EP4037690A1 - Kombinationstherapie mit einem hemmer der interleukin-17-aktivität und einem vitamin-d-rezeptoragonisten - Google Patents

Kombinationstherapie mit einem hemmer der interleukin-17-aktivität und einem vitamin-d-rezeptoragonisten

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Publication number
EP4037690A1
EP4037690A1 EP20785714.5A EP20785714A EP4037690A1 EP 4037690 A1 EP4037690 A1 EP 4037690A1 EP 20785714 A EP20785714 A EP 20785714A EP 4037690 A1 EP4037690 A1 EP 4037690A1
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EP
European Patent Office
Prior art keywords
vitamin
combination
inhibitor
receptor agonist
treatment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20785714.5A
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English (en)
French (fr)
Inventor
Miguel Giovanni Uriol Rivera
Gonzalo Gómez Marques
Paula Carrillo Garcia
Aina Remei Obrador Mulet
Olga Delgado Sanchez
Ana Gomez Lobon
María Ros Julià BENIQUE
Vanessa Cerisse Daza Cajigal
Angel Garcia Alvarez
Manuel LUQUE RAMÍREZ
Lia NATTERO CHÁVEZ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon Y Cajal
Servei de Salut de Les Illes Balears IBSalut
Original Assignee
Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon Y Cajal
Servei de Salut de Les Illes Balears IBSalut
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Application filed by Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon Y Cajal, Servei de Salut de Les Illes Balears IBSalut filed Critical Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon Y Cajal
Publication of EP4037690A1 publication Critical patent/EP4037690A1/de
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man

Definitions

  • Combined therapy comprising an inhibitor of interleukin-17 activity and a vitamin D receptor agonist
  • Present invention relates to the field of preventing and treating autoimmune and autoinflammatory diseases, in particular those being refractory to common treatments.
  • Autoimmune diseases are a group of diseases of high complexity, in several of which autoinflammatory processes may occur, that lead to chronic inflammation of tissues.
  • ADs autoimmune diseases
  • the innate immune system activates, against self-antigens, the adaptive immune system which, in turn, is also responsible for the inflammatory process.
  • AIDs autoinflammatory diseases
  • ADs autoinflammatory diseases
  • autoimmune and autoinflammatory diseases There seems to be a narrow relationship between autoimmune and autoinflammatory diseases, and recently it has been discovered that in traditionally considered autoimmune diseases (i.e. psoriasis, systemic lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), autoinflammatory processes plays also a critical role.
  • autoimmune diseases i.e. psoriasis, systemic lupus, inflammatory bowel disease, rheumatoid arthritis, etc.
  • autoinflammatory processes plays also a critical role.
  • IL-17 interleukin-17
  • IL-17 interleukin-17
  • contradictory effects are linked to this cytokine.
  • IL-17 has regulatory roles in host defence and chronic inflammation, which result in tissue damage and autoimmunity. So, the IL-17 links innate and adaptive immunity, but it has also been seen that IL-17 has both beneficial and pathological effects on the immune system.
  • IL-17 is a cytokine whose gene was isolated from a rat-mouse T cell hybridoma in 1993.
  • CTLA-8 cytotoxic T-lymphocyte-associated protein
  • IL- 17E is also known as IL-25, and because it presents low homology with other molecules of the family and contributes to the induction of allergies, it is thought to have functions different from those of IL-17A.
  • IL-17A Several types of immune cells produce IL-17A, and Th17 cells, the newly established subset of helper T cells, have received particular attention.
  • secukinumab did was effective in a case of refractory lupus nephritis in a patient suffering from psoriasis and systemic lupus erythematosus, as explained by Satoh et al., “A case of refractory lupus nephritis complicated by psoriasis vulgaris that was controlled with secukinumab”, Case Report Lupus (2016) 0, 1-5. The authors administered secukinumab after realising of the presence of Th17 cells in peripheral blood and the presence of IL-17 positive lymphocytes infiltrated in renal tissue, to which presence the worsening of some parameters in the patient were correlated.
  • IL-17A-/- IL-17 deficient mice
  • IL-17A-/- chronic kidney disease was simulated after 5/6 nephrectomy
  • albuminuria increased throughout the experiment.
  • Crohn’s disease and immunoglobulins A nephropathy are highly impeding diseases, supposing high costs to health authorities and also to society since they are common in working-age population.
  • Other complex autoimmune and autoinflammatory concomitant diseases include autoimmune thyroid diseases (i.e. Grave’s disease and Hashimoto’s thyroiditis).
  • Another highly impeding disease with indicia of being an autoimmune and autoinflammatory concomitant disease is the neurological disease multiple sclerosis.
  • Immunoglobulins A nephropathy is the most prevalent primary glomerulonephritis. Prognostic is good but about 30 % of the patients will likely develop an advanced kidney disease that will need of chronic substitutive kidney therapy (dialysis or kidney transplantation). Evolution of the IgAN is followed by determining hematuria, proteinuria and arterial blood pressure. Main control of IgAN is performed by means of corticosteroid therapy, renin angiotensin system inhibitors, as well as immunosuppressive therapy (i.e mycophenolate) and biologic compounds (i.e. Rituximab, a chimeric monoclonal antibody targeted against the pan-B-cell marker CD2); unfortunately, without controversial results.
  • immunosuppressive therapy i.e mycophenolate
  • biologic compounds i.e. Rituximab, a chimeric monoclonal antibody targeted against the pan-B-cell marker CD2
  • IgAN is considered a multi-cause or multi-hit disease comprising an autoimmune component but also other factors.
  • the autoimmune component mainly derives from abnormalities in mucosal immunity and is well known the presence of elevated amounts of a galactose deficient IgA (Gd-lgA), the presence of autoantibodies recognizing Gd-lgA, and the presence of circulating immune complexes containing the Gd-lgA (complexes form of autoantibodies and of Gd-lgA).
  • Gd-lgA and the immune complexes induces the permanent and increasing mesangial proliferation cells, which are the responsible for the disruption of the glomerular filtration barrier (GFB) with two different implications:
  • hematuria The onset of hematuria. In normal health status the endothelium fenestrations (50- 100 nm) are too small in comparison with red blood cells (RBC) diameter (6.2-8.2 pm) which maintain the RBCs away from the glomerular basal membrane (GBM). Hematuria results in heme group release in the glomeruli with high toxic effects, denature cellular proteins and altering cellular integrity and also increasing inflammation through nuclear factor Kappa beta (NF-kb) pathway.
  • RBC red blood cells
  • NF-kb nuclear factor Kappa beta
  • IgAN autoinflam matory diseases
  • AIDs autoinflam matory diseases
  • IgAN has been reported associated with some genes altered leading disorders in the innate immune response.
  • Familial Mediterranean Fever the IgAN has been described, and also in other AIDs named hyper IgE syndrome the plasma levels of the Immunoglobulin A are elevated which suggest that AIDs are associated with the IgAN.
  • hyperuricemia hyperuricemia
  • the mortality risk is independent of the renal function, condition that suggests that hyperuricemia “per se” indicates systemic disorders.
  • physiologic levels of uric acid are the predominant anti-oxidant molecule in plasma and is necessary and sufficient for induction of type 2 immune responses.
  • the uric acid acts as a danger signal promoting the generation of inflammatory monocyte-derived dendritic cells.
  • the uric acid results from the metabolism of the purines derived from damage, dyeing and dead cells and are typically increased in chronic renal disease patients and it has been associated with mesangial and proximal tubular cells damage.
  • a therapy that decreases plasma uric acid represents a potential benefit not only for preventing the direct mesangial and tubular cells and also because lowering plasma uric acid may be associated with a normalized type 2 immune response.
  • the type 2 immune disorders are recently described as an initial pathogenic step which alters intestinal epithelial barrier.
  • Proteinuria Excess of serum proteins in urine
  • Proteinuria is a feature of nephrotic syndromes (intrinsic renal failure), toxic lesions of kidney, glomerular diseases, stress, diabetes mellitus, and some infections (HIV, post-streptococcal infection, hepatitis), among other conditions. Since it finally supposes a stress for kidney, it is highly desired to find methods directed to control proteinuria.
  • the invention provides, as a first aspect, a combination comprising: a) an inhibitor of interleukin-17; and b) a vitamin D receptor agonist.
  • Inventors have surprisingly found that the combination in a sequential manner of a selective vitamin D receptor activator, in particular paricalcitol and subsequently an inhibitor of IL-17 activity, in particular the monoclonal antibody secukinumab, are associated with a significantly reduction in proteinuria in relation to initial basal proteinuria in IgAN patients, indicating that the introduction in a sequential manner of the paricalcitol and subsequently the secukinumab may restore the filtration proteins process at the glomeruli; while if the secukinumab is used alone or in different IgAN glomerular diseases, the proteinuria may dramatically worsen.
  • the sequential treatment was also capable to restore the glomerular filtration barrier, fact explained by the sequential therapy where hematuria completely disappeared in IgAN patients, indicating an important benefit related to the immunocomplexes deposition due to autoimmune component control.
  • IgAN is considered as a multi-cause disease catalogued as an autoimmune disease; however, the clinical and pathophysiologic effects observed in the IgAN and previously disclosed in detail in the background, induced the inventors to assumption that the IgAN is indeed a dual disease with autoimmune and autoinflammatory concomitant disease and conceived a particular treatment protocol that surprisingly allowed controlling autoimmune and autoinflammatory components with extremely beneficial results.
  • IL-17 blocking To avoid potential damage induced by the IL-17 blocking, as was reported in several case reports, inventors surprisingly found that by inducing in the patient an anti-inflammatory milieu increasing the expression of the IL-10 and inhibiting the Th1 cells prior to blocking IL-17, any adverse effect induced by IL-17 blocking was actually avoided. Moreover, it is known that the administration of inhibitors of the IL-17 are associated with a decrease in the expression of the Treg lymphocytes.
  • the Treg are T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease, so, a lowering number of Treg is also an undesirable effect of the IL-17 blocking.
  • treatment with a selective Vitamin D receptor agonist prior to IL-17 blocking or inhibition represents an effective and safety therapeutic schedule for the prevention and/or treatment of several diseases catalogued as autoimmune and autoinflammatory concomitant disease.
  • Inhibitors of IL-17 activity have caused in several cases serious adverse effects, as illustrated in the case of Crohn’s disease, another multi-cause disease considered an autoimmune disease with a concomitant autoinflammatory component, as previously disclosed. Therefore, the positive effect observed now by inventors with the sequential treatment was really unexpected. Without being bound to any theory, inventors consider that when administered in combination with a vitamin D receptor agonist, in particular with a selective vitamin D receptor agonist; a context of anti-inflammatory environment is achieved allowing reducing any adverse effect that could be caused directly or indirectly by the inhibitor of IL-17 activity.
  • Th1 lymphocytes Another surprising effect observed by inventors was that of a change of immunophenotype of the Th1 lymphocytes, or which is the same, a change of the set of proteins that are expressed by this cell type. Inhibition of IL-17 activity as well as of Th17 and Treg blockade provide harmful effects (glomerulonephritis and colitis) if this blockade is accompanied by the presence and complete activation of Th1. This change of phenotype would make that recruitment of Th1 due to blockade of IL-17 be less negative in terms of adverse side-effects or even to supress any of them because Th1 cells do not act as proinflammatory actors.
  • Th1 is a type of T helper cells that mainly produce interferon-gamma, essential for macrophage activation and clearance of pathogens, but they are also involved in cell-mediated autoimmune diseases (see. Turner et al., “The Th17 immune response in renal inflammation”, Kidney International -2010, vol. no. 77, pp.: 1070-1075).
  • the invention encompasses also, as a second aspect, a package or kit of parts comprising: i) a first pharmaceutical or veterinary composition which comprises an amount of an inhibitor of IL-17 as defined in any of claims 1-7, together with one or more pharmaceutically or veterinary acceptable excipients or carriers; and ii) a second pharmaceutical or veterinary composition which comprises an amount of vitamin D receptor agonist, together with one or more pharmaceutically or veterinary acceptable excipients or carriers; wherein the first and second compositions are separate compositions, and wherein the amount of the compound of inhibitor of IL-17 of i) and the amount of vitamin D receptor agonist of ii) in combination are therapeutically effective.
  • the combination of the invention is for use as a medicament.
  • the combination of the invention may be used in autoimmune and concomitant autoinflam matory diseases or conditions.
  • a fourth aspect of the invention relates to the combination or a package or kit of parts as defined above, for use in the treatment and/or prevention of an autoimmune and concomitant autoinflammatory disease or condition (also termed in this description as synonymous of the term autoimmune disease or condition with autoinflammatory concomitant component)
  • This later aspect may also be formulated as a method of treatment and/or prevention of an autoimmune and concomitant autoinflammatory disease or condition, which comprises administering to a mammal subject in need thereof, including a human subject, either a) a therapeutically effective amount of the combination comprising a) an inhibitor of interleukin-17; and b) a vitamin D receptor agonist; or alternatively b) the package or kit of parts as defined above.
  • a combination comprising: (a) an inhibitor of interleukin-17; and (b) a vitamin D receptor agonist; for the preparation of a medicament for the treatment and/or prevention of an autoimmune and concomitant autoinflammatory disease or condition.
  • the combination or a package or kit of parts as defined above is also proposed to be used as immunotherapy in the prevention and/or treatment of malign neoplasia.
  • another aspect of the invention is a combination or a package or kit of parts as defined above, for use in the treatment and/or prevention of a cancer, optionally with metastatic behaviour, in which deregulation of immune system takes place.
  • a Vitamin D receptor agonist in particular a selective Vitamin D receptor activator, such as paricalcitol
  • an inhibitor of interleukin-17 activity inhibits tumor progression by restoring the immune response against tumoral cells and by blocking pathogenic mechanisms favoring tumor immune tolerance.
  • This aspect may also be formulated as a method of treatment and/or prevention of a cancer, optionally with metastatic behaviour, in which deregulation of immune system takes place, which comprises administering to a mammal subject in need thereof, including a human subject, either a) a therapeutically effective amount of the combination comprising a) an inhibitor of interleukin-17; and b) a vitamin D receptor agonist; or alternatively b) the package or kit of parts as defined above.
  • a combination comprising: (a) an inhibitor of interleukin-17; and (b) a vitamin D receptor agonist; for the preparation of a medicament for the treatment and/or prevention of a cancer, optionally cancer with metastatic behaviour, in which deregulation of immune system takes place.
  • Another aspect of the invention is a combination or a package or kit of parts as defined above, for use in the treatment and/or prevention of proteinuria.
  • the cocktail of cytokines involved in a pathological condition involving tumor immune tolerance, or autoimmunity and autoinflammation concomitant conditions is modulated in such a way that anti- inflammatory environment is first promoted with the vitamin D receptor agonist, and then inhibition of pro-inflammatory items are blocked, reduced or effectively minimized in a safe way with the inhibitor of IL-17 activity.
  • the proposed combination of actives works as a multi-cytokine normalization levels therapy (abbreviated by inventors as MNL). It is in particular useful in those pathological conditions cursing with exacerbation of Th17 and Th1 cells, being this exacerbation the main cause of the disease or one of them.
  • the proposed combination therapy provokes an increasing of lysosomal activity in kidney cells, being useful then in all those diseases where this technical effect can suppose a way to reduce inflammation and a way to eliminate accumulation of dangerous immunocomplexes or dangerous protein residual compounds accumulated in the cytosol of cells.
  • inhibitor of interleukin-17 (IL-17) activity or “IL-17 inhibitor” or “inhibitor of IL-17”, used indistinctly as synonymous in this description, is to be understood any agent, either a compound, mixture of compounds or cells, capable of blocking IL-17 activity by directly contacting the cytokine and avoiding it can take contact with the receptor sited in several cells (e.g. Th17 cells), or indirectly by blocking the receptor of IL-17.
  • particular inhibitors are compounds capable of blocking, totally or at some extent or particular inhibitory concentrations at certain inhibition percentage (i.e. IC50), IL-17 interaction with its cell receptors.
  • Particular inhibitors are antibodies (monoclonal or polyclonal) and fragments of these antibodies that specifically recognize IL-17.
  • This activity of IL-17 can be determined by any known method, in which IL-17 is involved, such as for example the presence or absence in a tissue of inflammatory cells, such as Th17, neutrophils, monocytes, Th1 cells (e.g. measured by flux cytometry), and/or the presence or absence of further proinflammatory cytokines (e.g. CXCL1, CCL2, CCL20) downstream the signal cascade measured using immunoassays (ELISA).
  • a tissue of inflammatory cells such as Th17, neutrophils, monocytes, Th1 cells (e.g. measured by flux cytometry), and/or the presence or absence of further proinflammatory cytokines (e.g. CXCL1, CCL2, CCL20) downstream the signal cascade measured using immunoassays (ELISA).
  • the expression “formulated for sequentially administration” or “sequentially” as appears in this description means that both drugs are not administered simultaneously, but within a spaced time.
  • This spaced time can be of hours among the same day, or of days between administration of one of inhibitor of IL-17 activity and the vitamin D receptor agonist.
  • therapeutically effective amount refers to the amount of a compound that, when administered, is enough to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed.
  • therapeutically effective refers to the amount of a compound or combination of compounds that, when administered, is enough to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed. In this particular description, it is the amount of a compound, combination of compounds, or composition that produces a desired therapeutic effect in a subject, such as treating autoimmune and concomitant autoinflammatory diseases or conditions, or cancer, optionally with metastatic behaviour, in which deregulation of immune system takes place.
  • the precise therapeutically effective amount is an amount of the composition that will yield the most effective results in terms of therapeutic efficacy in a given subject.
  • the specific dose of the compound of the invention to obtain a therapeutic benefit may vary depending on the particular circumstances of the individual patient including, among others, the size, weight, age and sex of the patient, the nature and stage of the disease, the aggressiveness of the disease, and the route of administration.
  • the specific dose of the compound of the invention to obtain a therapeutic benefit when administered in said combinations, compositions or kit of parts, may vary in relation with the specific dose of the compound used as single active agent.
  • pharmaceutically or veterinary acceptable excipients or carriers refers to pharmaceutically or veterinary acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical or veterinary composition. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • the first aspect of the invention is a combination comprising: a) an inhibitor of interleukin-17; and b) a vitamin D receptor agonist.
  • inhibitors of IL-17 can be used.
  • the inhibitor of IL-17 is an antibody or a fragment of said antibody, both of which specifically recognize one or more epitopes of a mammal IL-17, including human IL-17, and being capable of blocking IL-17 activity.
  • the inhibitor of IL-17 activity is an inhibitor of any of the members of the IL-17 family: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F.
  • IL-17E is also known as IL-25. More in particular, it is an inhibitor of IL-17A. In mammals, the sequences of these cytokines are highly conserved and have a high percentage of identity.
  • the inhibitor is an inhibitor of mammal IL-17 A, more in particular an inhibitor of human IL-17A.
  • Human IL-17A corresponds to protein sequence identified with UniProtKB database accession number Q16552-1, version 1 of November 1, 1996. It has a length of 155 amino acids and it is further processed into a mature form.
  • the inhibitor of IL-17 is secukinumab or a fragment thereof, said fragment specifically recognize one or more epitopes of human IL-17 A and being capable of blocking IL-17 A activity.
  • fragments there are included Fab, F(ab’)2, Fc, and combinations of them.
  • the inhibitor of IL-17 (i.e. secukinumab) may be administered at a dose comprised from 75 mg/week to 300 mg/week, which doses are therapeutically effective.
  • vitamin D receptor agonist or “Vitamin D receptor activator” (used as synonymous) includes any compound capable of interacting with vitamin D receptor (VDR) and to provoke an affect as active metabolite of Vitamin D does.
  • Vitamin D3 is made in the skin and modified in the liver and kidney to form the active metabolite, 1,25-dihydroxyvitamin D3 (calcitriol). Calcitriol binds to a nuclear receptor, the vitamin D receptor, and activates VDR to recruit cofactors to form a transcriptional complex that binds to vitamin D response elements in the promoter region of target genes.
  • VDRAs VDR agonists
  • CKD chronic kidney disease
  • this vitamin D receptor agonist is selected from the group consisting of calcitriol (CAS number 32222-06-3), paricalcitol (CAS number 131918-61-1), calcipotriene, tacalcitol, ercalcitriol (CAS number 60133-18-8) any pharmaceutically or veterinary acceptable salt or ester thereof, and combinations thereof.
  • vitamin D receptor agonists particular ones are the known as “selective Vitamin D receptor activators”, which act as agonists but have minimal undesirable effects on calcium absorption in the intestine, and calcium and phosphorus mobilisation in the bone compared with nonselective VDRAs.
  • the vitamin receptor agonist is a selective VDRA.
  • the vitamin D receptor agonist is paricalcitol or a pharmaceutically or veterinary acceptable salt or ester thereof.
  • Paricalcitol is a selective VDRA, with a low hypercalcemia induction in relation with other nonselective VDRAs, and for this reason is a more particular embodiment. Paricalcitol allows obtention of the desired effect of receptor activation without the disadvantageous increase of calcium in blood. Paricalcitol is a therapeutic compound, classified as an antiparathyroid compound.
  • the vitamin D agonist i.e. paricalcitol
  • the vitamin D agonist may be administered at a dose comprised from 0.4 micrograms/day (mcg/day) to 2 mcg/day, which doses are therapeutically effective. Even more particular doses are comprised from 0.4 mcg/day to 1.0 mcg/day, and more in particular f from 0.70 mcg/day to 2.0 mcg/day. Other more in particular doses are from 0.75 mcg/day to 1 mcg/day. 0.75 mcg/day is a safety and low enough dose.
  • doses of 0.75 mcg/day and lower (0.4 mcg/day-0.75 mcg/day) suppose being using a known antiparathyroid compound with a new indication, namely as an anti-inflammatory compound with these lower doses.
  • the combination comprises: a) an inhibitor of IL-17, and b) a vitamin D receptor agonist, wherein the amount of a) and the amount of b) in combination are therapeutically effective.
  • the vitamin D receptor agonist is the selective VDRA, paricalcitol, and the inhibitor of IL-17 activity is secukinumab.
  • the present invention also relates to a package or kit of parts comprising: i) a first pharmaceutical or veterinary composition which comprises an amount of an inhibitor of IL-17 activity as defined in any of claims 1-7, together with one or more pharmaceutically or veterinary acceptable excipients or carriers; and ii) a second pharmaceutical or veterinary composition which comprises an amount of vitamin D receptor agonist, together with one or more pharmaceutically or veterinary acceptable excipients or carriers; wherein the first and second compositions are separate compositions, and wherein the amount of the compound of inhibitor of IL-17 of i) and the amount of vitamin D receptor agonist of ii) in combination are therapeutically effective.
  • present invention also relates, in a more particular embodiment, to a combination comprising an inhibitor of IL-17 activity and a vitamin D receptor agonist, wherein both are provided in a packaging comprising a support with separate compartments, each compartment comprising one of the inhibitor of IL-17 activity and a vitamin D receptor agonist, said packaging comprising schedule means for appliance of a prescribed dosage regimen.
  • dose and “dosage” are used interchangeably herein.
  • the election of the pharmaceutical or veterinary formulation will depend upon the nature of the active compound and its route of administration. Any route of administration may be used, for example oral, parenteral and topical administration.
  • the pharmaceutical or veterinary composition may be formulated for oral administration and may contain one or more physiologically compatible carriers or excipients, in solid or liquid form. These preparations may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents.
  • the vitamin D receptor agonist is for oral administration.
  • the pharmaceutical or veterinary composition may be formulated for parenteral administration in combination with conventional injectable liquid carriers, such as water or suitable alcohols.
  • conventional pharmaceutical or veterinary excipients for injection such as stabilizing agents, solubilizing agents, and buffers, may be included in such compositions.
  • These pharmaceutical or veterinary compositions may be injected subcutaneously, intramuscularly, intraperitoneally, or intravenously.
  • the inhibitor of IL-17 activity is for subcutaneous administration.
  • compositions may be in any form, including, among others, tablets, pellets, capsules, aqueous or oily solutions, suspensions, emulsions, or dry powdered forms suitable for reconstitution with water or other suitable liquid medium before use, for immediate or retarded release.
  • excipients and/or carriers can readily be determined by those skilled in the art according to the type of formulation being prepared.
  • the proposed combination is, in particular, for use in the treatment and/or prevention of any metabolic alteration, more in particular uric acid levels in plasma, proteinuria and insulin resistance in autoimmune diseases.
  • the autoimmune disease or condition with autoinflammatory concomitant component is selected from an autoimmune kidney disease, an autoimmune joint disease, a skin autoimmune disease, an autoimmune neurological disease, an autoimmune thyroid disease, and gout disease.
  • IgAN is considered as a multi-cause disease catalogued as an autoimmune disease; however, the clinical and pathophysiologic effects observed in the IgAN and previously disclosed in detail in the background, induced the inventors to assumption that the IgAN is indeed a dual disease with autoimmune and autoinflammatory concomitant disease. As will be detailed in examples surprising results were observed in patients to which the combination of the invention was applied.
  • nephropathy IgA nephropathy
  • the disease is IgA nephropathy, in particular refractory to other treatments for IgA nephropathy or as a relapse of the disease after kidney transplantation.
  • the combination or kit of parts is for use in the prevention and/or treatment of proteinuria in a subject suffering from a kidney autoimmune and autoinflammatory disease.
  • the combination or kit of parts is for use in the prevention and/or treatment of an autoimmune neurological disease, more in particular is for use in the prevention and/or treatment of multiple sclerosis.
  • the combination or kit of parts is for use in the prevention and/or treatment of a gut disease, which is Chron’s disease.
  • the combination or kit of parts is for use in the prevention and/or treatment of an autoimmune thyroid disease, which is selected from hypothyroidism, Hashimoto's thyroiditis, hyperthyroidism, and Grave’s disease.
  • an autoimmune thyroid disease which is selected from hypothyroidism, Hashimoto's thyroiditis, hyperthyroidism, and Grave’s disease.
  • Th1 The control of the Th1, Th17 is considered as a potential treatment in autoimmune thyroid disease.
  • Autoimmune thyroid diseases such as Grave ' s disease and Hashimoto’s thyroiditis are closely related from a pathogenic point of view. In both, environmental factor and genetic susceptibility interact leading to a humoral and cellular immune response against thyroid antigens.
  • Th1 CD4+ lymphocytes predominate in thyroid tissue of patients with Hashimoto’s disease, and there is solid evidence that regulatory mechanisms of immune cells are disturbed in those patients.
  • the biochemical control of hypothyroidism in patients with Hashimoto’s thyroiditis is straightforward. Nonetheless, there is a substantial percentage of biochemically well-controlled patients who complaint of persisting and life-limiting symptoms to the extreme to be willing to be operated.
  • the combination or kit of parts is for use in the prevention and/or treatment of an autoimmune joint disease, which is rheumatoid arthritis.
  • an autoimmune joint disease which is rheumatoid arthritis.
  • Other more systemic autoimmune diseases include systemic lupus.
  • the combination or kit of parts is for use in the prevention and/or treatment of an autoimmune skin disease, which is psoriasis.
  • the combination, or the package or kit of parts as defined above is also for use in the treatment and/or prevention of a cancer, optionally with metastatic behaviour, in which deregulation of immune system takes place.
  • the cancer thyroid cancer also named thyroid carcinoma.
  • Th17 cells are an important mediator in inflammation-associated cancer: i) patients with thyroid tumors appears to have a higher proportion of Th17 and lower proportion of Tc17 cells in peripheral blood; ii) several polymorphisms in IL-17 receptor (IL17R) are associated with the development of papillary thyroid cancer; and iii) high IL-17 expression in tumoral tissues is associated with a worse prognosis in terms of recurrence and mortality. But Th17 immunologic-mediated pathways may promote or inhibit tumor progression.
  • the sequential administration of a selective Vitamin D receptor activation, such as paricalcitol, with in vitro evidence of an antitumoral effect, and an inhibitor of interleukin-17 activity is inhibiting tumor progression by restoring the immune response against tumoral cells and by blocking pathogenic mechanisms favoring tumor immune tolerance.
  • the combination, or a package or kit of parts as defined above, is also for use in the treatment and/or prevention of proteinuria, in particular in any disease or condition cursing with this symptom.
  • both the inhibitor of IL-17 and vitamin D receptor agonist are formulated for first administration of the vitamin D receptor agonist for a period of time comprised from 2 to 4 weeks before administration of the inhibitor of IL-17.
  • the inhibitor of IL-17 activity is for use in combination with a vitamin D receptor agonist in the prevention and/or treatment of the above listed diseases or conditions, and wherein said inhibitor of IL-17 and vitamin D receptor agonist are formulated for sequentially administration of a therapeutically effective amount of any of them.
  • they are formulated for first administration of the vitamin D receptor agonist and second the administration of the inhibitor of IL-17 activity after a period in which vitamin D receptor agonist has been previously administered.
  • the combination or a package or kit of parts are for use in the diseases and conditions previously disclosed, and both inhibitor of IL-17 and vitamin D receptor agonist are formulated for sequentially administration according to the following schedule:
  • the inhibitor of IL-17 is for use subcutaneously and the vitamin D receptor agonist is for use orally.
  • the daily dose of vitamin D receptor agonist is comprised from 0.4 mcg/day to 2 mcg/day
  • the weekly dose of inhibitor of IL-17 activity is comprised from 75 mg/week to 300 mg/week.
  • the dose of vitamin D receptor agonist is from 0.70 mcg/day to 2.0 mcg/day. In a more particular embodiment is from 0.70 mcg/day to 1.0 mcg/day. More in particular, vitamin D receptor agonist is the selective vitamin D receptor activator paricalcitol with a dose from 0.70 mcg/day to 2.0 mcg/day, even more in particular from 0.70 mcg/day to 1.0 mc/day, and even more in particular a dose from 0.75 mcg/day to 1.0 mcg/day.
  • the dose of inhibitor of IL-17 activity is of 300 mg/week. More in particular, inhibitor of IL-17 activity is secukinumab with a dose from 75 mg/week to 300 mg/week, even more in particular a dose from 100 mg/week to 300 mg/week.
  • the daily dose of vitamin D receptor agonist is for use for a period of time of at least 6 weeks.
  • the use of the vitamin D receptor agonist is conceived as a chronic treatment, which means that the subject is receiving the compound along life, optionally with resting periods in which no treatment is administered. The time of these resting periods, if any, are scheduled by prescriber (i.e. doctor).
  • the weekly dose of inhibitor of IL-17 activity is for use for a period of time from at least 5 weeks. More in particular is of 300 mg/week.
  • the administration schedule further includes a monthly dose of inhibitor of IL-17 activity for a period of at least 6 months.
  • both inhibitor of IL-17 and vitamin D receptor agonist are formulated for sequentially administration according to the following schedule:
  • patients treated with the proposed combination therapy experienced a high reduction of proteinuria, in relation to basal value before therapy. Therefore, present description proposes this combination therapy for use in the treatment of the symptoms of kidney damage or of kidney disease.
  • treating proteinuria may not result in the treatment of the main cause of the disease, even more when several are the causes involved in the disease, at least the treating of proteinuria will minimize the worsening of the pathological condition.
  • Inclusion criteria 1.- Biopsy-proven IgA nephropathy.
  • the treatment consists of two phases: a) Induction Phase: from month 0 to month 1. b) Maintenance Phase: from month 1 to month 6.
  • any of the induction phase (a) and maintenance phase (b) some patients could equally have received a dose of paricalcitol from 0.4 to 1 mcg/day. Indeed, in any of the induction phase (a) and maintenance phase (b), other patients (data not shown) received an average of 0.71 mcg/day of paricalcitol (5 days of treatment in a week at a dose of 1 mcg/day of paricalcitol). This dose of paricalcitol gave also good results.
  • Patient 1 and patient 2 is the same in two time points.
  • Table II shows the evolution of the proteinuria determined by its quantification in 24-hours colleted urine.
  • initial increase in the proteinuria level was observed, however it decreased proatively at month 3 and 6.
  • the patient 1, 2 and 3 decreased the 24 hours proteinuria in 62%, 44% and 58% respectively, which is clinically significant.
  • patient 5 was included as a control nephropathy patient. That patient was treated with secukinumab for his reumatologic disease (Ankylosing spondylitis) as is indicated by data sheet.
  • secukinumab for his reumatologic disease (Ankylosing spondylitis) as is indicated by data sheet.
  • the moderate proteinuria level increased to a nephrotic level (> 3,5 g/24h) which is a life-threatening condition. It was the reason why secukinumab needs to be stopped.
  • this patient only received secukinumab and no paricalcitol was administered. This fact represents a crucial aspect that reinforces the invention.
  • the proteinuria changes during the follow-up indicates a rapid decline in their values, when it was evaluated as a whole.
  • de % decrease was 28%, while the antiproteinuric effect was more pronounced in month 3 of the follow up, when lowering proteinuria reached nearly than 50%.
  • the decrease in the UA values indicates a decrease in the purine metabolism, it means a decrease in damage, dying and dead cells in the body. This was surprising, but nonetheless it could be confirmed that peripheric red blood cells and the platelets number did not decrease during the study, thus, the decrease may represent a decrease in white blood cells, in particular related to theTH17 cells evolution as is show in Table XIII. Moreover, hematuria disappeared, which is another important reason for the UA lowering effect. The decrease of the UA was more important at the end of the induction phase, showing during the study levels considered in the normal range (3,5 to 7,2 mg/dl).
  • the decrease in UA may reflect the control in the autoimmune component, because UA is necessary for the type 2 immune response, which is the direct immune disorder for treating in the sequential MNL therapy.
  • Plasma triglycerides levels evolution The triglycerides levels (See Table IV) show a desirable evolution; in particular in patient 3 and 4, who initially presented higher triglycerides levels. The explanation for its positive effect is consistent with the evolution of the proteinuria. Importantly, the benefit in blood pressure, UA and the triglycerides, keeping the same weight indicates a positive effect on the metabolic syndrome.
  • the plasma total proteins increased as shown in table V in patients 1-3.
  • patient 4 its values decreased proliferatively, indicating no response of the sequential MNL therapy in this no IgAN patient.
  • Table V Total plasma proteins VI. Renal lysosomal activity evolution One of the most important component of the sequential MLN therapy is the controlled influence on the lysosomal activity in safe manner.
  • the lysosomal activity increased in patients 1 , 2 and 3; however its activity decreases in patient 4 (see data in Table VI).
  • the mean of the lysosomal activity determined by the urine determination of the N-Acetyl-b-D-glucoaminidase activity increased as shown in Table X. This condition informs conversely with the current state of the art, that a renal damage is not associated as the investor inform in the present application.
  • Table VI Lysosomal activity. Urine N-Acetyl-B-D-glucosaminidase U/ g creatinine
  • the lysosomal activity decreased progenitor in every patients and as a whole. Those changes occurred after the induction phase and was associated with a progressive decrease in the proteinuria levels.
  • the progressive decrease on renal lysosomal activity was associated with a progressive decrease in the proteinuria levels, during that period of time the doses of the secukinumab was lower that in the induction phase; however the dosage of the paricalcitol and the secukinumab was the same which clearly indicates that the beneficial effect on proteinuria was maintained during all the maintenance phase.
  • patient 4 the lysosomal activity decreased from the basal high levels, but the proteinuric response in this patient was unsatisfactory, and completely opposite in comparison with patients 1, 2 and 3.
  • hematuria is a hallmark sing of the glomerulonephritis process.
  • this kind of glomerular disorder was completely restored in all patients, confirming that the immunocomplexes deposition (autoimmune component of the disease) in the mesangial area of the glomerulus improved after treatment.
  • the effect on hematuria was permanent indicating a clear repairing process of the glomerular filtration barrier.
  • the selective vitamin D receptor activation may play a role in the Th1 expression through the inhibition of the IL-6 and TGF-beta. After the decrease percentage of the Th1 during the induction phase a potent increase in the same Th1 percentage was observed. Because the month 0 (M0) and month 3 (M3) time points were associated with changes in proteinuria from 2.1 to 0.8g/24hours respectively (about 60% in proteinuria reduction) it could be concluded that this was not a escape phenomenon, but represented a change in the phenotype of these cells obtained after treating with the sequential therapy.
  • the changes of the Treg as a whole indicates a weak benefit in this type of cells.
  • the underline effect responsible of this effect may be related to the inhibition of the TGF-beta as a consequence of the selective vitamin D receptor activator. This induced condition is also interesting, due to the following reasons
  • the no reduction of Treg also may be reflecting that an increase in the Treg is no longer needed after the treatment with paricalcitol.
  • Th17 cells evolution Changes in the Th17 cells could only be quantified in patient 1, the changes in patient 3 and 4 were unquantifiable. The progressive decrease in these cells are consistent with the previous report. The decrease in Th17 could be due to the proposed sequential therapy. It is well accepted that paricalcitol and secukinumab have the potential to decrease these cells (see data of patient 1 in Table XIII above).
  • Thyroid-stimulating hormone Thyroid-stimulating hormone
  • T4 free thyroxine

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EP20785714.5A 2019-09-30 2020-09-29 Kombinationstherapie mit einem hemmer der interleukin-17-aktivität und einem vitamin-d-rezeptoragonisten Pending EP4037690A1 (de)

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LIU X ET AL: "Anti-IL-33 antibody treatment inhibits airway inflammation in a murine model of allergic asthma", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ELSEVIER, AMSTERDAM NL, vol. 386, no. 1, 14 August 2009 (2009-08-14), pages 181 - 185, XP026467441, ISSN: 0006-291X, [retrieved on 20090607], DOI: 10.1016/J.BBRC.2009.06.008 *
SABNIS RAM W.: "Imidazo[1,2- b ]pyridazines as IL-17A Inhibitors for Treating Psoriasis, Rheumatoid Arthritis, and Multiple Sclerosis", ACS MEDICINAL CHEMISTRY LETTERS, vol. 12, no. 10, 13 September 2021 (2021-09-13), US, pages 1526 - 1527, XP055958394, ISSN: 1948-5875, DOI: 10.1021/acsmedchemlett.1c00470 *
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