TREATMENT OF IgG-RELATED DISEASES

Abstract

Provided is a method of treating a disease susceptible to a response by reducing the level of immunoglobulin G ("IgG"), comprising administering to a subject in need of such treatment: (i) a loading dose of a first agent to reduce level of IgG by a desired amount; and (ii) a therapeutically effective amount of a second agent to treat the disease, wherein the second agent is a degrader of IgG.

Description

[0001] TREATMENT OF IgG-RELATED DISEASES

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to treatment of diseases. More specifically, the present invention is related to treatment of diseases susceptible to a response by reducing the level of immunoglobulin G ("IgG") using molecular degraders of IgG.

[0004] BACKGROUND OF THE INVENTION

[0005] Increased levels of IgG can be a contributing factor in the progression of diseases, such as, for example, IgG myeloma, liver disease, sarcoidosis, chronic infection, autoimmune disorders, malignancy and parasitic diseases.

[0006] Rheumatoid arthritis ("RA") is an autoimmune disorder that can lead to joint destruction, deformity, and loss of function. The disease is usually characterized by swelling of the small joints, especially in the hands and feet, however, most joints in the body can eventually become affected. In addition to the joints, other manifestations of the disease can be seen including subcutaneous nodules, eye inflammation, lowering of the white blood count, and lung disease. Frequent symptoms include fatigue and joint stiffness, especially in the morning and after prolonged periods of rest.

[0007] Presently, there is no known cure for rheumatoid arthritis. In the last few years, discovery of the drugs modifying the earlier institution of disease and the availability of new classes of medications have greatly improved the expected disease outcomes. The goal of rheumatoid arthritis treatment now aims toward achieving the lowest possible level of arthritis disease activity and remission if possible, minimizing joint damage, and enhancing physical function and quality of life. 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.

[0008] SUMMARY OF THE INVENTION

[0009] The present invention is directed to treatment of diseases susceptible to a response by reducing the level of immunoglobulin G in a subject in need of such treatment.

[0010] In an aspect, provided is a method of treating a disease susceptible to a response by reducing the level of IgG, comprising administering to a subject in need of such treatment: (i) a loading dose of a first agent to reduce level of IgG by a desired amount; and (ii) a therapeutically effective amount of a second agent to treat the disease, wherein the second agent is a degrader of IgG.

[0011] In another aspect, provided is a method of reducing the level of IgG in a subject, comprising reducing the level of immunoglobulin G ("IgG") in a subject, comprising administering to the subject: (i) a loading dose of a first agent to reduce level of IgG by a desired amount; and (ii) one or more doses of a second agent to maintain the level of IgG in a therapeutically effective range.

[0012] DETAILED DESCRIPTION OF THE INVENTION

[0013] The following detailed description is provided to aid those skilled in the art in practicing the present invention. Exemplary embodiments will hereinafter be described in detail. However, these embodiments are only exemplary, and the present disclosure is not limited thereto but rather is defined by the scope of the appended claims. Those of ordinary skill in the art may make modifications and variations in the embodiments described herein without departing from the spirit or scope of the present disclosure.

[0014] Accordingly, the embodiments are merely described below, by referring to structures and schemes, to explain aspects of the present description. As used herein, 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.

[0015] It will be understood that 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. In contrast, when an element is referred to as being "directly on" another element, there are no intervening elements present.

[0016] It will be understood that, although the terms first, second, third etc. may be used herein to describe various elements, components, regions, layers, and / or sections, these elements, components, regions, layers, and / or sections should not be limited by these terms. These terms are only 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 present embodiments. It is understood that 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.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting. It will be further understood that the terms, such as those 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 present disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

[0018] 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 present invention.

[0019] The articles "a" and "an" refer to one or to more than one ( / .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.

[0020] As used herein, when specific definition is not otherwise provided, the term "substituted" refers to a group substituted with deuterium, a halogen (-F, -Cl, -Br, -I), a hydroxy group (-OH), an amino group (-NH2), a carboxyl group (-CO2H), a substituted or unsubstituted C1-C10 amine group, a nitro group (- NO2), a C1-C10 alkyl group, a C3-C10 cycloalkyl group, a C6-C12 aryl group, a C1-C10 alkoxy group, a Cl to CIO trifluoroalkyl group such as a trifluoromethyl group (-CF3) and the like, or a cyano group (-CN) instead of at least one hydrogen of a substituting group or compound.

[0021] Additional aspects will be set forth in part in the description which follows and, in part, will be apparent from the description.

[0022] The starting materials useful for making the pharmaceutical compositions of the present invention are readily commercially available or can be prepared by those skilled in the art. Solvates are compounds formed by solvation, which is the combination of solvent molecules with molecules or ions of the solute. Solvation is an interaction of a solute with the solvent, which leads to stabilization of the solute species in the solution. One may also refer to the solvated state, whereby an ion in a solution is complexed by solvent molecules. The difference in the physical properties of different solvates and polymorph ic forms thereof results from different orientation and intermolecular interactions of adjacent molecules in the solid. Polymorphic forms of compounds or solvates can be distinguished by X-ray diffraction and by other methods such as, infrared spectroscopy or Raman spectroscopy.

[0023] In an aspect, provided is a method of treatment of rheumatoid arthritis comprising administering to a patient in need of such treatment a therapeutically effective amount of a molecular degrader of immunoglobulin G ("IgG") and an anti-arthritis agent.

[0024] In another aspect, provided is a pharmaceutical composition including a degrader of immunoglobulin G and an anti-arthritis agent.

[0025] IgG DEGRADER

[0026] In an embodiment, the molecular 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);

[0027] [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; iLis an integer from 0 to 15; with the proviso that at least one of h, h' and iLis at least 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. Various IgG Binding Moieties [CPBM], Cellular Receptor Binding Moieties [CRBM], and connecting group [LINKER] and [CON] are known in the art and described, for example, in International Patent Publication No. WO 2019 / 199634 published October 17, 2019, International Patent Publication No. WO 2019 / 199634 published October 17, 2019, and International Patent Publication No. WO 2024 / 227119 published October 31, 2024, the contents of which publications are incorporated herein in their entireties by reference.

[0028] In an embodiment of the above general chemical structure,

[0029] [CPBM] may be an immunoglobulin G binding moiety [IgGBM] having the structure:

[0030] v) a peptide moiety selected from the group consisting of PAM; D-PAM; D-PAM-O;

[0031] TWKTSRISIF (SEQ ID NO:1); FGRLVSSIRY (SEQ ID NO:2); Fclll; FcBP-1; FcBP-2; Fc-ll l-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 NQ: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);

[0032] 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:

[0033] each [CON] may independently be at each occurrence selected from the group consisting of: wherein:

[0034] K'" may be 1, 2, 3, or 4; RMmay be H or Ci-C3alkyl;

[0035] 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;

[0036] 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; iLmay 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.

[0037] In another embodiment, h and h' may be each independently 1, 2, 3, 4, or 5.

[0038] In another embodiment, each occurrence of X2may be independently CH2, NR4, or C(O);

[0039] R1may be H; and R4may be H.

[0040] In another embodiment, ZBmay be absent or -C(O)-(CH2)IM-.

[0041] In another embodiment, the [CPBM] may be the [IgGBM] of structure:

[0042] In another embodiment, the [CPBM] may be the [IgGBM] of structure:

[0043]

[0044] In another embodiment, the [CPBM] may be the [IgGBM] of structure :

[0045] In another embodiment, the [CPBM] may be the [IgGBM] of structure:

[0046] In another embodiment, the [CPBM] may be the [IgGBM] of structure:

[0047]

[0048] In another embodiment, the compound may have the structure :

[0049] In another embodiment, the compound may have the structure:

[0050]

[0051] In another embodiment, the compound may have the structure:

[0052] In an embodiment, the molecular degrader of IgG ("IgG degrader") may have one of the following general chemical structures:

[0053]

[0054]

[0055]

[0056]

[0057] (II-d-Tri),

[0058]

[0059]

[0060] or a. pharmaceutically acceptable salt thereof

[0061] In the above formulae, "Extracellular Protein Targeting Ligand" refers to an IgG Binding Moiety [CPBM] or [IgGBM] 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).

[0062] In the above formulae,

[0063] X ' is I to 5 groups independently selected from O, S, N(R6), and C(R )(&”), wherein if X1group then X1is O, S, N(R°), or C(R4XR4), if X’ is 2 groups then no more than 1 group of X’, S, or N(R6), if X1is 3, 4. or 5 groups then no more than 2 groups of X1are O, S, or NCR6),

[0064] R2is selected from

[0065] (s) aryl, heterocycle, and heteroatyl containing 1 or 2 heteroatoms independently selected from N, O, and S, each of which aryl, heterocycle, and heteroaryi is optionally substituted with i , 2, 3, or 4 substituents. optionally substituted with 1, 2, 3, or 4 substituents; and

[0066] Linker^ is a chemical group that links each Linker* to the Extracellular Protein Targeting Ligand; and

[0067] Linker1’ is a chemical group that links each Linker* to the Extracellular Protein Targeting Ligand, and wherein, when R2is NR6-alkenyL -NR':'-aLkynyl,-NRikC(O)R1!l. -NRs-S(O)2-aikenyL “NRB"S(O)2-alkyny1, -NR6-heteroaryl, or -NRMryl, then Extracellular Protein Targeting Ligand dots not comprise an oligonucleotide, and the optional substituents are- selected from alkyl, alkenyl, alkynyi, haloaikyl, -OR*1, F, Cl,

[0068] Br, I, -NR0R', beteroalkyl, cyano, nitro, C(O)R?, as allowed by valence such that a stable compound results.

[0069] Various moieties [Linker*], [Linker6], [Linker6], [Linke Dc], [Cycle], and X1are known in the art and described, for example, in International Patent Publication No. WO 2021 / 155317 published August 5, 2021 and International Patent Publication No. WO 2022 / 235699 published November 10, 2022, the contents of which publications are incorporated herein in their entireties by reference.

[0070] LOADING DOSE

[0071] The first agent suitable for use in accordance with the present invention can be any agent that is effective to reduce the IgG level in the subject by a desired amount. The first agent may, or may not, be the same agent as the second agent, i.e., an IgG degrader.

[0072] Types of first agents that may be used in accordance with the invention include, for example, neonatal Fc receptors (FcRn) and enzymes.

[0073] Typical FcRn's include efgartigimod alfa, rozanolixizumab, batoclimab, nipocalimab and SYNT001. Efgartigimod is a modified human IgGl-derived Fc fragment harboring amino acid modifications, available under the brand name Vyvgart from Argenx. Rozanolixizumab is a subcutaneously (SC) administered, humanized, anti-FcRn monoclonal antibody, available under the brand name Rystiggo from UCB, Inc. Batoclimab is a fully human, IgGl monoclonal anti-FcRn antibody, the Fc portion of which was modified to reduce antibody-dependent cell-mediated cytotoxicity being developed by Immunovant Sciences GmbH. Nipocalimab is an aglycosylated, fully human, IgGl monoclonal anti-FcRn antibody that shows high affinity for FcRn being developed by Johnson & Johnson. SYNT001 is a humanized, de-immunized lgG4 monoclonal antibody harboring a S241P mutation being developed by Alexion Pharmaceuticals, Inc. Typical enzymes include cysteine proteases, such as, for example, imlifidase, a cysteine protease derived from the immunoglobulin G -degrading enzyme of Streptococcus pyogenes, is available under the brand name, Idefirix, from Hansa Biopharma.

[0074] DISEASES

[0075] The diseases suitable for treatment according to the present invention can be any disease that is susceptible to a response by reducing the level of IgG. Such diseases may include, for example, IgG myeloma, liver disease, sarcoidosis, chronic infection, autoimmune disorders, malignancy and parasitic diseases.

[0076] EXAMPLES

[0077] Harnessing a New Modality with Transformational Potential for the Treatment of Immunological and Inflammatory Disorders

[0078] A Phase 1 clinical study in human subjects was conducted with an IgG degrader (an ASGPR- bispecific degrader known as BHV-1300. Results in healthy subjects confirmed that BHV-1300 rapidly and selectively lowers IgG in a dose-dependent manner in the first 3 cohorts (see Figure 1). Preliminary IgG lowering data is consistent with modeling based on non-clinical experience, with dose- and timedependent IgG lowering observed even in initial low dose cohorts. Some subjects experienced IgG reductions as low as 50 to 70% of baseline even in these initial 3 low dose cohorts. Modeling suggests additional cohorts in the Phase 1 study could achieve > 70-80% lowering of IgG. BHV-1300 demonstrated reduction of IgG without significantly impacting LFTs, albumin or LDL cholesterol. BHV-1300 has been safe and well tolerated to date, with no serious or severe adverse events. Most AEs were mild, deemed unrelated to study drug and resolved spontaneously. As expected from the selectivity of the molecule for IgG, when compared to placebo, there were no reductions in average IgA, IgM or IgE levels during the week after dosing. No adverse trends have been observed in vital signs or ECGs. The Phase 1 SAD study is currently ongoing and cohort 4 is underway. Given the levels of IgG lowering observed to date, the approximately 6 cohorts of BHV-1300 are planned. Given the promising results of the SAD study thus far, the MAD study will proceed in patients with rheumatoid arthritis. Table IB, below, lists the total IgG values for subjects in the clinical trial at doses of 50mg, 125mg and 250mg at different times.

[0079]

[0080] Figure 1

[0081] Figure 1: Data shows rapid, dose-dependent, maximal mean reductions (% change from baseline) in IgG for each cohort observed within 24hrs after administration of BHV-1300 in its ongoing Phase 1 Study. lgGl-4 analyzed at Mayo Clinic Laboratories, Rochester MN. Throughout this application, various publications are referenced by author name and date, or by patent number or patent publication number. The disclosures of these publications are hereby incorporated in their entireties by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. However, the citation of a reference herein should not be construed as an acknowledgement that such reference is prior art to the present invention.

[0082] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. For example, pharmaceutically acceptable salts other than those specifically disclosed in the description and Examples herein can be employed. Furthermore, it is intended that specific items within lists of items, or subset groups of items within larger groups of items, can be combined with other specific items, subset groups of items or larger groups of items whether or not there is a specific disclosure herein identifying such a combination.

Claims

CLAIMS1. A method of treating a disease susceptible to a response by reducing the level of immunoglobulin G ("IgG"), comprising administering to a subject in need of such treatment: (i) a loading dose of a first agent to reduce level of IgG by a desired amount; and (ii) a therapeutically effective amount of a second agent to treat the disease, wherein the second agent is a degrader of IgG.

2. The method according to claim 1, wherein the desired amount is from about 20-99% of baseline IgG level of the subject prior to administration of the first agent.

3. The method according to claim 2, wherein the desired amount is from about 40-99% of baseline IgG level of the subject prior to administration of the first agent.

4. The method according to claim 3, wherein the desired amount is from about 60-99% of baseline IgG level of the subject prior to administration of the first agent.

5. The method according to claim 1, wherein the level of IgG % in the subject prior to the administration of the second agent is less than 90% of the subject's baseline IgG level prior to the administration of the first agent.

6. The method according to claim 5, wherein the level of IgG % in the subject prior to the administration of the second agent is less than 70% of the subject's baseline IgG level prior to the administration of the first agent.

7. The method according to claim 6, wherein the level of IgG % in the subject prior to the administration of the second agent is less than 50% of the subject's baseline IgG level prior to the administration of the first agent.

8. The method according to claim 1, wherein the level of IgG % in the subject prior to the administration of the second agent is less than 1500 mg / dL.

9. The method according to claim 8, wherein the level of IgG % in the subject prior to the administration of the second agent is less than 1000 mg / dL.

10. The method according to claim 9, wherein the level of IgG % in the subject prior to the administration of the second agent is less than 800 mg / dL.

11. The method according to claim 10, wherein the level of IgG % in the subject prior to the administration of the second agent is less than 600 mg / dL.

12. The method according to claim 1, wherein the first agent is a neonatal Fc receptor (FcRn).

13. The method according to claim 12, wherein the FcRn is selected from efgartigimod alfa, rozanolixizumab, batoclimab, nipocalimab and SYNT001.

14. The method according to claim 1, wherein the first agent is an enzyme.

15. The method according to claim 14, wherein the enzyme is a cysteine protease.

16. The method according to claim 14, wherein the cysteine protease is imlif idase.

17. The method according to claim 1, wherein the second agent is an IgG degrader.

18. The method according to Claim 17, wherein the IgG degrader has the following structure:or a pharmaceutically acceptable salt thereof.

19. The method according to claim 1, wherein the first agent is an IgG degrader.

20. The method according to Claim 19, wherein the IgG degrader has the following structure:or a pharmaceutically acceptable salt thereof.

21. A method of reducing the level of immunoglobulin G ("IgG") in a subject, comprising administering to the subject: (i) a loading dose of a first agent to reduce level of IgG by a desired amount; and (ii) one or more doses of a second agent to maintain the level of IgG in a therapeutically effective range.

22. The method according to claim 21, wherein the therapeutically effective range is from about 20-99% of baseline IgG level of the subject prior to administration of the first agent.

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