CN116940359A - Treatment of autoimmune diseases with inhibitors of dihydroorotate dehydrogenase (DHODH) - Google Patents
Treatment of autoimmune diseases with inhibitors of dihydroorotate dehydrogenase (DHODH) Download PDFInfo
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- CN116940359A CN116940359A CN202180069893.3A CN202180069893A CN116940359A CN 116940359 A CN116940359 A CN 116940359A CN 202180069893 A CN202180069893 A CN 202180069893A CN 116940359 A CN116940359 A CN 116940359A
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Abstract
The present invention provides a method of treating an autoimmune disease in a patient comprising administering a therapeutically effective amount of a DHODH inhibitor or a pharmaceutically acceptable salt thereof. Formulations or compositions suitable for use in the treatment of autoimmune diseases are also provided.
Description
The present disclosure relates to the use of DHODH inhibitors alone or in combination with another therapy for the treatment of autoimmune diseases.
Background
The pathology of autoimmune diseases is characterized by the body attacking itself with aberrant T cells and/or B cells. Although "autoimmune disease" encompasses many specific diseases, there are some underlying mechanisms that are fundamentally similar to drive biological processes. Common symptoms of many autoimmune diseases include: fatigue, joint pain and swelling, skin problems, allodynia or digestive problems, repeated heat and gland swelling.
Risk factors for autoimmune diseases include inheritance (particularly Multiple Sclerosis (MS)), obesity, smoking, and certain drugs (such as antibiotics, statins, and some drugs for lowering blood pressure).
The resulting diseases are difficult to diagnose, treat, and can be very debilitating. There is a truly unmet need for patients with autoimmune diseases. In some cases, when MS is severe, the method is to clear the patient's immune system and perform stem cell transplantation. This is a dangerous, difficult and expensive procedure, and is the last treatment method.
Purine and pyrimidine nucleotides play a key role in DNA and RNA synthesis, membrane lipid biosynthesis and protein glycosylation. They are necessary for the development and survival of mature T lymphocytes. Activation of T lymphocytes correlates with an increase in the pool of purines and pyrimidines, which in turn leads to a significant increase in the activity of key enzymes involved in the de novo synthesis of purines and pyrimidines.
Pyrimidine is believed to be important in controlling the progression of the T cell life cycle from early to mid S phase. Inhibition of pyrimidine also causes apoptosis of activated T cells.
Similarly, pyrimidine biosynthesis is also important in the life cycle of activated B cells.
While not wishing to be bound by theory, the inventors believe that blocking pyrimidine biosynthesis will result in cell cycle arrest and/or apoptosis in activated T cells and/or B cells that have aberrant activity in autoimmune diseases.
Dihydroorotate dehydrogenase (DHODH) is an enzyme that catalyzes the fourth step of the pyrimidine biosynthetic pathway, i.e. conversion of dihydroorotate to orotate, while transferring electrons to ubiquinone (cofactor Q) via flavin mononucleotide intermediates (Loffler MoI Cell Biochem, 1997). Mammalian cells have an additional salvage pathway compared to parasites (plasmodium falciparum) (McRobert et al, no. MoI Biochem Parasitol 2002) and bacteria (e.coli) that use only this de novo pathway as a source of pyrimidine.
During steady state proliferation, the salvage pathway independent of DHODH appears to be sufficient to supply pyrimidine bases to cells. However, in cells with high turnover rates, a de novo pathway is required in order to proliferate. In these cells DHODH inhibition stops cell cycle progression by inhibiting DNA synthesis and ultimately cell proliferation (Breedveld f.c. ann Rheum Dis 2000).
It is thought that inhibition of mitochondrial cytochrome bc1 (a component of electron transfer chain complex III) will lead to activation of p53, followed by induction of apoptosis. The mitochondrial respiratory chain is coupled to the de novo pyrimidine biosynthetic pathway via the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH).
The pharmaceutical characteristics of individual DHODH inhibitors vary greatly, for example, the side effects of leflunomide (leflunomide) include arterial hypertension, myelosuppression, nausea and hair loss. Bucona (brequinar) is generally used only as a model compound, as clinical trials indicate that the molecule lacks the necessary activity in vivo. Vidofludimus is a new generation of DHODH inhibitors that inhibit the production of pro-inflammatory cytokines (such as IL-17) by activated lymphocytes. However, the latter is believed to be independent of DHODH activity.
While DHODH inhibitors have been of interest as therapeutic agents, it is difficult to find molecules that balance all of the necessary criteria to provide therapeutic agents that are effective in vivo.
The present disclosure provides for the use of a specific DHODH inhibitor ASLAN003 in the treatment of autoimmune diseases such as multiple sclerosis, autoimmune skin diseases and inflammatory bowel diseases (e.g., crohn's disease).
ASLAN003 has activity on the root cause of autoimmune disease (i.e. anamorphic T cells and/or B cells), which surprisingly translates in vivo into broad spectrum activity on autoimmune disease with minimal off-target effects (in particular hepatotoxicity). ASLAN003 has high affinity for DHODH and is clinically effective. ASLAN003 is a new generation of DHODH inhibitors, which is well tolerated and provides excellent results for patients. It can positively impact the quality of life of a patient to control the disease state and prevent its progression and/or to alleviate the disease. Advantageously, healthy cells with lower metabolic burden are generally unaffected by the treatment. The balance of the treatment is highly beneficial to the patient.
While not wishing to be bound by theory, it is believed that in one embodiment, the treatment of the present invention is a disease modifying treatment. That is, after a period of treatment, the body is able to self-reset and bring the autoimmune disease into remission, e.g., without continuing to administer the therapy or wherein the therapy continues to be administered at a low dose for maintenance.
Disclosure of Invention
The disclosure is summarized in the following paragraphs:
1. a method of treating an autoimmune disease in a patient comprising administering a therapeutically effective amount of the DHODH inhibitor 2- (3, 5-difluoro-3' -methoxybiphenyl-4-ylamino) nicotinic acid or a pharmaceutically acceptable salt thereof.
1A DHODH inhibitor 2- (3, 5-difluoro-3' -methoxybiphenyl-4-ylamino) nicotinic acid, or a pharmaceutically acceptable salt thereof, for use in treating a patient suffering from or suspected of suffering from an autoimmune disease.
Use of the 1B DHODH inhibitor 2- (3, 5-difluoro-3' -methoxybiphenyl-4-ylamino) nicotinic acid or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an autoimmune disease.
2. The method, inhibitor or use of paragraph 1, 1A or 1B wherein the autoimmune disease is selected from the group comprising or consisting of: pyogenic sweat gland, scleroderma (systemic scleritis), lichen planus, scleroderma, psoriasis, type 1 diabetes, autoimmune thyroiditis, graves 'disease, endometriosis, celiac disease, crohn's disease, ulcerative colitis, axial spondylitis, juvenile arthritis, recurrent rheumatism, psoriatic arthritis, rheumatoid arthritis, sarcoidosis, systemic Lupus Erythematosus (SLE), undifferentiated Connective Tissue Disease (UCTD), multiple sclerosis type II, restless leg syndrome, optic neuritis, uveitis, scleritis, predatory keratohelpers, meniere's disease, graves' eye disease, neuromyelitis optica, susac syndrome and lupus erythematosus.
3. The method, inhibitor or use of paragraph 1, 1A or 1B wherein the autoimmune disease is inflammatory bowel disease, e.g., celiac disease, crohn's disease or ulcerative colitis, such as crohn's disease.
4. The method, inhibitor or use of paragraph 1, 1A or 1B wherein the autoimmune disease is a skin lesion.
5. The method, inhibitor or use of any of paragraphs 1, 1A or 1B to 4, wherein the autoimmune disease is characterized by a distorted T cell response.
6. The method, inhibitor or use of any of paragraphs 1, 1A or 1B to 5, wherein the autoimmune disease is characterized by a distorted B cell response.
7. The method, inhibitor or use of any of paragraphs 1, 1A or 1B to 6, wherein the autoimmune disease is not adequately controlled, e.g. by standard of care drugs.
8. The method, inhibitor or use of any of paragraphs 1, 1A or 1B to 7, wherein autoimmune disease is a disorder.
9. The method, inhibitor or use of any one of paragraphs 1, 1A or 1B to 8, wherein the autoimmune disease is not one or more of: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, welch granulomatosis, systemic lupus erythematosus, psoriasis, sarcoidosis polyarthritis idiopathic arthritis, inflammatory bowel disease (such as ulcerative enteritis and Crohn's disease), lyter's syndrome, fibromyalgia, or type 1 diabetes.
10. The method, inhibitor or use according to any of paragraphs 1, 1A or 1B to 8, wherein the autoimmune disease is inflammatory bowel disease, e.g. colitis, including ulcerative colitis, crohn's disease and/or celiac disease (and complications thereof such as arthritis, uveitis, erythema nodosum and jaundice)
11. The method, inhibitor or use of any of paragraphs 1, 1A or 1B to 8, wherein the autoimmune disease is a skin disorder, such as atopic dermatitis (including autoimmune progestin dermatitis), psoriasis, erythema (including nodular erythema), scleroderma and lupus.
12. The method, inhibitor or use according to any one of claims 1, 1A or 1B to 8, wherein the autoimmune disease is rheumatoid arthritis.
13. The method, inhibitor or use of any one of paragraphs 1, 1A or 1B to 8, wherein the autoimmune disease is multiple sclerosis.
14. The method, inhibitor or use of paragraph 13 wherein the multiple sclerosis is relapsing-remitting multiple sclerosis.
15. The method, inhibitor or use of paragraph 13 or 14 wherein the multiple sclerosis is secondary progressive multiple sclerosis.
16. The method, inhibitor or use of paragraph 13 wherein the multiple sclerosis is primary progressive multiple sclerosis.
17. The method, inhibitor or use according to any of paragraphs 13 to 16, wherein the severity of symptoms is reduced, such as improvement of motor function, spasticity, muscle spasticity and/or stiffness, by treatment.
18. The method, inhibitor or use of any one of paragraphs 13 to 17, wherein the frequency or severity of relapse is reduced by treatment.
19. The method, inhibitor or use of any of paragraphs 1 to 18, wherein aberrant T cell activation is minimized, e.g., progression of the T cell life cycle from early S-phase to intermediate S-phase is inhibited.
20. The method, inhibitor or use of paragraph 19 wherein there is reduced activation of memory T cells.
21. The method, inhibitor or use of paragraphs 19 or 20, wherein aberrant activation of TH 1T cells is inhibited.
22. The method of any one of paragraphs 1, 1A or 1B to 21, wherein TH 2T cell activation is not inhibited.
23. The method of any one of paragraphs 1, 1A or 1B to 22, wherein activation of the aberrated B cells is inhibited, e.g., by limiting progression of S phase in the cell life cycle.
24. The method, inhibitor or use of any one of paragraphs 1, 1A or 1B to 23, wherein apoptosis of an aberrant immune cell is stimulated.
25. The method, inhibitor or use of any one of paragraphs 1, 1A or 1B to 24, wherein the treatment is against an outbreak of an autoimmune disease.
26. The method, inhibitor or use of any of paragraphs 1, 1A or 1B to 25, wherein the treatment is continuous, e.g. 100 to 400mg per dose (such as daily), in particular 300 to 400mg per dose (such as daily), for at least a period of time, and optionally maintaining each dose (such as daily), e.g. 100 to 200mg.
27. The method, inhibitor or use of any of paragraphs 1, 1A or 1B to 25, wherein the treatment is intermittent or stopped after a period of time (e.g., after a defined endpoint).
28. The method, inhibitor or use of any one of paragraphs 1, 1A or 1B to 27, wherein the DHODH inhibitor is used as monotherapy.
29. The method, inhibitor or use of any one of paragraphs 1, 1A or 1B to 27, wherein the DHODH inhibitor is employed in combination therapy.
30. The method, inhibitor or use of paragraph 29, wherein the combination therapy comprises a treatment independently selected from the group consisting of: corticosteroids (e.g., oral prednisone and intravenous methylprednisolone), plasmapheresis (plasmapheresis), interferon beta drugs, glatiramer acetate, fingolimod, dimethyl fumarate, desipramine fumarate, teriflunomide, cinnimod, cladribine, orelobutramine, natalizumab, anti-CD 20 agents, or biomimetics thereof such as rituximab, alemtuzumab, and Bruton's Tyrosine Kinase (BTK) inhibitors.
31. The method, inhibitor or use according to paragraph 29 or 30, wherein the combination therapy comprises a treatment that alleviates or alleviates symptoms of multiple sclerosis, e.g., muscle relaxants (such as baclofen, tizanidine and cyclobenzaprine), fatigue-alleviating agents (such as amantadine, modafinil and methylphenidate), and/or walking speed-improving agents (such as daphnidine).
32. The method, inhibitor or use according to any one of paragraphs 29 to 31, wherein the combination therapy comprises an antidepressant, e.g. a tricyclic antidepressant such as chlorimipramine.
33. The method, inhibitor or use of any one of paragraphs 29 to 32, wherein the combination therapy comprises duloxetine.
34. The method, inhibitor or use of any of paragraphs 29 to 33, wherein the combination comprises mirabegron and/or desmopressin.
35. The method, inhibitor or use of any one of paragraphs 29 to 34, wherein the combination therapy comprises interferon beta (IFN- β), such as interferon beta-1 a or interferon beta-1 b.
36. The method, inhibitor or use of any one of paragraphs 29 to 35, wherein the combination therapy comprises an anti-CD 20 agent or a biomimetic thereof, such as Rituxan, rituximab, an anti-biomimetic Gazyva, kesimpta, ocrevus (orelbuzumab), ruxience, truxima, zevalin, arzerra, acellBia, HLX, reditux, ritucad or Zytux.
37. The method, inhibitor or use of any one of paragraphs 29 to 36, wherein the combination therapy comprises a Bruton's Tyrosine Kinase (BTK) inhibitor, such as Ibrutinib (ibutinib), acalabrutinib (Acalabrutinib), zebutinib (zaubrutinib), angstrom Wo Bulu tinib (Evobrutinib), ABBV-105, non-nebutinib (fenebutinib), GS-4059, capetinib (speedutinib) and HM71224.
38. The method, inhibitor or use of any of paragraphs 29 to 37, wherein the combination does not comprise methotrexate.
39. The method, inhibitor or use of any one of paragraphs 29 to 38, wherein the combination comprises an inhibitor of purine synthesis, such as azathioprine.
40. The method, inhibitor or use of any of paragraphs 29 to 39, wherein the combination comprises a biotherapeutic agent such as an antibody or binding fragment thereof, in particular a dupilumab or anti-IL-13 ra 1 antibody or antigen binding fragment thereof such as ASLAN004, including pharmaceutical formulations of any of them.
41. The method, inhibitor or use according to any one of paragraphs 1, 1A or 1B to 40, wherein the DHODH inhibitor is administered in a dose in the range of 1mg to 400mg per day, for example 100mg to 400mg per day, such as 100mg, 200mg, 300mg or 400mg per day.
42. The method, inhibitor or use of any one of paragraphs 1, 1A or 1B to 41, wherein the DHODH inhibitor is administered daily, e.g. once daily.
43. The method, inhibitor or use of any one of paragraphs 1, 1A or 1B to 42, wherein the patient is a human.
44. The method, inhibitor or use of any one of paragraphs 1, 1A or 1B to 43, wherein the patient is at least 40 years (e.g. 45 years), at least 50 years, at least 55 years, at least 60 years, at least 65 years, at least 70 years, at least 75 years old.
45. The method, inhibitor or use of any of paragraphs 1, 1A or 1B to 44, wherein the patient has a concurrent disease.
46. The method, inhibitor, or use of paragraph 45, wherein the concomitant disease is selected from obesity, allergy, asthma, COPD, diabetes, renal failure, heart disease (including heart failure), cancer, dementia, liver disease, and combinations thereof.
Drawings
Fig. 1 is a graph showing the in vivo results of an ASLAN003 (LAS 186323) study in a multiple sclerosis Experimental Autoimmune Encephalomyelitis (EAE) model. The graph shows the dose-dependent response when ASLAN003 was administered.
Fig. 2 is a graph showing the area under the clinical score curve (AUC) mean for each treatment group.
Fig. 3 is a graph showing CNS histological scores.
Fig. 4 is a graph showing the evolution of the disease over time. Y-axis = clinical score, X-axis = days of treatment, V = vehicle, F = positive control F, T = positive control T, L = ASLAN003 (LAS 186323). The numbers following abbreviations correspond to the oral daily doses of the compounds administered in mg/kg.
Fig. 5 is a graph showing a blood cell count. Y-axis = cell count, WBC = white blood cell, RBC = red blood cell, HGB = hemoglobin, net = neutrophil, LYMPH = lymphocyte. For each cell type, the data bars are, in order from left to right: primary treatment, V, F-0.1, T-1, T-3, T-10, L-1, L-3, L-10 and L-15.
V = vehicle, F = positive control, T = positive control, L = ASLAN003 (LAS 186323). The numbers following abbreviations correspond to the oral daily doses of the compounds administered in mg/kg.
Fig. 6 is a graph showing the (AUC) scores for each treatment group in a Rheumatoid Arthritis (RA) adjuvant arthritis (AIA) model. T-3: positive control T,3mg/kg, one-way ANOVA with Bonferroni post test, p < 0.05
Fig. 7 is a graph showing X-ray examination scores for each treatment group in the RAAIA model. T-3: positive control T,3mg/kg.
Fig. 8A is a graph showing body weight of each treatment group in a sodium dextran sulfate (DSS) induced Inflammatory Bowel Disease (IBD) model.
Figure 8B is a graph showing the percentage change in body weight for each treatment group in DSS-induced IBD model.
Figure 9A is a graph showing stool consistency scores for each treatment group in a DSS-induced IBD model.
Figure 9B is a graph showing the bloodstool scores for each treatment group in a DSS-induced IBD model.
Figure 10 is a graph showing Disease Activity Index (DAI) for each treatment group in a DSS-induced IBD model.
Figure 11 is a graph showing the results of intestinal permeability tests (FITC concentration) for each treatment group in a DSS-induced IBD model.
Figure 12A is a graph showing colon weight for each treatment group in a DSS-induced IBD model.
Figure 12B is a graph showing colon length for each treatment group in a DSS-induced IBD model.
Figure 12C is a graph showing colon weight/length for each treatment group in a DSS-induced IBD model.
Figure 12D is a graph showing spleen weights for each treatment group in a DSS-induced IBD model.
Figure 13 is a graph showing the data of lipocalin in feces for each treatment group in a DSS-induced IBD model.
* Error bars indicate Standard Error (SEM) compared to the mean.
Detailed Description
2- (3, 5-difluoro-3' -methoxybiphenyl-4-ylamino) niacin (referred to herein as ASLAN 003) has the structure:
Autoimmune diseases
An autoimmune disease as used herein refers to any disease or condition in which the immune system of an individual erroneously targets normal "healthy" cells of the individual themselves, particularly characterized by aberrant T-cell and/or B-cell activation.
Aberrant T cell and/or B cell activation as used herein refers to aberrant T cell and/or B cell activation, particularly where the aberrant cell recognizes itself or an autoantigen.
Severe autoimmune disease refers to where the disease is not controlled by standard of care drugs/treatments.
Outbreaks refer to the period of disease progression.
As used herein, "under-controlled" refers to where standard-of-care drugs fail to alleviate or control symptoms, particularly where the quality of life of the patient is adversely affected.
As used herein, "defined endpoint" refers to a clinically defined point, such as alleviation or stabilization of a disease.
In one embodiment, ASLAN003 is used in maintenance therapy, for example, at a low dose. Maintenance therapy as used herein refers to continuous therapy that stabilizes or maintains remission of the disease, e.g., where low doses are administered and are particularly frequent. For example, a dose of 100 to 200mg administered once or twice daily may be used as maintenance therapy.
In one embodiment, the autoimmune disease is an autoimmune skin disease, i.e. an autoimmune disease that is manifested or present in the skin, in particular the dermis and/or epidermis, such as lupus.
Thus, in one embodiment, the autoimmune disease is selected from the group comprising or consisting of: acute disseminated encephalomyelitis (adem), acute necrotizing hemorrhagic encephalomyelitis, addison's disease, adrenal insufficiency, hypoglucocorticoid, amyloidosis, ankylosing spondylitis, spondyloarthropathies, strumell-Marie disease, anti-GBM/anti-TBM nephritis, anti-phospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune autonomic nerve dysfunction, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune deficiency, autoimmune Inner Ear Disease (AIED), autoimmune lymphoproliferative syndrome (ALPS), canale-Smith syndrome, autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis (AIP) autoimmune polyadenopathy (types I, II and III), autoimmune Retinopathy (AR), autoimmune Thrombocytopenic Purpura (ATP), autoimmune thyroiditis, autoimmune urticaria, axonal/neuronal neuropathy, ballosis, behcet's disease, bullous pemphigoid, cardiomyopathy, kaschmann's disease, celiac disease, trypanosomiasis, chronic Inflammatory Demyelinating Polyneuropathy (CIDP), chronic Recurrent Multifocal Osteomyelitis (CRMO), churg-Strauss syndrome, cicatricial pemphigoid/benign mucosal pemphigoid (CP), crohn's disease, inflammatory bowel disease, colitis (including ulcerative colitis), enteritis, ileitis, cogans syndrome, colletosomiasis, congenital heart conduction block, coxsackie viral myocarditis, cristae disease, cryoglobulinemia, demyelinating neuropathy, dermatitis herpetiformis, du Linshi disease, dermatomyositis, type I diabetes, discoid Lupus Erythematosus (DLE), post myocardial infarction syndrome, endometriosis, epidermolysis Bullosa (EB) and acquired EB (EBA), eosinophilic gastroenteritis, esophagitis, eosinophilic fasciitis, schulman syndrome, erythema nodosum, experimental allergic encephalomyelitis, iwinian syndrome, fibroalveolar inflammation, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis (nonproliferative: focal segmental glomerulosclerosis and membranous glomerulonephritis; proliferation type IgA nephropathy), pneumorrhagia-nephritis syndrome, granulomatous Polyangiitis (GPA) (formerly known as Web granulomatous disease), graves' disease, guillain-Barre syndrome, miller-Fisher syndrome, acute motor shaft-Soxhlet neuropathy, acute motor sensory shaft-Soxhlet neuropathy, acute full-autonomic neuropathy, bickertaff brain stem encephalitis, hashimoto thyroiditis, hemolytic anemia, allergic purpura, pregnancy herpes, hypogammaglobemia, idiopathic pulmonary fibrosis, idiopathic Thrombocytopenic Purpura (ITP), igA nephropathy (IGAN), berger syndrome, concurrent pharyngitis glomerulonephritis (synpharyngitic glomerulonephritis), igA pemphigus, igG 4-related sclerosing disease, immunomodulatory infertility, inclusion body myositis, insulin dependent diabetes mellitus, interstitial cystitis, isaac syndrome, neuromuscular rigidity, juvenile arthritis, juvenile myositis, kawasaki syndrome, lambert-eaton syndrome, white cell disruption vasculitis, lichen planus, lichen sclerosus, wood-like conjunctivitis, linear IgA skin disease (LAD), pemphigoid, lupus (SLE), lyme disease, meniere's disease, polyarteritis Microscopic (MPA), mixed Connective Tissue Disease (MCTD), monoclonal gammaglobosis, predatory corneal ulcers, mucha-Habermann disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis (Devic disease), neuromuscular rigidity, isaac syndrome (acquired, paraneoplastic, hereditary), neutropenia, ocular scarring pemphigoid, optic neuritis, oophoritis, strabismus eye contracture-myoclonus syndrome orchitis, recurrent rheumatism, pandas disease (pediatric autoimmune neuropsychiatric disorder associated with streptococci), paraneoplastic autoimmune multiple organ syndrome (PAMS), paraneoplastic cerebellar degeneration, paraneoplastic pemphigus (PNP), paroxysmal sleep hemoglobinuria (PNH), pari-Long Beige syndrome, parsonne-Turner syndrome, ciliary panamatis (peripheral uveitis), gestational Pemphigoid (PG), pemphigus Vulgaris (PV), deciduous Pemphigus (PF), peripheral neuropathy, peripheral encephalomyelitis, pernicious anemia, poims syndrome, polyarteritis nodosa (PAN), polymyalgia rheumatica, polymyositis, post myocardial infarction syndrome, post pericardial osteotomy syndrome, primary biliary cirrhosis of progestin dermatitis, hanot syndrome, primary Sclerosing Cholangitis (PSC), sclerosing cholangitis, psoriasis, psoriatic arthritis, pyoderma gangrenosum, pure red cell aplasia, rassmasen encephalitis, chronic Focal Encephalitis (CFE), reynolds phenomenon, reactive arthritis, lyer syndrome, restorative protein-associated retinopathy (RAR), reflex neurotrophic deficiency, lyer syndrome, recurrent polychondritis, restless leg syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, schmidt syndrome, scleritis, scleroderma, systemic sclerosis, sicca syndrome, sperm and testis autoimmunity, stiff person syndrome Subacute Bacterial Endocarditis (SBE), susac syndrome, sympathotic ophthalmia, aortic arteritis, temporal arteritis/giant cell arteritis, thromboangiitis obliterans, buerger's disease, thrombocytopenic purpura (TTP), tolossa-hunter syndrome, transverse myelitis, undifferentiated connective tissue disease (uccd), uveitis, aortic inflammation, temporal arteritis, buerger's disease, cutaneous vasculitis, kawasaki disease, polyarteritis nodosa, bai Saizeng syndrome, allergic granulomatosis vasculitis, cutaneous vasculitis, allergic purpura, microscopic polyangiitis, wegiar granulomatosis, golfer vasculitis, bullous dermatitis and wegener's granulomatosis (now called Granulomatosis Polyangiitis (GPA)).
In one embodiment, the autoimmune disease is selected from the group comprising or consisting of: ANCA vasculitis, igA nephropathy (Berger's disease), pemphigus vulgaris/bullous pemphigoid, ITP, primary biliary cirrhosis, autoimmune thyroiditis (graves ' disease), hashimoto's disease, lupus nephritis, membranous glomerulonephritis (or membranous nephropathy), APS, myasthenia gravis, neuromyelitis optica, primary xerosis, autoimmune neutropenia, autoimmune pancreatitis, dermatomyositis, autoimmune uveitis, autoimmune retinopathy, behcet's disease, IPF, systemic sclerosis, liver fibrosis, autoimmune hepatitis, primary sclerosing cholangitis, goodpasture's syndrome, alveolar protein deposition, chronic autoimmune urticaria, psoriasis, rheumatoid arthritis, psoriatic arthritis Axis type spondylitis, transplantation (including GvHD), asthma, COPD, giant cell arteritis, refractory autoimmune cytopenia, iwinian syndrome (autoimmune hemolytic anemia), type I diabetes, sarcoidosis, polymyositis, ulcerative colitis, crohn's disease, celiac disease, waldenster's macroglobulinemia, focal segmental glomerulosclerosis chronic lyme disease (lyme borreliosis), lichen planus, stiff person syndrome, dilated cardiomyopathy, autoimmune (lymphocytic) oophoritis, epidermolysis bullosa, autoimmune atrophic gastritis, pernicious anemia, atopic dermatitis, atherosclerosis, multiple sclerosis, lasmassen encephalitis, guillain-Barre syndrome, acquired neuromuscular rigidity and stroke.
In one embodiment, the autoimmune disease is selected from the group comprising or consisting of: pyogenic sweat gland, scleroderma (systemic scleritis), lichen planus, scleroderma, psoriasis, type 1 diabetes, autoimmune thyroiditis, graves 'disease, endometriosis, celiac disease, crohn's disease, ulcerative colitis, axial spondylitis, juvenile arthritis, recurrent rheumatism, psoriatic arthritis, rheumatoid arthritis, sarcoidosis, systemic Lupus Erythematosus (SLE), undifferentiated Connective Tissue Disease (UCTD), multiple sclerosis type II, restless leg syndrome, optic neuritis, uveitis, scleritis, predatory keratohelpers, meniere's disease, graves' eye disease, neuromyelitis optica, susac syndrome and lupus erythematosus.
In one embodiment, the autoimmune disease is selected from the group comprising or consisting of: lichen planus, sweat gland suppurative, celiac disease, ulcerative colitis, crohn's disease, graves' disease, autoimmune thyroiditis, endometriosis, multiple sclerosis and optic neuritis.
Multiple Sclerosis (MS) is a disease in which myelin sheath that isolates brain and spinal cord nerve cells is damaged. As a result of this injury, the ability of the nervous system to properly transmit signals is compromised. This in turn leads to a serious series of physical and mental problems such as double vision, monocular blindness, muscle weakness, sensory or coordination problems, speech problems, acute or chronic pain, bladder and bowel difficulties, depression and mood swings.
In most cases, the condition begins within days with clinically isolated syndrome, with most people suffering from motor or sensory problems. The course of symptoms is initially in two modes, either a sudden exacerbation episode (known as recurrence) lasting from several days to several months, then improved in most cases, or a gradual exacerbation over time without a recovery period. Recurrence is generally unpredictable and occurs without symptoms.
The etiology of multiple sclerosis is currently unknown, although the underlying mechanism is thought to be the destruction of myelin by the individual's autoimmune system, i.e., multiple sclerosis is at least partially regarded as an autoimmune disease. It is the most common immune-mediated disorder affecting the central nervous system, with about 230 tens of thousands of people worldwide affected. However, there are many autoimmune diseases that have serious negative impact on the lives of many patients.
In one embodiment, the autoimmune disease is Multiple Sclerosis (MS). Multiple sclerosis is generally further divided into one of four variants: clinically Isolated Syndrome (CIS), relapsing Remitting MS (RRMS), primary Progressive MS (PPMS), and Secondary Progressive MS (SPMS). Thus, in one embodiment, the autoimmune disease is selected from the group comprising CIS, RRMS, PPMS and SPMS.
Relapsing-remitting MS (RRMS) is characterized by unpredictable relapses followed by a relatively calm (remitting) period of months to years, during which there are no signs of new disease activity. The condition is typically manifested by progressive, sustained demyelination and associated loss of axons. In one embodiment, the autoimmune disease is RRMS.
Attacks are also known as relapses or exacerbations (also referred to herein as bursts), followed by a period of partial or complete recovery (remission). During relief, all symptoms may disappear entirely, or some symptoms may persist and become permanent. However, there was no apparent disease progression during remission. RRMS can be further described as either active (evidence of recurrence and/or new MRI activity over a specified period of time) or inactive as well as worsening (increased confirmed disability after recurrence) or no worsening.
The relapsing remitting subtype usually begins with Clinically Isolated Syndrome (CIS). In CIS, patients have an onset that suggests demyelination, but do not meet the criteria for multiple sclerosis. From 30% to 70% of patients experiencing CIS subsequently develop MS. In one embodiment, the autoimmune disease is CIS.
Primary Progressive MS (PPMS) occurs in approximately 10% to 20% of individuals, which is not relieved after initial symptoms. It is characterized by no or only occasional and slight relief and improvement from onset, i.e. progression to disability. In one embodiment, the autoimmune disease is PPMS.
Secondary Progressive MS (SPMS) occurs in approximately 65% of patients initially suffering from relapsing remitting MS who eventually develop progressive neurological decline between episodes without any definite remission phase. Occasionally, recurrence and mild remission occur. SPMS may be further described as active (evidence of relapse and/or new MRI activity during a specified period of time) or inactive, as well as progressive (evidence of disability accumulating over time, with or without relapse or new MRI activity) or no progressive. In one embodiment, the autoimmune disease is SPMS.
In one embodiment, the disease is chronic inflammatory demyelinating polyneuropathy.
In one embodiment, the disease is transverse myelitis.
In one embodiment, the disease is neuromyelitis optica.
In one embodiment, the autoimmune disease is one or more of the following: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, welch granulomatosis, systemic lupus erythematosus, psoriasis, sarcoidosis polyarthritis idiopathic arthritis, inflammatory bowel disease (such as ulcerative enteritis and Crohn's disease), lyter syndrome, fibromyalgia, and type 1 diabetes. In one embodiment, the autoimmune disease is not any of the same group of diseases.
In one embodiment, the autoimmune disease is psoriatic arthritis. In one embodiment, the autoimmune disease is not psoriatic arthritis.
In one embodiment, the autoimmune disease is ankylosing spondylitis. In one embodiment, the autoimmune disease is not ankylosing spondylitis.
In one embodiment, the autoimmune disease is multiple sclerosis. In one embodiment, the autoimmune disease is not multiple sclerosis.
In one embodiment, the autoimmune disease is Welch granulomatosis. In one embodiment, the autoimmune disease is not Webster granulomatosis.
In one embodiment, the autoimmune disease is systemic lupus erythematosus. In one embodiment, the autoimmune disease is not systemic lupus erythematosus.
In one embodiment, the autoimmune disease is psoriasis. In one embodiment, the autoimmune disease is not psoriasis.
In one embodiment, the autoimmune disease is sarcoidosis. In one embodiment, the autoimmune disease is not sarcoidosis.
In one embodiment, the autoimmune disease is polyarthritis juvenile idiopathic arthritis. In one embodiment, the autoimmune disease is not polyarthritis juvenile idiopathic arthritis
In one embodiment, the autoimmune disease is inflammatory bowel disease (such as ulcerative colitis or crohn's disease). In one embodiment, the autoimmune disease is not an inflammatory bowel disease (such as ulcerative colitis or crohn's disease).
In one embodiment, the autoimmune disease is Lyter's syndrome. In one embodiment, the autoimmune disease is not Laterer's syndrome.
In one embodiment, the autoimmune disease is fibromyalgia. In one embodiment, the autoimmune disease is not fibromyalgia.
In one embodiment, the autoimmune disease is type 1 diabetes. In one embodiment, the autoimmune disease is not type 1 diabetes.
In one embodiment, the autoimmune disease is arthritis (such as rheumatoid arthritis). In one embodiment, the autoimmune disease is not arthritis (such as rheumatoid arthritis).
Formulations
DHODH inhibitors are moieties (such as compounds) that inhibit (e.g., reduce or block) the activity of DHODH enzymes (see "background for definition).
In one embodiment, the DHODH inhibitor is provided as a pharmaceutical formulation.
The pharmaceutical compositions of the present invention may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intraventricular, transdermal (see, for example, WO 98/20734), subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, intravaginal or rectal routes.
In one embodiment, the pharmaceutical formulation is for oral administration, e.g., formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries and suspensions, for ingestion by a patient.
Excipients may include lactose, dextrin, dextrose, sucrose, sorbitol, starch, sugar alcohols and cellulose.
Other suitable forms of administration include parenteral administration, for example injection or infusion, such as bolus injection or continuous infusion.
In the case of products for injection or infusion, they may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, preservative, stabilizing and/or dispersing agents. Alternatively, the molecules may be in dry form for reconstitution with a suitable sterile liquid prior to use. The pharmaceutically acceptable carrier in the therapeutic composition may additionally contain liquids such as water, saline, glycerol and ethanol. In addition, auxiliary substances, such as wetting agents, emulsifiers, lubricants or pH buffering substances, may be present in such compositions.
For a complete discussion of pharmaceutically acceptable carriers see Remington's Pharmaceutical Sciences (Mack Publishing Company, n.j.1991).
Treatment of
Treatment as used herein refers to where the patient has a disease or disorder, such as an autoimmune disease (particularly one of the autoimmune diseases disclosed herein), and the administration of a medicament according to the present disclosure to stabilize the disease, delay the disease, ameliorate the disease, alleviate the disease, maintain a disease-modifying state, or cure the disease. Treatment as employed herein includes administration of a medicament according to the present disclosure for treatment or prophylaxis.
Treatment or therapy may be employed prophylactically.
A therapeutically effective amount as used herein is an amount that simultaneously minimizes side effects within the scope of its producing the desired physiological effects.
Disease modifying therapy (disease modifying therapy) as used herein refers to the self-resetting and rebalancing of the immune system so that it appears more normal after treatment.
The DHODH inhibitors of the present disclosure or formulations comprising the same may be administered at dosages within the following ranges: 1 to 400mg per day, such as 10 to 400mg per day, 50 to 400mg per day, 100 to 400mg per day, 150 to 400mg per day, 200 to 400mg per day, 250 to 400mg per day, 300 to 400mg per day, or 350 to 400mg per day.
In particular, at a dose in the range 100mg to 400mg per day.
Thus, a daily dose may be, for example, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg or 400mg.
In one embodiment, the treatment is administered daily, for example once or twice daily.
In one embodiment, the treatment is once per day.
In one embodiment, ASLAN003 is administered orally, for example in the form of a tablet or capsule or caplet.
Concurrent disease, as used herein, refers to a condition in which a patient has a second or potential health condition.
Combination therapies (including additional therapies) as employed herein wherein two or more treatment regimens are employed, particularly simultaneously. The treatment may be in separate formulations or co-formulated. They may be administered simultaneously or at different times. However, the pharmacological effects of the treatment will coexist in the patient.
Additional therapies (furthertreatment) as employed herein refer to therapies other than DHODH inhibitors.
Such additional therapies may be anti-inflammatory agents including, but not limited to, non-steroidal anti-inflammatory agents (NSAIDs), disease modifying anti-rheumatic drugs (DMARDs), statins (including HMG-CoA reductase inhibitors such as simvastatin), biologies (biologies), steroids, immunosuppressants, salicylates, and/or microbiocides.
Non-steroidal anti-inflammatory agents include antimetabolites (such as methotrexate) and anti-inflammatory gold agents (including gold sodium thiomalate, gold thiomalate, or gold salts such as auranofin). Biological products include anti-TNF agents (including adalimumab, etanercept, infliximab, anti-IL-1 agents, anti-IL-6 agents, anti-CD 20 agents, anti-B cell agents such as rituximab), anti-T cell agents (anti-CD 4 antibodies), anti-IL-15 agents, anti-CLTA 4 agents, anti-RAGE agents), antibodies, soluble receptors, receptor binding proteins, cytokine binding proteins, mutant proteins with altered or reduced function, RNAi, polynucleotide aptamers, antisense oligonucleotides, or omega 3 fatty acids. Steroids (also known as corticosteroids) including cortisone, prednisolone or dexamethasone may also be employed in combination therapy.
Immunosuppressants used in combination therapies according to the present disclosure include cyclosporin, FK506, rapamycin, mycophenolate mofetil. The salicylates used in the combination therapy include aspirin, sodium salicylate, choline salicylate, and magnesium salicylate. Microbiocides include quinine and chloroquine.
Anti-inflammatory as used herein refers to the moiety that reduces inflammation, is used for non-steroidal anti-inflammatory, steroids, and the like.
In one embodiment, the combination therapy comprises an anti-CD 20 agent or a biomimetic thereof, such as Rituxan (rituximab), rituximab biomimetic, gazyva, kesimpta, ocrevus (orelbuzumab), ruxience, truxima, zevalin, arzerra, acellBia, HLX, reditux, ritucad, or Zytux.
In one embodiment, the combination therapy comprises a treatment independently selected from the group consisting of: corticosteroids (e.g., oral prednisone and intravenous methylprednisolone), plasmapheresis (plasmapheresis), interferon beta drugs, glatiramer acetate, fingolimod, dimethyl fumarate, desipramine fumarate, teriflunomide, cinnimod, cladribine, orelbizumab, natalizumab, and alemtuzumab.
In one embodiment, the combination therapy comprises a treatment that alleviates or alleviates symptoms of multiple sclerosis, e.g., muscle relaxants (such as baclofen, tizanidine, and cyclobenzaprine), fatigue-alleviating agents (such as amantadine, modafinil, methylphenidate, or agents that increase walking speed (such as dapagliflozin).
In one embodiment, the combination therapy comprises cannabis or a derivative thereof, such as cannabis oil.
In one embodiment, the combination therapy comprises a second DHODH inhibitor. In one embodiment, the additional therapy comprises teriflunomide. In one embodiment, the additional therapy comprises vidofludimus. In one embodiment, the combination therapy does not comprise a second DHODH inhibitor. In embodiments, the combination therapy does not comprise teriflunomide and/or vedoflulamide (vidofludimus).
In one embodiment, the combination therapy comprises a disease modifying therapy, e.g., selected from alemtuzumab, avenex, betaferon, cladribine, dalizumab, dimethyl fumarate, extavia, fingolimod, glatiramer acetate, natalizumab, orelbizumab, plegridy, rebif, cinnimod, and combinations of two or more thereof.
In one embodiment, the additional therapy comprises interferon beta (IFN- β), such as interferon beta-1 a or interferon beta-1 b. Thus, in one embodiment, the additional therapy comprises interferon beta-1 a. In an alternative embodiment, the additional therapy comprises interferon beta-1 b.
In one embodiment, the combination therapy comprises a Bruton's Tyrosine Kinase (BTK) inhibitor, such as ibrutinib, acotinib, zebuttinib, angstrom Wo Bulu tinib, ABBV-105, fenebutinib, GS-4059, capetinib, and/or HM71224.
In one embodiment, the additional therapy comprises glatiramer acetate. In one embodiment, the additional therapy comprises natalizumab. In one embodiment, the additional therapy comprises mitoxantrone. In one embodiment, the additional therapy comprises fingolimod. In one embodiment, the additional therapy comprises cilnimod. In one embodiment, the additional therapy comprises dimethyl fumarate. In one embodiment, the additional therapy comprises alemtuzumab. In one embodiment, the additional therapy comprises cyclophosphamide. In one embodiment, the additional therapy comprises cladribine. In one embodiment, the additional therapy comprises orelizumab. In one embodiment, the additional therapy comprises dimethyl fumarate. In one embodiment, the additional therapy comprises up to Li Zhushan antibody. In one embodiment, the additional therapy comprises azathioprine. In one embodiment, the additional therapy comprises methotrexate. In an alternative embodiment, the additional therapy does not comprise methotrexate. In one embodiment, the additional therapy comprises laquinimod (lacquinimod).
"comprising" in the context of the present specification is intended to mean "including".
Where technically appropriate, embodiments of the application may be combined.
The embodiments described herein include certain features/elements. The disclosure also extends to individual embodiments consisting of, or consisting essentially of, the features/elements described.
Technical references such as patents and applications are incorporated herein by reference.
Any embodiment specifically and explicitly recited herein may form the basis of disclaimers alone or in combination with one or more additional embodiments.
The present application claims priority from singapore application serial No. 10202010254Q filed on 10/15/2020 and 10202012817S filed on 12/21/2020, both of which are incorporated herein by reference. These files can be used as the basis for correction.
The background art contains technical information and can be used as a basis for modification.
The application will now be described with reference to the following examples, which are illustrative only and should not be construed as limiting the scope of the present disclosure.
Examples
Example 1 in vivo study of ASLAN003 in the EAE model of multiple sclerosis
Experimental Autoimmune Encephalomyelitis (EAE) is an animal model of well-studied demyelinating diseases such as human Multiple Sclerosis (MS). EAE is induced by injection of purified myelin fraction, central Nervous System (CNS) extract or synthetic specific peptides emulsified in an adjuvant to a susceptible animal. These peptides are derived, for example, from Myelin Basic Protein (MBP), myelin Oligodendrocyte Glycoprotein (MOG), or proteolipid protein (PLP).
To study the effect of ASLAN003 on multiple sclerosis, ASLAN003 was orally administered to the EAE model at a dose of 1mg/kg, 3mg/kg, 10mg/kg or 15mg/kg from day 8 after induction of the disease. Vehicle controls were included.
The results are shown in fig. 1. As can be seen from the figure, ASLAN003 (LAS 186323) resulted in a significant decrease in clinical scores compared to vehicle controls. Furthermore, ASLAN003 appears to prevent disease progression in a dose-dependent manner.
Thus, these data provide strong evidence for the potential of ASLAN003 for treating autoimmune diseases such as multiple sclerosis.
Example 2 ASLAN003 compared to in vivo study of positive control T in EAE model
1. Experimental protocol
Induction and clinical scoring of EAE
For the induction of EAE, guinea pig Myelin Basic Protein (MBP) (Sigma, M2295) suspended in 0.9% saline solution at a concentration of 2mg/ml was used. The solution was emulsified with an equal volume of Freund's complete adjuvant (Sigma, F5881) containing 4mg/ml heat-inactivated Mycobacterium tuberculosis H37Ra (Difeo laboratories, reference 231141). Male Lewis rats were immunized by subcutaneous injection of 0.1ml of an emulsion containing 100 μg MBP/rat into the left and right hind paw pads.
A group of naive animals without induced disease was included in each EAE experiment (n=5) as healthy controls for comparison purposes.
Individual animals were examined daily for clinical symptoms of neurological deficit and scored according to a 0 to 5 component table as follows:
TABLE 1 neurological deficit scoring system
Clinical signs of disease were observed from day 8 to day 9 post induction. When about 10% of animals showed clinical symptoms, they were randomized into different groups (n=7 to 8) and treatment was started.
Animals scored as 4 were sacrificed according to animal welfare criteria if disability indicated little opportunity for recovery as the disease progressed. Death due to sacrifice or spontaneous EAE-related death was recorded as 5 points on a given date. The mortality score continued to be included in the clinical assessment, but the weight measurement was not continued.
1.2. Compounds of formula (I)
LAS 186323 (ASLAN 003), positive control T and positive control F were freshly prepared daily and suspended in 0.5% methylcellulose and 0.1% tween 80 in water at the indicated doses and administered by oral gavage at a volume of 10 ml/kg.
1.3. Hematology cell count
At the end of the assay, 24h after the last administration, blood samples from the retroorbital plexus were obtained under light anesthesia from all animals. The samples were used to determine whole blood count (XT-2000 i/XT-1800i,Sysmex Corporation). Absolute values of all cell types are reported.
Histology of CNS
At the end of the experiment, animals were sacrificed by bleeding and necropsies were performed in the blind state. Spinal cords (CNS; spinal cord, medulla oblongata, cerebellum) of EAE animals were obtained, fixed in 4% formalin in PBS, and embedded in paraffin. Sections were prepared at 6 μm thick and then stained with hematoxylin and eosin. Histological scoring was evaluated as follows:
0: no focus exists;
1: there was isolated lesions throughout the section with low cell density cellular infiltrates;
2: in each of several fields of view, there are several lesions that infiltrate with moderate cells;
3: many lesions and massive cellular infiltrates with edema were present in almost all fields of view (Kataoka, 2005).
2. Results
2.1. Clinical scoring
Disability was assessed daily and each animal was scored clinically as previously described. For each animal, a clinical score of area under the curve (AUC) was generated from the data recorded throughout the experiment. Percent inhibition of AUC was calculated for each animal compared to the vehicle group AUC average. The average percent inhibition for each treatment and dose was calculated.
Figure 2 shows the mean of the clinical scores AUC for each treatment group; vehicle (V) and LAS186323 (ASLAN 003) (L). The numbers following abbreviations correspond to the oral daily doses of the compounds administered in mg/kg.
Fig. 4 shows the evolution of the disease over time. Each point represents the average (Y-axis) of clinical scores for that particular treatment day (X-axis). Vehicle (V), positive control (F), positive control (T) and LAS186323 (L). The numbers following abbreviations correspond to the oral daily doses of the compounds administered in mg/kg.
Table 2 below shows the percent inhibition of clinical scores, which is a measure of clinical efficacy.
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TABLE 2 percent inhibition of clinical scores (%)
Although the appropriate ED for the positive control T could not be calculated 50 But an estimated value of 1.5mg/kg has been calculated. ED of ASLAN003 calculated by linear regression 50 2.7 mg/kg/day.
Cns histological evaluation
Fig. 3 shows CNS histological scores. A correspondence between clinical score improvement and histological score was observed. Good dose response was obtained in both positive control T and ASLAN003, with steeper slopes for the former compound observed. At the highest dose tested, animals treated with positive control T or ASLAN003 showed significant improvement in CNS lesions under the microscope compared to animals treated with vehicle.
2.3. Hematology cell count
Blood samples were collected 24 hours after the last administration and hematology cell counts were performed as described above. FIG. 5 shows absolute cell count x 10 for each treatment group 3 Mu.l. The observed significant effect of positive control F on total lymphocyte count was expected due to its mechanism of action. A decrease in neutrophil count was observed in animals treated with 10mg/kg of positive control T and 3mg/kg and 15mg/kg of ASLAN003, but not in animals treated with 10mg/kg of ASLAN 003. However, no statistically significant difference was observed compared to vehicle. A slight dose response of red blood cell count (RBC) was observed in positive control T.
3. Conclusion(s)
Based on the above results, in the EAE Lewis rat model, ASLAN003 appears to inhibit disease progression in a dose-dependent manner when administered once daily to animals with existing disease by the oral route. Improvement in external nervous system symptoms corresponds to a reduction in CNS mesoscopic damage. Treatment with ASLAN003 had no significant effect on blood cell count.
Example 3-in vivo study of ASLAN003 in Rheumatoid Arthritis (RA) AIA model compared to positive control T
Adjuvant arthritis (AIA) is an experimental model of Rheumatoid Arthritis (RA) induced in rats by plantar injection of Complete Freund's Adjuvant (CFA). The disease progresses to severe inflammation on the paw receiving the injection. Systemic inflammation and immune changes due to CFA are converted to inflammation of the contralateral paw from day 7 to day 10 post induction.
The ability of AIA models to predict therapeutic effects clinically is well recognized.
Therefore, to study the effect of ASLAN003 on RA, ASLAN003 was applied to the AIA rat model.
1. Experimental protocol
1.1. Test compounds
A prescribed dose of ASLAN003 as a suspension in 0.5% methylcellulose and 0.1% tween 80 in water was freshly prepared daily and administered by oral gavage in a volume of 10 ml/kg.
1.2 animals
Male Wistar rats weighing 175 to 200g were used.
1.3 arthritis Induction
A suspension of 75mg of dry extract of Mycobacterium tuberculosis H37 RA (Difco, # 231141) was prepared by adding 15ml of paraffin oil (Merck, # 7162) and a few drops of distilled water. The concentration of Mycobacteria in CFA was 5mg/ml. The suspension was sonicated for 10 minutes and kept in the shaker during the entire procedure. Rats were anesthetized and 0.1ml of CFA suspension was plantarly injected into their left hind paw.
Inflammation of the hind paw of each rat was measured by organ fullness measurement (Ugo Basile, # 7140) 10 days after disease induction. Inflammation is expressed in ml. On day 1, the first day of administration, two rats of similar paw volumes (n=6 to 7) were assigned to the treatment group.
Rats were administered CFA daily in the morning for 10 consecutive days. Body weight was measured daily and paw volume was measured every other day. On day 11 post-treatment (24 hours after the last administration), rats were anesthetized, blood samples were collected from their retroorbital plexus to determine cell counts, and then sacrificed. The hind paws were excised for X-ray analysis and scored for radiological lesions in the blind state by an unknowing scientist.
The radiological score is a combination of 5 different parameters evaluated from the X-ray image of each paw. The 5 parameters are: bone demineralization, periostitis, joint space stenosis, cystic degeneration and soft tissue inflammation. For each parameter, a value of 0 to 4 is assigned, which is proportional to the observed severity. The sum of the scores of these 5 parameters provides the radiological score for each animal.
1.4 calculation
For each animal, inflammation was measured as area under the curve (AUC) of right paw volume. AUC was calculated by plotting paw inflammation (in ml) versus time (in days). Mean values for vehicle-treated groups were also obtained.
The treatment efficacy was calculated as the percent inhibition of each animal compared to the mean of vehicle. The average value for each treatment group was calculated. In the case of more than one experiment for a given compound and dose, the mean ± standard error of the mean (SEM) was calculated.
The effect of treatment on the inhibition of the radiological score was measured by calculating the percent inhibition of the radiological score of each animal belonging to the treatment group compared to the mean value of the vehicle treatment group. In the case where multiple experiments were performed, the values provided are the mean and SEM of the individual experiments.
2. Results
Fig. 6 shows AUC of paw inflammation, and table 3 below shows the values of AUC and percent inhibition of AUC, expressed as mean ± SEM values from 2 to 5 independent experiments.
One-way ANOVA with Bonferroni post test, p < 0.05 (compared to vehicle)
TABLE 3 AUC and percent inhibition (%) of ASLAN003 in AIA model
3mg/kg and 10mg/kg ASLAN003 significantly reduced right paw swelling compared to vehicle treated rats. In the group treated with 10mg/kg positive control T and ASLAN003, the AUC values were lowest, indicating a higher anti-inflammatory effect.
Calculation of ED for ASLAN003 using the average percent reduction in paw volume from 2 to 5 independent experiments 50 The value was 4.6mg/kg.
Table 4 below shows White Blood Cell (WBC) and platelet counts in different treatment groups. Comparison of blood count between different treatment groups showed that induction of arthritis resulted in a significant increase in both WBC and platelets (vehicle compared to naive rats). In arthritic rats treated with 3mg/kg positive control Tat or 10mg/kg ASLAN003, a significant reduction in WBC numbers compared to vehicle was observed. ASLAN003 also significantly reduced platelet count compared to rats treated with vehicle at the same dose.
#p < 0.05 (compared to the initial animal), p < 0.05 (compared to vehicle)
TABLE 4 WBC and platelet counts in AIA model
The radiological scores of the paws of arthritic rats treated with the highest doses (3 mg/kg and 10 mg/kg) of ASLAN003 or positive control T are shown in FIG. 7. The values are shown in table 5 below. Results are expressed as mean ± SEM of 2 to 3 independent experiments.
TABLE 5X-ray examination scoring in AIA model
The results showed that although the average score for both 3mg/kg positive control T and 10mg/kg ASLAN003 was lower than the average score for rats treated with vehicle, the difference was not statistically significant.
3. Conclusion(s)
ASLAN003, administered orally once daily, showed anti-inflammatory effects in the paws of rats with existing arthritis. Dose-dependent reduction in WBC and platelet numbers in peripheral blood was also observed, which was statistically significant at the highest dose tested. ASLAN003 improved the radiological scoring of the paws, indicating its potential for disease modification.
In summary, this study demonstrates the potential of ASLAN003 as an effective treatment for RA.
Example 4-in vivo study of ASLAN003 in sodium dextran sulfate (DSS) induced Inflammatory Bowel Disease (IBD) mouse model compared to positive control V
1. Experimental protocol
1.1 animals
Male C57BL/6 mice of 6 to 7 weeks old were purchased from Shanghai Ling Biotech Co., ltd.
1.2 treatment planning, sample collection and parameters
Animals were randomly divided into the following groups according to body weight:
group 01: purified water, ad libitum, day 1 to day 8; vehicle, 5mL/kg, PO, QD, day 0 to day 9, n=6
Group 02:3% dss in water, ad libitum, day 1 to day 8; vehicle, 5mL/kg, PO, QD, day 0 to day 9, n=8
Group 03:3% dss in water, ad libitum, day 1 to day 8; positive control V,20mg/kg, PO, QD, day 0 to day 9, n=8
Group 04:3% dss in water, ad libitum, day 1 to day 8; ASLAN003, low dose, PO, QD, days 0 to 9, n=8a
Group 05:3% dss in water, ad libitum, day 1 to day 8; ASLAN003, high dose, PO, QD, days 0 to 9, n=8
Abbreviations: QD = once per day; PO = oral gavage.
Duration of study: a 3 week adaptation period, and a 10 day treatment period (day 0 to day 10) from day 0.
Colitis model induction: to induce acute experimental colitis, mice in groups 02 to 05 were provided with a solution of 3% dss in purified water for 7 days (day 1 to day 7) and then purified water for 2 days (day 9 to day 10). The drinking water containing DSS was changed every two days. During days 1 to 7, mice in group 01 were provided with purified water as a control.
Measured living body parameters:
water and food consumption was monitored once daily during days 0 to 10.
Body weight was measured once daily during days 0 to 10, with two clinical monitors per day.
Faecal observations were made once daily during the period 0 to 10 days. Disease Activity Index (DAI) was determined to quantify the induction of colitis.
Intestinal permeability was assessed on day 0 and day 9.
Stool was collected on day 0, day 4, day 8 and day 10 for lipocalin-2 detection.
Study termination: mice were sacrificed on day 10 and the sacrificed animals were treated as follows:
collecting blood
Mice were bled to prepare serum and stored at-60 ℃ to-80 ℃ for potential cytokine determination.
Collecting colon
The entire colon (from cecum to anus) was harvested and its length from the ileocecum to anus was measured.
Take a photograph of the entire colon for each mouse.
Open colon along mesenteric border, rinse with saline, blot and measure its weight.
The colon was treated as "spiral swiss coil" (spiral Swiss Rolls), fixed in 10% neutral buffered formalin for 24 to 48 hours, and embedded in paraffin (one block per mouse) for hematoxylin-eosin (H & E) staining and histopathological evaluation.
Spleen weight
Dissecting spleen, measuring its tissue weight and recording, then discarding.
2. Results
The results of the study are shown in figures 8 to 13.
Figures 8A and 8B show the weight measurements of animals during the course of the study. DSS-induced weight loss was similar in vehicle group 2 and both ASLAN003 treatment groups (groups 4 and 5), while positive control V treatment group 3 had the most severe weight loss.
Figures 9A and 9B show stool scores for animals during the study. The higher stool hardness score in fig. 9A indicates lower stool hardness, while the higher blood stool score in fig. 9B indicates more blood is observed.
As can be seen from the figure, the overall stool consistency for positive control V treatment group 3 was lower at the early stage of the study compared to other DSS-induced animals, eventually reaching an optimal stool consistency on day 10. ASLAN00375mg/kg group 5 had the best overall stool consistency on days 2 through 9, and then the study was ended on day 10 with a stool consistency score similar to vehicle group 2 and ASLAN00325mg/kg group 4.
In terms of bloodstool, the results indicate that ASLAN00375mg/kg treatment group 5 had the lowest incidence of bloodstool during the course of the study. Interestingly, the incidence of bloodstool was highest for positive control V treatment group 3, which appeared to even exceed that of vehicle treatment group 2.
Figure 10 shows the Disease Activity Index (DAI) of animals during the study. DAI is a scoring mechanism for assessing patient colitis, based on a combination of weight loss, stool consistency, and hemorrhage. The results showed that the DAI increase was greatest in positive control V treatment group 3, eventually declining to a level similar to vehicle group 2 and ASLAN00325mg/kg group 4 on study day 10. Furthermore, the results appear to show that the overall increase in DAI was lower for ASLAN00375mg/kg group 5 over 10 days and lower DAI scores on day 10 compared to all other treatment groups.
Fig. 11 shows the results of studying intestinal permeability (FITC-dextran concentration) of animals on day 0 and day 9. ASLAN00325mg/kg treatment group 4 and vehicle group 2 appeared to have similar FITC-dextran concentration measurements on day 9. Surprisingly, the measurement of positive control V-treated group 3 on day 9 was significantly higher than all other treated groups, indicating a significant change in intestinal permeability for animals of this group compared to control group 1.
Fig. 12 shows colon and spleen measurements for different treatment groups at the end of the study. When the colon weight and length were considered simultaneously as shown in fig. 12C, the results appear to indicate that vehicle group 2 was very similar to the colon/length measurements of ASLAN003 treatment groups 4 and 5. The colon/length measurement of positive control V-treated group 3 was more similar to control group 1.
Fig. 12D appears to show that the spleen weights of ASLAN00375mg/kg treatment group 5 are most similar to control group 1, with the spleen weights of the other treatment groups being similar to each other.
Figure 13 shows lipocalin data in animal feces during the course of the study. Lipocalins are sensitive non-invasive biomarkers of intestinal inflammation. The results indicate that ASLAN003 treated groups 4 and 5 had less intestinal inflammation than vehicle treated group 2. In contrast, positive control V-treated group 3 appeared to exhibit a greater degree of intestinal inflammation than vehicle-treated group 2.
In summary, the results show that:
1. the DAI, stool consistency, blood stool, and lipid carrier in stool were improved for ASLAN003 treatment groups 4 and 5 compared to DSS-induced vehicle group 2.
2. In particular, ASLAN00375mg/kg treatment group 5 had the lowest overall increase in DAI, the best overall stool hardness, the lowest blood stool incidence, and the lowest lipocalin in stool compared to the other DSS-induced groups. The treatment group also had a spleen weight most similar to control group 1.
3. Positive control group V3 had the greatest weight loss, greatest total increase in DAI, lowest total stool hardness, highest blood stool incidence, highest intestinal permeability, and highest lipocalin in stool compared to the other DSS-induced groups. The treatment group also had colon/length measurements most similar to control group 1.
These results demonstrate that animals treated with ASLAN003 improved over the control group over a range of different parameters, indicating that ASLAN003 has great potential for treating inflammatory bowel disease. The results also show that the use of ASLAN003 (especially at a higher concentration of 75 m/kg) resulted in a greater improvement in animals compared to the control group. Unexpectedly, the results further demonstrate that animals treated with positive control V have less than ideal results on some of the parameters tested compared to vehicle group 2.
Claims (18)
1. A method of treating an autoimmune disease comprising administering a therapeutically effective amount of the DHODH inhibitor 2- (3, 5-difluoro-3' -methoxybiphenyl-4-ylamino) nicotinic acid or a pharmaceutically acceptable salt thereof.
2. A DHODH inhibitor 2- (3, 5-difluoro-3' -methoxybiphenyl-4-ylamino) nicotinic acid or a pharmaceutically acceptable salt thereof for use in the treatment of an autoimmune disease.
Use of the dhodh inhibitor 2- (3, 5-difluoro-3' -methoxybiphenyl-4-ylamino) nicotinic acid or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an autoimmune disease.
4. A method, inhibitor or use according to any one of claims 1 to 3, wherein the autoimmune disease is selected from the group comprising or consisting of: pyogenic sweat gland, scleroderma (systemic scleritis), lichen planus, scleroderma, psoriasis, type 1 diabetes, autoimmune thyroiditis, graves 'disease, endometriosis, celiac disease, crohn's disease, ulcerative colitis, axial spondylitis, juvenile arthritis, recurrent rheumatism, psoriatic arthritis, rheumatoid Arthritis (RA), sarcoidosis, systemic Lupus Erythematosus (SLE), undifferentiated Connective Tissue Disease (UCTD), multiple sclerosis type II, restless leg syndrome, optic neuritis, uveitis, scleritis, predatory keratohelpers, meniere's disease, graves' eye disease, neuromyelitis, susac syndrome, and lupus erythematosus.
5. The method, inhibitor or use according to any one of claims 1 to 4, wherein the autoimmune disease is selected from the group comprising or consisting of: multiple sclerosis, rheumatoid arthritis and inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.
6. The method, inhibitor or use of any one of claims 1 to 3, wherein the autoimmune disease is not one or more of: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, welch granulomatosis, systemic lupus erythematosus, psoriasis, sarcoidosis, polyarthritis idiopathic arthritis, inflammatory bowel disease such as ulcerative colitis or Crohn's disease, lyter's syndrome, fibromyalgia or type 1 diabetes.
7. The method, inhibitor or use according to any one of claims 1 to 5, wherein the autoimmune disease is multiple sclerosis, such as primary progressive multiple sclerosis.
8. The method, inhibitor or use according to any one of claims 1 to 5, wherein the autoimmune disease is rheumatoid arthritis.
9. The method, inhibitor or use according to any one of claims 1 to 5, wherein the autoimmune disease is an inflammatory bowel disease, e.g. celiac disease, crohn's disease or ulcerative colitis, such as crohn's disease.
10. The method, inhibitor or use according to any one of claims 1 to 9, wherein the autoimmune disease is characterized by aberrant T cell and/or B cell activation.
11. The method, inhibitor or use according to any one of claims 1 to 10, wherein the autoimmune disease is a disorder.
12. The method, inhibitor or use according to any one of claims 1 to 11, wherein the DHODH inhibitor is used as monotherapy.
13. The method, inhibitor or use according to any one of claims 1 to 11, wherein the DHODH inhibitor is employed in combination therapy.
14. The method, inhibitor or use of claim 13, wherein the combination therapy comprises a treatment independently selected from the group consisting of:
i. corticosteroids (e.g., oral prednisone and intravenous methylprednisolone), plasmapheresis (plasmapheresis), interferon beta drugs, glatiramer acetate, fingolimod, dimethyl fumarate, desipramine fumarate, teriflunomide, cinnimod, cladribine, orelizumab, natalizumab, anti-CD 20 agents or biomimetics thereof such as rituximab, alemtuzumab, and Bruton's Tyrosine Kinase (BTK) inhibitors;
Treatment to alleviate or mitigate symptoms of multiple sclerosis, e.g., muscle relaxants (such as baclofen, tizanidine, and cyclobenzaprine), fatigue-reducing agents (such as amantadine, modafinil, and methylphenidate), and walking-improving agents (such as dapsone);
antidepressants, such as duloxetine, tricyclic antidepressants such as chlorimipramine;
interferon beta (IFN-beta), such as interferon beta-1 a or interferon beta-1 b;
anti-CD 20 agents or biomimetics such as Rituxan, rituximab, gazyva, kesimpta, ocrevus (orelobizumab), ruxience, truxima, zevalin, arzerra, acellBia, HLX, reditux, ritucad and Zytux; and
bruton's Tyrosine Kinase (BTK) inhibitors such as Ibrutinib (ibutinib), acalabrutinib (Acalabrutinib), zebutinib (Zanubrutinib), angstrom Wo Bulu tinib (Evobrutinib), ABBV-105, non-nebutinib (fenebutinib), GS-4059, capetinib (Spebrutinib) and HM71224.
15. The method, inhibitor or use according to any one of claims 13 or 14, wherein the combination therapy does not comprise methotrexate.
16. The method, inhibitor or use according to any one of claims 13 to 15, wherein the combination therapy comprises a purine synthesis inhibitor, such as azathioprine.
17. The method, inhibitor or use according to any one of claims 1 to 16, wherein the DHODH inhibitor is administered at a dose in the range of 1mg to 400mg per day, for example 100mg to 400mg per day such as 100mg, 200mg, 300mg or 400mg.
18. The method, inhibitor or use according to any one of claims 1 to 17, wherein the DHODH inhibitor is administered daily, such as once daily.
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SG10202010254Q | 2020-10-15 | ||
SG10202012817S | 2020-12-21 | ||
SG10202012817S | 2020-12-21 | ||
PCT/SG2021/050625 WO2022081095A1 (en) | 2020-10-15 | 2021-10-15 | Treatment of autoimmune diseases with a dihydroorotate hehydrogenase (dhodh) inhibitor |
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CN116940359A true CN116940359A (en) | 2023-10-24 |
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