Compositions and methods for treating graft-versus-host disease - Patents.com

Abstract

The present application relates to methods of treating graft-versus-host disease (GvHD), in particular acute GvHD and acute gastrointestinal GvHD, using apraglutide.

Description

[Technical field]

[0001] Related Applications This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 142,905, filed January 28, 2021, and U.S. Provisional Patent Application No. 63 / 248,074, filed September 24, 2021. The contents of each of the foregoing patent applications are incorporated herein by reference in their entirety.

[0002] Sequence Listing This application contains a Sequence Listing that was submitted in ASCII format via EFS-Web and is incorporated herein by reference in its entirety. The ASCII copy, created on January 28, 2022, is named "VECT-003_001WO_SeqList" and is approximately 849 bytes in size. [Background technology]

[0003] Graft-versus-host disease (GvHD) is a condition that arises after the transplantation of a subject. GvHD is most commonly observed in the context of allogeneic transplants, including hematopoietic stem cell transplants (AHCT) for the treatment of blood cancers. However, there is growing evidence that GvHD arises in the context of autologous transplants (Hammami et al., Gastroenterol Res., 2018, 11(1):52-57; Cogbill et al. Modern Pathology, 2011, 24:117-125). GvHD arises when immune cells present in an allogeneic transplant recognize the transplant recipient's tissues as foreign and proceed to attack the recipient's tissues. GvHD can manifest as either acute GvHD or chronic GvHD. Acute GvHD is typically characterized by inflammation and tissue damage in the skin, oral and genital mucosa, eyes, intestine, liver, lungs, joints, and muscles. Chronic GvHD can induce the same type of damage, but over a longer period of time, it can also cause damage to connective tissues of exocrine glands, tissue fibrosis and limited joint mobility, pulmonary and hepatic fibrosis, immune dysregulation and autoimmunity. In particular, acute GvHD of the gastrointestinal tract can result in severe intestinal inflammation, mucosal shedding, severe diarrhea, abdominal pain, nausea and vomiting. Severe symptoms of acute gastrointestinal GvHD are often seen in patients with poorer post-transplant prognosis. First-line treatment of acute gastrointestinal GvHD typically involves the use of systemic and / or oral non-absorbable corticosteroids. However, many patients do not respond to first-line treatment. Thus, there is a need in the art for compositions and methods directed to the treatment and prevention of GvHD, more specifically, acute gastrointestinal GvHD, in subjects who have received AHCT. The present disclosure addresses that need. Summary of the Invention

[0004] The present disclosure provides a method for treating or preventing graft-versus-host disease (GvHD) in a subject, the method comprising administering to the subject at least one therapeutically effective amount of apraglutide or a pharma- ceutically acceptable salt thereof. The GvHD can be acute GvHD. The GvHD can be acute gastrointestinal GvHD. The GvHD can be chronic GvHD. The GvHD can be steroid-resistant. The GvHD can be steroid-naïve.

[0005] In some aspects, at least one therapeutically effective amount of apraglutide can be administered to a subject before the subject is transplanted.

[0006] In some aspects, at least one therapeutically effective amount of apraglutide can be administered before the subject receives radiation therapy, chemotherapy, or radiation-like therapy in connection with the transplant.

[0007] In some aspects, the subject has already been transplanted.

[0008] In some aspects, at least one therapeutically effective amount of apraglutide may be administered to the subject after the subject has been transplanted.

[0009] In some aspects, the subject may have already received radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof in connection with the transplant.

[0010] In some aspects, at least one therapeutically effective amount of apraglutide can be administered to a subject after the subject has been administered radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof.

[0011] In some aspects, at least one therapeutically effective amount of apraglutide can be administered to a subject after the subject has been administered radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof, and before the subject undergoes a transplant.

[0012] In some aspects, at least one therapeutically effective amount of apraglutide can be administered to the subject simultaneously with the transplant.

[0013] In some aspects, at least one therapeutically effective amount of apraglutide can be administered to the subject in conjunction with transplantation, radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof.

[0014] In some aspects, administration of apraglutide can prevent and / or attenuate loss of colon length in a subject following transplantation.

[0015] In some aspects, administration of apraglutide can prevent and / or attenuate the loss of colon length in a subject following conditioning therapy and transplantation.

[0016] In some embodiments, the transplant can include hematopoietic stem cells derived from bone marrow, peripheral blood, umbilical cord blood, or any combination thereof. The transplant can include T cells. The T cells can be chimeric antigen receptor (CAR) T cells.

[0017] In some aspects, radiation therapy can include total body irradiation.

[0018] In some aspects, the pharma- ceutically acceptable salt of apraglutide can be a sodium salt of apraglutide.

[0019] In some aspects, apraglutide or a pharma- ceutically acceptable salt thereof can be administered by subcutaneous injection.

[0020] In some embodiments, apraglutide, or a pharma- ceutically acceptable salt thereof, can be administered in an amount of about 1 mg to about 10 mg.

[0021] In some embodiments, apraglutide can be administered in an amount of about 2.5 mg.

[0022] In some embodiments, apraglutide can be administered in an amount of about 5 mg.

[0023] In some embodiments, apraglutide can be administered in an amount of about 10 mg.

[0024] In some aspects, the transplant may be an allogeneic transplant. In some aspects, the transplant may be an autologous transplant.

[0025] In some embodiments, the subject may already be administered at least one anti-GvHD therapy. In some embodiments, the at least one anti-GvHD therapy may include steroid therapy.

[0026] Any of the above aspects, or any other aspects described herein, may be combined with any other aspect described herein.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. In this specification, the singular also includes the plural unless the context clearly indicates otherwise, and by way of example, the terms "a", "an", and "the" are understood to be singular or plural, and the term "or" is understood to be inclusive. By way of example, "element" means one or more elements. Throughout this specification, the phrase "comprises" or variations such as "comprises" or "comprises" will be understood to imply the inclusion of the specified element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. Unless otherwise clear from the context, all numerical values ​​provided herein are modified by the term "about". Unless specifically stated or clear from the context, as used herein, the term "or" is understood to be inclusive, covering both "or" and "and".

[0028] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references described herein are incorporated by reference in their entirety. References cited herein are not admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting. Other features and advantages of the present disclosure will be apparent from the following detailed description and claims. [Brief description of the drawings]

[0029] The above and further features will be more clearly understood from the following detailed description when taken in conjunction with the accompanying drawings.

[0030] [Figure 1] FIG. 1 is a series of graphs showing colon length in an acute GvHD mouse model following treatment with apraglutide.

[0031] [Figure 2a] Figures 2a-2b are a series of graphs showing the results of various histological analyses of the intestine of an acute GvHD mouse model following treatment with apraglutide. [Figure 2b] Same as above. [Figure 2c]

[0032] [Diagram 3]Figures 3a-3b are a series of graphs showing colon and small intestine lengths in an acute GvHD mouse model after treatment with apraglutide. Data are presented as mean ± SEM length of intestine. N-5-10 / group. Each dot represents data for one mouse. Data show that colon lengths of TBI / BMT animals are significantly shorter compared to vehicle or BMT / TBI groups treated with apraglutide (Kruskal-Wallis non-parametric test followed by Dunn's test for multiple comparisons) (*p<0.05, ***<0.001). No differences were observed between vehicle and TBI / BMT animals treated with apraglutide. BMT=bone marrow transplantation, ns=not significant, SEM=standard error of the mean, TBI=total body irradiation.

[0033] [Figure 4] FIG. 4 is a series of graphs showing the effect of apraglutide on human PBMC engraftment in NOG irradiated mice.

[0034] [Diagram 5] FIG. 5 is a series of graphs showing that apraglutide protects BALB / cJ mice from acute GVHD-induced intestinal injury.

[0035] [Figure 6] FIG. 6 is a series of graphs showing that apraglutide protects against chemotherapy-induced damage to the small intestine.

[0036] [Figure 7] FIG. 7 is a series of graphs showing that the combination of apraglutide and chemotherapy preserves gut mass as indicated by plasma citrulline levels.

[0037] [Figure 8] FIG. 8 is a series of graphs showing that apraglutide reduces chemotherapy-induced weight loss.

[0038] [Figure 9]FIG. 9 is a series of graphs showing that the combination of apraglutide and chemotherapy improves animal survival.

[0039] [Figure 10a] Figure 10a is a series of graphs showing that apraglutide maintains the composition of fecal microbiota during chemotherapy. F = Firmicutes and B = Bacteroidetes. Data is presented as % relative abundance of phylum-level taxa in stool / condition. [Figure 10b] FIG. 10b is a series of graphs showing that apraglutide stabilizes gut microbiota diversity (mean relative abundance in feces at the phylum level) that was significantly altered by chemotherapy.

[0040] [Figure 11a] FIG. 11a is a series of graphs showing that apraglutide does not reduce the antitumor effect of cytarabine.

[0041] [Figure 11b] FIG. 11b is a series of graphs showing the effect of vehicle or cytarabine±apraglutide treatment on bone marrow and spleen hCD45 positive cells in mice injected with human leukemia cells.

[0042] [Figure 12] FIG. 12 is a series of graphs showing the effect of apraglutide on immunosuppressive activity induced by cytarabine (mean / group±SEM).

[0043] [Figure 13] FIG. 13 is a series of graphs showing the effect of apraglutide on immunosuppressive activity induced by melphalan (mean / group±SEM).

[0044] [Figure 14]FIG. 14 is a series of graphs showing that treatment with apraglutide improves animal survival in TBI / BMT treated animals. Kaplan-Meier curves-animal survival were monitored daily. N=10 at time=0 for each treatment group. Survival of animals treated with apraglutide starting prior to TBI / BMT showed significant differences compared to TBI / BMT animals as determined by log-rank (Mantel-Cox) test *p<0.03, but not significant compared to control animals (ns). TBI / BMT survival was significantly different when compared to the control group ###p=0.0007. BMT=bone marrow transplant, TBI=total body irradiation.

[0045] [Figure 15] Figure 15a is a series of graphs showing that apraglutide improves the overall pathological score after induction of acute GvHD. Figure 15b is a series of graphs showing that apraglutide improves the pathological bowel score after induction of acute GvHD.

[0046] [Figure 16a] Figures 16a-c are a series of graphs showing the effect of apraglutide on percent body weight loss in TBI / BMT treated animals. [Figure 16b] Same as above. [Figure 16c] Same as above.

[0047] [Figure 17] FIG. 17 is a series of graphs showing the dose-dependent effect of apraglutide on animal survival following cytarabine treatment.

[0048] [Figure 18] FIG. 18 is a series of graphs showing the dose-dependent effect of apraglutide on the body of animals following chemotherapy.

[0049] [Figure 19] FIG. 19 is a series of graphs showing the dose-dependent effect of apraglutide on serum citrulline concentrations following cytarabine treatment.

[0050] [Figure 20] FIG. 20 is a series of graphs showing the dose-dependent effect of GP-2R agonists on polymorphonuclear cell counts following chemotherapy. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] The present disclosure provides a method for treating or preventing GvHD in a subject, the method comprising administering to the subject at least one therapeutically effective amount of apraglutide or a pharma- ceutically acceptable salt thereof.

[0052] The present disclosure provides a method of treating GvHD in a subject, the method comprising administering to the subject at least one therapeutically effective amount of apraglutide or a pharma- ceutically acceptable salt thereof.

[0053] The present disclosure provides a method for preventing GvHD in a subject, the method comprising administering to the subject at least one therapeutically effective amount of apraglutide or a pharma- ceutically acceptable salt thereof.

[0054] The present disclosure provides a method of treating or preventing GvHD in a subject, the method comprising administering to the subject apraglutide or a pharma- ceutically acceptable salt thereof.

[0055] The present disclosure provides a method of treating GvHD in a subject, the method comprising administering to the subject apraglutide or a pharma- ceutically acceptable salt thereof.

[0056] The present disclosure provides a method for preventing GvHD in a subject, the method comprising administering to the subject apraglutide or a pharma- ceutically acceptable salt thereof.

[0057] The present disclosure provides apraglutide or a pharma- ceutical acceptable salt thereof for use in treating or preventing GvHD in a subject, wherein the apraglutide or a pharma-ceutical acceptable salt thereof is for administration to the subject in at least one therapeutically effective amount.

[0058] The present disclosure provides apraglutide, or a pharma- ceutical acceptable salt thereof, for use in treating or preventing GvHD in a subject.

[0059] The present disclosure provides apraglutide or a pharma- ceutical acceptable salt thereof for use in treating GvHD in a subject, wherein the apraglutide or a pharma-ceutical acceptable salt thereof is for administration to the subject in at least one therapeutically effective amount.

[0060] The present disclosure provides apraglutide, or a pharma- ceutical acceptable salt thereof, for use in treating GvHD in a subject.

[0061] The present disclosure provides apraglutide or a pharma- ceutical acceptable salt thereof for use in preventing GvHD in a subject, wherein the apraglutide or a pharma-ceutical acceptable salt thereof is for administration to the subject in at least one therapeutically effective amount.

[0062] The present disclosure provides apraglutide, or a pharma- ceutically acceptable salt thereof, for use in preventing GvHD in a subject.

[0063] The present disclosure provides the use of apraglutide, or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of GvHD in a subject, wherein the apraglutide, or a pharma-ceutical acceptable salt thereof, is for administration to the subject in at least one therapeutically effective amount.

[0064] The present disclosure provides the use of apraglutide, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of GvHD in a subject.

[0065] The present disclosure provides the use of apraglutide, or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for treating GvHD in a subject, wherein the apraglutide, or a pharma-ceutical acceptable salt thereof, is for administration to the subject in at least one therapeutically effective amount.

[0066] The present disclosure provides the use of apraglutide, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating GvHD in a subject.

[0067] The present disclosure provides the use of apraglutide, or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for preventing GvHD in a subject, wherein the apraglutide, or a pharma-ceutical acceptable salt thereof, is for administration to the subject in at least one therapeutically effective amount.

[0068] The present disclosure provides the use of apraglutide, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for preventing GvHD in a subject.

[0069] Also provided is a suitable therapeutically effective amount of apraglutide or its pharma- ceutical acceptable salt that can be used or administered to a subject to treat or prevent GvHD. The present disclosure provides a method for treating GvHD-induced intestinal damage in a subject already diagnosed with GvHD, comprising administering to the subject at least one therapeutically effective amount of apraglutide or its pharma-ceutical acceptable salt. The present disclosure provides a method for treating GvHD-induced intestinal damage in a subject already diagnosed with GvHD, comprising administering to the subject apraglutide or its pharma-ceutical acceptable salt. In some embodiments, the subject has already been diagnosed with GvHD, and GvHD is ongoing at the time of administration of apraglutide. In some embodiments, the subject has already been diagnosed with GvHD, and GvHD has been sufficiently treated before administration of apraglutide.

[0070] In some embodiments of the methods and uses described herein, the subject is over 65 years old. In some embodiments, the subject is between 18 and 64 years old. In some embodiments, the subject is under 18 years old.

[0071] In some embodiments of the methods and uses described herein, the subject weighs more than 50 kg. In some embodiments, the subject weighs between 50 kg and 40 kg. In some embodiments, the subject weighs less than 40 kg. The present disclosure provides apraglutide or a pharma- ceutically acceptable salt thereof for use in treating GvHD-induced intestinal damage in a subject, wherein the apraglutide or a pharma- ceutically acceptable salt thereof is for administration to the subject in at least one therapeutically effective amount. The present disclosure provides apraglutide or a pharma- ceutically acceptable salt thereof for use in treating GvHD-induced intestinal damage in a subject. In some embodiments, the subject has already been diagnosed with GvHD, and the GvHD is ongoing at the time of administration of apraglutide. In some embodiments, the subject has already been diagnosed with GvHD, and the GvHD is sufficiently treated prior to administration of apraglutide.

[0072] The present disclosure provides the use of apraglutide, or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for treating GvHD-induced intestinal damage in a subject, wherein apraglutide, or a pharma-ceutical acceptable salt thereof, is for administration to a subject in at least one therapeutically effective amount.The present disclosure provides the use of apraglutide, or a pharma-ceutical acceptable salt thereof, in the manufacture of a medicament for treating GvHD-induced intestinal damage in a subject.In some embodiments, the subject has already been diagnosed with GvHD, and GvHD is ongoing at the time of administration of apraglutide.In some embodiments, the subject has already been diagnosed with GvHD, and GvHD is sufficiently treated before administration of apraglutide.

[0073] In some aspects, GvHD-induced intestinal damage may include, but is not limited to, malabsorption, diarrhea, abdominal pain, mucositis, mucosal ulceration, nausea, shortened colon, shortened small intestine, and any other GvHD-induced gastrointestinal complications known in the art.

[0074] In some embodiments of the methods and uses of the present disclosure, the GvHD can be acute GvHD. In some embodiments, the acute GvHD can be late acute GvHD. In some embodiments, the acute GvHD is acute gastrointestinal GvHD.

[0075] In some embodiments of the methods and uses of the present disclosure, the GvHD may be steroid-resistant GvHD. In some embodiments of the methods and uses of the present disclosure, the GvHD may be steroid-naïve GvHD.

[0076] In some embodiments of the methods and uses of the present disclosure, the GvHD may be steroid-resistant acute GvHD. In some embodiments of the methods and uses of the present disclosure, the GvHD may be steroid-naive acute GvHD.

[0077] In some embodiments of the methods and uses of the present disclosure, the GvHD may be steroid-resistant acute gastrointestinal GvHD. In some embodiments of the methods and uses of the present disclosure, the GvHD may be steroid-naive acute gastrointestinal GvHD.

[0078] In the present disclosure, GvHD may be acute GvHD, such as late acute GvHD. Acute GvHD may be steroid-naive acute GvHD. Alternatively, acute GvHD may be steroid-resistant acute GvHD. Acute GvHD may be acute gastrointestinal GvHD, such as steroid-resistant acute gastrointestinal GvHD. For example, apraglutide, or a pharma- ceutically acceptable salt thereof, may be used to prevent acute GvHD, such as gastrointestinal GvHD, in a subject. For example, apraglutide, or a pharma-ceutically acceptable salt thereof, may be used to treat steroid-resistant acute GvHD, such as steroid-resistant acute gastrointestinal GvHD, in a subject.

[0079] In some aspects of the methods and uses of the present disclosure, the GvHD may be chronic GvHD.

[0080] In some embodiments of the methods and uses of the present disclosure, the chronic GvHD can be chronic gastrointestinal GvHD. In some embodiments of the methods and uses of the present disclosure, the GvHD can be steroid-resistant chronic gastrointestinal GvHD. In some embodiments of the methods and uses of the present disclosure, the GvHD can be steroid-naive chronic gastrointestinal GvHD.

[0081] In the present disclosure, GvHD can be chronic GvHD, such as late stage chronic GvHD. Chronic GvHD can be steroid-naive chronic GvHD. Alternatively, chronic GvHD can be steroid-resistant chronic GvHD. Chronic GvHD can be chronic gastrointestinal GvHD, such as steroid-resistant chronic gastrointestinal GvHD. For example, apraglutide, or a pharmaceutically acceptable salt thereof, can be used to prevent chronic GvHD, such as gastrointestinal GvHD, in a subject. For example, apraglutide, or a pharmaceutically acceptable salt thereof, can be used to treat steroid-resistant chronic GvHD, such as steroid-resistant chronic gastrointestinal GvHD, in a subject.

[0082] In some aspects of the methods and uses of the present disclosure, GvHD may be an overlap syndrome.

[0083] In the present disclosure, GvHD may be an overlap syndrome.

[0084] In some embodiments of the methods and uses of the present disclosure, the subject has GvHD grade II-IV according to the MAGIC scale. In some embodiments, the subject has GvHD grade III-IV according to the MAGIC scale. In some embodiments, the subject has GvHD grade II-III according to the MAGIC scale. In some embodiments, the subject has GvHD grade II, III, or IV according to the MAGIC scale.

[0085] In some embodiments of the methods and uses of the disclosure, the GvHD is upper intestinal graft-versus-host disease.

[0086] In some embodiments of the methods and uses of the disclosure, the GvHD is mid-gut graft-versus-host disease.

[0087] In the present disclosure, GvHD can be hepatic GvHD.In some embodiments of the method and use of the present disclosure, GvHD is hepatic GvHD.For example, apraglutide or its pharmacologic acceptable salt can be used to prevent or treat hepatic GvHD in subjects.

[0088] In some embodiments of the disclosed methods and uses, the subject may be diagnosed with cancer.In some embodiments, the cancer is blood cancer.In some embodiments, the cancer is at least one of acute myeloid leukemia, myelodysplastic syndrome, follicular lymphoma, diffuse large B-cell lymphoma, acute lymphoblastic leukemia, multiple myeloma, Hodgkin's lymphoma, chronic myelogenous leukemia, T-cell non-Hodgkin's lymphoma, lymphoblastic B-cell non-Hodgkin's lymphoma (non-Burkitt's), Burkitt's lymphoma, anaplastic large cell lymphoma, germ cell tumor, Ewing's sarcoma, soft tissue sarcoma, neuroblastoma, Wilms' tumor, osteosarcoma, medulloblastoma, acute promyelocytic leukemia, mantle cell lymphoma, T-cell lymphoma, lymphoplasmacytic lymphoma, cutaneous T-cell lymphoma, plasmablastic, chronic lymphocytic leukemia, breast cancer, and kidney cancer.

[0089] In the present disclosure, the subject may be diagnosed with cancer. The cancer may be a blood cancer. The cancer may be at least one of acute myeloid leukemia, myelodysplastic syndrome, follicular lymphoma, diffuse large B-cell lymphoma, acute lymphoblastic leukemia, multiple myeloma, Hodgkin's lymphoma, chronic myeloid leukemia, T-cell non-Hodgkin's lymphoma, lymphoblastic B-cell non-Hodgkin's lymphoma (non-Burkitt's), Burkitt's lymphoma, anaplastic large cell lymphoma, germ cell tumor, Ewing's sarcoma, soft tissue sarcoma, neuroblastoma, Wilms' tumor, osteosarcoma, medulloblastoma, acute promyelocytic leukemia, mantle cell lymphoma, T-cell lymphoma, lymphoplasmacytic lymphoma, cutaneous T-cell lymphoma, plasmablastic, chronic lymphocytic leukemia, breast cancer, and kidney cancer. For example, the subject may be diagnosed with cancer and designated to receive an allogeneic transplant. Alternatively, the subject may be diagnosed with cancer and have already undergone an autologous transplant. Alternatively, the subject may be diagnosed with cancer and have already undergone an allogeneic transplant. Alternatively, the subject may be diagnosed with cancer and have already undergone an autologous transplant. In some aspects, the transplant is in a subject with, for example, myelofibrosis. In some aspects, the transplant is an autologous transplant in a subject with multiple myeloma.

[0090] In some embodiments of the methods and uses of the present disclosure, the subject may be diagnosed with a disease or disorder. In some embodiments, the disease or disorder may be hemoglobinopathies, congenital hemoglobinopathies, beta thalassemia major (TM), sickle cell disease (SCD), severe aplastic anemia, Fanconi anemia, dyskeratosis congenita, Blackfan-Diamond anemia, thalassemia, congenital amegakaryocytic thrombocytopenia, severe combined immunodeficiency, T cell immunodeficiency, T cell immunodeficiency-SCID variant, Wiskott-Aldrich syndrome, hemophagocytic disorder, lymphoproliferative disorder, severe congenital neutropenia, chronic granulomatous disease, phagocytic disorder, IPEX disease. The disease may be at least one of: myelofibrosis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic sclerosis, autoimmune disorders, immune dysregulation disorders, mucopolysaccharidoses, MPS-I, MPS-VI, osteopetrosis, metabolic disorders, globoid cell leukodystrophy (Krabbe), metachromatic leukodystrophy, cerebral X-linked adrenoleukodystrophy, myelofibrosis disease, myeloproliferative disorders, plasma cell disorders, mastocytosis, common variable immunodeficiency, chronic granulomatous disease, multiple sclerosis, systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, and polymyositis-dermatomyositis.

[0091] In the present disclosure, a subject may be diagnosed with a disease or disorder, including hemoglobinopathies, congenital hemoglobinopathies, beta thalassemia major (TM), sickle cell disease (SCD), severe aplastic anemia, Fanconi anemia, dyskeratosis congenita, Blackfan-Diamond anemia, thalassemia, congenital amegakaryocytic thrombocytopenia, severe combined immunodeficiency, T cell immunodeficiency, T cell immunodeficiency-SCID variant, Wiskott-Aldrich syndrome, hemophagocytic disorder, lymphoproliferative disorder, severe congenital neutropenia, chronic granulomatous disease, phagocytic cell disorder, IPEX syndrome, juvenile The disease or disorder may be at least one of rheumatoid arthritis, systemic sclerosis, autoimmune disorders, immune dysregulation disorders, mucopolysaccharidoses, MPS-I, MPS-VI, osteopetrosis, metabolic disorders, globoid cell leukodystrophy (Krabbe), metachromatic leukodystrophy, cerebral X-linked adrenoleukodystrophy, myelofibrosis disease, myeloproliferative disorders, plasma cell disorders, mastocytosis, common variable immunodeficiency, chronic granulomatous disease, multiple sclerosis, systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, and polymyositis-dermatomyositis. For example, the subject may be diagnosed with a disease or disorder and designated to receive an allogeneic transplant. For example, the subject may be diagnosed with a disease or disorder and designated to receive an autologous transplant. Alternatively, the subject may be diagnosed with a disease or disorder and has already received an allogeneic transplant. Alternatively, the subject may be diagnosed with a disease or disorder and has already received an autologous transplant.

[0092] In some aspects of the methods and uses of the present disclosure, the subject may be diagnosed with cancer and designated to receive a transplant to treat the cancer. In some aspects of the methods and uses of the present disclosure, the subject may be diagnosed with cancer and has already received a transplant to treat the cancer.

[0093] In some aspects of the methods and uses of the present disclosure, the subject may be diagnosed with cancer and designated to receive an allogeneic transplant to treat the cancer. In some aspects of the methods and uses of the present disclosure, the subject may be diagnosed with cancer and has already received an allogeneic transplant to treat the cancer.

[0094] In some aspects of the methods and uses of the present disclosure, the subject may be diagnosed with cancer and designated to receive an autologous transplant to treat the cancer. In some aspects of the methods and uses of the present disclosure, the subject may be diagnosed with cancer and has already received an autologous transplant to treat the cancer.

[0095] In some aspects of the methods and uses of the present disclosure, the subject may be diagnosed with a disease or disorder and designated to receive a transplant to treat the disease or disorder. In some aspects of the methods and uses of the present disclosure, the subject may be diagnosed with a disease or disorder and has already received a transplant to treat the disease or disorder.

[0096] In some aspects of the methods and uses of the present disclosure, the subject may be diagnosed with a disease or disorder and designated to receive an allogeneic transplant to treat the disease or disorder. In some aspects of the methods and uses of the present disclosure, the subject may be diagnosed with a disease or disorder and has already received an allogeneic transplant to treat the disease or disorder.

[0097] In some aspects of the methods and uses of the present disclosure, the subject may be diagnosed with a disease or disorder and designated to receive an autologous transplant to treat the disease or disorder. In some aspects of the methods and uses of the present disclosure, the subject may be diagnosed with a disease or disorder and has already received an autologous transplant to treat the disease or disorder.

[0098] In some embodiments of the methods and uses of the present disclosure, the subject may have already undergone a transplant. Thus, in some embodiments, at least one therapeutically effective amount of apraglutide can be administered to the subject after the subject has been transplanted.

[0099] In the present disclosure, the subject may already have undergone a transplant. Thus, apraglutide, or a pharma- ceutically acceptable salt thereof, may be administered to the subject after transplantation.

[0100] In some embodiments of the methods and uses of the present disclosure, the subject may have already undergone an allogeneic transplant. Thus, in some embodiments, at least one therapeutically effective amount of apraglutide can be administered to the subject after the subject has undergone an allogeneic transplant.

[0101] In the present disclosure, the subject may have already received an allogeneic transplant. Thus, apraglutide, or a pharma- ceutically acceptable salt thereof, may be administered to the subject after the allogeneic transplant has been received.

[0102] In some embodiments of the methods and uses of the present disclosure, the subject may have already undergone an autologous transplant. Thus, in some embodiments, at least one therapeutically effective amount of apraglutide can be administered to the subject after the subject has undergone an autologous transplant.

[0103] In the present disclosure, the subject may have already undergone an autologous transplant. Thus, apraglutide, or a pharma- ceutically acceptable salt thereof, can be administered to the subject after the subject has undergone an autologous transplant.

[0104] In some aspects of the methods and uses of the present disclosure, the subject may already have undergone conditioning therapy in connection with transplantation. In some aspects of the methods and uses of the present disclosure, the subject may already have undergone conditioning therapy in connection with allogeneic transplantation. In some aspects of the methods and uses of the present disclosure, the subject may already have undergone conditioning therapy in connection with autologous transplantation. In some aspects, the conditioning therapy may include administration of radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof. In some aspects, the radiation therapy may include total body irradiation.

[0105] Conditioning therapy may be administered in conjunction with an allogeneic transplant. Conditioning therapy may consist of, include, or consist of radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof. Radiation therapy may include total body irradiation.

[0106] Thus, in some embodiments, at least one therapeutically effective amount of apraglutide can be administered to a subject after the subject has undergone a conditioning therapy in connection with a transplant. In some embodiments, at least one therapeutically effective amount of apraglutide can be administered to a subject after the subject has undergone a conditioning therapy in connection with an allogeneic transplant. In some embodiments, at least one therapeutically effective amount of apraglutide can be administered to a subject after the subject has undergone a conditioning therapy in connection with an autologous transplant. In some embodiments, at least one therapeutically effective amount of apraglutide can be administered to a subject after the subject has undergone radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof.

[0107] Thus, apraglutide, or a pharma- ceutically acceptable salt thereof, can be administered to a subject after the subject has undergone a conditioning therapy in connection with a transplant. Thus, apraglutide, or a pharma- ceutically acceptable salt thereof, can be administered to a subject after the subject has undergone a conditioning therapy in connection with an allogeneic transplant. Thus, apraglutide, or a pharma- ceutically acceptable salt thereof, can be administered to a subject after the subject has undergone a conditioning therapy in connection with an autologous transplant.

[0108] In some embodiments of the methods and uses of the present disclosure, at least one therapeutically effective amount of apraglutide can be administered to the subject before the subject undergoes transplantation.In some embodiments of the methods and uses of the present disclosure, at least one therapeutically effective amount of apraglutide can be administered to the subject before the subject undergoes radiotherapy, chemotherapy, or radiation-like therapy in association with transplantation.In some embodiments of the methods and uses of the present disclosure, at least one therapeutically effective amount of apraglutide is administered to the subject after the subject undergoes radiotherapy, chemotherapy, radiation-like therapy, or any combination thereof, and before the subject undergoes transplantation.

[0109] In some aspects of the method and use of the present disclosure, apraglutide can be administered to the subject before the subject undergoes transplantation.In some aspects of the method and use of the present disclosure, apraglutide can be administered to the subject before the subject undergoes radiotherapy, chemotherapy, or radiation-like therapy in association with transplantation.In some aspects of the method and use of the present disclosure, apraglutide is administered to the subject after the subject undergoes radiotherapy, chemotherapy, radiation-like therapy, or any combination thereof, and before the subject undergoes transplantation.

[0110] In some aspects of the method and use of the present disclosure, apraglutide can be administered to the subject before the subject undergoes organ transplantation.In some aspects of the method and use of the present disclosure, apraglutide can be administered to the subject before the subject undergoes radiotherapy, chemotherapy, or radiation-like therapy in association with organ transplantation.In some aspects of the method and use of the present disclosure, apraglutide is administered to the subject after the subject undergoes radiotherapy, chemotherapy, radiation-like therapy, or any combination thereof, and before the subject undergoes organ transplantation.

[0111] In some embodiments of the method and use of the present disclosure, at least one therapeutically effective amount of apraglutide can be administered to the subject before the subject undergoes allogeneic transplantation.In some embodiments of the method and use of the present disclosure, at least one therapeutically effective amount of apraglutide can be administered to the subject before the subject receives radiation therapy, chemotherapy, or radiation-like therapy in association with allogeneic transplantation.In some embodiments of the method and use of the present disclosure, at least one therapeutically effective amount of apraglutide is administered to the subject after the subject receives radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof, and before the subject receives allogeneic transplantation.

[0112] In some aspects of the method and use of the present disclosure, apraglutide can be administered to the subject before the subject undergoes allogeneic transplantation.In some aspects of the method and use of the present disclosure, apraglutide can be administered to the subject before the subject receives radiation therapy, chemotherapy, or radiation-like therapy in association with allogeneic transplantation.In some aspects of the method and use of the present disclosure, apraglutide is administered to the subject after the subject receives radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof, and before the subject receives allogeneic transplantation.

[0113] In some embodiments of the method and use of the present disclosure, at least one therapeutically effective amount of apraglutide can be administered to the subject before the subject undergoes autologous transplantation.In some embodiments of the method and use of the present disclosure, at least one therapeutically effective amount of apraglutide can be administered to the subject before the subject receives radiotherapy, chemotherapy, or radiation-like therapy in association with autologous transplantation.In some embodiments of the method and use of the present disclosure, at least one therapeutically effective amount of apraglutide is administered to the subject after the subject receives radiotherapy, chemotherapy, radiation-like therapy, or any combination thereof, before the subject undergoes autologous transplantation.

[0114] In some embodiments of the method and use of the present disclosure, at least one therapeutically effective amount of apraglutide can be administered to the subject before the subject undergoes autologous transplantation.In some embodiments of the method and use of the present disclosure, at least one therapeutically effective amount of apraglutide can be administered to the subject before the subject receives radiotherapy, chemotherapy, or radiation-like therapy in association with autologous transplantation.In some embodiments of the method and use of the present disclosure, at least one therapeutically effective amount of apraglutide is administered to the subject after the subject receives radiotherapy, chemotherapy, radiation-like therapy, or any combination thereof, before the subject undergoes autologous transplantation.

[0115] In the present disclosure, apraglutide, or a pharma- ceutically acceptable salt thereof, can be administered to a subject before the subject undergoes an allogeneic transplant. For example, this can be before the subject undergoes radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof in connection with the allogeneic transplant, or after the subject undergoes radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof, but before the subject undergoes an allogeneic transplant.

[0116] In the present disclosure, apraglutide, or a pharma- ceutically acceptable salt thereof, can be administered to a subject before the subject undergoes an autologous transplant.For example, this can be before the subject undergoes radiotherapy, chemotherapy, radiation-like therapy, or any combination thereof in connection with an autologous transplant, or after the subject undergoes radiotherapy, chemotherapy, radiation-like therapy, or any combination thereof, but before the subject undergoes an autologous transplant.

[0117] In some embodiments of the method and use of the present disclosure, at least one therapeutically effective amount of apraglutide can be administered to the subject at the same time as transplantation.In some embodiments of the method and use of the present disclosure, at least one therapeutically effective amount of apraglutide can be administered to the subject at the same time as allogeneic transplantation.In some embodiments of the method and use of the present disclosure, at least one therapeutically effective amount of apraglutide can be administered to the subject at the same time as autologous transplantation.

[0118] In the present disclosure, apraglutide, or a pharma- ceutically acceptable salt thereof, can be administered to a subject simultaneously with transplantation. In the present disclosure, apraglutide, or a pharma-ceutically acceptable salt thereof, can be administered to a subject simultaneously with allogeneic transplantation. In the present disclosure, apraglutide, or a pharma-ceutically acceptable salt thereof, can be administered to a subject simultaneously with autologous transplantation.

[0119] In some embodiments of the methods and uses of the present disclosure, at least one therapeutically effective amount of apraglutide can be administered to a subject simultaneously with a conditioning therapy. In some embodiments, at least one therapeutically effective amount of apraglutide, at least one therapeutically effective amount of apraglutide can be administered to a subject simultaneously with radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof.

[0120] In the present disclosure, apraglutide, or a pharma- ceutically acceptable salt thereof, can be administered to a subject concomitantly with a conditioning therapy, such as a conditioning therapy defined above.

[0121] In some embodiments of the methods and uses of the present disclosure, the subject may already be diagnosed with GvHD and undergo primary GvHD treatment. In some embodiments, the primary GvHD treatment may include administration of anti-GvHD treatment. In some embodiments, the anti-GvHD treatment may include administration of steroid therapy. Thus, in some embodiments of the methods and uses of the present disclosure, the subject may already be undergoing steroid therapy. As will be understood by those skilled in the art, the steroid therapy may include administration of at least one corticosteroid. As will be understood by those skilled in the art, the steroid therapy may include administration of prednisone, methylprednisolone, dexamethasone, beclomethasone, budesonide, or any combination thereof.

[0122] In some embodiments of the disclosed methods and uses, administration of apraglutide can prevent and / or attenuate the decrease in colon length in a subject after allogeneic transplantation.In some embodiments, administration of apraglutide prevents and / or attenuates the decrease in colon length in a subject after conditioning therapy and transplantation.In some embodiments, administration of apraglutide prevents and / or attenuates the decrease in colon length in a subject after conditioning therapy and allogeneic transplantation.In some embodiments, administration of apraglutide prevents and / or attenuates the decrease in colon length in a subject after conditioning therapy and autogeneic transplantation.

[0123] Administration of apraglutide according to the present disclosure can prevent and / or attenuate the decrease in colon length in a subject after transplantation. Administration of apraglutide can prevent and / or attenuate the decrease in colon length in a subject after conditioning therapy and allogeneic transplantation. Administration of apraglutide according to the present disclosure can prevent and / or attenuate the decrease in colon length in a subject after allogeneic transplantation. Administration of apraglutide can prevent and / or attenuate the decrease in colon length in a subject after conditioning therapy and autologous transplantation.

[0124] Administration of apraglutide according to the present disclosure can stabilize the intestinal microbiota, as described in the Examples herein.

[0125] The present disclosure provides a method for treating GvHD-induced intestinal damage in a subject already diagnosed with GvHD, comprising administering to the subject at least one therapeutically effective amount of apraglutide or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject has already been diagnosed with GvHD, and GvHD is ongoing at the time of administration of apraglutide. In some embodiments, the subject has already been diagnosed with GvHD, and GvHD is sufficiently treated before administration of apraglutide. In some embodiments, the present disclosure provides a method for treating GvHD-induced intestinal damage in a subject, comprising administering to the subject a therapeutically effective amount of apraglutide before, simultaneously with, or after administration of a therapeutically effective amount of immunosuppressive therapy. In some embodiments of the present disclosure, the immunosuppressive therapy is, for example, ruxolitinib, a systemic corticosteroid. In some aspects, the disclosure provides a method of treating GvHD-induced intestinal damage in a subject, the method comprising administering to the subject a therapeutically effective amount of apraglutide prior to, concurrently with, or following administration of a therapeutically effective amount of a calcineurin inhibitor.

[0126] The present disclosure provides a method for treating GvHD-induced intestinal damage in a subject already diagnosed with GvHD, comprising administering apraglutide or a pharma- ceutically acceptable salt thereof to the subject. In some embodiments, the subject has already been diagnosed with GvHD, and GvHD is ongoing at the time of administering apraglutide. In some embodiments, the subject has already been diagnosed with GvHD, and GvHD has been sufficiently treated before administering apraglutide. In some embodiments, the present disclosure provides a method for treating GvHD-induced intestinal damage in a subject, comprising administering apraglutide to the subject before, simultaneously, or after administering a therapeutically effective amount of immunosuppressive therapy. In some embodiments of the present disclosure, the immunosuppressive therapy is, for example, ruxolitinib, a systemic corticosteroid. In some embodiments, the present disclosure provides a method for treating GvHD-induced intestinal damage in a subject, comprising administering apraglutide to the subject before, simultaneously, or after administering a therapeutically effective amount of a calcineurin inhibitor.

[0127] The present disclosure provides a method of treating cancer comprising administering to a subject a combination of apraglutide, or a pharma- ceutically acceptable salt thereof, and at least one chemotherapy.

[0128] In some aspects, administration of apraglutide, or a pharma- ceutically acceptable salt thereof, can treat chemotherapy-induced intestinal damage in a subject.Accordingly, the present disclosure provides a method for treating chemotherapy-induced intestinal damage in a subject, comprising administering to the subject at least one therapeutically effective amount of apraglutide, or a pharma- ceutically acceptable salt thereof.The present disclosure provides a method for treating chemotherapy-induced intestinal damage in a subject in need thereof, comprising administering to the subject apraglutide, or a pharma- ceutically acceptable salt thereof.The present disclosure provides apraglutide, or a pharma- ceutically acceptable salt thereof, for use in treating chemotherapy-induced intestinal damage in a subject.

[0129] The present disclosure provides a method for treating cancer in a subject, the method comprising administering a therapeutically effective amount of apraglutide to the subject before, simultaneously, or after administering a therapeutically effective amount of a conditioning therapy.The present disclosure provides a method for treating cancer in a subject, the method comprising administering a therapeutically effective amount of apraglutide to the subject before, simultaneously, or after administering a therapeutically effective amount of a conditioning therapy.In some aspects of the present disclosure, the conditioning therapy is, for example, chemotherapy.In some aspects, the chemotherapy comprises a combination therapy.

[0130] The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) a therapeutically effective amount of apraglutide; and b) a transplant. The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) a therapeutically effective amount of a conditioning therapy; b) a therapeutically effective amount of apraglutide; and c) a transplant. The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) a therapeutically effective amount of radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof; b) a therapeutically effective amount of apraglutide; and c) a transplant.

[0131] The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) apraglutide; and b) a transplant. The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) a conditioning therapy; b) apraglutide; and c) a transplant. The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) radiation therapy, chemotherapy, radiation-like therapy or any combination thereof; b) apraglutide; and c) a transplant.

[0132] The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) a therapeutically effective amount of apraglutide; and b) an allograft. The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) a therapeutically effective amount of a conditioning therapy; b) a therapeutically effective amount of apraglutide; and c) an allograft. The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) a therapeutically effective amount of radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof; b) a therapeutically effective amount of apraglutide; and c) an allograft.

[0133] The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) apraglutide; and b) an allograft. The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) a conditioning therapy; b) apraglutide; and c) an allograft. The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) radiation therapy, chemotherapy, radiation-like therapy or any combination thereof; b) apraglutide; and c) an allograft.

[0134] The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) a therapeutically effective amount of apraglutide; and b) an autologous transplant. The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) a therapeutically effective amount of a conditioning therapy; b) a therapeutically effective amount of apraglutide; and c) an autologous transplant. The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) a therapeutically effective amount of radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof; b) a therapeutically effective amount of apraglutide; and c) an autologous transplant.

[0135] The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) apraglutide; and b) an autologous transplant. The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) a conditioning therapy; b) apraglutide; and c) an autologous transplant. The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a) radiation therapy, chemotherapy, radiation-like therapy or any combination thereof; b) apraglutide; and c) an autologous transplant.

[0136] The effect of the present disclosure of apraglutide on GvHD can be useful in the context of anti-cancer therapy.The GvHD occurring in this context can also be called anti-cancer therapy-associated GvHD.The typical anti-cancer therapy that can benefit from the effect of the present disclosure of apraglutide includes administering to the subject of allograft or autograft, such as administering conditioning therapy and administering allograft or autograft thereafter.In this context, it can be advantageous to further administer apraglutide.For example, apraglutide can be administered before administering allograft or autograft, such as between administering conditioning therapy and administering allograft or autograft to the subject.

[0137] Thus, the present disclosure provides apraglutide, or a pharma- ceutically acceptable salt thereof, for use in treating or preventing anti-cancer therapy-associated GvHD in a subject.

[0138] The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a) a therapeutically effective amount of apraglutide; and b) a transplant. The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a) a therapeutically effective amount of a conditioning therapy; b) a therapeutically effective amount of apraglutide; and c) a transplant. The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a) a therapeutically effective amount of radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof; b) a therapeutically effective amount of apraglutide; and c) a transplant.

[0139] The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a) apraglutide; and b) a transplant. The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a) a conditioning therapy; b) apraglutide; and c) a transplant. The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a) radiation therapy, chemotherapy, radiation-like therapy or any combination thereof; b) apraglutide; and c) a transplant.

[0140]

[0141] The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a) a therapeutically effective amount of apraglutide; and b) an allograft. The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a) a therapeutically effective amount of a conditioning therapy; b) a therapeutically effective amount of apraglutide; and c) an allograft. The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a) a therapeutically effective amount of radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof; b) a therapeutically effective amount of apraglutide; and c) an allograft.

[0142] The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a) apraglutide; and b) an allograft. The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a) a conditioning therapy; b) apraglutide; and c) an allograft. The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a) radiation therapy, chemotherapy, radiation-like therapy or any combination thereof; b) apraglutide; and c) an allograft.

[0143] The present disclosure provides a method for treating a disease or disorder in a subject, the method comprising administering to the subject a) a therapeutically effective amount of apraglutide; and b) an autologous transplant. The present disclosure provides a method for treating a disease or disorder in a subject, the method comprising administering to the subject a) a therapeutically effective amount of a conditioning therapy; b) a therapeutically effective amount of apraglutide; and c) an autologous transplant. The present disclosure provides a method for treating a disease or disorder in a subject, the method comprising administering to the subject a) a therapeutically effective amount of radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof; b) a therapeutically effective amount of apraglutide; and c) an autologous transplant.

[0144] The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a) apraglutide; and b) an autologous transplant. The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a) a conditioning therapy; b) apraglutide; and c) an autologous transplant. The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a) radiation therapy, chemotherapy, radiation-like therapy or any combination thereof; b) apraglutide; and c) an autologous transplant.

[0145] In any of the methods of use described herein, a reference to apraglutide also includes pharma- ceutically acceptable salts of apraglutide.

[0146] In some aspects of the methods or uses described herein, the subject may already be administered ruxolitinib prior to administration of apraglutide.

[0147] In any of the methods or uses described herein, apraglutide, or a pharma- ceutically acceptable salt thereof, can be administered in combination with at least one second effective agent. In some embodiments, at least one second effective agent can be ruxolitinib. In some embodiments, at least one second effective agent can be a calcineurin inhibitor.

[0148] In some aspects of the methods and uses described herein, apraglutide, or a pharma- ceutically acceptable salt thereof, can be administered close in time to another therapeutic intervention described herein (e.g., transplantation, conditioning therapy, chemotherapy, a second active agent, etc.).

[0149] In some aspects of the methods and uses of the present disclosure, the transplantation can include hematopoietic stem cells. In some aspects, the hematopoietic stem cells can be derived from bone marrow, peripheral blood, umbilical cord blood, or any combination thereof. In some aspects of the methods and uses of the present disclosure, the transplantation can be an allogeneic transplant or an autologous transplant.

[0150] In some aspects of the methods and uses of the present disclosure, the allogeneic transplant can include allogeneic hematopoietic stem cells. In some aspects, the allogeneic hematopoietic stem cells can be derived from bone marrow, peripheral blood, umbilical cord blood, or any combination thereof.

[0151] In some aspects of the methods and uses of the present disclosure, the autologous transplant can include hematopoietic stem cells. In some aspects, the autologous hematopoietic stem cells can be derived from bone marrow, peripheral blood, umbilical cord blood, or any combination thereof.

[0152] In some embodiments of the methods and uses of the present disclosure, the transplant can include T cells. In some embodiments, the T cells can be chimeric antigen receptor (CAR) T cells.

[0153] In some embodiments of the methods and uses of the present disclosure, the allogeneic transplant can include allogeneic T cells. In some embodiments, the allogeneic T cells can be allogeneic chimeric antigen receptor (CAR) T cells. In some embodiments of the methods and uses of the present disclosure, the autologous transplant can include autologous T cells. In some embodiments, the autologous T cells can be autologous chimeric antigen receptor (CAR) T cells.

[0154] In the present disclosure, allogeneic transplantation can include transplantation of allogeneic hematopoietic stem cells, which can be derived from bone marrow, peripheral blood, umbilical cord blood, or any combination thereof.

[0155] In the present disclosure, allogeneic transplantation can include transplantation of allogeneic T cells. The allogeneic T cells can be allogeneic chimeric antigen receptor (CAR) T cells.

[0156] In the present disclosure, autologous transplantation can include transplantation of autologous hematopoietic stem cells, which can be derived from bone marrow, peripheral blood, umbilical cord blood, or any combination thereof.

[0157] In the present disclosure, autologous transplantation can include transplantation of autologous T cells. The autologous T cells can be allogeneic chimeric antigen receptor (CAR) T cells.

[0158] In some aspects of the methods and uses of the present disclosure, the pharma- ceutically acceptable salt of apraglutide may be the sodium salt of apraglutide.

[0159] In the present disclosure, a pharma- ceutically acceptable salt of apraglutide can be a base addition salt, such as the sodium salt of apraglutide.

[0160] In some aspects of the method and use of the present disclosure, apraglutide can be administered as part of pharmaceutical composition.The pharmaceutical composition of apraglutide can include any pharmaceutically acceptable carrier and / or excipient.The non-limiting examples of pharmaceutically acceptable carrier and / or excipient include mannitol, glycine, L-histidine or any combination thereof.

[0161] Thus, in some aspects of the methods and uses described herein, apraglutide, or a pharma- ceutically acceptable salt thereof, is administered as part of a pharmaceutical composition comprising apraglutide, or a pharma- ceutically acceptable salt thereof, mannitol, glycine and L-histidine.

[0162] In the present disclosure, apraglutide can be part of pharmaceutical composition.Pharmaceutical composition can further comprise any pharmaceutically acceptable carrier and / or excipient.Non-limiting examples of pharmaceutically acceptable carrier and / or excipient include mannitol, glycine, L-histidine or any combination thereof.

[0163] definition Unless expressly indicated otherwise, the term "apraglutide" refers to a compound having the following structure: [ka]

[0164] As will be appreciated by those skilled in the art, apraglutide is a GLP-2 agonist having the amino acid sequence His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Nle-D-Phe-Thr-Ile-Leu-Asp-Leu-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp (SEQ ID NO: 1), where Nle is norleucine and D-Phe is the D-amino acid phenylalanine.

[0165] Apraglutide and its preparations are disclosed in PCT Publication No. 2011 / 050174, U.S. Patent No. 8,580,918, U.S. Patent Application Publication No. 2022-0000985 A1 and PCT Publication No. 2021 / 252659, which publications are incorporated herein by reference in their entireties.

[0166] Unless expressly indicated otherwise, the terms "approximately" and "about" are synonymous. In some embodiments, "approximately" and "about" refer to ±5%, ±4.5%, ±4%, ±3.5%, ±3%, ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.09%, ±0.08%, ±0.07%, ±0.06%, ±0.05%, ±0.04%, ±0.03%, ±0.02%, or ±0.01% of the recited amount, value, or duration. In some embodiments, "approximately" and "about" refer to ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5% of the recited amount, value, or duration. In some embodiments, "approximately" and "about" refer to ±1% of the recited amount, value, or duration. In some embodiments, "approximately" and "about" refer to ±0.5% of the recited amount, value, or duration. In some embodiments, "approximately" and "about" refer to ±0.1% of the recited amount, value, or duration.

[0167] As will be understood by those skilled in the art, the term "graft-versus-host disease" or "GvHD" refers to a condition that occurs in a subject after allogeneic or autologous transplantation (e.g., HSCT), in which immune cells present in the allogeneic or autologous transplant material (called the "graft") attack the transplant recipient's own tissues. As will be understood by those skilled in the art, GvHD may be classified using the MAGIC classification scale, as described in Biol Blood Marrow Transplant. 2016;22(1):4-10.

[0168] As will be understood by those skilled in the art, the terms "acute graft-versus-host disease", "acute GvHD", "classical acute graft-versus-host disease" and "classical acute GvHD" refer to graft-versus-host disease that occurs in transplant recipients within about 100 days after transplantation and exhibits clinical features typically associated with acute graft-versus-host disease, including, but not limited to, inflammation and tissue damage in the skin, oral and genital mucosa, eyes, intestine, liver, lungs, joints, and muscle.

[0169] As will be understood by one of skill in the art, the term "late acute graft-versus-host disease" or "late acute GvHD" refers to a state of persistent acute graft-versus-host disease, recurrent acute graft-versus-host disease, and / or new-onset acute graft-versus-host disease that exhibits clinical features of acute graft-versus-host disease, but is a form of graft-versus-host disease that occurs more than 100 days after transplantation.

[0170] As will be understood by one of skill in the art, the terms "acute gastrointestinal graft-versus-host disease" and "acute gastrointestinal GvHD" refer to any of the forms of acute GvHD described above that manifest in a subject with gastrointestinal symptoms and / or damage, including, but not limited to, diarrhea, abdominal pain, mucositis, mucosal ulcers, nausea, shortened colon, and shortened small intestine.

[0171] As will be understood by those skilled in the art, the terms "steroid-resistant", "steroid-resistant GvHD" and "SR-GvHD" refer to GvHD that has been previously treated with steroid therapy but has become refractory to steroid therapy. Thus, in a non-limiting example, steroid-resistant acute gastrointestinal GvHD refers to acute gastrointestinal GvHD that has been previously treated with steroid therapy but has become refractory to steroid therapy. In some embodiments, a subject with steroid-resistant GvHD is administered a pharmaceutical composition comprising ruxolitinib. In some embodiments, a subject with steroid-resistant GvHD is administered a pharmaceutical composition comprising apraglutide. In some embodiments, a subject with steroid-resistant GvHD is administered a therapeutically effective amount of apraglutide before, simultaneously, or after administration of a therapeutically effective amount of immunosuppressive therapy. In some embodiments, a subject with steroid-resistant GvHD is administered a therapeutically effective amount of apraglutide before, simultaneously, or after administration of a therapeutically effective amount of ruxolitinib and / or systemic steroid.

[0172] As will be understood by those skilled in the art, the term "steroid naive" refers to GvHD that has not been previously treated with steroid therapy. Thus, in a non-limiting example, steroid naive acute gastrointestinal GvHD refers to acute gastrointestinal GvHD that has not been previously treated with steroid therapy.

[0173] As will be understood by one of skill in the art, the term "chronic graft-versus-host disease" or "chronic GvHD" refers to graft-versus-host disease that develops more than 100 days after transplantation and exhibits clinical features typically associated with chronic graft-versus-host disease, including, but not limited to, damage to exocrine connective tissue, tissue fibrosis and restricted joint mobility, pulmonary and hepatic fibrosis, immune dysregulation and autoimmunity.

[0174] As will be understood by one of skill in the art, the terms "chronic gastrointestinal graft-versus-host disease" and "chronic gastrointestinal GvHD" refer to any of the forms of chronic GvHD described above that manifest in subjects with gastrointestinal symptoms and / or damage, including, but not limited to, diarrhea, abdominal pain, mucositis, mucosal ulcers, nausea, shortened colon, and shortened small intestine.

[0175] As will be understood by one of skill in the art, the term "overlap syndrome" refers to graft-versus-host disease that can be present any time after transplantation and that exhibits clinical features of both acute and chronic graft-versus-host disease.

[0176] As will be understood by those skilled in the art, "upper intestinal graft-versus-host disease", "upper intestinal GvHD", "upper intestinal GvHD phenotype" and "upper intestinal phenotype of GvHD" refer to graft-versus-host disease that presents with persistent appetite loss, satiety, nausea, vomiting, and weight loss accompanied by variable amounts of diarrhea. Symptoms may be slow, and therapy with prednisone at a dose of 1 mg / kg / day and topical oral corticosteroids is effective. In some embodiments, the upper intestinal GvHD phenotype does not progress to the mid-lower intestinal GvHD phenotype. In some embodiments, the upper intestinal GvHD phenotype is limited to grade I of GvHD.

[0177] As will be understood by those skilled in the art, the terms "mid-lower intestinal graft-versus-host disease", "mid-lower intestinal GvHD", "mid-lower intestinal GvHD phenotype" and "mid-lower intestinal phenotype of GvHD" refer to graft-versus-host disease that presents with secretory protein-rich and bile salt diarrhea and abdominal pain resulting from intestinal distension. In some embodiments, mid-lower intestinal GvHD is severe, and the entire small intestine and colon are edematous and inflamed, with greater diarrhea volumes and evidence of mucosal ulceration and bleeding. In some embodiments, subjects with severe mid-lower intestinal GvHD require prolonged hospitalization for supportive care, including total parenteral nutrition and pain control. In some embodiments, subjects with severe mid-lower intestinal GvHD require standard initial therapy, including prednisone, with or without other immunosuppressive therapy.

[0178] As will be understood by those skilled in the art, the term "GI-aGVHD response" refers to a one-stage reduction in GI-aGVHD signs and symptoms without the intervening events of discontinuation of assigned apraglutide treatment, initiation of new systemic therapy, or death. In some embodiments, a complete GI-aGVHD response refers to the disappearance of all GI-aGVHD signs and symptoms GVHD without the intervening events of discontinuation of assigned apraglutide treatment, initiation of new systemic therapy, or death. In some embodiments, a partial response refers to an improvement of one stage in one or more organs involved in aGVHD signs or symptoms without progression in other organs or sites, without administration of additional systemic therapy for early progression, mixed response, or non-response of aGVHD. In some aspects, GI-aGVHD erythema refers to any increase in signs or symptoms of GI-aGVHD that persists for >24 hours after an initial response and requires re-escalation of immunosuppressive therapy (e.g., corticosteroids, calcineurin inhibitors, and / or ruxolitinib administration).

[0179] The term "subject" includes any living organism that has GvHD or is at risk of developing GvHD. In some embodiments, the term "subject" refers to a mammal that has GvHD or is at risk of developing GvHD. In some embodiments, the term subject refers to a human that has GvHD or is at risk of developing GvHD. A human at risk of developing GvHD may be a human that should receive, is currently receiving, or has already received a transplant (allogeneic or autologous). A human at risk of developing GvHD may be a human that should receive, is currently receiving, or has already received a conditioning regimen in conjunction with HSCT.

[0180] The term "patient" is synonymous with and may be used interchangeably with "subject," unless expressly indicated otherwise.

[0181] The term "allogeneic" refers to biological material isolated from a donor that is to be transplanted into a recipient, the donor and recipient being two different subjects.

[0182] The term "autologous" refers to biological material isolated from a donor that is to be transplanted into a recipient, the donor and recipient being the same subject.

[0183] The term "conditioning therapy" refers to the use of radiation therapy, such as total body irradiation, chemotherapy, or radiation-like therapy, which is usually administered to subjects before HSCT. As understood by those skilled in the art, the purpose of conditioning therapy includes a) eradication of the underlying disease (e.g., cancer, blood cancer) to be treated with HSCT, b) creation of space in the bone marrow for donor stem cells to engraft, and c) immunosuppression to reduce the risk of rejection of donor cells by host cells. As used herein, conditioning therapy can refer to any conditioning therapy known in the art, including, but not limited to, total body irradiation. The term "radiation-like therapy" refers to any drug, compound, or treatment known in the art that mimics the action of radiation. As understood by those skilled in the art, chemotherapy includes the administration of a therapeutically effective amount of at least one chemotherapeutic agent. In some embodiments, the at least one chemotherapeutic agent can include, but is not limited to, actinomycin, all-trans retinoic acid, azacitidine, azathioprine, bleomycin, bortezomib, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, irinotecan, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, thioguanine, topotecan, valrubicin, vemurafenib, vinblastine, vincristine, vindesine. In some embodiments, the at least one chemotherapeutic agent comprises cytarabine. In some embodiments, the at least one chemotherapeutic agent comprises melphalan.

[0184] As used herein, the term "treating" or "treat" describes the management and care of a subject for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharma- ceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treat" can also include the treatment of a cell in vitro or in an animal model.

[0185] References to "treating" or "treatment" should be understood to include the alleviation of established symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder or condition includes (1) delaying the appearance of clinical symptoms of a condition, disorder or condition that develops in a person who may be afflicted with or predisposed to the condition, disorder or condition, but who has not yet experienced clinical or asymptomatic symptoms of the condition, disorder or condition, (2) inhibiting the condition, disorder or condition, i.e., arresting, reducing, or delaying the onset of the disease or its recurrence (in the case of controlled treatment) or at least one clinical or asymptomatic symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the condition, disorder or condition, or at least one clinical or asymptomatic symptom thereof.

[0186] As used herein, the terms "preventing," "prevent" or "protecting against" describe reducing or eliminating the onset of symptoms or complications of such a disease, condition or disorder.

[0187] As used herein, the term "therapeutically effective amount" refers to the amount of a pharmaceutical agent, such as apraglutide, for treating or preventing a specified disease or condition, such as GvHD, or exhibiting detectable therapeutic or inhibitory effects. The effect can be detected by any assay method known in the art. The exact effective amount for a subject depends on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0188] For any compound, the therapeutically effective amount can be estimated in an animal model, usually a rat, a mouse, a rabbit, a dog, or a pig. An animal model may be used to determine an appropriate concentration range and an administration route. Such information can then be used to determine a dose and a route useful for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined using standard pharmaceutical techniques in cell cultures or experimental animals, e.g., ED 50 (therapeutically effective dose in 50% of the population) and LD 50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 Dosages can vary within this range depending on the dosage form used and the susceptibility of the subject.

[0189] As used herein, the terms "administer", "administering", "administration" and the like refer to methods that can be used to allow the delivery of a composition to a desired biological site of action. These methods include, but are not limited to, intra-articular (into a joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be utilized with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0190] In addition, apraglutide can be co-administered with other therapeutic agents. As used herein, the terms "co-administration", "administered in combination" and their grammatical equivalents are meant to encompass the administration of two or more therapeutic agents to a single subject, and are intended to include therapeutic regimens in which agents are administered by the same or different administration routes or at the same or different times. In some embodiments, apraglutide is co-administered with other agents. These terms include the administration of two or more agents to a subject such that both agents and / or their metabolites are present in the subject at the same time. These include co-administration in separate compositions, administration at different time points in separate compositions, and / or administration in a composition in which both agents are present (i.e., co-formulation). Thus, the compounds described herein and other agents may be administered in a single composition.

[0191] The particular method of administration and dosing regimen will be selected by the attending physician, taking into consideration the particulars of the case (e.g., subject, disease, disease state involved, particular treatment). Treatment can include daily or multi-day or sub-daily (e.g., weekly or monthly) doses over a period of several days to several months or years. However, those skilled in the art will readily recognize appropriate and / or equivalent doses that examine the dosages of apraglutide used to treat other diseases and conditions, including, but not limited to, short bowel syndrome.

[0192] Doses generally range from about 1 mg to about 10 mg per week for about 1 week to about 100 weeks. In some embodiments, the weekly dose is about 1 mg to 10 mg. In some embodiments, the subject is administered for about 1 week to about 100 weeks, about 1 week to about 80 weeks, about 1 week to about 60 weeks, about 1 week to about 48 weeks, about 1 week to about 26 weeks, about 1 week to about 13 weeks, about 1 week to about 8 weeks, about 2 weeks to about 24 weeks, about 2 weeks to about 20 weeks, or about 2 weeks to about 16 weeks. In some embodiments, the subject may be administered a weekly dose range of about 1 mg to about 30 mg. In some embodiments, the subject may be administered a weekly dose range of about 1 mg to about 28.4 mg. In some embodiments, the subject may be administered about 10 mg once per week. In some embodiments, the subject may be administered about 5 mg once per week. In some embodiments, the subject may be administered about 2.5 mg once a week. In some embodiments, the subject may be administered about 1 mg once a week. For example, the subject may be administered a dose about once a week. The subject may be administered a dose about once every two weeks or about twice a month. About once every two weeks or about twice a month. Patients weighing less than 50 kg may be administered apraglutide in an amount of 2.5 mg to prevent high exposure. In some embodiments, patients weighing 50 kg or more may be administered apraglutide in an amount of 5 mg or more.

[0193] In some embodiments, a subject weighing 50kg to 60kg can be administered apraglutide in an amount of about 2.5mg to about 5mg. In some embodiments, a subject weighing 50kg to 60kg can be administered apraglutide in an amount of about 2.5mg. In some embodiments, a subject weighing 50kg to 60kg can be administered apraglutide in an amount of about 5mg.

[0194] In some embodiments, a subject weighing 50kg to 60kg can be administered apraglutide in an amount of about 2.5mg to about 5mg per week. In some embodiments, a subject weighing 50kg to 60kg can be administered apraglutide in an amount of about 2.5mg per week. In some embodiments, a subject weighing 50kg to 60kg can be administered apraglutide in an amount of about 5mg per week.

[0195] In some embodiments, a subject weighing 60kg to 80kg can be administered apraglutide in an amount of about 3.75mg to about 7.5mg. In some embodiments, a subject weighing 60kg to 80kg can be administered apraglutide in an amount of about 4mg to about 7.5mg. In some embodiments, a subject weighing 60kg to 80kg can be administered apraglutide in an amount of about 3.75mg. In some embodiments, a subject weighing 60kg to 80kg can be administered apraglutide in an amount of about 4mg. In some embodiments, a subject weighing 60kg to 80kg can be administered apraglutide in an amount of about 7.5mg.

[0196] In some embodiments, a subject weighing 60kg to 80kg can be administered apraglutide in an amount of about 3.75mg to about 7.5mg per week. In some embodiments, a subject weighing 60kg to 80kg can be administered apraglutide in an amount of about 4mg to about 7.5mg per week. In some embodiments, a subject weighing 60kg to 80kg can be administered apraglutide in an amount of about 3.75mg. In some embodiments, a subject weighing 60kg to 80kg can be administered apraglutide in an amount of about 4mg per week. In some embodiments, a subject weighing 60kg to 80kg can be administered apraglutide in an amount of about 7.5mg per week.

[0197] In some embodiments, subjects weighing 80 kg or more can be administered apraglutide in an amount of about 5 mg to about 10 mg. In some embodiments, subjects weighing 80 kg or more can be administered apraglutide in an amount of about 5 mg. In some embodiments, subjects weighing 80 kg or more can be administered apraglutide in an amount of about 10 mg.

[0198] In some embodiments, a subject weighing 80 kg or more can be administered apraglutide in an amount of about 5 mg to about 10 mg per week. In some embodiments, a subject weighing 80 kg or more can be administered apraglutide in an amount of about 5 mg per week. In some embodiments, a subject weighing 80 kg or more can be administered apraglutide in an amount of about 10 mg per week.

[0199] In some embodiments, a subject may be administered a single dose range of about 1 mg to about 60 mg. In some embodiments, a subject may be administered a single dose range of about 1 mg to about 56.9 mg.

[0200] In some embodiments, apraglutide is at least about 0.5, or at least about 1 mg, or at least about 1.5 mg, or at least about 2 mg, or at least about 2.5 mg, or at least about 3 mg, or at least about 3.5 mg, or at least about 4 mg, or at least about 4.5 mg, or at least about 5 mg, or at least about 5.5 mg, or at least about 6 mg, or at least about 6.5 mg, or at least about 7 mg, or at least about 7.5 mg, or at least about 8 mg, or at least about 8.5 mg, or at least about 9 mg, or at least about 9.5 mg, or at least about 10 mg, or at least about 10 mg. In one embodiment, the compound can be administered to a subject in an amount of about 0.5 mg, or at least about 11 mg, or at least about 11.5 mg, or at least about 12 mg, or at least about 12.5 mg, or at least about 13 mg, or at least about 13.5 mg, or at least about 14 mg, or at least about 14.5 mg, or at least about 15 mg, or at least about 15.5 mg, or at least about 16 mg, or at least about 16.5 mg, or at least about 17 mg, or at least about 17.5 mg, or at least about 18 mg, or at least about 18.5 mg, or at least about 19 mg, or at least about 19.5 mg, or at least about 20 mg.

[0201] In some embodiments, apraglutide is about 0.5, or about 1 mg, or about 1.5 mg, or about 2 mg, or about 2.5 mg, or about 3 mg, or about 3.5 mg, or about 4 mg, or about 4.5 mg, or about 5 mg, or about 5.5 mg, or about 6 mg, or about 6.5 mg, or about 7 mg, or about 7.5 mg, or about 8 mg, or about 8.5 mg, or about 9 mg, or about 9.5 mg, or about 10 mg, or about 10.5 mg, or It can be administered to a subject in an amount of about 11 mg, or about 11.5 mg, or about 12 mg, or about 12.5 mg, or about 13 mg, or about 13.5 mg, or about 14 mg, or about 14.5 mg, or about 15 mg, or about 15.5 mg, or about 16 mg, or at least about 16.5 mg, or about 17 mg, or about 17.5 mg, or about 18 mg, or about 18.5 mg, or about 19 mg, or about 19.5 mg, or about 20 mg.

[0202] In some embodiments, apraglutide can be administered to a subject once a day, twice a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days (once a week), once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, once every 14 days (once every two weeks), once every 15 days, once every 16 days, once every 17 days, once every 18 days, once every 19 days, once every 20 days, once every 21 days (once every three weeks), once every 22 days, once every 23 days, once every 24 days, once every 25 days, once every 26 days, once every 27 days, once every 28 days (once every four weeks), or once a month.

[0203] The pharmaceutical composition comprising apraglutide and / or its pharmaceutically acceptable salt may further comprise at least one pharmaceutically acceptable carrier.In some embodiments, at least one pharmaceutically acceptable carrier is selected from pharmaceutically acceptable vehicle and pharmaceutically acceptable adjuvant.In some embodiments, at least one pharmaceutically acceptable carrier is selected from pharmaceutically acceptable filler, disintegrant, surfactant, binder, lubricant.As used herein, the term "at least one pharmaceutically acceptable carrier" includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonicity agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants that are suitable for the specific dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York disclose various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation.Unless any conventional carrier is incompatible with apraglutide by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated within the scope of this disclosure.Non-limiting examples of suitable pharma- ceutical acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fats, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium phosphate ... Examples of suitable pharmacopoeitic carriers include, but are not limited to, cellulose, ethyl cellulose, and cellulose acetate, powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, saffron oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavorings, fragrances, preservatives, and antioxidants. In some embodiments, the at least one pharmacopoeitic carrier is selected from glycine, L-histidine, mannitol, and sodium hydroxide.

[0204] The compounds taught herein or corresponding pharmaceutical compositions can be administered to patients in various forms depending on the selected administration route, as understood by those skilled in the art.The compounds of the present teachings may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and pharmaceutical compositions formulated accordingly.Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary, intrathecal, rectal and topical administration modes.Parenteral administration can be performed by continuous infusion over a selected period of time.

[0205] The pharmaceutical composition of the present application is formulated to be compatible with its intended route of administration. The composition may be formulated according to routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans. In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0206] Oral therapeutic administration may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0207] Parenteral administration may generally be prepared in water appropriately mixed with a surfactant such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0208] Injectable administration may be prepared as a sterile aqueous solution or dispersion, and sterile powders of apraglutide for the extemporaneous preparation of sterile injectable solutions or dispersions are suitable.

[0209] Apraglutide can be administered via subcutaneous injection. For example, Apraglutide can be administered via a single bolus subcutaneous injection.

[0210] Apraglutide can be administered via a two-chamber syringe or a dual cartridge injector, one example of which is described in PCT / EP2012 / 000787, the contents of which are incorporated herein by reference.

[0211] GLP-2 agonist, such as apraglutide, may be administered parenterally, for example, by injection.The preparation suitable for parenteral administration includes aqueous and non-aqueous isotonic isotonic sterile injection solution, which may contain antioxidant, buffer, bacteriostatic agent, and the solute that makes the preparation isotonic with the blood of intended recipient, and the aqueous and non-aqueous sterile suspension, which may contain suspending agent, solubilizing agent, thickening agent, stabilizer, and preservative.The liquid carrier for injection solution includes but is not limited to water, physiological saline, aqueous dextrose and glycol, for example.

[0212] Apraglutide can be administered as part of pharmaceutical composition.The pharmaceutical composition of Apraglutide can include any pharma- ceutical acceptable carrier and / or excipient.The pharmaceutical composition of Apraglutide can include glycine, L-histidine, mannitol, and any combination thereof.

[0213] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by uncontrolled cell growth. This definition includes benign and malignant cancers. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, leukemia, and germ cell tumors. More specific examples of such cancers include adrenocortical carcinoma, bladder urothelial carcinoma, neoplastic breast cancer, cervical squamous cell carcinoma, cervical adenocarcinoma, cholangiocarcinoma, intestinal adenocarcinoma, lymphoid neoplasm diffuse large B-cell lymphoma, esophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, renal non-chromatic cell, renal clear cell carcinoma, renal papillary cell carcinoma, acute myeloid leukemia, low grade glioma of the brain, hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, prostate cancer, rectal adenocarcinoma, sarcoma, cutaneous melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid carcinoma, thymoma, uterine carcinosarcoma, uveal melanoma. Other examples include breast cancer, lung cancer, lymphoma, melanoma, liver cancer, colorectal cancer, ovarian cancer, bladder cancer, kidney cancer, or gastric cancer.Further examples of cancer include neuroendocrine cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, biliary tract cancer, esophageal cancer, anal cancer, salivary gland cancer, vulvar cancer, cervical cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenal tumors, anal cancer, bile duct cancer, bladder cancer, bone cancer, intestinal cancer, brain tumor, breast cancer, cancer of unknown primary site (CUP), cancer that has spread to bone, and cancer that has spread to brain. Cancer that has spread to the liver, cancer that has spread to the lungs, carcinoid, cervical cancer, childhood cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colorectal cancer, ear cancer, endometrial cancer, eye cancer, follicular dendritic cell sarcoma, gallbladder cancer, stomach cancer, gastroesophageal junction cancer, germ cell tumors, gestational trophoblastic disease (GIT), hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma , kidney cancer, laryngeal cancer, leukemia, gastric plastic gastritis, liver cancer, lung cancer, lymphoma, malignant schwannoma, mediastinal germ cell tumor, melanoma skin cancer, male cancer, Merkel cell skin cancer, mesothelioma, molar pregnancy, oral and oropharyngeal cancer, myeloma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors, non-Hodgkin's lymphoma (NHL), esophageal cancer, ovarian cancer, pancreatic cancer, cystic These include stalk cancer, persistent trophoblastosis and choriocarcinoma, pheochromocytoma, prostate cancer, pseudomyxoma peritonei, rectal cancer, retinoblastoma, salivary gland cancer, secondary cancers, signet ring cell carcinoma, skin cancer, small intestine cancer, soft tissue sarcoma, gastric cancer, T-cell childhood Non-Hodgkin's lymphoma (NHL), testicular cancer, thymic adenocarcinoma, thyroid cancer, tongue cancer, tonsillar cancer, adrenal tumors, uterine cancer, vaginal cancer, vulvar cancer, Wilms' tumor, uterine cancer, and gynecological cancers. Examples of cancer also include, but are not limited to, hematological malignancies, lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myelofibrosis, biliary tract cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, thyroid carcinoma, renal cell carcinoma, pancreatic cancer, bladder cancer, skin cancer, malignant melanoma, Merkel cell carcinoma, uveal melanoma, or glioblastoma multiforme.

[0214] In some aspects, the cancer is carcinoma, lymphoma, blastoma, sarcoma, leukemia, brain cancer, breast cancer, blood cancer, bone cancer, lung cancer, skin cancer, liver cancer, ovarian cancer, bladder cancer, kidney cancer, renal cancer, stomach cancer, thyroid cancer, pancreatic cancer, esophageal cancer, prostate cancer, cervical cancer, uterine cancer, gastric cancer, soft tissue cancer, laryngeal cancer, small intestine cancer, testicular cancer, anal cancer, vulvar cancer, joint cancer, oral cancer, pharyngeal cancer, or colorectal cancer.

[0215] In some aspects, the cancer is a hematological cancer.

[0216] In some embodiments, the cancer is acute myeloid leukemia, myelodysplastic syndrome, follicular lymphoma, diffuse large B-cell lymphoma, acute lymphoblastic leukemia, multiple myeloma, Hodgkin's lymphoma, chronic myeloid leukemia, T-cell non-Hodgkin's lymphoma, lymphoblastic B-cell non-Hodgkin's lymphoma (non-Burkitt), Burkitt's lymphoma, anaplastic large cell lymphoma, germ cell tumors, Ewing's sarcoma, soft tissue sarcoma, neuroblastoma, Wilms' tumor, osteosarcoma, medulloblastoma, acute promyelocytic leukemia, mantle cell lymphoma, T-cell lymphoma, lymphoplasmacytic lymphoma, cutaneous T-cell lymphoma, plasmablastic, chronic lymphocytic leukemia, breast cancer, and kidney cancer.

[0217] In some embodiments, the disease or disorder is hemoglobinopathies, congenital hemoglobinopathies, beta thalassemia major (TM), sickle cell disease (SCD), severe aplastic anemia, Fanconi anemia, dyskeratosis congenita, Blackfan-Diamond anemia, thalassemia, congenital amegakaryocytic thrombocytopenia, severe combined immunodeficiency, T cell immunodeficiency, T cell immunodeficiency-SCID variant, Wiskott-Aldrich syndrome, hemophagocytic disorder, lymphoproliferative disorder, severe congenital neutropenia, chronic granulomatous disease, phagocytic cell disorder, IPEX syndrome, juvenile rheumatoid arthritis, systemic sclerosis, autoimmune disorders, immune dysregulation disorders, mucopolysaccharidoses, MPS-I, MPS-VI, osteopetrosis, metabolic disorders, globoid cell leukodystrophy (Krabbe), metachromatic leukodystrophy, cerebral X-linked adrenoleukodystrophy, myelofibrotic disease, myeloproliferative disorders, plasma cell disorders, mastocytosis, common variable immunodeficiency, chronic granulomatous disease, multiple sclerosis, systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease or polymyositis-dermatomyositis.

[0218] As used herein, the term "temporal proximity" refers to the administration of a therapeutic composition (e.g., apraglutide, or a pharma- ceutically acceptable salt thereof) occurring before or after the administration of another therapeutic composition (e.g., transplantation, conditioning therapy, a second active agent) such that the therapeutic effect of the therapeutic agent overlaps with the therapeutic effect of the other therapeutic agent. In some embodiments, the therapeutic effect of the therapeutic agent completely overlaps with the therapeutic effect of the other therapeutic agent. In some embodiments, "temporal proximity" means that the administration of a therapeutic agent occurs before or after the administration of another therapeutic agent such that there is a synergistic effect between the therapeutic agent and the other therapeutic agent. "Temporal proximity" may vary depending on a variety of factors, including, but not limited to, the age, sex, weight, genetic background, medical condition, medical history, and treatment history of the subject to whom the therapeutic agent is administered; the disease or condition to be treated or ameliorated; the therapeutic result to be achieved; the dosage, frequency, and duration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route(s) by which the therapeutic agent is administered. In some embodiments, "temporal proximity" means within 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks. In some embodiments, multiple administrations of one therapeutic agent can be administered in temporal proximity to a single administration of another therapeutic agent. In some embodiments, the temporal proximity may vary during a treatment cycle or within a dosing regimen.

[0219] Exemplary embodiments Embodiment 1. A method for treating or preventing graft-versus-host disease (GvHD) in a subject, comprising administering to the subject at least one therapeutically effective amount of apraglutide or a pharma- ceutical acceptable salt thereof.

[0220] Embodiment 2. 2. The method of embodiment 1, wherein the GvHD is acute GvHD.

[0221] Embodiment 3. The method of embodiment 1 or embodiment 2, wherein the GvHD is acute gastrointestinal GvHD.

[0222] Embodiment 4. 2. The method of embodiment 1, wherein the GvHD is chronic GvHD.

[0223] Embodiment 5. The method according to any one of embodiments 1 to 4, wherein the GvHD is steroid-resistant.

[0224] Embodiment 6. The method according to any one of embodiments 1 to 4, wherein the GvHD is steroid naïve.

[0225] Embodiment 7. The method according to any one of embodiments 1 to 6, wherein at least one therapeutically effective amount of apraglutide is administered to the subject before the subject is transplanted.

[0226] Embodiment 8. The method according to any one of embodiments 1 to 7, wherein at least one therapeutically effective amount of apraglutide is administered before the subject receives radiation therapy, chemotherapy, or radiation-like therapy in connection with the transplant.

[0227] EMBODIMENT 9. The method of any one of embodiments 1-6, wherein the subject has already been transplanted.

[0228] Embodiment 10. The method of embodiment 9, wherein at least one therapeutically effective amount of apraglutide is administered to the subject after the subject is transplanted.

[0229] Embodiment 11. The method according to any one of embodiments 1-6 and 9-10, wherein the subject has already received radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof in connection with the transplant.

[0230] Embodiment 12. The method of embodiment 11, wherein at least one therapeutically effective amount of apraglutide is administered to the subject after the subject has been administered radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof.

[0231] Embodiment 13. The method of embodiment 11, wherein at least one therapeutically effective amount of apraglutide is administered to the subject after the subject has been administered radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof, and before the subject is transplanted.

[0232] Embodiment 14. The method according to any one of embodiments 1 to 6, wherein at least one therapeutically effective amount of apraglutide is administered to the subject simultaneously with transplantation.

[0233] EMBODIMENT 15. The method according to any one of embodiments 1 to 6, wherein at least one therapeutically effective amount of apraglutide is administered to the subject simultaneously with radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof in connection with the transplant.

[0234] Embodiment 16. The method of any one of embodiments 1-15, wherein administration of apraglutide prevents and / or attenuates loss of colon length in the subject after transplantation.

[0235] EMBODIMENT 17. The method according to any one of embodiments 1-16, wherein administration of apraglutide prevents and / or attenuates loss of colon length in the subject following conditioning therapy and transplantation.

[0236] Embodiment 18. 18. The method of any one of embodiments 1-17, wherein the transplant comprises hematopoietic stem cells derived from bone marrow, peripheral blood, umbilical cord blood, or any combination thereof.

[0237] EMBODIMENT 19. 19. The method of any one of embodiments 1-18, wherein the transplant comprises T cells.

[0238] EMBODIMENT 20. 20. The method of embodiment 19, wherein the T cells comprise chimeric antigen receptor (CAR) T cells.

[0239] EMBODIMENT 21. 21. The method according to any one of the preceding embodiments, wherein radiation therapy comprises total body irradiation.

[0240] EMBODIMENT 22. The method according to any one of embodiments 1-21, wherein the pharma- ceutical acceptable salt of apraglutide is a sodium salt of apraglutide.

[0241] EMBODIMENT 23. The method according to any one of embodiments 1-22, wherein apraglutide, or a pharma- ceutical acceptable salt thereof, is administered by subcutaneous injection.

[0242] EMBODIMENT 24. The method according to any one of embodiments 1 to 23, wherein apraglutide, or a pharma- ceutical acceptable salt thereof, is administered in an amount of about 1 mg to about 10 mg.

[0243] EMBODIMENT 25. The method according to any one of embodiments 1-24, wherein apraglutide is administered in an amount of about 2.5 mg.

[0244] 26. The method according to any one of the preceding embodiments, wherein apraglutide is administered in an amount of about 5 mg.

[0245] EMBODIMENT 27. The method of any one of embodiments 1-26, wherein apraglutide is administered in an amount of about 10 mg.

[0246] 28. 28. The method according to any one of embodiments 1 to 27, wherein the transplant is an allogeneic transplant.

[0247] 29. 29. The method according to any one of embodiments 1 to 28, wherein the transplant is an autologous transplant.

[0248] EMBODIMENT 30. The method according to any one of embodiments 1 to 29, wherein the subject has already been administered at least one anti-GvHD therapy.

[0249] EMBODIMENT 31. 31. The method of embodiment 30, wherein the at least one anti-GvHD therapy comprises steroid therapy.

[0250] EMBODIMENT 32. Apraglutide, or a pharma- ceutically acceptable salt thereof, for use in treating or preventing graft-versus-host disease (GvHD) in a subject.

[0251] EMBODIMENT 33. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use according to embodiment 32, wherein the use is for preventing GvHD.

[0252] EMBODIMENT 34. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use according to embodiment 32 or 33, wherein GvHD is acute GvHD.

[0253] EMBODIMENT 35. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use according to embodiment 34, wherein the GvHD is acute gastrointestinal GvHD.

[0254] 36. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use according to embodiment 35, wherein the use is for treating and the GvHD is steroid-resistant acute gastrointestinal GvHD.

[0255] 37. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use according to any one of embodiments 32 to 36 in a subject designated to subsequently receive an allogeneic transplant.

[0256] 38. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use as described in embodiment 6 in a subject designated to subsequently be administered radiation therapy, chemotherapy, or radiation-like therapy in connection with an allogeneic transplant.

[0257] 39. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use according to any one of embodiments 32 to 36 in a subject who has already received an allogeneic transplant.

[0258] EMBODIMENT 40. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use according to any one of embodiments 32-35 and 38-39, wherein the subject has already been administered radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof in connection with an allogeneic transplant.

[0259] EMBODIMENT 41. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use as described in embodiment 40 in a subject designated to receive radiation therapy, chemotherapy, radiation-like therapy or any combination thereof, followed by an allogeneic transplant.

[0260] EMBODIMENT 42. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use according to any one of embodiments 32 to 36 in a subject designated to be administered an allogeneic transplant concomitantly.

[0261] EMBODIMENT 43. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use according to any one of embodiments 32 to 36 in a subject designated for administration simultaneously with radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof in connection with an allogeneic transplant.

[0262] EMBODIMENT 44. Apraglutide, or a pharma- ceutical or pharma-ceutical acceptable salt thereof, for use according to any one of embodiments 32 to 43, wherein the treatment or prevention of GvHD comprises preventing and / or attenuating loss of colon length in a subject subsequently designated to receive an allogeneic transplant or who has already received an allogeneic transplant.

[0263] EMBODIMENT 45. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use according to any one of embodiments 32 to 44, wherein the treatment or prevention of GvHD comprises preventing and / or attenuating loss of colon length in a subject who is subsequently designated to receive conditioning therapy and co-transplant or who has already received conditioning therapy and co-transplant.

[0264] EMBODIMENT 46. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use according to any one of embodiments 37 to 45, wherein the allogeneic transplantation comprises transplantation of allogeneic hematopoietic stem cells derived from bone marrow, peripheral blood, umbilical cord blood, or any combination thereof.

[0265] EMBODIMENT 47. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use according to any one of embodiments 37 to 45, wherein the allogeneic transplantation comprises transplantation of allogeneic T cells.

[0266] 48. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use according to embodiment 47, wherein the allogeneic T cells are allogeneic chimeric antigen receptor (CAR) T cells.

[0267] 49. Apraglutide, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 38 to 48, wherein radiation therapy comprises total body irradiation.

[0268] EMBODIMENT 50. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use according to any one of embodiments 32 to 49, wherein the pharma- ceutical acceptable salt of apraglutide is a sodium salt of apraglutide.

[0269] EMBODIMENT 51. Apraglutide, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 32 to 50, wherein the apraglutide, or a pharma- ceutically acceptable salt thereof, is administered by subcutaneous injection.

[0270] EMBODIMENT 52. Apraglutide, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 32 to 51, wherein the apraglutide, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 1 mg to about 10 mg.

[0271] EMBODIMENT 53. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use according to any one of embodiments 32 to 52, wherein apraglutide is administered in an amount of about 2.5 mg.

[0272] EMBODIMENT 54. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use according to any one of embodiments 32 to 53, wherein apraglutide is administered in an amount of about 5 mg.

[0273] EMBODIMENT 55. Apraglutide, or a pharma- ceutical acceptable salt thereof, for use according to any one of embodiments 32 to 54, wherein apraglutide is administered in an amount of about 10 mg. EXAMPLES

[0274] Working Example

[0275] The following non-limiting examples describe experiments directed to testing the use of apraglutide for the prevention and / or treatment of acute gastrointestinal GvHD in a mouse model in which intestinal damage was induced by total body irradiation of mice intended to simulate the conditioning regimen typically used prior to AHCT in human subjects.

[0276] Example 1

[0277] In the first experiment, BALB / cJ male mice were divided into two groups, group A and group B. Each group consisted of 10 mice.

[0278] Mice in group A received subcutaneous injections of apraglutide at a dose of 3 mg / kg / mouse (administered in 300 μl of vehicle) every two days from day -9 to day +7 (days: -9, -7, -5, -3, -1, +1, +3, +5, +7).

[0279] Mice in group B received subcutaneous injections of 300 μl of vehicle control every two days from day −9 to day +7 (days: −9, −7, −5, −3, −1, +1, +3, +5, +7).

[0280] On day −1 of the experiment, all mice in groups A and B were irradiated with 8.5 Gy using a linac X-ray source.

[0281] On day 0 of the experiment, bone marrow and T cells from C57BL / 6J mice were collected, prepared, and transplanted into mice in groups A and B. Mice in groups A and B were intravenously injected with 10 million bone marrow cells extracted from the femurs of C57BL / 6J mice and 2.5 million spleen cells extracted from C57BL / 6J mice. Mice #3 (group A), #13 (group B), and #20 (group B) received cells by subcutaneous injection instead of intravenous injection. Mice #5 (group B) and #10 (group B) received half of the cells by intravenous injection and half of the cells by subcutaneous injection.

[0282] Mice from groups A and B were monitored for morbidity, mortality, body weight, clinical signs (diarrhea, appearance and behavior), intestinal segment length, and histopathology of intestine, skin, spleen and liver. All mice were sacrificed on day +14 at the latest.

[0283] Induction of acute GvHD was observed in mice of groups A and B after transplantation, as indicated by weight loss and histological analysis, especially lymphocytic infiltration.

[0284] After the mice were sacrificed, the colon lengths of the mice in groups A and B, as well as the control group of BALB / c mice (untreated), were measured. The results of this analysis are shown in FIG. 1. As shown in FIG. 1, there was a clear difference in colon length in group A compared to group B, as the mice treated with apraglutide showed an increase in colon length that was nearly the same as the control mice. Thus, treatment with apraglutide protected the mice in group A from a decrease in colon length, typically due to inflammation caused by acute gastrointestinal GvHD.

[0285] Various histological parameters of the jejunum were also measured, including single-cell necrosis level, total crypt necrosis, ciliary body shortening, crypt hyperplasia (regeneration), cellular infiltration, and crypt abscesses. These histological parameters were graded with a standard histological grading system (1-3). The results of the histological analysis are shown in Figures 2a-2c. In mice treated with apraglutide, the overall mean severity scores of mucosal degeneration / inflammatory changes (shortening of ciliary body [ciliary atrophy], mononuclear cell [lymphohistiocytic] / neutrophil infiltration in the lamina propria / intracrypt epithelium, reduced numbers of cathodal and cathodal abscesses) were slightly decreased in the jejunum compared to vehicle-treated animals. Furthermore, the mean severity score of regenerative crypt hyperplasia was slightly increased when compared to vehicle-treated animals. These indicate that administration of apraglutide has effective protection against jejunal mucosal injury induced by irradiation and GvHD.

[0286] In the second experiment, BALB / cJ male mice were divided into three groups: Group A, Group B, and Group C. Groups A and B consisted of 10 mice, and Group C consisted of 5 mice.

[0287] Mice in group A received subcutaneous injections of apraglutide at a dose of 3 mg / kg / mouse (administered in 300 μl of vehicle) every two days from day -9 to day +7 (days: -9, -7, -5, -3, -1, +1, +3, +5, +7).

[0288] Mice in group B received subcutaneous injections of 300 μl of vehicle control every two days from day −9 to day +7 (days: −9, −7, −5, −3, −1, +1, +3, +5, +7).

[0289] Mice in group C received subcutaneous injections of 300 μl of vehicle control every two days from day −9 to day +7 (days: −9, −7, −5, −3, −1, +1, +3, +5, +7).

[0290] On day -1 of the experiment, all mice in groups A and B were irradiated with 7.0 Gy using a linac X-ray source. Group C was not irradiated but was injected with vehicle only.

[0291] On day 0 of the experiment, bone marrow and T cells from C57BL / 6J mice were collected, prepared, and transplanted into mice in groups A and B. Each mouse in groups A and B was intravenously injected with 10 million bone marrow cells extracted from the femurs of C57BL / 6J mice and 2.5 million spleen cells extracted from C57BL / 6J mice.

[0292] Irradiated mice in group A treated with apraglutide showed improved survival compared to untreated, non-irradiated mice in group B. Group A had a median survival of 9 days and group B had a median survival of 8.5 days. Furthermore, 40% of mice treated with apraglutide survived beyond day 9 of the experiment. Mice in group C received only the vehicle and were expected to survive. FIG.

[0293] Mice from groups A, B and C were monitored for morbidity, mortality, body weight, clinical signs (diarrhea, appearance and behavior), intestinal segment length, and histopathology of intestine, skin, spleen and liver. All mice were sacrificed on day +14 at the latest.

[0294] The mice's diarrhea, appearance and behavior were coded into a pathology score (0 being the least severe to 4 being the most severe) (Figure 15a). Macroscopically, 4 out of 10 mice in group A showed a pathology score of 0 compared to only a single mouse in group B (Figure 15b).

[0295] Weight loss was monitored in all three groups. No significant difference in weight loss was observed between groups A and B. In group A, mice surviving after day 9 regained weight, whereas mice in group C did not gain weight (Figure 16a-c).

[0296] After the mice were sacrificed, the colon length and small intestine length of the mice in groups A, B and C were measured. The results of this analysis are shown in FIG. 3. As shown in FIG. 3, the mice treated with apraglutide showed an increase in colon length that was almost the same as the mice in group C, so there was a clear difference in the colon length of group A compared to group B. Thus, treatment with apraglutide protected the mice in group A from a decrease in colon length, which is typically involved in inflammation caused by acute gastrointestinal GvHD, without wishing to be bound by theory, and the results of the above experiment show that apraglutide can be used to treat acute gastrointestinal GvHD. As shown in FIG. 3, no difference was observed in the small intestine length in any of the three groups. Without wishing to be bound by theory, the results of the above experiment show that apraglutide can be used to treat acute gastrointestinal GvHD. Specifically, apraglutide protects against intestinal pathology and loss of colon length in the context of acute gastrointestinal GvHD induced by radiation and allogeneic transplantation.

[0297] Example 2

[0298] In the first experiment, total body irradiated (TBI) (1.44 Gy) immunodeficient (NOG) mice (day 0) were injected with human peripheral blood mononuclear cells (hPBMCs; 3 × 10 7 Mice were injected with 0.1 mg / kg apraglutide (day 2) and treated with apraglutide 3.3 mg / kg or vehicle from days -6 to 18. Engraftment rates were determined via CD45 expression in blood, bone marrow, and spleen.

[0299] In a second experiment, TBI-induced intestinal injury BALB / cJ mice received allografts and were treated with apraglutide (3.3 mg / kg) or vehicle on days -9, -7, -5, -3, -1, +1, +3, +5, and +7. Intestinal damage indicative of GvHD (histological changes, length, bleeding, inflammation), body weight, and survival were assessed.

[0300] In the first experiment, hPBMC engraftment was successful. The engraftment rate in blood, spleen and bone marrow was not affected by apraglutide (ranging from 22.2 to 47.6% in blood at D20). hCD45+ cell infiltration was observed in the intestinal wall, with no difference between apraglutide and vehicle (Figure 4).

[0301] In the second experiment, lymphocyte engraftment was successfully achieved in both apraglutide- and vehicle-treated mice. Weight loss and median survival were similar in both groups, but apraglutide-treated mice achieved significantly higher overall survival compared to vehicle on day +9 (40% vs. 0%, respectively, p=0.0134). Postmortem histological examination revealed less mucosal degenerative / inflammatory changes (ciliary atrophy, mononuclear / neutrophil infiltration in the lamina propria / intracrypt epithelium, crypt necrosis) in apraglutide-treated mice compared to vehicle. The mean colon length of the apraglutide group (8.6±0.35 cm) was comparable to mice that did not receive irradiation or transplantation (9.6±0.33 cm), whereas a significant reduction was evident in the vehicle group (7.19±0.10 cm; p<0.05) (Figure 5).

[0302] Without wishing to be bound by theory, the results of the above experiments show that apraglutide treatment prior to allogeneic transplantation in immunodeficient mice did not affect successful engraftment or engraftment rate. Furthermore, apraglutide showed significant protective effects in TBI and allogeneic transplantation-induced GvHD, which reduced ciliary atrophy, minimized colon shortening, and reduced the severity of intestinal damage, indicating survival benefits. These findings support the beneficial role of apraglutide in reducing GI damage and limiting mortality due to GvHD. Without wishing to be bound by theory, the results of the above experiments support that apraglutide reduces the severity of intestinal damage from acute gastrointestinal graft-versus-host disease (GI-GvHD) after allogeneic transplantation without affecting engraftment.

[0303] Example 3

[0304] In the first experiment, four groups of Balb / c mice were treated with: (A) vehicle only; (B) cytarabine on days 5-9, no apraglutide; (C) cytarabine on days 5-9, apraglutide on days 5-18; (D) cytarabine on days 5-9, apraglutide pretreatment on days 1, 3, and continued as combination therapy on days 5, 8, 11, 14, and 17. Treatment groups received 30 mg / kg cytarabine and / or apraglutide 3.3 mg / kg.

[0305] In a second experiment, three treatment groups of Balb / c mice were treated with: (A) vehicle only; (B) melphalan on day 9, no apraglutide; (C) melphalan on day 9, apraglutide pretreatment on days 1, 3, 5, and 7, and continued as combination therapy on days 9, 11, and 13.

[0306] In both models, untreated mice receiving vehicle served as controls. Intestinal tissue histology, body weight, survival, and plasma citrulline, a marker of total mucosa and intestinal growth, were assessed in both models.

[0307] Histological examination showed that the degenerative intestinal changes (ciliary and crypt atrophy) caused by cytarabine or melphalan were reduced by the co-administration of apraglutide (Figure 6). This was demonstrated by the similarity of tissue morphology between vehicle- and apraglutide-treated mice. Furthermore, the duodenum, ileum and jejunum increased in weight with apraglutide. The intestinal protective effect of apraglutide was further supported by the preservation of plasma citrulline (indicating intestinal weight) with apraglutide-treated mice having similar levels as vehicle-treated ones (Figure 7). Apraglutide attenuated chemotherapy-induced weight loss (Figure 8) and improved overall survival compared to vehicle-only or chemotherapy-only groups (Figure 9). The effect of apraglutide was optimal when apraglutide was administered as a pre-treatment prior to chemotherapy.

[0308] Without wishing to be bound by theory, the results of microscopy showed that apraglutide protected GI epithelial structures from chemotherapy-induced damage, improved survival, and prevented severe weight loss in mice receiving chemotherapy. It also preserved intestinal weight, as indicated by maintaining plasma citrulline levels comparable to mice not receiving chemotherapy.

[0309] Without wishing to be bound by theory, the results of the above experiments support that apraglutide treatment reduces chemotherapy-induced gastrointestinal (GI) damage in mice and preserves cellular integrity during chemotherapy.

[0310] Example 4

[0311] In the first experiment, Balb / c mice were administered cytarabine 30 mg / kg on days 5–9 and apraglutide 3.3 mg / kg on days 1–18. Control mice received vehicle on days 1–18. Fecal samples were collected for bacterial phenotyping for approximately 24 h before treatment and the day before the scheduled end of treatment, as well as for animals confirmed dead or sacrificed prior to termination. Microbiota composition was determined by 16S taxonomic metasequencing. Bacteroidetes and Firmicutes were the two predominant bacterial strains identified (Figures 10a and 10b). Chemotherapy with cytarabine significantly altered bacterial species composition, increasing the Bacteroidetes population and decreasing the proportion of bacteria in the Firmicutes phylum. The change in levels of bacteria of the phyla Bacteroidetes and Firmicutes from days 0 to 18 was significantly greater in both cytarabine-only and cytarabine + apraglutide mice compared to vehicle (Table 1a and Table 1b). However, this effect was reduced by concomitant administration of apraglutide. The difference in changes between the cytarabine-only and cytarabine + apraglutide groups reached statistical significance for both Bacteroidetes (0.2486; p<0.0001) and Firmicutes (0.2037; p<0.0001). Furthermore, the ratio of bacteria of the phylum Bacteroidetes to bacteria of the phylum Firmicutes present was more constant in the cytarabine + apraglutide than in the cytarabine-only group.

[0312] Table 1a: Apraglutide treatment reduces chemotherapy-induced changes in fecal bacterial composition. [Table 1] For each classification, an analysis of variance for repeated measures (repeated ANOVA) was performed, including treatment, day, and treatment by day interactions as fixed factors in the statistical model. Post-hoc tests were performed to perform pairwise comparisons of treatment groups on day 0 (pre-treatment) and day 18 (post-treatment) using Tukey's adjustment for multiple testing.

[0313] Table 1b: Apraglutide treatment stabilizes chemotherapy-induced changes in gut microbiota diversity [Table 2] *p<0.005 compared with control and compared with cytarabine alone # p < 0.001, B, Bacteroides species (Gram -ve , anaerobic bacteria including opportunistic pathogen strains); F, Firmicutes species (Gram +ve , aerobic and anaerobic bacteria);RX, treatment

[0314] Treatment of mice with chemotherapy had a significant impact on the homeostasis of bacteria in the gut, with a significant increase in the opportunistic pathogen population. When apraglutide was combined with chemotherapy, the proportion of different bacterial phyla in the feces tended to remain close to normal. Without wishing to be bound by theory, the results of the above experiments indicate that treatment with apraglutide resulted in the preservation of the general homeostatic environment of the gut microbiota, which is likely to contribute to the improved clinical outcomes (weight loss, increased survival) observed when apraglutide was administered in combination with chemotherapy agents. Furthermore, as will be appreciated by those skilled in the art, imbalances in the gut microbiota are known to be drivers of the pathogenesis of GvHD (see Fredricks, J. Clin. Invest. 2019, 129(5):1808-1817). Thus, the ability of apraglutide to stabilize the gut microbiota indicates that it can be used to effectively treat and prevent GvHD.

[0315] Example 5

[0316] In the first experiment, the antitumor effect of cytarabine was evaluated in leukemic NOD / SCID mice (Figure 11a). Apraglutide or vehicle was administered on days -4 to 4. Cytarabine or vehicle was administered on days 0 to 4. Bone marrow and spleen samples were collected on day 7 and the percentage of hCD45+ cells was determined. After treatment, there was no significant difference in the % of hCD45 cells detected in bone marrow or spleen samples between the cytarabine + vehicle and cytarabine + apraglutide treated groups (Figure 11b).

[0317] In the second experiment, the effect of apraglutide on the ability of cytarabine to induce immunosuppression was evaluated. The experiment included three groups of Balb / c mice: (A) vehicle; (B) cytarabine on days 5-9; (C) co-administration of cytarabine on days 5-9 and apraglutide on days 5-18. RBCs, platelets, WBCs, NEU, and lymph were assessed. Cohorts were allowed to survive for 4 weeks to evaluate the effect of apraglutide on immunosuppression recovery (Figure 12).

[0318] In the third experiment, the effect of apraglutide on melphalan-induced immunosuppression was evaluated (Figure 13). Three groups of Balb / c mice were included: (A) vehicle; (B) melphalan on day 9; (C) melphalan on day 9, apraglutide pretreatment on days 1, 3, 5, and 7, and continued as combination therapy on days 9, 11, and 13. WBC, NEU, and lymph were assessed.

[0319] In the first experiment, the reduction in human leukemia cells was not significantly different between cytarabine alone and cytarabine plus apraglutide, but was significantly greater than vehicle. The percentage of hCD45 in bone marrow after chemotherapy was 35.5 ± 4 with cytarabine alone and 33.9 ± 4.2 with cytarabine plus apraglutide.

[0320] The dramatic reduction in white blood cells at the end of the treatment period in the second study indicated that cytarabine-induced immunosuppression was not compromised by apraglutide coadministration (91% reduction in lymphocytes with both cytarabine + apraglutide and cytarabine alone) (Table 2).Apraglutide did not affect the recovery of hematological parameters 4 weeks after the end of treatment.

[0321] Table 2. Apraglutide does not affect the immunosuppression of cytarabine. [Table 3] a Administered from 4 days before the start of cytarabine treatment to 9 days after the end of cytarabine treatment

[0322] The third experiment shows that melphalan induced immune suppression as indicated by leukopenia. Mice treated with melphalan, with or without apraglutide, showed severe reductions in WBC and lymphatic fluid compared to vehicle.

[0323] Without wishing to be bound by theory, the results of the above experiments show that the use of apraglutide before and in combination with cytarabine does not impair the effectiveness of cytarabine in destroying human leukemia cells in vivo.In addition, the use of apraglutide in combination with cytarabine did not have a negative effect on cytarabine or melphalan-induced immunosuppression.This pharmacological action of apraglutide is specific to the intestine and does not affect the antitumor or immunosuppressive effects of cytarabine or melphalan.Apraglutide does not affect the antitumor and immunosuppressive efficacy of conditioning chemotherapy in mice.

[0324] Example 6

[0325] In the first experiment, BALB / cJ female mice were divided into six groups for a dose-response study to evaluate the pharmacological effects of increasing doses of apraglutide (0.11, 0.3, and 1.1 mg / kg) administered subcutaneously. Cytarabine was administered intraperitoneally at 30 mg / kg twice daily for 5 days (days 0 to +4). Apraglutide was administered daily for a total of 9 days, 4 days before and 5 days during chemotherapy administration (days -4 to +4). Apraglutide effects were compared to unmodified hGLP-2 in combination with cytarabine, administered twice daily from days -4 to +4 at a nominal dose of 0.60 mg / kg. Animal survival results showed a significant improvement in animal survival compared to cytarabine alone (Figure 17).

[0326] Animal survival with increasing doses of apraglutide was 11 / 16 at 0.11 mg / kg, 14 / 16 at 0.33 mg / kg, and 16 / 16 at 1.1 mg / kg. The improvement in animal survival was statistically significant in all apraglutide treatment groups. Treatment with 0.11 mg / kg apraglutide or the combination of hGLP-2 and cytarabine did not reduce the initial weight loss, although there was a trend toward increased weight gain and survival in those animals that recovered from cytarabine treatment (Figure 18).

[0327] The gut-protective effect of apraglutide was supported by preservation of plasma citrulline (indicative of gut weight) accompanied by improved cytarabine concentrations when cytarabine was co-administered with apraglutide (0.33 mg / kg and 1.1 mg / kg) compared to animals treated with cytarabine alone (Figure 19).

[0328] The dose-dependent impact of apraglutide on the immunosuppressive effects of cytarabine was evaluated. The effect of cytarabine treatment on polymorphonuclear (PMN) cell counts was determined (Figure 20). Animals treated with cytarabine alone showed depleted PMN counts, which were not reversed by hGLP-2 or apraglutide combination therapy, suggesting that the improvement in animal survival and weight was not the result of improved neutrophil granulocyte counts, but rather the result of preservation of GI integrity. In a separate study, animals received cytarabine alone or combination treatment with apraglutide starting before cytarabine (days -4 to +12) and survived for an additional 4 weeks.

[0329] Example 7

[0330] The first study will evaluate the safety and efficacy of apraglutide in subjects with grade II-IV (MAGIC) steroid-refractory gastrointestinal (GI) acute graft-versus-host disease on best available therapy in a randomized, double-blind study.

[0331] Inclusion criteria for randomized, double-blind, Phase II trials of apraglutide: 1. Participants must be 12 years of age or older and weigh 40 kg or more at the time of consent. 2. Participants undergoing alloSCT from any donor source (matched unrelated donor, sibling, haploidentical) using bone marrow, peripheral blood stem cells, or umbilical cord blood. Recipients of non-myeloablative, myeloablative, and reduced-intensity conditioning are eligible. 3. Participant has demonstrable bone marrow and platelet engraftment (confirmed prior to starting study drug): a) absolute neutrophil count >1000 / mm3; and b) platelets ≥20,000 / mm3. 4. Tolerate participant's use of growth factor supplementation (granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor) and transfusion support. 5. Participants with histologically diagnosed GI-aGVHD at screening (with clinically confirmed SR GI-aGVHD at the time of ruxolitinib initiation and prior to apraxon initiation) will be defined as eligible to receive SS alone or in combination with a calcineurin inhibitor (CNI), defined as either: a) disease progression based on organ assessment after 3 days of systemic methylprednisolone (MP) at 2 mg / kg ± CNI; or b) Failure to improve after 7 days of treatment with MP 2 mg / kg / day; or c) Progression to new organs following treatment with MP 2 mg / kg / day for skin and upper GI-aGVHD; or d) Recurrence during or after steroid taper. All subjects were required to have lower GI-aGVHD stages 1-4 at the time of enrollment. 6. Participants may be treated with systemic steroids (SS) and ruxolitinib (RUX) (RUX at the recommended dose twice daily for 0-3 days). Calcineurin inhibitors are tolerated as concomitant medications, if needed.

[0332] Participants weighing 50.0 kg or greater will be randomized into one of two treatment groups (low or high dose within three weight bands). The exact dose they receive at each visit will vary depending on the weight band they are in (Table 3). Participants weighing 40.0-49.9 kg will receive apraglutide 2.5 mg. Apraglutide will be administered subcutaneously once weekly for 8-13 weeks. If subjects benefit from continued administration of apraglutide, it may be administered for up to 26 weeks. Table 3: Treatment group and dose of study drug based on weight [Table 4]

[0333] Initially, participants will undergo screening assessments and provide informed consent during a 14-day screening period, including but not limited to analysis of vital signs, height and weight, colonoscopy, intestinal biopsy, and medical history.

[0334] This study is a randomized, double-blind, multiple-dose study to evaluate the safety and efficacy of apraglutide in subjects with grade II-IV SR GI-aGVHD receiving BAT. Thirty-four subjects are receiving RUX for 0-3 days on a background of SS and will receive apraglutide SC once weekly for 8 or 13 weeks. In addition to N=30 subjects (based on three weight bands) randomized to receive low- or high-dose apraglutide SC once weekly for 8 or 13 weeks, a separate non-randomized cohort of up to 4 subjects weighing 40.0-49.9 kg will be assigned to receive apraglutide 2.5 mg. All subjects will complete a safety follow-up visit at week 17 (120 (± 7) days) after the first dose of study drug. Safety and efficacy follow-up assessments will continue for 2 years (week 104) after the first dose of apraglutide.

[0335] The primary objective is to evaluate the safety and tolerability of apraglutide in subjects with SR GI-aGVHD of the mid-lower GI tract treated with SS and RUX for days 0-3.The primary efficacy endpoint is to evaluate the gastrointestinal-aGVHD response at day 56 in subjects with GI-aGVHD treated with apraglutide, SS, and RUX compared with SS and RUX alone.

[0336] The foregoing discussion discloses and describes only exemplary embodiments of the present disclosure. Those skilled in the art will readily recognize from such discussion and the accompanying drawings and claims that various changes, modifications, and variations can be made therein without departing from the spirit and scope of the present disclosure, as defined in the following claims.

[0337] Sequence Listing The details of one or more embodiments of the present disclosure are described in the attached description above. Although any method and material similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred method and material are described here. Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In this specification and the appended claims, the singular form includes plural references unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference.

[0338] The foregoing description has been presented for illustrative purposes only and is not intended to be limiting to the precise form of the disclosure, but is contemplated by the claims appended hereto.

Claims

1. A pharmaceutical composition comprising apraglutide or a pharma- ceutical acceptable salt thereof for use in a method for treating or preventing graft-versus-host disease (GvHD) in a subject.

2. The pharmaceutical composition according to claim 1 , wherein the GvHD is acute GvHD.

3. The pharmaceutical composition according to claim 1 or 2, wherein the GvHD is acute gastrointestinal GvHD.

4. The pharmaceutical composition according to claim 1 , wherein the GvHD is chronic GvHD.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the GvHD is steroid-resistant.

6. The pharmaceutical composition according to any one of claims 1 to 4, wherein the GvHD is steroid-naive.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the GvHD is grade II to IV GvHD according to the MAGIC scale.

8. The apraglutide or a pharma- ceutical acceptable salt thereof is (a) the subject is before being transplanted; or (b) the pharmaceutical composition according to any one of claims 1 to 7, wherein the composition is administered to the subject before the subject is administered radiation therapy, chemotherapy, or radiation-like therapy in connection with a transplant.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the subject has already been transplanted, and preferably the apraglutide or a pharma- ceutically acceptable salt thereof is administered to the subject after the subject has been transplanted.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the subject has already been administered radiation therapy, chemotherapy, radiation-like therapy or any combination thereof in connection with transplantation, and preferably the apraglutide or a pharma- ceutical acceptable salt thereof is administered to the subject after the subject has been administered radiation therapy, chemotherapy, radiation-like therapy or any combination thereof.

11. The pharmaceutical composition of any one of claims 1 to 10, wherein the apraglutide or a pharma- ceutically acceptable salt thereof is administered to the subject after the subject has been administered radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof, and before the subject is transplanted.

12. The apraglutide or a pharma- ceutical acceptable salt thereof is (a) simultaneously with transplantation; or (b) The pharmaceutical composition according to any one of claims 1 to 11, which is administered to the subject simultaneously with radiation therapy, chemotherapy, radiation-like therapy, or any combination thereof in connection with the transplant.

13. The administration of apraglutide or a pharma- ceutical acceptable salt thereof, (a) transplantation; (b) preventing and / or attenuating the loss of colon length in a subject following conditioning therapy and transplantation.

14. The transplant comprises hematopoietic stem cells derived from bone marrow, peripheral blood, umbilical cord blood or any combination thereof, preferably the transplant comprises T cells, preferably The pharmaceutical composition according to any one of claims 8 to 13, wherein the T cells are chimeric antigen receptor (CAR) T cells.

15. The pharmaceutical composition according to any one of claims 8 to 14, wherein the radiation therapy comprises total body irradiation.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the pharma- ceutically acceptable salt of apraglutide is a sodium salt of apraglutide.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the apraglutide or a pharma- ceutically acceptable salt thereof is administered by subcutaneous injection.

18. The pharmaceutical composition of any one of claims 1 to 17, wherein the apraglutide or a pharma- ceutically acceptable salt thereof is administered in an amount of about 1 mg to about 10 mg.

19. The pharmaceutical composition of any one of claims 1 to 18, wherein the apraglutide or a pharma- ceutically acceptable salt thereof is administered in an amount of about 2.5 mg, about 5 mg or about 10 mg.

20. (a) the subject has a body weight of less than about 50 kg and the apraglutide is administered in an amount of about 2.5 mg; (b) the subject has a body weight of about 50 kg to about 60 kg and the apraglutide is administered in an amount of about 2.5 mg or about 5 mg; (c) the subject has a body weight of about 60 kg to about 80 kg and the apraglutide is administered in an amount of about 4 mg or about 7.5 mg; or (d) The pharmaceutical composition of any one of claims 1 to 19, wherein the subject has a body weight of more than about 80 kg and the apraglutide is administered in an amount of about 5 mg or about 10 mg.

21. The transplantation (a) allogeneic transplantation; or (b) The pharmaceutical composition according to any one of claims 1 to 20, which is an autologous transplant.

22. The pharmaceutical composition according to any one of claims 1 to 21, wherein the subject has already been administered at least one anti-GvHD therapy, preferably wherein the at least one anti-GvHD therapy comprises a steroid therapy.

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