 1275-1291, the relevant contents of which are incorporated herein by reference in their entirety.

[0145] When a subject having a hematological cancer such as AML is described herein as being "measurable residual disease negative", "minimal residual disease negative", "MRD negative" or "MRD" without further qualifiers such as by MFC or by RT-qPCR, the subject is MRD negative according to at least one of the ELN criteria described herein (e.g., MFC, molecular biology). In some embodiments, the subject is MRD negative by MFC performed according to the ELN guidelines for MRD testing. In some embodiments, the subject is MRD negative by RT-qPCR performed according to the ELN guidelines for MRD testing. In some embodiments, the subject is MRD negative by both MFC and RT-qPCR performed according to the ELN guidelines for MRD testing. In some embodiments, the subject is MRD negative by MFC performed according to the ELN guidelines for MRD testing and MRD positive by RT-qPCR performed according to the ELN guidelines for MRD testing.

[0146] In some embodiments, the subject is MRD positive by MFC performed according to the ELN guidelines for MRD testing and MRD negative by RT-qPCR performed according to the ELN guidelines for MRD testing. If the subject is MRD negative according to one of the ELN criteria described herein (e.g., MFC criteria) but MRD negative according to another of the ELN criteria described herein (e.g., RT-qPCR criteria), the subject can still be described as MRD negative according to the use of that term herein, since the subject is MRD negative according to at least one of the ELN criteria described herein.

[0147] In this specification, when a subject having a hematological cancer such as AML is described as being "measurable residual disease positive", "minimal residual disease positive", "MRD positive" or "MRD+", the subject is MRD positive by the ELN criteria for MFC and RT-qPCR described herein.For example, a subject who is MRD positive for AML can be MRD positive by MFC performed according to the ELN guidelines for MRD testing in AML, and MRD positive by RT-qPCR performed according to the ELN guidelines for MRD testing in AML.

[0148] Thus, in some embodiments of the methods described herein, the methods further include a step of detecting the subject's MRD status (e.g., prior to administering an S1P receptor modulator HSCT treatment method as described herein).

[0149] Treatment S1P receptor modulators as disclosed in the previous sections, more preferably moclavimod and pharmaceutical compositions thereof, are useful as drugs in a method for treating AML in subjects undergoing HSCT, more particularly in the subpopulation of patients as defined above.

[0150] The S1P receptor modulators, more preferably moclavimod and pharmaceutical compositions thereof as disclosed in the previous sections are also useful as drugs in a method for preventing chronic GVHD in subjects undergoing HSCT, in particular in subjects undergoing HSCT to treat AML, more particularly in the subpopulation of patients as defined above.

[0151] Detailed embodiments of such methods are disclosed below.

[0152] The method of the present disclosure includes at least the following steps: 1) administering to a subject an effective amount of an S1P receptor modulator, e.g., a compound of formula (I) or (II), or a pharma- ceutically acceptable salt thereof; 2) conditioning the subject to substantially destroy the bone marrow and immune system, comprising treating the subject with an effective amount of a chemotherapeutic agent, e.g., cyclophosphamide, and / or treating the subject with high dose chemotherapy; 3) transplanting donor-derived allogeneic hematopoietic stem cells into the subject; 4) optionally, co-administering an effective amount of one or more immunosuppressants to prevent acute GVHD, particularly during the first three months after initiation of S1P receptor modulator treatment; Includes.

[0153] Detailed embodiments of each step are described below.

[0154] Administering an S1P receptor modulator (1) To practice the methods of treatment as disclosed herein, an effective amount of an S1P receptor modulator (preferably moclavimod or other S1P receptor modulator as disclosed above) is administered to a subject in need of such treatment.

[0155] As used herein, "effective amount" refers to the amount of S1P receptor modulator (e.g., moclavimod) required to confer a therapeutic effect on a subject, either alone or in combination with one or more other active agents. Effective amounts vary, as one of skill in the art will recognize, depending, for example, on the route of administration, the use of excipients, and the concurrent use of other active agents. When treating a particular disease or condition, the desired therapeutic effect is to inhibit the progression of the disease. This may include only a temporary slowing of disease progression, but more preferably includes a permanent halt in disease progression. This can be monitored by routine methods or can be monitored according to the diagnostic methods discussed herein. The desired response to treatment of a disease or condition can also be to delay or even prevent the onset of the disease or condition. In a specific embodiment, the desired response can be to delay or prevent the onset of acute GVHD, chronic GVHD, recurrent AML, or death. In a specific embodiment, the desired response can delay or prevent the onset of GVHD resistant to systemic immunosuppressive treatment (grade III / IV) while delaying or preventing the onset of AML relapse. In other embodiments, the desired response may be to increase survival at 3, 6, 12 and 24 months post-HSCT, hi other embodiments, the desired response may be to improve quality of life, particularly at 3, 6, 12 and 24 months post-HSCT, as compared to the same HSCT treatment without administration of an S1P receptor modulator.

[0156] Administration of the S1P receptor modulator, preferably moclavimod, is initiated prior to allogeneic hematopoietic stem cell transplantation (HSCT). Preferably, administration is initiated at least 7 days prior to HSCT, such as 14, 13, 12, 11, 10, 9, 8 or 7 days prior to HSCT, preferably 11 days prior.

[0157] The S1P receptor modulator, preferably mocravimod, is then administered daily for a set period of at least 80 days, or at least 100 days, or more, following HSCT.

[0158] In a preferred embodiment, the S1P receptor modulator, preferably mocravimod, is administered for a longer period (continuous use), for example daily for at least 6, 7, 8, 9, 10, 11, 12, 18, 24 months or more after HSCT, typically for the life of the subject or until relapse. In a specific embodiment, the S1P receptor modulator, preferably mocravimod, is administered daily for 6-24 months, for example 12 months, after HSCT.

[0159] The daily dosage and dose of the S1P receptor modulator, preferably mocravimod, described herein may depend on the condition of the subject, i.e., the stage of the disease, the severity of the symptoms caused by the disease, the general health condition, as well as age, sex and weight, and other factors that are obvious to those skilled in the medical field.Similarly, the dose of the S1P modulator, preferably mocravimod, for treating a human subject suffering from AML and undergoing allogeneic HSC transplantation can be determined according to parameters that are understood by those skilled in the medical field.

[0160] In some embodiments, the amount of S1P receptor modulator, preferably moclavimod, administered per day is a fixed amount. In some embodiments, the fixed daily dosage is 0.05 mg to 40 mg per day, preferably 0.1 mg to 35 mg, more preferably 0.5 mg to 30 mg, even more preferably 1 mg to 15 mg per day, even more preferably 1.5 mg to 7 mg, even more preferably 2 mg to 5 mg, even more preferably about 3 mg per day or about 1 mg per day.

[0161] In some embodiments, the S1P receptor modulator is mocravimod, and said mocravimod is administered daily at a dosage of 3 mg per day for at least 6, 7, 8, 9, 10, 11, 12, 18, 24 or more months following HSCT.

[0162] Daily dosage can be administered as one dose per day or multiple doses on a single day.In preferred embodiments, daily dosage is administered once a day.In some embodiments, dosage is administered several times a day, preferably three times a day.In some embodiments, the minimum dosage sufficient to provide effective treatment can be used.

[0163] In another embodiment, said S1P receptor modulator is mocravimod, said mocravimod is administered at a daily dose of 3 mg, for example, three 1 mg solid dosage forms per day.Indeed, three 1 mg solid dosage forms, for example capsules or tablets, administered at intervals, are easier to swallow than a single 3 mg solid dosage form.

[0164] Step 2 of myeloablative conditioning Prior to allogeneic hematopoietic stem cell transplantation, patients should be preconditioned by using high-dose chemotherapy according to national guidelines adapted to institutional practice, also called chemoradiotherapy, and / or performing total body irradiation (TBI).Preferably, the standard treatment is a myeloablative regimen.However, non-myeloablative regimens or low-intensity conditioning may also be used for some subgroups of patients (Jethava et al., Bone Marrow Transplant. 2017 Nov;52(11):1504-1511).

[0165] High-dose chemotherapy, high-dose total body irradiation (TBI), or a combination thereof is administered.

[0166] As used herein, "chemotherapeutic agent" and "chemotherapy" refer to drugs and treatments, respectively, that inhibit (e.g., stop) the growth of cancer cells, for example, by killing the cells or inhibiting cell division. "Chemotherapeutic agent for AML" and "chemotherapy for AML" refer to chemotherapy and chemotherapy, respectively, that are administered to a subject for the purpose of treating AML in the subject.

[0167] Examples of chemotherapeutic agents may include cyclophosphamide (CY), cytarabine (CA), etoposide (ETP), busulfan (BU), fludarabine (FLU), melphalan (MEL), methotrexate (MTX), cyclosporine A (CsA), and the like, and mixtures thereof, such as fludarabine / busulfan, busulfan / cyclophosphamide, and fludarabine / melphalan.

[0168] For example, one of the following conditioning regimens may be administered (days are relative to the day of HSCT):

[0169] Examples of conditioning regimens include, for example: Fludarabine; 30 mg / m 2 IV once daily for 5 days from days -8 to -4 (150 mg / m 2 ) Thiotepa: 5 mg / kg IV twice daily for 1 day on day -7 (10 mg / kg) Melphalan: 60 mg / m 2 IV once daily for 2 days on days -2 and -1 (120 mg / m 2 ) Examples include:

[0170] Dose modifications in the conditioning regimen may be made to suit patient condition and / or local practice.

[0171] According to institutional practice, the following three conditioning regimens may be selected next to the standard regimens described herein above: Melphalan can be substituted for busulfan. Thiotepa can be substituted for cyclophosphamide. 1. Busulfan + Fludarabine + Cyclophosphamide: - Busulfan 110 mg / m 2 IV, days -7 to -4 (440mg / m 2 ) - Fludarabine 25mg / m 2 , for 5 days from -6 to -2 (125 mg / m2 ) - Cyclophosphamide 14.5 mg / kg IV on days -3 and -2 (29 mg / kg) 2. Busulfan + Fludarabine + Thiotepa: - Busulfan 3.2 mg / kg / day IV for 3 days from days -5 to -3 (9.6 mg / kg) - Fludarabine 50mg / m 2 / day IV for 3 days (days -5 to -3) (150 mg / m 2 ) - Thiotepa 5 mg / kg / day IV for 2 days (10 mg / kg) on ​​days -7 and -6 3. Melphalan + Thiotepa + Fludarabine: - Melphalan 100 or 140 mg / m 2 IV, day -6 - Fludarabine 40mg / m 2 IV, for 4 days from days -5 to -2 (160 mg / m 2 ) - Thiotepa 5-10 mg / kg IV on day -7 (Days are relative to the day of HSCT).

[0172] For example, treatment consisting of administration of cyclophosphamide followed by total body irradiation, treatment consisting of administration of busulfan and cyclophosphamide, etc. may be mentioned.

[0173] Step 3 of HSC treatment The conditioning treatment is followed by allogeneic HSCT, the goal of which is two-fold: first, to replace the patient's diseased hematopoietic system with new HSC stemmings derived from a genetically distinct healthy donor, and second, to explore the immunotherapeutic effect of the donor graft, i.e., the graft-versus-leukemia effect, termed "GVL."

[0174] For example, allogeneic HSCT can involve transplanting donor-derived HSCs into the patient. HSCs are harvested from the donor and administered to the patient by intravenous infusion.

[0175] HSCs can be collected from different sources. HSCs mobilized into peripheral blood by granulocyte colony-stimulating factor (G-CSF) are the preferred source for transplantation today. Alternative sources of HSCs in clinical use are bone marrow and umbilical cord blood. Suitable donors should be HLA-matched related or unrelated donors with 8 / 8 or better matches at the HLA-A, -B, -C, -DRB1 and / or -DQB1 loci as determined by high-resolution HLA typing.

[0176] Allogeneic hematopoietic stem cell transplantation may be performed as standard of care. Suitable methods are described, for example, in Boglarka Gyurkocza, Andrew Rezvani & Rainer F Storb (2010) Allogeneic hematopoietic cell transplantation: the state of the art, Expert Review of Hematology, 3:3, 285-299, DOI: 10.1586 / ehm.10.21.

[0177] Preferably, the stem cell source is mobilized peripheral blood collected via apheresis by a matched donor. The minimum recommended CD34+ cell dose in the graft is 2×10 6 / kg, the recommended target dose is approximately 5 × 10 6 / kg.

[0178] Immunosuppressant treatment step (4) The S1P receptor modulator, preferably moclavimod, may also be used alone and / or in suitable association as well as combination with other pharma- ceutical active compounds.

[0179] To reduce the risk of acute GVHD, an S1P receptor modulator, preferably moclavimod, is co-administered in conjunction with immunosuppressants, especially for at least the first 3 months after HSCT.

[0180] Examples of immunosuppressants include, without limitation, cyclosporin A, sirolimus, tacrolimus, methotrexate, and mycophenolate.

[0181] In certain embodiments, the immunosuppressant comprises or consists essentially of an effective amount of cyclosporine A.

[0182] Administration of cyclosporine A or a related immunosuppressant may be initiated, for example, within the period between the start of administration of the S1P receptor modulator, preferably moclavimod, and the day of HSC transplantation, preferably 3 or 2 days prior to HSC transplantation or 1 day prior to HSC transplantation.

[0183] For example, intravenous administration of cyclosporine A may be performed at an initial dosage of 2-6 mg / kg / day, preferably 3-5 mg / kg / day. Dosage adjustments are performed based on cyclosporine A toxicity or concentration relative to the target trough concentration (150-400 mg / L). Cyclosporine A administration may be changed to oral administration if the patient tolerates oral administration. The initial dosage for oral administration may be set to the current dosage for intravenous administration. Cyclosporine A dosage is monitored at least weekly and changed to a clinically appropriate dosage.

[0184] In one embodiment, dosage levels of 2-6 mg / kg / day, preferably 3-5 mg / kg / day, may be continued for a period of up to 2 weeks before the oral maintenance therapy is changed during the day of HSC transplantation. Preferably, when the change to oral maintenance therapy is made, the daily dose of cyclosporine A may be about 12.5 mg / kg. Preferably, maintenance therapy is continued for at least 3 months, preferably 6 months, before reducing the dose. In particular, the dose of cyclosporine A may be gradually reduced to zero over the course of one year after transplantation.

[0185] The use of S1Pr drugs facilitates accelerated dose reduction of calcineurin inhibitors such as cyclosporine A (CsA) and tacrolimus (TAC), which is a major benefit to the patient, minimizing the toxicity of the calcineurin inhibitors used and may be advantageous in reconstituting the immune system (HSCT) to better fight against cancer.

[0186] When methotrexate is used together with S1Pr drug, the dosing schedule and dosage of methotrexate will be adapted to the standard of hospital.For example, on the day of administration of HSCT (e.g., 11 days after the first administration of S1PR modulator, preferably mocrabimod), 10mg / kg methotrexate is administered, and 2 and 5 days after the first administration and 16 days after that, 6mg / kg methotrexate is administered, respectively.The use of S1Pr drug also facilitates the acceleration of methotrexate dose reduction, which is the main benefit to patients, and can be advantageous to minimize methotrexate toxicity and reconstruct immune system (HSCT) to fight against cancer better.

[0187] The present methods advantageously allow for the reduction of the amount of immunosuppressants typically administered following allogeneic HSC transplantation while preventing acute and chronic GVHD and preserving the graft-versus-leukemia effect, thus reducing the deleterious effects of such immunosuppressant treatment.

[0188] In another embodiment, the immunosuppressant used in the method does not include tacrolimus.In another embodiment, the immunosuppressant used in the method does not include cyclosporine A.

[0189] Calcineurin inhibitors such as cyclosporine A (CsA) and tacrolimus (TAC) suppress donor T cell activation and remain the most commonly used immunosuppressants for acute GVHD prophylaxis, however, these drugs also inhibit leukemia-specific T cell responses, resulting in impaired GVL efficacy.

[0190] According to this method, chronic administration of an S1P receptor modulator, preferably moclavimod, significantly prevents chronic GVHD and allows for a reduction (tapering) in the amount of cyclosporine A or other immunosuppressant drugs administered to a subject in need thereof, thereby reducing the deleterious effects of such immunosuppressant compounds while still preventing chronic GVHD and improving the GVL effect.

[0191] In a preferred embodiment where the S1P receptor, preferably moclavimod, is administered for an extended period of time (continuous use), for example for at least 6 months, preferably 12, 18 or 24 months, typically for the life of the subject or until relapse, said subject is further treated with an effective amount of an immunosuppressant comprising at least cyclosporine A, and said immunosuppressant treatment is reduced or stopped prior to 6 months post-HSCT, preferably within a period of 3-6 months, or 3-5 months, or 3-4 months post-HSCT.

[0192] In specific embodiments, the immunosuppressant treatment (e.g., cyclosporine A treatment) is substantially reduced (tapered), e.g., by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% as compared to the starting dose of the immunosuppressant.

[0193] Tapering of immunosuppressant treatment may be performed rapidly or gradually, for example, by stepwise reduction of the dose over 1, 2, 3, 4, 5 or 6 weeks 1, 2 or 3 months after HSC transplantation, and / or treatment may be discontinued at least 3, 4, 5 or 6 months after HSC transplantation. For example, the immunosuppressant dose may be gradually reduced from 6 weeks to 2 months and discontinued 3 to 4 months after HSC transplantation. The physician will determine the most appropriate tapering regimen depending on the patient's condition.

[0194] In another embodiment, the methods of the disclosure comprise administration of an S1P receptor modulator, preferably moclavimod, to achieve a reduction in the incidence of refractory GVHD, a delay in relapse or an increase in relapse-free survival, an increase in overall survival or progression-free survival, or an improvement in quality of life.

[0195] In specific embodiments, the disclosed methods delay or prevent the onset of acute GVHD, chronic GVHD, recurrent AML, or death, particularly for at least 3, 6, 9, 12, 18, or 24 months after HSCT. In specific embodiments, the disclosed methods delay or prevent the onset of GVHD resistant to systemic immunosuppressive treatment (grade III / IV), while delaying or preventing the onset of AML recurrence, particularly for at least 3, 6, 9, 12, 18, or 24 months after HSCT.

[0196] In a specific embodiment, the method reduces morbidity or mortality in a population of subjects, particularly through GVHD-free relapse-free survival, and both relapse-related and transplant-related mortality. For example, the method reduces the incidence or severity of either GVHD, refractory GVHD, relapse, or death in a population of subjects for at least 3, 6, 9, 12, 18, or 24 months after HSCT.

[0197] In a specific embodiment, said patient is free of refractory GvHD and relapse-free (rGRFS) at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 months following HSCT.

[0198] As used herein, rGRFS is calculated similarly to conventional GRFS, which treats grade III-IV acute GVHD, chronic GVHD requiring systemic treatment, and disease recurrence / progression as events, except that GVHD that has resolved and does not require systemic treatment is excluded at last evaluation as an event in rGRFS.

[0199] Thus, in a specific embodiment of the method, said subject receives at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months post-HSCT one or more of the following: Grade III / IV acute graft-versus-host disease (GVHD) refractory to at least two lines of immunosuppressive treatment, - widespread chronic GVHD refractory to systemic immunosuppressive treatment, Disease recurrence, ·death does not indicate one or more of

[0200] Also disclosed herein are methods for improving overall survival in subjects, comprising, for each subject, treating the subject with any of the methods using an S1P receptor modulator disclosed herein.

[0201] In a specific embodiment, the method improves the subject's quality of life at 3, 6, 12 or 24 months, preferably as measured by the Foundation for Accreditation of Cellular Therapy Bone Marrow Transplant (FACT-BMT) questionnaire and / or the MD Anderson Symptom Assessment Inventory (MDASI), compared to subjects treated according to standard of care for HSCT without administration of an S1P receptor modulator. The improvement can be significant, e.g., an increase of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more.

[0202] In another embodiment, an S1P receptor modulator for use in accordance with the present disclosure is a maximum plasma level (Cmax) of 0.4 ng / mL to 1 ng / mL, preferably 0.55 ng / mL to 0.85 ng / mL, more preferably 0.65 ng / mL to 0.75 ng / mL, Time to maximum plasma level (Tmax) of 2 h to 10 h, preferably 4 h to 8 h, more preferably 5 h to 7 h, and Area under the plasma concentration curve (AUClast) of 60h*ng / mL to 74h*ng / mL, preferably 64h*ng / mL to 70h*ng / mL, more preferably 66.5h*ng / mL to 67.5h*ng / mL has.

[0203] In another embodiment, an S1P receptor modulator for use in accordance with the present disclosure is a maximum plasma level (Cmax) of 0.6 ng / mL to 1.20 ng / mL, preferably 0.75 ng / mL to 1.05 ng / mL, more preferably 0.85 ng / mL to 0.95 ng / mL, Time to maximum plasma level (Tmax) of 6 h to 14 h, preferably 8 h to 12 h, more preferably 9 h to 11 h, and A plasma concentration area under the curve (AUClast) of 63.5h*ng / mL to 77.5h*ng / mL, preferably 67.5h*ng / mL to 73.5h*ng / mL, more preferably 69.5h*ng / mL to 71.5h*ng / mL has.

[0204] In another embodiment, an S1P receptor modulator for use according to the present disclosure has a half-life (T1 / 2) of between 110 h and 134 h, preferably between 116 h and 128 h, more preferably between 121 h and 123 h.

[0205] In another embodiment, an S1P receptor modulator for use according to the present disclosure has a half-life (T1 / 2) of between 100 h and 122 h, preferably between 105 h and 117 h, more preferably between 110 h and 112 h. EXAMPLES

[0206] [Example 1] HSCT with moclavimod for the treatment of AML The method of the present disclosure can be carried out according to the following method.

[0207] Human patients who are in first complete remission (CR1) or second complete remission or later (CR2) and eligible for HSCT from peripheral blood stem cells harvested from a sibling or matched unrelated donor may be candidates for this treatment.

[0208] Treatment involves daily chronic administration of an oral composition of moclavimod at a dose of 3 mg per day starting on day -11 prior to HSCT and continuing for at least 6 months, preferably at least 12 months or until relapse, for the life of the subject (chronic administration).

[0209] Along with KRP203, patients will receive standard of care GVHD prophylaxis, preferably beginning on day -4 prior to allogeneic HSCT, which includes a combination of cyclosporine A and methotrexate.

[0210] Patients will be subjected to the following conditioning regimen: Fludarabine; 30 mg / m 2 iv once daily for 5 days from days -8 to -4 (150 mg / m 2 ), thiotepa; 5 mg / kg iv twice daily for 1 day on day -7 (10 mg / kg), and melphalan; 60 mg / m 2 iv once daily for 2 days on days -2 and -1 (120 mg / m 2 ). Conditioning is followed by allogeneic HSCT. Granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSC) are the preferred source of hematopoietic stem cells (HSC). Donors should be HLA-matched related or unrelated with 8 / 8 or greater matches at the HLA-, -B, -C, -DRB1, and / or -DQB1 loci as determined by high-resolution HLA typing.

[0211] [Example 2] Clinical studies to treat AML patients at high risk of relapse A prospective example is provided herein describing a prospective, randomized, open-label, multicenter, phase II comparative study to evaluate the efficacy and safety of moclavimod in patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation (HSCT). overview

[0212] [Table 2-1]

[0213] [Table 2-2]

[0214] [Table 2-3]

[0215]

Table 2-4

[0216]

Table 2-5

[0217]

Table 2-6

[0218]

Table 2-7

[0219]

Table 2-8

[0220]

Table 2-9

[0221]

Table 2-10

[0222]

Table 2-11

[0223]

Table 2-12

[0224]

Table 2-13

[0225] [Table 2-14]

[0226] [Table 2-15]

[0227] [Table 2-16]

[0228] [Table 2-17]

[0229] [Table 2-18]

[0230] Introduction Rationale for the use of moclavimod Mocravimod is a sphingosine 1 phosphate receptor modulator (S1P) developed by the applicant as an adjuvant therapy for allogeneic hematopoietic stem cell transplantation (allo-HSCT). S1P is a class of products with effects on the immune system. Some products are in development or already approved as immunotherapies for the treatment of autoimmune diseases. Fingolimod (Gilenya; FTY720) is approved for the treatment of multiple sclerosis (MS). The mechanism of action of mocravimod is similar to fingolimod. Both are prodrugs and their active phosphorylated metabolites block lymphocyte egress from lymph nodes, thereby reducing circulating lymphocyte counts. However, the mocravimod profile is of interest for development in conjunction with allo-HSCT and standard of care (SoC) to improve disease progression rate, overall survival and quality of life in patients with acute myeloid leukemia. Treatment with moclavimod (starting 11 days before HSCT and continuing for up to 1 year after HSCT) results in the sequestration of lymphocytes in secondary lymphoid organs. The sequestration process induces two positive effects: 1) the graft-versus-host effect (GvH) is reduced because alloreactive T cells do not migrate to peripheral tissues, and 2) the graft-versus-leukemia effect (GvL) is increased due to eradication of residual disease by alloreactive T cells sequestered in lymphoid tissues such as lymph nodes and white pulp. Leukemic cells (blasts) originate from the bone marrow and spread to peripheral blood and other tissues if morphological relapse occurs. However, if a patient achieves complete remission, only a minimal number of blasts can survive in the bone marrow and lymphoid tissues, even until induction / consolidation therapy. Progressive immune reconstitution after HSCT supports GvL by alloreactive cells in the bone marrow and lymphoid tissues. Lymphocytes such as alloreactive T cells play a key role in the GvL effect and are primarily present in lymphoid tissues. Thus, moclavimod is not immunosuppressive, allowing alloreactive T cells to retain anti-leukemic reactivity and boost GvL without off-target reactivity translating into GVHD. A strong improvement in morbidity-mortality from the addition of moclavimod to SoC in patients undergoing HSCT is expected via both relapse-related mortality (RRM) and transplant-related mortality (TRM).

[0231] Compared to alternative treatment options such as targeted therapy that focus on molecular biomarkers determined by the genetic profile of the tumor at diagnosis, alloreactive T cells have a broader specificity profile. Thus, control of escape mutant leukemias via mocravimod-assisted HSCT to a broader target population could address some of the strong limitations of targeted therapy. Mocravimod will be evaluated against placebo, as no clinically relevant comparator has been approved. These and other data support moving forward with a pivotal clinical study to evaluate mocravimod as adjuvant therapy in allo-HSCT in combination with SoC. SoC regimens will vary according to local practice and may include the use of a calcineurin inhibitor (CNI), such as CsA, in conjunction with another immunosuppressant, such as MTX. Study treatment will begin in the early pre-transplant period (11 days before HSCT) and will be administered throughout the entire treatment phase (1 year) in conjunction with a CsA and MTX-based GVHD prophylaxis regimen in the mogravimod arm and in the control arm according to the clinical site's institutional practice.

[0232] Allogeneic hematopoietic stem cell transplantation in high-risk AML Allo-HSCT is an important component of the current standard of care in the management of AML and is indicated for induction failure after relapse (refractory) and for consolidation of complete remission.

[0233] Compared with chemotherapy, allo-HSCT reduces the risk of relapse, but the risk of treatment-related mortality is higher. In AML, allo-HSCT is indicated when the risk of relapse is >35% (Dohner et al., Blood 2017 Jan 26;129(4):424-447) and when the patient's age, comorbidities and frailty make them suitable for the procedure.

[0234] Allo-HSCT in high-risk AML is currently the only potentially curative option. Although benefiting from the GvL effect, this procedure is currently associated with a high risk of non-relapse morbidity and death due to GVHD. The risk of GVHD is currently related to the strength of the GvL effect and is mitigated by immunosuppressant prophylaxis, which in turn reduces the GvL effect. Investigational treatments that compete with HSCT in AML, such as targeted drugs, monoclonal antibodies and immunoconjugates, checkpoint inhibitors, T cell engagers, and CAR-T cells, may result in sustained remission and thus compete with HSCT by prolonging survival without the prospect of a cure. The potential for moclavimod to reduce the GvH effect while preserving GvL holds promise as a way to maintain the prospect of a cure while reducing transplant-related mortality and morbidity.

[0235] HSCT and GVHD Graft-versus-host disease (GVHD) is indeed considered an off-target effect of the expected graft-versus-leukemia effect involving donor T cells.

[0236] Alloreactivity is the basis of the graft-versus-leukemia effect (GvL), which limits the probability of relapse after transplantation.

[0237] Alloreactive stems from mismatches: alloantigens, minor HLA mismatches (donor-recipient polymorphisms), major HLA mismatches (A, B, C, DR, DQ, DP) and tumor alloantigens. GvHD can occur acutely or chronically (aGvHD, cGvHD).

[0238] GvHD is common after allo-HSCT with a high prevalence: aGvHD 30-70%, cGvHD 20-50% (Magenau et al., Br J Haematol. 2016 Apr;173(2):190-205). GvHD is the leading cause of post-transplant mortality and morbidity, as well as impaired quality of life after transplantation. Despite some recent improvements in GvHD management, GvHD remains problematic. First-line treatment with T-cell suppression via immunosuppressive prophylaxis with CNIs and MTX, or systemic corticosteroids, carries the risk of opportunistic infections, organ toxicity, and minimal GvL effects. Alternatively, manipulation of specific immunomodulatory agents can increase regulatory T cells and downregulate inflammatory pathways, while reducing effector T cells involved in GvHD and GvL.

[0239] The combination of CsA and MTX has been demonstrated to have a lower incidence of grade II-IV aGvHD (Storb et al., N Engl J Med 1986 Mar 20;314(12):729-35), while efficacy remains suboptimal at approximately 50% and tolerability is associated with nephrotoxicity and infection. Alternative prophylactic regimens have been proposed in various settings, including tacrolimus, mycophenolate mofetil (MMF), post-transplant cyclophosphamide, and alpha-1 antitrypsin (AAT). JAK inhibitors, such as ruxolitinib, have shown moderate efficacy and have recently been approved for steroid-refractory GvHD therapy. Second-line treatments include anti-TNF antibodies, antithymocyte globulin (ATG), sirolimus, and MMF.

[0240] Extracorporeal photochemotherapy (ECP) has also been proposed in high-risk / refractory aGvHD, possibly in combination with mesenchymal stem cells (MSCs). Additionally, fecal microbial transplantation is under investigation in aGvHD.

[0241] Management of cGvHD includes systemic corticosteroids with long-term tapering in the first line and ECP, rituximab or ibrutinib in the second line.

[0242] Several high-risk biomarkers for GvHD have been identified: ST2 (IL-1R) and REG3 alpha (a biomarker of intestinal injury).

[0243] Post-HSCT and Transplant Relapse Post-transplant relapse in AML is biologically and clinically heterogeneous. Several factors may affect the incidence of post-transplant relapse in AML.

[0244] The following risk factors have been identified: - Type of conditioning regimen: Reduced-intensity conditioning is associated with a higher risk of recurrence - Type of GvHD prophylaxis: intensive regimens based on antithymocyte globulin (ATG) or anti-T cell antibodies; T cell-depleted grafts are associated with a high risk of recurrence - Absence of chronic GVHD is associated with high risk of relapse via insufficient GvL - HLA mismatch and loss of complete chimerism - Measurable residual disease (MRD) after transplant: persistent or recurrent.

[0245] All patients who achieve beyond first relapse (CR2) require HSCT and are at very high risk of relapse.

[0246] Clinical outcomes of HSCT vary depending on the depth of remission and complications such as fungal infections or organ failure during induction.

[0247] HSCT outcomes in CR2 AML are limited by the substantial number of patients who acquire complications and cumulative chemotherapy toxicity compared with patients who have HSCT in CR1.

[0248] Because HSCT baseline performance may vary depending on CR status, interpretation of the mocrabimod study results requires stratification into CR2 versus CR1.

[0249] Standardization of definitions of recurrence and methods for assessing MRD is needed.

[0250] The post-transplant clonal profile will often differ from the clonal profile at diagnosis.

[0251] Due to the polyclonal nature of AML, clones that evade prior molecular testing may determine relapse.

[0252] Various prevention and treatment approaches have been investigated to reduce recurrence rates. - High dose conditioning regimens / newer agents, - early discontinuation of immunosuppressive therapy, - Post-transplant therapy to change MRD positive status to negative status Includes.

[0253] However, there is a need to combine customized molecular monitoring (NGS), multiparameter flow cytometry, and chimerism assessment to routinely evaluate MRD status in AML.

[0254] - Prophylactic DLI - Maintenance of remission via targeted therapy, epigenetic manipulation, and immune-based approaches.

[0255] In higher-risk AML patients, relapse rates remain above 60% with an overall median disease-free survival (DFS) of <1 year (range: 4-11 months).

[0256] With the exception of HSCT, no maintenance therapy has demonstrated sufficient efficacy in AML to be considered the standard.

[0257] Small molecules such as FLT3 inhibitors, hypomethylating agents or prophylactic donor lymphocyte infusions are maintenance therapies.

[0258] Although there has been some progress in reducing non-relapse mortality (NRM), the risk of relapse after HSCT has not been significantly reduced in the last decade.

[0259] Uncoupling GvL and GvH through limiting off-target effects and improving T cell availability to targets is a desirable approach to reduce the risk of relapse without increasing the risk of GVHD. Moclavimod is the only investigational product currently in clinical development with a favorable pharmacological profile and scientific rationale to meet this objective.

[0260] HSCT and survival, GVHD-free relapse-free survival (GRFS) endpoint Post-transplant survival is largely related to AML relapse after HSCT, with significant non-relapse mortality. Various strategies have been investigated to reduce relapse and thus improve OS.

[0261] The dose intensity of the conditioning regimen matters, as reduced intensity conditioning is associated with higher relapse rates, whereas myeloablative conditioning improves survival and reduces relapse. However, the impact of dose intensity may be genomics dependent.

[0262] Immune checkpoint blockade (CTLA4, PD1, PDL1, etc.), targeted therapies (TKIs), maintenance hypomethylating agents (HMAs) and vaccines are under investigation and may be associated with poor tolerability.

[0263] The goal of moclavimod therapy is to make allo-HSCT as safe and simple as autologous HSCT while preserving the allogeneic GvL effect.

[0264] The performance of HSCT was assessed by GRFS, a composite endpoint for the evaluation of investigational drugs proposed as adjuvant to HSCT: GVHD-free / relapse-free survival (GRFS), including events grade 3-4 acute GVHD within 1 year after HSCT, chronic GVHD requiring systemic treatment, relapse or death (Holtan et al., Biol Blood Marrow Transplant. 2015 Jun;21(6):1029-36).

[0265] More recently, refractory GRFS (rGRFS) has been proposed as an accurate endpoint for long-term HSCT evaluation. rGRFS is calculated similarly to conventional GRFS, which treats grade III-IV acute GVHD, chronic GVHD requiring systemic treatment, and disease relapse / progression as events, except that GVHD that has resolved and does not require systemic treatment is excluded at the last evaluation as an event in rGRFS.

[0266] The rGRFS is more accurate than the GRFS for mocrabimod assessment: death, recurrence, or persistent severe GVHD.

[0267] Research intervention and IMP development programme. Related non-clinical findings KRP203 (moclavimod) is an immunomodulatory agent that selectively targets sphingosine 1-phosphate (S1P) receptors via its phosphorylated active metabolites. KRP203-phosphate is a potent agonist for human S1P1 and S1P4 and a potent but partial agonist for hS1P3 and S1P5. The therapeutic effect is thought to result from the prevention of effector lymphocyte recirculation from lymphoid tissues to susceptible target organs such as the gut, skin or CNS.

[0268] KRP203-phosphate induces a long-lasting and complete internalization of S1P1, which renders these cells insensitive to S1P and removes the inevitable signals emanating from lymphoid organs. KRP203 does not inhibit allogeneic stimulated T-cell proliferation in mixed lymphocyte reactions (MLR) at therapeutic concentrations in vitro, does not exhibit hematological cytotoxicity, and does not induce apoptosis of CD4+ T cells. KRP203 reduces lymphocyte counts in peripheral blood by more than 80%.

[0269] Using off-target binding assays including GPCRs, ion channels, transporters, nuclear receptors and enzymes, a large safety margin was demonstrated with a 7×10 -3Calculations were made relative to estimated KRP203-P-free plasma concentrations in nM. Therefore, secondary pharmacological effects are unlikely to result from non-specific receptor activation at therapeutic doses.

[0270] Safety pharmacology studies revealed no significant effects on respiratory function in dogs at doses up to 20 mg / kg (the highest dose tested), nor on bronchoconstrictor responses induced by sensitizers in rats pretreated with 3 mg / kg KRP203. No adverse neuropharmacological effects were found in rats at doses up to 2000 mg / kg, except for some piloerection. In a VEGF-induced vascular leak model, KRP203 proved to be vasoprotective (barrier-protective), while mildly reducing the pulmonary endothelial barrier after a single oral dose. In vitro cardiovascular safety pharmacology evaluations showed a slight inhibitory potential of KRP203 (0.5-10 μM) on the hERG channel; however, the active moiety showed no significant effects up to the highest concentration tested of 3 μM. No APD prolongation was found in guinea pig papillary muscle preparations at a concentration of 3 μM of KRP203 or its phosphate salts. Although no indication of QT prolongation was observed in telemetered dogs or anesthetized guinea pigs, KRP203 was shown to have the potential to decrease heart rate (isolated rabbit hearts or guinea pigs; extrapolated exposure ≥ 0.1 μM) or increase blood pressure (dogs; extrapolated exposure ≥ 0.3 μM). Based on available in vitro and in vivo data, KRP203 has not been shown to cause arrhythmias or QT prolongation in humans, except for the potential to cause negative chronotropic effects and some mild increases in blood pressure.

[0271] After oral administration of [14C]KRP203, radioactivity Tmax was 7 and 9.3 hours in male rats and dogs, respectively, indicating slow absorption. Blood distribution of [14C]KRP203-associated radioactivity was species-dependent, and plasma protein binding of [14C]KRP203 was found to be high in all species investigated (including >99% in human plasma). After intravenous administration of [14C]KRP203, radioactivity was readily distributed to rat and dog tissues with similar volumes of distribution (Vss=8.0 L / kg in rats).

[0272] After po dosing (0.5 mg / kg) of [14C]KRP203 to Wistar rats, compound-associated radioactivity showed maximum tissue concentrations at 8–24 h post-dosing. Highly exposed tissues were the liver and, to a lesser extent, the kidneys, small intestine, adrenal glands, lungs, spleen, and mesenteric lymph nodes. Radioactivity in CNS tissues (cerebrum, cerebellum, and medulla oblongata) was lower than in plasma up to 24 h post-dosing after a single dose. Radioactivity was eliminated very slowly from these tissues, and [14C]KRP203-associated radioactivity was 5–6-fold higher in CNS tissues than in plasma at 168 h post-dosing. After 14 days of multiple oral doses of [14C]KRP203 (0.5 mg / kg / day), more total radioactivity accumulated in the brain compared to plasma, and was eliminated much more slowly.

[0273] Examination of the in vitro metabolite profile of KRP203 showed that only phosphorylated KRP203 was detected in the blood of rats, dogs and humans in all species, with the highest formation rate in rat blood, followed by dog ​​and human blood. In human hepatocytes, quantitatively, phosphorylated KRP203 was the more prominent metabolite among them.

[0274] The in vivo ratio of plasma phosphorylated KRP203 to KRP203 was up to 45 in rats. The metabolic activity for KRP203 in human blood and hepatocytes was lower than that of other species, so the metabolic clearance of KRP203 in humans is expected to be lower than that in rats and dogs. Using in vitro tests, KRP203 did not show any associated potential for inhibition of the activity of human cytochrome P450 isoenzymes. KRP203 and KRP203 phosphate did not show significant induction of CYP3A4 via the human PXR receptor up to concentrations of 6.15 μM and 50 μM, respectively. KRP230 formed small amounts of covalent drug-protein adducts in human hepatocytes in vitro. The detection level was low (68 pmol / 10 at 3 h). 6 Due to the nature of the cellular mechanisms of action of agonists in vivo (e.g., in vivo adduct formation is unlikely to be associated with clinically relevant findings at low dose levels (e.g., less than 10 mg).

[0275] Plasma toxicokinetic data in dogs after single and multiple doses (4 and 13 weeks) demonstrated a trend towards greater than proportionality between exposure and dose at higher doses for KRP203, and a trend towards less than proportionality at all dose levels for KRP203 phosphate. In rats, there was clear proportionality between exposure and dose for both KRP203 and KRP203 phosphate after single and multiple dosing. KRP203 phosphate / KRP203 ratios (based on AUC0-24h) of 1.4 to 6.6 and 10.9 to 19.1 were observed in dogs and rats, respectively. There was no evidence of accumulation for either KRP203 or KRP203 phosphate after repeated dosing (4 and 13 weeks) in dogs, while in rats, exposure was increased 2- to 5-fold at the end of 13 weeks of treatment compared to a single dose. No sex differences in exposure were observed for both KRP203 and KRP203 phosphate in rats and dogs.

[0276] Acute toxicity studies have shown that KRP203 was well tolerated up to high dose levels and was lethal only at oral doses of 1000 mg / kg in rats or intravenous doses above 50 mg / kg in rats or mice. No deaths were observed following single oral doses up to 2000 mg / kg in dogs.

[0277] Repeated dose toxicity studies in mice (2 weeks) revealed mortality in this species at doses of ≥ 45 mg / kg / day, while no mortality was observed in rats and dogs (up to 26 and 52 weeks, respectively) at daily doses of 50 mg / kg and 15 mg / kg, respectively. As expected from the mode of pharmacological action, effects and characteristic changes related to lymphodepletion in lymphoid organs were observed in all species and at all dose levels tested in the repeated dose toxicity studies. In addition to these effects, the primary target organs for toxicity were the lungs (mice, rats, and dogs), liver (mice and rats), and kidneys (mice).

[0278] The lung was shown to be a consistent target organ in all animal species tested. At the end of the 13-, 26-, and 52-week rat and / or dog studies, no histopathological changes were observed with systemic exposure similar to the changes in pulmonary effects that occurred in the 4-week toxicity study. Transient activation of phagocytes and increased secretion of soluble markers by these cells are believed to be the primary contributors to smooth muscle hypertrophy / hyperplasia.

[0279] Hepatic effects (bile duct hyperplasia, fluid accumulation in the bile duct (rats only), bile duct fibrosis and focal necrosis) were seen in rats and mice but not in dogs. Rat liver findings did not worsen significantly upon extension of treatment from 4 to 26 weeks.

[0280] In general, liver effects were mild and, in combination with general clinical signs (e.g., body weight and food consumption), occurred only at high dose levels in some studies, possibly exceeding the MTD. Furthermore, KRP203 did not show in silico warning signs of human liver side effects, and liver gene profiling in a 2-week exploratory toxicity study in rats showed no hepatotoxicity-related changes.

[0281] The kidney was a target organ of toxicity only in mice and only in 2-week studies at doses ≥45 mg / kg. Minimal to severe lesions were seen in both sexes and consisted of glomerular degeneration and / or glomerulopathy with tubular vacuolization, dilatation, degeneration, regeneration, hyaline droplets, hyaline casts, increased mitotic figures, and fibrinoid deposits.

[0282] Renal injury was most likely the primary cause of death / near-death seen in this study.

[0283] In a 13-week mouse study, no renal changes were observed up to the highest dose level of 20 mg / kg, and systemic exposure (AUC0-24h) was approximately 7250 ng·h / mL.

[0284] There is no evidence for genotoxic potential of KRP203 or its phosphates from two in vitro genotoxicity studies in mice with KRP203 (bacterial mutation and chromosomal aberrations) and a micronucleus study.

[0285] Reproductive toxicity studies in rats and rabbits have shown teratogenicity and effects on the reproductive system resulting in fetal death and malformations at low doses (no NOAEL in rat studies). No effects on male fertility were observed in reproductive toxicology studies or from histopathological evaluation in 4 or 13 week toxicity studies up to the highest dose of 20 mg / kg, the highest dose tested.

[0286] When given by oral dosing to rats or dogs for up to 26 or 13 weeks, respectively, there is no indication that the local tolerance induced by KRP203 in the gastrointestinal tract was impaired. In 26- and 52-week dog toxicity studies, gastrointestinal disorders with loose / mucoid stools and diarrhea occurred only in males at the higher dose levels. KRP203 causes significant eye irritation but not skin irritation in rabbits and has no contact sensitivity potential.

[0287] Overall, the preclinical studies completed to date have not generated data that would preclude the use of this compound in investigational clinical studies.

[0288] Related clinical studies and dosing rationale Table 1 summarizes the clinical studies by the number of subjects exposed to KRP203.

[0289] Overall, 325 HV and 66 patients (27 patients with ulcerative colitis, 10 with subacute cutaneous lupus erythematosus, and 29 with Crohn's disease) were included in the placebo-controlled trial of KRP203, which was well tolerated and showed a favorable safety profile.

[0290] A clinical study with KRP203 in patients undergoing allogeneic HSCT for hematological malignancies (study KRP203A2105) has been completed.

[0291] [Table 3-1]

[0292] [Table 3-2]

[0293] Study CKRP203A2105 in HSCT for hematological malignancies A Phase Ib 2-Part Open-Label Study to Evaluate the PK, Safety, Tolerability, Pharmacokinetics and Efficacy (Part 2 Only) in Patients Undergoing Allogeneic HSCT for Hematological Malignancies Part 1 was a single-arm, open-label study to investigate the safety of 3 mg / day KRP203 added to standard of care GvHD prophylaxis (cyclosporine A (CsA) / methotrexate) in 10 HSCT recipients. Part 2 is a randomized, two-arm, open-label study to compare the safety, efficacy, and PK of KRP203 3 mg / day in combination with tacrolimus / methotrexate with KRP203 1 mg / day in combination with CsA / methotrexate in 20 patients.

[0294] The study population consisted of male or female subjects diagnosed with a hematological malignancy and eligible for standard allogeneic HSCT with an available HLA-matched stem cell source. Such malignancies included, but were not limited to, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndromes (MDS), chronic lymphocytic leukemia (CLL), marginal zone and follicular lymphoma, large cell lymphoma, lymphoblastic Burkitt's and other high-grade lymphomas; mantle cell lymphoma, lymphoplasmacytic lymphoma; prolymphocytic leukemia or multiple myeloma.

[0295] Part 1 consisted of a screening period (days -50 to -2), baseline (day -1), a treatment period from days 1 to 111 with KRP203, and a follow-up period of up to 365 days (from transplant). Subjects were admitted to the study site during the screening period (approximately 2-5 days prior to baseline) and received the investigational product, 3 mg KRP203, once daily from days 1 to 111, along with cyclosporine A (CsA) given as standard of care (SOC) GvHD prophylaxis. HSCT was performed on day 11. In addition to study treatment with KRP203, activities included conditioning, standard GvHD prophylaxis, infusion of stem cells, pre- and post-transplant supportive care, and follow-up evaluations, in accordance with institutional practice. Subjects remained hospitalized for 2-5 days after the bone marrow transplant was performed. Subsequent study visits were outpatient or, if necessary, inpatient, depending on the subject's health status.

[0296] Part 2 consisted of a screening period (days -50 to -2), a treatment period with KRP203 from days 1 to 111, and a follow-up visit. Myeloablative conditioning was performed using chemotherapy between days 2 and 10 according to the SOC. Subjects who met the eligibility criteria were randomized to receive either: 1mg KRP203 once daily for 111 days plus CsA given as SOC GvHD prophylaxis, or · 3mg KRP203 once daily for 111 days and tacrolimus (Tac) were given as SOC GvHD prophylaxis.

[0297] As in part 1, HSCT was performed on day 11 and all other procedures / visits were the same as in part 1.

[0298] The study was terminated early due to strategic considerations. This decision was not related to any safety concerns of KRP203. The study had a shortened ongoing patient follow-up period for subjects who signed informed consent on the day the decision to terminate the study early was made, but maintained adequate safety follow-up for 6 months after the last dose of KRP203.

[0299] Of the total 25 subjects enrolled in the study, 23 subjects received study treatment. Two patients did not receive study treatment due to an ineligible donor and a screening failure. In Part I, 10 subjects received 3 mg KRP203 + CSA, and in Part II, 6 subjects received 1 mg KRP203 + CsA, and 7 subjects received 3 mg + Tac.

[0300] Overall, 14 / 23 subjects completed the study, including all 10 subjects in Part I, and 3 / 6 subjects in the 1 mg KRP203+CsA group and 1 / 7 subjects in the +3 mg+Tac group, respectively, in Part II.

[0301] The main reasons for study discontinuation were intention to withdraw (n=14, 17%), followed by AEs (n=3, 13%) and death (n=2, 9%).

[0302] Most frequent adverse events Part 1 Overall, all subjects in part 1 reported AEs 30 days after study treatment, 9 subjects reported AEs by 30 days before transplant, and 7 subjects reported AEs from the start of treatment to just before transplant.

[0303] The majority of AEs were related to gastrointestinal system organ classes from the start of treatment until just before transplantation (6 patients, 60%). From transplantation to 30 days after transplantation, the most frequently affected system organ classes were gastrointestinal (7 patients, 70%), respiratory, thoracic and mediastinal (4 patients, 40%), vascular (3 patients, 30%), immune system (3 patients, 30%), and nervous system (3 patients, 30%). After 30 days after transplantation, the most frequent AEs belonged to immune system (10 patients, 100%), general and administration site conditions (6 patients, 60%), and infections and infestations (5 patients, 50%).

[0304] From the start of treatment to just before implantation, the most frequent AEs in at least two subjects were vomiting (4 subjects, 40%), nausea (2 subjects, 20%), and bradycardia (2 subjects, 20%). Bradycardia (2 subjects, 20%), hypertension (1 subject, 10%), and sinus arrest (1 subject, 10%) were suspected by the investigator to be related to the study treatment.

[0305] From transplantation to 30 days post-transplant, the most frequent AEs (in at least 2 subjects) were vomiting (6 subjects, 60%), nausea (2 subjects, 20%), acute GvHD of the intestine (3 subjects, 30%), pleural effusion (2 subjects, 20%), and capillary leak syndrome (2 subjects, 20%). Of these events, pleural effusion (2 subjects, 20%) and capillary leak syndrome (2 subjects, 20%) were suspected by the investigator to be related to study treatment.

[0306] Thirty days after transplantation, the most frequent AEs (in at least 2 subjects) were chronic GvHD (7 subjects, 70%), chronic GvHD of the liver (5 subjects, 50%), peripheral edema (4 subjects, 40%), acute GvHD of the skin, acute GvHD of the intestine, and chronic GvHD of the skin (3 subjects, 30%), followed by diarrhea, nausea, rash, eyelid edema, and chronic GvHD of the intestine (2 subjects, 20%). Of these, the peripheral edema (2 subjects, 20%) event was suspected by the investigator to be related to the study treatment.

[0307] Part 2 All subjects randomized in both treatment arms, Part 2 (13 subjects [100%]) experienced at least one AE from the start of treatment to just before transplant, from transplant to 30 days after transplant, and 30 days after transplant.

[0308] From the start of treatment until just before transplant, the top three affected organ classes (in both the 1 mg KRP203+CsA and 3 mg KRP203+Tac treatment groups) were gastrointestinal disorders, laboratory tests, and general / systemic disorders and administration site conditions. By 30 days post-transplant, the top three reported organ classes were vascular disorders along with gastrointestinal disorders and laboratory tests. Thirty days after transplant, the major (top three) AEs were the organ classes immune system disorders, infections and infestations, and general / systemic disorders and administration site conditions.

[0309] The most frequent AEs reported from the start of treatment until just before transplantation (at least 2 subjects in either the 1 mg KRP203+CsA or 3 mg KRP203+Tac treatment groups) were nausea, vomiting, weight gain, elevated blood creatinine, and diarrhea. Of these, the event of elevated blood creatinine in one subject (in the 1 mg KRP203+CsA treatment group) was suspected by the investigator to be related to study treatment.

[0310] The most frequent AEs reported from transplant through 30 days post-transplant (at least 2 subjects in both the 1 mg KRP203+CsA or 3 mg KRP203+Tac treatment groups) were vomiting, stomatitis, hypertension, thrombocytopenia, back pain, bone pain, increased C-reactive protein, diarrhea, and hypomagnesemia. Of these, the C-reactive protein events (1 mg KRP203+CsA treatment group) and hypertension (3 mg KRP203+Tac treatment group) in 2 subjects were suspected by the investigator to be related to study treatment.

[0311] The most frequent AEs reported 30 days after transplant (in at least two subjects in the 1 mg KRP203+CsA or 3 mg KRP203+Tac treatment groups) were chronic GvHD, peripheral edema, acute GvHD in the skin, acute GvHD in the intestine, increased ALT, diarrhea, and oral candidiasis. Of these, peripheral edema in one subject (1 mg KRP203+CsA group) and increased ALT in two subjects (one each in the 1 mg KRP203+CsA and 3 mg KRP203+Tac treatment groups) were suspected by the investigator to be related to study treatment.

[0312] Deaths and other serious or clinically significant adverse events Overall, seven deaths were reported during the study at 1 year and during the long-term follow-up period. Three subjects died due to grade 3 or grade 4 serious AEs of aspiration pneumonia, hepatic failure, or Hodgkin's disease.

[0313] Liver failure and Hodgkin's disease were suspected by the investigators to be related to the study treatment. However, an independent pathologist and data monitoring committee also reviewed the cases of liver failure and concluded, based on histopathological findings, that the liver damage was rather caused by allogeneic immune-mediated hepatitis secondary to acute GvHD (hence, liver failure was unlikely to be related to KRP203). Regarding Hodgkin's disease, the investigators suspected a link between Hodgkin's disease and KRP203. In the investigators' view, KRP203, as an immunosuppressant, may blunt the GVL effect, which may lead to relapse of the underlying blood disorder.

[0314] Serious or clinically significant adverse events Part 1 One subject (10%) reported a serious AE of vomiting from the start of treatment to just prior to implantation.

[0315] Two subjects (20%) reported three serious AEs by 30 days post-transplant: acute GvHD, dyspnea, and weight gain.

[0316] There was a sharp increase in the number of serious AEs reported 30 days after implantation. Four subjects (40%) reported systemic organ class SAEs, primarily general disorders and administration site conditions (3 subjects, 30%), infections and infestations (2 subjects, 20%), and benign, malignant, and unspecified neoplasms (including cysts and polyps) (2 subjects, 20%). No serious AEs were reported in more than one subject during this time period.

[0317] Part 2 No serious AEs were reported from the start of treatment until just before implantation. One subject (10%) in the 1 mg KRP203 + CsA treatment group reported two serious AEs by 30 days after implantation: blepharitis and cystoid macular edema.

[0318] There was a sharp increase in the number of serious AEs reported 30 days after transplant, primarily due to GvHD events. The most frequent serious AEs reported (in at least 2 subjects in part 2) were acute GvHD of the intestine (3 subjects, 23%), diarrhea (2 subjects, 15%), and general deterioration of physical health (2 subjects, 15%).

[0319] Serious adverse events related to study drug Part 1 Three serious AEs, cystoid macular edema, exertional dyspnea, and peripheral edema, were reported in one subject (10%) 30 days after implantation and were suspected by the investigator to be related to study treatment. All of these events were mild in severity.

[0320] Part 2 Two serious AEs reported in one subject (17%) in the KRP203+CsA treatment group from implantation through 30 days post-implantation were suspected by the investigator to be related to study treatment: blepharitis (grade 2) and cystoid macular edema (grade 3).

[0321] Thirty days after transplant, 5 serious AEs reported by 4 subjects (31%) that were suspected by the investigator to be related to study treatment included 1 (8%) case each of febrile bone marrow aplasia (grade 3), hepatic failure, Hodgkin's disease (grade 3), macular ischemia (grade 3), and retinal ischemia (grade 3).

[0322] Adverse events leading to discontinuation Overall, 2 subjects (29%) in the 3 mg KRP203 + CsA group, 2 subjects (33%) in the 1 mg KRP203 + CsA group, and 1 subject (14%) in the 3 mg KRP203 + Tac group had an AE that led to discontinuation of study drug. All events leading to discontinuation of study drug were suspected to be related to study treatment, except for 2 serious events in Part 1: dyspnea and weight gain.

[0323] Advantages of the Invention For patients with high-risk acute myeloid leukemia, allogeneic HSCT remains the only treatment option. This protocol offers these patients the opportunity to receive a promising adjuvant treatment that may improve HSCT-associated overall survival, and / or relapse-free survival without refractory GVHD (rGRFS), and / or quality of life. Prediction of benefit is based on results from the previous Phase IIb CKRP2032105 study.

[0324] As shown in Figure 1, the incidence of mild chronic GVHD is reduced in patients receiving 3 mg KRP203 and cyclosporine A compared to patients receiving 3 mg KRP203 and tacrolimus or 1 mg KRP203 and cyclosporine A. Furthermore, the onset of moderate chronic GVHD is delayed in patients receiving 3 mg KRP203 and cyclosporine A compared to other treatment groups (see Figure 3). The incidence of relapse in patients receiving 3 mg KRP203 and cyclosporine A is lower compared to patients receiving 3 mg KRP203 and tacrolimus or 1 mg KRP203 and cyclosporine A. Taken together, these initial data in humans support the long-term administration of 3 mg KRP203 for a period of more than 111 days to delay the onset of chronic GVHD and prevent relapse of the primary disease in AML patients undergoing HSCT.

[0325] Assessment of potential risks and benefit / risk management The expected risks are based on clinical experience with moclavinib and are not expected to exceed the expected benefits. Subjects will be fully and clearly informed about the burden of participating in this clinical trial: frequency of screening and follow-up visits, prolonged hospitalization and unscheduled visits if necessary. Subjects will also be informed about the frequency of blood tests and bone marrow sample collection and will be asked to carefully consider all information before deciding to participate in the study. Subjects will be closely monitored for the occurrence of significant clinical events and treatment will continue only if it is considered safe and appropriate to do so. The early clinical development of moclavinib has demonstrated that its use is generally safe and well tolerated, justifying the evaluation of its use in this Phase IIb study. Data obtained in the Phase IIb study also demonstrated that moclavinib has potential therapeutic activity in patients with AML.

[0326] Study objectives and endpoints the purpose The objective of this study is to compare the safety and efficacy of moclavimod versus control as an adjuvant treatment to allogeneic HSCT in subjects with acute myeloid leukemia. An additional objective of the study is to compare the effect of the two treatments on quality of life.

[0327] Main purpose To evaluate the effect of moclavimod on relapse and GVHD as an adjuvant treatment to HSCT to improve the safety and efficacy of HSCT.HSCT is performed in subjects with AML in first (CR1) or subsequent morphologic complete remission (CR2) using an HLA-matched sibling or unrelated donor.

[0328] secondary purpose To assess the effects of moclavimod on overall survival at two years, disease progression-free survival at two years, and quality of life.

[0329] Primary Endpoint The primary endpoint of the study was relapse-free survival (rGRFS) free of refractory GVHD.

[0330] rGRFS was randomized to Grade III / IV acute graft-versus-host disease (GVHD) refractory to at least two lines of treatment, - widespread chronic GVHD refractory to systemic immunosuppressive treatment, Disease recurrence, ·death is defined as the time until the first occurrence of either

[0331] This composite endpoint captures both safety and efficacy. It grades a variety of serious events. Composite endpoints such as GRFS confirmation are clinically relevant when testing new treatments.

[0332] rGRFS is calculated similarly to conventional GRFS, which treats grade III-IV acute GVHD, chronic GVHD requiring systemic treatment, and disease recurrence / progression as events, except that GVHD that has resolved and does not require systemic treatment is excluded at last evaluation as an event in rGRFS.

[0333] Secondary endpoints The key secondary endpoint of the study is overall survival.

[0334] Overall survival (OS) is defined as the time from randomization to death from any cause. Other secondary endpoints for efficacy evaluation are progression-free survival (PFS) and cumulative incidence of recurrence. PFS is defined as the time from randomization to disease recurrence or death from any cause. Cumulative incidence of recurrence is defined as the incidence of morphologic or clinical recurrence from randomization.

[0335] Secondary endpoints for safety evaluation were: Incidence of macular edema Incidence of liver dysfunction leading to dose reduction / treatment discontinuation Incidence of severe bradycardia Incidence of post-transplant lymphoproliferative disorders Incidence of severe infectious complications due to viruses, bacteria and fungi, including EBV / CMV, and incidence of preemptive therapeutic use of antiviral therapy Cumulative incidence of NCI CTCAE grade 3-5 adverse events It is.

[0336] Secondary endpoints for the study purposes were: Time to engraftment Time to acute GvHD Cumulative incidence of grades II-IV and III-IV acute GVHD at 1 year Time to chronic GvHD Cumulative incidence of moderate to severe chronic GVHD at 1 year Cumulative incidence of chronic GVHD requiring systemic immunosuppressive treatment at 1 year Antibody titer response to influenza vaccination Median duration and mean dose (mg / kg / day) of GvHD prophylaxis with cyclosporine A during the first year of treatment Incidence of concomitant therapy and cumulative dose of corticosteroids during the first year of treatment Incidence of concomitant therapy and cumulative dose of ruxolitinib over the first year of treatment Cumulative incidence of NCI CTCAE grade 2-5 and grade 3-5 infections It is.

[0337] Other endpoints Quality of life will be assessed via questionnaires with a primary endpoint at 12 months.

[0338] The Foundation for Certification of Cellular Therapy Bone Marrow Transplantation (FACT-BMT, version 4), the 36-item Short-Form Health Survey (SF-36, version 2), and the MD Anderson Symptom Assessment Inventory (MDASI) will be scored at screening, 3, 6, 12, and 24 months, provided certified translations into the local language are available.

[0339] research design Overall design This is a phase IIb randomized controlled, multicenter, open-label study comparing two parallel groups. After signing informed consent, a total of approximately 160 subjects will be randomized in a 1:1 fashion to receive either the active group of mocravimod in combination with CsA- and mocravimod-based GVHD prophylaxis, or the control group of standard care without mocravimod.

[0340] Randomization will use a minimization method that balances treatment arms with respect to complete remission status (CR1 vs. CR2) and center. A probabilistic treatment assignment procedure will be used to ensure randomization of treatment assignment for all subjects entered into the study.

[0341] Subjects randomized to the moclavimod group will receive three capsules at a 1 mg dose starting on day -11 prior to HSCT for a period of 12 months or until all immunosuppressants have been tapered and withdrawal is complete for at least 4 weeks.

[0342] Subjects who complete the first year of treatment will be offered to continue receiving study treatment for one additional year in an open-label setting.

[0343] All patients will be followed up for 24 months after HSCT.

[0344] The study is designed to confirm the results of non-comparative phase IIa clinical trials in hematological malignancies and to compare the outcomes of patients receiving mocravimod as adjuvant therapy to HSCT with a control group of patients receiving a similar setting without mocravimod. The study aims to show the superiority of the mocravimod group compared to the control group.

[0345] Study population Study population Male or female subjects aged 18-75 years with AML in complete remission (CR1, CR2) who are eligible for HSCT from peripheral blood collected from a sibling or matched unrelated donor. In total, we plan to randomize 160 patients, and 60 centers in Europe, Israel, and North America plan to enroll participants in the study.

[0346] Inclusion criteria Each patient must meet the following criteria to be enrolled in this study: Subjects diagnosed with AML and related precursors (excluding acute promyelocytic leukemia) according to the WHO 2016 classification, including secondary AML after antecedent hematological disorders (e.g., myelodysplastic syndrome) and therapy-related AML Subjects plan to undergo allogeneic HSCT from a fully matched sibling donor or an unrelated donor with 8 / 8 match for HLA-A, -B, -C and DRB1 with high resolution by DNA-based typing, and the stem cell source is mobilized peripheral blood collected via apheresis from a matched donor. The minimum recommended CD34+ cell dose in the graft is 2 × 10 6 / kg, with the recommended target dose being approximately 5 × 10 6 / kg. Subjects with AML in first cytomorphologic remission (CR1) and ELN adverse classification, or subjects in subsequent cytomorphologic remission (CR2) CR was defined as leukemia clearance (<5% bone marrow blasts and no circulating peripheral blasts) along with morphologic complete response, normal absolute neutrophil and platelet counts, no signs of extramedullary leukemia, and no need for repeated transfusions. CRi is defined as fulfilling all CMR criteria except absolute neutrophil count <1,000 / μL or platelet count <100,000 / μL. Life expectancy at time of screening ≥ 6 months Karnofsky Performance Status (KPS) ≥ 70% Male or female aged ≥ 18 and ≤ 75 years Subjects ≥ 65 years old must have a Sorror score ≤ 3 -Able and willing to provide written informed consent and comply with the study protocol and procedures For sexually active women of childbearing potential and men who have sexual contact with women of childbearing potential: Willing to use a reliable method of contraception (oral contraceptives, intrauterine device, hormonal implant, contraceptive injection, or coital abstinence) during participation in the study. A woman is considered fertile after menarche until menopause, unless she is completely infertile. A woman is considered postmenopausal and not fertile if she has had 12 months of natural (spontaneous) amenorrhea with the appropriate clinical profile (e.g., appropriate age, history of vasomotor symptoms) or has had bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks previously. In the case of oophorectomy alone, she is considered not fertile only if her reproductive status has been confirmed by follow-up hormone level evaluation. · Enrollment in the National Health Insurance Scheme (subject to applicable local requirements)

[0347] Exclusion criteria Patients who meet any of the following criteria will be excluded from the study: Subjects who have previously undergone allogeneic HSCT or solid organ transplant recipients -Subjects with acute promyelocytic leukemia Diagnosis of any prior or concomitant malignancy is an exclusion criterion unless the subject has completed curative treatment (chemotherapy and / or surgery and / or radiation therapy) for that malignancy at least 6 months prior to enrollment. Blast crisis of chronic myeloid leukemia · Clinically significant pulmonary fibrosis - Tuberculosis, except for a history of successfully treated tuberculosis or prophylactic treatment following a positive PPD skin reaction Patients receiving chronic (daily) treatment for asthma Patients with any other type of clinically significant bronchoconstrictive disease Diabetes that is not controlled by the investigator or that is complicated with organ damage such as diabetic nephropathy or retinopathy Uncontrolled seizure disorder History of unmanaged depression or suicide attempts / ideations Co-occurring serious and / or uncontrolled medical conditions, including · Myocardial infarction within 3 months prior to the end of study participation, or Decreased left ventricular function with ejection fraction <40% as measured by multi-gated acquisition (MUGA) scan or echocardiography within 28 days prior to screening, or History or presence of stable or unstable ischemic heart disease (IHD), myocarditis or cardiomyopathy, or New York Heart Association (NYHA) class II to IV congestive heart failure, or Unstable cardiac arrhythmias, including a history or presence of symptomatic bradycardia, Resting heart rate (medical examination or 12-lead ECG) <60 bpm History or current diagnosis of ECG abnormalities indicating a significant safety risk, e.g., presence of a clinically relevant cardiac conduction disorder including coexistent clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, sick sinus syndrome or sinoatrial heart block, clinically significant AV block, bundle branch block or resting QTc (Fridericia preferred, but Bazzet also acceptable) >450 msec (males) and >470 msec (females) on screening or baseline ECG History or presence of symptomatic arrhythmias or arrhythmias requiring treatment or that are otherwise clinically significant Uncontrolled arterial hypertension; if controlled, medication must have been stable for 3 months prior to the baseline visit Treatment with medications that impair cardiac conduction (e.g., beta-blockers, verapamil- and diltiazem-type calcium channel blockers, or cardiac glycosides) Concomitant use of medications known to prolong the QT interval, unless they can be permanently discontinued for the duration of the study. Treatment with quinidine History of stroke suspected to be of cardiac origin Known family history of familial long QT syndrome or polymorphic ventricular tachycardia Cardiac dysfunction as defined by Pulmonary impairment defined by oxygen saturation <90% on room air. Pulmonary function tests (PFTs) are required only in cases of symptomatic or previously known impairment within 28 days prior to screening, with pulmonary function <50% corrected for diffusion capacity of the lung for carbon monoxide (DLCO) and forced expiratory volume in 1 second (FEV1). Significant liver disease or damage, or a known history of alcohol abuse, chronic liver or bile duct disease Liver dysfunction defined by AST and / or ALT >5×ULN Renal dysfunction with serum creatinine >2.0mg / dL (176μmol / L) - Vaccination with a live attenuated vaccine within 4 weeks prior to screening Immunosuppressant medications for comorbid conditions. Subjects must be able to discontinue prednisone or other immunosuppressant medication for at least 3 days prior to beginning study treatment. History of stroke or intracranial hemorrhage within 6 months prior to screening Active infection (viral, bacterial or fungal) requiring specific treatment. Acute anti-infective therapy must have been completed within 14 days prior to study treatment. History of active infection with human immunodeficiency virus (HIV) or hepatitis B virus (HBV) or hepatitis C virus (HCV), defined as positive HIV antibody, hepatitis B surface antigen, or hepatitis C History of a previous malignancy, treated or untreated within the past 5 years, with or without evidence of local recurrence or metastasis, except for localized basal cell carcinoma of the skin or in-situ cervical carcinoma Current combination chemotherapy, radiation therapy or immunotherapy Major surgery or large wounds that have not fully healed within 4 weeks prior to screening · Subject has a positive pregnancy test or is breastfeeding (women of childbearing age only) -Estimated probability of survival less than 3 months Known allergy to any of the components of moclavimod (e.g. excipients) Any contraindication to GVHD prophylaxis with cyclosporine A or methotrexate Diagnosis of macular edema during screening. Patients with a history of macular edema may participate in the study provided they do not have macular edema on ophthalmologic examination at screening. Participation in another interventional clinical trial within 4 weeks prior to study enrollment, or participation in a concurrent interventional clinical trial Any other condition that, in the opinion of the investigator, makes the patient or donor ineligible for the study Subjects who are under legal guardianship (guardianship, fiduciary or judicial custody) and / or who are unable or unwilling to comply with the requirements and procedures of this exam.

[0348] research intervention Identification of IMPs and associated non-investigational medicinal products (NIMPs) IMP is mokravimod.

[0349] IMP active substance: 2-Amino-2-[2-[2-chloro-4-[[3-(phenylmethoxy)phenyl]thio]phenyl]ethyl]-1,3-propanediol hydrochloride

[0350] Description of study intervention All patients in the study will receive moclavimod at a daily dosage regimen of three capsules by the oral route starting on day -11 and continuing for one year after HSCT.

[0351] NIMPS is a product used in HSCT for conditioning, GVHD prophylaxis and prophylaxis of infectious complications and is commercially available for human use under various brand names.

[0352] Medication and Administration Moclavimod is formulated as a hard gelatin capsule, an immediate release dosage form for oral administration, containing a white to off-white powder in a size #4 opaque pink (orange in Sweden) capsule.

[0353] The hard gelatin capsules will be administered at a daily dosage regimen of 3 capsules by the oral route starting on day -11 pre-HSCT and continuing for 1 year post-HSCT.

[0354] Preparation / Handling / Storage / Measuring Control In this study, traceability of Mokravimod is defined as the ability to locate and identify each individual unit of Mokravimod during any step from storage to distribution to subjects or disposal. This also implies the ability to locate and identify subjects at the study site, as well as the ability to locate and identify all relevant data regarding products and materials that come into contact with Mokravimod.

[0355] The metrological controls of moclavimod will be documented at the study site. Detailed instructions regarding metrological controls are provided in the Regulatory Affairs Manual.

[0356] In accordance with international guidelines, the funder will keep records of all products dispensed worldwide. All waste materials used in the preparation of moclavimod at the manufacturing facilities and study sites will be disposed of on an ongoing basis in accordance with local regulations.

[0357] Subject traceability is ensured by documenting subject identity including subject number at the study site. Subject identity is protected and identified only by a code number that can be linked to their full identity at the study site. Traceability of mokravimod batches from manufacture to transportation to the clinical site is ensured by contract manufacturing organization procedures. Training of mokravimod at the study site is ensured by maintaining an metrological control log of mokravimod.

[0358] Formulation, appearance, packaging and labelling Moclavimod is prepared as a hard gelatin capsule for oral administration as an immediate release form. In addition to the drug substance, the capsule contains the following standard pharmacopoeia excipients: mannitol; microcrystalline cellulose / cellulose, microcrystalline; sodium starch glycolate; magnesium stearate and colloidal silicon dioxide / silica; colloidal anhydrous.

[0359] The hard gelatin capsule contains a white to off-white powder in a size #4 opaque pink (orange in Sweden) capsule.

[0360] The packaging is in HDPE bottles, each containing 30 capsules, ie a 10 day treatment.

[0361] Product Storage and Safety Available safety data indicate that moclavimod 1 mg hard gelatin capsules stored at 5°C / ambient RH are stable for 48 months when packaged in HDPE bottles and for 24 months when packaged in PVC / PCTFE / PVC (Aclar) blister packs.

[0362] Additionally, moclavimod 1 mg hard gelatin capsules are stable for 36 months in HDPE bottles after storage at 25°C / 60% RH. The drug product is also stable for 6 months when packaged in both HDPE bottles at 40°C / 75% RH.

[0363] Previous and concomitant medications and treatments In addition to the study intervention, all concomitant prescribed medications used during the study are considered concomitant. The following concomitant medications should be recorded on the electronic case report form (eCRF): Medication for the treatment of GVHD Medication for the treatment of infectious diseases, including prophylactic or preemptive use of anti-infective medications Medication to treat disease recurrence Medications for the treatment of other reported AEs Post-transplant prophylactic use of immunosuppressive medications other than cyclosporine A and methotrexate in the moclavimod group - Medications to prevent pretreatment-induced AEs Additional hematopoietic stem cell transplants Donor lymphocyte infusion ·Hematopoietic growth factors Vaccination

[0364] Posttransplant immunosuppressive therapy with corticosteroids in the absence of GVHD should be avoided unless medically indicated.

[0365] Subjects in the moclavimod group will receive a cyclosporine A and methotrexate-based immunosuppressive regimen for GVHD prophylaxis for approximately 6 months, with tapering and weaning occurring according to institutional practice at the clinical site.

[0366] Posttransplant prophylaxis against GVHD other than cyclosporine A and methotrexate is not permitted in the moclavimod group.

[0367] To prevent infection with cytomegalovirus (CMV), patients who are CMV positive or have a CMV positive donor may receive prophylactic treatment including ganciclovir, valganciclovir, letermovir and foscarnet, and all patients are subjected to regular quantitative PCR monitoring.

[0368] For prophylactic CMV treatment, the following dosing schedule is recommended (day 0 is the day of HSCT): Days -9 to -2: Ganciclovir 5 mg / kg IV q12h. Days 4-20: Foscarnet 90mg / kg IV q24h. · Days 21 through 100: Valganciclovir 900 mg PO daily, 5 days per week, or ganciclovir 5 mg / kg IV q24h, 5 days per week. Dosage is adjusted according to renal function.

[0369] If quantified viral DNA levels exceed the institutional threshold for CMV treatment (as established at each study center prior to study entry), patients should be preemptively treated with ganciclovir (recommended dose 5 mg / kg IV q12h) or valganciclovir (recommended dose 900 mg PO twice daily).

[0370] To prevent infection with Epstein-Barr virus (EBV), patients who are EBV positive or have an EBV positive donor should be subjected to appropriate (preemptive) treatment, if indicated, after regular quantitative PCR monitoring. If the quantified viral DNA level exceeds the institutional threshold for EBV treatment (as established in each study center before participation in the study), patients should be treated with rituximab. Also, if a previously EBV positive patient shows lymph node enlargement, initiation of rituximab is recommended, even if the PCR for EBV is low or negative.

[0371] The following schedule is recommended: Rituximab (anti-CD20) 375mg / m immediately after elevated EBV DNA was detected 2 IV is started weekly until PCR for EBV is negative. If PTLD is suspected based on clinical symptoms, CT scans of the chest, abdomen, and pelvis, as well as bone marrow aspiration and biopsy, and, when possible, lymph node biopsy, should be obtained. If the CT scan, bone marrow, and lymph node results indicate PTLD, rituximab is repeated weekly for at least 2 weeks.

[0372] Other viral, fungal and bacterial prophylaxis will be given according to local institutional guidelines.

[0373] Considering that KRP203 is expected to be metabolized in the liver only to a limited extent by CYP3A4 and 2D6 (based on in vitro data), and the lack of effects of KRP203 and KRP203-P on cytochrome P450 enzymes and transporters, we consider the risk of PK DDIs of KRP203 and CsA or TAC or other similar concomitant drug treatments to be low. The weak inhibitory effect of cyclosporine on hepatic CYP3A4 is unlikely to have a relevant impact on the PK of KRP203. As a result, even if drug-drug interactions (DDIs) cannot be excluded, the PK of CsA or tacrolimus (TAC) is more likely to be affected than that of KRP203, especially due to other concomitant drug treatments that may modify the PK of CsA or TAC.

[0374] Nevertheless, for conservative reasons, caution should be exercised when combining KRP203 with CsA or TAC. In studies in which KRP203 was coadministered with CsA or TAC (e.g., Study CKRP203A2105), the PK properties of KRP203 and KRP203-P, as well as the concentrations of CsA and TAC, were continually evaluated to reduce the risk of DDI.

[0375] Clinical trial plan research minister Each subject trial will have four phases: Informed Consent Screening and Enrollment Phase Treatment Phase EOT follow-up visit at 24 months after HSCT It consists of:

[0376] Treatment Phase The treatment phase corresponds to the start of the phase IMP regimen on day -11 before HSCT in the mocrabimod group until the last IMP intake. The treatment phase in the control group starts on the day of HSCT and lasts up to 1 year after HSCT.

[0377] Subjects enrolled in the moclavimod arm will receive three capsules daily for one year after HSCT, with an additional 7-day window permitted if HSCT cannot be performed as planned for medical reasons (e.g., infection, AE monitoring) after conditioning.

[0378] Subjects undergo HSCT on day 0. The last IMP intake corresponds to the end of treatment for the mocrabimod group.

[0379] The treatment phase begins in an outpatient setting, followed immediately by an inpatient (hospitalization) setting, according to the facility's practice for conditioning and HSCT. Subjects are hospitalized from the start of the conditioning regimen until discharged at the investigator's discretion. Thus, the treatment phase begins on day -11 before HSCT, and conditioning is administered on days -6, -5, -4, and -3 before HSCT.

[0380] Efficacy evaluation Standard of Care Research Procedures Eligible subjects will be randomized to either the moclavimod or control group. Subjects in both groups will undergo HSCT after a conditioning regimen as part of the general standard of clinical care. This section describes the conditioning regimen and HSCT procedures.

[0381] Conditioning regimen All patients undergo a conditioning regimen prior to HSCT.

[0382] One of the following conditioning regimens will be administered (days are relative to the day of HSCT): Any planned deviations from these conditioning regimens will be discussed between the Principal Investigator and the medical monitor of the study. Fludarabine; 30 mg / m 2 IV once daily for 5 days from days -8 to -4 (150 mg / m 2 ) Thiotepa: 5 mg / kg IV twice daily for 1 day on day -7 (10 mg / kg) Melphalan: 60 mg / m 2 IV once daily for 2 days on days -2 and -1 (120 mg / m 2).

[0383] Dose variations in the conditioning regimen are possible to suit patient condition and / or local practice.

[0384] Depending on institutional practice, the following three conditioning regimens are possible following the standard regimen described herein above: Melphalan can be substituted for busulfan. Thiotepa can be substituted for cyclophosphamide. 1. Busulfan + Fludarabine + Cyclophosphamide: - Busulfan 110 mg / m 2 IV, days -7 to -4 (440mg / m 2 ) - Fludarabine 25mg / m 2 , for 5 days from -6 to -2 (125 mg / m 2 ) - Cyclophosphamide 14.5 mg / kg IV (29 mg / kg) on ​​days -3 and -2 2. Busulfan + Fludarabine + Thiotepa: - Busulfan 3.2 mg / kg / day IV for 3 days (9.6 mg / kg) on ​​days -5 to -3 - Fludarabine 50mg / m 2 / day IV for 3 days (days -5 to -3) (150 mg / m 2 ) - Thiotepa 5 mg / kg / day IV for 2 days (10 mg / kg) on ​​days -7 and -6 3. Melphalan + Thiotepa + Fludarabine: - Melphalan 100 or 140 mg / m 2 IV, day -6 - Fludarabine 40mg / m 2 IV, for 4 days from days -5 to -2 (160 mg / m 2 ) - Thiotepa 5-10 mg / kg IV on day -7 (Days are relative to the day of HSCT)

[0385] Disease evaluation rGRFS was the primary efficacy endpoint. Progression-free survival and cumulative incidence of recurrence were secondary efficacy endpoints.

[0386] AML hematological status will be assessed by the local laboratory morphologically by BM biopsy or aspirate at the screening visit, the 3-, 6-, and 12-month treatment visits, and the 18- and 24-month follow-up visits, unless relapse has already been confirmed. AML disease evaluation will also be performed if relapse is suspected.

[0387] Morphologic recurrence is defined as morphologic evidence of leukemia in the bone marrow or other extramedullary sites.

[0388] Details of recurrence or disease progression will be recorded on the Recurrence / Disease Progression Assessment page of the eCRF.

[0389] If a bone marrow biopsy cannot be obtained, a bone marrow aspirate may be substituted. If a bone marrow aspirate and / or biopsy has already been obtained within 6 weeks prior to the planned visit, there is no need to repeat the evaluation. In addition, if relapse is suspected after HSCT, chimerism is evaluated to support the diagnosis.

[0390] Graft-versus-host disease evaluation GVHD events are diagnosed and classified based on NIH criteria as summarized in Table 3 (Filipovich et al., Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56; Jagasia et al., Biol Blood Marrow Transplant 2015 Mar;21(3):389-401.e1).

[0391] [Table 4]

[0392] Acute GVHD is graded according to the modified Glucksberg scale (Harris et al., Biol Blood Marrow Transplant 2016 Jan;22(1):4-10) (see below). Chronic GVHD is graded based on the NIH criteria, as summarized in Table 3 (Filipovich et al., Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56; Jagasia et al., Biol Blood Marrow Transplant 2015 Mar;21(3):389-401.e1) (see below). Whenever possible, tissue biopsies are obtained to confirm the diagnosis of GVHD diagnosis and to assess its severity. However, acute and chronic GVHD are still clinical diagnoses, which are considered to be present when diagnosed and treated without biopsy confirmation.

[0393] Details of all GVHD events, including start date, end date, NCI CTCAE severity grade, GVHD grade, outcome, and action taken, are recorded on the GVHD AE page of the eCRF. For chronic GVHD events, whether systemic immunosuppressive treatment was required is also recorded. The start date of a GVHD event is defined as the start date of GVHD treatment or the date of biopsy confirmation of GVHD, whichever occurs first. Resolution of a GVHD event is defined as a complete response, i.e., resolution of all signs and symptoms.

[0394] mortality rate Following the death of a subject, the following information must be recorded in the eCRF: ·Date of death ·Cause of death (details) Researchers classify the causes of death as follows: Disease recurrence ·Disease progression Transplant-related mortality (TRM), defined as death due to causes other than disease recurrence or disease progression.

[0395] All causes of death are subject to independent adjudication.

[0396] Quality of life The Foundation for Certification of Cellular Therapy Bone Marrow Transplantation (FACT-BMT, version 4 and the MD Anderson Symptom Assessment Inventory (MDASI) will be scored at screening, day +14, day +28, day +60, 3 months, 6 months, 12 months and 24 months, provided certified translations into the local language are available.

[0397] Statistical considerations Statistical hypotheses A separate Statistical Analysis Plan (SAP), providing technical details of the statistical analyses outlined below, will be prepared and approved prior to analysis of the study data. Deviations from these analyses will be justified in the clinical study report.

[0398] For the primary endpoint rGRFS, the objective is to focus on whether the risk ratio in the active group is significantly different from the risk ratio in the control group. Thus, the null and alternative hypotheses are: H 0 Risk ratio moclavimod / control = 1 H 1 Risk ratio moclavimod / control ≠ 1 It is.

[0399] Sample size determination For the primary endpoint, rGRFS, the 12-month rGRFS is predicted to be at least 60% in the moclavimod group compared with a maximum of 40% in the control group (hazard ratio 0.55). A power of 0.8 is required for a treatment effect of this magnitude, with a two-sided significance level set at 0.05.

[0400] Based on these assumptions, the required sample size is 140 subjects with 116 events required for the final analysis of rGRFS. To compensate for dropouts and loss to follow-up at 1 year, a total of 160 subjects will be enrolled in the study.

[0401] Population for analysis All enrolled patients who were randomized will be included in the analysis. The following analysis datasets will be identified:

[0402] Intention to Treat (ITT) population The ITT population consists of all randomized patients. The ITT population is the primary efficacy data set for the primary and secondary endpoints.

[0403] Corrective Intent to Treat (MITT) Population The MITT population consisted of all randomized patients who underwent HSCT and moclavimod (active group) or at least one dose of GVHD-resistant (control group).

[0404] Per Protocol (PP) Group Prior to database lock, the funder will define the PP population as a subset of patients in the MITT population without major protocol deviations. The PP population will be used to (1) shed light on potential reasons why the primary analysis of the ITT population did not reach significance or (2) explore how major protocol deviations could have had an impact on the magnitude of treatment benefit. The definition of a "major" protocol deviation will be agreed upon by a team blinded to treatment assignment, and all instances of such major deviations will be adjudicated prior to database lock.

[0405] Safety Group The safety population consisted of all patients who underwent HSCT.

[0406] statistical analysis General method Standard statistical methods will be used, including Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models for time to event endpoints. The proportional hazards assumption will be tested. All analyses will be stratified by morphologic complete response status (CR1 vs. CR2).

[0407] For binary endpoints, treatment groups will be compared by Cochran-Mantel-Haenszel test and stratified by CR1 vs. CR2. The impact of prognostic factors on these endpoints will be assessed by logistic regression models.

[0408] Unless otherwise specified, descriptive statistics (cumulative incidence or proportion of patients free of the event of interest) are presented for time-to-event endpoints at 3, 6, 12 and 24 months. 95% confidence intervals are calculated for treatment contrasts.

[0409] For the primary efficacy endpoint and secondary endpoints, the following missing data handling strategies will be used: Missing values ​​will not be imputed. There is no "administrative" censoring for any reason, i.e., all events are used in the analysis. The only censored observations are for patients who do not experience the event of interest. For example, patients who die due to disease recurrence or disease progression are censored in the analysis of time to TRM.

[0410] Analysis of primary efficacy endpoints The primary endpoint of the study is rGRFS, treated as a time-to-event variable. The main approach for the primary efficacy analysis is a randomized trial that mirrors the treatment allocation procedure. The randomized trial is based on a number of simulated trials, S, in which treatments are reallocated to patients who actually participate in the study (in the same order of participation), using the same minimization algorithm. Each simulated trial uses a different seed for the random number generator. A trial statistic, Δ, is calculated for the number of actual trials (Δobs) and for each simulated trial (Δi, i=1,…,S). The significance probability (P-value) of the randomized trial is calculated directly from the empirical distribution of Δ under the null hypothesis. s is the number of ΔI_ for which |Δi|≥|Δobs|. The two-sided randomized P-value is equal to s / S. The number of simulated trials S is selected to ensure that the P value is accurately estimated to two significant figures (Buyse M., Stat Med. 2010 Dec 30;29(30):3245-57).

[0411] Secondary endpoint analysis The secondary endpoints are tested for significance using the Hochberg procedure. The procedure followed is as follows: Let p1, p2, p3, and p4 be the p-values ​​of the test for each of the four secondary endpoints. p1≧p2≧p3≧p4. Let α be the appropriate significance level for the analysis (e.g., 5%). If p1≦α, all four secondary endpoints show a significant treatment effect. If p1>α and p2≦α / 2, the endpoints corresponding to p2, p3, and p4 show a significant treatment effect. If p1>α, and p2>α / 2, and p3≦α / 3, the endpoints corresponding to p3 and p4 show a significant treatment effect. If Ip1>α, and p2>α / 2, and p3>α / 3, and p4≦α / 4, the endpoint corresponding to p4 shows a significant treatment effect. If p1>α, and p2>α / 2, and p3>α / 3, and p4>α / 4, none of the secondary endpoints show a significant treatment effect.

[0412] List of abbreviations and definitions World Health Organization (WHO) 2016 classification of AML and related precursor neoplasms (Arber DA, Semin Hematol. 2019 Apr;56(2):90-95).

[0413] [Table 5-1]

[0414] [Table 5-2]

[0415] others Disease Risk Index (DRI) The DRI is in the public domain and therefore available for public use (Armand P., et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood. 2014; 123(23): 3664-3671).

[0416] [Table 6]

[0417] European Group for Blood and Marrow Transplantation (EBMT) Risk Score The EBMT risk score is in the public domain and therefore available for public use (Gratwohl A. The EBMT risk score. Bone Marrow Transplant. 2012; 47(6):749-56).

[0418] [Table 7]

[0419] Glucksberg Acute Graft-versus-Host (GVHD) Score The Glucksberg Acute GVHD score is in the public domain and therefore available for public use (Gratwohl A. The EBMT risk score. Bone Marrow Transplant. 2012; 47(6):749-56).

[0420] skin Stage 0: Active (erythematous) GVHD No rash Stage 1: A maculopapular rash involving <25% of the body surface Stage 2: A maculopapular rash involving 25-50% of the body surface Stage 3: A maculopapular rash involving >50% of the body surface Stage 4: Generalized erythroderma (>50% of body surface) + blistering and desquamation (>5% of body surface)

[0421] liver Stage 0: Bilirubin < 2mg / dL Stage 1: Bilirubin 2-3mg / dL Stage 2: Bilirubin 3.1-6mg / dL Stage 3: Bilirubin 6.1-15mg / dL Stage 4: Bilirubin >15mg / dL

[0422] Upper gastrointestinal tract (GI) Stage 0: No or intermittent nausea, vomiting, or loss of appetite Stage 1: Persistent nausea, vomiting or loss of appetite Stage 2: n / a Stage 3: n / a Stage 4: n / a

[0423] Lower GI (diarrhea volume / day for adults) Stage 0: <500 mL / day or <3 episodes / day Stage 1: 500–999 mL / day or 3–4 episodes / day Stage 2: 1000-1500 mL / day or 5-7 episodes / day Stage 3: >1500 mL / day or >7 episodes / day Stage 4: Severe abdominal pain with or without intestinal blockage or excessive blood in the stool (regardless of stool volume)

[0424] [Table 8]

[0425] National Institutes of Health (NIH) Chronic GVHD Score The NIH Chronic GVHD Score is in the public domain and therefore available for public use (Filipovich et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11(12):945-56; Jagasia et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015;21(3):389-401).

[0426] The NIH Comprehensive Scoring System for Chronic GVHD reflects the clinical effect of chronic GVHD on the functional status of the patient. Eight organs or sites (skin, mouth, eyes, gastrointestinal tract, liver, lungs, joints and fascia, and reproductive tract) are considered to calculate the comprehensive score. Elements included in the proposed comprehensive scoring include both the number of organs or sites involved and a severity score within each affected organ. Performance status scoring is not incorporated into the comprehensive scoring system. The comprehensive descriptions of mild, moderate, and severe were selected to reflect the degree of organ impact and dysfunction caused by chronic GVHD. It should be noted that the comprehensive scoring system can only be applied after the diagnosis of chronic GVHD has been confirmed by either (1) the presence of diagnostic features or, in the absence of diagnostic features, (2) at least one overt appearance of chronic GVHD with the diagnosis supported by histological, radiological, or clinical evidence of GVHD from any site.

[0427] Mild chronic GVHD: ○ Involvement of 1 or 2 organs with a score of 1 or less + pulmonary score of 0 ·Moderate chronic GVHD: ○ Involvement of 3 or more organs with a score of 1 or less; At least one organ (not lung) with a score of 2 or Lung score 1 ·Severe chronic GVHD: At least one organ with a score of 3 or Lung score of 2 or 3

[0428] [Table 9]

[0429] [Example 3] KRP203 prevents chronic GVHD in mice method To investigate whether KRP203 has a beneficial effect on the development of chronic GVHD, a clinically relevant and well-established mouse model of cutaneous chronic GVHD was used. Briefly, Balb / c mice were pretreated with 5.5–6 Gy total body irradiation (TBI) and then inoculated with 2.5 × 10 IgG from an allogeneic B10.D2 donor to induce chronic GVHD. 7 Splenocytes were supplemented with 8 × 10 6 This was followed by intravenous injection of bone marrow (BM). Controls without GVHD received donor cells from syngeneic Balb / c mice. Some recipients in the GVHD group received 3 mg / kg KRP203 starting on day -1 (i.e., 1 day before bone marrow transplantation (BMT) on day 0 and chronic GVHD induction) until final analysis. Chronic GVHD was evaluated at different time points up to day 42 after BMT. Classical pathological changes of chronic cutaneous GVHD, such as hair follicle loss and fibrosis, were analyzed in collected skin samples.

[0430] To investigate whether treatment with KRP203 could alleviate established chronic GVHD, allogeneic mice were treated with 3 mg / kg KRP203 from day 21 to day 42. Some allogeneic mice received vehicle. Controls without GVHD received donor cells derived from syngeneic BALB / c mice.

[0431] Chronic GVHD was assessed by overall survival, GVHD score, chronic GVHD skin score, tear excretion test, histological analysis of skin and lacrimal gland, and Sircol collagen assay of skin and lacrimal gland.The effect of KRP203 on immune cell trafficking was analyzed by analysis of immune cell phenotyping of spleen, skin and lacrimal gland.

[0432] result KRP203 as a prophylaxis for chronic GVHD Skin pathology of GVHD recipients was evaluated from days 0 to 42. Mice that received KRP203 as a prophylactic treatment starting on day -1 did not show pathological skin changes caused by chronic GVHD, and the fur appeared normal, unlike any of the control recipients without GVHD (Figure 4A). This was in contrast to mice with chronic GVHD that received vehicle treatment from day -1 onwards. These mice suffered from chronic GVHD with pathological skin changes and visible hair loss. As a result, their skin clinical scores were increased compared to mice that received KRP203 as a chronic GVHD prophylaxis. Furthermore, Schirmer's test to determine tear production, performed on day 42 after bone marrow transplantation, showed low test results (<5 mm) in GVHD mice that received vehicle, supporting the diagnosis of ocular chronic GVHD with severe dry eye (Figure 4B). Prophylactic treatment with KRP203 ameliorated this condition.

[0433] Taken together, these data indicate that KRP203 can be used as a prophylactic treatment for chronic GVHD, reducing clinical pathology and improving survival.

[0434] conclusion KRP203 treatment from days -1 to 42 (i.e., final analysis) was effective in preventing the development of chronic GVHD in mice that received bone marrow and T cells from genetically mismatched donors, indicating that long-term treatment with KRP203 is beneficial in improving quality of life and transplant outcomes.

[0435] [Example 4] Preparation of pharmaceutical compositions containing S1P receptor modulators Twelve excipients were selected for compatibility study of KRP203 (S1P receptor modulator). In order to select the optimal combination of excipients, taking into account the risk of stability loss, the following 17 blends were prepared according to Table 4 below.

[0436] [Table 10]

[0437] [Example 5] Stability Data of the Pharmaceutical Composition of Example 1 Stored at 50° C. The 17 blends of Example 1 were prepared in both dry and wet conditions and stored at the indicated conditions for 6 weeks. The 17 blends were stored at the indicated conditions for 3 and 6 weeks and analyzed for assay and degradation products.

[0438] [Table 11-1]

[0439] [Table 11-2]

[0440] [Table 11-3]

[0441] The generic blends in dry and wet conditions showed some incompatibility and the degree of degradation was more evident in wet conditions. Hence, wet granulation was not selected as the process for development. Among the different combinations of dry blends, blends 7, 10, 16 and 17 were found to be highly compatible with assay data of 98.7%, 98.4%, 99.5% and 98.4% respectively at the end of 6 weeks. Of these, blend 17 was found to be the optimal blend of choice as it showed the best stability while containing the excipients required for capsule or tablet formulation of S1P receptor modulators, i.e., filler, disintegrant, lubricant and glidant.

[0442] [Example 6] Pharmaceutical compositions according to the present invention

[0443] [Table 12]

[0444] [Table 13]

[0445] A batch of 1 mg KRP203 capsules was manufactured using the following process: · Dispense the required amount of KRP203 Hydrochloride, Colloidal Silicon Dioxide, Mannitol, Sodium Starch Glycolate and Magnesium Stearate into appropriately labelled containers / bags. · Aliquot the required amount of microcrystalline cellulose into five separate sublots as detailed in Table 7. Place the input bottle in the VSE. · In the VSE, the first sublot of microcrystalline cellulose, KRP203 hydrochloride and colloidal silicon dioxide are added to a grey polypropylene container and blended in a Turbula mixer at 24 rpm for 3 minutes. At the VSE, the blend from the polypropylene container is sieved through a 500 micron mesh into a PE bag. Rinse the polypropylene container with sublot 2 of cellulose, then sift sublot 2 into the PE bag. Transfer the sifted blend into a dosing bottle. Sift sublot 4 of the microcrystalline cellulose directly into a 50L IBC. Clean the outside of the input bottle and then remove it from the VSE. · Transfer the blend from the dosing bottle into a 50L IBC using the Ezi-dock system. Sift sublot 3 of the microcrystalline cellulose into the used PE bag and then transfer to the dosing bottle. · Agitate the charge bottle to ensure it is thoroughly rinsed, then use the Ezi-dock system to transfer the cellulose from the charge bottle into a 50L IBC. · Sift sublot 5 of cellulose into a 50L IBC. Blend for 18 minutes at 22 rpm. · Remove the blend into a PE bag, transfer to the VSE and manually sift through a 500 micron mesh into the PE bag. · Transfer the blend from the PE bag into a 50L IBC. · Pre-weighed mannitol is manually sieved through a 500 micron mesh and the sieved blend is added to a 50L IBC. Blend for 9 minutes at 22 rpm. · Remove the blend into a PE bag, transfer to the VSE and manually sift through a 500 micron mesh into the PE bag. · Transfer the blend from the PE bag into a 50L IBC. · Manually sift pre-weighed Sodium Starch Glycolate through 500 micron mesh and add the sieved blend to a 50L IBC. Blend for 5 minutes at 22 rpm. · Pre-weighed magnesium stearate is manually sieved through a 500 micron mesh and the blend is added to a 50L IBC. Blend for 5 minutes at 22 rpm. · Remove the blend and place into a labeled double layer polyethylene bag. · Move to Building 6 for encapsulation. A capsule filling speed challenge will be carried out on the MG2 Labby and captured in the development log. · Encapsulate the blend (100mg fill weight) into capsules (size 4) using an MG2 Labby Encapsulator. In-process weight checks are performed every 20 minutes on 20 capsules. Manually de-dust the capsules. · The capsules are placed in double PE bags and closed with cable ties. ·Place the PE bag in an aluminum foil bag and close it with a heat seal. The production ran smoothly and without any issues.

[0446] [Example 7] Effect of short-term or long-term administration of cyclosporine A (CsA) on KRP203 treatment. method Mice: Female B6 (H-2b) and B6D2F1 (H-2b / d) mice were purchased from CLEA Japan (Tokyo, Japan) and used for allogeneic bone marrow transplantation at 8–12 weeks of age. All animal experiments were performed under the auspices of the Institutional Animal Care and Research Advisory Committee.

[0447] Bone marrow transplantation: B6D2F1 recipients were lethally irradiated (11–13 Gy) on day 0 and received 5 × 10 6 1 x 10 T-cell depleted bone marrow cells and 1 x 10 6 5 × 10 purified T cells were injected i.v. T cell purification and T cell depletion were performed on an AutoMACS Pro Separator (Miltenyi Biotec) using a Mouse Pan T Cell Isolation Kit II (Miltenyi Biotec, Auburn, CA) and anti-CD90 microbeads (Miltenyi Biotec). To assess graft-versus-leukemia effects, 5 × 10 4 P815-luc+ cells were injected into mice on day 0 of stem cell transplantation (SCT).

[0448] Reagents: KRP203 (Priothera, Dublin, Ireland) was dissolved in sterile water and orally administered at a dose of 1–3 mg / kg from day 0 to 14, 28 or the last day of analysis after transplantation. Cyclosporine A (CsA; Novartis, Tokyo, Japan) at a dose of 25 mg / kg / day was orally administered daily from day 0 to 14 or 28 after transplantation.

[0449] Graft-versus-host disease assessment: Survival was monitored daily and clinical GVHD was assessed by using a GVHD scoring system with five parameters: weight, activity, posture, fur texture, and alopecia. For pathological scoring, tissue samples were fixed in 10% formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin (H&E). T cell infiltration into target tissues, including liver, intestine, and skin, was assessed by flow cytometry analysis.

[0450] Assessment of graft-versus-leukemia effect: In vivo bioluminescence imaging (BLI) was performed weekly after transplantation. Mice were subcutaneously injected with 500 μg d-lucifen (Promega, Madison, WI) and in vivo imaging was performed 5 min later. Luciferase+ cells were detected using an IVIS Imaging System ver. 4.3.1 (Perkin Elmer, Waltham, MA). Luminescence was expressed as photons per second per square centimeter per steradian (ph / s / cm 2 / sr).

[0451] result Mice with GVHD received either KRP203 treatment alone, KRP203 + Cyclosporine A short-term (i.e., until day 14), KRP203 + Cyclosporine A long-term (i.e., the entire observation period until the final analysis), or placebo. Control mice without GVHD received only T cell-depleted bone marrow without T cells. Short-term application of Cyclosporine A showed no survival benefit compared to long-term CsA treatment, while GVHD+ mice that received KRP203 treatment alone had the best survival (Figure 5A). None of the control mice without GVHD that did not receive T cells had a graft-versus-leukemia (GVL) effect, and therefore tumor growth in this group was the highest, and eventually all mice died due to leukemia (Figure 5B). Among mice with GVHD, tumor growth was best controlled in the group that received KRP203 treatment alone, and no leukemia deaths were recorded in this group. Quantification of tumor numbers showed that short-term cyclosporine A on KRP203 resulted in fewer tumor cells compared to long-term cyclosporine A on KRP203 treatment. No mice died of GVHD. These data indicate that cyclosporine A can be stopped early without compromising GVHD, but graft-versus-leukemia is better if KRP203 treatment is continued.

[0452] conclusion Tumor growth was better controlled when cyclosporine A was reduced or stopped early compared with long-term administration in combination with KRP203.

[0453] [Example 8] Clinical studies to treat AML patients undergoing HSCT A prognostic example is provided herein describing a prospective, randomized, double-blind, placebo-controlled, multicenter Phase IIb study to evaluate the efficacy and safety of moclavimod as adjuvant and maintenance treatment in adult acute myeloid leukemia (AML) patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT).

[0454] Introduction Rationale for the use of moclavimod Allogeneic HSCT is the standard curative treatment for AML. The main limitation of successful outcomes of allogeneic HSCT is disease relapse. Graft-versus-leukemia (GVL) is important to prevent disease relapse and is mediated by donor T cells contained in the HSCT graft, which induce an immune response against leukemic cells. Graft-versus-host disease (GVHD), an off-target effect of the desired GVL effect, remains the main complication of HSCT with significant morbidity and mortality, especially when refractory to initial management. New strategies are designed to maintain or re-confer GVL to reduce disease relapse while preventing GVHD. Due to its novel mechanism of action, the potential of moclavimod to reduce GVHD while retaining the desired GVL effect is a promising way to maintain the chances of cure while reducing transplant-related mortality and morbidity in AML patients undergoing allogeneic HSCT.

[0455] The positive effects of mocravimod on disease relapse, stem cell engraftment and GVHD inhibition have been shown in previous preclinical and clinical studies. The dosing regimen of mocravimod in the HSCT setting for hematological malignancies in adults has been established in the Phase Ib study CKRP203A2105 (ClinicalTrials.gov Identifier: NCT01830010), in which mocravimod (1 mg / day or 3 mg / day) was administered in combination with various immunosuppressive GVHD prophylactic regimens for a treatment duration of approximately 3 months. The data support proceeding with pivotal clinical studies to evaluate the efficacy and safety of mocravimod as adjuvant and maintenance therapy for allogeneic HSCT over longer treatment durations up to 1 year, which may improve survival.

[0456] To date, there are no approved comparators across the range of proposed indications. Therefore, a placebo-controlled design was selected for this study. The objective of this study is to evaluate the efficacy and safety of mocravimod (1 mg / day and 3 mg / day) compared with placebo as adjuvant and maintenance therapy for allogeneic HSCT in AML patients in CR1 or CR2, with a treatment period of 1 year. In this study, treatment with mocravimod or placebo will begin 2 days before conditioning and will end 12 months after the first dose.

[0457] Objectives and Endpoints

[0458] [Table 14-1]

[0459] [Table 14-2]

[0460] [Table 14-3]

[0461] research design This Phase IIb study is designed as follows: A prospective, multicenter, randomized, double-blind, placebo-controlled, and parallel-group study Approximately 300 subjects will be screened and randomized to approximately 249 subjects with AML in CR1 or CR2 undergoing allogeneic HSCT. The research will take place at approximately 80 study sites across North America, Europe and possibly Asia-Pacific. Eligible subjects will be stratified by complete remission status (CR1 vs. CR2) and treatment used for GVHD prophylaxis (CsA vs. TAC). An automated voice / web response system (IxRS) will be used for randomization (mocravimod 1 mg, mocravimod 3 mg, or matching placebo [1:1:1 ratio]). 1 mg / day mocravimod (1 mg group): Approximately 83 subjects will receive 1 mg of mocravimod orally once daily from day -9 ± 1 day until 12 months after first intake of the investigational medicinal product (IMP). 3 mg / day mocrabimod (3 mg group): Approximately 83 subjects will receive 3 mg of mocrabimod orally once daily from day -9 ± 1 day until 12 months after first IMP intake. Placebo (placebo group): Approximately 83 subjects will receive a placebo orally once daily from day -9 ± 1 day until 12 months after their first IMP intake. Subjects will be required to record each administration of IMP in their subject diary to ensure treatment compliance. The study duration will be approximately 24 months and will include the following phases: Screening and enrollment phase (screening phase up to 28 days prior to randomization on or before the start of study treatment) - Double-blind treatment phase (from 2 days before the start of pretreatment until the end of the 12th month or end of treatment due to onset of relapse or death or intolerable toxicity or due to any other reason). RFS follow-up phase (for subjects who discontinued study treatment early but did not relapse or die; through completion of 12 months) OS follow-up phase (12 months of treatment-free time from either the end of treatment or the end of the RFS follow-up phase or recurrence) Subjects will be admitted to hospital 2 days prior to the start of consolidation for randomization and administration of IMP, followed by the conditioning regimen and allogeneic HSCT (day 0). Length of hospital stay after HSCT will depend on subject condition, investigator discretion, and local practice. The study consisted of the following visits: Screening and randomization phase: Screening visit within 28 days prior to initiation of study treatment; randomization on or before the start of study treatment. Double-blind treatment phase: - Day 2 prior to start of consolidation (admitted 2 days prior to start of conditioning regimen, baseline and start of IMP) - Moclavimod PK blood sampling (24 hours after pretreatment and first IMP administration) - Day 7 ± 1 (start of conditioning regimen) - Day 5 (Mocrabimod PK blood sampling) - Day 2 (CsA / TAC PK blood sampling) - Day 0 (HSCT) - 14th day ± 2 days - 1st month (28th day) ±2 days - 2nd month (56th day) ±2 days - 3rd month (84th day) ±2 days - 4th month (112th day) ±2 days - 5th month (140th day) ±2 days - 6th month (168th day) ±2 days - 7th month (196th day) ±2 days - 8th month (224th day) ± 2 days - 9th month (252nd day) ±2 days - 10th month (280th day) ± 2 days - 11th month (308th day) ±2 days - Month 12 (day 336) ± 2 days (end of treatment [EOT] / early discontinuation [ED] visit) ○RFS follow-up phase - Monthly visits during the double-blind treatment phase OS follow-up phase: - 13th month (day 364) ± 7 days (28 days after last IMP intake) - 15th month (420th day) ±7 days - 18th month (504th day) ±7 days - 21st month (588th day) ±7 days - Month 24 (day 672) ± 7 days (end of study [EOS] / ED) Unscheduled visits may be arranged as needed. Safety will be reviewed by an Independent Data Monitoring Committee (IDMC). Adjudication of the primary endpoint will be conducted by an Independent Review Committee (IAC). · A futility interim analysis will be performed if 14 events of disease recurrence or death occur. This will only be performed if no treatment arms have been stopped early due to safety findings and if recruitment of at least 20 subjects is pending. Recruitment will be frozen once the event is reached and will resume once the analysis is complete. A dedicated unblinded team at the Clinical Research Organization (CRO) will perform the analysis and the results will be shared with the IDMC, which will assess and decide whether to stop or not the futility arm.

[0462] Scientific basis for study design This study is designed as a prospective, multicenter, randomized, double-blind, placebo-controlled, and parallel-group study. The purpose of this study is to evaluate the efficacy and safety of moclavimod (1 mg / day and 3 mg / day) compared with placebo as adjuvant and maintenance treatment for AML patients in CR1 or CR2 undergoing allogeneic HSCT, using local standard of care GVHD prophylaxis of MTX+CsA or MTX+TAC. To date, there are no approved comparators for the proposed indications. Therefore, a placebo-controlled design was selected for this study to prospectively evaluate the magnitude of possible efficacy and safety changes.

[0463] Treatment assignment will be blinded to the investigator, the research team involved in the conduct of the study, and the subjects throughout the double-blind treatment phase to reduce potential bias during data collection and assessment of study endpoints. Study data will be unblinded once all subjects have completed the EOT visit or RFS follow-up phase.

[0464] A futility interim analysis will be performed if 14 events of disease recurrence or death occur. This will only be performed if no treatment arms have been stopped early due to safety findings and there are at least 20 subjects pending recruitment. The purpose of the futility interim analysis is to evaluate the efficacy of the 1 mg arm versus the 3 mg arm to avoid exposing subjects to a potentially inferior treatment.

[0465] Dosage Justification In this study, treatment with mocravimod (1 mg / day or 3 mg / day) or placebo begins 2 days prior to the start of pretreatment and ends 12 months after the first study drug intake.

[0466] In a Phase Ib study (CKRP203A2105) of moclavimod (1 mg / day + CsA or 3 mg / day + CsA or TAC), the safety profile was comparable between the 1 mg and 3 mg moclavimod dose groups. A model-based PK / PD analysis was performed with data from this study. Due to sparse available data, exposure-response analysis could not provide information on potential differences between the 1 mg and 3 mg doses for the GRFS efficacy endpoint of this study. However, in modeling and simulation analyses, when the surrogate endpoints absolute lymphocyte count (ALC), CD4+ and CD8+ T cell counts were related to dose, a more pronounced decrease in CD8+ T cell counts was revealed with the 3 mg dose given with SOC+CsA, while maximum or near-maximum cell count decreases were seen for CD4+ and ALC counts.

[0467] Clinical experience with mocravimod includes single doses of up to 40 mg in healthy volunteers and multiple doses of up to 3 mg / day in healthy volunteers and patients. A total of 325 healthy volunteers participated in a Phase I placebo-controlled study of mocravimod, and mocravimod was well tolerated and showed a favorable safety profile. Mocravimod was also well tolerated in a Phase II study in patients with ulcerative colitis, subacute cutaneous lupus erythematosus, and Crohn's disease. In a Phase Ib / IIa study, mocravimod was administered for up to approximately 3 months to patients with several different hematological malignancies undergoing allogeneic HSCT. Both the 1 mg and 3 mg dose levels evaluated in this study showed no significant differences in terms of safety and efficacy. However, the number of patients was small, and the efficacy results justify obtaining more data in a more homogenous patient population. To gather more data at both doses, this Phase IIb study will investigate moclavimod at two different dose levels: 1 mg and 3 mg daily doses.

[0468] In the study population selected for this study, most relapses occur early (<1 year) and most GVHD events occur by 1 year. Therefore, a treatment duration of 1 year is selected for this study.

[0469] Dosing of moclavimod in this study is not weight related as no dose-related effects on preliminary signs of safety and efficacy were observed in the Phase Ib / IIa study.

[0470] Study population Inclusion criteria Each subject must meet the following criteria to be enrolled in this study: Subject type and disease characteristics 1. AML (acute myelodysplastic syndromes) according to the World Health Organization 2016 classification of AML and related precursor tumors, including secondary AML after antecedent hematological disorders (e.g., myelodysplastic syndromes) and therapy-related AML. Subjects diagnosed with leukemia (excluding promyelocytic leukemia). 2. Subjects with ELN high-risk AML in CR1 or any other AML in CR2 (complete remission with incomplete count recovery [CRi] is permitted). Complete remission is defined as leukemia clearance (<5% bone marrow blasts and no circulating peripheral blasts) along with normal absolute neutrophil and platelet counts, no signs of extramedullary leukemia, and no need for repeated blood transfusions. CRi is defined as fulfilling all criteria for complete remission except absolute neutrophil count <1,000 / μL or platelet count <100,000 / μL. 3. Subjects who plan to undergo allogeneic HSCT and meet all of the following parameters: Use of a fully matched related or unrelated donor (10 / 10 HLA match), and Use of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells, and o Planned use of a protocol-validated (myeloablative) conditioning regimen; and -Planning for use of MTX+CsA or MTX+TAC as GVHD prophylaxis 4. Life expectancy at screening ≥ 6 months. 5. Karnofsky performance status (KPS) ≥ 70%. Gender and age 6. Male or female aged ≥ 18 and ≤ 75 years Subjects ≧65 years of age must have a Sorror (Hematopoietic Cell Transplantation Specific Comorbidity Index [HCT-CI]) score ≦3. Informed consent 7. Be able and willing to provide written informed consent and comply with the study protocols and procedures. Contraception / Barrier Requirements 8. For sexually active women of childbearing potential and men who have sexual contact with women of childbearing potential: Willing to use a reliable method of contraception (oral contraceptives, contraceptive injections, male vasectomy, spermicide-impregnated condoms, or coitus abstinence) during participation in the study. Contraception will be used from the Screening visit through the EOT visit and, in any case, for at least 6 months after the last dose of IMP. Women are considered fertile after menarche until menopause, unless they are completely infertile. Women are considered postmenopausal and not fertile if they have had 12 months of natural (spontaneous) amenorrhea with the appropriate clinical profile (e.g., appropriate age, history of vasomotor symptoms) or have undergone bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks prior to the IMP procedure. In the case of oophorectomy alone, a woman is considered not fertile only if her reproductive status is confirmed by follow-up hormone level evaluation. Women of childbearing potential must be willing to undergo monthly pregnancy tests. 9. Sexually active men must use condoms during sexual intercourse from the screening visit until at least 6 months after their last dose of IMP and should not father a child during this period. Vasectomized men should also use condoms to prevent delivery of IMP through semen. Other inclusions 10. Enrollment in the National Health Insurance Scheme (subject to applicable local requirements).

[0471] Exclusion criteria Subjects who meet any of the following criteria will be excluded from the study: Previous / concomitant therapy 1. Plan to use antithymocyte globulin (ATG), post-transplant cyclophosphamide, or mycophenolate mofetil for GVHD prophylaxis. 2. Plan to use serum therapy during conditioning including ATG and alemtuzumab. 3. Plan for ex vivo large graft engineering including T cell depletion or CD34+ selection. 4. Subjects who have previously undergone allogeneic HSCT or are solid organ transplant recipients. 5. Vaccination within 4 weeks prior to randomization. 6. Immunosuppressant medications for comorbid conditions. Subjects must be able to discontinue prednisone (>10 mg / day) or other immunosuppressant medication for at least 3 days prior to the start of study treatment. Physiological replacement dosing of hydrocortisone is permitted. 7. Major surgery or large wounds that have not completely healed within 4 weeks prior to randomization. 8. Cardiac insufficiency requires one of the following treatments: Treatment with medications that impair cardiac conduction (e.g. beta-blockers, verapamil- and diltiazem-type calcium channel blockers or cardiac glycosides), or Concomitant use of medications known to prolong the QT interval, unless they can be permanently discontinued for the duration of the study, or o Treatment with quinidine. Medical conditions 9. Subjects with acute promyelocytic leukemia. 10. Diagnosis of any prior or concomitant malignancy, except for subjects who have been diagnosed with localized basal cell carcinoma of the skin or in-situ cervical carcinoma, or who have completed curative-intent treatment (chemotherapy and / or surgery and / or radiation therapy) for that malignancy at least 3 years prior to enrollment. 11. Blast crisis of chronic myeloid leukemia. 12. Clinically significant pulmonary fibrosis - Tuberculosis, except for a history of successfully treated tuberculosis or prophylaxis following a positive purified protein derivative (PPD) skin reaction - Subjects receiving chronic (daily) treatment for asthma Subjects with any other type of clinically significant obstructive pulmonary disease Diabetes that is not controlled as assessed by the investigator, or diabetes complicated with organ damage such as diabetic nephropathy or retinopathy Uncontrolled seizure disorder History of unmanaged depression or suicide attempts / ideations Concurrent serious and / or uncontrolled medical conditions, including 13. Myocardial infarction within the last 3 months of study participation, or Decreased left ventricular function with ejection fraction < 40% as measured by multi-gated acquisition (MUGA) scan or cardiac ultrasound (echocardiogram) within 6 weeks prior to signing informed consent, or History or presence of stable or unstable ischemic heart disease (IHD), myocarditis or cardiomyopathy, or New York Heart Association (NYHA) class II to IV congestive heart failure, or Unstable cardiac arrhythmias, including a history or presence of symptomatic bradycardia, or Resting heart rate (physical examination or 12-lead electrocardiogram [ECG]) < 60 bpm, or o History or current diagnosis of ECG abnormalities indicating a significant safety risk, e.g., presence of a clinically relevant cardiac conduction disorder including coexistent clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, sick sinus syndrome or sinoatrial heart block, clinically significant atrioventricular (AV) block, bundle branch block or resting QTc (Fridericia preferred, but Bazett also acceptable) >450 msec (males) and >470 msec (females) on screening or baseline ECG, or History or presence of symptomatic arrhythmias or arrhythmias requiring treatment or that are otherwise clinically significant, or Uncontrolled arterial hypertension; if controlled, medication must have been stable for 3 months prior to the baseline visit, or - Requiring treatment with prohibited medications as listed under "Exclusion Criteria - Previous / Concomitant Medications" A history of stroke suspected to be of cardiac origin, or History of familial long QT syndrome or known family history of polymorphic ventricular tachycardia Cardiac dysfunction as defined by. 14. Pulmonary impairment defined by oxygen saturation <90% on room air. Pulmonary function tests (PFTs) are required only in cases of symptomatic or previously known impairment within 6 weeks prior to signing informed consent, and include measurements of diffusing capacity of the lung for carbon monoxide (DLCO) and forced expiratory volume in 1 second (FEV) <50% predicted. 1 ) corrected lung function <50%. 15. Significant liver disease or injury, or known history of alcohol abuse, chronic liver or bile duct disease. Hepatic dysfunction defined by aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) >2.5 × ULN; or total bilirubin >1.5 mg / dL, <3 mg / dL if attributable to Gilbert syndrome. 16. Modification of Diet in Renal Disease (MDRD) estimated creatinine clearance <60 ml / min / m 2 Renal dysfunction with 17. History of stroke or intracranial hemorrhage within 1 year prior to screening. 18. Active clinically significant infection (viral, bacterial or fungal) requiring ongoing antimicrobial therapy and representing, in the investigator's judgment, a risk for progressing to HSCT. 19. History of active infection with human immunodeficiency virus (HIV) or hepatitis B virus (HBV) or hepatitis C virus (HCV), defined as positive HIV antibody, hepatitis B surface antigen, or hepatitis C antigen. 20. Subjects who are breastfeeding or have a positive pregnancy test (a serum pregnancy test is mandatory at screening for women of childbearing potential). 21. Known allergy to any of the non-investigational medicinal products (NIMPs), including any of the components of moclavimod (e.g., excipients), conditioning regimen agents and GVHD prophylaxis, as well as any concomitant medications and treatments possibly used in this study. 22. Any contraindication to NIMP, including conditioning regimen agents and GVHD prophylaxis, as well as concomitant medications and treatments possibly used in this study, as described in the local prescribing information for the NIMP drug. 23. Diagnosis of Macular Edema During Screening. Subjects with a history of macular edema may participate in the study provided they do not have macular edema on ophthalmologic examination at screening. Previous / concurrent clinical research experience 24. Participation in another interventional clinical trial within 4 weeks prior to randomization or participation in a concurrent interventional clinical trial. Other Exclusions 25. Any other condition which, in the opinion of the investigator, makes the subject ineligible for the study. 26. Subjects who are under legal guardianship (guardianship, fiduciary or judicial custody) and / or who are unable or unwilling to comply with the requirements and procedures of this Examination.

[0472] Study treatments and combination therapies Study treatments are defined as any investigational treatment, marketed product, and placebo intended to be administered to study subjects according to the study protocol. IMP includes moclavimod and placebo. NIMP includes products used in HSCT for conditioning and standard of care GVHD prophylaxis (MTX+CsA or MTX+TAC).

[0473] Investigational drugs administered by group

[0474] [Table 15]

[0475] Treatment Group

[0476] [Table 16]

[0477] Non-clinical drug NIMP includes products used in HSCT for conditioning and GVHD prophylaxis (MTX+CsA or MTX+TAC). They are commercially available for human use under various brand names and are administered according to local practice unless otherwise stated.

[0478] Conditioning regimen All patients will receive a conditioning regimen prior to HSCT. One of the following conditioning regimens will be administered. The conditioning regimen should begin on day -7 ± 1. Modifications in dosage and timing in the conditioning regimen are possible to accommodate subject status and / or local practice. Any modifications in dosage or timing in the conditioning regimen will be discussed between the investigator and medical monitor and recorded in the electronic case report form (eCRF).

[0479] One of the following regimens must be used: 1. Melphalan + Fludarabine + Thiotepa Fludarabine 120-180mg / m 2 Intravenous (IV) Melphalan 110-140mg / m 2 IV Thiotepa 5-10 mg / kg IV 2. Busulfan + Fludarabine: Busulfan 9.6-12.8 mg / kg IV Fludarabine 120-180mg / m 2 IV 3. Busulfan + Cyclophosphamide: Busulfan 9.6-12.8 mg / kg IV Cyclophosphamide 120mg / kg IV 4. Busulfan + Fludarabine + Thiotepa: Busulfan 9.6-12.8 mg / kg IV Fludarabine 150-180mg / m 2 IV Thiotepa 5-10 mg / kg IV

[0480] If busulfan is utilized as a component of the conditioning regimen, appropriate PK monitoring with dose adjustments as necessary should be performed based on the institution's standard of care. The suggested AUC range for daily exposure is 3600-6000 μM × min (approximately 14.4-24.6 mg × h / L). Dosing frequency (e.g., daily vs. q6h) is at the discretion of the investigator, but all busulfan must be administered intravenously.

[0481] Graft-versus-host disease prophylaxis Calcineurin inhibitor (CNI) treatment CsA and TAC should be initiated on days -1 or -2 prior to stem cell infusion. CNI prophylaxis should be continued until at least 3 months after HSCT, tapered according to institutional standards, with the goal of discontinuing by 6 months after HSCT in the absence of GVHD. Appropriate clinical monitoring and management of toxicities (e.g., hypertension, hyperglycemia, hypomagnesemia, neurological complications) should be performed according to institutional practice. Care should be taken to adjust doses based on potential drug-drug PK interactions (e.g., azole antifungals). Cyclosporine A (CsA) - CsA should be initiated at a dose of 3 mg / kg / day IV (divided into 2 bolus infusions twice daily). Conversion to oral administration should be based on clinical circumstances with conversion ratios based on institutional practice. If initiating CsA via the oral route, the starting dose is 12 mg / kg / day divided BID (Ruutu et al 2014). - Drug monitoring: CsA trough levels should be measured 12 hours after the dose (just before administration of the next scheduled dose) and monitored periodically; doses are adjusted to maintain a target concentration of 200-300 μg / L for the first 3-4 weeks after HSCT. In the absence of GVHD, doses are subsequently reduced until a concentration of 100-200 μg / L is reached. Tacrolimus (TAC) - TAC should be initiated at a dose of 0.02-0.03 mg / kg / day (either continuous infusion or divided into 2 bolus infusions twice daily). Conversion to oral dosing should be based on clinical circumstances with conversion ratios based on institutional practice. - Drug monitoring: TAC trough levels should be measured 12 hours after dose (just before administration of the next scheduled dose) and monitored periodically; doses should be adjusted to maintain target concentrations of 5-10 ng / mL.

[0482] MTX dose / schedule: ○+1st day: 15mg / m 2 1 IV. Days +3, +6, and +11: 10 mg / m 2 1 IV. o The use of leucovorin rescue is permitted and recommended (same dose as MTX given for 3 doses every 6 hours starting 24 hours after the MTX dose; given orally or IV).

[0483] Modifications of this regimen to reduce clearance or MTX toxicity are permitted but should be discussed with medical monitors.

[0484] Preparation, handling, storage and measurement control The IMP used in this study will be prepared, packaged and labelled under the responsibility of the funder's qualified person or designee in accordance with the funder's or designee's Standard Operating Procedures (SOPs), the Pharmaceutical Inspection and Control Collaboration Scheme (PIC / S) Good Manufacturing Practice (GMP) guidelines, the International Council on Harmonisation Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines, and applicable local laws / regulations. The product will be labelled with the statement "For Clinical Research Use Only" in the local language, and any other required information in accordance with local regulatory requirements.

[0485] The IMP will be supplied to the study site by the funder or nominee ready for use. No further preparation is required prior to administration of the IMP. Upon randomization, subjects will be provided with enough IMP corresponding to their assigned treatment group to cover the period between visits in the double-blind treatment phase. The IMP can be stored at room temperature. Please refer to the Regulatory Manual for further details.

[0486] Available stability data indicates that moclavimod 1 mg hard gelatin capsules and placebo capsules, when packaged in high density polyethylene (HDPE) bottles, are stable for 48 months when stored at 5°C / ambient relative humidity (RH); 36 months when stored at 25°C / 60% RH, and 6 months when stored at 40°C / 75% RH.

[0487] Once received, IMPs are stored on-site at the clinical site in accordance with storage requirements specified in the Regulatory Affairs Manual until distribution to subjects. All IMPs must be stored in accordance with labeled storage conditions in a secured, environmentally controlled, and monitored (manual or automated) area with access limited to investigators and authorized site staff.

[0488] Accountancy of IMP is documented at the study site. Each time an IMP is dispensed to a subject, this must be recorded in the Drug Dispensing / Accountancy Log. At regular intervals, a Clinical Research Associate (CRA) will perform "Drug Reconciliation Visits" to ensure that all IMP shipped to the study site can be accounted for in the receipt, distribution and disposition records. Undispensed unused IMP may be disposed of only after approval by the designated CRO representative, and disposal should be fully documented. Alternatively, IMP may be returned to the funder. Please refer to the Regulatory Affairs Manual for further details.

[0489] At EOT, it must be possible to match records of delivery with records of stock used and disposed or returned. It is essential that the researcher or study site be briefed on the IMP and any discrepancies be explained and documented.

[0490] Measures to minimize bias: randomization and blinding Each subject will receive a subject number of seven digits: a four-digit study site number followed by a consecutive three-digit individual subject number (e.g., 0001-001), which will be assigned at the screening visit at the study site and used throughout the study.

[0491] Randomization This study is designed as a randomized, double-blind, placebo-controlled study. Subjects will be stratified by complete remission status (CR1 or CR2) and GVHD prophylaxis treatment (CsA vs. TAC) and randomized (1:1:1 ratio) to receive either 1 mg / day or 3 mg / day moclavimod or matching placebo as adjuvant treatment for HSCT.

[0492] All eligible subjects will be centrally assigned to a randomized IMP using the IxRS. Prior to study initiation, each site will be provided with an Interactive Voice Response System (IVRS) telephone number and instructions for telephone contact or an Interactive Web Response System (IWRS) login information and instructions for use.

[0493] Blinding Treatment assignment will be blinded to the investigator, the study team involved in the conduct of the study, and the subjects throughout the double-blind treatment phase to reduce potential bias during data collection and assessment of study endpoints. Study data will be unblinded once all subjects have completed the EOT visit or RFS follow-up phase.

[0494] A futility interim analysis will be performed if 14 events of disease recurrence or death occur. This will only be performed if no treatment arms have been stopped early due to safety findings and if recruitment of at least 20 subjects is pending. Recruitment will be frozen once the event has been reached and will resume once the analysis is complete. A dedicated unblinded team at the clinical research organization (CRO) will perform the analysis and the results will be shared with the IDMC, which will assess and decide whether to stop or not the futility arm.

[0495] Each study site will be supplied with identically packaged IMP. Moclavimod and placebo capsules will be identical in appearance: opaque pink (orange in Sweden) capsule, size #4, white to off-white powder.

[0496] Emergency unblinding procedure The IxRS will be programmed with instructions for unblinding. In case of emergency, the investigator has sole responsibility to decide whether unblinding of the subject's treatment assignment is warranted. In making such a decision, the subject's safety must always be the primary consideration. If the investigator decides to warrant unblinding, the investigator must make every effort to contact the funder before unblinding the subject's treatment assignment, unless this would delay the subject's emergency treatment. If the subject's treatment assignment is unblinded, the funder must be notified of this within 24 hours. Email notification allows pre-designated email recipients to be informed when a subject or inventory item is unblinded. The date and reason for unblinding must be recorded.

[0497] The IMP must be discontinued after emergency unblinding and subjects will follow the OS follow-up phase. In the case of subjects whose procedure code is inadvertently corrupted or for any non-emergency reason, the IMP may or may not be discontinued at the investigator's discretion.

[0498] Investigational Drug Compliance Subjects should record each administration of IMP in their diary to ensure treatment compliance. Investigators should encourage compliance by instructing subjects to take IMP exactly as prescribed and by explaining that compliance is necessary for the subject's safety and the validity of the study. Subjects will be instructed to contact the investigator if, for any reason, they are unable to take IMP as prescribed.

[0499] Treatment compliance will be achieved by documenting in records (i.e., drug metering administration, administration log, and subject's eCRF) information including, but not limited to, IMP batch number, potential discontinuation / interruption of treatment administration, total number of IMP units administered, and signature of the designated investigator who delivered the IMP to the subject as described in the drug manual. Any deviations from the prescribed dosage regimen should be recorded.

[0500] Standard of Care GVHD Prophylaxis Exposure: Exposure data for standard of care GVHD prophylaxis of MTX+CsA or MTX+TAC will be collected. If subjects are medicated on-site, they will receive MTX and CsA or MTX+TAC directly from the investigator or qualified study site staff under medical supervision. The dose, date and time of each dose administered on-site, as well as the reason for dose changes (if any), will be recorded on source documents and relevant forms.

[0501] If subjects self-administer CsA or TAC at home, compliance will be assessed at each visit and recorded on source documents and relevant forms. Deviations from the prescribed dosage regimen should be recorded. Records of the amount of treatment dispensed to and administered by each subject must be maintained and matched with compliance records. Treatment start and stop dates, including dates of treatment delays and / or dose reductions, will also be recorded.

[0502] CsA and TAC levels are closely monitored.

[0503] Dose modification All medications prescribed and dispensed to subjects by the investigator during the study and all dose changes will be recorded.

[0504] IMP dose modifications, including dose reduction (down-titration) and dose escalation, are not permitted during the study.

[0505] An IMP may be temporarily suspended for a documented reason, such as an AE. The circumstances surrounding the suspension of the IMP must be discussed with the medical oversight officer, and the IMP will be resumed as soon as possible. These changes must be documented on the source document and in the eCRF.

[0506] Continued evaluation of investigational drugs after the study is completed Moclavimod is an investigational IMP and, as a result, will not be available for treatment of subjects after completion of the double-blind treatment phase, after relapse, or in the event of withdrawal of the study by the subject or funder.

[0507] After enrollment, subjects will be managed according to local clinical practice, ie, according to local guidelines and standards of care.

[0508] Treatment of overdose A daily dose of more than 3 capsules is a protocol deviation and will be considered an overdose. AEs due to overdose should be reported.

[0509] The funders did not recommend any specific treatment for overdoses.

[0510] In the event of an overdose, investigators should: · Contact medical supervisor immediately. Increased monitoring of subjects with 12-lead ECG for bradycardia events over a period of at least 3 days. In consultation with medical oversight, evaluate the subject to determine if IMP should be discontinued. If requested by the medical monitor (determined on a case-by-case basis), obtain plasma samples for PK analysis within 2 days of the date of the last dose.

[0511] Document the amount of the overdose and the duration of the overdose.

[0512] Concomitant and Prohibited Medication and Treatment Any medication or vaccine (including over-the-counter or prescription medications, vitamins and / or herbal supplements) or treatment that a subject is receiving at the time of enrollment or during the study is considered concomitant, with the exception of IMP, HSCT, conditioning regimens, and MTX+CsA or TAC used for GVHD prophylaxis. All concomitant medications must be recorded in the eCRF.

[0513] Medical monitors should be contacted if there are any questions regarding concomitant or prior therapy.

[0514] Combination medications and treatments Prophylactic treatment for cytomegalovirus infection To prevent infection with cytomegalovirus (CMV), subjects who are CMV positive or have a CMV positive donor may be administered prophylactic treatment including ganciclovir, valganciclovir, letermovir and foscarnet according to institutional practice. All subjects, regardless of chemoprevention strategy, are subjected to regular quantitative polymerase chain reaction (PCR) monitoring.

[0515] Indications for CMV prophylaxis and treatment of CMV reactivation should follow local SoC.

[0516] Preemptive Treatment for Epstein-Barr Virus Infection To prevent infection with Epstein-Barr virus (EBV), subjects who are EBV seropositive or have had an EBV seropositive donor should be subjected to appropriate (preemptive) treatment, if indicated, after regular quantitative PCR monitoring. If the quantified viral DNA level exceeds the institutional threshold for treatment of EBV reactivation, the subject should be treated with rituximab. Also, if a previously EBV-positive subject shows lymph node enlargement, initiation of rituximab is recommended, even if the PCR for EBV is low or negative.

[0517] The following schedule is recommended: Immediately after elevated EBV DNA levels were detected, rituximab (anti-CD20 monoclonal antibody) was administered at 375 mg / m 2 IV is started weekly until PCR for EBV is negative. If post-transplant lymphoproliferative disorder (PTLD) is suspected based on clinical symptoms, computed tomography (CT) scans of the neck, chest, abdomen, and pelvis should be performed, as well as bone marrow aspiration and biopsy, and lymph node biopsy, if possible. PET / CT should also be considered for diagnosis and response evaluation. If CT scan, bone marrow, and lymph node results indicate PTLD, rituximab should be administered weekly for at least 2 weeks, with subsequent dosing and additional treatments based on response.

[0518] Preemptive treatment of human herpesvirus 6 reactivation Human Herpesvirus 6 (HHV-6) PCR predictive monitoring will be performed at the investigator's discretion based on subject risk and investigational standard of care. HHV-6 reactivation should also be suspected in the event that a subject develops otherwise unexplained fever, erythematous skin rash, delayed engraftment, or post-transplant cytopenias, pneumonitis, encephalitis, or hepatitis. HHV-6-related symptoms or sufficient viral load (investigator's judgment) should prompt initiation of appropriate antiviral therapy based on the subject's clinical status and comorbidities, including the following options: Foscarnet 90mg / kg IV q2h or 60mg / kg IV q8h Cidofovir 5 mg / kg IV weekly or 1 mg / kg IV three times weekly (with probenecid) Ganciclovir or valganciclovir

[0519] Donor Selection HLA-identical siblings are the preferred donors. If this option is not available, unrelated donors matched for HLA-A, -B, -C, -DRB1, and -DQB1 (10 / 10) based on DNA-based typing are the second choice. When two or more suitable donor options are available, an institutional algorithm for donor selection should be used that incorporates non-HLA characteristics such as donor age, sex, ABO compatibility, CMV serostatus, and parity, among others.

[0520] Stem Cell Source and Graft Infusion Peripheral blood stem cells obtained by leukapheresis after high-dose hematopoietic growth factor mobilization are the preferred stem cell source. The minimum CD34+ cell dose is 2×10 6 cells / kg of recipient body weight, with a target dose of 5 x 10 6 cells / kg of recipient body weight. Stem cell grafts should be infused into patients using the institution's standard practice for prior drug treatment.

[0521] Although infusion of fresh peripheral blood stem cells (PBSCs) is preferred, cryopreservation of previously collected cells may be necessary due to factors outside the investigator's control, such as COVID-19-related restrictions, and this is acceptable.

[0522] hematopoietic growth factors Routine preemptive use of hematopoietic growth factors after HSCT is permitted but not required, and can be initiated as soon as 24 hours after stem cell infusion and continued until adequate neutrophil recovery has been achieved.

[0523] Other supportive care Appropriate antimicrobial prophylaxis and monitoring should be used based on institutional practice. Other than viral monitoring and prophylaxis / preemptive treatment described elsewhere, there is no study-specified antimicrobial prophylaxis regimen and institutional standards should be observed. However, it is suggested that all subjects receive chemoprophylaxis against fungal and bacterial organisms (at least during the neutropenic period), as well as Pneumocystis (during lymphopenic or immunosuppressive therapy) at timing after HSCT based on patient-specific factors. Subjects who develop GVHD may require reinstatement or increase in antimicrobial prophylaxis, including antibacterial prophylaxis against encapsulated organisms (in the event of cGVHD). Additionally, intravenous immunoglobulin (IVIg) supplementation is permitted based on investigator preference.

[0524] Administration of blood product support during pancytopenia should adhere to institutional standards; however, routine use of granulocyte transfusions is not permitted.

[0525] Prohibited Drug Treatment and Treatment The following medications or treatments are prohibited during the study: Maintenance Therapy: Targeted treatment with FLT3 inhibitors Hypomethylating agents IDH inhibitors Bcl-2 inhibitors HDAC inhibitors Any other maintenance therapy after allo-HSCT, including immunotherapy or any investigational drug Donor lymphocyte infusion (DLI) for relapse treatment - For example, preemptive use of DLI in the event of MRD-positive disease is not permitted GVHD prevention: ○ATG before transplantation Post-transplant cyclophosphamide Mycophenolate mofetil Use of serum therapy during pretreatment: ○ATG Alemtuzumab CYP3A4 inhibitors and inducers: Moclavimod is primarily metabolized by the enzyme CYP3A4 and strong CYP3A4 inhibitors and inducers should be avoided if possible. · Live or live-attenuated vaccines are prohibited while the subject is receiving study treatment and for 2 months after discontinuation of study treatment. Antihypertensives Because bradycardia is an AESI of mocrabimod, drugs that generally cause a decrease in heart rate, such as calcium channel blockers and beta-blockers, should be avoided. In the event of a life-threatening situation, these agents should be used at the investigator's discretion, with subject safety taking priority. For routine treatment of hypertension, other classes of agents should be used when possible. Calcium channel blockers and beta-blockers may be utilized after discussion with medical monitors if other options are contraindicated and the subject does not demonstrate bradycardia after IMP exposure.

[0526] Dose Selection After Study Completion If no safety findings are observed in the 3 mg group, and if efficacy is comparable between 1 mg and 3 mg at the time of analysis of the primary endpoint, 3 mg / day moclavimod will be selected for further study and manuscript submission.

[0527] Efficacy evaluation Disease evaluation AML disease assessments will be assessed at visits at the local laboratory by bone marrow aspiration and / or biopsy for morphology until confirmation of relapse. AML disease assessments will also be performed if relapse is suspected between study visits. MRD positivity without morphologic relapse is not considered a relapse. For subjects with a history of extramedullary disease, disease assessment will include evaluation of radiographs (and / or cerebrospinal fluid [CSF]).

[0528] Morphologic relapse is defined as morphologic evidence of leukemia in the bone marrow (≧5% leukemic blasts) or the appearance of blasts in the peripheral blood or other extramedullary sites. Details of relapse will be recorded on the eCRF.

[0529] If a bone marrow aspirate and / or biopsy has already been obtained between monthly visits during the double-blind treatment phase or between monthly visits during the RFS follow-up phase, or within 6 weeks prior to a scheduled visit during the OS follow-up phase, there is no need to repeat the evaluation.In addition, if relapse is suspected after allo-HSCT, chimerism is assessed to support the diagnosis.

[0530] Subjects who relapse during the double-blind treatment phase will discontinue IMP treatment. Subjects will enter the OS follow-up phase and be observed for an additional 12 months.

[0531] Mortality assessment Mortality assessment will be performed at the visit.

[0532] Following the death of a subject, the following information must be recorded in the eCRF: ·Date of death ·Cause of death (details) Researchers' classification of causes of death: Leukemia recurrence Transplant-related mortality (TRM), defined as death due to causes other than disease recurrence or disease progression ○Other

[0533] Graft-versus-host disease evaluation GVHD assessments will be performed at each visit. Overall GVHD events will be classified based on consensus criteria. aGVHD will be graded according to the MAGIC scale (Harris et al. 2016). cGVHD will be graded according to the National Institutes of Health (NIH) criteria (Filipovich et al. 2005; Jagasia et al. 2015).

[0534] [Table 17]

[0535] Whenever possible, tissue biopsies are obtained to confirm the diagnosis of GVHD and to assess its severity. However, acute and chronic GVHD remain clinical diagnoses, which are considered to be present when diagnosed and treated in the absence of biopsy confirmation.

[0536] Details of all GVHD events will be recorded in the eCRF. For cGVHD and aGVHD events, use of systemic immunosuppressive treatment will be recorded. The start date of a GVHD event will be defined as the start date of GVHD treatment or the date of biopsy confirmation of GVHD, whichever occurs first.

[0537] Treatment of GVHD is at the investigator's discretion based on GVHD organ dysfunction, severity, and the patient's clinical status. Details of treatment directed at GVHD will be recorded in the eCRF, including initiation of treatment, dose, duration (start / stop), and timing and magnitude of best response. This includes non-absorbable enteral steroids for upper / lower GI GVHD, and topical therapy for cutaneous, oral, or ocular GVHD.

[0538] Quality of life assessment The Foundation for Certification of Cellular Therapy Bone Marrow Transplantation (FACT BMT, version 4) is a 47-item self-report questionnaire that assesses multiple domains including physical, functional, social / family, emotional well-being, and transplant-specific concerns. The questionnaire is scored at the visit.

[0539] Experimental immune-related assessment engraftment Engraftment will be assessed at the visit.

[0540] Neutrophil engraftment was defined as neutrophil counts ≥ 0.5 × 10 for 3 consecutive days without transfusion within the previous 7 days. 9 / L, and platelet recovery was defined as a platelet count ≥ 20 × 10 on 3 consecutive days. 9 / L. The first day of occurrence of both criteria is recorded.

[0541] Primary graft failure is defined as the lack of initial engraftment of donor cells. In this case, subjects must be neutropenic (neutrophil count <0.5×10 9 In these cases, patients do not recover from the primary graft failure (PFS), develop pancytopenia, and require urgent retransplantation. Secondary graft failure is defined as the loss of donor cells after initial engraftment. In this case, autologous recovery is common, however, bone marrow aplasia and pancytopenia can also develop.

[0542] Chimerism Chimerism will be assessed in whole blood by PCR amplification at the local laboratory at the time of visit. Chimerism will also be assessed in cases of suspected recurrence.

[0543] Immunophenotyping Blood samples will be collected for immunophenotyping at the visit. Biomarkers (T / B / NK panel) include CD3 (CD3 T cells), CD4 (CD4 T cells), CD8B (CD8 T cells), LRP5 (B cells), OSBPL5 (NK cells). Potential expansion of the T / B / NK panel may be considered in the future.

[0544] Immunophenotyping will be performed by a central laboratory using validated analytical methods and following SOPs or laboratory manuals. Details regarding sample processing, handling, storage and transport will be provided separately in a study-specific central laboratory manual prior to study initiation.

[0545] Experimental pharmacokinetic evaluation Mokrabimod Blood samples are collected at the visits for determination of moclavimod systemic concentrations. One pre-dose sample is collected at each PK visit. Trough levels are determined at all PK visits and blood concentration-time profiles over 12 hours are performed on Day -9, Month 1 and Month 6.

[0546] On Day -9, Month 1, and Month 6, a standard 12-lead ECG assessment followed by pulse and blood pressure measurements should be performed 5 minutes prior to PK blood sample collection at 6 h post-dose. The exact date and time of sample collection will be recorded.

[0547] The exact dates and sample collection times of blood sample collection and ECG assessment will be recorded on the eCRF.

[0548] Bioanalytical determinations will be performed by the central laboratory using a validated LC-MS / MS analytical method and following SOPs and laboratory manuals. All blood samples will be taken either by direct venipuncture or by an indwelling cannula inserted into a forearm vein. Blood samples (2 mL) for PK assessment will be collected in EDTA tubes. EDTA tubes will be stored in an on-site freezer until transport to the central laboratory. Details regarding sample processing, handling, storage and transport will be provided separately in a study-specific central laboratory manual prior to study initiation.

[0549] Blood samples for PK analysis may be used for experimental metabolite identification using unauthenticated cold metabolite identification methods. PK (and optional metabolic) assessments will be reported separately.

[0550] Results will not be disclosed to funders, study staff, or subjects until the study data have been unblinded.

[0551] Cyclosporine A / tacrolimus Blood samples will be collected at the visit for determination of CsA / TAC systemic concentrations. Assessments will be performed according to local practice. CsA / TAC target concentration ranges are listed in the "Graft-versus-host disease prophylaxis" section. The exact date and time of sample collection will be recorded on the eCRF.

[0552] statistical analysis In general, measured variables and derived parameters will be listed and tabulated by subject. Tables of results will be presented by treatment group and total population, and by visit, where applicable. Data from all study sites will be pooled for statistical analysis.

[0553] Unless otherwise specified, continuous variables will be summarized descriptively by number of subjects, mean, median, standard deviation (SD), interquartile range (IQR), range (minimum and maximum), and 95% confidence intervals (CI) of the mean and median (as appropriate). Categorical variables will be summarized by frequency and percentage of subjects and / or number of events (where applicable). The number of missing values, if present, will also be identified. For summary tables by visit, the number of subjects with missing values ​​includes subjects with missing assessments or visits up to the treatment discontinuation visit.

[0554] Baseline value is defined as the last nonmissing value prior to randomization unless otherwise stated.

[0555] Time-to-event endpoints will be analyzed using the Kaplan-Meier method to estimate survival distributions, median times to events with 95% CI, and survival probabilities at selected time points; numbers at risk, with an event, and censored at selected time points will also be reported.

[0556] Descriptive statistics (cumulative incidence or proportion of subjects free of the event of interest) are presented for time-to-event endpoints unless otherwise specified.

[0557] All statistical tests are two-sided and performed at the 0.05 alpha level unless otherwise specified.

[0558] Protocol deviations, including those that generally constitute major (important) protocol deviations, may be detailed in the SAP according to ICH guidelines. All protocol deviations are reviewed in a data review meeting prior to the primary analysis and are ultimately classified as either major or minor.

[0559] Demographics and baseline characteristics All background and demographic data, including baseline and disease characteristics, will be tabulated and listed on an ITT basis.

[0560] Medical and surgical history data will be compiled by Medical Dictionary for Regulatory Affairs (MedDRA) System Organ Class (SOC) and Preferred Term (PT) and included in the data list.

[0561] Treatment exposure All study treatment data will be compiled using the SAF setting, including IMP and standard of care GVHD prophylaxis backgrounds (MTX+CsA or MTX+TAC).

[0562] At a minimum, the following variables will be summarized along with any changes in dose schedule and the reasons for those changes: Total treatment exposure (weeks) is the time interval between the last dosing date and the first dosing date, including any periods of temporary discontinuation of study treatment. A clinically relevant dose interruption is a dose interruption of study treatment due to an AE and lasting >15 days. Total treatment duration (weeks) is the cumulative number of days that the subject received their assigned study treatment (i.e., this calculation does not include any interruption periods). Actual dose intensity (mg / day) is the actual dose received during the entire study (total dose) divided by the duration of exposure. For dose interruption periods, the dose is equal to zero. Actual dose is the cumulative daily dose (mg) over the period. Actual dose intensity is summarized using descriptive statistics.

[0563] Previous and concomitant drug treatments Medications discontinued before the start of the IMP and medications taken after the start of the IMP will be summarized as frequency statistics by medication category using the Anatomical Therapeutic Chemical (ATC) codes from the World Health Organization (WHO) Dictionary of Medication. Prohibited medications will also be summarized.

[0564] Concomitant medications taken during the double-blind treatment phase will be presented separately from those taken during the follow-up phase.

[0565] Efficacy analysis Efficacy analyses will be performed on an ITT basis.

[0566] The safety review will be conducted by the IDMC.

[0567] 1) Primary endpoint analysis The primary endpoint is RFS at 12 months. The 3 mg group will be evaluated versus placebo unless the 3 mg group is discontinued due to safety findings, in which case the 1 mg group will be evaluated versus placebo. The analysis is a landmark analysis at 12 months, i.e., only the first 12 months of data (planned treatment period) for each subject will be included in the analysis. The variable for the primary endpoint is defined as the duration from randomization to the first occurrence of disease recurrence or death (any cause).

[0568] The primary efficacy variable will be described using a visual display of Kaplan-Meier estimates and a table reporting these estimates by quarterly intervals. Median estimates are provided with hazard ratio estimates along with two-sided 95% CIs and the 25th and 75th percentiles.

[0569] A stratified Grank test using the stratification factor used for subject randomization will be performed to compare the mocravimod group versus the placebo group.

[0570] Furthermore, after confirmation of proportional hazards, a Cox regression model is used to compare treatment groups. The list of factors used to adjust the model may include, but is not limited to, complete remission status (CR1 vs. CR2), GVHD prophylaxis treatment (CsA vs. TAC), age, donor type (sibling vs. unrelated), donor-recipient gender combination, AML disease stage, and time interval from diagnosis to transplant.

[0571] Subjects without an event (i.e., recurrence or death) at the time of analysis will be censored at the last date the subject was known to be recurrence-free or alive, or at the end of 12 months from randomization, whichever occurs first.

[0572] The times of censoring will also be depicted using inverse Kaplan-Meier plots, presented and tabulated over the period considered, by monthly intervals.

[0573] The distribution of the components defining the primary endpoint, ie, earliest, will be tabulated by treatment group.

[0574] In addition, overall follow-up time from randomization will be described using plots of Kaplan-Meier estimates for each of the treatment groups and compared by log-rank test.

[0575] Overall follow-up time is defined as the time interval (in weeks) from randomization to the date of the first occurrence of an event, or to the date of censoring if no event had occurred at the time of analysis, respectively.

[0576] Please note that subjects who choose to switch doses if a treatment arm is discontinued due to safety or lower efficacy will not be included in the primary analysis. The impact of potential treatment switches will be explored and discussed in the SAP.

[0577] 2) Sensitivity analysis The impact of potential departures from the proportional hazards assumed in this study will be assessed using a combination of Fleming-Harrington weighted log-rank statistics.

[0578] Other sensitivity analyses are detailed in the SAP.

[0579] 3) Secondary efficacy endpoint analysis Key secondary efficacy analyses The first key secondary endpoint will be assessed after the 12-month OS follow-up period for each subject, comparing between the mocravimod and placebo groups. The 3 mg group will be assessed vs. placebo unless the 3 mg group is discontinued due to safety findings, in which case the 1 mg group will be assessed vs. placebo. The second key secondary endpoint will be RFS, assessed after the double-blind treatment period or the 12-month pre-RFS follow-up period, compared between the second mocravimod and placebo groups, if applicable.

[0580] The corresponding analysis variable will be defined as the time interval from the date of randomization to the date of death due to any cause within the first 24 months, and the analysis will be performed when all subjects have completed the study (i.e., 24 months, including the follow-up period).

[0581] OS analysis will be performed using the same methods as the primary endpoint. Subjects who are still alive at the end of the 24-month study follow-up or who are lost to follow-up will be censored at the last time the subject is known to be alive.

[0582] Information on death occurring within 24 months will be collected for all subjects randomized into the study.

[0583] The statistical hypotheses and analyses for the second key secondary endpoint were the same as for the primary endpoint.

[0584] Other secondary analyses Other secondary variables analyzed in the ITT included: RFS after 24 months Time to recurrence Cumulative incidence of recurrence at 12 and 24 months Non-relapse-related mortality at 12 and 24 months OS of the second dose of mocrabimod vs. placebo (only applicable if all three arms reach the primary analysis) Grade III.IV aGVHD-free survival at 12 months Time to aGVHD Moderate / severe cGVHD-free survival at 24 months Time to cGVHD GRFS at 12 and 24 months rGRFS at 12 and 24 months ·Safety Quality of life

[0585] Grade III / IV aGVHD-free survival at 12 months Grade III / IV aGVHD-free survival is defined as the time interval (in weeks) from randomization to the first occurrence of either death from any cause or the first occurrence of grade III / IV aGVHD as defined by MAGIC score.

[0586] If no events are reported for a subject, observation will be censored at the last date the subject was known to be free of grade III / IV aGVHD.

[0587] Grade III / IV aGVHD-free survival will be summarized by treatment group using Kaplan Meier plots and survival estimate summaries. The presence of statistically significant differences between each mocravimod and placebo group separately will be assessed using a stratified log-rank test using the stratification factor used for subject randomization.

[0588] Additionally, as a supporting analysis, a Cox regression model is used to compare treatment groups after confirmation of proportional hazards. The list of factors used to adjust the model may include, but is not limited to, complete remission status (CR1 vs. CR2), GVHD prophylaxis treatment (CsA vs. TAC), age, donor type (sibling vs. unrelated), donor-recipient gender combination, AML disease stage, and time interval from diagnosis to transplant.

[0589] Grade III / IV aGVHD at 12 months will be summarized as the cumulative proportion of subjects with at least one occurrence of grade III / IV aGVHD during the RFS follow-up period. Each moclavimod group will be compared with placebo separately using the stratified CMH test, and odds ratios and corresponding 95% CIs will be provided.

[0590] Time to aGVHD Time to aGVHD is defined as the time interval (in weeks) from randomization to the first occurrence of grade III / IV aGVHD as defined by MAGIC.

[0591] Time to aGVHD will be summarized descriptively by treatment group using mean, standard deviation, minimum, lower quartile, median, upper quartile and maximum for patients with incident grade III / IV aGVHD only.

[0592] If a descriptive summary is insufficient due to imbalance or insufficient events in groups for comparison, further investigation including all subjects will be performed. For this analysis, if a subject dies before the onset of grade III / IV aGVHD, the date of death will be used as the last follow-up time and death will be considered a competing event. If the onset of grade III / IV aGVHD or death is not reported for a subject, the time to aGVHD will be censored at the last date the subject was known to be free of aGVHD.

[0593] Time to aGVHD will be summarized by treatment group using cumulative incidence function plots and survival estimate summaries. The presence of statistically significant differences between each mocravimod and placebo group separately will be assessed using Gray's test using the stratification factor used for subject randomization.

[0594] A competing risks model is used to provide an adjusted estimate of treatment effect. The list of factors used to adjust the model may include, but is not limited to, complete remission status (CR1 vs. CR2), GVHD prophylaxis treatment (CsA vs. TAC), age, donor type, donor-recipient gender combination, disease stage of AML, and time interval from diagnosis to transplant.

[0595] Moderate / severe cGVHD-free survival at 24 months Moderate / severe cGVHD-free survival at 24 months is defined as the time interval (in weeks) from randomization to the first occurrence of moderate / severe cGVHD refractory to systemic immunosuppressive treatment during the entire study period.

[0596] If no events are reported for a subject, observation will be censored at the last date the subject was known to be free of moderate / severe cGVHD.

[0597] Moderate / severe cGVHD-free survival will be summarized by treatment group using Kaplan-Meier plots and survival estimate summaries. The presence of statistically significant differences between each mocravimod group and placebo separately will be assessed using a stratified log-rank test using the stratification factor used for subject randomization.

[0598] Cox regression models are used to provide adjusted estimates of treatment effect for remission status, GVHD prophylaxis treatment (CsA vs. TAC), age, donor type, donor-recipient gender combination, AML disease stage, and time interval from diagnosis to transplant.

[0599] Moderate / severe cGVHD at Month 24 will be summarized as the cumulative proportion of subjects with at least one occurrence of moderate / severe cGVHD during the entire study period. Each moclavimod group will be compared to placebo separately using stratified Cochran-Mantel-Haenszel (CMH) tests, and odds ratios and corresponding 95% CIs will be provided.

[0600] Time to cGVHD Time to cGVHD is defined as the time interval (in weeks) from randomization to the first occurrence of moderate / severe cGVHD.

[0601] Time to cGVHD will be summarized descriptively by treatment group using mean, standard deviation, minimum, lower quartile, median, upper quartile, maximum, and CI for the mean and median (as appropriate) for patients with incident moderate / severe cGVHD only.

[0602] If a descriptive summary is insufficient due to imbalance or insufficient events in groups for comparison, further investigation including all subjects will be performed. For this analysis, if a subject dies before the occurrence of moderate / severe cGVHD, the date of death will be used as the last follow-up time and death will be considered a competing event. If the occurrence of moderate / severe cGVHD or death is not reported for a subject, the time to cGVHD will be censored at the last date the subject was known to be free of cGVHD.

[0603] Time to cGVHD will be summarized by treatment group using cumulative incidence function plots and survival estimate summaries. The presence of statistically significant differences between each mocravimod and placebo group separately will be assessed using Gray's test using the stratification factor used for subject randomization.

[0604] A competing risk model is used to provide an adjustment of the treatment effect estimate. The list of factors used to adjust the model may include, but is not limited to, complete remission status (CR1 vs. CR2), GVHD prophylaxis treatment (CsA vs. TAC), age, donor type, donor-recipient gender combination, AML disease stage, and time interval from diagnosis to transplant.

[0605] Non-relapse mortality at 12 and 24 months Non-relapse mortality is defined as death without evidence of leukemia recurrence.

[0606] If sufficient events have occurred, the cumulative incidence of non-relapse mortality at 12 months will be summarized by treatment group with 95% confidence intervals.

[0607] A CMH stratification test using the stratification factors for subject randomization was performed, and odds ratios are presented comparing each mocravimod group separately with the placebo group.

[0608] If a subject relapses, the date of relapse is used as the last follow-up time and relapse is considered a competing event. If the occurrence of non-relapse mortality is not reported for a subject, the time to non-relapse mortality is censored at the last date the subject is known not to have died.

[0609] Non-relapse mortality will be summarized by treatment group using cumulative incidence function plots and survival estimate summaries if sufficient events have occurred. The presence of statistically significant differences between each mocravimod and placebo group separately will be assessed using Gray's test using the stratification factor used for subject randomization.

[0610] A competing risks model is used to provide an adjustment of the treatment effect estimate. The list of factors used to adjust the model may include, but is not limited to, remission status (CR1 vs. CR2), GVHD prophylaxis treatment (CsA vs. TAC), age, donor type, donor-recipient gender combination, disease stage of AML, and time interval from diagnosis to transplant.

[0611] In addition, non-relapse mortality at 24 months will be analyzed using the same methods as non-relapse mortality at 12 months.

[0612] GRFS at 12 and 24 months GVHD is defined as grade III / IV aGVHD or moderate / severe cGVHD.

[0613] GVHD-free survival at 12 and 24 months is defined as the time interval (in weeks) from randomization to death from any cause, or the first occurrence of GVHD, or recurrence, whichever occurs first.

[0614] If no event is reported for a subject, observation is censored at the last date the subject was known to be free of GVHD.

[0615] GVHD-free survival will be summarized by treatment group using Kaplan-Meier plots and survival estimate summaries. The presence of statistically significant differences between each mocravimod group and placebo separately will be assessed using a stratified log-rank test using the stratification factor used for subject randomization.

[0616] GVHD at month 24 will be summarized as the cumulative proportion of subjects with at least one occurrence of moderate / severe cGVHD during the entire study period. Each moclavimod group will be compared with placebo separately using a stratified CMH test, and odds ratios and corresponding 95% CIs will be provided.

[0617] rGRFS at 12 and 24 months rGRFS at 12 and 24 months will be summarized as the cumulative proportion of subjects with at least one occurrence of the events defining rGRFS during the entire study period. rGRFS is defined as the duration (in weeks) from randomization to the first occurrence of the following (Kawamura et al., 2018): Grade III / IV active aGVHD that persists despite treatment Active cGVHD that does not resolve despite needing systemic treatment Disease recurrence Death from any cause

[0618] GVHD that was resolved at last evaluation and did not require systemic treatment will not be considered an event.

[0619] The rGRFS will be summarized by treatment group using Kaplan-Meier plots and survival estimate summaries. The presence of statistically significant differences between each mocrabimod group and placebo separately will be assessed using a stratified log-rank test using the stratification factor used for subject randomization.

[0620] A stratified CMH criterion test using the stratification factor used for subject randomization was performed between each moclavimod and placebo group separately, and for months 12 and 24 separately, and odds ratios and corresponding 95% CIs are provided.

[0621] Other Efficacy Analyses Recurrence-free survival at 24 months RFS will be defined as the time interval (in weeks) from randomization to disease recurrence or death from any cause, whichever occurs first, and will be analyzed at 24 months.

[0622] If no death or recurrence is reported for a subject, the RFS is censored at the last date the subject is known to be recurrence-free.

[0623] RFS will be summarized by treatment group using Kaplan-Meier plots and survival estimate summaries. The presence of statistically significant differences between each mocrabimod and placebo group separately will be assessed using the log-rank test using the stratification factor used for subject randomization.

[0624] Furthermore, after confirmation of proportional hazards, a Cox regression model is used to compare treatment groups. The list of factors used to adjust the model may include, but is not limited to, complete remission status (CR1 vs. CR2), GVHD prophylaxis treatment (CsA vs. TAC), age, donor type (sibling vs. unrelated), donor-recipient gender combination, AML disease stage, and time interval from diagnosis to transplant.

[0625] Cumulative incidence of recurrence at 12 and 24 months Cumulative incidences of relapse at 12 and 24 months will be summarized by treatment group with 95% confidence intervals.

[0626] Separate CMH stratification tests using the stratification factors used for subject randomization were performed for each moclavimod group and placebo, and odds ratios are presented.

[0627] In addition, the cumulative incidence of recurrence at 24 months will be analyzed using the same methods as the cumulative incidence of recurrence in the primary analysis.

[0628] Time to recurrence (TTR) TTR is defined as the time interval (in weeks) from randomization to disease recurrence.

[0629] TTR will be summarized descriptively by treatment group using mean, standard deviation, minimum, lower quartile, median, upper quartile, maximum for subjects with recurrence only.

[0630] If a descriptive summary is insufficient due to imbalance or events in groups that are insufficient for comparison, a further investigation including all subjects will be performed. For this analysis, if a subject dies before the occurrence of recurrence, the date of death will be used as the last follow-up time, and death will be considered a competing event. If the occurrence of recurrence or death is not reported for a subject, the time to recurrence will be censored at the last date the subject is known to be recurrence-free.

[0631] TTR will then be summarized by treatment group using cumulative incidence function plots and survival estimate summaries.

[0632] Competing risk models may also be used. The models may include factors such as, but are not limited to, complete remission status (CR1 vs. CR2), GVHD prophylaxis treatment (CsA vs. TAC), age, donor type, donor-recipient gender combination, disease stage of AML, and time interval from diagnosis to transplant.

Claims

1. S1P receptor modulators of formula (II) or formula (IIa) or formula (IIb): 【Chemistry 13】 or a pharma- ceutical acceptable salt thereof, the dosage strength of the S1P receptor modulator is about 1 mg / unit; The pharmaceutical composition comprises: at least one filler selected from (i) mannitol, (ii) microcrystalline cellulose and (iii) mixtures thereof; - sodium starch glycolate as a disintegrant; - magnesium stearate as a lubricant; - With colloidal silicon dioxide as a lubricant 23. A pharmaceutical composition comprising:

2. - mannitol with a content of 48 to 88 mg / unit; - microcrystalline cellulose with a content of 5 to 45 mg / unit; sodium starch glycolate with a content of 1 to 8 mg / unit; - magnesium stearate in a content of 0.025 to 4 mg / unit; and - colloidal silicon dioxide at a content of 0.125-2 mg / unit The pharmaceutical composition of claim 1 , comprising:

3. - mannitol with a content of 58-78 mg / unit; - microcrystalline cellulose with a content of 15 to 35 mg / unit; sodium starch glycolate with a content of 2 to 6 mg / unit; - magnesium stearate in a content of 0.5 to 2 mg / unit; and - colloidal silicon dioxide at a content of 0.25-1 mg / unit The pharmaceutical composition according to claim 1 or 2, comprising:

4. - mannitol with a content of 68 mg / unit; - microcrystalline cellulose with a content of 25 mg / unit; - sodium starch glycolate with a content of 4 mg / unit; - magnesium stearate in a content of 1 mg / unit; and - colloidal silicon dioxide at a content of 0.5 mg / unit The pharmaceutical composition according to any one of claims 1 to 3, comprising:

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the S1P receptor modulator is the hydrochloride salt of formula (II).

6. The pharmaceutical composition according to any one of claims 1 to 5, which is in the form of a capsule.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the solid dosage form is an immediate release dosage form.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the S1P receptor modulator has an average particle size of 8 μm or less.

9. The pharmaceutical composition described in any one of claims 1 to 8, wherein the S1P receptor modulator has a D90 of 25 μm or less.

10. The pharmaceutical composition according to any one of claims 1 to 9, which is stable at 25°C for at least 24 months.

11. A method for preparing a pharmaceutical composition according to any one of claims 1 to 10, comprising the steps of: a. blending the S1P receptor modulator with microcrystalline cellulose, colloidal silicon dioxide; b. adding mannitol and blending the resulting mixture; c. adding sodium starch glycolate and blending the resulting mixture; d. adding magnesium stearate and blending the resulting pharmaceutical composition; e. Recovering the pharmaceutical composition. The method includes:

12. f. filling the resulting pharmaceutical composition into a capsule; g. Recovering the resulting capsules filled with the pharmaceutical composition. The method of claim 11 further comprising:

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