Methods of removal of pathogenic proteins

Abstract

Provided is a method of treating a disease susceptible to a response by reducing the level of a pathogenic protein, comprising subcutaneously administering to a subject in need of such treatment a therapeutically effective amount of a degrader having affinity for (i) an asialoglycoprotein (ASGPR) receptor of hepatocytes expressed in the subject's liver, and (ii) the pathogenic protein. Also provided is a method of reducing the level of a pathogenic protein in a subject by administering the degrader.

Description

METHODS OF REMOVAL OF PATHOGENIC PROTEINSFIELD OF THE INVENTION

[0001] The invention relates to treatment of diseases mediated by pathogenic proteins. More specifically, the invention is related to treatment of diseases susceptible to a response by reducing the level of pathogenic proteins using degraders, e.g., molecular degraders such as bifunctional molecular degraders.BACKGROUND OF THE INVENTION

[0002] Increased levels of circulating pathogenic proteins can be a contributing factor in the progression of various oncological, immune mediated and other diseases. While certain classes of drugs are currently available in the field, there is a need for new medicines that can effectively treat or delay the progression of the disease.SUMMARY OF THE INVENTION

[0003] The invention is directed to treatment of diseases susceptible to a response by reducing the level of a pathogenic protein in a subject in need of such treatment.

[0004] The subcutaneous delivery of bifunctional degraders was found to be unexpectedly superior to their intravenous administration by providing rapid and sustainable reductions of pathogenic immunoglobulins. This observation was found to be consistent across several bifunctional degrader classes and species. We have found, quite surprisingly, that the adsorption of degraders may occur via diffusion first into the lymphatic circulation with subsequent delivery into venous and ultimately systemic circulations. By virtue of the present invention, it is now possible to allow early saturation of the degrader binding sites with immunoglobulin. We have discovered that lymphatic flows from a subcutaneous injection site and antibody target can direct a degrader and degrader target, relatively undiluted, to a common anatomic confluence for admixing and high affinity before systemic dissemination. This directed, target-mediated drug disposition can promote the delivery of the immunoglobulin-laden degrader to hepatic ASGPR with high efficiency, thereby reducing "first-pass" of drug unbound by target being cleared by the liver. In addition, we have found that a desirable free molar excess of the degrader can be disseminated into venus circulation by regulating the molar excess of the degrader in the extravascular system, e.g., lymphatics, thereby permitting intravascular binding of immunoglobulin.

[0005] In one embodiment, the invention provides a composition of matter, or compound, e.g., a bifunctional degrader, for use in reducing the level of a pathogenic protein in a subject. This use includes contacting the bifunctional degrader with a component of the subject's extravascular system, where the bifunctional degrader has an affinity for (i) an asialoglycoprotein (ASGPR) receptor of hepatocytes expressed in the subject's liver, and (ii) the pathogenic protein, in an amount effective to promote the reduction in the level of the pathogenic protein in the subject. In related embodiment, the invention provides a method of reducing the level of a pathogenic protein in a subject by contacting the pathogenic protein with the bifunctional degrader in an amount of the bifunctional degrader effective to promote the reduction in the level of the pathogenic protein in the subject. This method may further comprise the step of assaying the subject to determine that subcutaneous administration of the composition of matter is advantageously reducing the level of a pathogenic protein in a subject. The reduction in the level of the pathogenic protein in the subject after the administration of the bifunctional degrader to the subject can be 10% or greater, 20% or greater, 30% or greater, 40% or greater, 50% or greater, 60% or greater, 70% or greater, 80% or greater, or 90% or greater.

[0006] In another embodiment, the invention provides a composition of matter (a bifunctional degrader) for use in treating a disease susceptible to a response by reducing the level of a pathogenic protein. This use includes subcutaneously administering to a subject in need of such treatment a therapeutically effective amount of a bifunctional degrader having affinity for (i) an asialoglycoprotein (ASGPR) receptor of hepatocytes expressed in the subject's liver, and (ii) the pathogenic protein. In related embodiment, the invention provides a method of treating a disease susceptible to a response by reducing the level of a pathogenic protein by subcutaneously administering to a subject a therapeutically effective amount of the bifunctional degrader. This method may further comprise the step of assaying the subject to determine that subcutaneous administration of the composition of matter is advantageously treating the disease susceptible to a response by reducing the level of a pathogenic protein. The reduction in the level of the pathogenic protein in the subject after the administration of the bifunctional degrader to the subject can be 10% or greater, 20% or greater, 30% or greater, 40% or greater, 50% or greater, 60% or greater, 70% or greater, 80% or greater, or 90% or greater.

[0007] In still another embodiment, the invention provides a composition of matter (a bifunctional degrader) for use in reducing the level of a pathogenic protein in a subject. This use includes administering to the subject a bifunctional degrader having affinity for (i) an asialoglycoprotein (ASGPR) receptor of hepatocytes expressed in the subject's liver, and (ii) the pathogenic protein, in an amounteffective to promote the reduction in the level of the pathogenic protein in the subject, to provide the pharmacodynamics / pharmacokinetics ratio (EC50 / AUC) measured 7-14 days after administration is at least 1.0-1.8 for a monovalent degrader and 1.5-3.0 for a bivalent degrader. In a related embodiment, the invention provides a method for reducing the level of a pathogenic protein in a subject by administering to the subject the bifunctional degrader in an amount effective to promote the reduction in the level of the pathogenic protein in the subject, to provide the pharmacodynamics / pharmacokinetics ratio (EC50 / AUC). This method may further comprise the step of assaying the subject to determine that subcutaneous administration of the composition of matter is advantageously reducing the level of a pathogenic protein in the subject. For example, the measured pharmacodynamics / pharmacokinetics ratio for a monovalent degrader (EC50 / AUC) for an IgG species of 7-14 days after administration may be at least 1.0-1.8, for example, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least, 1.5, at least 1.6, at least 1.7, or at least 1.8. For example, the measured pharmacodynamics / pharmacokinetics ratio for a bivalent degrader (EC50 / AUC) for an IgG species of 7-14 days after administration may be at least 1.5-3.0, for example, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2.0, at least 2.1, at least 2.2, at least 2.3, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, or at least 3.0. In an embodiment, the pathogenic protein may be a pathogenic IgG species. In another embodiment, the pathogenic protein may be a pathogenic IgA species, such as Gd-lgAl. In another embodiment, the pathogenic protein may be a pathogenic IgD species. In another embodiment, the pathogenic protein may be a pathogenic IgE species. In another embodiment, the pathogenic protein may be a pathogenic IgM species. In an embodiment, a single SC dose of 500 mg a molecular degrader may achieve a sustained lowering of the pathogenic protein of at least 60% for 10 days.

[0008] In yet another embodiment, the invention provides a composition of matter (a bifunctional degrader) for use in treating a disease in a subject. This use includes administering to the subject bifunctional degrader having affinity for (i) an ASGPR receptor of hepatocytes expressed in the subject's liver, and (ii) the pathogenic protein, in an amount effective to promote the reduction in the level of the pathogenic protein in the subject, said administration being conducted in (a) a first step wherein the bifunctional degrader is administered intravenously, and (b) a second step wherein the bifunctional degrader is administered by a modality other than intravenously. In a related embodiment, the invention provides a method for treating a disease in a subject by administering the bifunctional degrader to the subject in an amount effective to promote the reduction in the level of the pathogenic protein in the subject, said administration being conducted in (a) a first step wherein the bifunctionaldegrader is administered intravenously, and (b) a second step wherein the bifunctional degrader is administered by a modality other than intravenously. This method may further comprise the step of assaying the subject to determine that subcutaneous administration of the composition of matter is advantageously treating the disease in the subject.

[0009] The invention also provides for the subcutaneous use of bifunctional degraders of proteins ("MODE®"). In one embodiment, the invention provides for treating a disease susceptible to a response by reducing the level of a pathogenic protein, comprising subcutaneously administering to a subject in need of such treatment a therapeutically effective amount of a bifunctional degrader having affinity for (i) an asialoglycoprotein (ASGPR) receptor of hepatocytes expressed in the subject's liver, and (ii) the pathogenic protein. This use or method may further comprise the step of assaying the subject to determine that subcutaneous administration of the composition of matter is advantageously treating the disease susceptible to a response by reducing the level of a pathogenic protein. The reduction in the level of the pathogenic protein in the subject after the administration of the bifunctional degrader to the subject can be 10% or greater, 20% or greater, 30% or greater, 40% or greater, 50% or greater, 60% or greater, 70% or greater, 80% or greater, or 90% or greater.

[0010] In another embodiment, the bifunctional degrader is administered by the subject or patient using and autoinjector.

[0011] In one aspect, the subcutaneous use of MoDE™ degraders provides for the use of a precision tool to rapidly, profoundly, and selectively target the pathogenesis of the disease itself rather than the patient's entire immune system, and which can be administered in the comfort of the patient's own home. MoDE degraders target a class of proteins implicated in pathogenesis of disease.

[0012] In another embodiment of this method, the bifunctional degrader has a chemical formula selected from the Markush group of Chemical formula (I), Chemical formula (II), and Chemical formula (HI):Chemical Formula (III) wherein in Chemical Formulas (I), (II), and (III), R2is NHC(=O)CH3; R5is CH2OH; the Pathogenic Protein Targeting Ligand is a ligand having affinity to the pathogenic protein; Linker* is a chemical group that connects the ASGPR ligand to Linker6, Linker6, or Linker0; Linker6is a chemical group that connects Linker* to the Pathogenic Protein Targeting Ligand; Linker6is a chemical group that connects Linker6to the Pathogenic Protein Targeting Ligand; and Linker0is a chemical group that connects Linker* to the Pathogenic Protein Targeting Ligand. In still another embodiment, Linker*, Linker6, Linker6, and Linker0are as they are defined in International Patent Publication WO 2021 / 155317.

[0013] In another embodiment of this use or method of treating a disease, the bifunctional degrader has the following general chemical structure:wherein [CPBM] is a Pathogenic Protein Binding Moiety which binds to pathogenic forms of a pathogenic protein as identified herein, which are related to and / or mediate a disease state and / or condition and is to be removed by the action of hepatocytes or other cells on the circulating protein (the compounds preferably selectively binding to the IgG in plasma of the subject or patient); [CRBM] is a Cellular Receptor Binding Moiety, preferably an [ASGPRBM] group, which is a binding moiety which binds to hepatocytes or other cells through asialoglycoprotein receptors or other receptors as identified herein which are on the surface of hepatocytes and other degrading cells, preferably in a patient or subject; each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [CRBM] or connects the [LINKER] to [CPBM] or to [CRBM] and [LINKER] is a chemical moiety having a valency from 1 to 15 which covalently attaches to one or more [CRBM] and / or [CPBM] group, optionally through a [CON], including a [MULTICON] group, wherein said [LINKER] optionally itself contains one or more [CON] or [MULTICON] group(s); k' is an integer from 1 to 15; j' is an integer from 1 to 15; h and h' are each independently an integer from 0 to 15; i is an integer from 0 to 15; with the proviso that at least one of h, h' and i is at least 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. In still another embodiment, [CPBM], [CON], [LINKER], and [CRBM] are as they are defined in International Patent Publication WO 2019 / 199634.

[0014] In another embodiment of this use or method of treating a disease, the bifunctional degrader of a pathogenic protein is an Immunoglobulin G ("IgG") degrader.

[0015] In still another embodiment, the IgG degrader has the following structure, FCIII-GN3, as shown in FIG. 15:or a pharmaceutically acceptable salt thereof. FCIII-GN3 is a small molecule MoDE degrader in development for the treatment of IgG mediated disease, such as Graves' Disease. FCIII-GN3 is designed for self-administration via an easy-to-use and patient-friendly autoinjector.

[0016] In still another embodiment, the IgG degrader has the following structure, as shown in FIG. 16:or a pharmaceutically acceptable salt thereof.

[0017] In still another embodiment, the IgG degrader has the following structure, as shown in FIG.Y1-.or a pharmaceutically acceptable salt thereof.

[0018] In still another embodiment, the IgG degrader has the following structure, as shown in FIG.18:or a pharmaceutically acceptable salt thereof.

[0019] The invention also provides for the subcutaneous use of bifunctional degraders of proteins ("TRAP™"). In one embodiment, the invention provides for treating a disease susceptible to a response by reducing the level of a pathogenic protein, comprising subcutaneously administering to a subject in need of such treatment a therapeutically effective amount of a bifunctional degrader having affinity for (i) an asialoglycoprotein (ASGPR) receptor of hepatocytes expressed in the subject's liver, and (ii) the pathogenic protein. This use or method may further comprise the step of assaying the subject todetermine that subcutaneous administration of the composition of matter is advantageously treating the disease susceptible to a response by reducing the level of a pathogenic protein. In another embodiment of the use or method of reducing the level of a pathogenic protein, the reduction in the level of the pathogenic protein in the subject is 10% or greater, 20% or greater, 30% or greater, 40% or greater, 50% or greater, 60% or greater, 70% or greater, 80% or greater, or 90% or greater.

[0020] In one aspect, the subcutaneous use of TRAP degraders provides for the use of a precision tool to rapidly, profoundly, and selectively target the pathogenesis of the disease itself rather than the patient's entire immune system, and which can be administered in the comfort of the patient's own home. The TRAP degraders remove specific aberrant disease-causing proteins and leave the healthy components of the immune system intact. For example, COMPOUND l is a precision tool that removes only the entity that causes disease, then degrade IgA more profoundly, rapidly, and potentially without the off-target effects of less precise therapies.

[0021] In another embodiment of this use or method of treating a disease, the bifunctional degrader of a pathogenic protein is a degrader of galactose-deficient Immunoglobulin A ("Gd-lgA").

[0022] In still another embodiment, the Gd-lgA degrader has the following structure, COMPOUND1, as shown in FIG. 19:or a pharmaceutically acceptable salt thereof.

[0023] In another embodiment of this use or method of treating a disease, the bifunctional degrader of a pathogenic protein is a degrader of a nti-PiECI I autoantibodies. In still another embodiment, the bifunctional degrader of anti-0iECII autoantibodies has the following structure, COMPOUND 2, as shown in FIG. 20, or a pharmaceutically acceptable salt thereof.

[0024] In another embodiment of this use or method of treating a disease, the bifunctional degrader of a pathogenic protein is an Immunoglobulin E ("IgE") degrader. In another embodiment, the bifunctional degrader of a pathogenic protein is an Immunoglobulin M ("IgM") degrader.

[0025] In one embodiment, the invention provides a bifunctional degrader for use in reducing the level of a pathogenic protein in a subject, comprising subcutaneously administering to the subject a therapeutically effective amount of a bifunctional degrader of a pathogenic protein. This use or method may further comprise the step of assaying the subject to determine that subcutaneous administration of the bifunctional degrader is advantageously treating the disease susceptible to a response by reducing the level of a pathogenic protein, i.e., that the bifunctional degrader is being administered in a therapeutically effective amount. In another embodiment of the use or method of reducing the level of a pathogenic protein, the reduction in the level of the pathogenic protein in the subject is 10% or greater, 20% or greater, 30% or greater, 40% or greater, 50% or greater, 60% or greater, 70% or greater, 80% or greater, or 90% or greater.

[0026] In another embodiment of this use or method of reducing the level of a pathogenic protein, the bifunctional degrader of a pathogenic protein is an IgG degrader. In still another embodiment, the IgG degrader is FCIII-GN3, with the structure as shown in FIG. 15, or a pharmaceutically acceptable salt thereof.

[0027] In still another embodiment, the IgG degrader has structure as shown in FIG. 16, or a pharmaceutically acceptable salt thereof.

[0028] In still another embodiment, the IgG degrader has the structure as shown in FIG. 17, or a pharmaceutically acceptable salt thereof.

[0029] In still another embodiment, the IgG degrader has the structure as shown in FIG. 18, or a pharmaceutically acceptable salt thereof.

[0030] In another embodiment of this use or method of reducing the level of a pathogenic protein, the bifunctional degrader of a pathogenic protein is a degrader of galactose-deficient Immunoglobulin A ("Gd-lgA")

[0031] In still another embodiment, the Gd-lgA degrader has the structure as shown in FIG. 19, or a pharmaceutically acceptable salt thereof.

[0032] In another embodiment of this use or method of reducing the level of a pathogenic protein, the bifunctional degrader of a pathogenic protein is a degrader of anti-0iECII autoantibodies.

[0033] In another embodiment of this use or method of reducing the level of a pathogenic protein, the bifunctional degrader of anti-0iECII autoantibodies has the structure shown in FIG. 20, or a pharmaceutically acceptable salt thereof.

[0034] In another embodiment of this use or method of reducing the level of a pathogenic protein, the bifunctional degrader of a pathogenic protein is an Immunoglobulin E ("IgE") degrader. In another embodiment, the bifunctional degrader of a pathogenic protein is an Immunoglobulin M ("IgM") degrader.

[0035] The invention provides another subcutaneous use of bifunctional degraders of proteins ("MODE®"), for reducing a level of pathogenic protein by contacting a component of extravascular system. In a related embodiment, the invention provides methods of reducing a level of pathogenic protein by contacting a component of extravascular system in an amount effective to promote the reduction in the level of the pathogenic protein in the subject. In another embodiment, the pathogenic protein mediates a disease selected from cancer, a heart disease, an autoimmune disease, or an inflammatory disease. This use or method may further comprise the step of assaying the subject to determine that this subcutaneous administration of the bifunctional degrader is advantageously reducing a level of pathogenic protein by contacting a component of extravascular system in an amount effective to promote the reduction in the level of the pathogenic protein in the subject.

[0036] In another embodiment of the use or method of reducing the level of a pathogenic protein, the pathogenic protein is an aberrant form of immunoglobulin. In still another embodiment, the immunoglobulin is Immunoglobulin A ("IgA"), Immunoglobulin D ("IgD"), Immunoglobulin E ("IgE"), Immunoglobulin G ("IgG"), or Immunoglobulin M ("IgM"). In still another embodiment, the aberrant form of IgA is galactose-deficient Immunoglobulin Al ("Gd-lgA").

[0037] In another embodiment of the use or method of reducing the level of a pathogenic protein, the extravascular system is lymphatic system. In still another embodiment, the component of the lymphatic system is lymph, a lymphatic vessel, a lymph node, and a lymphoid organ. In still another embodiment, the lymphoid organ is thymus, spleen, a tonsil, bone marrow, or Peyer's patch.

[0038] In another embodiment of the use or method of reducing the level of a pathogenic protein, the bifunctional degrader has a chemical formula selected from the Markush group of Chemical formula(I), Chemical formula (II), and Chemical formula (III), as described above; wherein in chemical formulas (I), (II), and (III), R2is NHC(=O)CH3; R5is CH2OH; the Pathogenic Protein Targeting Ligand is a ligand having affinity to the pathogenic protein; LinkerAis a chemical group that connects the ASGPR ligand to Linker6, Linker6, or Linker0; Linker6is a chemical group that connects LinkerAto the Pathogenic Protein Targeting Ligand; Linker6is a chemical group that connects Linker6to the Pathogenic Protein Targeting Ligand; and Linker0is a chemical group that connects LinkerAto the Pathogenic Protein Targeting Ligand. In still another embodiment, LinkerA, Linker6, Linker6, and Linker0are as they are defined in International Publication WO 2021 / 155317.

[0039] In another embodiment of the use or method of reducing the level of a pathogenic protein, the bifunctional degrader has the following general chemical structure:as described in greater detail above. In still another embodiment, [CPBM], [CON], [LINKER], and [CRBM] are as they are defined in International Publication WO 2019 / 199634.

[0040] In another embodiment of the use or method of reducing the level of a pathogenic protein, the bifunctional degrader is administered to the subject before contacting the component of the subject's extravascular system. In still another embodiment, the administration is subcutaneous. In still another embodiment, the administration is transdermal. In still another embodiment, the administration is intramuscular.

[0041] In another embodiment of the use or method of reducing the level of a pathogenic protein, the reduction in the level of the pathogenic protein in the subject is 10% or greater, 20% or greater, 30% or greater, 40% or greater, 50% or greater, 60% or greater, 70% or greater, 80% or greater, or 90% or greater.

[0042] In another embodiment of the use or method of reducing the level of a pathogenic protein, the reduction in the level of the pathogenic protein is sustained for at least ten hours, at least twenty hours, at least thirty hours, at least forty hours, at least 50 hours, at least 60 hours, at least 70 hours, at least 80 hours, at least 90 hours, or at least 100 hours following the administration.

[0043] In another embodiment of the use or method of reducing the level of a pathogenic protein, the bifunctional degrader is an IgG degrader.

[0044] In still another embodiment, the IgG degrader is FCIII-GN3, with the structure as shown in FIG. 15, or a pharmaceutically acceptable salt thereof.

[0045] In still another embodiment, the IgG degrader has the structure as shown in FIG. 16, or a pharmaceutically acceptable salt thereof.

[0046] In still another embodiment, the IgG degrader has the structure as shown in FIG. 17, or a pharmaceutically acceptable salt thereof.

[0047] In still another embodiment, the IgG degrader has the structure as shown in FIG. 18, or a pharmaceutically acceptable salt thereof.

[0048] In another embodiment of the method of reducing the level of a pathogenic protein, the bifunctional degrader is a degrader of galactose-deficient Immunoglobulin A ("Gd-lgA").

[0049] In still another embodiment, the Gd-lgA degrader has the structure as shown in FIG. 19, or a pharmaceutically acceptable salt thereof.

[0050] In another embodiment of the method of reducing the level of a pathogenic protein, the bifunctional degrader of a pathogenic protein is a degrader of anti-PiECI I autoantibodies.

[0051] In still another embodiment, the bifunctional degrader of anti-PiECI I autoantibodies has the structure shown in FIG. 20, or a pharmaceutically acceptable salt thereof.

[0052] In another embodiment of the use or method of reducing the level of a pathogenic protein, the bifunctional degrader of a pathogenic protein is an Immunoglobulin E ("IgE") degrader. In another embodiment, the bifunctional degrader of a pathogenic protein is an Immunoglobulin M ("IgM") degrader.

[0053] The invention also provides another use of bifunctional degraders of proteins ("MODE®"), for reducing levels of pathogenic protein to provide specific pharmacodynamics / pharmacokinetics ratios. This use or method may further comprise the step of assaying the subject to determine that this subcutaneous administration of the bifunctional degrader is advantageously reducing the levels of pathogenic protein to provide the specific pharmacodynamics / pharmacokinetics ratios.

[0054] In an embodiment, the use or method of reducing the level of a pathogenic protein in a subject comprises administering to the subject a bifunctional degrader having affinity for (i) an asialoglycoprotein (ASGPR) receptor of hepatocytes expressed in the subject's liver, and (ii) the pathogenic protein, in an amount effective to promote the reduction in the level of the pathogenic protein in the subject, to provide the pharmacodynamics / pharmacokinetics ratio (EC50 / AUC) measured 7-14 days after administration is at least 1.0-1.8 for a monovalent degrader and 1.5-3.0 for a bivalent degrader.

[0055] In another embodiment of the use or method of reducing the level of a pathogenic protein, the administration is subcutaneous. In another embodiment, the administration is transdermal. In another embodiment, the administration is intramuscular.

[0056] In another embodiment of the use or method of reducing the level of a pathogenic protein, the bifunctional degrader has a chemical formula selected from the Markush group of Chemical Formula (I), Chemical Formula (II), and Chemical Formula (III), as described above; wherein in Chemical Formulas (I), (II), and (III), R2is NHC(=O)CH3; R5is CH2OH; the Pathogenic Protein Targeting Ligand is a ligand having affinity to the pathogenic protein; Linker* is a chemical group that connects the ASGPR ligand to Linker6, Linker6, or Linker0; Linker6is a chemical group that connects Linker* to the Pathogenic Protein Targeting Ligand; Linker6is a chemical group that connects Linker6to the Pathogenic Protein Targeting Ligand; and Linker0is a chemical group that connects Linker* to the Pathogenic Protein Targeting Ligand. In still another embodiment, Linker*, Linker6, Linker6, and Linker0are as they are defined in International Publication WO 2021 / 155317.

[0057] In another embodiment of the use or method of reducing the level of a pathogenic protein, the bifunctional degrader has the following general chemical structure:as described in greater detail above. In still another embodiment, [CPBM], [CON], [LINKER], and [CRBM] are as they are defined in International Publication WO 2019 / 199634.

[0058] In another embodiment of the method of reducing the level of a pathogenic protein, the bifunctional degrader is an IgG degrader.

[0059] In still another embodiment, the IgG degrader is FCIII-GN3, with the structure as shown in FIG. 15, or a pharmaceutically acceptable salt thereof.

[0060] In still another embodiment, the IgG degrader has the structure as shown in FIG. 16, or a pharmaceutically acceptable salt thereof.

[0061] In still another embodiment, the IgG degrader has the structure as shown in FIG. 17, or a pharmaceutically acceptable salt thereof.

[0062] In still another embodiment, the IgG degrader has structure as shown in FIG. 18, or a pharmaceutically acceptable salt thereof.

[0063] In another embodiment of the method of reducing the level of a pathogenic protein, the bifunctional degrader is a degrader of galactose-deficient Immunoglobulin A ("Gd-lgA").

[0064] In still another embodiment, the Gd-lgA degrader has the structure as shown in FIG. 19, or a pharmaceutically acceptable salt thereof.

[0065] In another embodiment of the method of reducing the level of a pathogenic protein, the bifunctional degrader of a pathogenic protein is a degrader of anti-0iECII autoantibodies.

[0066] In still another embodiment, the bifunctional degrader of anti-0iECII autoantibodies has the structure shown in FIG. 20, or a pharmaceutically acceptable salt thereof.

[0067] In another embodiment of the method of reducing the level of a pathogenic protein, the bifunctional degrader of a pathogenic protein is an Immunoglobulin E ("IgE") degrader. In another embodiment, the bifunctional degrader of a pathogenic protein is an Immunoglobulin M ("IgM") degrader.

[0068] The invention provides for reducing levels of pathogenic protein by administering a bifunctional degrader using different modalities. This use or method may further comprise the step of assaying the subject to determine that this subcutaneous administration of the bifunctional degrader is advantageously reducing levels of pathogenic protein by the modality.

[0069] In one embodiment, the use or method of treating a disease in a subject, comprising administering to the subject a bifunctional degrader having affinity for (i) an ASGPR receptor of hepatocytes expressed in the subject's liver, and (ii) the pathogenic protein, in an amount effective to promote the reduction in the level of the pathogenic protein in the subject. The administration is conducted in (a) a first step wherein the degrader is administered intravenously, and (b) a second step wherein the degrader is administered by a modality other than intravenously.

[0070] In another embodiment of the use or method of treating a disease, the pathogenic protein mediates a disease selected from cancer, a heart disease, an autoimmune disease, or an inflammatory disease. This use or method may further comprise the step of assaying the subject to determine that this subcutaneous administration of the bifunctional degrader is advantageously reducing levels of the specific pathogenic protein.

[0071] In another embodiment of the use or method of treating a disease, the pathogenic protein is an aberrant form of immunoglobulin.

[0072] In still another embodiment, the immunoglobulin is Immunoglobulin A ("IgA"), Immunoglobulin D ("IgD"), Immunoglobulin E ("IgE"), Immunoglobulin G ("IgG"), or Immunoglobulin M ("IgM"). In still another embodiment, the aberrant form of IgA is galactose-deficient Immunoglobulin A ("Gd-lgA").

[0073] In another embodiment of the use or method of treating a disease, in the second step, the bifunctional degrader is administered subcutaneously. In another embodiment of the method of treating a disease, in the second step, the degrader is administered transdermally. In another embodiment, in the second step, the degrader is administered intramuscularly.

[0074] In another embodiment of the use or method of treating a disease, the bifunctional degrader has a chemical formula selected from the Markush group of Chemical formula (I), Chemical formula (II), and Chemical formula (III), as described above; wherein in chemical formulas (I), (II), and (III), R2is NHC(=O)CH3; R5is CH2OH; the Pathogenic Protein Targeting Ligand is a ligand having affinity to the pathogenic protein; LinkerAis a chemical group that connects the ASGPR ligand to Linker6, Linker6, or Linker0; Linker6is a chemical group that connects LinkerAto the Pathogenic Protein Targeting Ligand;Linker6is a chemical group that connects Linker6to the Pathogenic Protein Targeting Ligand; and Linker0is a chemical group that connects LinkerAto the Pathogenic Protein Targeting Ligand. In still another embodiment, LinkerA, Linker6, Linker6, and Linker0are as they are defined in International Publication WO 2021 / 155317.

[0075] In another embodiment of the method of treating a disease, the bifunctional degrader has the following general chemical structure:as described in greater detail above. In still another embodiment, [CPBM], [CON], [LINKER], and [CRBM] are as they are defined in International Publication WO 2019 / 199634.

[0076] In another embodiment of the method of treating a disease, the bifunctional degrader is an IgG degrader.

[0077] In still another embodiment, the IgG degrader is FCIII-GN3, with the structure as shown in FIG. 15, or a pharmaceutically acceptable salt thereof.

[0078] In still another embodiment, the IgG degrader has the structure as shown in FIG. 16, or a pharmaceutically acceptable salt thereof.

[0079] In still another embodiment, the IgG degrader has the structure as shown in FIG. 17, or a pharmaceutically acceptable salt thereof.

[0080] In still another embodiment, the IgG degrader has structure as shown in FIG. 18, or a pharmaceutically acceptable salt thereof.

[0081] In another embodiment of the method of treating a disease, the bifunctional degrader is a degrader of galactose-deficient Immunoglobulin A ("Gd-lgA").

[0082] In still another embodiment, the Gd-lgA degrader has the structure as shown in FIG. 19, or a pharmaceutically acceptable salt thereof.

[0083] In another embodiment of the use or method of treating a disease, the bifunctional degrader of a pathogenic protein is a degrader of a nti-0iECI I autoantibodies.

[0084] In still another embodiment, the bifunctional degrader of anti-0iECII autoantibodies has the structure shown in FIG. 20, or a pharmaceutically acceptable salt thereof.

[0085] In another embodiment of the use or method of treating a disease, the bifunctional degrader of a pathogenic protein is an Immunoglobulin E ("IgE") degrader. In another embodiment, the degrader of a pathogenic protein is an Immunoglobulin M ("IgM") degrader.

[0086] In an aspect, provided is a method of treating a disease susceptible to a response by reducing the level of IgG, comprising subcutaneously administering to a subject in need of such treatment a therapeutically effective amount of a degrader of a pathogenic protein.

[0087] In another aspect, provided is a method of reducing the level of IgG in a subject, the method including subcutaneously administering to the subject a therapeutically effective amount of a degrader of a pathogenic protein.

[0088] Several objects, features, aspects, and advantages of the invention will become more apparent from the following detailed description of embodiments of the invention, along with the accompanying drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0089] For illustration, some embodiments of the invention are shown in the drawings described below. Like numerals in the drawings indicate like elements throughout. The invention is not limited to the precise arrangements, dimensions, and instruments shown.

[0090] FIG. 1 is a line graph showing pharmacodynamic data from FCIII-GN3 treated subjects. The Y axis shows the sum of subclasses IgGl, lgG2, and lgG4 as a percent of baseline (pre-dose). The X axis shows Day 0 to Day 36 on a fixed time scale. The data is shown in the table below.

[0091] FIG. 2 is a line graph showing pharmacodynamic data from FCIII-GN3 treated subjects. The Y axis shows the total IgG percent of the baseline (pre-dose). The X axis shows Day 0 to Day 36 on a fixed time scale. The data is shown in the table below.

[0092] FIG. 3 is a table showing the results of the subcutaneous administration of FCIII-GN3.

[0093] FIG. 4 is a table showing the results of the subcutaneous administration of FCIII-GN3.

[0094] FIG. 5 is a line graph showing the results of the subcutaneous administration of 500 mg of FCIII-GN3. The Y axis shows the total IgG percent of the baseline (pre-dose).

[0095] FIG. 6 is a line graph showing pharmacodynamic data from FCIII-GN3 treated subjects. The Y axis shows the total IgG percent of the baseline (pre-dose). The X axis shows first fifteen days on a continuous scale. The timepoints show means for treatments with >= five observations.

[0096] FIG. 7 is a line graph showing pharmacodynamic data from FCIII-GN3 treated subjects. The Y axis shows the sum of subclasses IgGl, lgG2, and lgG4 as a percent of baseline (pre-dose). The X axis shows Day 0 to Day 36 on a fixed time scale. The data is shown in the table below.

[0097] FIG. 8 is a line graph showing the results of FCIII-GN3 administration, showing the concentration versus time curves after intravenous and subcutaneous doses of 500 mg. This result demonstrates a favorable safety and dose-dependent rapid IgG lowering with a profile suitable for subcutaneous dosing.

[0098] FIG. 9 is a line graph showing the results of FCIII-GN3 administration at 2000 mg weekly. The baseline is the average of Day -1 and Day 1 Pre-dose. For Weeks 1 through 4, the solid dot is the median of the maximal total IgG % change from baseline for the week. The bars show the 25th and 75th percentiles. For more description, see EXAMPLE 1.

[0099] FIG. 10 is a line graph showing the results of FCIII-GN3 administration at 1000 mg and 2000 mg. The baseline is the average of Day -1 and Day 1 pre-dose. The solid dot is the median of the maximal total IgG % change from baseline at each day. The bars show the 25th and 75th percentiles. For more description, see EXAMPLE 1.

[0100] FIG. 11 is a line graph showing the results of FCIII-GN3 administration at 1000 mg and 2000 mg. The graph shows the rapid and deeper IgG reduction, surpassing VYVAGART Hytrulo’ by week 3. The baseline is the average of Day -1 and Day 1 pre-dose. For weeks 1 through 4, the solid dot is the median of the maximal total Ig % change from baseline for the Week and bars represent the 25th and 75th percentiles. For more description, see EXAMPLE 1.

[0101] FIG. 12 is a line graph showing the results of the administration. The baseline is the average of Day -1 and Day 1 pre-dose. The median of the maximal total IgG % change from baseline for the week. The bars represent the 25th and 75th percentiles. For more description, see EXAMPLE 1.

[0102] FIG. 13 is a line graph showing that a single subcutaneous dose of COMPOUND 1 delivers rapid, selective, deep, and sustained removal of Gd-lgAl.

[0103] FIG. 14 is a line graph showing the results of the administration of a 500 mg subcutaneous single dose of COMPOUND 1. The baseline is Day 1, pre-dose. A solid dot is the median Gd-lgAl % change from baseline each day. The bars represent the 25th and 75th percentiles.

[0104] FIG. 15 shows the FCIII-GN3 chemical structure. FCIII-GN3 has a beta-anomeric carbon stereochemistry.

[0105] FIG. 16 shows the COMPOUND 4 chemical structure. COMPOUND 4 has an alpha-anomeric carbon stereochemistry.

[0106] FIG. 17 shows the chemical structure of another IgG degrader.

[0107] FIG. 18 shows the chemical structure of another IgG degrader.

[0108] FIG. 19 shows the COMPOUND 1 structure. COMPOUND 1 has a beta-anomeric carbon stereochemistry.

[0109] FIG. 20 shows the chemical structure of COMPOUND 2.

[0110] FIG. 21 is a line graph showing the Day 1 and Day 10 mean plasma concentration profiles of COMPOUND 4 in male cynomolgus monkeys following twice weekly subcutaneous administration of COMPOUND 4 at 3 mg / kg, 10 mg / kg, and 30 mg / kg for two weeks. The individual and mean plasma concentrations of COMPOUND 4 are illustrated.

[0111] FIG. 22 is a line graph showing the subcutaneous administration of COMPOUND 1 (500 mg single dose) delivers rapid, selective, deep and sustained removal of Gd-lgAl. Solid dots show the mean Gd-lgAl% change from baseline each day and bars represent standard error.

[0112] FIG. 23 is a line graph showing intravenous and subcutaneous COMPOUND 3 Injection (0.77 mg / kg) reduces circulating lgG4 bolus (2 mg / kg intravenous) in nude mice. Mice that received COMPOUND 3 intravenously or subcutaneously fifteen minutes following hlgG4, demonstrated significant hlgG4 depletion compared to hlgG4 only control mice.

[0113] FIG. 24 is a bar graph showing intravenous bolus and subcutaneous COMPOUND 3 Injection reduces circulating lgG4 in nude mice. hlgG4 reduction was further quantified as area under the curve, which showed that COMPOUND 3 intravenous and subcutaneous administration depleted hlgG4 by 71% and 87.3%, respectively, compared to control group. This graph shows potent lgG4-depletion and high subcutaneous bioavailability.

[0114] FIG. 25 is a line graph showing the pharmacokinetics of COMPOUND 3 administration intravenously or subcutaneously (0.77 mg / kg) was detected in the blood plasma up to two hours postinjections.

[0115] FIG. 26 is a line graph showing the pharmacokinetics of COMPOUND 3 after subcutaneous versus intravenous administration (0.77 mg / kg). Subcutaneous bioavailability was calculated using the formula: F=AUC subcutaneous (two hours) / AUC intravenous (two hours), F=71%.

[0116] FIG. 27 is a set of scatter-plot graphs showing the detection of islet autoantibodies in human plasma samples.

[0117] FIG. 28 is a line graph showing TRAP 2-mediated cellular internalization and degradation of proinsulin antibodies. ASGPR-expressing HEK293 cells were incubated for 18 hours with 50 nM fluorescently labeled monoclonal antibodies targeting distinct epitopes of proinsulin and a dose-curve of TRAP 2. Dose-dependent internalization of fluorescent antibody was captured using live-cell imaging.

[0118] FIG. 29 is a bar graph showing TRAP 2-mediated cellular internalization and degradation of proinsulin antibodies. ASGPR-expressing HEK293 cells were incubated for three hours with 100 nM of monoclonal anti-proinsulin antibody number 3 ± 200 nM of TRAP 2 to facilitate ASGPR-mediated internalization. Following internalization, cells were washed of excess antibody and drug and then incubated with fresh medium for up to 24 hours. Throughout the 24-hour period, lysates were collected and analyzed by Western blot with fluorescent anti-human IgG to show lysosomal degradation of anti- proinsulin.

[0119] FIG. 30 is a line graph showing blood glucose levels with TRAP 1 vs TRAP 2.

[0120] FIG. 31 shows the TRAP bioavailability, antibody binding, and antibody clearance. NOD mice were injected with 3 mpk TRAP 2 by subcutaneous or intravenous injection in the pharmacokinetic assay. Nude mice were injected with human insulin antibody conjugated with Alexa Fluor 594 and vehicle (left) or TRAP 2 (right). Livers were removed 30 min after injections. Presence of anti-insulin antibody (red) was observed on hepatic sinusoids. NOD mice were screened for insulin autoantibodies and proinsulin autoantibodies by MSD assay for inclusion in the pharmacodynamics analysis.

[0121] FIG. 32 shows that in the pharmacodynamics analysis, the selected mice were injected with 3 mpk or 8 mpk TRAP 2 by subcutaneous injection.

[0122] FIG. 33 shows TRAP 1 and TRAP 2 Binding to autoantibodies from patients with Type 1 diabetes.DETAILED DESCRIPTION OF THE INVENTION

[0123] The following detailed description is provided to aid those skilled in the biomedical art in practicing the invention. Exemplary embodiments will hereinafter be described in detail. However, these embodiments are only exemplary, and the disclosure is not limited thereto but rather is defined by the scope of the appended claims. Those of ordinary skill in the biomedical art may make modifications and variations in the embodiments described herein without departing from the spirit or scope of the disclosure.

[0124] Accordingly, the embodiments are merely described below, by referring to structures and schemes, to explain aspects of the description.INDUSTRIAL APPLICABILITY

[0125] Subcutaneous administration of IgG degrader FCIII-GN3 has continued to demonstrate rapid, deep, and sustained lowering of total IgG. Clinical data shows that FCIII-GN3 dosed at 2000 mg weekly achieved rapid, deep, and sustained lowering of total IgG, with reductions up to 85%, within sixteen days following a single dose.

[0126] The range of IgG reductions possible with varying FCIII-GN3 doses allows for tunable dosing regimens for acute and chronic disease management, with higher dose levels planned for acute disease management and lower, less frequent dosing planned for chronic disease management.

[0127] Subcutaneous administration of Gd-lgAl degrader COMPOUND 1 achieved rapid, deep, selective, and sustained lowering of Gd-lgAl, differentiating this TRAP degrader from the complement and BLyS / APRIL inhibitor competition. Up to 81% reduction of Gd-lgAl was observed with reductions from baseline sustained for weeks after a single subcutaneous dose administration. COMPOUND 1 offers to bring precision immunology to the treatment landscape of IgAN as it was rationally designed to selectively remove galactose-deficient IgAl (Gd-lgAl), the pathogenic antibody driver of the disease while sparing healthy antibodies IgG, IgA, IgD, IgE, and IgM. Preservation of immunoglobulins, the complement system, and cell-mediated and humoral immunity offers key differentiation against immunosuppressive BLyS / APRIL inhibitors, complement inhibitors, and budesonide.DEFINITIONS

[0128] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the biomedical art. The terminology used in the description is for describing embodiments only and is not intended to be limiting. The terms, such asthose defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

[0129] As used in this application, except as otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application. In instances where a term is not specifically defined herein, that term is given an art- recognized meaning by those of ordinary skill applying that term in context to its use in describing the invention.

[0130] Although the terms first, second, third etc. may be used herein to describe various elements, components, regions, layers, and sections, these elements, components, regions, layers, and sections should not be limited by these terms. These terms are used to distinguish one element, component, region, layer, or section from another element, component, region, layer, or section. Thus, a first element, component, region, layer, or section discussed below could be termed a second element, component, region, layer, or section without departing from the teachings of the embodiments.

[0131] The articles "a" and "an" refer to one or to more than one, i.e., to at least one of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, "an element" means one element or more than one element.

[0132] The term "ABT" as used in this specification means a binding moiety in a composition of interest (agent) that is an antibody, an antibody variant, or an antigen-binding fragment thereof that binds to a sFLTl of interest in a subject or patient.

[0133] The term "active Ingredient" has the United States Food & Drug Administration-provided meaning of any component that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of a human body or an animal body.

[0134] The term "adverse event" (AE) has the United States Food & Drug Administration-provided meaning of any untoward medical occurrence associated with the use of a drug product in humans, whether or not it is considered related to the drug product. An adverse event can occur during the use of a drug product; from overdose of a drug product, whether accidental or intentional; from abuse of a drug product; from discontinuation of the drug product (e.g., physiological withdrawal); and it includes any failure of expected pharmacological action. 21 C.F.R. § 251.2. Adverse events can be coded using a current version of the Medical Dictionary for Regulatory Activities.

[0135] The term "agent" has the biomedical art-recognized meaning of a composition of matter useful for performing a function. Several biomedically useful functions are described in this specification.

[0136] The term "alleviate" has the biomedical art-recognized meaning of a process by which the severity of a sign or symptom of a disorder is reduced. A sign or symptom can be alleviated without being eliminated. The administration of compositions or pharmaceutical compositions of the invention may or can lead to the elimination of a sign or symptom. However, elimination is not required. Effective dosages should be expected to decrease the severity of a sign or symptom.

[0137] The term "analogue" has the biomedical art-recognized meaning of a molecule that is not identical but has analogous functional or structural features. Biochemical modifications could increase the analogue's protease resistance, membrane permeability, or half-life, without altering ligand binding. Insulin analogues are known in the biomedical art, such as the fast-working insulins called rapid-acting insulin.

[0138] The term "and / or" includes any and all combinations of one or more of the associated listed items. The term "or" means "and / or." Expressions such as "at least one of," when preceding a list of elements, modify the entire list of elements and do not modify the individual elements of the list.

[0139] The term "anti-drug antibody (ADA)" has the biomedical art-recognized meaning. Many antidrug antibodies are lgG4 antibodies, such as those in Factor 8 hemophilia.

[0140] The term "anti-galactose-deficient IgAl (Gd-lgAl) antibody" has the biomedical art- recognized meaning of an antibody that selectively binds galactose-deficient IgAl. In several embodiments of the invention, the anti-galactose-deficient IgAl antibody is the published Km55 antibody, a Km55 variant, or an antigen-binding fragment thereof.

[0141] The term "anti-insulin antibody" has the biomedical art-recognized meaning and includes insulin autoantibodies (IAA). Anti-C-peptide antibodies are commercially available. See recombinant mouse anti-c-peptide antibody (CB2931), available from Creative Biolabs, Shirley, NY, USA, product number CBMAB-MD1611-LY. See also Mouse Anti-C-Peptide Monoclonal Antibody (CBFYR0644), available from Creative Biolabs, product number CBMAB-R0644-FY. See also human (chimeric) AntiInsulin Recombinant Antibody (clone mAb49), available from Creative Biolabs, product number FAMAB- 0225WJ. The inventors found that synthetic insulin MoDE have similar affinities to mAb49.

[0142] The term "antigen-binding fragment thereof" has the biomedical art-recognized meaning of (1) a fragment of an intact antibody that binds to the same antigen recognized by the full-length antibody, such as F(ab')2, F(ab)2, Fab', Fab, Fv, sFv, or other fragments consisting of the variable regions,or (2) any synthetic or genetically engineered protein that acts like an antibody by binding to a specific antigen to form a complex. The term antigen-binding portion of an antibody encompasses single-chain antibodies.

[0143] The term "asialoglycoprotein receptor (ASGPR)" has the biomedical art-recognized meaning of lectins, which bind asialoglycoprotein and glycoproteins from which a sialic acid was removed to expose galactose residues. These cellular receptors are located on mammalian hepatocytes and other cells, such as glandular cells of the gallbladder and the stomach. ASGPR removes glycoproteins from circulation.

[0144] The term "at least one of," when preceding a list of elements, modifies the entire list of elements and does not modify the individual elements of the list.

[0145] The term "AT" as used in this specification means a moiety in the composition of matter (agent) that binds to sFLTl of interest in a subject or patient.

[0146] The term "autoimmune disease" is used in this specification to refer to a disease or illness that occurs when the body tissues are attacked by its own immune system. The immune system is a complex organization within the body that is designed normally to "seek and destroy" invaders of the body, including infectious agents. In diseases which are described as autoimmune diseases, MIF levels are often elevated. Embodiments of the invention seek to inhibit or lower elevated MIF levels in patients with autoimmune disease (as well as inflammatory diseases and conditions and cancer) and by decreasing MIF levels, ameliorate many of the symptoms and secondary effects of these disease states and conditions. Examples of autoimmune diseases which often exhibit high expressed levels of MIF including, for example, systemic lupus erythematosus, Sjogren syndrome, Hashimoto thyroiditis, rheumatoid arthritis, juvenile (type 1) diabetes, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, and pulmonary fibrosis, among numerous others.

[0147] The term "binding moiety" has the biomedical art-recognized meaning of a moiety on a binding protein, e.g., an antibody, an antibody variant, or an antigen-binding fragment thereof, that binds to the sFLTl.

[0148] The term "cancer" is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease. Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted removal and to cause thedeath of the patient unless adequately treated. Neoplasms include, without limitation, morphological irregularities in cells in tissue of a subject or host, as well as pathologic proliferation of cells in tissue of a subject, as compared with normal proliferation in the same type of tissue. Neoplasms include benign tumors and malignant tumors (e.g., colon tumors) that are either invasive or noninvasive. Malignant neoplasms (cancer) are distinguished from benign neoplasms in that the former show a greater degree of anaplasia, or loss of differentiation and orientation of cells, and have the properties of invasion and metastasis. Examples of neoplasms or cancers from which the target cell of the invention may be derived include, without limitation, carcinomas (e.g., squamous cell carcinomas, adenocarcinomas, hepatocellular carcinomas, and renal cell carcinomas), particularly those of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, particularly Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, and synovial sarcoma; tumors of the central nervous system, e.g., gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; germ-line tumors, e.g., bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, and melanoma; mixed types of neoplasias, particularly carcinosarcoma and Hodgkin's disease; and tumors of mixed origin, such as Wilms' tumor and teratocarcinomas (Beers and Berkow (eds.), The Merck Manual of Diagnosis and Therapy, 17.sup.th ed. (Whitehouse Station, N.J.; Merck Research Laboratories, 1999) 973-74, 976, 986, 988, 991 ).

[0149] The term "cellular receptor-binding moiety" has the biomedical art-recognized meaning. In several embodiments of this specification, the cellular receptor-binding moiety is an asialoglycoprotein receptor (ASGPR) binding group.

[0150] The term "cellular receptor" has the biomedical art-recognized meaning of a protein on the surface of a cell that binds to a compound, e.g., a ligand, e.g., a protein, in solution or on another cell. Generally, ligand-receptor binding induces one or more biological responses. In this specification, an asialoglycoprotein receptor (ASGPR) is a cellular receptor on the surface of hepatocytes or other cells that binds to an asialoglycoprotein or a derivative thereof.

[0151] The term "chemistry, manufacturing, and controls" (pharmaceutical quality, CMC) has the biomedical art-recognized meaning of the several procedures used to assess the physical and chemical characteristics of drug products, to ensure their quality and consistency during manufacturing, and to prepare data for submissions to regulatory authorities.

[0152] The term "chimerized" has the biomedical art-recognized meaning. Chimeric antibodies are made by fusing variable domains from one species, such as a mouse, with constant domains from another species, such as a human being. With such biotechnical manipulation, chimeric antibodies retain the foreign antibody's antigen specificity and affinity.

[0153] The term "diabetes mellitus" has the biomedical art-recognized meaning. See Wikipedia, the free encyclopedia, Dipeptidyl peptidase-4 inhibitor (online, accessed July 3, 2024). In type 1 diabetes mellitus, the destruction of insulin-producing 0-pancreatic cells results in an inability to control blood glucose levels since insulin signals glucose uptake into cells. Type 1 diabetes mellitus is a systemic disease that can lead to severe complications. Hyperglycemia is a symptom of diabetes. A human diabetic patient is someone whose blood sugar level is elevated or is expected to be elevated, and therefore someone who desires to inhibit from rising or to lower a blood sugar level.

[0154] The term "diabetic macular edema" (DME) has the biomedical art-recognized meaning of a diabetic retinopathy. See Landry et al., Assay Drug Dev. Technol. 11(5), 326-32 (June 2013). Tiny bulges, called microaneurysms, form in the blood vessels, leaking fluid into the retina.

[0155] The term "dilated cardiomyopathy" (DCM) is defined as progressive cardiac dilatation and systolic dysfunction without coronary heart disease. Dilated cardiomyopathies can be caused by a humoral autoimmune response to 01AR. In contrast to ischemic heart failure, dilated cardiomyopathy commonly affects a younger age population with most patients presenting between the ages of twenty to sixty. Dilated cardiomyopathy frequently progresses to severe heart failure and may progress to require mechanical support with left ventricular assist device or heart transplantation.

[0156] The term "DMPK" has the biomedical art-recognized meaning of drug metabolism and pharmacokinetics, which is a discipline that helps identify drugs that are likely to be suitable for further development.

[0157] The term "drug product" has the United States Food & Drug Administration definition described in 21 C.F.R. § 314.3 of a finished dosage form, e.g., tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients.

[0158] The term "drug substance" has the United States Food & Drug Administration definition described in 21 C.F.R. § 314.3 of an active ingredient that is intended to furnish pharmacological activityor other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body but does not include intermediates used in the synthesis of such ingredient.

[0159] The term "EC50" has the biomedical art-recognized meaning of the ligand concentration required to achieve 50% of maximal receptor activation.

[0160] The term "Gal" has the biomedical art-recognized meaning of galactose.

[0161] The term "galactose-deficient IgAl (Gd-lgAl) binding moiety" has the biomedical art- recognized meaning of a moiety on a binding protein, e.g., an IgG antibody or a fragment thereof, that binds to a galactose-deficient IgAl. In some embodiments described in this specification, a "glycan- specific IgG antibody-binding moiety" is a galactose-deficient IgAl binding moiety on an IgG antibody, such as the published Km55 antibody, a Km55 variant, or an antigen-binding fragment thereof.

[0162] The term "GalNAc" has the biomedical art-recognized meaning of N-acetylgalactosamine.

[0163] The term "glomerular mesangium" has the biomedical art-recognized meaning of a component of the kidney glomerulus, forming the supporting framework in which the glomerular tuft capillaries ramify. The mesangium includes an extracellular matrix comprising Type IV collagen, proteoglycans, other proteins, and two cell types.

[0164] The term "GN3" as used in this specification is a tri-aminogalactosyl moiety. Examples are provided in this specification.

[0165] The term "Good Laboratory Practice" (GLP) has the United States Food & Drug Administration-provided meaning. See e.g., 21 C.F.R. Part 58.

[0166] The term "Good Laboratory Practice" has the United States Food & Drug Administration definition described in 21 C.F.R. Part 58, Good Laboratory Practice for Nonclinical Studies.

[0167] The term "hepatocyte has the biomedical art-recognized meaning of a cell of the main parenchymal tissue of the liver. Hepatocytes make up 55-65% of the liver's mass.

[0168] The term "humanized" has the biomedical art-recognized meaning a protein, e.g., an antibody, is genetically engineered so it closely resembles the polypeptide structure of the human homologue. A variable domain of an antibody of rodent origin can be fused to a constant domain of human origin, thus retaining the specificity of the rodent antibody. The human origin domain need not originate directly from a human in that it is first synthesized in a human. Instead, human domains can be generated in rodents whose genome incorporates human immunoglobulin genes. The antibody can be partially or completely humanized. In one approach, there are four general steps used to humanize a monoclonal antibody, These are (1) determining the nucleotide and predicted amino acid sequence ofthe starting antibody light and heavy variable domains; (2) designing the humanized antibody, i.e., deciding which antibody framework region to use during the humanizing process; (3) the actual humanizing methodologies / techniques; and (4) the transfection and expression of the humanized antibody.

[0169] The term "IC5o" has the biomedical art-recognized meaning of an amount, concentration, or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.

[0170] The term "IgA antibody" has the biomedical art-recognized meaning. Two molecules of IgA are joined and associated with a protein that enables the newly formed IgA molecule to be secreted across epithelial cells that line several ducts and organs.

[0171] The term "IgA nephropathy (IgAN)," also known as Berger disease, has the biomedical art- recognized meaning of the most common form of primary glomerulonephritis worldwide. The condition was named based on the pathologic characteristics of IgA deposition in the glomeruli. An estimated 15- 20% of the patients with IgAN progress to end-stage renal disease within 20 years of the disease onset. Kuroyanagi et al., Galactose-deficient IgAl is involved in IgA deposition in renal grafts biopsied one hour after kidney transplantation. Intern Med. (October 26, 2022). The IgA in the mesangial deposits is exclusively from the IgAl subclass and is aberrantly glycosyl with the hinge-region O-linked glycans being deficient in galactose (Gal). The IgAl in the circulation of patients with IgAN also carries Gal-deficient O- glycans, although Gal-deficient variants are rarely found in the IgAl in sera from normal individuals. The production of these variants is due to altered expression of specific glycosyltransferases in the IgAl- producing cells. The binding of IgAl-containing immune complexes with aberrantly glycosylated IgAl to mesangial cells induces the renal manifestations characteristic of IgAN. See Suzuki et al., J. Clin. Invest., 119, 1668-1677 (2009).

[0172] The term "IgG" antibody has the biomedical art-recognized meaning. Each IgG molecule consists of the basic four-chain immunoglobulin structure— two y (gamma) heavy chains and two identical light chains (either kappa or lambda)— and carries two identical antigen-binding sites. There are four subclasses of IgG, each with minor differences in its H chains but with distinct biological properties.

[0173] The term "IgGl" antibody has the biomedical art-recognized meaning of an IgG antibody, where the Ig y-1 chain C region is a protein encoded by the IGHG1 gene in humans.

[0174] The term "lgG2" antibody has the biomedical art-recognized meaning of an IgG antibody where the Ig y-2 chain C region is a protein that in humans is encoded by the IGHG2 gene.

[0175] The term "lgG4" antibody has the biomedical art-recognized meaning of an IgG antibody where the Ig y-4 chain C region is a protein encoded by the IGHG4 gene in humans. lgG4 has little effector function. lgG4 cannot fix complement.

[0176] The term "inflammatory disease" is used in this specification to describe a disease or illness with acute, but more often chronic inflammation as a principal manifestation of the disease or illness. Inflammatory diseases include diseases of neurodegeneration, including, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease; other ataxias, diseases of compromised immune response causing inflammation, e.g., dysregulation of T cell maturation, B cell and T cell homeostasis, counters damaging inflammation, chronic inflammatory diseases including, for example, inflammatory bowel disease, including Crohn's disease, rheumatoid arthritis, lupus, multiple sclerosis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, cystic fibrosis, Sjogren's disease; hyperglycemic disorders, diabetes (1 and II), affecting lipid metabolism islet function and / or structure, pancreatic b-cell death and related hyperglycemic disorders, including severe insulin resistance, hyperinsulinemia, insulin-resistant diabetes, e.g. Mendenhall's Syndrome, Werner Syndrome, leprechaunism, and lipoatrophic diabetes, and dyslipidemia, e.g. hyperlipidemia as expressed by obese subjects, elevated low-density lipoprotein (LDL), depressed high-density lipoprotein (HDL), elevated triglycerides and metabolic syndrome, liver disease, renal disease (apoptosis in plaques, glomerular disease), cardiovascular disease (especially including infarction, ischemia, stroke, pressure overload and complications during reperfusion), muscle degeneration and atrophy, low grade inflammation, gout, silicosis, atherosclerosis and associated conditions such as cardiac and neurological (both central and peripheral) manifestations including stroke, age-associated dementia and sporadic form of Alzheimer's disease, and psychiatric conditions including depression), stroke and spinal cord injury, arteriosclerosis, among others. In these diseases, elevated M1F is very often observed, making these disease states and / or conditions response to therapy using compounds and / or pharmaceutical compositions according to the invention. There is some overlap between certain autoimmune diseases and inflammatory diseases as described herein.

[0177] The term "insulin growth factor" (IGF) has the biomedical art-recognized meaning. Human IGF-1 means comprising the amino acid sequence corresponding to human IGF native to human tissue. Human IGF-1 may include fusion proteins.

[0178] The term "insulin receptor" has the biomedical art-recognized meaning. The insulin receptor has two main subunits, a and p. There is a single disulfide bridge between a and 3 subunits between Cys647 in the insert domain and Cys872 The a subunit contains five main domains, LI (AA 28-174) CR(AA 182-339), and L2 (AA 340-497), and two fibronectin subunits, Fnlll-1 (residue 624-726) and Fn 111-2 (757-842). The two a-subunits are linked by four disulfide bonds. The insulin receptor 0 has different isoforms (IRA isoform and IRB isoform), depending on the gene splicing of exon 11. Insulin receptor B differs from insulin receptor A by including exon 11. The twelve-amino acid sequence (residues 745- 756) derived from exon 11 is present in the insulin receptor B isoform but absent in the insulin receptor A isoform. The isoforms have functionally different internalization and recycling. Insulin receptor A exhibits a greater internalization and recycling rate than insulin receptor B. Insulin receptor A exhibits a higher affinity for IGFs than the IRB isoform. Both isoforms have similar affinity for insulin Binding to these isoforms very different to proinsulin. Insulin receptor B is preferentially associated with metabolic and differentiating signals. Insulin receptor A mainly favors cell growth, proliferation, and survival. See Beneit et al., Cardiovasc. Diabetol., 15, 161 (2016).

[0179] The term "insulin-like growth factor 2" (IGF-2) has the biomedical art-recognized meaning of the well-characterized neutral peptide secreted by the liver to circulate in the blood. IGF-2 has growthregulating, insulin-like and mitogenic activities.

[0180] The term "insulin" has the biomedical art-recognized meaning. Insulin can be produced by chemical synthesis.

[0181] The term "KD" has the biomedical art-recognized meaning of the measured equilibrium dissociation constant between a compound or ligand and a protein or binding domain of a protein.

[0182] The term "Km55" in this specification refers to a group of anti-galactose-deficient IgAl antibodies. In some embodiments, Km55 may be the published Km55 antibody, a Km55 variant, or an antigen-binding fragment thereof. In some embodiments, Km55 may be chimerized, partially humanized, or humanized Km55 variants thereof, or an antigen-binding fragment thereof.

[0183] The term "linker moiety" has the biomedical art-recognized meaning of a moiety of a chemical compound that links one moiety of the chemical compound to another moiety of the same compound.

[0184] The term "Markush group" has the patent law-recognized meaning.

[0185] The term "modality" has the biomedical art-recognized meaning of a method of treatment. See National Cancer Institute's Dictionary of Cancer Terms.

[0186] The term "MoDE" has the proprietary meaning of a degrader platform described in this specification. The MoDE degraders target a class of proteins implicated in pathogenesis of disease. MoDE is a trademark of Biohaven Therapeutics Ltd.

[0187] The term "MoDE" has the proprietary meaning of degraders. See International Pat. Publ. WO 2019 / 199634 (Yale University) and WO 2019 / 199621 (Yale University).

[0188] The term "moiety" has the biomedical meaning of a defined chemical group or entity with a particular structure or activity. A moiety generally refers to a part of a molecule. In some embodiments, a binding moiety maintains one or more desired structural features, properties, functions, or properties, e.g., 3-dimensional structure, antigen specificity, antigen-binding capacity, or immunological functions, etc., comparable to its corresponding binding protein, e.g., an antibody. In some embodiments, a moiety is monovalent. In some embodiments, a moiety is bivalent. In other embodiments, a moiety is polyvalent.

[0189] The term "Multimodal Antibody Therapy Enhancers (MATE or MATES)" has the proprietary meaning. See Inti. Pat. Publ. WO 2021 / 102052 (Kleo Pharmaceuticals).

[0190] The term "Multiple Ascending Dose" (MAD) has the United States Food & Drug Administration-provided meaning. In Phase lb multiple ascending dose studies to investigate the pharmacokinetics and pharmacodynamics of multiple doses of a drug to assess safety and tolerability, a group of patients receives multiple low doses of the drug, while samples (of blood, and other fluids) are collected at various time points and analyzed to acquire information on how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level. See Types and phases of clinical trials. American Cancer Society (August 18, 2020).

[0191] The term "neoplasia" has the biomedical art-recognized meaning of a cancerous disease states and embraces or encompasses the pathological process associated with malignant hematogenous, ascitic and solid tumors.

[0192] The term "on" has the plain meaning. When an element is referred to as being on another element, it can be directly in contact with the other element, or intervening elements may be present therebetween. When an element is referred to as being "directly on" another element, no intervening elements are present.

[0193] The term "or" as used in this specification, includes all combinations of one or more of the associated listed items.

[0194] The term "parenteral" as used in this specification includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

[0195] The term "pathogenic protein" refers to a protein that is capable of causing a disease. It may be a misfolded, abnormal, or aberrant form of protein that can induce disease. Pathogenic proteins may be extracellular or extravascular.

[0196] The term "pharmaceutically acceptable excipient" has the biomedical art-recognized meaning of an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use and human pharmaceutical use. A "pharmaceutically acceptable excipient," as used in the specification and claims, includes both one and more than one such excipient. A thorough discussion of pharmaceutically acceptable excipients is available in Remington's Pharmaceutical Sciences 23rd edition (Elsevier, 2020).

[0197] The term "pharmaceutically acceptable" has the biomedical art-recognized meaning of those compounds, anions, cations, materials, compositions, carriers, or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0198] The term "protein-binding moiety" has the biomedical art-recognized meaning of a region of a chemical composition, e.g., a polypeptide region of a chemical composition, that specifically binds to a protein, e.g., a specific protein.

[0199] The term "ROC" has the biomedical art-recognized meaning of receiver operating characteristic curve.

[0200] The term "Single Ascending Dose" (SAD) has the United States Food & Drug Administration- provided meaning. In Phase la single ascending dose studies, small groups of subjects are given a single dose of a drug, then observed and tested to confirm the drug's safety. See Types and phases of clinical trials. American Cancer Society (August 18, 2020).

[0201] The term "subject" and the term "patient" have the biomedical art-recognized meanings. The term patient includes human and other mammalian subjects that receive either prophylactic or therapeutic treatment.

[0202] The term "TBT" has the biomedical art-recognized meaning of a cellular receptor-binding moiety. In some embodiments of this specification, the TBT binds to ASGPR.

[0203] The term "TRAP" has the meaning described in this specification of an agent for the targeted removal of protein. A TRAP is a bifunctional degrader.

[0204] The term "TRAP" has the proprietary meaning of a degrader platform described in this specification. The TRAP degraders remove specific aberrant disease-causing proteins and leave the healthy components of the immune system intact. For example, COMPOUND 1 is a precision tool that removes only the entity that causes disease, then degrade IgA more profoundly, rapidly, and potentially without the off-target effects of less precise therapies. TRAP is a trademark of Biohaven Therapeutics Ltd.

[0205] The term "treatment-emergent adverse event" is any event that is not present before the initiation of the drug treatment, or any event already present that worsens in either intensity or frequency following exposure to the drug treatment.

[0206] The term "tumor" has the biomedical art-recognized meaning.

[0207] The term "Type 1 diabetes mellitus" has the biomedical art-recognized meaning of a chronic autoimmune disease that occurs when the immune system attacks the pancreas' insulin-producing cells, resulting in the autoimmune eradication of P-cells in pancreatic islets. Insulin can no longer be synthesized or be secreted into the blood. Other autoantibodies directed to islet cells may also be present in Type 1 diabetics.

[0208] The term "Type 2 diabetes mellitus" has the biomedical art-recognized meaning of the progressive loss of insulin receptors Inducing hyperglycemia. Hyperglycemia induces more production of insulin by P-cells to compensate. The accumulation of amyloid in the pancreatic islets likely disrupts islet anatomy and physiology. Eventually, P-cells wear out leading to decreased insulin over time.

[0209] The terms "an effective amount" and "a therapeutically effective amount" have the biomedical art-recognized meaning of an amount effective to achieve its intended purpose. The effect can be detected by any assay method known in the biomedical art. The precise effective amount for a subject depends on the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0210] The terms "comprises" and / or "comprising," or "includes" and / or "including" when used in this specification, specify the presence of stated features, regions, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof.

[0211] The terms "comprises," "comprising," "includes," and "including" specify the presence of stated features, regions, integers, steps, operations, elements, or components but do not preclude thepresence or addition of one or more other features, regions, integers, steps, operations, elements, components, or groups thereof.

[0212] The terms "treating" and "treat" have the biomedical art-recognized meaning of managing and caring for a patient to combat a disease, condition, or disorder. Treating includes administering a composition described in this specification to alleviate the symptoms or complications of a disease, condition, or disorder or to eliminate the disease, condition, or disorder.

[0213] This specification does not concern a process for cloning humans, methods for modifying the germ line genetic identity of humans, uses of human embryos for industrial or commercial purposes, or procedures for modifying the genetic identity of animals likely to cause them suffering with no substantial medical benefit to humans or animals resulting from such processes.

[0214] Additional aspects are set forth in part in the description which follows and should be apparent from the description.INTRODUCTION AND RATIONALE FOR SUBCUTANEOUS ADMINISTRATION

[0215] The degraders of extracellular proteins and targeted removal of aberrant protein degraders according to embodiments of the invention that are delivered by subcutaneous injection offer significantly enhanced immunoglobulin lowering (pharmacodynamic efficacy) compared to intravenous injection. This phenomenon deliberately exploits a novel combination of multiple properties unique to this extracellular degrader platform, to the subcutaneous delivery of biologies, and the production, distribution and recirculation of antibodies in the body, allowing simultaneous removal of intra- and extra-vascular antibody or protein targets. Similarly to many biologies when injected subcutaneously, the adsorption of degraders occurs via diffusion first into the lymphatic circulation with subsequent delivery into venous and ultimately systemic circulations.

[0216] Immunoglobulins are largely produced within lymph nodes and lymphoplasmacytic infiltrates in tissues, draining from lymphatics into the system circulation. Exploiting common disposition of target and drug, subcutaneous administration according to the present invention allows early saturation of MoDE or TRAP binding sites with immunoglobulin. As the majority of the body's lymphatics drain into the thoracic duct, the site of subcutaneous injection and site of antibody production do not require co-location. Both lymphatic flows from injection site and antibody target direct drug and drug target, relatively undiluted, to a common anatomic confluence for admixing and high affinity binding by MoDE or TRAP in the thoracic duct before systemic dissemination. This directed, target-mediated drug disposition (TMDD) can ensure that the immunoglobulin-laden MoDE or TRAP is delivered to hepaticASGPR with maximal efficiency, thereby eliminating any "first-pass" of drug unbound by target being cleared by the liver. Deliberate extravascular targeting of immunoglobulin capture in lymphatics is novel and unprecedented, as is this mechanism for bypassing hepatic first-pass clearance. The combination of these two novel approaches (for drug to capture target and for drug to avoid first pass) has resulted in an unprecedented pharmacodynamic efficiency of subcutaneously delivered MoDE and TRAP degraders.

[0217] The molar excess of drug over antibody concentration in lymphatics ensures a calibrated proportion of unbound drug is also delivered to the blood circulation. This delivery occurs at the confluence of the thoracic lymphatic duct and subclavian vein, whence the drug is disseminated to the systemic circulation, this free molar excess then binding free intravascular immunoglobulin before its ultimate removal by the liver. The dosage of drug is designed to set a molar excess gauged precisely to optimize both lymphatic extravascular and intravascular binding of immunoglobulin and minimize first pass clearance.

[0218] All other classes of therapeutics that reduce immunoglobulin in the circulation do so through removal of the intravascular component with gradual lowering of extravascular immunoglobulin by equilibration of intra- and extra-vascular compartments, or by cytotoxic targeting of plasma cells or their precursor B cells with generalized immunosuppression. Biohaven's MoDE and TRAP degraders, by directly accessing both compartments, demonstrates significantly accelerated kinetics of lowering of pathogenic antibodies, which is expected to result in a commensurate slowing of associated disease processes. B cell targeting therapies or therapies which lower all IgG subclasses have demonstrated immunosuppression with chronic usage. Accelerated efficacy of MoDE and TRAP degraders, courtesy of simultaneous intra and extravascular antibody targeting and depletion, is expected to occur without immunosuppression.

[0219] In an embodiment, the degrader of IgG ("IgG degrader") may have the following general chemical structure:wherein [CPBM] is an IgG Binding Moiety which binds to pathogenic forms of IgG as identified herein, which are related to and / or mediate a disease state and / or condition and is to be removed by the action of hepatocytes or other cells on the circulating protein (the compounds preferably selectively binding to the IgG in plasma of the subject or patient); [CRBM] is a Cellular Receptor Binding Moiety, preferably an[ASGPRBM] group, which is a binding moiety which binds to hepatocytes or other cells through asialoglycoprotein receptors or other receptors as identified herein which are on the surface of hepatocytes and other degrading cells, preferably in a patient or subject; each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [CRBM] or connects the [LINKER] to [CPBM] or to [CRBM] and

[0220] [LINKER] is a chemical moiety having a valency from 1 to 15 which covalently attaches to one or more [CRBM] and / or [CPBM] group, optionally through a [CON], including a [MULTICON] group, wherein said [LINKER] optionally itself contains one or more [CON] or [MULTICON] group(s); k' is an integer from 1 to 15; j' is an integer from 1 to 15; h and h' are each independently an integer from 0 to 15; i is an integer from 0 to 15; with the proviso that at least one of h, h' and i is at least 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0221] Various IgG Binding Moieties [CPBM], Cellular Receptor Binding Moieties [CRBM], and connecting group [LINKER] and [CON] are known in the biomedical art and described, for example, in International Publication No. WO 2019 / 199634 published October 17, 2019, and International Publication No. WO 2019 / 199634 published October 17, 2019, the contents of which publications are incorporated herein in their entireties by reference.

[0222] In an embodiment, the degrader may be a degrader of Immunoglobulin G ("IgG"). In such embodiment, [CPBM] may be an immunoglobulin G binding moiety [IgGBM] having the structure:(v) a peptide moiety selected from the group consisting of PAM; D-PAM; D-PAM-O; TWKTSRISIF (SEQ ID NO: 1); FGRLVSSIRY (SEQ ID NO: 2); Fclll; FcBP-1; FcBP-2; Fc-lll-4c; EPIHRSTLTALL (SEQ ID NO: 3); APAR (SEQ ID NO: 4); FcRM; HWRGWV (SEQ ID NO: 5); HYFKFD (SEQ ID NO: 6); HFRRHL (SEQ ID NO: 7); HWCitGWV (SEQ ID NO: 8); D2AAG; DAAG; cyclo[(N-Ac)S(A)-RWHYFK-Lact-E] (SEQ ID NO: 9); cyclo[(N- Ac)-Dap(A)-RWHYFK-Lact-E] (SEQ ID NO: 10); cyclo[Link-M-WFRHYK] (SEQ ID NO:11); NKFRGKYK (SEQ ID NO: 12); NARKFYKG (SEQ ID NO:13); FYWHCLDE (SEQ ID NO: 14); FYCHWALE (SEQ ID NO:15); FYCHTIDE (SEQ ID NO: 16); RRGW (SEQ ID NO: 17); and KHRFNKD (SEQ ID NO: 18);[CRBM] may be a Cellular Receptor Binding Moiety having the structure:each [CON] may independently be at each occurrence selected from the group consisting of:wherein:K'" may be 1, 2, 3, or 4;RM may be H or C1-C3 alkyl;X1may be O; each occurrence of X2may be independently CH2, O, NR4, or C(O); each occurrence of R1and R4may be independently H or C1-C3 alkyl;ZBmay be absent (a bond), -(CH2)IM-, -C(O)-(CH2)IM-, or -C(O)-(CH2)|M-NRM-; each occurrence of IM may be independently 1, 2, or 3; k' may be 1; each occurrence of j may be independently 1, 2, 3, 4, or 5; j' may be 1; h and h' may be each independently 1, 2, 3, 4, 5, 6, 7, or 8; i may be 1; each occurrence of n may be independently 2 or 3; each occurrence of n" may be independently 2, 3, 4, or 5; or a salt, stereoisomer, or solvate thereof.

[0223] In another embodiment, h and h' may be each independently 1, 2, 3, 4, or 5.

[0224] In another embodiment, each occurrence of X2may be independently CH2, NR4, or C(O); R1may be H; and R4may be H.

[0225] In another embodiment, ZBmay be absent or -C(O)-(CH2)IM-.

[0226] In another embodiment, the [CPBM] may be the [IgGBM] of structure:

[0227] In another embodiment, the [CPBM] may be the [IgGBM] of structure:

[0228] In another embodiment, the [CPBM] may be the [IgGBM] of structure:

[0229] In another embodiment, the [CPBM] may be the [IgGBM] of structure:

[0230] In another embodiment, the [CPBM] may be the [IgGBM] of structure:

[0231] In another embodiment, the compound may have the structure:

[0232] In another embodiment, the compound may have the structure:

[0233] In another embodiment, the compound may have the structure:

[0234] In another embodiment, the compound may have the structure:

[0235] In another embodiment, the compound may have the structure:

[0236] In another embodiment, the compound may have the structure:

[0237] In another embodiment, the ™degrader may be a degrader of Immunoglobulin A ("IgA").Examples of such degraders are described in International Publication No. WO 2022 / 192478 published September 15, 2022, and International Publication No. WO 2024 / 228935 published November 7, 2024, the contents of which publications are incorporated herein in their entireties by reference.

[0238] In another embodiment, the degrader may be a degrader of antibodies to a thyroid- stimulating hormone receptor ("TSHR"). Examples of such degraders are described in International Publication No. WO 2024 / 155750 published July 25, 2024, the contents of which publications are incorporated herein in their entireties by reference.

[0239] In another embodiment, the degrader may be a degrader of a nti-piECI I autoantibodies.Examples of such degraders are described in International Publication No. WO 2023 / 028590 published March 2, 2023, and International Publication No. WO 2023 / 028597 published March 2, 2023, the contents of which publications are incorporated herein in their entireties by reference.

[0240] In another embodiment, the degrader may be a degrader of a pathogenic protein is anImmunoglobulin D ("IgD") degrader.

[0241] In another embodiment, the degrader may be a degrader of a pathogenic protein is an Immunoglobulin E ("IgE") degrader.

[0242] In another embodiment, the degrader may be a degrader of a pathogenic protein is an Immunoglobulin M ("IgM") degrader.

[0243] In an embodiment, the degrader may have one of the following general chemical structures:inor a. pharmaceutically acceptable salt thereof wherein:

[0244] R2may be N HC(=O)CH3;

[0245] R5may be CH2OH;

[0246] Extracellular Protein Targeting Ligand may be a ligand having affinity to the extracellular or extravascular pathogenic protein;

[0247] Linker* may be a chemical group that connects the ASGPR ligand to Linker6, Linker0, orLinker0;

[0248] Linker6may be a chemical group that connects Linker* to the Pathogenic Protein Targeting Ligand;

[0249] Linker0may be a chemical group that connects Linker0to the Pathogenic Protein TargetingLigand; and

[0250] Linker0may be a chemical group that connects Linker* to the Pathogenic Protein TargetingLigand.

[0251] In the above formulae, "Pathogenic Protein Targeting Ligand" refers to a Pathogenic Protein Binding Moiety [CPBM] which binds to pathogenic forms of extracellular or extravascular proteins as identified herein, which are related to and / or mediate a disease state and / or condition and is to be60 removed by the action of hepatocytes or other cells on the circulating protein (the compounds preferably selectively binding to the IgG in plasma of the subject or patient).

[0252] In the above formulae,Xxis 1 io 5 groups independently selected from O, S. N(R"), arid C(R4X^4)> wherein if X:is I group then X’ is O, S, N(R'’), or C(R4)(R4), ifX1is 2 groups then no more than 1 group of X' is O, S, or N(R6), if X1is 3, 4, or 5 groups then no more than 2 groups of X1are O, S, or N(R&);R is selected from(0 aryl, heterocycle, and heteroaryl containing I or 2 heteroatoms independently selected from N, O, and S, each of which aryl, heterocycle., and heteroaryl is optionally substituted with i , 2, 3, or 4 substituents;(iii) -NRs-S(O)-R\ -NR*-C(S)-R?, -NRs-S(O)(NR6)-Rf -N-S(O)(R3)2, -NRxC(O)NR9S(O)2R3t-NR^-SfOVR10, and -NR8-C(NR6)-R3each of which is optionally substituted with 1, 2, 3, or 4 substituents; and(iv) hydrogen, Riu, alkyl-C(O)-R3, -C(O)-R3, alkyl, haloalkyl, -OC(O)R}, and -NRS-C(O)R!0;Rl!lis selected from ani, alkyi-NR*-C(O}-R5, alkyl-atyl, alkyl-heleroavyl with I , 2, or 4 heteroatoms, alkyl-cyano, alkyl-OR6, alkyl-MVR*, NR8-NR6-C(O)R3, NRs-S(O>R-\ alkenyl, allyl, alkynyl, -MR^alkenyl, -O-alkenyl, -NR6-alkynyi, -NRMjeteroaryl, -NRh-aryl, -O-heteroatyl , -O-aryl, and -O-alkynyl, each of which Rl‘!is optionally substituted with 1, 2, 3, or 4 substituents;R1and Rsare independently selected from hydrogen, heteroalkyl, Co-Csalky 1 -cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Ci, Br. I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, Co-Cgalkyl- OR6, Co-Csaikyl-SR6, Co-Qalkyl-NlVR7, Co-Qalky l-C(O)R\ ('«-Cf,alkyl-S(O)R5, C8-€5a!kyL C(S)R3, Co-Qalkyl-StOliR3, C()-C6alkyl-N(R8>C(O)R3, Cy-C6alkyl-N(R8)-S(O)R\ Co-Calkyl- N(R8)-C(S)R3, Ct>-Cbalkyi-N(R8)-S(O)jR?C<rCf,a!kyLO-C(())R3, Co-Galkyi-O-SCOM Cu- Cc^kyi-O-C(S)R-’, -N~S(O)(R-’)2, G-CsaJkylNj, and Cc-Coalkyl -O-S(O)iR5, each of which is optionally substituted with I, 2, .3, or 4 substituents;R‘ at each occurrence is independently selected from hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF?, -CHF3, -CH2F, -ClfcCFs, -CH2CH2F, and -CF2CF3), arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR*. and -NR*R“;R‘ is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR”, -■NRi’R7, C(O)R3, S(O)R3, C(S)R5, and S(O)>R3,R,;and R are independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl. heterocycle, -alkyl-OR8, - alkyl-WR9, C(O).R3, S(O)R\ C(S)R\ and S(O.hRRBand R9are independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle;Cycle is a 3-8 membered fused cyclic group optionally substituted with 1, 2, 3, or 4 substituents; each Linker''' is a bond or a moiety that covalently links the A8GPR ligand to Linker’;Linked is a bond or a moiety that covalently links Linker* to an 'Extracellular Protein Targeting Ligand;

[0253] Various moieties [Linker*], [Linker6], [Linker6], [Linker6], [Cycle], and X1as well as moieties binding to pathogenic proteins are known in the biomedical art and described, for example, in International Publication No. WO 2021 / 155317 published August 5, 2021, International Publication No. WO 2022 / 035997 published February 17, 2022, International Publication No. WO 2022 / 235699 published November 10, 2022, International Publication No. WO 2023 / 009554 published February 2, 2023, and International Publication No. WO 2023 / 028338 published March 2, 2023, the contents of which publications are incorporated herein in their entireties by reference.METHODS OF MAKING THE BIFUNCTIONAL DEGRADER

[0254] The starting materials useful for making the pharmaceutical compositions of the invention are readily commercially available or can be prepared by those skilled in the biomedical art.

[0255] Other methods of making the bifunctional degraders disclosed in this specification may be found in published patent applications.

[0256] Methods of making COMPOUND 1 are disclosed in International Patent Publication WO 2024 / 228935 (Biohaven Therapeutics Ltd.).METHODS OF REMOVAL OF PATHOGENIC PROTEINS FROM A SUBJECT OR PATIENT.

[0257] Method of administering the bifunctional degrader. The best mode of administration depends on where treatment is taking place, whether a hospital or outpatient.

[0258] The removal of pathogenic proteins from a subject or patient can be measured by methods known to persons having ordinary skill in the biomedical art and disclosed in this specification.METHODS OF TREATING DISEASES

[0259] The degraders of pathogenic proteins disclosed herein may be useful for treating cancer. Neoplasms may be treated using compounds according to embodiments of the invention.

[0260] Representative common cancers to be treated with compounds according to the invention include, for example, prostate cancer, metastatic prostate cancer, stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, testis, bladder, renal, central nervous system, head and neck, throat, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth / pharynx, esophagus, larynx, kidney cancer and lymphoma, among others, which may be treated by one or more compounds according to the invention. Because of the activity of the present compounds, the invention has general applicability treating virtually any cancer in any tissue, thus the compounds, compositions and methods of the invention are generally applicable to the treatment of cancer and in reducing the likelihood of development of cancer and / or the metastasis of an existing cancer.

[0261] In some aspects of the invention, the cancer which is treated is metastatic cancer, a recurrent cancer or a drug-resistant cancer, especially including a multiple drug-resistant cancer. Separately, metastatic cancer may be found in virtually all tissues of a cancer patient in late stages of the disease, typically metastatic cancer is found in lymph system / nodes (lymphoma), in bones, in lungs, in bladder tissue, in kidney tissue, liver tissue and in virtually any tissue, including brain (brain cancer / tumor). Thus, embodiments of the invention are generally applicable and may be used to treat any cancer in any tissue, regardless of etiology.

[0262] The degraders of pathogenic proteins disclosed herein may be useful for treating autoimmune diseases. A more complete list of autoimmune diseases which may be treated by compounds and pharmaceutical compositions according to embodiments of the invention includes Addison's disease, autoimmune polyendodrine syndrome (APS) types 1, 2, and 3, autoimmune pancreatitis (AIP), diabetes mellitus type I, autoimmune thyroiditis, Ord's thyroiditis, Grave's disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjogren's syndrome, autoimmune enteropathy, coeliac disease, Crohns' disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (APIS), aplastic anemia, autoimmune hemolytica anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease,essential mixed cryoglulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, adiposis dolorosa, adult-onset Still's disease, anklyosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis- related arthritis, esosiniphilic fasciitis, Felty syndrome, AgG4- related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), palindromic rheumatism, Parry Romberg syndrome, Parsonage-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal Fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schnitzler syndrome, systemic lupus erythematosus, undifferentiated connective tissue disease (UCTD), dematomyositis, fibromyalgia, myositis, inclusion body myositis, myasthenia gravis, neuromyotonia, paraneoplastic cerebellar degeneration, polymysositis, acute disseminated encephalomyelitis (ADEM), acute motor axonic neuropathy, anti-NMDA receptor encephalitis, Balo concentric sclerosis, Bickerstaffs encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating diseases, Lambert- Eaton myasthenic syndrome, multiple sclerosis, pattern 11, Oshtoran Syndrome, Pendiatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS), progressive inflammatory neuropathy, restless leg syndrome, stiff person syndrome, Syndenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves ophthalmopathy, intermediate uveitis, ligneous conjunctivitis, Mooren's ulcer, neuromyelitis optica, opsoclonus myoclonus syndrome, optic neuritis, scleritis, Susac's syndrome, sympathetic ophthalmia, Tolosa-Hunt syndrome, autoimmune inner ear disease (AIED), Meniere's disease, Behcet's disease, eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), Kawasaki's disease, leukocytoclastic vasculitis, lupus vasculitis, rheumatoid vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immune deficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esopagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency and pyoderma gangrenosum, among others.

[0263] The degraders of pathogenic proteins disclosed herein may be useful for treating inflammatory diseases.REDUCING PATHOGENIC PROTEIN LEVELS BY CONTACTING COMPONENTS OF EXTRAVASCULAR SYSTEM

[0264] The lymphatic system includes a network of vessels generally separate from veins and arteries. Rather than whole blood, the lymphatic vessels carry lymphatic fluid. The lymphatic system serves a variety of physiologic purposes, including returning interstitial fluid to the vascular space,transporting fats from the digestive tract, and transporting immune-mediating cells. The composition of lymphatic fluid is similar to plasma. It contains white blood cells, but generally does not contain red blood cells, platelets, or various other components of whole blood. The lymphatic system may be involved in a variety of pathologic states, including lymphatic obstruction leading to lymphedema, leakage of lymphatic fluid, which may lead to chylothorax, or the invasion and spread of malignant cells leading to metastasis. The lymphatic system is involved in nearly any immune mediated response, whether to infectious agents, e.g., viruses, bacteria, parasites, etc., malignancy, or in the setting of autoimmune disorders. The lymphatic system may serve as a repository for infected cells in disorders or may contain a higher concentration of malfunctioning cells in various immune system disorders. To achieve diagnosis and / or treatment of these and other conditions, it may be desirable to access the lymphatic system.

[0265] In an embodiment, the invention provides a method of reducing the level of a pathogenic protein in a subject, includes contacting a component of the subject's extravascular system with a degrader having affinity for (i) an asialoglycoprotein (ASGPR) receptor of hepatocytes expressed in the subject's liver, and (ii) the pathogenic protein, in an amount effective to promote the reduction in the level of the pathogenic protein in the subject.

[0266] The component of the lymphatic system may be a lymph, a lymphatic vessel, a lymph node, and a lymphoid organ. The lymphoid organ may be thymus, spleen, a tonsil, bone marrow, or Peyer's patch.METHODS OF DEGRADER ADMINISTRATION AND PHARMACOKINETICS / PHARMACODYNAMICS VARIABILITY

[0267] The compositions of the invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and may also be administered in controlled-release formulations. Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0268] The compositions of the invention may be administered parenterally, orally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, among others. Preferably, the compositions are administered subcutaneously.

[0269] The inventors unexpectedly found that different methods of degrader administration result in different degrees of pathogenic protein lowering. As described in the following examples, intravenous administration of the degrader results in prompt and robust lowering of the pathogenic protein levels, while subcutaneous administration results in sustained, longer lowering of the degrader level.

[0270] The reduction in the level of the pathogenic protein in the subject may be 10% or greater, 20% or greater, 30% or greater, 40% or greater, 50% or greater, 60% or greater, 70% or greater, 80% or greater, or 90% or greater.

[0271] The above reductions in the level of the pathogenic protein may be sustained for at least ten hours, at least twenty hours, at least thirty hours, at least forty hours, at least 50 hours, at least 60 hours, at least 70 hours, at least 80 hours, at least 90 hours, or at least 100 hours following the administration.EXAMPLES

[0272] The invention is further illustrated by non-limited EXAMPLES.EXAMPLE 1Deep, rapid, and tunable lowering of pathogenic IgG by subcutaneous administration of FCIII-GN3

[0273] This EXAMPLE shows that the subcutaneous administration of FCIII-GN3 achieves deep, rapid and tunable IgG reductions customized to the needs of specific IgG-related diseases.

[0274] FCIII-GN3 is a bispecific, small molecule with a relatively short half-life designed to selectively and transiently lower IgG as an intravenous or subcutaneous injection. The molecule is comprised of a peptide IgG binder, short PEG linker and GalNac ASGPR binder to target IgG for hepatic lysosomal degradation. FCIII-GN3 was specifically designed to mediate the formation of ternary complexes between target proteins (specifically human IgGl, lgG2, and lgG4) and ASGPR, which is expressed abundantly on hepatocytes. FCIII-GN3 was designed to selectively and transiently target IgG subclasses IgGl, lgG2 and lgG4 while preserving subclass lgG3. The preservation of lgG3 by FCIII-GN3 is expected to maintain the robustness of host defense for a given degree of IgG lowering and may offer advantages compared to agents that reduce all IgG subclasses, like FcRn targeting antibody fragments. FCIII-GN3 potentially offers a significantly improved benefit-risk for treating IgG-mediated diseasesbased on important mechanistic advantages including rapid onset of IgG-lowering, shortened time to maximal effect, depth of IgG lowering, brief period of exposure, potential for reduced immunosuppression given lack of effect on lgG3, low likelihood of immunogenicity, ability to be coadministered with biologies, and lack of effects on albumin, cholesterol or triglycerides.

[0275] FCIII-GN3 has improved benefit-risk for use in immune-mediated diseases. FCIII-GN3 has been safely administered in humans with intravenous and subcutaneous single doses up to a dose of 500 mg. For further details, see the FCIII-GN3 Investigator's Brochure.

[0276] In vitro and in vivo nonclinical studies demonstrated the FCIII-GN3 binding to ASGPR CRD and human IgG subclasses. Concentration-dependent FCIII-GN3 mediated uptake of IgG into HepG2 cells and human primary hepatocytes. In safety pharmacology assessments, there were no dose-dependent FCIII-GN3 adverse effects on central nervous system, respiratory, or cardiovascular systems. The potential effects of FCIII-GN3 on central nervous, respiratory, and cardiovascular systems were evaluated in studies in compliance with Good Laboratory Practice regulations and according to ICH guidelines. In cynomolgus monkey at doses up to 500 mg / kg, FCIII-GN3 did not result in findings in functional observational battery evaluations, electrocardiogram, hemodynamic, or respiratory function parameters. In a hERG assay, the half maximal inhibitory concentration (IC5o) was 2191.1 pM. These results are not indicative of significant human risk.

[0277] This EXAMPLE shows that the IgG degrader (500 mg) FCIII-GN3 (see FIG. 15) was administered subcutaneously ("SC") to a patient.

[0278] The results are shown in FIG. 1 to FIG. 7. These Figures show that peak did not occur until between a range of six to twelve hours (versus at the first time point after intravenous infusion). The peak was only <20% lower than after intravenous infusion despite much later Tmax. Drug concentrations from subcutaneous exceeded those of intravenous infusion through the last measurable time point starting at twelve hours after the infusion. Bioavailability was on average at least 30% higher with subcutaneous versus intravenous infusion (with twenty-four hour time point included). In this case (a non-linear system with the target-mediated drug disposition), the target mediated disposition is somewhat prolonged after subcutaneous administration. Subcutaneous administration may mechanistically result in improved pharmacodynamics for all degraders of pathogenic proteins.

[0279] This EXAMPLE demonstrates favorable safety and dose-dependent rapid IgG lowering with profile suitable for subcutaneous dosing. See FIG. 8.

[0280] FCIII-GN3 is a small-molecule with a short half-life. FCIII-GN3 can be administered more frequently if needed or dosed in the same day as a biologic. With a short half-life and a directmechanism, FCIII-GN3 has its effects and is then rapidly cleared from circulation while the pharmacodynamic effects persist. This activity means less time for off-target effects with the long- lasting reductions in disease-causing proteins. Subcutaneous administration of FCIII-GN3 provides sustained effects long after the last dose.

[0281] A care provider, such as a physician, can increase FCIII-GN3 dose early to get a subject to a quicker IgG reduction. A care provider can maintain reduced IgG with less frequent dose. The dose may vary from specific IgG-related disease to specific IgG-related disease. Important curve to understand. Show you a little more about how we can achieve a faster response which might be important for indications like acute MG.

[0282] Subcutaneous FCIII-GN3 injection at 2000 mg achieved average maximal reductions in total IgG of 81% by Day 18.

[0283] FCIII-GN3 at 2000 mg provides a modality for management of acute disease, by lowering IgG as rapidly and deeply as plasma exchange.Administration of FCIII-GN3 to humans in clinical studies

[0284] Completed dose cohorts: FCIII-GN3 was administered intravenously at 50 mg, 125 mg, 250 mg, and 500 mg. FCIII-GN3 was administered subcutaneously at 500 mg. No severe adverse events were observed. Most adverse events were unrelated to FCIII-GN3. No clinically meaningful trends occurred in electrocardiograms or laboratory results.

[0285] Subcutaneous cohort. Confirms high subcutaneous bioavailability with IgG lowering and injection volume compatible with autoinjector.

[0286] Pharmacokinetics confirms high subcutaneous bioavailability. AUC = 144% Cmax = 80% versus intravenous.

[0287] Pharmacodynamics shows meaningful IgG lowering. Four / six subjects with ~40-60% IgG lowering within ninety-six hours. Low injection volume compatible with autoinjector.

[0288] Subcutaneously administered FCIII-GN3 achieved deep lowering of targeted IgG, with reductions > 60% in the lowest subcutaneous dose tested in the Multiple Ascending Dose study. Subcutaneous FCIII-GN3 administration achieved progressive reduction in IgG within hours of each weekly dose administration in the Multiple Ascending Dose, and pharmacodynamic effects were sustained relative to baseline over the four-week study period. FCIII-GN3 was safe and well-tolerated across this EXAMPLE. There were no clinically significant effects on albumin or liver function, and no increases in cholesterol were noted. Further enhancing the competitive safety profile and asintentionally designed, plasma lgG3levels were preserved through the end of study week 4 to allow for healthy immune effector functioning. All adverse events were mild, any drug-related adverse events resolved, and there were no discontinuations due to study drug related adverse events. The optimized subcutaneous formulation in the Multiple Ascending Dose also showed substantially less inter-patient variability compared to previously reported intravenous FCIII-GN3. Escalating dose level cohorts of subcutaneous FCIII-GN3 are ongoing to explore the full range of IgG reductions possible with FCIII-GN3 for a wide range of future disease indications.

[0289] FCIII-GN3 is a small molecule and potential first-in-class extracellular IgG degrader, rationally designed to leverage the body's natural hepatic clearance mechanisms to selectively target and remove IgGi, lgG2, and lgG4, the underlying cause of the disease. FCIII-GN3 spares lgG3to preserve patient immune protection against bacteria, viruses and parasites. The results of this EXAMPLE confirm that FCIII-GN3 produces deep reductions in total IgG, is selective, sparing lgG3, is tunable, and is safe and well-tolerated.

[0290] In the EXAMPLE, subcutaneously administered FCIII-GN3 at a dose of 2000mg weekly achieved IgG reductions up to 85%, with max median reductions of 81% by Day 17. Biohaven recently reported the 1000 mg weekly dose achieved rapid, deep and sustained reductions in total IgG of up to 84%, with a median reduction of 80%. See FIGS. 11-14. Reductions at all doses occurred within hours of administration, were progressive, and effects were durable between dosing intervals. The range of IgG lowering enabled by different FCIII-GN3 dose levels offers tunability and flexibility in dosing paradigm, with higher doses planned for management of acute conditions, and lower, less frequent dosing planned for the management of chronic disease.

[0291] FCIII-GN3 at 1000 mg weekly has a short half-life with durable IgG reduction lasting months. FCIII-GN3 was safe and well-tolerated in subcutaneous doses up to 2000 mg with no clinically significant increases in ALT, AST, or bilirubin, no clinically significant reductions in albumin, and no clinically significant increases in cholesterol over the four-week dosing period compared to placebo. There were no clinically significant reductions in lgG3, IgA, IgD, IgE, or IgM compared to baseline. Most adverse events were mild and self-resolving. There were no serious or severe adverse events.

[0292] Evaluating single and multiple doses of an optimized subcutaneous formulation of FCIII-GN3 placebo-controlled study. This EXAMPLE describes a placebo-controlled, single dose and multiple dose study that includes two parts. Part 1 included three single dose cohorts. Part 2 included four multiple dose cohorts.

[0293] The study population was about sixty-four adult male humans and non-childbearing female humans. The planned dose range across Part 1 and Part 2 cohorts was 500-2000 mg of BHV 1300 or placebo.

[0294] FCIII-GN3 was administered as a subcutaneous dose in the subject's abdomen. FCIII-GN3 was provided as 250 mg / mL in a clear, colorless solution essentially free of visible particulates. Each vial contained 3 mL (750 mg) of extractable volume. The corresponding placebo for FCIII-GN3 is 0.9% saline, a homogeneous, clear, colorless liquid.

[0295] The primary objective of this EXAMPLE was to assess FCIII-GN3 safety and tolerability following single and multiple dose subcutaneous administration. The secondary objectives of this EXAMPLE were to characterize the FCIII-GN3 pharmacokinetics profile following single and multiple dose subcutaneous administration. Other objectives of this EXAMPLE were to characterize FCIII-GN3 pharmacodynamics effects after single and multiple dose subcutaneous administration, to characterize FCIII-GN3 binding to plasma proteins, to assess FCIII-GN3 immunogenicity, to evaluate the effect of FCIII- GN3 on electrocardiogram parameters after single FCIII-GN3 doses, and to characterize the urine pharmacokinetics of single FCIII-GN3 doses.

[0296] For assays of the primary endpoint of this EXAMPLE, safety and tolerability were assessed by reporting the frequency of unique subjects with adverse events. For assays of the secondary endpoints of this EXAMPLE, (1) for Part 1 and Day 1 of Part 2, AUC0-72h (for Part 2b), AUC0-96hr (Part 1 and Part 2a), AUC in Cmax, Tmax / T%, CL / F, and d / F; (2) for day 22 of Part 2, AUC0-72h (for Part 2b), AUC0-96hr, AUC inb Cmax, Tmax, T / „ RAAUC0-96hr, RAC max / CL / F, and Vd / F.

[0297] For assays during the Single Ascending Dose part 1 of this EXAMPLE, (1) a total of fifteen blood samples were collected for pharmacokinetics analysis relative to the end of injection dose time on Day 1 at pre-dose, 0.33 hours, one hour, two hours, three hours, four hours, six hours, eight hours, ten hours, twelve hours, twenty-four hours, forty-eight hours, seventy-two hours, ninety-six hours, and 168 hours (Day 8). (2) Plasma samples were collected and analyzed for protein binding following the Day 1 dose at six hours and forty-eight hours after the end of injection time. (3) pharmacodynamics blood samples for the following tests were collected at the following times, (a) total IgA, IgE, IgM, assayed at Day -1 pre-dose, Day 1 pre-dose, ninety-six hour, and on Day 36; (b) Total IgG, including subclasses IgGl, lgG2, lgG3, and lgG4), assayed at Day -1 pre-dose, Day 1 pre-dose, four hours, eight hours, twenty-four hours, forty-eight hours, seventy-two hours, ninety-six hours) and on Day 8, Day 15, Day 22, Day 29, and Day 36; (c) circulating Immune Complex C3 at Day 1 at pre-dose, four hours, twenty-four hours, fortyeight hours, and seventy-two hours, and on Day 8, Day 22, and Day 29; (d) circulating Immune ComplexClq at Day 1 (pre-dose, four hours, twenty-four hours, forty-eight hours, and seventy-two hours), and on Day 8, Day 22, and Day 29; (e) cytokines, including IL-6, TNF-a, IFN-y, and I L-l-|3: Day 1 (pre-dose and four hour), Day 2, and Day 5; and (f) banked serum at Day 1 at pre-dose, twenty-four hours, seventy-two hours, and ninety-six hours, and on Days 15 and 36. (4) pharmacokinetics urine samples were collected on Day 1 for pharmacokinetics analysis at the following intervals: 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, 24-48 hours, 48-72 hours, and 72-9six hours post-dose. (5) Standard biochemistry, HbAlc at initial Screening Day, hematology, and urinalysis tests at Day-1, Day 2, Day 4, Day 5, Day 8, Day 15, Day 22, Day 29, and Day 36.

[0298] For assays during the Multiple Ascending Dose Part 2 of this EXAMPLE, (1) thirty-two blood samples were collected for pharmacokinetics plasma analysis relative to the end of dose administration time on: Day 1 (pre-dose), thirty minutes, one hour, two hours, four hours, six hours, eight hours, ten hours, twelve hours, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours), Day 8 (pre-dose, eight hours, and twenty-four hours), Day 15 (pre-dose, eight hours, and twenty-four hours), and on Day 22 (pre-dose, thirty minutes, one hour, two hours, four hours, six hours, eight hours, ten hours, twelve hours, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours) (2) A total of six blood samples were collected and analyzed for protein binding on Day 1 (one hour, four hours, and twelve hours) and on Day 22 (one hour, four hours, and twelve hours)' (3) Pharmacodynamics blood samples for the following tests were collected at the following times: (a) Total IgA, IgE, and IgM: Day 1 (pre-dose) and Day 25; (b) Total IgG, including subclasses IgGl, lgG2, lgG3, and lgG4, assayed at Day -1, Day 1 at pre-dose, four hours, eight hours, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours, Day 8 at pre-dose, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours, Day 15 at pre-dose, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours, Day 22 at pre-dose, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours, and on Day 36, Day 50, and Day 64. (4) Assays were performed for samples from Day - 1, Day 1 at eight hours and twenty-four hours), Day 5, Day 8 (at eight and twenty-four hours, Day 12, Day 15 at eight and twenty-four hours, Day 19, Day 22 at eight hours and twenty-four hours, Day 26, Day 36, Day 50, and Day 64. (5) Standard biochemistry assays, HbAlc at Screening Day, hematology, and urinalysis tests were performed at Day -1, Day 2, Day 4, Day 7, Day 9, Day 11, Day 14, Day 16, Day 18, Day 21, Day 23, Day 26, Day 36, Day 50, and Day 64.

[0299] For assays during the Part 2b (Split First Dose Multiple Ascending Dose) of this EXAMPLE, (1) A total of 32 blood samples were collected for pharmacokinetics plasma analysis relative to the end of dose administration time on: Day 1 at pre-dose, thirty minutes, one hour, two hours, four hours, sixhours, eight hours, ten hours, twelve hours, twenty-four hours, forty-eight hours) Day 5 (pre-dose, and twenty-four hours), Day 8 (pre-dose, eight hours, and twenty-four hours), Day 15 (pre-dose, eight hours, and twenty-four hours), and on Day 22 (pre-dose, thirty minutes, one hour, two hours, four hours, six hours, eight hours, ten hours, twelve hours, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours). (2) A total of six blood samples were collected and analyzed for protein binding on Day 1 (one hour, four hours, and twelve hours) and on Day 22 (one hour, four hours, and twelve hours). (3) Pharmacodynamics blood samples for the following tests were collected at the following times: (a) Total IgA, IgE, and IgM. Screening was done on Day 1 (pre-dose) and Day 25. (b) Total IgG (including subclasses IgGl, lgG2, lgG3, and lgG4). Screening was done on Day -1, Day 1 (pre-dose, twenty-four hours, forty-eight hours, seventy-two hours, ninety-six hours, 120 hours, and 144 hours), Day 8 (predose, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours), Day 15 (pre-dose, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours), Day 22 (pre-dose, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours), and on Day 36, Day 50, and Day 64. (4) Standard biochemistry (HbAlc at Screening Day), hematology, and urinalysis tests were performed at Screening Day, on Day 1, Day 2, Day 4, Day 5, Day 7, Day 9, Day 11, Day 14, Day 16, Day 18, Day 21, Day 23, Day 26, Day 36, Day 50, and Day 64.

[0300] Pre-clinical studies - pharmacokinetics / toxicokinetics of intravenous or subcutaneous FCIII- GN3 administration in rats. As part of a non-GLP toxicity study, FCIII-GN3 toxicokinetics were determined in Sprague Dawley rats at doses of 250 or 500 mg / kg / day once daily for seven consecutive days by intravenous infusion over approximately sixty minutes. Exposure following intravenous infusion increased in a slightly less than dose-proportional manner between the 250 mg / kg dose and 500 mg / kg dose levels. There was no evidence of accumulation.

[0301] As part of a non-GLP toxicity study, FCIII-GN3 toxicokinetics were determined in Sprague Dawley rats administered 75 mg / kg / day, 250 mg / kg / day, or 400 mg / kg / day once daily for fourteen consecutive days by intravenous bolus (75 mg / kg / day and 250 mg / kg / day groups) or intravenous slow injection (400 mg / kg / day group). Toxicokinetics was also determined in Sprague Dawley rats administered 250 mg / kg / day subcutaneous daily for fourteen consecutive days. After intravenous dosing, systemic FCIII-GN3 exposure (AUCiast) generally increased in a dose-proportional manner from 75 mg / kg / day to 400 mg / kg / day. No FCIII-GN3 accumulation was observed after multiple intravenous or subcutaneous dosing.

[0302] In a toxicity study, FCIII-GN3 toxicokinetics were determined in Sprague Dawley rats administered 50, 100, or 150 mg / kg / day once daily by intravenous bolus (50 and 100 mg / kg / day orintravenous slow injection (150 mg / kg / day for twenty-eight consecutive days. Systemic FCIII-GN3 exposure (Coand AUCiast) generally increased in a dose-proportional manner from 50 mg / kg / day to 150 mg / kg / day in both sexes. No accumulation was observed after multiple intravenous dosing in rats. No sex-related differences were observed. At the NOAEL of 150 mg / kg / dose, the mean Coand AUCiastvalues were 651,000 ng / mL and 359,000 ng»h / mL (sexes combined) after twenty-eight days.

[0303] As part of a thirteen-week toxicity study, FCIII-GN3 toxicokinetics were determined in Sprague Dawley rats administered vehicle or 150, 250, or 500 mg / kg subcutaneous twice weekly for thirteen weeks. Exposure to FCIII-GN3 was not significantly different (< two-fold) between sexes. Exposure to FCIII-GN3 did not appear to change following repeated FCIII-GN3 administration. There was no FCIII-GN3 accumulation. The systemic NOAEL was defined at 500 mg / kg resulting in a sex combined Cmaxand AUC0-24hr values of 49,000 ng / mL and 623,000 ng-h / mL, respectively after thirteen weeks.

[0304] Pharmacokinetics / toxicokinetics of intravenous / subcutaneous FCIII-GN3 administration in cynomolgus monkeys. FCIII-GN3 toxicokinetics were determined in cynomolgus monkeys administered 1 mg / kg FCIII-GN3, 3 mg / kg FCIII-GN3, and 10 mg / kg FCIII-GN3 by intravenous bolus once a week for three consecutive weeks on Day 1, Day 8, and Day 15. Systemic FCIII-GN3 exposure (AUCiast) generally increased in a greater than dose-proportional manner from 1 mg / kg / week to 10 mg / kg / week in both sexes. Systemic exposure on Day 15 was similar to that on Day 1 at 1 and 3 mg / kg / week and was higher at 10 mg / kg / week. No sex-related differences were noted.

[0305] FCIII-GN3 toxicokinetics were determined in cynomolgus monkeys administered 75 mg / kg, 250 mg / kg, 375 mg / kg, and 500 mg / kg FCIII-GN3 by intravenous slow bolus once on Day 1, Day 8, and Day 15. The systemic exposure (Cmaxand AUCiast) of FCIII-GN3 increased in a less than dose-proportional manner over the dose range of 75 mg / kg to 300 mg / kg, and exposures were similar at 375 mg / kg and 500 mg / kg. No FCIII-GN3 accumulation or sex-related differences were observed.

[0306] FCIII-GN3 toxicokinetics were also determined in cynomolgus monkeys administered doses of 75 mg / kg, 250 mg / kg, or 500 mg / kg FCIII-GN3 slow intravenous bolus injection twice weekly on Days 1, 4, 8, 11, 15, 18, 22, 25, and 29. The systemic exposure (AUC0-24) of FCIII-GN3 increased in a less than a dose-proportional manner over the dose range of 75 to 500 mg / kg, and no sex-related differences were observed. At the NOAEL of 1000 mg / kg / week (500 mg / kg dosed twice a week), the mean Coand AUCiastvalues were 5,360,000 ng / mL and 26,200,000 ng»h / mL / week (sexes combined), respectively, on Day 1. Systemic exposure (Co and AUCiast) decreased following repeated FCIII-GN3 administration (accumulation ratios ranged from 0.318 to 0.555).

[0307] As part of a thirteen-week toxicity study (CRL 20457823), FCIII-GN3 toxicokinetics were determined in cynomolgus monkeys administered doses of 250, 500, or 1000 mg / kg FCIII-GN3 by subcutaneous injection twice weekly. Individual plasma concentration-time profiles, Cmax, and AUC values were similar between males and females on Day 1 and Day 89. Cmax and AUCo-24 of FCIII-GN3 increased in a less than dose-proportional manner with increasing doses and individual Cmaxand AUCo-24 values overlapped between doses for both Day 1 and Day 89.

[0308] Systemic exposure (Cmaxand AUCiast) decreased following repeated FCIII-GN3 administration. Accumulation ratios ranged from 0.473 to 0.676. The NOAEL was defined as 2000 mg / kg / week (1000 mg / kg twice weekly). The mean sex combined Cmaxand AUC0-72 values were 900,000 ng / ml and 20,000,000 ng-h / ml on Day 1, respectively.

[0309] Nonclinical Toxicology studies demonstrated an acceptable safety profile that supports evaluation of FCIII-GN3 in clinical studies in humans.

[0310] Cynomolgus monkey is the most relevant toxicology species for the FCIII-GN3 risk assessment. FCIII-GN3 binds IgG with high affinity and lowers circulating IgG in cynomolgus as it does in humans.

[0311] Results in similar drug disposition to humans based on comparable protein binding and hepatic metabolism. NOAEL doses in cynomolgus monkeys were the highest doses tested (1000 mg / kg / dose 2X weekly [2000 mg / kg weekly] for 3 months). The Day 1 AUC and Cmaxvalues associated with this dose are associated with 1.45x and 2. Ox multiples, respectively, to the highest projected human AUC and Cmaxassociated with a 2000 mg dose

[0312] In a four-week cynomolgus monkey pivotal study, FCIII-GN3 administration by twice weekly intravenous administration was well tolerated at dose levels of 75 mg / kg, 250 mg / kg, and 500 mg / kg (150 mg / kg, 500 mg / kg, and 1000 mg / kg / week). In all treated males and females, serum IgG concentrations decreased by two-fold to 4-fold at seventy-two hours post-dose on Day 1, when compared to pre-dose values, and remained decreased until the end of the treatment period. This decrease was considered a FCIII-GN3 pharmacological effect of. The NOAEL was considered to be 500 mg / kg twice weekly (1000 mg / kg / week).

[0313] In the thirteen-week study, FCIII-GN3 was administered by subcutaneous injection to cynomolgus monkeys at 250 mg / kg, 500 mg / kg, or 1000 mg / kg twice weekly (500 mg / kg / week, 1000 mg / kg / week, and 2000 mg / kg / week). FCIII-GN3-related changes in immunoglobulins were noted for IgG in animals receiving > 250 mg / kg / dose, starting from Day 1 at forty-eight hours post-dose until the lasttime point post-dose on Day 89. This effect is related to the FCIII-GN3 pharmacological activity. The NOAEL for this EXAMPLE was 2000 mg / kg / week (1000 mg / kg twice weekly), the highest dose tested.

[0314] FCIII-GN3 administration at doses of 500 mg / kg was well tolerated in the rat when delivered via slow sixty-minute intravenous infusion daily for seven days. In addition, FCIII-GN3 was administered at 750, 1500, and 2000 mg / kg via slow sixty-minute intravenous infusion in a single dose study. FCIII- GN3-related clinical observations were noted immediately following dosing at 2000 mg / kg and included decreased activity, cold to touch, uncoordinated movement / abnormal gait, and shallow breathing with full recovery by Day 2. FCIII-GN3-related microscopic results at the Day 3 euthanasia were noted in the kidneys, heart, skeletal muscle, and Harderian gland, with these results showing recovery at Day 8, suggesting reversibility. At 2000 mg / kg, adverse minimal to mild degeneration and necrosis of cardiomyocytes were noted in 3 / 10 males and 3 / 10 females euthanized at Day 3; minimal to mild degeneration and necrosis of myocytes in the skeletal muscle in 4 / 10 males and 2 / 10 females; minimal to marked degeneration and necrosis of acinar cells, and minimal to moderate mixed cell inflammation in the Harderian gland of 6 / 10 males and 1 / 10 female. Regeneration was observed for these results in the heart, skeletal muscle and Harderian gland at the Day 8 euthanasia, demonstrating recovery. Nonadverse minimal tubular vacuolation was noted in kidneys at 2000 mg / kg in males and females. The NOAEL was 750 mg / kg in rats with mean AUC0-25hr of 706,000 ng-h / mL and mean Cmax of 700,000 ng / mL.

[0315] In the four-week rat pivotal study, minimal vacuolation of renal tubular epithelium was noted in males and females (> 50 mg / kg / day of FCIII-GN3); 31% of FCIII-GN3 is excreted in the urine in rats at a dose of 150 mg / kg / day, but < 1% is excreted in cynomolgus at clinically relevant concentrations or in humans. Renal histology was normal in cynomolgus monkeys. The NOAEL for the four-week pivotal study was 150 mg / kg / day, the highest dose administered in that study.

[0316] In the thirteen-week study, FCIII-GN3 was administered twice weekly by subcutaneous injection to rats at 150, 250, and 500 mg / kg / dose. FCIII-GN3-related local injection site clinical signs and microscopic results were noted at > 150 mg / kg / dose which comprised a clinically observed combination of swollen, dry lesions with or without discharge, scabbed, flaking, bruised, thickened, and / or discolored skin, as well as skin abrasion, and microscopic results of myofiber mixed cell inflammation, degeneration / necrosis, severe ulceration / erosion, with minimal to marked crusts, epidermal hyperplasia / hyperkeratosis, and dermal and subcutaneous tissue inflammation with marked dermal fibrosis. The systemic NOAEL was considered 500 mg / kg / dose, the highest dose tested, based on the lack of any adverse systemic results being noted.

[0317] FCIII-GN3 was not cytotoxic, phototoxic, genotoxic, or clastogenic.

[0318] The standard battery of in vitro and in vivo toxicology studies supports the multiple FCIII- GN3 dosing at doses of up to 2000 mg per week subcutaneous for four weeks at formulation concentrations of up to 250 mg / mL.

[0319] Summary of clinical studies. FCIII-GN3 is currently under clinical investigation and has not been approved for any therapeutic use. FCIII-GN3 was evaluated in a Single Ascending Dose (SAD) study conducted in subjects. Subjects received single FCIII-GN3 doses (six each receiving intravenous doses of 50 mg, 125 mg, 250 mg, and 500 mg and a subcutaneous dose of 500 mg), and a total of ten subjects have received placebo.

[0320] The cumulative preliminary safety data from the first five cohorts of the ongoing Single Ascending Dose study indicate that FCIII-GN3 in single doses from 50 mg to 500 mg via intravenous infusion over thirty minutes or in a single dose of 500 mg administered subcutaneously have been well tolerated. There were no severe adverse events.

[0321] Dose selection. The geometric mean Cmax and AUCinf from the intravenous 500 mg cohort in the Single Ascending Dose study were ~139 pg / mL and ~2,193 pg-h / mL, respectively. The geometric mean Cmax and AUCinf from the subcutaneous 500 mg cohort in the Single Ascending Dose study were ~115.6 pg / mL and 3172 pg-h / mL, respectively. Tmaxwas reached six hours to twelve hours after a subcutaneous injection. Given the short half-life (< eight hours) and rapid FCIII-GN3 clearance (~ 99% eliminated in seventy-two hours).

[0322] The safety margins were calculated as the ratio of the highest tolerated first dose exposure in cynomolgus monkeys, the relevant species to human safety, to the model-derived simulated weekly exposure in humans.

[0323] Pharmacokinetics / pharmacodynamics modeling based on cynomolgus monkey data predicts dosing FCIII-GN3 at 500 mg subcutaneous provides a mean reduction in baseline total IgG of ~32% following dose #1. The predicted mean maximum % reduction in total IgG following the fourth and final dose of study drug (Day 22) is '“64%. The mean IgG reduction is predicted to increase with increasing dose and with multiple doses; the net decreases are predicted to be greatest following the first 3 doses; the decrease in IgG approaches steady-state.

[0324] Across all subsequent multiple-dose cohorts, no FCIII-GN3 total weekly dose exceeds that previously evaluated as a single dose in humans and no predicted exposures associated with repeat FCIII-GN3 dosing exceeds the established NOAEL weekly exposures from preclinical studies.

[0325] General safety considerations. FCIII-GN3 is a next generation immune modulator designed to have potential benefits over FcRn targeting agents (which also reduce IgG levels). First, FCIII-GN3 wasdesigned to selectively and transiently target IgGl, lgG2, and lgG4 while preserving subclass lgG3. The preservation of lgG3 by FCIII-GN3 is expected to increase the robustness of host defense for a given degree of IgG lowering and may offer benefits to those who require chronic therapy. Second, FCIII-GN3 is a small molecule that provides easy-to-administer clinical formulations versus healthcare provider- administered subcutaneous formulations of FcRns. Third, FCIII-GN3 is not expected to demonstrate immunogenicity seen with biologies. Fourth, FCIII-GN3 is expected to have a short half-life in humans that provides for coadministration with standard of care Fc-containing biologies. Finally, FCIII-GN3 is not expected to have effects on albumin, cholesterol, or triglycerides related to the FcRn mechanism of action.

[0326] Antibody or antibody fragments targeting the neonatal Fc receptor (FcRn) with subsequent IgG lowering are currently being developed to treat multiple immune-related disorders. Importantly, increased infections were not seen in FcRn inhibitor studies with IgG reductions up to 85% in subjects followed for approximately 3 months. See Ulrichts et al. The Journal of Clinical Investigation, 128(10), 4372-4386 (2018); Ling et al., Clin. Pharmacol. Then, 105(4), 1031-1039 (2019); Kiessling et al., Science Translational Medicine, 9(414) (2017).

[0327] The cumulative evidence based on the nonclinical toxicology, previous studies with FcRn inhibitors, and safety data from the ongoing Single Ascending Dose study supports the multiple FCIII- GN3 dosing at doses of up to 2000 mg per week subcutaneous for four weeks at formulation concentrations of up to 250 mg / mL.

[0328] FCIII-GN3 was administered as a subcutaneous dose in the abdomen. The maximum dose volume to be administered is 2 mL per syringe per abdominal quadrant. Several syringes were used for dose escalation levels exceeding 500 mg doses or equivalent placebo.

[0329] Glomerular filtration rate was calculated using the following 2021 CKD-EPI equation: estimated glomerular filtration rate = 142 x min (Scr / K, 1)“ x max (Scr / K, l)L2x 0.9938Agex 1.012, if female. Scr is serum creatinine (mg / dL), K is 0.7 for females and 0.9 for males, a = -0.241 (females) or - 0.302 (males), min indicates the minimum of Scr / K or 1.0, and max indicates the maximum of Scr / K or 1.0.

[0330] Pharmacokinetic parameters were calculated for FCIII-GN3 plasma concentrations:

[0331] For Part 1 and for Part 2 Day 1 and 22, the following pharmacokinetics parameters were calculated. AUCo gehr: Area under the concentration versus time curve from time 0 to time ninety-six hours. AUC0-96hr / Dose: Dose normalized AUC0-96hr. AUCinf: Area under the concentration from time 0 extrapolated to infinity. AUCinf / Dose: Dose normalized AUCinf. Cl / F: Apparent total clearance. Cmax:Maximum observed concentration. Cmax / Dose: Dose normalized Cmax. T%: Apparent first order terminal elimination half life. Tmax: Time when the maximal concentration is observed. d / F: Apparent volume of distribution.

[0332] Other pharmacokinetics parameters for Part 2 were calculated based on Day 1 and 22. For pharmacokinetics, RAAUco-96hr, the observed accumulation ratio was based on AUC0-96hr, calculated as AUC0-96hr on Day 22 / AUC0-96hr on Day 1.

[0333] For Part 2b, RAAUco-72hr: observed accumulation ratio based on AUC0-72hr, calculated as AUC0-72hr on Day 22 / AUC0-72hr on Day 1. For RACmax, the observed accumulation ratio was based on Cmax, calculated as Cmaxon Day 22 / Cmaxon Day 1. The area under the concentration versus time curve from the initial time to time seventy-two hours (AUC0-72hr) was calculated and dose normalized.

[0334] Pharmacokinetic statistical analyses. Pharmacokinetics parameter determination was performed using Phoenix’ WinNonlin’. Individual and mean plasma concentration versus time curves were presented for both linear and semi-log scales. Descriptive statistics of the plasma concentrations versus time were presented by day, as appropriate, as well for the pharmacokinetics parameters. The power model approach was performed on AUCo-96, AUCinf, and Cmaxfor Part 1 and Part 2 to assess doseproportionality.

[0335] Subcutaneous FCIII-GN3 administration achieved deep and sustained IgG reductions with an expected rebound of IgG levels after the drug was removed (See FIGs. 9-12) Subcutaneous FCIII-GN3 injection at 2000 mg achieved an average maximal reduction in total IgG of 81% by day 18 (three doses). Subcutaneous FCIII-GN3 administration achieved a deep, rapid, and tunable IgG Reduction customized to the needs of specific IgG-related diseases. These results compared favorably to the IgG lowering results achieved at week 4 using an FcRn-targeted therapeutic in ADAPT-SC. See Howard, et al.Neurotherapeutics (2024). In FIGs. 11-12, the solid dots represent the median of the maximal total IgG % change from baseline for the Week and bars represent the 25th and 75th percentiles.

[0336] FCIII-GN3 subcutaneous administration (2000 mg) offers a new potential paradigm for management of acute disease, lowering IgG as rapidly and deeply as plasma exchange. Two doses of FCIII-GN3 lower IgG as deeply and quickly as these invasive methods including plasma exchange.

[0337] FCIII-GN3 subcutaneous administration targets the root cause of a broad autoimmune disease to treat and prevent multi-organ complications. The IgG degrader remove Graves' diseasecausing autoantibodies. Graves' disease is a classic antibody mediated disease with traditional therapies that have not addresses the underlying antibody. This IgG degrader removes IgG to eliminate the disease driver of Graves' disease, Thyroid Eye Disease, and Thyroid Dermopathy.Evaluating single and multiple doses of an optimized subcutaneous formulation of FCIII-GN3 in a randomized, open-label, placebo-controlled study.

[0338] FCIII-GN3 was administered as a subcutaneous dose. FCIII-GN3 was provided as 250 mg / mL and is a clear, colorless solution essentially free of visible particulates. Each vial contains three mL (750 mg) of extractable volume. The corresponding placebo for FCIII-GN3 is 0.9% saline, a homogeneous, clear, colorless liquid.

[0339] For the single dose study and multiple dose study, the primary objective was to assess the safety and tolerability of FCIII-GN3 following single dose and multiple dose subcutaneous administration. For the single dose study and multiple dose study, the secondary objective is to characterize the pharmacokinetics profile of FCIII-GN3 following single and multiple dose subcutaneous administration. Other objectives are (1) To characterize the pharmacodynamic effects of FCIII-GN3 following single and multiple dose subcutaneous administration. (2) To characterize the FCIII-GN3 binding to plasma proteins. (3) To assess FCIII-GN3 immunogenicity. (4) To evaluate the effect of FCIII- GN3 on electrocardiogram (ECG) parameters after single FCIII-GN3 doses. (5) To characterize the urine pharmacokinetics of single FCIII-GN3 doses.

[0340] For the single dose study and multiple dose study, the primary endpoint is to assess safety and tolerability by reporting the frequency of unique subjects with severe adverse events and Grade 3-4 (CTCAE / DAIDS) treatment-emergent laboratory abnormalities. For the single dose study and multiple dose study, the secondary endpoints are (1) For Part 1 and Day 1 of Part 2: AUC0-72h (for Part 2b), AUC0. 96hr (Part 1 and Part 2a), AUCinf, Cmax, Tmax, T%, CL / F, and Vd / F. (2) Day 22 of Part 2: AUC0-72h (for Part 2b), AUCo-96hr , AUCinf, Cmax, Tmax, T%, RAAUC0-96hr, RACmax, CL / F, and Vd / F .

[0341] This EXAMPLE describes a randomized, open-label, placebo controlled, single and multiple dose study. This EXAMPLE includes two parts. Part 1 includes three single dose cohorts, and Part 2 includes four multiple dose cohorts.

[0342] Part 1 (Single Ascending Dose). A staggered dosing schedule was used for the dosing of each Single Ascending Dose cohort. The schedule includes two sentinel subjects (one active and one placebo) dosed initially. The remaining six subjects (five active and one placebo) was dosed after a review of at least twenty-four hours of the available safety and tolerability data from the two sentinel subjects.

[0343] Part 2 (Multiple Ascending Dose). Each Multiple Ascending Dose cohort included approximately ten subjects (eight active and two placebo). The planned dose range across Part 1 and Part 2 cohorts is 500-2000 mg of FCIII-GN3 or placebo. The subcutaneous injection was administered in the abdomen.

[0344] Safety and tolerability: Safety and tolerability of FCIII-GN3 was assessed by reporting the frequency of unique subjects with severe adverse events and Grade 3-4 (CTCAE / DAIDS) laboratory abnormalities. Adverse events were coded using the current version of the Medical Dictionary for Regulatory Activities (MedDRA). Laboratory test results were graded according to numeric laboratory test criteria in the latest version of CTCAE if criteria for that test are available, otherwise according to the descriptive terminology in the latest version of the DAIDS Table for Grading the Severity of Adult and Pediatric AE Corrected.

[0345] Pharmacokinetics. Summary statistics was used to describe the plasma concentrations and pharmacokinetics parameters. The power model approach was performed on AUCo-96, AUCinf, and Cmax for Part 1 and Part 2 Day 22 to assess dose-proportionality.

[0346] A total of fifteen blood samples was collected for pharmacokinetics analysis relative to the end of injection dose time on Day 1: at pre-dose, twenty minutes, one hour, two hours, three hours, four hours, six hours, eight hours, ten hours, twelve hours, twenty-four hours, forty-eight hours, seventy-two hours, ninety-six hours, and 168 hours (Day 8).

[0347] Plasma samples was collected and analyzed for protein binding following the Day 1 dose at six hours and forty-eight hours after the end of injection time.

[0348] Pharmacodynamic blood samples for the following tests was collected at the following times: (1) Total IgA, IgE, IgM at Day -1, Day 1 pre-dose, 96 hour, and on Day 36. (2) Total IgG (including subclasses 1, 2, 3, and 4): Screening Day, D-l, Day 1 (pre-dose, four hours, eight hours, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours) and on Day 8, Day 15, Day 22, Day 29, and Day 36. (3) Circulating Immune Complex C3: Day 1 (pre-dose, four hours, twenty-four hours, fortyeight hours, and seventy-two hours) and on Day 8, Day 22, and Day 29. (4) Circulating Immune Complex Clq at Day 1 (pre-dose, four hours, twenty-four hours, forty-eight hours, and seventy-two hours) and on Day 8, Day 22, and Day 29. (5) Cytokines (including IL-6, TNF-a, IFN-y, and I L-l-|3) were assayed from samples obtained Day 1 (pre-dose and four hours), Day 2, and Day 5.

[0349] Pharmacokinetics urine samples was collected on Day 1 for pharmacokinetics analysis at the following intervals: 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, 24-48 hours, 48-72 hours, and 72-96 hours post-dose.

[0350] A 12-lead safety electrocardiogram (ECG) was collected at Day -1, on Day 1 at pre-dose, 1.5 hours, three hours, six hours, and twelve hours post-dose, on Day 2, Day 3, and Day 4.

[0351] Standard biochemistry (HbAlc at Screening Day), hematology, and urinalysis tests at Day -1, Day 2, Day 4, Day 5, Day 8, Day 15, Day 22, Day 29, and Day 36.

[0352] A total of 32 blood samples was collected for pharmacokinetics plasma analysis relative to the end of dose administration time on Day 1 (pre-dose, thirty minutes, one hour, two hours, four hours, six hours, eight hours, ten hours, twelve hours, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours), Day 8 (pre-dose, eight hours, and twenty-four hours), Day 15 (pre-dose, eight hours, and twenty-four hours), and on Day 22 (pre-dose, thirty minutes, one hour, two hours, four hours, six hours, eight hours, ten hours, twelve hours, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours).

[0353] A total of six blood samples was collected and analyzed for protein binding on Day 1 (one hour, four hours, and twelve hours) and on Day 22 (one hour, four hours, and twelve hours).

[0354] Pharmacodynamic blood samples for the following tests was collected at the following times: (1) Total IgA, IgE, and IgM: Day 1 (pre-dose) and Day 25. (2) Total IgG (including subclasses IgGl, lgG2, lgG3, and lgG4): Day -1, Day 1 (pre-dose, four hours, eight hours, twenty-four hours, forty-eight hours, seventy-two hours, and 96), Day 8 (pre-dose, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours), Day 15 (pre-dose, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours), Day 22 (pre-dose, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours), and on Day 36, Day 50, and Day 64.

[0355] A 12-lead safety electrocardiogram was collected at Day -1, Day 1 (pre-dose, 2, 4, 8, 12, and 24 hour), Day 8 (pre-dose, two hours, four hours, eight hours, twelve hours, and twenty-four hours), Day 15 (pre-dose, two hours, four hours, eight hours, twelve hours, and twenty-four hours), Day 22 (predose, two hours, four hours, eight hours, twelve hours, and twenty-four hours), and on Day 26.

[0356] Standard biochemistry (HbAlc at Screening Day), hematology, and urinalysis tests was performed at Day -1, Day 2, Day 4, Day 7, Day 9, Day 11, Day 14, Day 16, Day 18, Day 21, Day 23, Day 26, Day 36, Day 50, and Day 64.

[0357] Thirty-two blood samples was collected for pharmacokinetics plasma analysis relative to the end of dose administration time on: Day 1 (pre-dose, thirty minutes, one hour, two hours, four hours, six hours, eight hours, ten hours, twelve hours, twenty-four hours, forty-eight hours) Day 5 (pre-dose, and twenty-four hours), Day 8 (pre-dose, eight hours, and twenty-four hours), Day 15 (pre-dose, eight hours, and twenty-four hours), and on Day 22 (pre-dose, thirty minutes, one hour, two hours, four hours, six hours, eight hours, ten hours, twelve hours, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours).

[0358] A total of 6 blood samples was collected and analyzed for protein binding on Day 1 (one hour, four hours, and twelve hours) and on Day 22 (one hour, four hours, and twelve hours).

[0359] Pharmacodynamic blood samples for the following tests were collected and assayed for (1) Total IgA, IgE, and IgM: Day 1 (pre-dose) and Day 25. (2) Total IgG (including subclasses IgGl, lgG2, lgG3, and lgG4): Day -1, Day 1 (pre-dose, twenty-four hours, forty-eight hours, seventy-two hours, ninety-six hours, 120 hours, and 144 hours), Day 8 (pre-dose, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours), Day 15 (pre-dose, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours), Day 22 (pre-dose, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours), and on Day 36, Day 50, and Day 64.

[0360] A 12-lead safety electrocardiogram was collected at Day -1, Day 1 (pre-dose, two hours, four hours, eight hours, twelve hours, and twenty-four hours), Day 4 (pre-dose, two hours, four hours, eight hours, twelve hours, and twenty-four hours), Day 8 (pre-dose, two hours, four hours, eight hours, twelve hours, and twenty-four hours), Day 15 (pre-dose, two hours, four hours, eight hours, twelve hours, and twenty-four hours), Day 22 (pre-dose, two hours, four hours, eight hours, twelve hours, and twenty-four hours), and on Day 26.

[0361] Standard biochemistry assays included HbAlc from Screening Day, hematology, and urinalysis tests was performed at Day -1, Day 2, Day 4, Day 5, Day 7, Day 9, Day 11, Day 14, Day 16, Day 18, Day 21, Day 23, Day 26, Day 36, Day 50, and Day 64.

[0362] Approximately 3-10% of the population is affected by autoimmune disease, many of which are associated with pathogenic IgG autoantibodies, and targeting IgG is an essential strategy for treating these disorders. Emerging IgG-targeting therapeutics, including neonatal Fc receptor antagonists, e.g., Vyvgart, efgartigimod alfa-fcab; and Rystiggo, rozanolixizumab-noli, reduce total IgG but are limited by suboptimal pharmacology and pharmacodynamic effects, cannot be co-administered with monoclonal antibodies, have mechanism-based potential effects on cholesterol and albumin, and a relatively long- half life that prevents recovery of IgG until the antibody Fc fragment is cleared.1

[0363] Summary of nonclinical studies. In vitro and in vivo nonclinical studies demonstrate the binding of FCIII-GN3 to ASGPR1 CRD and human IgG subclasses and concentration-dependent FCIII-GN3 mediated uptake of IgG into HepG2 cells and human primary hepatocytes. In safety pharmacology assessments, there were no dose-dependent FCIII-GN3 adverse effects on central nervous system, respiratory, or cardiovascular systems.

[0364] The potential effects of FCIII-GN3 on central nervous, respiratory, and cardiovascular systems were evaluated in studies in compliance with regulations and according to ICH guidelines. In cynomolgus monkey at doses up to 500 mg / kg, FCIII-GN3 did not result in results in functional observational battery evaluations, electrocardiogram, hemodynamic, or respiratory functionparameters. In the hERG assay the half maximal inhibitory concentration (IC50) was 2191.1 pM. These results are not indicative of significant human risk.

[0365] Pharmacokinetics and product metabolism. Absorption. The apparent permeability of FCIII- GN3 was examined in vitro by assessing concentration-dependent, bidirectional transport using MDCKII cell monolayers. FCIII-GN3 at 0.5 pM or 5 pM demonstrated low permeability in MDCKII-BCRP and AbcblKO MDCKII-MDR cells as the permeability values were below those of the relevant control.

[0366] Absorption after a single dose. Following intravenous administration, FCIII-GN3 plasma clearance was moderate in mice (42.3 mL / min / kg; hepatic flow 90 mL / min / kg) and low in rats (6.39 mL / min / kg; hepatic blood flow 77 mL / min / kg) and rabbits (ranging from 0.24 to 0.97 mL / min / kg; hepatic blood flow 70.8 mL / min / kg). Vsswas high in mice (137 L / kg) and low in rats (0.332 L / kg) and rabbits (ranging from 0.03 to 0.11 L / kg). The T1Z was 234 hours in mice, 2.52 to 10.6 hours in rats, 3.70 to 9.18 hours in rabbits, and 16.1 to 88.3 hours in monkeys.

[0367] In a single high-dose intravenous infusion study, rats were administered 750 mg / kg, 1500 mg / kg, or 2000 mg / kg FCIII-GN3 via sixty-minute intravenous infusion. Systemic exposure to FCIII-GN3 was similar between the sexes. Individual plasma concentration-time profiles, Cmax, and AUCiastvalues were similar between males and females. Sex-combined Cmaxand AUCiastvalues of FCIII-GN3 increased with increasing dose from 750 to 2000 mg / kg. The increase in systemic exposure was approximately dose proportional. The NOAEL was defined as 750 mg / kg resulting in Cmaxand AUC0-25hr values of 700,000 ng / mL and 706,000 ng-hr / mL (sex combined), respectively.

[0368] In rats, FCIII-GN3 exposure, based on Coand AUCiast, increased in a dose-proportional manner, and no sex-related differences were observed. In cynomolgus monkeys, exposure based on Cmaxincreased with dose in a less than dose-proportional manner, and exposure based on AUCiastdid not consistently increase with dose.

[0369] Absorption after repeated doses. Repeat-dose TK / pharmacokinetics studies were conducted in Sprague Dawley rats and cynomolgus monkeys.

[0370] Pharmacokinetics / TK of intravenous / subcutaneous administration of FCIII-GN3 in Rats

[0371] As part of a non-GLP toxicity study, TK of FCIII-GN3 was determined in Sprague Dawley rats at doses of 250 mg / kg / day or 500 mg / kg / day once daily for seven consecutive days by intravenous infusion over approximately sixty minutes. Exposure after intravenous infusion increased in a slightly less than dose-proportional manner between the 250 and 500 mg / kg dose levels. There was no evidence of accumulation.

[0372] As part of a non-GLP toxicity study, TK of FCIII-GN3 was determined in Sprague Dawley rats administered 75, 250, or 400 mg / kg / day once daily for fourteen consecutive days by intravenous bolus (75 and 250 mg / kg / day groups) or intravenous slow injection (400 mg / kg / day group). TK was also determined in Sprague Dawley rats administered 250 mg / kg / day subcutaneous daily for fourteen consecutive days. After intravenous dosing, systemic exposure (AUCiast) of FCIII-GN3 generally increased in a dose-proportional manner from 75 to 400 mg / kg / day in both sexes. No accumulation of FCIII-GN3 was observed after multiple intravenous or subcutaneous dosing.

[0373] In a toxicity study, TK of FCIII-GN3 was determined in Sprague Dawley rats administered 50 mg / kg / day, 100 mg / kg / day, or 150 mg / kg / day once daily by intravenous bolus (50 and 100 mg / kg / day) or intravenous slow injection (150 mg / kg / day) for 28 consecutive days. Systemic exposure (Coand AUCiast) of FCIII-GN3 generally increased in a dose-proportional manner from 50 to 150 mg / kg / day in both sexes. No accumulation was observed after multiple intravenous dosing in rats, and no sex-related differences were observed. At the NOAEL of 150 mg / kg / dose, the mean Coand AUCiast values were 651,000 ng / mL and 359,000 ng»h / mL (sexes combined) after 28 days.

[0374] As part of a thirteen-week toxicity study, TK of FCIII-GN3 was determined in Sprague Dawley rats administered vehicle or 150, 250, or 500 mg / kg subcutaneous twice weekly for thirteen weeks.Exposure to FCIII-GN3 was not significantly different (< two-fold) between sexes and did not appear to change following repeated administration of FCIII-GN3. There was no accumulation of FCIII-GN3. The systemic NOAEL was defined at 500 mg / kg resulting in a combined Cmaxand AUC0-24hr values of 49,000 ng / mL and 623,000 ng-h / mL, respectively after thirteen weeks.

[0375] Pharmacokinetics / TK of intravenous / subcutaneous administration of FCIII-GN3 in monkeys.As part of a non-GLP toxicity study, TK of FCIII-GN3 was determined in cynomolgus monkeys administered 1 mg / kg, 3 mg / kg, and 10 mg / kg FCIII-GN3 by intravenous bolus once a week for three consecutive weeks on Day 1, Day 8, and Day 15. Systemic exposure (AUCiast) of FCIII-GN3 generally increased in a greater than dose-proportional manner from 1 mg / kg / week to 10 mg / kg / week in both sexes. Systemic exposure on Day 15 was similar to that on Day 1 at 1 mg / kg / week and 3 mg / kg / week and was higher at 10 mg / kg / week. Overall, no sex-related differences were noted.

[0376] As part of a non-GLP toxicity study, TK of FCIII-GN3 was determined in cynomolgus monkeys administered 75 mg / kg, 250 mg / kg, 375 mg / kg, and 500 mg / kg FCIII-GN3 by intravenous slow bolus once on Day 1, Day 8, and Day 15. The systemic exposure (Cmaxand AUCiast) of FCIII-GN3 increased in a less than dose-proportional manner over the dose range of 75 to 300 mg / kg, and exposures were similar at 375 and 500 mg / kg. No accumulation of FCIII-GN3 or sex-related differences were observed.

[0377] As part of a toxicity study, TK of FCIII-GN3 was determined in cynomolgus monkeys administered doses of 75, 250, or 500 mg / kg FCIII-GN3 slow intravenous bolus injection twice weekly on Day 1, Day 4, Day 8, Day 11, Day 15, Day 18, Day 22, Day 25, and Day 29. The systemic exposure (AUC0. 24) of FCIII-GN3 increased in a less than a dose-proportional manner over the dose range of 75 to 500 mg / kg, and no sex-related differences were observed. At the NOAEL of 1000 mg / kg / week (500 mg / kg dosed twice a week), the mean Coand AUCiastvalues were 5,360,000 ng / mL and 26,200,000 ng»h / mL / week (sexes combined), respectively, on Day 1. Systemic exposure (Coand AUCiast) decreased following repeated administration of FCIII-GN3 (accumulation ratios ranged from 0.318 to 0.555).

[0378] As part of a thirteen-week toxicity study (CRL 20457823), TK of FCIII-GN3 was determined in cynomolgus monkeys administered doses of 250, 500, or 1000 mg / kg FCIII-GN3 by subcutaneous injection twice weekly. Individual plasma concentration-time profiles, Cmax, and AUC values were similar between males and females on Day 1 and Day 89. Cmaxand AUC0-24 of FCIII-GN3 increased in a less than dose-proportional manner with increasing doses and individual Cmaxand AUC0-24 values overlapped between doses for both Day 1 and Day 89.

[0379] Systemic exposure (Cmaxand AUCiast) decreased following repeated administration of FCIII- GN3 (accumulation ratios ranged from 0.473 to 0.676). The NOAEL was defined as 2000 mg / kg / week (1000 mg / kg twice weekly); the mean sex combined Cmaxand AUC0-72 values were 900,000 ng / ml and 20,000,000 ng-h / ml on Day 1, respectively.

[0380] Distribution. FCIII-GN3 exhibited low plasma protein binding in mouse and rat that was independent of concentration and consistent in the range tested. In rabbit, monkey, and human plasma, FCIII-GN3 exhibited concentration-dependent protein binding that was low at 800 pM and very high at 8 and 80 pM. Across rabbit, monkey, and human, the unbound fraction ranged from 0.0% to 1.2% at 8 and 80 pM and was 31.7% in rabbits, 33.1% in humans, and 56.5% in monkeys at 800 pM. The very high binding observed at 8 and 80 pM in these species is likely due to binding to IgG in plasma, which is saturated at 800 pM.

[0381] FCIII-GN3 exhibited low binding to the plasma proteins human serum albumin and human al-acid glycoprotein that was independent of concentration (unbound fraction ranged from 49.0% to 58.9% in human serum albumin and 47.6% to 77.1% in human al-acid glycoprotein).

[0382] Monkey metabolism. After repeated intravenous administration of FCIII-GN3 in monkeys (375 mg / kg / week; 3 / sex), FCIII-GN3 was the major component in monkey liver homogenate and constituted 55.4% of drug-related material. The major metabolites included M1229a, M1229b, and M1114, which resulted from a combination of peptide hydrolysis and O-dealkylation of theacetylglucosamine moiety and accounted for 17.9%, 15.6%, and 10.5% of the drug-related material, respectively. In monkey plasma, FCIII-GN3 was the major circulating component and constituted 99.6% of drug-related material. In total, thirteen metabolites were identified in monkey plasma, which constituted less than 1% of drug-related material.

[0383] A qualitative mass spectrometric assessment of metabolites was performed in urine samples after intravenous administration of 500 mg / kg FCIII-GN3 twice weekly to cynomolgus monkeys. FCIII-GN3 was the major component in monkey urine and constituted approximately 75% of drug- related material at the 0 hour to forty-eight hour time points. In addition to unchanged FCIII-GN3, a total of 15 putative minor metabolites were detected in monkey urine, each constituting < 7.5% of drug- related material. The metabolites resulted from amide bond hydrolysis (peptide and linker), O- dealkylation of the acetylglucosamine moiety, oxidation, hydration, leucine conjugation, and dimerization.

[0384] Pharmacokinetic drug interactions. CYP studies. There was no potential for FCIII-GN3 to induce human CYP1A2, CYP2B6, or CYP3A4 enzymes observed in vitro in cryopreserved hepatocytes by mRNA analysis. These data suggest a low risk of FCIII-GN3 mediating a clinically relevant drug interaction via CYP induction at clinical doses.

[0385] FCIII-GN3 at concentrations up to 200 pM did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 in pooled HLM. Time- and NADPH-dependent inhibitions were assessed by the comparison of IC50 shift ratios between incubations with 0 or 30 minutes of test article preincubation, with and without NADPH. IC50 values were considered to be > 200 pM, the highest concentration tested, indicating low potential for inhibitory CYP-mediated drug interactions.

[0386] Pharmacokinetic drug interactions. Transporter studies. FCIII-GN3 was not an inhibitor of BCRP, BSEP, or P-gp at clinically relevant concentrations studied in inside-out membrane vesicles from HEK293 cells over-expressing human ATP-binding cassette efflux transporters. FCIII-GN3 did not inhibit BSEP-mediated uptake when tested up to an actual concentration of 85.28 pM (inhibition was < 20%).FCIII-GN3 did not inhibit MATE1-, MATE2-K-, OAT1-, OAT3-, OAT1B1-, OAT1B3-, OCTI- or OCT2- mediated uptake at clinically relevant concentrations.

[0387] FCIII-GN3 was incubated with HEK293 cells over-expressing each of the respective human SLC transporters in the presence or absence of inhibitors. FCIII-GN3 was likely not a substrate of MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCTI, and OCT2 transporters at clinically relevant concentrations. There was no significant (> 2-fold) uptake increase and ratio of transport activity in cellswith and without inhibitors. Because FCIII-GN3 demonstrated low permeability in the bidirectional permeability assay, the substrate potential of FCIII-GN3 for BCRP and MDR1 was not evaluated.

[0388] Nonclinical Toxicology studies demonstrated an acceptable safety profile that supports evaluation of FCIII-GN3 in clinical studies in humans.

[0389] Cynomolgus is the most relevant toxicology species for the risk assessment of FCIII-GN3 as FCIII-GN3 binds IgG with high affinity and lowers circulating IgG in cynomolgus as it does in humans. FCIII-GN3 does not bind or lower IgG in rats. This permits cynomolgus to be used in assessing host defense, and in addition, results in similar drug disposition to humans based on comparable protein binding and hepatic metabolism. NOAEL doses in cynomolgus are the highest doses tested (1000 mg / kg / dose 2X weekly [2000 mg / kg weekly] for three months). The Day 1 AUC and Cmax values associated with this dose are associated with 1.45x and 2. Ox multiples, respectively, to the highest projected human AUC and Cmax associated with a 2000 mg dose.

[0390] In a 4-week cynomolgus monkey pivotal study, administration of FCIII-GN3 by twice weekly intravenous administration was well tolerated at dose levels of 75 mg / kg, 250 mg / kg, and 500 mg / kg (150 mg / kg / week, 500 mg / kg / week, and 1000 mg / kg / week). In all treated males and females, serum IgG concentrations decreased by 2-fold to 4-fold at seventy-two hours post-dose on Day 1, when compared to pre-dose values, and remained decreased until the end of the treatment period. This decrease was considered a pharmacological effect of FCIII-GN3. The NOAEL was considered to be 500 mg / kg twice weekly (1000 mg / kg / week).

[0391] In a thirteen-week study, FCIII-GN3 was administered by subcutaneous injection to cynomolgus monkeys at 250, 500, or 1000 mg / kg twice weekly (500, 1000, 2000 mg / kg / week). FCIII- GN3-related changes in immunoglobulins were noted for IgG, in animals receiving > 250 mg / kg / dose, starting from Day 1 at forty-eight hours post-dose until the last time point post-dose on Day 89. This effect is related to the pharmacological activity of FCIII-GN3. The NOAEL for this study was 2000 mg / kg / week (1000 mg / kg twice weekly), the highest dose tested.

[0392] Intravenous bolus dosing of FCIII-GN3 in rat did not yield IgG lowering as expected. Intravenous bolus (thirty seconds to three minutes) injection of FCIII-GN3 at doses > 250 mg / kg in rat led to adverse clinical signs and mortality. Two investigative studies were conducted. A single dose investigative toxicity study suggested that the infusion reaction resulted from the short intravenous bolus time. Administration of FCIII-GN3 at doses of 500 mg / kg was well tolerated in the rat when delivered via slow 60-minute intravenous infusion daily for 7 days. In addition, FCIII-GN3 was administered at 750 mg / kg, 1500 mg / kg, and 2000 mg / kg via slow sixty-minute intravenous infusion in asingle dose study. FCIII-GN3-related clinical observations were noted immediately following dosing at 2000 mg / kg and included decreased activity, cold to touch, uncoordinated movement / abnormal gait, and shallow breathing with full recovery by Day 2. FCIII-GN3-related microscopic results at the Day 3 euthanasia were noted in the kidneys, heart, skeletal muscle, and Harderian gland, with these results showing recovery at Day 8, suggesting reversibility. At 2000 mg / kg, adverse minimal to mild degeneration and necrosis of cardiomyocytes were noted in 3 / 10 males and 3 / 10 females euthanized at Day 3; minimal to mild degeneration and necrosis of myocytes in the skeletal muscle in 4 / 10 males and 2 / 10 females; minimal to marked degeneration and necrosis of acinar cells, and minimal to moderate mixed cell inflammation in the Harderian gland of 6 / 10 males and 1 / 10 female. Regeneration was observed for these results in the heart, skeletal muscle and Harderian gland at the Day 8 euthanasia, demonstrating recovery. Nonadverse minimal tubular vacuolation was noted in kidneys at 2000 mg / kg in males and females. Considered together, the NOAEL for this study was 750 mg / kg in rats with mean AUC0-25hr of 706,000 ng-h / mL and mean Cmax of 700,000 ng / mL.

[0393] In the four-week rat pivotal study minimal vacuolation of renal tubular epithelium was noted in males and females (> 50 mg / kg / day of FCIII-GN3) and was considered non-adverse based on low severity, lack of corresponding clinical signs and clinical pathology changes, as well as partial recovery. Of note, 31% of FCIII-GN3 is excreted in the urine in rats at a dose of 150 mg / kg / day, but < 1% is excreted in cynomolgus at clinically relevant concentrations or in humans. Rat renal changes secondary to polyethylene glycol accumulation likely shows renal excretion of FCIII-GN3 and are considered not relevant to human risk assessment. Renal histology was normal in cynomolgus. The NOAEL for the four-week pivotal study was 150 mg / kg / day.

[0394] In the thirteen-week study, FCIII-GN3 was administered twice weekly by subcutaneous injection to rats at 150, 250, and 500 mg / kg / dose. FCIII-GN3-related local injection site clinical signs and microscopic results were noted at > 150 mg / kg / dose which comprised a clinically observed combination of swollen, dry lesions with or without discharge, scabbed, flaking, bruised, thickened, and / or discolored skin, as well as skin abrasion, and microscopic results of myofiber mixed cell inflammation, degeneration / necrosis, severe ulceration / erosion, with minimal to marked crusts, epidermal hyperplasia / hyperkeratosis, and dermal and subcutaneous tissue inflammation with marked dermal fibrosis. Based on these results, a local injection site NOAEL could not be established. The systemic NOAEL was considered 500 mg / kg / dose, the highest dose tested, based on the lack of any adverse systemic results being noted in any dose group.

[0395] FCIII-GN3 was not cytotoxic, phototoxic, genotoxic, or clastogenic. The standard battery of in vitro and in vivo toxicology studies supports the multiple dosing of FCIII-GN3 at doses of up to 2000 mg per week subcutaneous for 4 weeks at formulation concentrations of up to 250 mg / mL.

[0396] Administration of FCIII-GN3 in studies of pharmacologically relevant species (cynomolgus monkey) lowered IgG by approximately 80% without evidence of infection. In non-pharmacologically relevant species, as expected there was no lowering of IgG or evidence of infection in animals dosed with FCIII-GN3. Risk of infection in humans cannot be excluded due to the role of IgG in host defense.

[0397] Summary of clinical studies. FCIII-GN3 has been evaluated in a Single Ascending Dose (SAD) study conducted in subjects. Thirty subjects received single doses of FCIII-GN3 (six each receiving intravenous doses of 50, 125, 250, and 500 mg and a subcutaneous dose of 500 mg), and a total of 10 subjects have received placebo.

[0398] The cumulative preliminary safety data from the first five cohorts of the ongoing v study indicate that FCIII-GN3 in single doses from 50 mg to 500 mg via intravenous infusion over 30 minutes or in a single dose of 500 mg administered subcutaneously have been well tolerated. There have been no severe adverse events. Most adverse events have been mild, spontaneously resolving, and unrelated to FCIII-GN3. There has been no clinical evidence of infusion-related reactions in the four intravenous Single Ascending Dose cohorts. There was no clinical evidence of adverse dermatological reactions in the single subcutaneous Single Ascending Dose cohort. As a component of safety lab monitoring, subjects have IgG levels assessed throughout the course of the study and no a priori stopping rules with regards to IgG lowering have been met.

[0399] The objectives of this study are to evaluate the safety, tolerability, pharmacokinetics, and FCIII-GN3 pharmacodynamics after subcutaneous administration of single doses and multiple doses in subjects which support further FCIII-GN3 clinical development. This study was supported by safety, tolerability, pharmacokinetics, and pharmacodynamics from the Single Ascending Dose study. Single doses ranging from 50 to 500 mg have been safely administered in humans.

[0400] Rationale for the study population. For the study, subjects without concomitant diseases and medications represent a homogenous population allowing for proper evaluation of the safety, tolerability, pharmacokinetics, and pharmacodynamics profile of a drug without confounding factors.

[0401] Dose selection. Part 1 (Single Ascending Dose) dose escalation levels are anticipated to be up to 1000, up to 2000, and up to 2000 mg FCIII-GN3 or placebo. Part 2 (Multiple Ascending Dose) dose escalation levels are anticipated to be 500, up to 1000, up to 2000, and up to 2000 mg FCIII-GN3 orplacebo. Subjects in Part 2 may have the Day 1 dose amount split and dosed on Day 1 and Day 4 (Part 2b Schedule of Assessments).

[0402] Based on high affinity IgG binding by FCIII-GN3 in humans and cynomolgus, and therefore the low unbound fraction associated with drug in these species, cynomolgus is the relevant toxicology species. Completed nonclinical toxicology studies show the cynomolgus monkeys tolerate subcutaneous exposures of up 1000 mg twice weekly for thirteen weeks without adverse effects. In this EXAMPLE, an initial 1000 mg subcutaneous dose in cynomolgus monkeys was associated with a Day 1 sex-combined mean AUC0-72hr of 20,000 pg-h / mL and Cmax of 900 pg / mL, providing projected margins of 1.45x for AUC and 2. Ox for Cmax for the highest potential study participant dose of 2000 mg. Based on clearance data for FCIII-GN3, no drug accumulation is expected for FCIII-GN3.

[0403] The selected Multiple Ascending Dose starting dose of 500 mg is a dose that has already been evaluated as a single subcutaneous and intravenous dose in the Single Ascending Dose study (twelve active and four placebo).

[0404] The geometric mean Cmaxand AUCinf from the intravenous 500 mg cohort in the Single Ascending Dose study were ~139 pg / mL and ~2,193 pg-h / mL, respectively. The geometric mean Cmaxand AUCinf from the subcutaneous 500 mg cohort in the Single Ascending Dose study were ~115.6 pg / mL and 3172 pg-h / mL, respectively. Tmaxwas reached six hours to twelve hours after a subcutaneous injection. Given the short half-life (< eight hours) and rapid clearance (~99% eliminated in seventy-two hours) of FCIII-GN3, it is anticipated that there was no accumulation with repeat once-weekly dosing or on the proposed split or fractionated dosing schedule.

[0405] The safety margins are calculated as the ratio of the highest tolerated first dose exposure in cynomolgus monkeys, the relevant species to human safety, to the model-derived simulated weekly exposure in humans.

[0406] Pharmacokinetics / pharmacodynamics modeling, based on cynomolgus monkey data, predicts dosing FCIII-GN3 at 500 mg subcutaneously yields a mean reduction in baseline total IgG of ~32% following dose #1. The predicted mean maximum % reduction in total IgG following the fourth and final dose of study drug (Day 22) is '“64%. The mean IgG reduction is predicted to increase with increasing dose and with multiple doses; the net decreases are predicted to be greatest following the first three doses. The decrease in IgG approaches steady-state.

[0407] A second optional dosing regimen for Week 1 is introduced, where the total weekly dose was split or fractionated into two equal administrations on Day 1 and Day 4 (Part 2b), compared to administering the full dose on Day 1. This approach aims to optimize the initial decrease in IgG reduction by employing the same total dose given on a fractionated dosing schedule on the first week. After Week 1, all dosing reverts to the single, weekly, full dose admininstration schedule for three additional consecutive weeks. Fractionating the dose during the first week has a negligable effect on maximum IgG lowering after four weeks of weekly dosing.

[0408] Across all subsequent multiple-dose cohorts, no total FCIII-GN3 weekly dose exceeds that previously evaluated as a single dose in humans and no predicted exposures associated with repeat FCIII-GN3 dosing exceeds the established NOAEL weekly exposures from preclinical studies.

[0409] FCIII-GN3 is a next generation immune modulator designed to have potential benefits over FcRn targeting agents (which also reduce IgG levels). First, FCIII-GN3 was designed to selectively and transiently target IgGl, lgG2, and lgG4 while preserving subclass lgG3. The preservation of lgG3 by FCIII- GN3 is expected to increase the robustness of host defense for a given degree of IgG lowering and may offer benefits to those who require chronic therapy. Second, FCIII-GN3 is a small molecule that allows for easy-to-administer clinical formulations versus healthcare provider-administered subcutaneous formulations of FcRns. Third, FCIII-GN3 is not expected to demonstrate immunogenicity seen with biologies. Fourth, FCIII-GN3 is expected to have a short half-life in humans that ultimately allows for coadministration with standard of care Fc-containing biologies. Finally, FCIII-GN3 is not expected to have effects on albumin, cholesterol, or triglycerides related to the FcRn mechanism of action.

[0410] Antibody or antibody fragments targeting the neonatal Fc receptor (FcRn) with subsequent IgG lowering are currently being developed to treat multiple immune-related disorders. Importantly,increased infections were not seen FcRn inhibitor studies with IgG reductions up to 85% in subjects followed for approximately three months.

[0411] Results in humans recapitulate the FCIII-GN3 monkey study results that dose-dependent and transient lowering of IgGl, lgG2, and lgG4 was similar to FcRn targeting agents. Maximal IgG lowering is expected to occur by ninety-six hours after each dose. Similar to FcRns, it is expected that any transient lowering of IgG in humans returns to 50% of baseline in approximately two weeks and return to 20% in approximately four-six weeks.

[0412] The cumulative evidence based on the nonclinical toxicology, prior studies with FcRn inhibitors, and safety data from the Single Ascending Dose study supports the multiple dosing of FCIII- GN3 at doses of up to 2000 mg per week subcutaneous for 4 weeks at formulation concentrations of up to 250 mg / mL.

[0413] Benefit / risk assessment. FCIII-GN3 was given to subjects solely for research and development purposes and is not anticipated to provide any benefit to the study subjects. The use of placebo does not deprive subjects of any potential benefit from FCIII-GN3.

[0414] The primary objective of this EXAMPLE was to assess the safety and tolerability of FCIII-GN3 following single and multiple dose subcutaneous administration. The secondary objective was to characterize the pharmacokinetics profile of FCIII-GN3 following single and multiple dose subcutaneous administration. Other objectives included (1) To characterize the pharmacodynamics effects of FCIII-GN3 following single and multiple dose subcutaneous administration. (2) To characterize the binding of FCIII- GN3 to plasma proteins. (3) To assess the immunogenicity of FCIII-GN3. (4) To evaluate the effect of FCIII-GN3 on electrocardiogram parameters after single doses of FCIII-GN3. (5) To characterize the urine pharmacokinetics of single doses of FCIII-GN3.

[0415] The primary endpoint of this EXAMPLE was to assess safety and tolerability by reporting the frequency of unique subjects with severe AEs and Grade 3-4 (CTCAE / DAIDS) treatment-emergent laboratory abnormalities. The secondary endpoints of this EXAMPLE were (1) For Part 1 and Day 1 of Part 2: AUC0-72h (for Part 2b), AUC0-96hr, AUC in Cmax, Tmax^ T%, CL / F, and Vd / F. (2) Day 22 of Part 2: AUC0-72h (for Part 2b), AUCo-96hr, AUCinf, Cmax, Tmax, Ty2fRAAuco-96hr, RACmax, CL / F, and Vd / F.

[0416] The sample size of this study is not determined based on statistical calculations. A sample size of approximately eight subjects (six active and two placebo) for Part 1 and approximately ten subjects (eight active and two placebo) for Part 2 is judged adequate to achieve the EXAMPLE objectives. The additional subjects within Part 2 is to allow for dropouts as a result of the study duration.

[0417] This is a single center, randomized, open-label, placebo controlled, single and multiple dose study. This EXAMPLE include two parts. Part 1 includes three single dose cohorts. Part 2 includes four multiple dose cohorts.

[0418] Part 1 (Single Ascending Dose). Each Single Ascending Dose cohort included approximately eight subjects. A staggered dosing schedule was used for the dosing of each Single Ascending Dose cohort. The schedule includes two sentinel subjects (one active and one placebo) dosed initially. The remaining six subjects (five active and one placebo) was dosed after a review of at least twenty-four hours of the available safety and tolerability data from the two sentinel subjects. Part 1: Eligible subjects was randomized on Day 1 to receive either active FCIII-GN3 or placebo. Sentinel subjects was randomized one active and one placebo with the remaining subjects randomized five active and one placebo, for a total of approximately six subjects receiving FCIII-GN3 and two subjects receiving placebo for each Single Ascending Dose cohort.

[0419] Part 2 (Multiple Ascending Dose). Each Multiple Ascending Dose cohort includeed approximately ten subjects (eight active and two placebo). In Part 2, eligible subjects was randomized on Day 1 to receive either active FCIII-GN3 or placebo in a 4:1 ratio, for a total of approximately eight subjects receiving FCIII-GN3 and two subjects receiving placebo for each Multiple Ascending Dose cohort.

[0420] FCIII-GN3 was administered as a subcutaneous dose in the abdomen. The maximum dose volume to be administered is 2 mL per syringe per abdominal quadrant. Several syringes were used for dose escalation levels exceeding 500 mg doses or equivalent placebo. Subsequent doses were rotated to a new abdominal quadrant to avoid two consecutive doses in the same abdominal quadrant.

[0421] The time of day of study drug administration can be consistent for all dose administrations for a subject. A protocol deviation was recorded for any subsequent study drug administration that begins or ends more than sixty minutes from the Day 1 dose time.

[0422] Refer to the IB and the Pharmacy Manual for the detailed preparation and administration procedures.

[0423] Laboratory assessments. Clinical laboratory samples were collected after subjects have been fasting for a minimum of eight hours.

[0424] Glomerular filtration rate was calculated using the 2021 CKD-EPI equation: estimated glomerular filtration rate = 142 x min (Scr / K, 1)“ x max (Scr / K, l)12x 0.9938Agex 1.012. Scr is serum creatinine (mg / dL), K is 0.7 for females and 0.9 for males, a = -0.241 (females) or -0.302 (males), min indicates the minimum of Scr / K or 1.0, and max indicates the maximum of Scr / K or 1.0.

[0425] Subjects had samples collected for the following pharmacodynamic assessments at the timepoints: Total IgA, Total IgE, Total IgG (including subclasses IgGl, lgG2, lgG3, and lgG4), Total IgM, circulating immune complex C3, circulating immune complex Clq, IL-6, TNF a, IFN-y, and I L-l-|3.

[0426] Banked serum samples were collected at the timepoints within the Schedule of Assessments. Banked samples may be analyzed at a later date for: plasma proteins, markers of inflammation, antibodies (including anti-drug antibodies), immunogenicity, hypersensitivity markers, metabolites, lipids, electrolytes, and hormones.

[0427] Statistical analyses. A complete description of the statistical analyses to be performed on safety, pharmacokinetics, and pharmacodynamics data was presented in a statistical analysis plan (SAP). The screened population included all subjects who sign the informed consent form.

[0428] The safety population is defined as all subjects who receive at least one dose of the study medication (FCIII-GN3 or placebo). The safety population was used for the summaries of all safety assessments.

[0429] Pharmacokinetic concentration population. The pharmacokinetic concentration population includes subjects who receive a dose of FCIII-GN3, provide at least one evaluable post-dose pharmacokinetic concentration, and did not experience any protocol deviations or events thought to impact pharmacokinetic. The Holter Electrocardiogram Population included all subjects in the safety population who receive FCIII-GN3 or placebo with measurements at baseline as well as on-treatment with at least one post-dose timepoint with a valid Holter electrocardiogram value. The pharmacokinetic / Holter Electrocardiogram Population includes all subjects who are in the Holter Electrocardiogram Population with at least one pair of post-dose pharmacokinetic concentrations and AQTcF data from the same timepoint as well as subjects in the Holter Electrocardiogram Population who received placebo, for whom concentrations was set to 0.

[0430] Demographic parameters were summarized descriptively. Safety analysis was performed for subjects in the safety population.

[0431] Safety and tolerability were assessed by reporting the frequency of subjects with severe AEs and Grade 3-4 (CTCAE / DAIDS) treatment-emergent laboratory abnormalities. AEs was coded using the latest version of MedDRA.

[0432] Laboratory test results were graded according to numeric laboratory test criteria in CTCAE Version 5.0 (2017) if available, otherwise according to DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected Version 2.1 (2017).

[0433] Prior and concomitant medications was coded using the latest version of the World Health Organization Drug Dictionary (WHODrug).

[0434] Pharmacokinetic parameters. The following pharmacokinetic parameters was calculated for FCIII-GN3 plasma concentrations: For Part 1 and for Part 2 Day 1 and 22, the following pharmacokinetic parameters was calculated: For Part 2b, area under the concentration versus time curve from time 0 to time seventy-two hours. For Part 2b, (1) dose normalized AUC0-72hr, area under the concentration versus time curve from time 0 to time ninety-six hours, (2) dose normalized AUC0-96hr, area under the concentration from time 0 extrapolated to infinity, (3) dose normalized AUCinf, apparent total clearance, maximum observed concentration, (4) dose normalized Cmax, apparent first order terminal elimination half life, time when the maximal concentration is observed, and (5) apparent volume of distribution.

[0435] Additional pharmacokinetic parameters for Part 2 were calculated based on Day 1 and 22 pharmacokinetic, observed accumulation ratio based on AUC0-96hr, calculated as AUC0-96hr on Day 22 / AUC0-96hr on Day 1. For Part 2b, (1) observed accumulation ratio based on AUC0-72hr, calculated as AUC0-72hr on Day 22 / AUC0-72hr on Day 1, and (2) observed accumulation ratio based on Cmax, calculated as Cmaxon Day 22 / Cmaxon Day 1.

[0436] This EXAMPLE was conducted in compliance with the ethical principles that have their origins in the Declaration of Helsinki, the International Council for Harmonisation (ICH) Guideline E6 for Good Clinical Practice (GCP), the FDA GCP Code of Federal Regulations (CFR) Title 21 (part 56), the European regulation EU 536 / 2014 and the Tri Council Policy Statement.EXAMPLE 2Pharmacokinetics of COMPOUND 4 (IgG degrader) in plasma and IgG in serum, after repeat dose subcutaneous administration of COMPOUND 4 to male cynomolgus monkeys

[0437] The purpose of this EXAMPLE was to determine the pharmacokinetics of COMPOUND 4 in plasma and IgG in serum, following subcutaneous administration of COMPOUND 4 to male cynomolgus monkeys. COMPOUND 4 has a chemical formula of C141H219N27O54S2, with a measured molecular weight (g / mol) of 3220.56.

[0438] Nine male cynomolgus monkeys were divided into three groups with three monkeys / group. Monkeys in Group 1, Group 2, and Group 3 were administered COMPOUND 4 by subcutaneous administration twice weekly at 3 mg / kg, 10 mg / kg, and 30 mg / kg for two weeks (dose on Day 1, Day 4, Day 7 and Day 10), respectively. Plasma samples were collected at pre-dose, % hour, one hour, two hours, four hours, eight hours, twenty-four hours, forty-eight hours, and seventy-two hours post-doseon both Day 1 and Day 10 for all groups. Serum samples were collected at pre-dose, twenty-four hours, forty-eight hours, and seventy-two post- dose on Day 1 and Day 10, 120 hours, 168 hours, 240 hours, and 33six hours post-dose on Day 10 and pre-dose on Day 7. Concentrations of COMPOUND 4 in plasma samples were determined by a liquid chromatography tandem mass spectrometry (LC-MS / MS) method.

[0439] Following twice weekly subcutaneous administration of COMPOUND 4 at 3 mg / kg, 10 mg / kg, and 30 mg / kg for two weeks in male cynomolgus monkeys, systemic exposure (AUC0-iast) values of COMPOUND 4 on Day 1 were 277750145066 ng / mL, 27768461445099, ng / mL, and 1440060315351258 ng-h / mL, respectively. The Cmax values were 4379517168 ng / mL, 226473168003 ng / mL, and 5566621139888 ng / mL, while Tmax was reached at 3.3311.15, 5.3312.31 and 6.6712.31 h, respectively.

[0440] Following twice weekly subcutaneous administration of COMPOUND 4 at 3 mg / kg, 10 mg / kg, and 30 mg / kg for two weeks in male cynomolgus monkeys, systemic exposure (AUCO-last) values of COMPOUND 4 on Day 10 were 29832317387 ng-h / mL, 172329711061482 ng-h / mL, and 12393821575287 ng-h / mL, respectively. The Cmaxvalues were 3982612740 ng / mL, 141552171614 ng / mL, and 141732166950 ng / mL, while Tmaxwas reached at 4.0010.00 hours, 4.6713.00 hours, and 3.3311.15 hours, respectively.

[0441] On Day 1, the AUC0-iast of COMPOUND 4 increased greater than proportional to dose (except from 10 mg / kg to 30 mg / kg which was approximately proportional to dose) while Cmaxincreased approximately proportional to dose.

[0442] On Day 10, systemic exposure (AUCO-last and Cmax) of COMPOUND 4 increased less than proportional to dose except from 3 mg / kg to 10 mg / kg where the systemic exposure increased approximately proportional to dose.

[0443] After twice weekly subcutaneous administration of COMPOUND 4 for two weeks, no marked accumulation of COMPOUND 4 in male cynomolgus monkeys was observed when comparing the systemic exposure (AUCO-last and Cmax) on Day 10 versus on Day 1 at 1 mg / kg and 3 mg / kg. There is a decrease in exposure on Day 10 compared to Day 1 at 30 mg / kg with an accumulation index of 0.0861 for AUCO-last and 0.255 for Cmax. All animals tolerated COMPOUND 4 well during the entire course of the study. No adverse effect was observed during the in- life phase of the study.

[0444] The total IgG percentage compared with baseline was decreasing sharply from day 1 and up to day 11. At day 11 the total IgG % was the lowest level. Approximately 93% total IgG was cleared in G3 (30 mg / kg), approximately 72% of total IgG was cleared in G2 (10 mg / kg) and approximately 43% of total IgG was cleared in G1 (3 mg / kg) at day 11. After day 12, the total IgG % began to rise and at day 24 thetotal IgG % was comparable to the level at day 0. The results showed that the total IgG clearing was COMPOUND 4 dose dependent, the higher dose of COMPOUND 4 given, the lower the concentration of total IgG.

[0445] For the subcutaneous dose route, the following pharmacokinetic parameters were assayed: Cmax (ng / mL), Tmax (hours), T% (hours), AUCO-last (ng»h / mL), AUCO-24 (ng»h / mL), and AUCO-inf (ng»h / mL).

[0446] From the cynomolgus monkeys, approximately 0.5 mL blood were collected at each time point via peripheral vessel from each study animal. The actual time of each sample collection was recorded.

[0447] Pharmacokinetics data analysis. The plasma concentrations of COMPOUND 4 in study animals were subjected to a non-compartmental pharmacokinetic analysis by using the Phoenix WinNonlin software (version 8.3.5, Certara). The linear / log trapezoidal rule was applied in obtaining the pharmacokinetic parameters.

[0448] All animals tolerated COMPOUND 4 well during the entire course of the study. No adverse effect was observed during the in vivo phase of the study.

[0449] The actual doses were determined by UPLC-UV.

[0450] Pharmacokinetics of COMPOUND 4 in animals. Following twice weekly subcutaneous administration of COMPOUND 4 at 3 mg / kg, 10 mg / kg, and 30 mg / kg for two weeks in male animals.

[0451] Following twice weekly subcutaneous administration of COMPOUND 4 at 3 mg / kg, 10 mg / kg, and 30 mg / kg for two weeks in male cynomolgus monkeys, systemic exposure (AUCO-last) values of COMPOUND 4 on Day 1 were 277750145066 ng-h / mL, 27768461445099 ng-h / mL, and 1440060315351258 ng-h / mL, respectively. The Cmax values were 4379517168 ng-h / mL, 226473168003 ng-h / mL, and 5566621139888 ng / mL, while Tmax were reached at 3.3311.15 hours, 5.3312.31 hours, and 6.6712.31 hours, respectively.

[0452] Following twice weekly subcutaneous administration of COMPOUND 4 at 3 mg / kg, 10 mg / kg, and 30 mg / kg for two weeks in male cynomolgus monkeys, systemic exposure (AUCO-last) values of COMPOUND 4 on Day 10 were 29832317387 ng-h / mL, 172329711061482 ng-h / mL, and 12393821575287 ng-h / mL, respectively. The Cmaxvalues were 3982612740, 141552171614 and 141732166950 ng / mL, while Tmaxwere reached at 4.0010.00 hours, 4.6713. Osix hours, and 3.3311.15 hours, respectively.

[0453] On Day 1, the AUCO-last of COMPOUND 4 increased greater than proportional to dose (except from 10 mg / kg to 30 mg / kg which was approximately proportional to dose) while Cmax increased approximately proportional to dose.

[0454] On Day 10, systemic exposure (AUCO-last and Cmax) of COMPOUND 4 increased less than proportional to dose except from 3 mg / kg to 10 mg / kg where the systemic exposure increased approximately proportional to dose.

[0455] After twice weekly subcutaneous administration of COMPOUND 4 for two weeks, no marked accumulation of COMPOUND 4 in male cynomolgus monkeys was observed when comparing the systemic exposure (AUCO-last and Cmax) on Day 10 versus on Day 1 at 1 mg / kg and 3 mg / kg. There is a decrease in exposure on Day 10 compared to Day 1 at 30 mg / kg with an accumulation index of 0.0861 for AUCO-last and 0.255 for Cmax. All animals tolerated COMPOUND 4 well during the entire course of the study. No adverse effect was observed during the in vivo phase of the EXAMPLE.

[0456] Assay results were collected for Day 1 individual and mean plasma concentrations (ng / mL) of COMPOUND 4 in male cynomolgus monkeys following twice weekly subcutaneous administration of COMPOUND 4 at 3 mg / kg for two weeks. The individual and mean plasma concentrations of COMPOUND 4 are shown.

[0457] Assay results were collected for Day 1 individual and mean plasma concentrations (ng / mL) of COMPOUND 4 in male cynomolgus monkeys following twice weekly subcutaneous administration of COMPOUND 4 at 10 mg / kg for two weeks. The individual and mean plasma concentrations of COMPOUND 4 are shown.

[0458] Assay results were collected for Day 1 individual and mean plasma concentrations (ng / mL) of COMPOUND 4 in male cynomolgus monkeys following twice weekly subcutaneous administration of COMPOUND 4 at 30 mg / kg for two weeks. The individual and mean plasma concentrations of COMPOUND 4 are shown.

[0459] Assay results were collected for Day 10 individual and mean plasma concentrations (ng / mL) of COMPOUND 4 in male cynomolgus monkeys following twice weekly subcutaneous administration of COMPOUND 4 at 3 mg / kg for two weeks. The individual and mean plasma concentrations of COMPOUND 4 are shown.

[0460] Assay results were collected for Day 10 individual and mean plasma concentrations (ng / mL) of COMPOUND 4 in male cynomolgus monkeys following twice weekly subcutaneous administration of COMPOUND 4 at 10 mg / kg for two weeks. The individual and mean plasma concentrations of COMPOUND 4 are shown.

[0461] Assay results were collected for Day 10 individual and mean plasma concentrations (ng / mL) of COMPOUND 4 in male cynomolgus monkeys following twice weekly subcutaneous administration of COMPOUND 4 at 30 mg / kg for two weeks. The individual and mean plasma concentrations of COMPOUND 4 are shown.

[0462] Assay results were collected for Day 1 and Day 10 mean plasma pharmacokinetic parameters of COMPOUND 4 in male cynomolgus monkeys following twice weekly subcutaneous administration of COMPOUND 4 for two weeks. Following subcutaneous administration of COMPOUND 4 at 3 mg / kg, 10 mg / kg, and 30 mg / kg in male animals, mean plasma pharmacokinetic parameters of COMPOUND 4 are shown.

[0463] Assay results were collected for Day 1 individual and mean plasma pharmacokinetic parameters of COMPOUND 4 in male cynomolgus monkeys following twice weekly subcutaneous administration of COMPOUND 4 at 3 mg / kg for two weeks. Following twice weekly subcutaneous administration of COMPOUND 4 at 3 mg / kg, 10 mg / kg, and 30 mg / kg for two weeks at 3 mg / kg, 10 mg / kg, and 30 mg / kg in male animals, the individual and mean plasma pharmacokinetic parameters of COMPOUND 4 are shown.

[0464] Assay results were collected for Day 1 Individual and mean plasma pharmacokinetic parameters of COMPOUND 4 in male cynomolgus monkeys following twice weekly subcutaneous administration of COMPOUND 4 at 10 mg / kg for two weeks. Following twice weekly subcutaneous administration of COMPOUND 4 at 3 mg / kg, 10 mg / kg, and 30 mg / kg for two weeks at 3 mg / kg, 10 mg / kg, and 30 mg / kg in male animals, the individual and mean plasma pharmacokinetic parameters of COMPOUND 4 are shown.

[0465] Assay results were collected for Day 1 individual and mean plasma pharmacokinetic parameters of COMPOUND 4 in male cynomolgus monkeys following twice weekly subcutaneous administration of COMPOUND 4 at 30 mg / kg for two weeks. Following twice weekly subcutaneous administration of COMPOUND 4 at 3 mg / kg, 10 mg / kg, and 30 mg / kg for two weeks at 3 mg / kg, 10 mg / kg, and 30 mg / kg in male animals, the individual and mean plasma pharmacokinetic parameters of COMPOUND 4 are shown.

[0466] Assay results were collected for Day 10 individual and mean plasma pharmacokinetic parameters of COMPOUND 4 in male cynomolgus monkeys twice weekly subcutaneous administration of COMPOUND 4 at 3 mg / kg for two weeks. Following twice weekly subcutaneous administration of COMPOUND 4 at 3 mg / kg, 10 mg / kg, and 30 mg / kg for two weeks at 3 mg / kg, 10 mg / kg, and 30 mg / kgin male animals, the individual and mean plasma pharmacokinetic parameters of COMPOUND 4 are shown.

[0467] Assay results were collected for Day 10 individual and mean plasma pharmacokinetic parameters of COMPOUND 4 in male cynomolgus monkeys twice weekly subcutaneous administration of COMPOUND 4 at 10 mg / kg for two weeks. Following twice weekly subcutaneous administration of COMPOUND 4 at 3 mg / kg, 10 mg / kg, and 30 mg / kg for two weeks at 3 mg / kg, 10 mg / kg, and 30 mg / kg in male animals, the individual and mean plasma pharmacokinetic parameters of COMPOUND 4.

[0468] Assay results were collected for Day 10 Individual and mean plasma pharmacokinetic parameters of COMPOUND 4 in male cynomolgus monkeys twice weekly subcutaneous administration of COMPOUND 4 at 30 mg / kg for two weeks. Following twice weekly subcutaneous administration of COMPOUND 4 at 3 mg / kg, 10 mg / kg, and 30 mg / kg for two weeks at 3 mg / kg, 10 mg / kg, and 30 mg / kg in male animals, the individual and mean plasma pharmacokinetic parameters of COMPOUND 4.

[0469] Assay results were collected for dose proportionality of COMPOUND 4 in male cynomolgus monkeys following twice weekly subcutaneous administration of COMPOUND 4 for two weeks. The evaluation on the dose proportionality of COMPOUND 4 systemic exposure in animals are presented.

[0470] Assay results were collected for accumulation index of COMPOUND 4 in male cynomolgus monkeys following twice weekly subcutaneous administration of COMPOUND 4 for two weeks.

[0471] Assay results were collected for individual and mean body weights (kg) in Male cynomolgus monkeys following twice weekly subcutaneous administration of COMPOUND 4 at 3 mg / kg for two weeks.

[0472] Assay results were collected for individual and mean body weights (kg) in male cynomolgus monkeys following twice weekly subcutaneous administration of COMPOUND 4 at 10 mg / kg for two weeks.

[0473] Assay results were collected for individual and mean body weights (kg) in male cynomolgus monkeys following twice weekly subcutaneous administration of COMPOUND 4 at 30 mg / kg for two weeks.Total IgG level detection in serum of cynomolgus monkeys

[0474] Serum processing for IgG analysis. Each blood collection (about 0.5 mL per time point) was performed from peripheral vein of each animal into commercially available BD tubes containing polymer silica activator and was rested at room temperature for at least thirty minutes. Samples were centrifuged (3200xg for ten minutes at 2°C to 8°C) within one hour of collection. About 0.2 mL of eachserum sample was divided into approximately 0.1 mLx2 aliquots (one for BA, and the other one for back up).

[0475] Kit information. Human / MHP IgG kit, MSD, catalog number K150JLD-2, lot number: K00E0645.

[0476] Instrument information. MESO QuickPlex SQ 120MM.

[0477] Detection protocol. This MSD plates are pre-coated with capture antibodies. (1) Block plate. Add 150 pl of Blocker A solution to each well. Seal the plate with an adhesive plate seal and incubate for 30min with shaking at room temperature. (2) Wash and add sample. Wash the plate three times with 150 pl / well of phosphate-buffered saline-Tween. Add 25 pl of diluted sample or calibrator per well. Seal the plate with an adhesive plate seal and incubate at room temperature with shaking for two hours.(3) Wash and add detection antibody solution. Wash the plate three times with at least 150 pl / well of phosphate-buffered saline-Tween. Add 25 pl of detection antibody solution to each well. Seal the plate with an adhesive plate seal and incubate at room temperature with shaking for two hours. (4) Wash and read. Wash the plate three times with 150 pl / well of phosphate-buffered saline-Tween. Add 150 pl of 2x Read Buffer T to each well. Read the plate on the MSD instrument.

[0478] The total IgG percentage compared with baseline was decreasing sharply from day 1 and up to day 11. At day 11 the total IgG % was the lowest level. Approximately 93% total IgG was cleared in G3 (30 mg / kg). Approximately 72% of total IgG was cleared in G2 (10 mg / kg). Approximately 43% of total IgG was cleared in G1 (3 mg / kg) at day 11. After day 12, the total IgG % began to rise and at day 24 the total IgG % was comparable to the level at day 0. The results showed that the total IgG clearing was COMPOUND 4 dose dependent, the higher dose of COMPOUND 4 given, the lower the concentration of total IgG.Method summary for COMPOUND 4. Acceptance criteria for a bioanalytical run

[0479] Bioanalytical analysis. The concentrations of COMPOUND 4 in plasma were determined by using an LC-MS / MS method.

[0480] Calibration curve: The sample analysis should be performed concurrently with one set of calibration standards using the established LC-MS / MS method. A minimum of 6 calibration standards is back calculated to within ±20% of their nominal values in plasma.

[0481] Quality control (QC): The sample analysis should be performed concurrently with two sets of quality control samples using the established LC-MS / MS method. A set of quality control samples for the method consists of low, middle and high concentrations. A minimum of four out of six quality control samples is back calculated to within ±20% of their nominal values in plasma.

[0482] Specificity and sensitivity: A standard curve consists of at least six non-zero calibration standards for each LC-MS / MS method with a target lower limit of quantitation at <5 ng / mL. The mean calculated concentration in the single blank matrix should be <0.5 times the lower limit of quantitation.

[0483] Carryover: The mean calculated carry-over response in the blanks immediately after the highest standard injection should be < lower limit of quantitation.

[0484] Biological matrix. Plasma Blank male cynomolgus monkey plasma with K2-EDTA as anticoagulant was used for the preparation of calibration standards (C) and quality control samples.

[0485] Sample Processing. The Preparation Procedures for Plasma (for 100-40000 ng / mL), n aliquot of 20 pL sample was quenched with 200 pL internal standard solution (100 ng / mL Labetalol & 100 ng / mL Tolbutamide & 100 ng / mL Verapamil & 100 ng / mL Dexamethasone & 100 ng / mL Glyburide & 100 ng / mL Celecoxib in ACN / MeOH (25: 75, v / v) with 0.1% FA), the mixture was vortex-mixed for 10 min at 800 rpm and centrifuged at 3220xg for 15 min, 4°C. An aliquot of 50 pL supernatant was transferred to another clean 96-well plate and centrifuged at 3220 xg for 5 min, 4°C. Then the supernatant was injected into LC-MS / MS.

[0486] If the analyte is relatively polar, supernatant can be diluted further as below: An aliquot of 10 pL supernatant was transferred to another clean 96-well plate and diluted with 100 pL of ACN / MeOH (25: 75, v:v) with 0.1% FA, vortex-mixed for 10 min at 800 rpm and centrifuged for 5 min at 3220 xg, 4 °C, then sample was injected for LC-MS / MS analysis.

[0487] The preparation procedures for plasma (for 5-5000 ng / mL). An aliquot of 20 pL sample was quenched with 200 pL internal standard solution (100 ng / mL Labetalol & 100 ng / mL Tolbutamide & 100 ng / mL Verapamil & 100 ng / mL Dexamethasone & 100 ng / mL Glyburide & 100 ng / mL Celecoxib in ACN / MeOH ( 25:75, v / v) with 0.1% FA), the mixture was vortex-mixed for 10 min at 800 rpm and centrifuged at 3220xg for 15 min, 4°C. An aliquot of 50 pL supernatant was transferred to another clean 96-well plate and centrifuged at 3220 x for 5 min, 4°C. Then the supernatant was injected into LC- MS / MS.

[0488] Data processing. MultiQuant 3.0.3 software was used for processing the data of all samples. The regression mode was quadratic with l / x2 as weighting factor.EXAMPLE 3Sustained Lowering of Gd-lgA by COMPOUND 1 (Gd-lgAl degrader) in an IgA nephropathy study

[0489] COMPOUND 1 is an engineered bifunctional antibody conjugate designed to selectively recognize and degrade circulating pathogenic serum galactose-deficient immunoglobulin Al (Gd-lgAl)for the treatment of IgA nephropathy (IgAN). COMPOUND 1 is conjugated with asialoglycoprotein receptor (ASGPR) binding moieties to facilitate hepatic removal of bound Gd-lgAl followed by endolysosomal degradation. For more information about COMPOUND 1, see International Patent Publication WO 2024 / 228935 (Biohaven Therapeutics Ltd.).

[0490] IgAN is the most common form of glomerulonephritis worldwide with a clinical presentation that may vary from macroscopic hematuria following episodes of respiratory or gastrointestinal tract infections to insidious or rapidly progressive renal failure. A central finding in patients with IgAN is the presence of circulating and glomerular immune complexes consisting of Gd-lgAl and associated anti- Gd-lgAl auto-antibodies. Knoppova et al., J. Clin. Med., 10(19) (2021). Gd-lgAl plays a pivotal role in the disease pathogenesis, whereby increased circulating Gd-lgAl is bound by immunoglobulin, forming immune complexes which deposit in the glomeruli. These immune complexes are nephritogenic, eliciting glomerular inflammation and resulting in proliferation of mesangial cells leading to a progressive form of renal injury. Activation of the local and systemic renin angiotensin system and complement activation ultimately leads to glomerulosclerosis and tubulointerstitial fibrosis, with loss of renal function. Clinical evidence substantiates the primary role of Gd-lgAl immune complex deposition in initiating and propagating renal pathology. The targeted removal of both Gd-lgAl and associated immune complexes directly addresses disease etiology and therefore is an attractive therapeutic approach for patients with IgAN.

[0491] COMPOUND 1 targets pathogenic Gd-lgAl for protein degradation by selectively and directly degrading circulating levels of both Gd-lgAl and its immune complexes. By selective removal of Gd-lgAl, COMPOUND 1 avoids the immunosuppression seen in non-selective degraders. COMPOUND 1 is the first therapeutic designed to selectively target Gd-lgAl in IgAN, removing pathogenic immunoglobulin and immune complexes without broad immunosuppression. For further details, see the COMPOUND 1 Investigator's Brochure.

[0492] COMPOUND lis a galactose-deficient IgAl (Gd-lgAl)TRAP degrader for the treatment of IgA nephropathy achieved deep, rapid, and sustained reductions in Gd-lgAl.

[0493] IgA nephropathy is the leading cause of glomerular disease globally. IgA nephropathy is commonly diagnosed in individuals in their second and third decades of life, with most individuals progressing to renal failure over the ensuing 10-15 years. As a disease of the immune system, IgA nephropathy frequently returns even after renal transplant. While the 2021 KDIGO treatment guidelines recommended only standard chronic kidney disease treatments, the 2024 draft guidelines emphasize the importance of treating the underlying immune disease by removing aberrant forms of IgA. Galactosedeficient IgAl is the fundamental abnormality in IgA nephropathy. It is a group of IgA molecules that have changes to the sugars on the IgAl hinge region that fundamentally change the way this antibody behaves. It promotes immune complex formation and its these immune complexes that cause glomerular injury and damage and promote loss of kidney function.

[0494] In this EXAMPLE, a single dose of COMPOUND 1 was subcutaneously administered at a dose of 500 mg and achieved rapid, deep and sustained reductions in Gd-lgAl of up to 81%, with a median reduction of 66% (Figure 1). Reductions occurred within hours of each dose, were progressive, and were sustained for weeks after a single dose administration. Effects were selective, with no meaningful reductions caused in other immunoglobulins: IgA, IgG, IgD, IgE, or IgM.

[0495] COMPOUND l's selective approach has the potential to offer an improved safety profile compared to broadly immunosuppressive agents. COMPOUND 1 was safe and well tolerated across the ongoing study. There were no serious or severe adverse events related to drug. There were no clinically significant increases in alanine aminotransferase, aspartate aminotransferase, or bilirubin, no clinically significant reductions in albumin and no clinically significant increases in cholesterol compared to placebo over the four-week dosing period. There were no clinically significant reductions in other immunoglobulins including IgG, IgA, IgD, IgE, or IgM compared to baseline.

[0496] The Gd-lgAl is the same in both healthy volunteers and patients with IgAN it is present in excess quantity in the patients with IgAN. Suppressed levels of Gd-lgAl are observed in healthy subjects. The same effect was seen in patients with IgA nephropathy.

[0497] The graph on the left shows Gd-lgA lowering by Gd-lgA degrader COMPOUND 1 following intravenous ("IV") administration. The graph on the right shows Gd-lgA lowering by Gd-lgA degrader COMPOUND 1 following subcutaneous ("SC") administration. Lowering of Gd-lgAl is sustained longer following subcutaneous administration.

[0498] COMPOUND 1 differentiates from alternative approaches by virtue of its precision. While agents targeting the glucocorticoid receptors may have steroid-like side effects, those targeting complement require vaccination for encapsulated bacterial infections, and B-cell-directing therapies cause reductions in all isotypes of immunoglobulin, potentially increasing long-term infection risk.

[0499] COMPOUND 1 specifically targets the fundamental abnormality in IgA nephropathy while leaving the rest of the immune system untouched. It therefore has the potential to take away the major driver for immune complex formation while leaving other antibodies completely unaffected, meaning it has efficacy with unrivaled safety.

[0500] Placebo-controlled, Single Ascending Dose and Multiple Ascending Dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of COMPOUND 1 in subjects. Th is study was a single center, randomized, placebo-controlled, sequential Single Ascending Dose / Multiple Ascending Dose study conducted in three parts.

[0501] Part 1 - Single Ascending Dose cohorts (intravenous). Each cohort included approximately eight subjects (six subjects receiving active and two subjects receiving placebo), for a total of approximately forty-eight subjects. Subjects received a single intravenous dose of COMPOUND 1 on Day 1 at planned doses of 125 mg, up to 250 mg, and up to 500 mg, or placebo. Subsequent cohorts may explore lower or intermediate doses of COMPOUND 1. Predicted exposures at the highest dose did not exceed the NOAEL from the animal toxicology studies.

[0502] Part 2 - Multiple Ascending Dose cohorts (intravenous). Multiple Ascending Dose cohorts were dosed intravenous weekly for a total of three doses. Dosing in the subsequent Single Ascending Dose panels continued while the Multiple Ascending Dose is ongoing. The Multiple Ascending Dose part consists of approximately five cohorts (one cohort per dose level). Each cohort included approximately eight subjects (six subjects receiving active and two subjects receiving placebo), for a total of approximately forty subjects. Subjects were randomized (3:1) within each dose panel on Day 1 to receive COMPOUND 1 or matched placebo on Day 1, Day 8, and Day 15. Subjects in each Multiple Ascending Dose cohort received three intravenous doses of COMPOUND 1 once per week at planned doses ranging from 125 mg to 500 mg or placebo.

[0503] Part 3 - Single Ascending Dose cohorts (subcutaneous). Up to three cohorts may be completed. Each cohort includes approximately eight subjects (six subjects receiving active and two subjects receiving placebo), for a total of approximately twenty-four subjects. The first subcutaneous Single Ascending Dose cohort started after the dose to be used was tested in an intravenous Single Ascending Dose cohort and safety, tolerability, and pharmacokinetics data are available. Subjects receive a single subcutaneous dose of COMPOUND 1 or placebo on Day 1. The COMPOUND 1 starting dose was up to 500 mg. Subsequent doses were chosen based on emerging data from the intravenous Single Ascending Dose and Multiple Ascending Dose cohorts and the previous subcutaneous cohort. Predicted exposures at the highest dose did not exceed the no observed adverse effect level (NOAEL) from animal toxicology studies.

[0504] Approximately 112 adult males and females of non-childbearing potential are planned to be enrolled in the study, forty-eight in Part 1 Single Ascending Dose (intravenous), forty in Part 2 Multiple Ascending Dose, and twenty-four in Part 3 Single Ascending Dose.

[0505] Doses and follow-up period may be modified based on emerging safety and pharmacokinetics data.

[0506] The primary objectives of this study are (1) to evaluate the safety and tolerability of single and multiple dose intravenous administration of COMPOUND 1 in subjects, and (2) to evaluate the safety and tolerability of single dose subcutaneous administration of COMPOUND 1 in subjects.

[0507] The secondary objectives of this study are (1) to evaluate the plasma pharmacokinetics (PK) of single and multiple dose intravenous administration of COMPOUND 1 in subjects, (2) to evaluate the plasma pharmacokinetics (PK) of single dose subcutaneous administration of COMPOUND 1 in subjects, and (3) to evaluate the effect of COMPOUND 1 on electrocardiogram (ECG) parameters (QTcF, PR interval, QRS complex, heart rate [HR], and T-wave morphology) after single intravenous doses in subjects.

[0508] Other objectives of this study are (1) to evaluate the pharmacodynamic (PD) effects of single and multiple doses of COMPOUND 1 in subjects, (2) to evaluate the immunogenicity of COMPOUND 1 after single and multiple doses of COMPOUND 1 in subjects, and (3) to evaluate the metabolic profile of COMPOUND 1 in plasma.

[0509] The primary endpoints of this EXAMPLE are (1) safety and tolerability were assessed by reporting the frequency of unique subjects with adverse events and Grade 3 and Grade 4 laboratory abnormalities. The secondary endpoints of this EXAMPLE are: (1) For intravenous Single Ascending Dose cohorts: Area under the concentration-time curve (AUC) from time zero to infinity (AUCinf), AUC from time zero to the last quantifiable observation (AUC0-t), the maximum observed plasma concentration (Cmax), time of the maximum observed plasma concentration (Tmax), apparent first-order terminal elimination rate constant (Ty,), total plasma clearance (CL), and volume of distribution ( d). (2) For subcutaneous Single Ascending Dose cohorts: AUCinf, AUC0-t, Cmax, Tmax, Tiag, T / 2,Vd / F and CL / F were calculated. (3) For Day 1 in Multiple Ascending Dose cohorts: AUC from time zero to time 168 hours (AUCo-ies), Cmax, minimum observed plasma concentration (Cmin), Tmax- (4) For Day 15 in Multiple Ascending Dose cohorts: AUC for one dosing interval (T) at steady-state (AUCtau), maximum observed concentration at steady-state (Cmax,ss), minimum observed concentration during dosing interval at steady-state (Cminss), average observed concentration during one dosing interval at steady-state (Cav ss), time of the maximum observed plasma concentration at steady-stat (Tmaxss), Ty„ steady-state plasma concentration at the end of one dosing interval (Ctau), observed accumulation ratio based on AUCtau (RAAuctau), observed accumulation ratio based on Cmax(RACmax), clearance at steady-state (CLSS), volume of distribution at steady-state ( d,ss), and fluctuation ((Cmaxss- Cminss) / Cavss). (5) For Part 1 Single AscendingDose (intravenous): (a) Cardiac parameters as measured by Holter ambulatory monitoring, including change-from-baseline in HR, QTcF, PR, and QRS (AHR, AQTcF, APR, and AQRS). (b) Placebo-corrected AHR, AQTcF, APR, and AQRS (AAHR, AAQTcF, AAPR, and AAQRS) computed from mixed models for repeated measures, including categorical outliers for HR, QTcF, PR, and QRS. (c) Frequency of treatment-emergent changes of T-wave morphology and U-wave presence. (6) For placebo-corrected baseline-adjusted QTcF (AAQTcF), computed from a concentration-response (C-R) model between plasma concentration and changes from baseline in QTcF parameters.

[0510] Primary pharmacology. COMPOUND 1 was extensively characterized as a deglycosylated IgA (Dg-lgA, an enzymatically derived surrogate for Gd-lgAl) degrader in nonclinical in vitro and in vivo primary pharmacology studies. COMPOUND 1 has demonstrated high affinity binding to both its targets, ASGPR (KD =14.6 pM) and Gd-lgAl (KD = 1.8 nM), effectively facilitating hepatic uptake and degradation of Gd-lgAl through the endolysosomal system.

[0511] COMPOUND 1 uses targeted protein degradation to selectively reduce circulating levels of Gd-lgAl and its immune complexes. COMPOUND 1 is a bifunctional chimeric antibody conjugate designed to selectively recognize, bind and target circulating pathogenic Gd-lgAl for degradation via ASGPR in hepatocytes.

[0512] Biophysical and cell-based assay results suggest that COMPOUND 1 selectively binds deglycosylated IgA complexes, sparing fully glycosylated IgAl, and mediate their internalization in vitro at low nanomolar concentrations.

[0513] Safety pharmacology - Neurobehavioral evaluations in rats. COMPOUND 1 was administered intravenously via slow bolus injection (over at least two minutes) every other day for up to 29 days to male and female Wistar Han rats. Administration of COMPOUND 1 every other day was not associated with alterations in neurobehavioral function at doses up to and including 500 mg / kg / dose.

[0514] Safety pharmacology. Electrocardiogram examinations in monkeys. Cynomolgus macaques were dosed by intravenous slow bolus injection over three-five minutes in a one month repeat dose toxicity study in which electrocardiograms were measured once during acclimation, once in week 4, and once in recovery. No COMPOUND 1 abnormalities were observed in electrocardiogram rhythm or waveform morphology. No COMPOUND 1 effects were observed on heart rate, respiratory rate interval, PR interval, QRS duration, QT interval, or corrected QT interval were observed at any dose level based on comparison to group mean pretest and control values.

[0515] Safety pharmacology - Respiratory rate and blood pressure in cynomolgus macaques. Cynomolgus macaques were assessed for respiratory rate and blood pressure as part of the repeat dosestudy once during the acclimation period, once during week 4 and once during recovery. No COMPOUND 1 related effects on blood pressure or respiratory rate were observed during the dosing and recovery periods.

[0516] Pharmacokinetics. Concentrations of COMPOUND 1 were quantified using two bioanalytical methods in plasma samples due to the complex nature of COMPOUND 1. The total antibody method (referred to as Tab) binds at the Fc region of the antibody portion and the total conjugate method (referred to as Tc) binds at the ASGPR binding region. The Tab method detects all DRM containing the antibody portion of COMPOUND 1. The Tc method detects only the DRM containing the ASGPR binding region. Together these methods provide a more complete understanding of the exposure of COMPOUND 1 and related species.

[0517] Absorption. Single-dose non-GLP pharmacokinetics studies were conducted in male nude mice administered intravenous bolus and subcutaneous injection of COMPOUND 1 in the presence or absence of deglycosylated IgA. The COMPOUND 1 plasma exposures with and without coadministration of deglycosylated IgA were not observed to be significantly different. The clearance of COMPOUND 1 is low with values ranging from 0.024 to 0.0879 L / hr / kg over the dose range investigated. The volume of distribution at steady state (Vss) of COMPOUND 1 is greater than total body water with values ranging from 0.96 to 1.62 L / kg over the dose range investigated. The subcutaneous bioavailability in mice ranged from 23% to 91% using closest matched intravenous doses with Cmax values of 2.81 and 6.69 (pg / mL / kg). Tmax values ranged from 26.7 hours to forty-eight hours indicating slow absorption.

[0518] As part of a tolerability study, the toxicokinetics of COMPOUND 1 were determined in cynomolgus macaques that were administered a single dose intravenous slow bolus or subcutaneous. Mean Cmax increased approximately dose-proportionally. Mean AUC values increased greater than proportional to dose. Differences in exposure between males and females were generally less than 2- fold. Mean subcutaneous bioavailability was low (ranging from 2.20% to 9.05%) with Tmaxranging from 4.5 to twenty-seven hours, indicating slow absorption.

[0519] Repeat-dose toxicokinetics studies were conducted in Sprague-Dawley rats, Wistar Han rats, and cynomolgus macaques. After repeat dosing, mean Cmaxincreased approximately dose-proportionally, and mean AUC values increased greater than proportional to dose. No accumulation was observed.

[0520] Metabolism. The in vivo metabolism of COMPOUND 1 was investigated by analyzing Day 9 samples of rat plasma and liver homogenates following intravenous administration of 300 mg / kg every other day. Qualitative examination of the metabolic fate of COMPOUND 1 in plasma revealed a total ofeight metabolites. M1350 (amide hydrolysis and O-dealkylation of acetylglucosamine) was detected as the predominant circulating drug-related material (excluding COMPOUND 1) in rat plasma (AUC0-24) after intravenous dose, constituting more than 76% of drug-related material in plasma, based on MS responses. Qualitative examination of the metabolic fate of COMPOUND 1 in liver homogenates revealed a total of eight metabolites, including M1350 as the predominant drug-related material (excluding COMPOUND 1), constituting more than 83% of total. The metabolic profiles of COMPOUND 1 in rat plasma and liver were observed to be similar.

[0521] The in vivo metabolism of COMPOUND 1 was investigated by analyzing samples of cynomolgus macaque plasma after intravenous administration of a single dose of 500 mg / kg. Qualitative examination of the metabolic fate of BHV1400 in plasma revealed a total of six metabolites that were detected. M1350 (amide hydrolysis and O-dealkylation of acetylglucosamine) was detected as the predominant circulating drug-related material in cynomolgus macaque plasma (AUC0-24pool) after the intravenous dose, constituting more than 66% of total in both female and male cynomolgus macaque, based on MS responses. Metabolic profiles in female and male cynomolgus macaque plasma were observed to be similar.

[0522] Single dose toxicity. Cynomolgus macaques were administered escalating single doses of COMPOUND 1 by slow bolus intravenous injection over two to five minutes at 10 mg / kg / day, 30 mg / kg / day, 100 mg / kg / day, 300 mg / kg / day, and 500 mg / kg / day and once subcutaneous at 100 mg / kg. All doses (intravenous and subcutaneous) up to 500 mg / kg / day were well tolerated with limited differences in clinical pathology parameters (increased C-reactive protein and decreased inorganic phosphorous levels) at 10 mg / kg / dose and 30 mg / kg / dose on Day 2. At the highest dose level tested (500 mg / kg / day), the combined (male and female) Cmax and AUCiastwas 13,500 and 13,900 pg / mL, and the AUGast was 366,000 and 233,000 h»pg / mL, for Tab and Tc, respectively. Additionally, the bioavailability of COMPOUND 1 when administered via subcutaneous injection to cynomolgus macaques at a single dose of 100 mg / kg / dose as assessed by AUC0-72 values, was 9.05% for Tab (combined male and female; 11.6% for females and 6.95% for males) and 6.56% in females and 2.20% in males for Tc%.

[0523] Repeat dose toxicity. COMPOUND 1 was dosed in Wistar Han rats every other day by intravenous injection for at least two minutes for a total of five doses at 0, 30, 100, 300 mg / kg / dose. There were no COMPOUND 1 related effects on study in clinical observations, body weight or body weight gain, food consumption, clinical pathology parameters (hematology, coagulation, and clinical chemistry), or anatomic pathology parameters (organ weights, macroscopic observations, or microscopic results). The NOAEL was 300 mg / kg / dose (the highest dose tested). The plasmaconcentrations on Day 9 for Tab Cmax and AUCIast were 6,300 pg / mL and 25,600 h»pg / mL and for Tc Cmax and AUCIast 6,220 pg / mL and 21,100 h»pg / mL, respectively.

[0524] COMPOUND 1 was administered via intravenous injection for at least two minutes to Wistar Han rats every other day for twenty-nine days (fifteen doses) with vehicle, 50 mg / kg / dose, 150 mg / kg / dose, or 500 mg / kg / dose. No COMPOUND 1-related mortality or definitive effects were observed on clinical / veterinary observations, body weight, food consumption, ophthalmology evaluations, neurobehavioral evaluations, hematology, coagulation, urinalysis, urine chemistry, and renal biomarker parameters, cytokine parameters, organ weights, macroscopic or microscopic evaluations. No adverse results were noted in any parameter evaluated up to and including 500 mg / kg / dose. The NOAEL was 500 mg / kg / dose (the highest dose evaluated). At 500 mg / kg / dose the sex combined Cmaxand AUC for Tab is 9,750 pg / mL and 43,700 h»pg / mL and for Tc 9,990 pg / mL and 39,200 h»pg / mL, respectively.

[0525] Male and female cynomolgus macaques were dosed thrice weekly intravenous with vehicle, 30, 100 or 300 mg / kg / dose of COMPOUND 1 on Days 1, 5, 7, 9, 11, 13, 17, 19, 21, 23, 25, 27, and 29. All animals survived until scheduled termination. There were no COMPOUND 1-related clinical observations. There were no COMPOUND 1-related effects on body weight, food consumption, ophthalmology, electrocardiography including blood pressure and respiratory rate, and hematology, coagulation, urinalysis, and urine chemistry parameters. No adverse results were noted in any parameter evaluated up to and including 500 mg / kg / dose. The NOAEL was 500 mg / kg / dose (the highest dose evaluated). At 500 mg / kg / dose the sex combined Cmaxand AUC for Tab is 9,750 pg / mL and 43,700 h»pg / mL and for Tc 9,990 pg / mL and 39,200 h»pg / mL, respectively.

[0526] Local tolerability was assessed within the one-month intravenous repeat dose toxicity studies in rats and cynomolgus macaques. There were no effects at the injection sites in rat or cynomolgus macaque studies that varied from the vehicle control.

[0527] Local tolerability was assessed in New Zealand White rabbits by single dose subcutaneous administration in three males and three females per dose group. Vehicle and 125 or 250 mg / kg doses were administered in the right and left scapular regions of each rabbit. Mortality, clinical observations, dermal scoring, body weights, body weight gains, and macroscopic and microscopic examinations of selected tissues were evaluated in this study.

[0528] There were no unscheduled deaths or test article-related clinical observations during the course of this study. Body weights were similar for all animals during the study, and there were no test article-related gross pathology results or microscopic results.

[0529] Dermal observations attributable to COMPOUND 1 were minimal, limited to grade 1 erythema and edema in one 125 mg / kg / day female on Day 2, grade 1 erythema in one 250 mg / kg / day male on Day 3 that resolved by Day 4, grade 1 erythema and edema in one 250 mg / kg / day female on Day 2, and grade 1 erythema on Days 2 and 3 and grade 1 edema on Days 2-4 in another 250 mg / kg / day female.

[0530] In conclusion, administration of COMPOUND 1 as a single dose by subcutaneous injection was well tolerated in rabbits at levels of 125 and 250 mg / kg / day, with only minimal dermal irritation observed, primarily in females. Macroscopic and microscopic pathology results were considered procedure-related and were not related to administration of COMPOUND 1.

[0531] Immunotoxicity. Human whole blood was collected, and peripheral blood mononuclear cells (PBMCs) were isolated from ten human donors (five males and five females). PBMCs and whole blood were treated in vitro with varying concentrations of COMPOUND 1. There were no effects on cytokine (IFN-y, IL-2, IL-6, IL-10, IL-10, and TNF-a) release that could be attributed to BHV1400. All changes observed were generally sporadic and of low magnitude. Among the positive controls, anti-CD3 and lipopolysaccharide led to expected increases in all cytokines except IL-2.

[0532] Rationale for study conduct. The objectives of the study were to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of COMPOUND 1 following intravenous and subcutaneous administration of single ascending doses and intravenous multiple ascending doses in adult subjects.

[0533] Single Ascending Dose intravenous cohorts - Starting dose and dose escalation. The calculation of the starting dose for the Single Ascending Dose part of this study was based on the methodology described in the FDA Guidance on Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers and considering the recommendations laid down in the EMA Guideline on Strategies to Identify and Mitigate Risks for First-in-human and Early Clinical Trials with Investigational Medicinal Products.

[0534] The starting human dose of 125 mg COMPOUND 1 was selected based on the totality of the data from the nonclinical pharmacology, pharmacokinetics, and toxicology studies while allowing for a > 45-fold safety factor to the human equivalent dose (HED) of the NOAELs in rat and cynomolgus macaque to maximize participant safety and support a full dose range for the purposes of safety evaluations and pharmacokinetics analyses.

[0535] The preclinical twenty-eight-day toxicology studies in rat and cynomolgus macaque. The highest dose tested in both species was their respective NOAELs (500 mg / kg in rat and 300 mg / kg incynomolgus macaque), resulting in human equivalent doses of 80.6 mg / kg and 96.8 mg / kg, or a flat dose of 5645 mg and 6774 mg, respectively assuming a body weight of 70 kg. Applying a 10-fold safety factor, the rat NOAEL corresponds to a maximum recommended starting dose (MRSD) of approximately 560 mg for a 70 kg human. Two bioanalytical methods (Tc and Tab) are utilized to quantify COMPOUND 1.

[0536] Pharmacokinetics / pharmacodynamics modeling and translational simulations were conducted to support dose selection and dose justification for COMPOUND 1. The pharmacokinetics / pharmacodynamics model was developed with data in mice where COMPOUND 1 was dosed with and without a constructed human Gd-lgAl analog (Dg-lgA). A simplified target-mediated drug disposition (TMDD) model with receptor levels kept constant was used to describe the pharmacokinetics of COMPOUND 1. The final population pharmacokinetics / pharmacodynamics model was a 1-compartment TMDD model with two receptors. Receptor complex, Ml, was formed upon binding of COMPOUND 1 to ASGPR. Receptor complex, M2, was formed upon deglycosylated IgA binding to receptor complex, M2.

[0537] The pharmacokinetics of COMPOUND 1 were characterized with a population pharmacokinetics approach using data collected in cynomolgus macaque. The population pharmacokinetics model for cynomolgus macaque was developed as a one-compartment model with a simplified TMDD model where the total receptor population was held constant. Prediction of human COMPOUND 1 pharmacokinetics was accomplished using allometry and scaling of the TMDD model in cynomolgus macaque. Following modeling of the preclinical data, translational simulations were performed to predict clinical pharmacokinetics for both Tc and Tab quantitation of COMPOUND 1 and percent change of Gd-lgAl following single dose and weekly dosing (Q1W) over a range of COMPOUND 1 doses.

[0538] A starting dose of 125 mg intravenous of COMPOUND 1 was selected to maximize participant safety and support a full dose range for the purposes of safety evaluations, pharmacokinetics, and pharmacodynamics analyses. This dose is > 45-fold below the human equivalent dose of the NOAELs in preclinical toxicology species.

[0539] The predicted AUC,nf for a single 125 mg intravenous dose in a 70 kg human are 139 pg*h / mL for Tc and 858 pg*h / mL for Tab. Both methods have a predicted initial concentration (Co) of 125 pg / mL. These predicted exposure levels indicate margins of at least 70-fold for AUC and 56-fold for Cmaxwhen compared to the observed values at the NOAEL in both preclinical species. Furthermore, the highest planned dose (500 mg) is predicted to produce exposures well below the NOAEL toxicity limits (>thirteen-fold lower). Biohaven Therapeutics, Ltd. c / o Biohaven Pharmaceuticals Inc. (BPI), COMPOUND 1 Investigator's Brochure, Version 2.0 (November 19, 2024).

[0540] Pre-dose and post-dose samples for Gd-lgAl were collected from subjects. The proposed dose range to be studied allows a robust characterization of the pharmacokinetics / pharmacodynamics profile of COMPOUND 1 to inform dose selection for future patient trials. The planned starting dose of 125 mg is predicted to decrease Gd-lgAl; however, since Gd-lgAl is a small fraction (< 1%) of total functional IgA, there are no clinical consequences anticipated with even robust Gd-lgAl lowering.

[0541] Dose escalation scheme. The COMPOUND 1 dose was sequentially escalated cohort by cohort, from the starting dose of 125 mg in the Single Ascending Dose up to a maximum dose of 500 mg. Dose levels in the Single Ascending Dose are: 125 mg (Cohort 1), up to 250 mg (Cohort 2), and up to 500 mg (Cohort 3). Doses lower than 125 mg or intermediate doses to those tested in previous cohorts may be tested in subsequent cohorts, but doses did not exceed a maximum of 500 mg without an amendment. Doses may be adjusted based on emerging safety, tolerability, pharmacokinetics, and pharmacodynamics data. Projected exposures to COMPOUND 1 (Tcand Tab) following single intravenous dose administration in humans. At the highest planned dose level of 500 mg, projected exposure margins are > thirteen-fold based to exposure data at the NOAELs.

[0542] Translational model simulations were conducted to predict the percent change in Gd-lgAl in humans following an intravenous bolus dose of COMPOUND 1, assuming a baseline Gd-lgAl level of 9,000 ng / mL (60 nM). The elimination rate of Gd-lgAl was set to a half-life of five days and the human ASGPR liver receptor density was assumed to be 340 nM. With these assumptions and the projected exposures to COMPOUND 1, near maximum inhibition is predicted with a low dose of COMPOUND 1. In addition to providing safety and tolerability, the Single Ascending Dose portion of this EXAMPLE established the pharmacokinetics / pharmacodynamics relationship between COMPOUND 1 and Gd-lgAl, including time for Gd-lgAl to return to baseline to inform dosing frequency of COMPOUND 1 in later studies.

[0543] Single Ascending Dose subcutaneous starting dose and dose escalation scheme. The single subcutaneous doses of COMPOUND 1 evaluated in each cohort did not exceed dose levels that have been administered intravenous and deemed safe and tolerated; subcutaneous doses in the Single Ascending Dose did not exceed a maximum of 500 mg without an amendment. Following subcutaneous injection in preclinical species, subcutaneous bioavailability was lower than intravenous administration, ranging from 8.1% to 46.0% in mice and 4.13% to 15.5% in cynomolgus monkeys. The exposures following subcutaneous dosing in humans are expected to be lower than the same dose administeredintravenously, resulting in even higher exposure margins (»13-fold) at the highest planned clinical dose of 500 mg.

[0544] Multiple Ascending Dose - Starting dose and dose escalation scheme. The proposed starting dose for the Multiple Ascending Dose is 125 mg administered once weekly (Q1W) for three doses with seven days between doses (Day 1, Day 8, and Day 15). The dose was confirmed based on the safety, tolerability, and pharmacokinetics data, and pharmacodynamics data as available, from the first two dose levels of the Single Ascending Dose part.

[0545] The planned doses of 125 mg (Cohort 1), up to 250 mg (Cohort 2), and up to 500 mg (Cohort 3) may be revised based on predicted exposures from emerging data from the Single Ascending Dose cohorts and the previous Multiple Ascending Dose cohorts. A lower dose or an intermediate dose to those tested in previous cohorts may be tested in subsequent cohorts, but doses did not exceed a maximum of 500 mg without an amendment. The doses, dosing frequency, and follow-up period may be modified based on emerging data. The planned dosing frequency may be modified to every other week dosing based on observed pharmacokinetics or pharmacodynamics from Single Ascending Dose cohorts and preceding Multiple Ascending Dose cohorts. The total duration of dosing did not exceed twentyeight days. Human exposures did not exceed NOAEL exposures from the twenty-eight-day preclinical toxicology studies.

[0546] Predicted COMPOUND 1 steady-state Coand AUC (Tc and Tab) in humans following intravenous administration of COMPOUND 1 at anticipated doses based on preclinical models. At the highest planned dose level of 500 mg, the margin of safety is > 11-fold.

[0547] The primary objectives of this study were (1) to evaluate the safety and tolerability of single and multiple dose intravenous administration of COMPOUND 1 in subjects, and (2) to evaluate the safety and tolerability of single dose subcutaneous administration of COMPOUND 1 in subjects.

[0548] The secondary objectives of this study were (1) to evaluate the plasma pharmacokinetics of single and multiple dose intravenous administration of COMPOUND 1 in subjects, (2) to evaluate the plasma pharmacokinetics (PK) of single dose subcutaneous administration of COMPOUND 1 in subjects, and (3) to evaluate the effect of COMPOUND 1 on electrocardiogram parameters (QTcF, PR interval, QRS complex, HR, and T-wave morphology) after single intravenous doses in subjects.

[0549] Other objectives of this study were (1) to evaluate pharmacodynamics effects of single and multiple doses of COMPOUND 1 in subjects, (2) to evaluate the immunogenicity of COMPOUND 1 after single and multiple doses of COMPOUND 1 in subjects, and (3) to evaluate the metabolic profile of COMPOUND 1 in plasma.

[0550] The primary endpoint of this study was to assess the safety and tolerability by reporting the frequency of unique subjects with adverse events and Grade 3 and Grade 4 laboratory abnormalities

[0551] The secondary endpoint of this study was: (1) For intravenous Single Ascending Dose cohorts: AUCinf, AUC0-t, Cmax,Tmax, Ty„ CL, and d. (2) For subcutaneous Single Ascending Dose cohorts: AUCinf, AUCo-t, Cmax, Tmax, T|ag, Ty!,Vd / F and CL / F. For Day 1 in Multiple Ascending Dose: AUCo-ies, Cmax, Cmin, and T (3) For Day 15 in Multiple Ascend i ng Dose . AUCtau,(4) Cardiac parameters as measured by Holter ambulatory monitoring, including: (a) AHR, AQTcF, APR, and AQRS; (b) AAHR, AAQTcF, AAPR, and AAQRS computed from mixed models for repeated measures; (c) Categorical outliers for HR, QTcF, PR, and QRS. (d) Frequency of treatment-emergent changes of T-wave morphology and U-wave presence, (e) AAQTcF computed from a C-R model between plasma concentration and changes from baseline in QTcF parameters.

[0552] Part 1 - Single Ascending Dose cohorts (intravenous)* Six cohorts, each at a different dose level are planned, for a total of approximately forty-eight subjects.

[0553] The planned dose range is anticipated to be from 125 mg to 500 mg of COMPOUND 1 or placebo. Doses may be modified based on emerging safety and pharmacokinetic data, but did not exceed 500 mg.

[0554] A staggered dosing schedule was used for the dosing of each cohort and included two subjects (one active and one placebo) dosed initially. The remaining six subjects dosed at least fortyeight hours later after review of the available safety and tolerability data.

[0555] Part 2 - Multiple Ascending Dose intravenous cohorts. Dosing in the subsequent Single Ascending Dose panels continue while the Multiple Ascending Dose is ongoing. The Multiple Ascending Dose part consists of approximately five cohorts (one cohort per dose level), for a total of approximately forty subjects.

[0556] Subjects were randomized (3:1) within each dose panel on Day 1 to receive COMPOUND 1 or matched placebo on Day 1, Day 8, and Day 15.

[0557] The planned total daily Multiple Ascending Dose range is anticipated to be from 125 mg Q1W up to a maximum dose that did not exceed 500 Q1W mg of COMPOUND 1. Doses and dosing frequency may be modified based on emerging safety and pharmacokinetic data.

[0558] Part 3 - Single Ascending Dose Cohorts (subcutaneous). Up to three cohorts may be completed for a total of approximately twenty-four subjects. The first subcutaneous Single AscendingDose cohort start after the dose to be used was tested in an intravenous Single Ascending Dose cohort and safety, tolerability, and pharmacokinetic data are available.

[0559] A staggered dosing schedule was used for the dosing of each cohort and included two sentinel subjects (one active and one placebo) dosed initially. The remaining six subjects dosed at least forty-eight hours later after review of the available safety and tolerability data.

[0560] The starting dose of COMPOUND 1 was up to 500 mg. Subsequent doses were chosen based on emerging data from the intravenous Single Ascending Dose and Multiple Ascending Dose cohorts and the previous subcutaneous cohort. Predicted exposures at the highest dose did not exceed the no observed adverse effect level (NOAEL) from animal toxicology studies.

[0561] In Part 1 Single Ascending Dose (intravenous), a total of up to 21 blood samples were collected for pharmacokinetics analysis Day 1 at: pre-dose, at the end of the infusion, thirty minutes, 1- hour, 2-hours, 3-hours, 4-hours, 6-hours, 8-hours, and twelve hours post infusion, Day 2 (twenty-four hours post infusion), Day 3 (forty-eight hours post infusion), Day 4 (seventy-two hours post infusion), and Day 5 (ninety-six hours post infusion), and on Day 10, Day 15 ± one day, Day 30 ± three days, and on Day 45, Day 60, Day 75, and Day 90 ± five days.

[0562] In Part 3 Single Ascending Dose (subcutaneous), a total of up to 21 blood samples were collected for pharmacokinetics analysis Day 1 at pre-dose, thirty minutes, 1-hour, 2-hours, 3-hours, 4- hours, 6-hours, 8-hours, 10-hours, and Twelve hours post-dose, Day 2 (twenty-four hours post-dose), Day 3 (forty-eight hours post-dose), Day 4 (seventy-two hours post-dose), and Day 5 (ninety-six hours post-dose), and on Day 10, Day 15 ± one day, Day 30 ± three days, and on Days 45, 60, 75, and 90 ± five days.

[0563] Pharmacodynamics blood samples for the following tests were collected at the following times: (1) Total IgA, Day 1 (pre-dose), Day 3 (seventy-two hours post-dose), Day 5 (ninety-six-hours postdose), Day 10, Day 15 ± one day, and Day 30 ± three days. (2) Gd-lgAl: Day 1 at pre-dose, 4-, and 8-hrs post-dose, Day 2 (twenty-four hours post-dose), Day 3 (forty-eight hours post-dose), Day 4 (seventy-two hours post-dose), Day 5 (ninety-six hours post-dose), Day 10, Day 15 ± one day, Day 30 ± three days, and on Days 45, 60, 75, and 90 ± five days. (3) Total IgE, total IgG, total IgM: Day 1 (pre-dose), Day 3 (seventy-two hours post-dose), Day 5 (ninety-six hours post-dose), Day 10, Day 15 ± one day, and Day 30 ± three days. (4) Circulating Immune Complex C3: Day 1 at pre-dose and 4-hrs post-dose, Day 2 (twenty- four hours post-dose), Day 3 (forty-eight hours post-dose), Day 4 (seventy-two hours post-dose), Day 5 (ninety-six hours post-dose), Day 10, and on Day 15 ± one day. (5) Banked serum: Day 1 (pre-dose), Day 2 (twenty-four hours post-dose), Day 3 (forty-eight hours post-dose), Day 4 (seventy-two hours post-dose), Day 5 (ninety-six hours post-dose), Day 10, Day 15 ± one day, Day 30 ± three days, and on Days 45, 60, 75, and 90 ± five days.

[0564] Samples for anti-drug antibodies were collected on Day -1 and Day 30 ± three days.

[0565] A 12-lead safety electrocardiogram were collected at Day -1, on Day 1 (pre-dose, 1.5-hrs and 6-hrs post-dose), Day 2 (twenty-four hours post-dose), Day 3 (forty-eight hours post-dose), Day 4 (seventy-two hours post-dose), Day 5 (ninety-six hours post-dose). For eligibility purposes (Day -1, and pre-dose Day 1) an abnormal value may be verified with two repeats such that there are triplicate readings.

[0566] Holter Electrocardiogram Monitoring was done in Part 1 Single Ascending Dose (intravenous) and were performed for approximately 25 hours beginning on Day 1.

[0567] Standard biochemistry (HbAlc at Screening Day), hematology, and urinalysis tests were performed at Day -1, Day 2, Day 4, Day 5, Day 10, Day 15 ± one day, Day 30 ± three days, and on Days 45, 60, 75, and 90 ± five days. Serum chemistry tests were performed after at least an 8-hour fast; however, in case of dropouts or rechecks, subjects may not have fasted for eight hours before when the serum chemistry sample is taken.

[0568] Up to thirty-six blood samples were collected for pharmacokinetics analysis on Day 1 and Day 15 at pre-dose, at the end of the infusion, thirty minutes, one hour, two hours, three hours, four hours, six hours, eight hours, twelve hours, thirteen hours, forty-eight hours, seventy-two hours, and ninety-six hours post infusion. A single sample was collected in the morning on Day 8 (pre-dose) and Day 9. Additional pharmacokinetics samples were collected at Day 24, Day 30 ± one day, and on Day 60, Day 75, Day 90, and Day 105 ± five days.

[0569] Pharmacodynamics blood samples for the following tests were collected at the following times, (1) Total IgA: Screening Day, pre-dose on Day 1, Day 8, Day 15, Day 19, and Day 30 ± one day. (2) Gd-lgAl at Day 1 (pre-dose, four hours, and eight hours post-dose), Day 2 (twenty-four hours postdose), Day 4, Day 8 (pre-dose), Day 12, Day 15 (pre-dose), Day 19, Day 24, Day 30 ± one day, Day 45 ± three days, and on Days 75 and 105 ± five days. (3) Total IgE, total IgG, total IgM at pre-dose on Day 1, Day 8, Day 15, Day 19, and Day 30 ± one day. (4) Circulating Immune Complex C3: Day 1 (pre-dose), Day 2, Day 8 (pre-dose), Day 9, Day 15 (pre-dose), Day 16, and Day 19. (5) Banked serum at Day 1 (pre-dose), Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8 (pre-dose), Day 9, Day 10, Day 11, Day 12, Day 13, Day 14, Day 15 (pre-dose), Day 16, Day 17, Day 18, Day 19, Day 24, Day 30 ± one day, and on Day 60 and Day 105 ± five days.

[0570] A 12-lead safety electrocardiogram was collected at Day -1, Day 1, Day 8, and Day 15, at predose, 1.5-hours, six hours, twenty-four hours, forty-eight hours, and seventy-two hours post-dose, Day 19, and Day 24. For eligibility purposes (Day -1, and pre-dose Day 1) an abnormal value may be verified with two repeats such that there are triplicate readings.

[0571] Standard biochemistry (HbAlc at Screening Day), hematology, and urinalysis tests were performed at Day -1, Day 2, Day 4, Day 7, Day 9, Day 11, Day 14, Day 16, Day 19, Day 24, Day 30, and Day 45 ± one day, and on Day 60, Day 75, Day 90, and Day 105 ± two days. Serum chemistry tests were performed after at least an eight-hour fast.

[0572] The CKD-EPI equation was used to calculate the estimated glomerular filtration rate. See the CKD-EPI Creatine Equation - National Kidney Foundation (2021). Estimated glomerular filtration rate = 142 x min (Scr / K, 1)“ x max (Scr / K, I)1 209x 0.9938Agex 1.012 if female. Scr is serum creatinine (mg / dL), K is 0.7 for females and 0.9 for males, a = -0.241 (females) or -0.302 (males), min indicates the minimum of Scr / K or 1, and max indicates the maximum of Scr / K or 1.

[0573] Pharmacokinetic (PK) sample collection and processing. Plasma concentrations of the study drug were determined using validated analytical methods.

[0574] Pharmacodynamic (PD) blood sample collection and processing. Subjects had the following samples collected for the following pharmacodynamic assessments for the Multiple Ascending Dose part, Gd-lgAl, total IgA, total IgE, total IgG, total IgM, circulating immune complex C3, and anti-drug antibodies. Banked samples may be analyzed at a later date for plasma proteins, additional pharmacokinetics measurements, markers of inflammation, antibodies, immunogenicity, hypersensitivity markers, metabolites, lipids, electrolytes, and hormones.

[0575] The COMPOUND 1 drug product (DP) is colorless to slightly yellow, clear to slightly opalescent, and essentially free of visible particles. Each vial contains 2 mL (100 mg) of extractable volume. The corresponding placebo for COMPOUND 1 is 0.9% saline, homogeneous, clear, colorless liquid.Method of treatment assignment / randomization.

[0576] Part 1. Eligible subjects were randomized on Day 1 to receive either active COMPOUND 1 or placebo. Sentinel subjects were randomized one active to one placebo with the remaining subjects randomized five active to one placebo, for a total of approximately six subjects receiving COMPOUND 1 and two subjects receiving the placebo in each Single Ascending Dose intravenous cohort.

[0577] Part 2. Eligible subjects were randomized on Day 1 to receive either active COMPOUND 1 or placebo in a 3:1 ratio, for a total of approximately six subjects receiving COMPOUND 1 and two subjects receiving placebo for each Multiple Ascending Dose cohort.

[0578] Part 3. Eligible subjects were randomized on Day 1 to receive either active COMPOUND 1 or placebo. Sentinel subjects were randomized one active to one placebo with the remaining subjects randomized five active to one placebo, for a total of approximately six subjects receiving COMPOUND 1 and two subjects receiving the placebo in each Single Ascending Dose subcutaneous cohort.

[0579] One randomization scheme was produced for each cohort.

[0580] Subjects who complete the study screening assessments and meet all the eligibility criteria were assigned a unique identification number per the randomization code at the time of the first dosing, different from the screening number. Once a randomization number is assigned, it cannot be reassigned.

[0581] Study drug administration - intravenous. COMPOUND 1 and placebo were administered via a syringe intravenous pump. The syringe intravenous pumps should be programmed immediately before each dose and require a second staff member to verify the correct settings have been programmed compared to the Pharmacy Manual.

[0582] A syringe infusion was conducted. The beginning infusion time and end of infusion time of dose administrations were recorded. All post dose study procedures were scheduled based on the end of the infusion time. Refer to the the Pharmacy Manual for the detailed preparation and administration procedures.

[0583] Study drug administration - subcutaneous. COMPOUND 1 or placebo were administered as a subcutaneous dose in the abdomen. The maximum dose volume to be administered is 2 mL per syringe, so for doses greater than 100 mg, multiple injections were administered. Refer to the Pharmacy Manual for the detailed preparation and administration procedures.

[0584] The Holter Electrocardiogram Population include all subjects of the Single Ascending Dose portion of the study who receive COMPOUND 1 or placebo by intravenous with measurements at baseline as well as on-treatment with at least one post-dose timepoint with a valid Holter electrocardiogram value.

[0585] The pharmacokinetics / Holter Electrocardiogram Population include all subjects who are in the Holter Electrocardiogram Population with at least one pair of post-dose pharmacokinetics concentrations and AQTcF data result from the same timepoint as well as subjects in the Holter Electrocardiogram Population who received placebo.

[0586] Single Ascending Dose pharmacokinetic parameters. The following pharmacokinetic parameters were calculated for COMPOUND 1 plasma concentrations from the Single Ascending Dose cohorts: AUCinf, AUC0-t, Percentage of AUC(inf) extrapolated beyond the last measurable concentration, dose normalized AUC0-t, dose normalized AUCinf, CL (CL / F for subcutaneous cohorts), Cmax, dose normalized Cmax,Ty2, Tmax, Tiag(for subcutaneous cohorts), and d (Vd / F for subcutaneous cohorts).

[0587] Multiple Ascending Dose pharmacokinetics parameters. The following pharmacokinetics parameters were calculated for COMPOUND 1 plasma concentrations from the Multiple Ascending Dose cohorts. For Day 1 in Multiple Ascending Dose, (1) AUCo-ies, (2) Cmax, (3) Cmin, and (4) Tmax. For Day 15 in Multiple Ascending Dose, (1) AUCo-t, (2) AUCtau, (3) CaVgss, (4) CLSS, (5) CmaXss, (6) Cmin ss, (7) Ctau, (8) FfuCtUatiOn

[0588] Pharmacokinetic statistical analyses. Pharmacokinetic analysis was performed using Phoenix’ WinNonlin®. Inferential statistical analyses were performed using SAS®. Individual and mean plasma concentration versus time curves were presented for both linear and semi-log scales. Descriptive statistics of the plasma concentrations versus time were presented by dose / administration type and day, as appropriate, and for the pharmacokinetic parameters. Concentration exposure was compared across study parts, dose / administration type, and / or study days graphically. Power models were fitted to the log transformed AUC0-t, AUCinf, and Cmax for Single Ascending Dose separately by administration type and for Multiple Ascending Dose Dayau, and Ctau.

[0589] Cardiodynamic electrocardiogram endpoints. The electrocardiogram endpoints are (1) Change-from-baseline in HR, QTcF, PR, and QRS (AHR, AQTcF, APR, and AQRS). (2) Placebo-corrected AHR, AQTcF, APR, and AQRS (AAHR, AAQTcF, AAPR, and AAQRS). (3) Categorical outliers for HR, QTcF, PR, and QRS. (4) Frequency of treatment-emergent changes of T-wave morphology and U-wave presence. (5) Placebo-corrected baseline-adjusted QTcF (AAQTcF), computed from a concentration-response (C-R) model between plasma concentration and changes from baseline in QTcF parameters.

[0590] Cardiodynamic electrocardiogram baseline. For all continuous electrocardiogram parameters, the baseline is as the average of the measured electrocardiogram intervals from the three pre-dose timepoints on Day 1. For T-wave morphology and U-wave presence, baseline includes results observed in any of the replicates from the three timepoints before dosing on Day 1.

[0591] Concentration-QTc analysis. For Single Ascending Dose intravenous cohorts, the relationship between COMPOUND 1 plasma concentration and AQTcF were quantified using a linear mixed-effects modeling approach with AQTcF as the dependent variable, drug plasma concentration as an explanatoryvariate (0 for placebo), centered baseline QTcF, i.e., baseline QTcF for individual subject subtracting the population mean baseline QTcF for all subjects, as an additional covariate, study treatment (active = 1 or placebo = 0), and time, i.e., post-baseline timepoint, as fixed effects. Subject-specific random effects were included on the intercept and slope with an unstructured covariance matrix. When the unstructured covariance matrix was not supported by the data, other simplified or reduced structures were investigated, for example, variance components.

[0592] The degree of freedom estimates was determined by the Kenward-Roger method. Kenward & Roger, Biometrics, 53, 983-997 (1997). From the model, the slope, i.e., the regression parameter for the concentration, and the treatment effect-specific intercept (defined as the difference between active and placebo). The time effect was estimated together with the 2-sided 95% confidence interval.

[0593] The geometric mean of the individual Cmax values for subjects on each dose and each day of active drug were determined. The predicted effect and its two-sided 90% confidence interval for AAQTcF, i.e., slope estimate x geometric mean Cmax + treatment effect-specific intercept, at this geometric mean Cmaxwere obtained.

[0594] The plot of the observed median-quantile COMPOUND 1 concentrations and associated mean placebo-adjusted AQTcF (i.e., AAQTcF) with 90% confidence interval adjusted for diurnal effects together with the regression line presenting the predicted AAQTcF was used to evaluate the adequacy of the model fit to the assumption of linearity and the impact on quantifying the concentration-response relationship. The observed AQTcF values from the active groups were adjusted by the estimated time effect from the concentration-corrected QT interval model, i.e., the estimated diurnal effect under the placebo treatment. For evaluation of the HR-corrected QT interval, a scatter plot and quantile plot of QTcF and respiratory rate intervals by treatment with regression line and linear mixed-effects line (90% confidence interval), respectively, also were given. Additional exploratory analyses (via graphical displays and / or model fitting) include accounting for a delayed effect (hysteresis) and the justification for the choice of the pharmacodynamic model (linear versus nonlinear).EXAMPLE 4Subcutaneous administration of COMPOUND 3 lgG4 degrader results in potent lgG4-depletion and high subcutaneous bioavai lability in mice

[0595] COMPOUND 3 is a heterobifunctional molecule comprised of an anti-lgG4 nanobody and an ASGPR ligand, for the treatment of lgG4-AIDs. COMPOUND 3 specifically targets circulating lgG4 andredirects it to the liver for ASGPR-dependent lysosomal degradation in hepatocytes. For more details about the COMPOUND 3, see International patent application PCT / IB2025 / 050867.

[0596] This EXAMPLE shows a series of pharmacological studies conducted to evaluate COMPOUND 3 in an in vivo mouse model.

[0597] Of four optimized anti-lgG4 degraders, one form of COMPOUND 3 was_selected as the first candidate for a self-injectable device.

[0598] The objectives of this EXAMPLE were to determine the potential toxicity of COMPOUND 3 when given as an intravenous bolus injection as a single dose of 100 mg / kg to nude mice, and to evaluate pharmacokinetic profile of COMPOUND 3 and its pharmacodynamic effect when given as an intravenous bolus or as a subcutaneous injection on exogenously administered human lgG4 in nude mice.

[0599] Identification of test article and vehicle used in studies of tolerability, pharmacodynamics, and pharmacokinetics.

[0600] Phosphate-buffered saline (PBS) pH 7.4 (lx) is commercially available from Gibco.

[0601] Pharmacodynamic studies. On day 0 mice are weighed and randomized. All groups of mice received hlgG4 intravenously fifteen minutes before their treatment (intravenous or subcutaneous injections of 0.77 mg / kg COMPOUND 3). COMPOUND 3 was administered at a molar ratio of 4:1 (COMPOUND 3: lgG4). After an established period, groups of three animals for each route of administration were bled at two time points. For one time point, 100 pl of blood were collected using the submandibular vein. The same mice are subjected to a second blood collection at the later timepoint via exsanguination following CO2asphyxiation. Individual animal blood was harvested in K3E tubes and plasma was separated. All samples are stored at -80°C until they were evaluated.

[0602] Assay method to measure plasma concentrations of hlgG4. Anti-Dsg3 lgG4 concentrations were measured using Streptavidin plates (Cat#: L15SA-1- Meso Scale Discovery) according to the manufacturer's instructions. According to the manufacturer's instructions. Briefly, plates were blocked with MSD blocking buffer A for one hour. After three washes with MSD wash buffer (0.05% Tween-20 in phosphate-buffered saline), plates were coated with biotinylated anti-lgG4 antibody (catalogue #: 3854- 6-250 - Mabtech) for one hour. Plates were washed again three times with MSD wash buffer and plasma samples (diluted to 1:1000) and standards were added to the plate (one hour). Following incubation, the samples were removed, and the plates were washed three times with MSD wash buffer. Detection antibodies (human non-human primate kappa detection antibody - Cat# D20TF-6 and human non-human primate lambda detection antibody - Cat#D20QG-6 MSD) were then added and incubated for one hour. After removing the detection antibodies, the plates were washed three times more with MSD wash buffer. MSD reading buffer was added and the plate was read using the MSD reader.

[0603] All incubation steps were conducted at room temperature with shaking at 700 rpm.

[0604] The standard curve was generated using the same hlgG4 used for in vivo portion of the study and were serially diluted to cover a range of values (49 pg / ml to 200,000 pg / ml). The raw valueswere then fitted into a four-parameter logistic (4PL) curve to interpolate the hlgG4 concentration in the samples.

[0605] Assay method to measure plasma concentrations of COMPOUND 3. COMPOUND S concentrations were measured using Streptavidin plates (Cat#: L15SA-1- Meso Scale Discovery) according to the manufacturer's instructions. Briefly, plates were blocked with MSD blocking buffer A for one hour. After three washes with MSD wash buffer, plates were coated with monoclonal anti-VHH biotinylated antibody (Cat#: A01995 - Genscript) for 1.5 hours. Following incubation, plates were washed three times with MSD wash buffer and plasma samples (diluted to 1:1000) and standards were added to the plate (two hours). The samples were removed, and the plates were washed three times with MSD wash buffer. Detection antibody was labeled using an anti-VHH cocktail antibody (Cat# - A02014- Genscript) were then added and incubated for one hour. After removing the detection antibodies, the plates were washed three times with MSD wash buffer. MSD reading buffer was added and the plate was read using the MSD reader.

[0606] The standard curve was generated using COMPOUND 3 and were serially diluted to cover a range of values (0 ng / ml to 100 ng / ml). The raw values were then fitted into a four-parameter logistic (4PL) curve to interpolate the COMPOUND 3 concentration in the samples, ng / ml.

[0607] All incubation steps were conducted at room temperature with shaking at 700 rpm.

[0608] COMPOUND 3 was tolerated well at doses £100 mg / kg.

[0609] Mice dosed with 50 or 100 mg / kg of COMPOUND 3 did not show any signs of toxicity or behavioral changes compared to untreated mice.

[0610] COMPOUND 3 administered intravenous or subcutaneous significantly depletes hlgG4. Plasma hlgG4 antibodies that were administered exogenously were measured at 0 hours, 0.08 hours, 0.25 hours,1Z hour, one hour, two hours, eight hours, twenty-four hours, forty-eight hours, seventy-two hours, and ninety-six hours. In the control group, hlgG4 levels remained stable over ninety-six hours, with a slight, expected, reduction.

[0611] FIG. 23 is a line graph showing COMPOUND 3 reduces circulating lgG4 in nude mice. Mice that received COMPOUND 3 (intravenous or subcutaneous) fifteen minutes after hlgG4, demonstrated significant hlgG4 depletion compared to hlgG4 only control mice.

[0612] FIG. 24 is a bar graph showing COMPOUND 3 reduces circulating lgG4 in nude mice hlgG4 reduction was further quantified as area under the curve, which showed that COMPOUND 3 intravenous and subcutaneous administration depleted hlgG4 by 71% and 87.3%, respectively, compared to control group. Each data point is the mean value of hlgG4 plasma concentration (n = three per time point) at theindicated timepoint. The error bars represent standard deviations of the mean. Each bar is mean AUC of hlgG4 over a period of ninety-six hours. Error bars represent standard error of the mean. Statistical significance was calculated by performing one-way ANOVA.

[0613] COMPOUND 3 pharmacokinetics.

[0614] FIG. 25 is a line graph showing the pharmacokinetics of COMPOUND 3. COMPOUND 3 (intravenous and subcutaneous) was detected in the blood plasma up to two hours post-injections.

[0615] FIG. 26 is a line graph showing the pharmacokinetics of COMPOUND 3. Subcutaneous bioavailability was calculated using the formula: F=AUC subcutaneous (two hours) / AUC intravenous (two hours), F=71%.

[0616] Each data point is the mean value of COMPOUND 3 in blood plasma (n = three per time point). The error bars represent standard deviations of the mean. (B) Each bar is mean AUC of COMPOUND 3 (intravenous and subcutaneous) over a period of two hours. Error bars represent standard error of the mean.

[0617] Conclusions. The objective of this EXAMPLE was to characterize properties of COMPOUND 3 in an in vivo mouse model. COMPOUND 3 was found to be well tolerated at the doses tested (£100mg / kg). COMPOUND 3 mediated robust reductions in hlgG4 concentration. A single intravenous injection of COMPOUND 3 reduced exogenous hlgG4 by 71% whereas subcutaneous administration led to an 87.3% reduction. Pharmacokinetic studies showed that subcutaneous bioavailability of COMPOUND 3 was 71%. The results of this EXAMPLE show that COMPOUND 3 can target lgG4 and promote clearance in mice, consistent with its mechanism of action.EXAMPLE 5COMPOUND 2 (B1AR autoantibody degrader) for the treatment of cardiomyopathySingle Ascending Dose (SAD) / Multiple Ascending Dose (MAD)

[0618] A randomized, placebo-controlled, single ascending dose and multiple ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of COMPOUND 2 in adults. COMPOUND 2 injection, provided as 50 mg / mL, was administered as an on-site-prepared intravenous (IV) infusion or subcutaneous (SC) administration. The corresponding placebo for COMPOUND 2 is 0.9% saline.

[0619] COMPOUND 2 subcutaneous administration was assayed in the mouse. COMPOUND 2 is nearly 100% bioavailable subcutaneous in the mouse. At a lower dose (0.2 mpk) the Cmax is instant. The Cmax was not instant with a 2 mpk dose The formulation was neat phosphate-buffered saline. Sampletimes at five minutes, fifteen minutes, thirty minutes, one hours, two hours, four hours, eight hours, and twenty-four hours. The Tmax for the 2 mg / kg dose was fifteen minutes.

[0620] This EXAMPLE discloses is a randomized, open-label, placebo controlled, sequential Single Ascending Dose / Multiple Ascending Dose study in subjects. The parts are (1) Part 1 - Single Ascending Dose cohorts (intravenous dosing). (2) Part 2 - Multiple Ascending Dose cohorts (intravenous dosing) were dosed weekly for a total of three doses / cohort. (3) Part 3 - Single Ascending Dose cohorts (subcutaneous dosing). (4) Part 4 - Multiple Ascending Dose cohorts (subcutaneous dosing) were dosed weekly for a total of three doses / cohort.

[0621] Part 1 (Single Ascending Dose intravenous dosing). Part 1 comprises a Single Ascending Dose administration of COMPOUND 2 up to a maximum of four cohorts (one cohort per dose level). Each Single Ascending Dose cohort include approximately eight subjects (six subjects receiving active and two subjects receiving placebo, for a total of approximately thirty-two subjects.

[0622] A staggered dosing schedule was used for the dosing of each cohort. The schedule includes two sentinel subjects (one active and one placebo) dosed initially. The remaining six subjects (five active and one placebo) was dosed after a review of at least twenty-four hours of the available safety and tolerability data from the two sentinel subjects.

[0623] The planned Single Ascending Dose range is anticipated to be from 100 mg up to 500 mg single intravenous dose of COMPOUND 2. Predicted exposures at the highest dose are not expected to exceed the NOAEL from the animal toxicology studies.

[0624] Part 2 (Multiple Ascending Dose intravenous dosing). The Multiple Ascending Dose parts consist of up to 6 cohorts (one cohort per dose level) including Multiple Ascending Dose intravenous (Part 2) and Multiple Ascending Dose subcutaneous (Part 4) dosing. Each cohort include approximately eight subjects (six subjects receiving active and two subjects receiving placebo) for a total of approximately forty-eight subjects.

[0625] With the current EXAMPLE design including the evaluation of single dose levels prior to starting with multiple dose administration, the Single Ascending Dose cohorts functions similar to that of sentinel subjects for the Multiple Ascending Dose cohorts. Based on simulated human pharmacokinetic and the ASGPR-mediated clearance of COMPOUND 2, minimal accumulation of COMPOUND 2 in plasma is expected with multiple dose administration.

[0626] The planned total daily dose in the Multiple Ascending Dose part of the study is anticipated to range from 100 mg up to a maximum dose that does not exceed 500 mg of COMPOUND 2Q1W. Doses and dosing frequency may be modified based on emerging safety and pharmacokinetic data. Projected exposures at the highest dose tested did not exceed the NOAEL in rats.

[0627] Part 3 (Single Ascending Dose subcutaneous dosing). Up to two cohorts may be completed. Each cohort include approximately eight subjects (six subjects receiving active and two subjects receiving placebo), for a total of approximately sixteen subjects. The first subcutaneous Single Ascending Dose cohort started after the dose to be used was tested in an intravenous Single Ascending Dose cohort.

[0628] A staggered dosing schedule was used for the dosing of each cohort. The schedule two sentinel subjects (one active and one placebo) dosed initially. The remaining six subjects (five active and one placebo) was dosed after a review of at least twenty-four hours of the available safety and tolerability data from the two sentinel subjects.

[0629] Part 4 (Multiple Ascending Dose subcutaneous dosing). The Multiple Ascending Dose parts consist of up to six cohorts (one cohort per dose level) including Multiple Ascending Dose intravenous (Part 2) and Multiple Ascending Dose subcutaneous (Part 4) dosing.

[0630] The planned total daily dose in the Multiple Ascending Dose subcutaneous part of the EXAMPLE did not exceed 500 mg of COMPOUND 2 Q1W. The doses, dosing frequency, and follow-up period maybe modified based on emerging data. The planned dosing frequency may be modified to every other week dosing based on observed pharmacokinetics from Single Ascending Dose cohorts and preceding Multiple Ascending Dose cohorts.

[0631] For the single ascending dose, the primary objectives were (1) to characterize the safety and tolerability of single dose intravenous administration of COMPOUND 2 in subjects, and (2) to characterize the safety and tolerability of single dose subcutaneous administration of COMPOUND 2 in subjects. The secondary objectives were (1) To characterize the plasma pharmacokinetics (PK) of single dose intravenous administration of COMPOUND 2 in subjects, (2) to characterize the plasma pharmacokinetics of single dose subcutaneous administration of COMPOUND 2 in subjects, and (3). To characterize the effect of COMPOUND 2 on electrocardiogram (ECG) parameters (QTcF, PR Interval, QRS complex, HR, and T-wave morphology) after a single intravenous dose of COMPOUND 2. Other objectives were (1) to characterize the metabolic profile of COMPOUND 2 in plasma, (2) (to characterize the pharmacodynamic (PD) effects of COMPOUND 2 after single dose COMPOUND 2 administration in subjects, and (3) To characterize the immunogenicity of COMPOUND 2 after single dose administration of COMPOUND 2 in subjects. For the multiple ascending dose, the primary objectives were (1) to characterize the safety and tolerability of multiple dose intravenous administration of COMPOUND 2 insubjects, and (2) to characterize the safety and tolerability of multiple dose subcutaneous administration of COMPOUND 2 in subjects. The secondary objectives were (1) to characterize the plasma pharmacokinetics of COMPOUND 2 after multiple dose intravenous administration of COMPOUND 2 in subjects, and (2) to characterize the plasma pharmacokinetics of COMPOUND 2 after multiple dose subcutaneous BHV1600 administration in subjects. Other objectives were (1) to characterize the COMPOUND 2 pharmacodynamic effects after multiple dose administration of COMPOUND 2 in subjects, (2) to characterize the COMPOUND 2 immunogenicity after multiple dose administration of COMPOUND 2 in subjects, and (3) to characterize the BHV1600 urine pharmacokinetics after multiple dose intravenous and subcutaneous administration of COMPOUND 2 in subjects.

[0632] For the single ascending dose, the primary endpoint was to assess safety and tolerability by reporting the frequency of unique subjects with serious adverse events and Grade 3-4 (CTCAE / DAIDS) laboratory abnormalities. The secondary endpoints were (1) For intravenous Single Ascending Dose cohorts (Part 1): COMPOUND 2 AUC0-t, AUCinf, AUCo-ies, Cmax, Tmax, Ty„ CL, d, and T|ast, after a single dose. (2) For subcutaneous Single Ascending Dose cohorts (Part 3): AUCinf, AUC0-t, Cmax, Tmax, Tlag, T1 / 2,Vd / F and CL / F was calculated. (3) For Part 1 Single Ascending Dose (intravenous), cardiac parameters as measured by Holter ambulatory monitoring, including (a) Change-from-baseline in HR, QTcF, PR, and QRS (AHR, AQTcF, APR, and AQRS). (b) Placebo-corrected AHR, AQTcF, APR, and AQRS (AAHR, AAQTcF, AAPR, and AAQRS) computed from mixed models for repeated measures, (c) Categorical outliers for HR, QTcF, PR, and QRS. (d) Frequency of treatment-emergent changes of T-wave morphology and U-wave presence.(f) Placebo-corrected baseline-adjusted QTcF (AAQTcF), computed from a concentration-response (C-R) model between plasma concentration and changes from baseline in QTcF parameters.

[0633] For the multiple ascending dose, the primary endpoint was to assess safety and tolerability by reporting the frequency of unique subjects with SAEs, severe AEs, AEs leading to discontinuation, deaths, and Grade 3-4 (CTCAE / DAIDS) laboratory abnormalities. The secondary endpoints were (1) For intravenous cohorts (Part 2) and subcutaneous cohorts (Part 4) Day 1: AUC0-t, AUCo-ies, Cmin, Cmax, Tmax. (2) For intravenous cohorts (Part 2) Day 15 (steady state): AUCtau, Ctau, Cmax ss, taneous cohorts (Part Day(steady state):

[0634] Holter electrocardiogram (Part 1 Single Ascending Dose intravenous dosing): For continuous electrocardiogram recording (Holter monitoring) in the Single Ascending Dose cohorts, calculations from the Holter electrocardiogram data were completed for: (1) Change-from-baseline in HR, QTcF, PR, and QRS (AHR, AQTcF, APR, and AQRS). (2) Placebo-corrected AHR, AQTcF, APR, and AQRS(AAHR, AAQTcF, AAPR, and AAQRS) computed from mixed models for repeated measures. (3) Categorical outliers for HR, QTcF, PR, and QRS. (4) Frequency of treatment-emergent changes of T-wave morphology and U-wave presence. (5) Placebo-corrected baseline-adjusted QTcF (AAQTcF), computed from a concentration-response (C-R) model between plasma concentration and changes from baseline in QTcF parameters.

[0635] The analysis for the ECG recording was based on concentration QTc modeling of the relationship between COMPOUND 2 and change-from-baseline in QTcF (AQTcF) with the intent to exclude an effect of placebo-corrected AQTcF (AAQTcF) > 10 msec at observed COMPOUND 2 plasma concentrations.

[0636] Pharmacokinetics. Individual and mean plasma concentration versus time curves was presented for both linear and semi-log scales. Summary statistics was used to describe the plasma concentrations and pharmacokinetics parameters of COMPOUND 2 for each dose level / administration type.

[0637] The power model approached was performed on transformed

[0638] AUCo-t, AUCO-inf, and Cmax for Single Ascending Dose and for Multiple Ascending Dose Day 1 AUCo-t and Cmax,

[0639] Multiple Ascending Dose Day 15 AUCtau, Cmax ss, Ctau and AUC0-t to assess doseproportionality for the intravenous administration type and subcutaneous if applicable.

[0640] COMPOUND 2 is a bifunctional extracellular protein degrader designed to selectively bind circulating anti-01 adrenergic receptor (01AR) autoantibodies, redirecting them to the liver for asialoglycoprotein receptor (ASGPR)-mediated endolysosomal degradation. It consists of three parts: a peptide that mimics the second extracellular loop of the 01AR, an ASGPR binder, and a polyethylene glycol (PEG) linker.

[0641] Clinical evidence supporting the rationale for removal of autoantibodies in dilated cardiomyopathy is underpinned by studies reporting improved outcomes in dilated cardiomyopathy after immunoadsorption (IA) therapy. Dungen et al., Circ. Heart Fail., 13(1), e006155 (2020).

[0642] Immunoadsorption studies have consistently demonstrated that removal of total IgG, or selective removal of the lgG3 subclass, is associated with improved cardiac function, an increase in mean left ventricular ejection fraction, or a delay in time to or need of cardiac transplant. Dandel et al., Eur. J. Heart Fail., 14(12), 1374-88 (2012), Muller et al., Circulation, 101(4), 385-91 (2000), Felix et al., J. Am. Coll. Cardiol., 35(6), 1590-8 (2000), and Schimke et al., J. Clin. Apher., 20(3), 137-42 (2005).

[0643] Re-appearance of piAR-specific autoantibodies after immunoadsorption was correlated with worsening cardiac function. Magnusson et al., Circulation, 89(6), 2760-7.

[0644] Guideline-directed medical therapy (GDMT) for heart failure in this population utilizes the same supportive care that is used for heart failure with reduced ejection fraction, a condition impacting a different demographic with significantly distinct etiologies. Current GDMT does not address the underlying pathophysiology of autoimmune dilated cardiomyopathy, but rather offers supportive care, attempting to ameliorate the signs and symptoms of the disease, without impacting the cause of the myocardial dysfunction. Plasmapheresis and specific anti-piAR autoantibody IA have been used with moderate success in these clinical scenarios. These autoantibody removal approaches have shown both acute and long-term effects on cardiac function and remodeling. Bian, Wang, & Li, Medicine (Baltimore), 100(26), e26475 (2021). These therapies are expensive and complex due to the need for vascular access and repeated therapy, rendering these options demanding and impractical on a large scale. For further information, see COMPOUND 2 Investigator Brochure vl.0. Biohaven, 2024.

[0645] COMPOUND 2 exhibited low permeability and was not a substrate of human p- glycoprotein (P-gp).

[0646] The plasma pharmacokinetics profile for COMPOUND 2 was determined following bolus intravenous administration or subcutaneous injection in mice, rats, dogs, and cynomolgus macaques. Following intravenous administration or subcutaneous administration, clearance was low. Bioavailability was > 50% for all species.

[0647] Following once-every-other-day intravenous injection for at least 4 weeks at a dose level of 50, 150 or 500 mg / kg in Sprague Dawley rats or 30 250 mg / kg, 100 250 mg / kg, or 250 mg / kg in cynomolgus macaques, increases in Cmax and AUCiastwere approximately dose proportional on Day 1 and Day 29, there were no sex-related differences observed and there was little to no accumulation between Day 1 and Day 29.

[0648] Summary of Clinical Studies. The objectives of this EXAMPLE are to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of COMPOUND 2 after administration of single ascending doses and multiple ascending doses in adult subjects.

[0649] Single Ascending Dose - Starting dose selection (intravenous). The calculation of the intravenous starting dose for Single Ascending Dose part (Part 1) was based on the methodology described in the Food and Drug Administration (FDA) Guidance on Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers and considering therecommendations laid down in the European Medicines Agency (EMA Guideline on Strategies to Identify and Mitigate Risks for First-in-human and Early Clinical Trials with Investigational Medicinal Products.

[0650] The starting human dose of 100 mg COMPOUND 2 intravenous was selected based on the totality of the data from the nonclinical pharmacology, pharmacokinetics, and toxicology studies while allowing for a > 50-fold safety factor to maximize participant safety and support a full dose range for the purposes of safety evaluations and pharmacokinetics analyses.

[0651] In both rats and monkeys, the highest dose tested was the NOAEL (500 mg / kg in rats, 250 mg / kg in monkeys), resulting in the same human equivalent dose (HED) of the NOAELs of 80.6 mg / kg, or a flat dose of 5645 mg assuming a body weight of 70 kg. Mean sex-combined Cmax (2080 pg / mL) and AUGnf (1150 pg*h / mL) in rats at the NOAEL were slightly lower than those observed in monkeys and are the basis for projected exposure margins.

[0652] Pharmacokinetics modeling and translational simulation were conducted to support dose selection and dose justification for COMPOUND 2. The COMPOUND 2 pharmacokinetics were characterized with a population pharmacokinetics approach using data collected in monkeys. A three- compartment pharmacokinetics model with linear clearance was fit to available monkey data and allometric simulations were utilized to project human COMPOUND 2 pharmacokinetics. Linear elimination clearance and distribution clearance were assumed to scale to humans with the standard allometric exponent of 0.75. The volumes were assumed to scale to humans with allometric exponent of 1. These simulations provided exposure estimates across a range of fixed doses for single dosing and Q1W x three doses.

[0653] The proposed starting dose of COMPOUND 2 is 100 mg intravenous, providing a greater than 50-fold margin to the human equivalent dose of the twenty-eight-day NOAELs in rat and monkey. The predicted AUGnf and Cmax for a single 100 mg intravenous dose in a 70 kg human are 15.5 pg*h / mLand 22.3 pg / mL, respectively, providing a greater than seventy-four-fold margin to the twenty-eight-day exposure observed at the NOAEL in rats. This starting dose was selected to maximize participant safety and to support a full dose range for the purposes of safety evaluations, pharmacokinetics, and pharmacodynamics analyses. The highest dose (500 mg) was predicted to produce exposures > fifteenfold below the NOAEL toxicity limits in rats.

[0654] COMPOUND 2 degraded exogenously administered mouse anti-01 AR antibody in rats in a dose-dependent manner administration intravenous administration of COMPOUND 2 at doses of 0.05 mg / kg, 0.2 mg / kg, and 1 mg / kg. The translatability of mouse data to human is unclear. The proposed dose range inform the safety and tolerability of COMPOUND 2 over a wide range of doses and exposures. About 10% of asymptomatic, healthy adults have 01AR autoantibodies present. Becker et al., Autoimmun. Rev., 16(3), 269-286 (2017); Haghikia et al., Basic Res. Cardiol., 110(6), 60 (2015). Samples to quantify 01AR autoantibodies was collected from all subjects who receive study drug, and if detected, was used to assess the relationship between COMPOUND 2 exposures and change in 01AR autoantibodies to inform dose selection and dosing frequency in future patient populations.

[0655] Dose Escalation Scheme (intravenous). The intravenous dose of COMPOUND 2 was sequentially escalated cohort by cohort, from the starting dose of 100 mg in the Single Ascending Dose. Planned subsequent dose levels in the Single Ascending Dose are 200 mg, 400 mg, and < 500 mg. Doses may be adjusted based on available safety, tolerability, and pharmacokinetics data from preceding cohorts did not exceed the proposed dose for that cohort. Dose escalation did not exceed two-fold between cohorts. The highest planned dose level of 500 mg has projected single dose exposure margins of 19x and 15x, respectively to exposures in rats at the 28-day NOAEL.

[0656] A total of up to four cohorts of subjects was dosed in the Single Ascending Dose intravenous (Part 1) -portion of this study. The maximum dose of COMPOUND 2 administered do not exceed 500 mg.Lower or intermediate doses of COMPOUND 2 to those assessed in previous cohorts may be explored, but not exceed 500 mg.

[0657] Starting Dose Selection (subcutaneous). The subcutaneous COMPOUND 2 dose was sequentially escalated cohort by cohort. Doses may be adjusted based on available safety, tolerability, and pharmacokinetics data from preceding cohorts did not exceed the proposed dose for that cohort. The single subcutaneous COMPOUND 2 doses evaluated in each cohort did not exceed dose levels that have been administered intravenous and deemed safe and tolerated, Subcutaneous doses in the Single Ascending Dose does not exceed a maximum of 500 mg without an amendment. The population pharmacokinetics model yielded a bioavailability estimate of 67.8% and assumed an allometric exponent of -0.25 for the absorption rate constant.

[0658] Dose Escalation Scheme (subcutaneous). The highest planned dose level of 500 mg has projected subcutaneous single dose exposure margins of 196x and 15x, respectively to Cmax and AUC in rats at the twenty-eight-day NOAEL. Altogether, exposures after subcutaneous dosing in humans are expected to be similar if not lower than that of the same dose administered intravenous.

[0659] A total of up to two cohorts of subjects was dosed in the Single Ascending Dose subcutaneous (Part 3) portion of this study. The maximum COMPOUND 2 dose administered did not exceed 500 mg. Lower or intermediate COMPOUND 2 doses to those assessed in previous cohorts may be explored, but did not exceed 500 mg.

[0660] Starting dose selection (intravenous). The proposed starting dose for the Multiple Ascending Dose (Part 2) is 100 mg intravenously administered once weekly (Q1W) for three doses with a seven-day washout between doses (Day 1, Day 8, and Day 15). This dose was confirmed based on the safety, tolerability, and pharmacokinetics data from the first two dose levels of the Single Ascending Dose part.

[0661] The COMPOUND 2 dosing frequency is driven by pharmacodynamics, e.g., the degree and duration of 01AR autoantibody suppression. COMPOUND 2 is planned to be administered once weeklyfor three doses in the Multiple Ascending Dose portion of this study to inform safety and pharmacokinetics.

[0662] Dose escalation scheme (intravenous). The planned dose increments of 200 mg, 400 mg, and <500 mg may be revised based on predicted exposures from emerging data from the Single Ascending Dose cohorts and the previous Multiple Ascending Dose cohorts. The doses, dosing frequency, and follow-up period maybe modified based on emerging data. For instance, planned dosing frequency may be modified to every other week dosing based on observed pharmacokinetics from Single Ascending Dose cohorts and preceding Multiple Ascending Dose cohorts. Dose escalation did not exceed two-fold between cohorts.

[0663] Predicted COMPOUND 2 steady-state Cmax and AUC in humans after intravenous administration of COMPOUND 2 Q1W at anticipated doses based on the preclinical pharmacokinetics model described above are provided. The highest planned dose level of 500 mg Q1W has projected steady state exposure margins of 19x and 15x, respectively to Cmax and AUC in rats at the 28-day NOAEL.

[0664] Dose selection and dose escalation (subcutaneous). The starting subcutaneous dose and subsequent subcutaneous doses of COMPOUND 2 in Multiple Ascending Dose (Part 4) was chosen based on emerging data from the intravenous Single Ascending Dose and Multiple Ascending Dose cohorts and the previous single dose subcutaneous cohorts, but did not exceed 500 mg. The proposed dosing frequency for subcutaneous doses is once weekly (Q1W) for three doses with a seven day washout between doses (Day 1, Day 8, and Day 15). The highest planned subcutaneous dose level of 500 mg Q1W has projected steady state exposure margins of 196x and 15x, respectively to Cmaxand AUC in rats at the twenty-eight-day NOAEL.

[0665] A total of up to six cohorts total (intravenous and subcutaneous) of subjects was dosed in the Multiple Ascending Dose portions of this study. The maximum dose of COMPOUND 2 administered did not exceed 500 mg Q1W. Less frequent dosing schedules, e.g. every two weeks, may be explored if warranted, but no more than three doses of COMPOUND 2 was administered over a twenty-eight day period.

[0666] Rationale for the study population. For the study, subjects without concomitant diseases and medications represent a homogenous population allowing for proper evaluation of the safety, tolerability, pharmacokinetics, and pharmacodynamics profile of a drug without confounding factors. About 10% of asymptomatic, healthy adults have 01AR autoantibodies present. Becker et al., Autoimmun. Rev., 16(3), 269-286 (2017); and Haghikia et al. Basic Res. Cardiol., 110(6), 60 (2015).

[0667] Benefit / Risk Assessment. The nonclinical safety studies support the administration of COMPOUND 2 in humans. In nonclinical studies, COMPOUND 2 was well tolerated and did not produce adverse effects in animal species at dose levels significantly higher than the proposed human doses.

[0668] COMPOUND 2 was demonstrated to be stable in the plasma, and extracellular-free ECL2 peptide has not been detected. The ternary complex undergoes extensive metabolism in the liver and therefore the likelihood for immunogenicity is low.

[0669] The Single Ascending Dose primary objectives were (1) To characterize the safety and tolerability of single dose intravenous administration of COMPOUND 2 in subjects. To characterize the safety and tolerability of single dose subcutaneous administration of COMPOUND 2 in subjects. The Single Ascending Dose secondary objectives were (1) To characterize the plasma pharmacokinetics of single dose intravenous administration of COMPOUND 2 in subjects. (2) To characterize the plasma pharmacokinetics of single dose subcutaneous administration of COMPOUND 2 in subjects. (3) To characterize the effect of COMPOUND 2 on ECG parameters (QTcF, PR Interval, QRS complex, HR, and T-wave morphology) after a single intravenous dose of COMPOUND 2. Other objectives were (1) To characterize the metabolic profile of COMPOUND 2 in plasma. (2) To characterize the pharmacodynamic effects of COMPOUND 2 after single dose administration of COMPOUND 2 in subjects. (2) To characterize the immunogenicity of COMPOUND 2 after single dose administration of COMPOUND 2 in subjects.

[0670] The Multiple Ascending Dose primary objectives were (1) To characterize the safety and tolerability of multiple dose intravenous administration of COMPOUND 2 in subjects. (2) To characterize the safety and tolerability of multiple dose subcutaneous administration of COMPOUND 2 in subjects. The Multiple Ascending Dose secondary objectives were (1) To characterize the COMPOUND 2 plasma pharmacokinetics after multiple dose intravenous administration of COMPOUND 2 in healthy subjects.(2) To characterize the plasma pharmacokinetics of COMPOUND 2 after multiple dose subcutaneous administration of COMPOUND 2 in healthy subjects. Other objectives were (1) To characterize the pharmacodynamic effects of COMPOUND 2 after multiple dose administration of COMPOUND 2 in healthy subjects. (2) To characterize the immunogenicity of COMPOUND 2 after multiple dose administration of COMPOUND 2 in subjects. (3) To characterize the urine pharmacokinetics of COMPOUND 2 following multiple dose intravenous and subcutaneous administration of COMPOUND 2 in subjects.

[0671] The Single Ascending Dose primary endpoints were to assess safety and tolerability by reporting the frequency of unique subjects with serious adverse events and Grade 3-4 (CTCAE / DAIDS) laboratory abnormalities. For intravenous Single Ascending Dose cohorts (Part 1): COMPOUND 2 AUC0-t, AUCinf, AUCO-168, Cmax, Tmax, TJ4, CL, Vd, and Tlast, following a single dose. For subcutaneous Single Ascending Dose cohorts (Part 3): AUCinf, AUC0-t, Cmax, Tmax, Tlag, T1 / 2,Vd / F and CL / F was calculated

[0672] For Part 1 Single Ascending Dose (intravenous): Cardiac parameters as measured by Holter ambulatory monitoring, including: Change-from-baseline in HR, QTcF, PR, and QRS (AHR, AQTcF, APR, and AQRS). Placebo-corrected AHR, AQTcF, APR, and AQRS (AAHR, AAQTcF, AAPR, and AAQRS) computed from mixed models for repeated measures.

[0673] Categorical outliers for HR, QTcF, PR, and QRS. Frequency of treatment-emergent changes of T-wave morphology and U-wave presence.

[0674] Placebo-corrected baseline-adjusted QTcF (AAQTcF), computed from a concentrationresponse (C-R) model between plasma concentration and changes from baseline in QTcF parameters.

[0675] For the Multiple Ascending Dose, the primary endpoint is assessing the safety and tolerability by reporting the frequency of unique subjects with serious adverse events (SAEs), severeAEs, AEs leading to discontinuation, deaths, and Grade 3-4 (CTCAE / DAIDS) laboratory abnormalities. The secondary endpoints are (1) For intravenous cohorts (Part 2) and subcutaneous cohorts (Part 4): Day 1: AUCo-t, AUCO-168, Cmin, Cmax, Tmax. (2). For intravenous cohorts (Part 2) Day 15 (steady state): AUCtau, Ctau, Cmax,ss, Tmax, T1 / 2, RAAUCtau, RACmax, dss, CLSS. (3) For subcutaneous cohorts (Part 4) Day 15 (steady state): AUCtau, Ctau, Cmax,ss7 Tmax, T%, RAAUCtau, RAC max, Vdss / F, CLss / F.

[0676] Local injection site dosing reaction assessment. Dosing reaction assessment was performed at the times for the Single Ascending Dose parts and for the Multiple Ascending Dose parts.

[0677] Continuous ECG (Holter Monitoring) - Part 1 Single Ascending Dose intravenous Dosing. At each timepoint when an ECG is to be extracted from the continuous Holter recording, subjects was resting for fifteen minutes.

[0678] Glomerular filtration rate was calculated using the 2021 CKD-EPI equation. Estimated glomerular filtration rate = 142 x min (Scr / K, 1)“ x max (Scr / K, l)1 2x 0.9938Agex 1.012, if female. Scr is serum creatinine (mg / dL), K is 0.7 for females and 0.9 for males, a = -0.241 (females) or -0.302 (males), min indicates the minimum of Scr / K or 1.0, and max indicates the maximum of Scr / K or 1.0. See CKD-EPI Creatine Equation - National Kidney Foundation (2021).

[0679] The clinical laboratory assessments performed were anti-drug antibody; alanine aminotransferase; activated partial thromboplastin time; aspartate aminotransferase; blood urea nitrogen; assays from the Chronic Kidney Disease Epidemiology Collaboration; COVID-19; creatinine phosphokinase; estimated glomerular filtration rate; follicle-stimulating hormone; y- glutamyltransferase; glycated hemoglobin test (hemoglobin Ale, HbAlc); hepatitis B surface antigen; hepatitis C virus; high-density lipoprotein cholesterol; human immunodeficiency virus; lactate dehydrogenase; low-density lipoprotein cholesterol; mean cell hemoglobin; mean cell hemoglobin concentration; mean cell volume; pH; prothrombin time; red blood cell; RBC distribution width; and white blood cell.

[0680] Pharmacokinetic assessments. Blood samples for pharmacokinetic analysis were collected via an intravenous catheter or by direct venipuncture. Plasma concentrations of the study drug were determined using validated analytical methods.

[0681] Plasma pharmacokinetics sample collection and processing. Pharmacokinetics sample collections outside the pre-defined time windows were not considered as protocol deviations since actual post-dose sampling times was used for pharmacokinetics and statistical analyses. The remaining or backup plasma samples was stored for potential metabolite analysis, which was reported separately if analyzed.

[0682] Study drug administration - intravenous. The syringe infusion for all doses and across all cohorts is described in the Pharmacy Manual. Refer to the Investigator Brochure and the Pharmacy Manual for the detailed preparation and administration procedures.

[0683] Study drug administration - subcutaneous. COMPOUND 2 or placebo was administered as a subcutaneous dose up to 2 mL per injection. Refer to the Pharmacy Manual for the detailed preparation and administration procedures.

[0684] Potential Use of Higher Subcutaneous Volumes. Doses greater than lOOmg COMPOUND 2 or placebo in the subcutaneous cohorts may utilize a higher single dose volume greater than 2 mL / injection and could also utilize a syringe pump instead of direct injection. Volumes of administration up to 30 mL have been used safely in several other published studies. Dolton et al., Clin. Pharmacol. Ther., 110(5), 1337-1348 (2021); Nagy et al., J. Clin. Immunol., 44(1), 28 (2023); and Woodley et al., Clin. Transl. Sci., 15(1), 92-104 (2022). The potential use of higher volumes for administration are expected to be well- tolerated and safe. Refer to the Investigator Brochure and the Pharmacy Manual for the detailed preparation and administration procedures.

[0685] A complete de...

Claims

CLAIMSWe claim1. A composition of matter (a bifunctional degrader) for use in reducing the level of a pathogenic protein in a subject by administering to the subject the composition of matter in an amount effective to promote the reduction in the level of the pathogenic protein in the subject and provide a desired pharmacodynamics / pharmacokinetics ratio (EC50 / AUC), wherein the composition of matter comprises a bifunctional degrader having affinity for (i) an asialoglycoprotein (ASGPR) receptor of hepatocytes expressed in the subject's liver, and (ii) the pathogenic protein, wherein the desired EC50 / AUC measured 7-14 days after administration is at least 1.0-1.8 for a monovalent degrader and 1.5-3.0 for a bivalent degrader.

2. The composition of matter of claim 1, wherein the composition of matter is a MoDE degrader.

3. The composition of matter of claim 1, wherein the composition of matter is a TRAP degrader.

4. A method of treating a disease susceptible to a response by reducing the level of a pathogenic protein, comprising subcutaneously administering to a subject in need of such treatment a therapeutically effective amount of a degrader having affinity for (i) an asialoglycoprotein (ASGPR) receptor of hepatocytes expressed in the subject's liver, and (ii) the pathogenic protein.

5. The method of claim 4, further comprising assaying the subject to determine that subcutaneous administration of degrader is advantageously reducing the level of a pathogenic protein in a subject.

6. The method of Claim 4, wherein the degrader has chemical formulas (I), (II), or (III):- - - 1 tein dwherein in chemical formulas (I), (II), and (III),R2is NHC(=O)CH3;R5is CH2OH;[Pathogenic Protein Targeting Ligand] is a ligand having affinity to the pathogenic protein;[LinkerA] is a chemical group that connects the ASGPR ligand to LinkerB, LinkerC, or LinkerD;[LinkerB] is a chemical group that connects LinkerA to the Pathogenic Protein Targeting Ligand;[LinkerC] is a chemical group that connects LinkerC to the Pathogenic Protein Targeting Ligand; and[LinkerD] is a chemical group that connects LinkerA to the Pathogenic Protein Targeting Ligand.

7. The method of Claim 4, wherein the degrader has the following general chemical structure:wherein [CPBM] is a Pathogenic Protein Binding Moiety which binds to pathogenic forms of a pathogenic protein as identified herein, which are related to and / or mediate a disease state and / or condition and is to be removed by the action of hepatocytes or other cells on the circulating protein (the compounds preferably selectively binding to the IgG in plasma of the subject or patient);[CRBM] is a Cellular Receptor Binding Moiety, preferably an [ASGPRBM] group, which is a binding moiety which binds to hepatocytes or other cells through asialoglycoprotein receptors or other receptors as identified herein which are on the surface of hepatocytes and other degrading cells, preferably in a patient or subject; each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [CRBM] or connects the [LINKER] to [CPBM] or to [CRBM] and[LINKER] is a chemical moiety having a valency from 1 to 15 which covalently attaches to one or more [CRBM] and / or [CPBM] group, optionally through a [CON], including a [MULTICON] group, wherein said [LINKER] optionally itself contains one or more [CON] or [MULTICON] group(s); k' is an integer from 1 to 15; j' is an integer from 1 to 15; h and h' are each independently an integer from 0 to 15; iL is an integer from 0 to 15; with the proviso that at least one of h, h' and iL is at least 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

8. The method according to claim 4, wherein the degrader of a pathogenic protein is an Immunoglobulin G ("IgG") degrader.

9. The method according to claim 4, wherein the degrader of a pathogenic protein is a degrader of galactose-deficient Immunoglobulin A ("Gd-lgA").

10. The method according to claim 4, wherein the degrader of a pathogenic protein is a degrader of anti-PiECII autoantibodies.

11. The method according to claim 4, wherein the degrader of a pathogenic protein is an Immunoglobulin E ("IgE") degrader.

12. The method according to claim 4, wherein the degrader of a pathogenic protein is an Immunoglobulin M ("IgM") degrader.

13. A method of reducing the level of a pathogenic protein in a subject, comprising subcutaneously administering to the subject a therapeutically effective amount of a degrader of a pathogenic protein.

14. The method according to claim 13, wherein the degrader of a pathogenic protein is an IgG degrader.

15. The method according to claim 13, wherein the degrader of a pathogenic protein is a degrader of galactose-deficient Immunoglobulin A ("Gd-lgA").

16. The method according to claim 13, wherein the degrader of a pathogenic protein is a degrader of anti-piECII autoantibodies.

17. The method according to claim 13, wherein the degrader of a pathogenic protein is an Immunoglobulin E ("IgE") degrader.

18. The method according to claim 13, wherein the degrader of a pathogenic protein is an Immunoglobulin M ("IgM") degrader.

19. A method of reducing the level of a pathogenic protein in a subject, comprising contacting a component of the subject's extravascular system with a degrader having affinity for (i) an asialoglycoprotein (ASGPR) receptor of hepatocytes expressed in the subject's liver, and (ii) thepathogenic protein, in an amount effective to promote the reduction in the level of the pathogenic protein in the subject.

20. The method of Claim 19, wherein the pathogenic protein mediates a disease selected from cancer, a heart disease, an autoimmune disease, or an inflammatory disease.

21. The method of Claim 19, wherein the pathogenic protein is an aberrant form of immunoglobulin.

22. The method of Claim 21, wherein the immunoglobulin is Immunoglobulin A ("IgA"), Immunoglobulin D ("IgD"), Immunoglobulin E ("IgE"), Immunoglobulin G ("IgG"), or Immunoglobulin M ("IgM").

23. The method of Claim 22, wherein the aberrant form of IgA is galactose-deficient Immunoglobulin A ("Gd-lgA").

24. The method of Claim 19, wherein the extravascular system is lymphatic system.

25. The method of Claim 24, wherein the component of the lymphatic system is lymph, a lymphatic vessel, a lymph node, and a lymphoid organ.

26. The method of Claim 19, wherein the degrader has chemical formulas (I), (II), or (III):Extracellular ProteinTargeting LigandOHwherein in chemical formulas (I), (II), and (III),R2is NHC(=O)CH3;R5is CH2OH;[Pathogenic Protein Targeting Ligand] is a ligand having affinity to the pathogenic protein;[LinkerA] is a chemical group that connects the ASGPR ligand to LinkerB, LinkerC, or LinkerD;[LinkerB] is a chemical group that connects LinkerA to the Pathogenic Protein Targeting Ligand;[LinkerC] is a chemical group that connects LinkerC to the Pathogenic Protein Targeting Ligand; and[LinkerD] is a chemical group that connects LinkerA to the Pathogenic Protein Targeting Ligand.

1. The method of Claim 19, wherein the degrader has the following general chemical structure:wherein [CPBM] is a Pathogenic Protein Binding Moiety which binds to pathogenic forms of a pathogenic protein as identified herein, which are related to and / or mediate a disease state and / or condition and is to be removed by the action of hepatocytes or other cells on the circulating protein (the compounds preferably selectively binding to the IgG in plasma of the subject or patient);[CRBM] is a Cellular Receptor Binding Moiety, preferably an [ASGPRBM] group, which is a binding moiety which binds to hepatocytes or other cells through asialoglycoprotein receptors or other receptors as identified herein which are on the surface of hepatocytes and other degrading cells, preferably in a patient or subject; each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [CRBM] or connects the [LINKER] to [CPBM] or to [CRBM] and[LINKER] is a chemical moiety having a valency from 1 to 15 which covalently attaches to one or more [CRBM] and / or [CPBM] group, optionally through a [CON], including a [MULTICON] group, wherein said [LINKER] optionally itself contains one or more [CON] or [MULTICON] group(s); k' is an integer from 1 to 15; j' is an integer from 1 to 15; h and h' are each independently an integer from 0 to 15; iL is an integer from 0 to 15; with the proviso that at least one of h, h' and iL is at least 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

28. The method of Claim 19, wherein the degrader is administered to the subject prior to contacting the component of the subject's extravascular system.

29. The method of Claim 19, wherein the reduction in the level of the pathogenic protein in the subject is 10% or greater, 20% or greater, 30% or greater, 40% or greater, 50% or greater, 60% or greater, 70% or greater, 80% or greater, or 90% or greater.

30. The method of Claim 19, wherein the reduction in the level of the pathogenic protein is sustained for at least 10 hours, at least 20 hours, at least 30 hours, at least 40 hours, at least 50 hours, at least 60 hours, at least 70 hours, at least 80 hours, at least 90 hours, or at least 100 hours following the administration.

31. The method of Claim 19, wherein the degrader is an IgG degrader.

32. The method of Claim 19, wherein the degrader is a degrader of galactose-deficient Immunoglobulin A ("Gd-lgA").

33. The method of Claim 19, wherein the degrader of a pathogenic protein is a degrader of anti- PIECII autoantibodies.

34. The method of Claim 19, wherein the degrader of a pathogenic protein is an Immunoglobulin E ("IgE") degrader.

35. The method of Claim 19, wherein the degrader of a pathogenic protein is an Immunoglobulin M ("IgM") degrader.

36. A method of reducing the level of a pathogenic protein in a subject, comprising administering to the subject a degrader having affinity for (i) an asialoglycoprotein (ASGPR) receptor of hepatocytes expressed in the subject's liver, and (ii) the pathogenic protein, in an amount effective to promote the reduction in the level of the pathogenic protein in the subject, in order to provide the PD / PK ratio (EC50 / AUC) measured 7 to 14 days after administration is at least 1.0 to 1.8.

37. The method of claim 36, wherein the administration is conducted subcutaneously.

38. The method of Claim 36, wherein the degrader has chemical formulas (I), (II), or (III):tein dwherein in chemical formulas (I), (II), and (III), R2is NHC(=O)CH3;R5is CH2OH;[Pathogenic Protein Targeting Ligand] is a ligand having affinity to the pathogenic protein;[LinkerA] is a chemical group that connects the ASGPR ligand to LinkerB, LinkerC, or LinkerD;[LinkerB] is a chemical group that connects LinkerA to the Pathogenic Protein Targeting Ligand;[LinkerC] is a chemical group that connects LinkerC to the Pathogenic Protein Targeting Ligand; and[LinkerD] is a chemical group that connects LinkerA to the Pathogenic Protein Targeting Ligand.

39. The method of Claim 36, wherein the degrader has the following general chemical structure:wherein [CPBM] is a Pathogenic Protein Binding Moiety which binds to pathogenic forms of a pathogenic protein as identified herein, which are related to and / or mediate a disease state and / or condition and is to be removed by the action of hepatocytes or other cells on the circulating protein (the compounds preferably selectively binding to the IgG in plasma of the subject or patient);[CRBM] is a Cellular Receptor Binding Moiety, preferably an [ASGPRBM] group, which is a binding moiety which binds to hepatocytes or other cells through asialoglycoprotein receptors or other receptors as identified herein which are on the surface of hepatocytes and other degrading cells, preferably in a patient or subject; each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [CRBM] or connects the [LINKER] to [CPBM] or to [CRBM] and[LINKER] is a chemical moiety having a valency from 1 to 15 which covalently attaches to one or more [CRBM] and / or [CPBM] group, optionally through a [CON], including a [MULTICON] group, wherein said [LINKER] optionally itself contains one or more [CON] or [MULTICON] group(s); k' is an integer from 1 to 15; j' is an integer from 1 to 15; h and h' are each independently an integer from 0 to 15; iL is an integer from 0 to 15; with the proviso that at least one of h, h' and iL is at least 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

40. The method according to Claim 36, wherein the degrader is an IgG degrader.

41. The method according to claim 36, wherein the degrader is a degrader of galactose-deficient Immunoglobulin A ("Gd-lgA").

42. The method according to claim 36, wherein the degrader of a pathogenic protein is a degrader of anti-piECII autoantibodies.

43. The method according to claim 36, wherein the degrader of a pathogenic protein is an Immunoglobulin E ("IgE") degrader.

44. The method according to claim 36, wherein the degrader of a pathogenic protein is an Immunoglobulin M ("IgM") degrader.

45. A method of treating a disease in a subject, comprising administering to the subject an agent having affinity for (i) an ASGPR receptor of hepatocytes expressed in the subject's liver, and (ii) the pathogenic protein, in an amount effective to promote the reduction in the level of the pathogenic protein in the subject, said administration being conducted in (a) a first step wherein the degrader is administered intravenously, and (b) a second step wherein the degrader is administered by a modality other than intravenously.

46. The method of Claim 45, wherein the pathogenic protein mediates a disease selected from cancer, a heart disease, an autoimmune disease, or an inflammatory disease.

47. The method of Claim 45, wherein the pathogenic protein is an aberrant form of immunoglobulin.

48. The method of Claim 47, wherein the immunoglobulin is Immunoglobulin A ("IgA"), Immunoglobulin D ("IgD"), Immunoglobulin E ("IgE"), Immunoglobulin G ("IgG"), or Immunoglobulin M ("IgM").

49. The method of Claim 48, wherein the aberrant form of IgA is galactose-deficient Immunoglobulin A ("Gd-lgA").

50. The method of Claim 45, wherein, in the second step, the degrader is administered subcutaneously.

51. The method of Claim 45, wherein, in the second step, the degrader is administered transdermally.

52. The method of Claim 45, wherein, in the second step, the degrader is administered intramuscularly.

53. The method of Claim 45, wherein the degrader has chemical formulas (I), (II), or (III): tein d Iwherein in chemical formulas (I), (II), and (III),R2 is NHC(=O)CH3;R5 is CH2OH;[Pathogenic Protein Targeting Ligand] is a ligand having affinity to the pathogenic protein;[LinkerA] is a chemical group that connects the ASGPR ligand to LinkerB, LinkerC, or LinkerD;[LinkerB] is a chemical group that connects LinkerA to the Pathogenic Protein Targeting Ligand;[LinkerC] is a chemical group that connects LinkerC to the Pathogenic Protein Targeting Ligand; and[LinkerD] is a chemical group that connects LinkerA to the Pathogenic Protein Targeting Ligand.

54. The method of Claim 45, wherein the degrader has the following general chemical structure:wherein [CPBM] is a Pathogenic Protein Binding Moiety which binds to pathogenic forms of a pathogenic protein as identified herein, which are related to and / or mediate a disease state and / or condition and is to be removed by the action of hepatocytes or other cells on the circulating protein (the compounds preferably selectively binding to the IgG in plasma of the subject or patient);[CRBM] is a Cellular Receptor Binding Moiety, preferably an [ASGPRBM] group, which is a binding moiety which binds to hepatocytes or other cells through asialoglycoprotein receptors or other receptors as identified herein which are on the surface of hepatocytes and other degrading cells, preferably in a patient or subject; each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [CRBM] or connects the [LINKER] to [CPBM] or to [CRBM] and[LINKER] is a chemical moiety having a valency from 1 to 15 which covalently attaches to one or more [CRBM] and / or [CPBM] group, optionally through a [CON], including a [MULTICON] group, wherein said [LINKER] optionally itself contains one or more [CON] or [MULTICON] group(s); k' is an integer from 1 to 15; j' is an integer from 1 to 15; h and h' are each independently an integer from 0 to 15; iL is an integer from 0 to 15; with the proviso that at least one of h, h' and iL is at least 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

55. The method according to Claim 45, wherein the degrader is an IgG degrader.

56. The method according to claim 45, wherein the degrader is a degrader of galactose-deficient Immunoglobulin A ("Gd-lgA").

57. The method according to claim 45, wherein the degrader of a pathogenic protein is a degrader of anti-piECII autoantibodies.

58. The method according to claim 45, wherein the degrader of a pathogenic protein is an Immunoglobulin E ("IgE") degrader.

59. The method according to claim 45, wherein the degrader of a pathogenic protein is an Immunoglobulin M ("IgM") degrader.

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