WO2024252010A1 - Polythérapies à base d'inhibiteur de tnf - Google Patents

Polythérapies à base d'inhibiteur de tnf Download PDF

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WO2024252010A1
WO2024252010A1 PCT/EP2024/065836 EP2024065836W WO2024252010A1 WO 2024252010 A1 WO2024252010 A1 WO 2024252010A1 EP 2024065836 W EP2024065836 W EP 2024065836W WO 2024252010 A1 WO2024252010 A1 WO 2024252010A1
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compound
composition
mcim
disease
combination
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Martyn Leslie FOSTER
Lisa Patel
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Istesso 2 Ltd
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Istesso 2 Ltd
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Priority to KR1020267000500A priority Critical patent/KR20260022395A/ko
Priority to EP24732590.5A priority patent/EP4724054A1/fr
Priority to IL325051A priority patent/IL325051A/en
Priority to AU2024284360A priority patent/AU2024284360A1/en
Publication of WO2024252010A1 publication Critical patent/WO2024252010A1/fr
Priority to MX2025014530A priority patent/MX2025014530A/es
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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7151—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for tumor necrosis factor [TNF], for lymphotoxin [LT]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Definitions

  • the present invention relates to combination therapies that can have reparative effects on a range of progressive and/or degenerative diseases.
  • the combination therapies can be used for the treatment of autoimmune diseases such as arthritis, and in particular rheumatoid arthritis.
  • the combination therapies comprise a Tumor necrosis factor inhibitor and a therapeutic agent which can act by binding mitochondrial Complex I.
  • the therapeutic agent which can act by binding mitochondrial Complex I are referred to herein as Mitochondrial Complex I Modulator compounds (or MCIM compounds).
  • Mitochondrial Complex I (also known as NADH:ubiquinone oxidoreductase, Type I NADH dehydrogenase, respiratory Complex I, or simply ‘Complex I’) is the first enzyme complex of the respiratory chain (Yoga et al, 2021 , which is hereby incorporated by reference in its entirety).
  • Complex I is a very large protein complex comprising 45 subunits (Gutierrez-Fernandez, 2020) which is highly conserved in eukaryotes and prokaryotes.
  • Q10 the most common form of ubiquinone is known as ‘Q10’ because it has ten isoprenyl subunits in its ‘tail’ region.
  • Q10 is hydrophobic and it enters the Complex I enzyme from the mitochondrial inner membrane through a long binding channel (Bridges et al, 2020), which is often called the ‘Q tunnel’.
  • the Q-tunnel is long and heterogenous in nature.
  • Various compounds are known to bind within the Q tunnel, but there is no single consensus site for compound binding.
  • piericidin A is reported to bind within the Q-tunnel as a ‘short-form’ ubiquinone, with interactions at multiple residues from the top of the Q-tunnel to its midway point (Gutierrez- Fernandez, 2020; Bridges et al, 2020; Chung et al, 2021 , each of which is hereby incorporated by reference in its entirety).
  • Aureothin and pyridaben which are also quinone-like compounds, are also observed to bind at a similar site in T. thermophilus (Gutierrez-Fernandez, 2020; Chung et al, 2021).
  • IACS-2858 and BAY-87-2243 act like a “cork in a bottle”, binding a cluster of residues of subunits ND1 and NDUFS7 in the central charged region of the ubiquinone-binding pocket of mouse Complex I (Chung et al, 2021 ; Kurelac et al, 2022). Biguanides such as metformin are similarly thought to interact with Phe244 of ND1 and Arg77 of NDUFS7 in the Q-tunnel with a mode dependent on the active or inactive state of the enzyme.
  • Classical Complex I inhibitors such as those mentioned above, often cause cytotoxicity and cell death.
  • piercidin A is insecticidal and antibacterial
  • pyridaben is an acaricide (killing ticks and mites)
  • aureothin exhibits antitumor, antifungal and insecticidal activity.
  • IACS-010579 and IM156 also known as HL156A have been reported to possess anti-tumour effects due to profound impacts on cancer cell viability (Tsogbadrakh et al, 2018 and Izreig et al, 2020).
  • the known, classical, C1 inhibitors have not found use as approved therapeutics.
  • tissue repair is to restore the tissue to its original state of structure and function (Krafts, 2010 and Paul and Sharma, 2021). Attaining this goal has proved elusive, with the only effective examples being organ transplantation or surgical implants using natural or biomimetic structures such as aortic valves or joint replacement). Further, whilst there has been a significant increase in research into strategies to achieve repair in different organ systems, these approaches aim to remove the primary driver to tissue injury (e.g., the calcified heart valve) or to replace the dysfunctional matrix environment with an environment which favours homing of repair cells or local augmentation of soluble pro-repair factors (e.g., fibrin).
  • tissue injury e.g., the calcified heart valve
  • fibrin soluble pro-repair factors
  • Such examples include biomimetic scaffolds in orthopaedics, which simulate normal structural matrix for cell homing, and cellular products to simulate the soluble matrix microenvironment for cutaneous and ocular wound repair.
  • a therapeutic agent(s) which both attenuates the drive to tissue injury and concurrently promotes a pro-repair microenvironment, has proved elusive.
  • Tissue repair (healing) is a highly orchestrated and complex process involving a sequence of overlapping events that are precisely timed.
  • the process has three broad phases which were first delineated in the 19 th Century (Virchow, 1859) and have been since augmented by the addition of data on their cellular genotypes, phenotypes, and molecular mediators (Liehn, 2011 , Takeo, 2015, and Somer et al, 2021).
  • there are limited, if any, data available regarding the mechanisms underpinning repair in most chronic disease settings (Peyrin-Biroulet, 2020) and current understanding of tissue repair processes has not led to substantial improvements in the clinical care of tissue damage (Eming et al, 2014).
  • Functional repair involves the resolution of the primary inflammatory response to injury and the simultaneous activation of the inflammatory response consequent upon repair. These phases show different qualitative and kinetic properties; the first phase induces a proliferative response in both infiltrating and resident cells whilst the second involves repolarisation of the infiltrating cells.
  • the cells involved in the repair process show different responses to stress dependent on the progressing phase of repair.
  • immune cells of the myeloid lineage short-lived cells with high bioenergetic demand
  • mesenchymal and epithelial cells respond to similar microenvironmental stressors by activating effector pathways.
  • mesenchymal cells typically respond to low oxygen tension (hypoxia) by the expansion and activation of a repair phenotype.
  • autoimmune diseases such as rheumatoid arthritis (RA), psoriasis and inflammatory bowel disease (IBD) and progressive fibrosis such as idiopathic pulmonary fibrosis (IPF), non-alcoholic fatty liver disease (NAFLD)/ non-alcoholic steatohepatitis (NASH) and chronic kidney disease.
  • IPF idiopathic pulmonary fibrosis
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • chronic kidney disease Without treatment these conditions typically progress in severity over time and may, as in the case of pulmonary fibrosis, be fatal.
  • neurodegeneration such as multiple sclerosis (MS), in which suppression of the inflammatory drive to de-myelination does not result in concomitant increase in oligodendrocyte or Schwann cell-induced re-myelination;
  • MS multiple sclerosis
  • the pharmacological intervention might elicit cellular changes consistent with those required to orchestrate a controlled repair response.
  • the approach might elicit production of the key basement membrane collagen IV in a controlled manner, alongside production of growth factors important for angiogenesis, epithelialisation and matrix remodelling, such as VEGF, FGF21 and GDF15.
  • VEGF vascular endothelial growth factor
  • FGF21 and GDF15 growth factors important for angiogenesis, epithelialisation and matrix remodelling
  • Were this approach to be successful it would elicit repair in a pathology agnostic manner, i.e. the repair response would be seen in multiple settings regardless of the nature of the original injury.
  • it might alter the activation response of resident cells and de-sensitize' the microenvironment to the effects of a pro-inflammatory cell infiltrate, resulting in a ‘permission’ to repair.
  • ISR integrated stress response
  • the ISR can be harnessed to protect oligodendrocytes and myelin during inflammation (Way and Popko, 2016).
  • the ISR has been shown to regulate the health of cardiac progenitor cells by removing unhealthy cells to prevent their differentiation and selfrenewal (Searfoss et al, 2019), a property that may be shared across progenitor cells in other settings such as oligodendrocyte progenitors in the brain and spinal cord, alveolar type II epithelial cells (AT2) in the lung and mesenchymal stem cells and bone marrow progenitor cells.
  • AT2 alveolar type II epithelial cells
  • Roles for the ISR in obesity, neurodegeneration and heart failure have also been proposed.
  • the ISR should be moderate and tightly regulated, like a rheostat, in order to avoid pushing cells towards apoptosis (Kaspar et al, 2021).
  • An agent which could both control symptoms and elicit tissue repair/healing may have greater benefits for patients than existing therapy and lead to improved treatment outcomes.
  • TNF-a Tumor necrosis factor alpha
  • TNF-a Tumor necrosis factor alpha
  • RA rheumatoid arthritis
  • PsA psoriatic arthritis
  • IBD inflammatory bowel disease
  • CD Crohn’s disease
  • NNU non-infectious uveitis
  • the inventors have previously discovered that compounds which can bind to and modulate the activity of mitochondrial complex I (see European patent application No. 23162131.9, which is incorporated herein by reference) are beneficial in the treatment of inflammatory and/or progressive diseases such as inflammatory bowel disease (IBD), interstitial lung disease or pulmonary fibrosis, multiple sclerosis (MS), or rheumatoid arthritis (RA).
  • IBD inflammatory bowel disease
  • MS multiple sclerosis
  • RA rheumatoid arthritis
  • the present invention has been devised in light of the above considerations.
  • the mitochondrial Complex I modulator (MCIM) compounds of this invention modulate the activity of mitochondrial Complex I in a manner that differs from that of conventional complex I inhibitors. This elicits an adaptive phase which directs cell fate choices and mimics a wound repair-like microenvironment. Phenotypically, this can control inflammation, alter the activation response of resident cells and desensitizes the microenvironment to the effects of a pro-inflammatory cell infiltrate, and concurrently initiate repair signals in affected tissues, such as the lung and joint.
  • the MCIM compounds can stimulate the production of key growth factors such as VEGF, and collagen I, and the basement collagen IV. Together, these mechanisms support a reduction in inflammation and restoration of tissue architecture in multiple organ/tissue settings.
  • MCIM compounds can be used in combination with TNF inhibitors to further improve treatment of disease in which TNF dysregulation/overstimulation plays a role.
  • TNF inhibitors can be used in combination with TNF inhibitors to further improve treatment of disease in which TNF dysregulation/overstimulation plays a role.
  • Such combinations lead to a surprising and synergistic improvement in the levels of protection against the progression of disease pathology, and tissue repair observed compared to when either an MCIM compound or TNF inhibitor is administered alone.
  • a synergistic reduction in the level of bone damage is observed in arthritic mouse models when mice are treated with an MCIM compound of the invention and the TNF inhibitor compound etanercept.
  • the invention provides a combination of an MCIM compound and a TNF inhibitor compound.
  • the combination may be for use in therapy.
  • the MCIM compound and the TNF inhibitor compound may be administered separately, sequentially, or simultaneously, and may be administered in any order.
  • the combination may achieve reparative effects when used to treat inflammatory and/or progressive diseases in which TNF plays a role in disease pathology.
  • the MCIM compounds bind complex I and are able to modulate complex I function.
  • the invention provides a pharmaceutical combination comprising a mitochondrial complex I modulator (MCIM) compound and a TNF inhibitor compound.
  • the pharmaceutical combination may be formulated as a single composition comprising the MCIM compound and the TNF inhibitor compound.
  • the pharmaceutical combination may be formulated as two separate compositions, wherein each of the two separate compositions comprises either an MCIM compound or a TNF inhibitor compound.
  • the combination may comprise two or more TNF inhibitor compounds.
  • the pharmaceutical combination may comprise a single composition comprising the two or more TNF inhibitor compounds, or the two or more TNF inhibitor compounds may be comprised in separate compositions.
  • the invention provides a pharmaceutical composition comprising a mitochondrial complex I modulator (MCIM) compound and TNF inhibitor compound.
  • MCIM mitochondrial complex I modulator
  • the combination according to the first aspect or the composition of the second aspect may be for use as a medicament.
  • the invention provides a pharmaceutical composition comprising a mitochondrial complex I modulator (MCIM) compound for use in the treatment of an inflammatory and/or progressive disease in a subject.
  • the treatment comprises the separate, sequential or simultaneous administration of the pharmaceutical composition and a TNF inhibitor compound to the subject.
  • the treatment may achieve disease control, regression, or tissue repair, or any combination thereof.
  • the invention further provides a pharmaceutical composition comprising a TNF inhibitor compound for use in the treatment of an inflammatory and/or progressive disease in a subject.
  • the treatment comprises the separate, sequential or simultaneous administration of the pharmaceutical composition and a mitochondrial complex I modulator (MCIM) compound to the subject.
  • MCIM mitochondrial complex I modulator
  • the treatment may achieve disease control, regression, or tissue repair, or any combination thereof.
  • the invention further provides a method of treating an inflammatory and/or progressive disease in a subject, wherein the method comprises administering a pharmaceutical composition comprising a MCIM compound to the subject.
  • the method further comprises the separate, sequential, or simultaneous administration of a TNF inhibitor compound to the subject.
  • the treatment may achieve disease control, regression, or tissue repair, or any combination thereof.
  • the invention further provides a method of treating an inflammatory and/or progressive disease in a subject, wherein the method comprises administering a pharmaceutical composition comprising a TNF inhibitor compound to the subject.
  • the treatment further comprises the separate, sequential or simultaneous administration of a MCIM compound to the subject.
  • the treatment may achieve disease control, regression, or tissue repair, or any combination thereof.
  • the invention further provides a method of treating an inflammatory and/or progressive disease in a subject, wherein the method comprises administering a pharmaceutical composition comprising a MCIM compound and a TNF inhibitor compound to a subject.
  • the treatment may achieve disease control, regression, or tissue repair, or any combination thereof.
  • the treatment elicits disease control, regression, or tissue repair, or any combination thereof. In some embodiments, the treatment achieves disease control, regression, or tissue repair, or any combination thereof. In some embodiments, the treatment initiates an adaptive response in certain cell types that leads to pharmacodynamic evidence of disease control, regression or tissue repair, or any combination thereof. In some embodiments, the adaptive response leads to tissue repair and/or disease regression. In some embodiments, the tissue repair and/or disease regression induces a restoration of tissue architecture towards its healthy state, which is characterised by anatomically normal architecture. In some embodiments of the aspects of the invention, disease control comprises inhibition of disease progression. In some embodiments, inhibition of disease progression includes a prevention of disease progression.
  • inhibition of disease progression includes a reduced rate of disease progression.
  • disease control comprises the prevention of a loss of anatomically normal tissue architecture, or a reduction in the speed of the loss of anatomically normal tissue architecture.
  • the tissue repair and/or disease regression is characterised by an increased clinical repair score and/or comprises increased wound healing.
  • the inflammatory and/or progressive disease may be any condition in which an imbalance is seen between cellular pathology and cellular repair.
  • the inflammatory and/or progressive disease is associated with or caused by Tumor Necrosis Factor (TNF) overexpression, secretion, or stimulation.
  • TNF Tumor Necrosis Factor
  • the inflammatory and/or progressive disease is an autoimmune disease.
  • the disease or disorder may be an autoimmune disorder such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease, a fibrotic condition such as interstitial lung disease, a neurological disorder such as multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS), or a skeletal disorder such as osteoarthritis or osteoporosis.
  • RA rheumatoid arthritis
  • IBD inflammatory bowel disease
  • Crohn’s disease a fibrotic condition
  • a neurological disorder such as multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS), or a skeletal disorder such as osteoarthritis or osteoporosis.
  • the disease or disorder may be RA, psoriatic arthritis, inflammatory arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, reactive arthritis, gout, septic arthritis, enteropathic arthritis, or osteoarthritis.
  • Clinical repair scores can be used to objectively assess clinical repair in inflammatory and/or progressive diseases. Increased clinical repair score can be indicated by a decreased disease score.
  • disease control is characterised by a decreased rate of change in the disease score.
  • disease control is characterised by no change in disease score following treatment. - for example, disease control may be characterised by an inhibition of disease progression associated with an increase in disease score. Disease score may be calculated using any suitable method known in the art.
  • tissue repair and/or disease regression may be characterised by a decrease in the average arthritic index score, ACR/EULAR score, DAS38 score, HAQ-DI score, CDAI score, SDAI score, ACR20/50/70 score, EULAR score, mTSS score, or RAPID3 score, or any combination thereof, as described herein.
  • tissue repair and/or disease regression may be characterised by; i) a decrease in the serum concentration of C-reactive protein (CRP); ii) a decrease in serum concentration of Tartrate-resistant acid phosphatase 5 (TRAP5); iii) an increase in the serum concentration of procollagen 1 intact N-terminal (P1 NP); iv) an increase in the serum concentration of osteocalcin; or v) any combination of i)-iv).
  • CRP C-reactive protein
  • TRIP5 Tartrate-resistant acid phosphatase 5
  • P1 NP procollagen 1 intact N-terminal
  • osteocalcin or v) any combination of i)-iv.
  • the disease control or regression and/or tissue repair comprises an increased cell count of reparative cells and/or a decreased cell count of pathology driving cells. In some embodiments, the disease control or regression and/or tissue repair regression comprises an increased count of mesenchymal and/or epithelial cells. In some embodiments, the adaptive response is characterised by an increased count of mesenchymal and/or epithelial cells. In some embodiments, the adaptive response is characterised by an increase in the differentiation of mesenchymal and/or epithelial cells. For instance, when the inflammatory and/or progressive disease is an IBD, the reparative cells may comprise epithelial cells and/or mucus cells.
  • the cells may comprise fibroblasts or epithelial cells, or alternatively repair may be indicated by an increase in the overall number of mucus cells which indicate that epithelial differentiation is proceeding normally.
  • an increase in the number or activity of osteoblasts and/or myeloid cells, such as M2 macrophages may be seen.
  • a decrease in the number or activity of osteoclasts, transformed fibroblasts, fibroblast-like synoviocyte cells, proinflammatory macrophages, effector memory T-cells, plasmacytoid dendritic cells or transformed fibroblasts, or any combination thereof may be seen.
  • the adaptive response comprises a change in the function of mesenchymal or epithelial cells.
  • the cells may comprise PAS positive cells, or surfactant producing epithelial cells.
  • the tissue repair and/or disease regression comprises a decreased cell count or decreased function of activated immune cell subtypes.
  • the disease control, tissue repair and/or disease regression may comprise a decrease in the number of myeloid cells such as macrophages or osteoclasts, lymphocytes such as T-, B-, or Th17 cells, or fibroblasts such as FLS cells.
  • the decrease in immune cell activity or activated immune cell numbers is not accompanied by a decrease in the activity, function or numbers of adapting mesenchymal or epithelial cells.
  • the reparative cells may comprise oligodendrocyte precursor cells (OPCs).
  • the tissue repair and/or disease regression induces a restoration of tissue architecture towards its healthy state, which is characterised by anatomically normal architecture.
  • the inflammatory and/or progressive disease is RA and the tissue repair and/or disease regression comprises increased bone formation and/or decreased bone resorption, optionally alongside reduced oedema and/or erythema.
  • disease control comprises decreased bone resorption and/or preventing further loss of anatomically normal architecture.
  • the disease control, tissue repair and/or disease regression comprises a reduction in inflammatory cytokine production from pro-inflammatory myeloid cells.
  • the disease control, tissue repair and/or disease regression comprises an increase in growth factors that are important for angiogenesis, epithelialisation and matrix remodelling, such as VEGF, FGF21 and/or GDF15.
  • Cytokine and growth factor levels can be measured by any suitable method, e.g. via ELISA as described herein, or via ELISpot.
  • the disease control, tissue repair and/or disease regression comprises an increase in basement collagen IV. Collagen IV levels can be measured by any suitable method, e.g. via ELISA as described herein and/or by immunohistochemical analysis.
  • the invention also provides a pharmaceutical composition comprising an MCIM compound for use in combination with a TNF inhibitor to increase reparative cells and/or decrease destructive cells in a subject with an inflammatory and/or progressive disease, to achieve disease control and/or tissue repair and, as a result, disease, regression or resolution, or improved symptom control and quality of life.
  • the invention also provides a pharmaceutical composition comprising a TNF inhibitor for use in combination with an MCIM compound to increase reparative cells and/or decrease destructive cells in a subject with an inflammatory and/or progressive disease, to achieve disease control and/or tissue repair and, as a result, disease, regression or resolution, or improved symptom control and quality of life.
  • the method increases the adaptive response of mesenchymal or epithelial cells and/or decreases the activation of or numbers of pro-inflammatory/fibrotic/erosive cells in a subject with an inflammatory and/or progressive disease.
  • the invention also provides pharmaceutical compositions for use in reducing cytokine production from pro-inflammatory myeloid cells in a subject with an inflammatory and/or progressive disease, to achieve disease control, tissue repair and/or disease regression.
  • the invention also provides methods for reducing cytokine production from pro-inflammatory myeloid cells in a subject with an inflammatory and/or progressive disease, comprising administering the pharmaceutical composition to achieve disease control, tissue repair and/or disease regression.
  • the compounds and inflammatory and/or progressive diseases are defined herein.
  • the compound binds to Complex I and modulates Complex I activity.
  • the modulation of Complex I activity may be determined by detecting a reduction in cellular O2 consumption.
  • the reduction in cellular O2 consumption is not associated with a reduction of cell viability.
  • O2 consumption may be measured by any standard technique known in the art, for example, using a real-time cell metabolic analyser (e.g. a Seahorse Analyzer).
  • the modulation of Complex I activity may also lead to a reversible reduction of cell proliferation.
  • the reversibility of the reduction of cell proliferation means that the reduction of proliferation is reversed when the compound is removed.
  • an MCIM is applied to a cell culture, at a concentration to substantially reduce cell proliferation, for 24 hours at 37°C / 5% CO2. After 24 hours, the cell culture is washed and cultured under conditions conducive to cell growth and proliferation. Recovery of cell proliferation is measured after 24-hours incubation in these ‘growth’ conditions (37°C / 5% CO2, without MCIM present). Recovery of cell proliferation is observed.
  • the compound interacts with Complex I at a binding site at the top of or outside the Q tunnel.
  • the binding site comprises one or more amino acid residues from NDUSF2 (SEQ ID NO: 1) and/or NDUSF7 (SEQ ID NO: 2).
  • the compound interacts with at least one amino acid residues in NDUFS2 (SEQ ID NO: 1), for instance His92, Gly85, Tyr141 , His88, Leu95, Asp193, or Phe458. In some embodiments, the compound interacts with one or more amino acid residues in NDUFS2 (SEQ ID NO: 1) selected from Tyr141 , His92 and Asp193.
  • the response may include promotion of a repair phenotype during the same time course as control of inflammation.
  • the control of inflammation induced by compounds of the invention may be distinct from the control of inflammation induced by other anti-inflammatory drugs which rely on the suppression of inflammation before activation of tissue repair as a secondary effect.
  • the compound comprises four or more of the pharmacophore features of the pharmacophore model represented in Figure 24.
  • the three-dimensional arrangement of the pharmacophore features may be as described in Tables 7-A, 7-B and 7-C.
  • the compound is a compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, of the following formula: defined in claim 1 of WQ2010/032009 as follows: wherein:
  • -A is independently:
  • -Ar is independently phenyl, pyridinyl, or pyrimidinyl; and p is independently an integer from 0 to 3; and wherein: q is independently an integer from 0 to 3; and wherein:
  • -R SN is independently -H or saturated aliphatic Chalky I;
  • -D 1 - is independently cyclopentane-di-yl, cyclohexane-di-yl, cycloheptane-di-yl, bicyclo[3.1 .1]heptane-di-yl, or bicyclo[3.2.1]octane-di-yl, and is optionally substituted with one or more groups -R D ;
  • -D 2 is independently cyclopentane-yl-ylidene, cyclohexane-yl-ylidene, cycloheptane-yl-ylidene, bicyclo[3.1 .1]heptane-yl-ylidene, or bicyclo[3.2.1]octane-yl-ylidene, and is optionally substituted with one or more groups -R D ; each -R D is independently selected from -F, -Cl, -Br, -I, -R DD , -CF3, -OH, -OR DD , -NH2, -NHR DD , and -NR DD 2 ; and each -R DD is independently saturated aliphatic Ci-4alkyl; and wherein -Q 1 is independently selected from: 1 N wherein: each -R 1N is independently -H, -R CN , or -R CF ; each -R 2N
  • -NR 1N R 2N is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, thiomorpholino, azepino, or diazepino, each optionally substituted with one or more groups independently selected from saturated aliphatic Ci-4alkyl;
  • -R 1A is independently -H, -R c , or -R F ;
  • -R 2A is independently -H, -R c , or -R F ; or -R 1A and -R 2A together form a saturated aliphatic C2-4alkylene group; -R 1B is independently -H, -R c , or -R F ; and
  • -R 3A is independently -H, -R c , or -R F ;
  • -R 4A is independently -H, -R c , or -R F ; or -R 3A and -R 4A together form a saturated aliphatic C2-4alkylene group;
  • -R 5A is independently -H, -R c , -R F , or -R J ;
  • -R 6A is independently -H, -R c , or -R F ; or -R 5A and -R 6A together form a saturated aliphatic C2-4alkylene group;
  • -R 3B is independently -H, -R c , or -R F ;
  • -R 4B is independently -H, -R c , or -R F ; or -R 3B and -R 4B together form a saturated aliphatic C2-4alkylene group;
  • -R 5B is independently -H, -R c , -R F , -OH, or -OR 0 ;
  • -R 6B is independently -H, -R c , or -R F ; or -R 5B and -R 6B together form a saturated aliphatic C2-4alkylene group; each -R c is independently saturated aliphatic Ci-4alkyl; each -R F is independently saturated aliphatic Ci-4fluoroalkyl;
  • -R° is independently saturated aliphatic Chalky I
  • -R J is independently -NH 2 , -NHR JN1 , -NR JN1 2 , or -NR JN2 R JN3 ; each -R JN1 is independently saturated aliphatic Ci-4alkyl; and
  • -NR JN2 R JN3 is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, thiomorpholino, azepino, or diazepino, each optionally substituted with one or more groups independently selected from saturated aliphatic Ci-4alkyl; and wherein each -R x is independently:
  • each -R ⁇ is independently saturated aliphatic Ci-salkyl , phenyl, or benzyl, wherein said phenyl and benzyl are optionally substituted with one or more groups selected from: -F, -Cl, -Br, -I, -CF 3 , -OCF 3 , -R XXX , -OH, -OR XXX , or -SR XXX , wherein each -R xxx is independently saturated aliphatic Ci-4alkyl; and each -NR YY R ZZ is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperid
  • WO2010/032009 Claim 1 of WO2010/032009 is hereby incorporated by reference. Furthermore, WO2010/032009 is hereby incorporated by reference in its entirety.
  • the compound is a compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof as defined in WO2014/207445 A1 , which is incorporated herein by reference in its entirety.
  • the compound is a compound selected from compounds of the following formulae, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
  • the compound is a compound of the following formula, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
  • the compound is a compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof as defined in WO2016/097001 A1 , which is incorporated herein by reference in its entirety.
  • the compound is a compound selected from compounds of the following formulae, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
  • the substituents on one side of the cyclohexyl ring may be positioned “trans” / “cis” or “cis” / “trans” with respect to the rest of the molecule (that is, on the cyclohexyl ring to which they attached, with respect to the rest of the compound which is attached at the para position of the cyclohexyl ring).
  • the compound is a compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, of the following formula: defined in claim 1 of WO2010/032010, wherein:
  • -A is independently:
  • -Ar is independently phenyl, pyridinyl, or pyrimidinyl; and p is independently an integer from 0 to 3; and wherein: q is independently an integer from 0 to 3; and wherein:
  • -R SN is independently -H or saturated aliphatic Chalky I;
  • -R S1 is independently -H or saturated aliphatic Ci-4alkyl
  • -R S2 is independently -H or saturated aliphatic Ci-4alkyl
  • -R S3 is independently -H or saturated aliphatic Ci-4alkyl ;
  • -R S4 is independently -H or saturated aliphatic Ci-4alkyl ; and wherein -Q is independently selected from: wherein: each -R 1N is independently -H or -R CN ; each -R 2N is independently -H or -R CN ; each -R CN is independently saturated aliphatic Ci-4alkyl ; or:
  • -NR 1N R 2N is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, thiomorpholino, azepino, or diazepino, each optionally substituted with one or more groups independently selected from saturated aliphatic Chalky I;
  • -R 1A is independently -H, -R c , or -R F ;
  • -R 2A is independently -H, -R c , or -R F ; or -R 1A and -R 2A together form a saturated aliphatic C2-4alkylene group;
  • -R 3A is independently -R c , -R F , or -R J ;
  • -R 4A is independently -H, -R c , or -R F ; or -R 3A and -R 4A together form a saturated aliphatic C2-4alkylene group;
  • -R 5A is independently -R c or -R F ;
  • -R 6A is independently -H, -R c , or -R F ; or -R 5A and -R 6A together form a saturated aliphatic C2-4alkylene group;
  • -R 1B is independently -H, -R c , or -R F ;
  • -R 2B is independently -H, -R c , or -R F ; or -R 1B and -R 2B together form a saturated aliphatic C2-4alkylene group;
  • -R 3B is independently -H, -R c , -R F , -OH, or -OR 0 ;
  • -R 4B is independently -H, -R c , or -R F ; or -R 3B and -R 4B together form a saturated aliphatic C2-4alkylene group;
  • -R 5B is independently -H, -R c , or -R F ;
  • -R 6B is independently -H, -R c , or -R F ; or -R 5B and -R 6B together form a saturated aliphatic C2-4alkylene group; each -R c is independently saturated aliphatic Ci-4alkyl; each -R F is independently saturated aliphatic Ci-4fluoroalkyl;
  • -R° is independently saturated aliphatic Chalky I
  • -R J is independently -NH 2 , -NHR JN1 , -NR JN1 2 , or -NR JN2 R JN3 ; each -R JN1 is independently -R J1 , -R J2 -OH, -R J2 -O-R J1 ; each -R J1 is independently saturated aliphatic Ci -4alky I; each -R J2 - is independently saturated aliphatic C2-4alkylene;
  • -NR JN2 R JN3 is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, thiomorpholino, azepino, or diazepino, each optionally substituted with one or more groups independently selected from saturated aliphatic Chalky I; and wherein each -R x is independently:
  • each -R ⁇ is independently saturated aliphatic Ci-ealkyl , phenyl, or benzyl, wherein said phenyl and benzyl are optionally substituted with one or more groups selected from: -F, -Cl, -Br, -I, -CF3, -OCF3, -R xxx , -OH, -OR XXX , or -SR XXX , wherein each -Rxxx is independently saturated aliphatic Ci-4alkyl; and each -NRYYRZZ j s independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, pipe
  • WO2010/032010 is hereby incorporated by reference. Furthermore, WO2010/032010 is hereby incorporated by reference in its entirety.
  • the compound is a compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, of the following formula: defined in claim 1 of W02020/035560 A1 , wherein:
  • -R 1 is independently -H or -R 1X ;
  • -R 1X is independently -F, -Cl, -R 1C , -R 1F , or -CN;
  • Ci -salky I is independently saturated linear or branched Ci -salky I
  • -R 1F is independently saturated linear or branched Ci-3fluoroalkyl
  • -R 2 is independently -H or -R 2X ;
  • -R 2X is independently -F, -Cl, -R 2C , -R 2F , or -CN;
  • Ci -salky I is independently saturated linear or branched Ci -salky I
  • -R 2F is independently saturated linear or branched Ci-3fluoroalkyl
  • -R 3 is independently -H or -R 3X ;
  • -R 3X is independently -F, -Cl, -R 3C , -R 3F , or -CN;
  • Ci -salky I is independently saturated linear or branched Ci -salky I
  • -R 3F is independently saturated linear or branched Ci-3fluoroalkyl
  • -R 4 is independently -H or -R 4X ;
  • -R 4X is independently -F, -Cl, -R 4C , -R 4F , or -CN;
  • Ci -salky I is independently saturated linear or branched Ci -salky I
  • -R 4F is independently saturated linear or branched Ci-3fluoroalkyl
  • -R 5 is independently -H or -R 5X ;
  • -R 5X is independently -F, -R 5C , or -R 5F ;
  • Ci -salky I is independently saturated linear or branched Ci -salky I
  • -R 5F is independently saturated linear or branched Ci-3fluoroalkyl
  • -R 6 is independently -H or -R 6X ;
  • -R 6X is independently -F, -R 6C , or -R 6F ;
  • Ci -salky I is independently saturated linear or branched Ci -salky I
  • -R 6F is independently saturated linear or branched Ci-3fluoroalkyl; or -R 5 and -R 6 , taken together with the carbon atom to which they are attached, form saturated Cs ecycloalkyl.
  • W02020/035560 A1 Claim 1 of W02020/035560 A1 is hereby incorporated by reference. Furthermore, W02020/035560 A1 is hereby incorporated by reference in its entirety.
  • the compound is a compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, of the following formula: as defined in claim 1 of WO2020/212581 A1 , wherein
  • m is independently 0, 1 , 2, or 3; each -RA is independently -F, -Cl, -RAC, -RAF, or -CN;
  • -RAC is independently saturated linear or branched C1-3alkyl
  • -RAF is independently saturated linear or branched C1-3fluoroalkyl
  • n is independently 0, 1 , or 2; each -RB is independently -F, -Cl, -RBC, -RBF, or -CN;
  • -RBC is independently saturated linear or branched C1-3alkyl
  • -RBF is independently saturated linear or branched C1-3fluoroalkyl
  • -R1 is independently -H or -R1X;
  • -R1X is independently -F, -R1C, or -R1 F;
  • -R1C is independently saturated linear or branched C1-3alkyl
  • -R1 F is independently saturated linear or branched C1-3fluoroalkyl
  • -R2 is independently -H or -R2X;
  • -R2X is independently -F, -R2C, or -R2F;
  • -R2C is independently saturated linear or branched C1-3alkyl
  • -R2F is independently saturated linear or branched C1-3fluoroalkyl; or -R1 and -R2, taken together with the carbon atom to which they are attached, form saturated C3-6cycloalkyl;
  • -R3 is independently -H or -R3X
  • -R3X is independently -R3C or -R3F;
  • -R3C is independently saturated linear or branched C1-3alkyl
  • -R3F is independently saturated linear or branched C1-3fluoroalkyl
  • -R4 is independently -R4C, -R4CC, or -N(R4N1)(R4N2);
  • -R4C is independently saturated linear or branched C1-6alkyl
  • -R4CC is independently saturated C3-6cycloalkyl
  • -R4N1 is independently -H or -R4N1C;
  • -R4N1C is independently saturated linear or branched C1-4alkyl
  • -R4N2 is independently -H or -R4N2C;
  • -R4N2C is independently saturated linear or branched C1-4alkyl
  • -N(R4N1)(R4N2) is independently azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is optionally substituted with one or more saturated linear or branched C1-4alkyl groups.
  • WO2020/212581 A1 Claim 1 of WO2020/212581 A1 is hereby incorporated by reference. Furthermore, WO2020/212581 A1 is hereby incorporated by reference in its entirety.
  • the compound is a compound of the following formula, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
  • the compound is a compound of the following formula, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
  • the compound is a compound of the following formula, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
  • the compound is a compound of the following formula, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
  • the compound is a compound of the following formula, or a pharmaceutically acceptable salt, hydrate, or solvate thereof: In some embodiments, the compound is a compound of the following formula, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
  • the compound is a compound of the following formula, or a pharmaceutically acceptable salt, hydrate, or solvate thereof: In some embodiments, the compound is a compound of the following formula, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
  • the compound is a compound of the following formula, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
  • the TNF inhibitor compound is an antibody or a fusion protein. In some embodiments, the TNF inhibitor compound is etanercept, infliximab, adalimumab, golimumab, or certolizumab.
  • the invention includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.
  • FIG. 1 A graph of response over time of each of the three phases of repair (Inflammation, proliferation and tissue remodelling) which are proposed to be broadly similar across tissues. Cell types and soluble factors involved in each phase are shown below the graph along with changes in the extracellular matrix.
  • FIG. 1 High throughput integrative biology platform (BioMAP®) profile of the effects of MCIM compounds of the invention on multiple disease-associated regulatory pathways identified that these compounds have the potential to regulate inflammatory responses and the tissue remodelling collagen, collagen type IV, for ABD599 (A) and HMC-C-01-A (B) and (C).
  • BioMAP® High throughput integrative biology platform
  • FIG. 3 High throughput integrative biology platform (BioMAP®) profile of the effects of approved TNF inhibitors on multiple disease-associated regulatory pathways identified that these compounds show specific and restricted inflammatory responses for adalimumab and etanercept (A) and infliximab (B).
  • BioMAP® High throughput integrative biology platform
  • FIG. 4 Electron micrographs of human primary myeloid cells (osteoclasts) treated with Complex I binders of the invention show an adaptive response by changing mitochondrial morphology, with an increase in mitochondrial area without an overt increase in mitochondrial mass.
  • Figure 5. A) Three graphs showing the change in intracellular ATP levels (top left), nuclei count (top middle) and ATP readout per cell (top right) in response to increasing MCIM compound dose in standard, glucose supplemented media (squares), media supplemented with glucose and L-glutamine (open circles) or media supplemented with glucose, L-glutamine, and pyruvate (close circles).
  • FIG. 6 Cell proliferation inhibition measured by BrdU incorporation (A) and nucleic count (B) as a function of increasing dosage of either Rotenone (squares), IACS-010759 (closed circles) or MCIM compound (open circles). Comparison of cells without washout vs washout of test compounds on cell proliferation measure by BrdU incorporation (C) and nuclei count (D). Non-washout and washout of rotenone are shown in grey and open grey, respectively. Non-washout and washout of IACS-010759 are shown in black and open black, respectively. Non-washout and washout of MCIM compound are shown in checkboard fill and open fill pattern, respectively. MCIM compounds of the invention reversibly inhibit cell proliferation whereas cells treated with typical Complex I inhibitors IACS-010759 and rotenone do not recover cell proliferative capacity after compound washing out.
  • Figure 7 Seven graphs each showing the average arthritic index as a function of time (dosing day) for test compound dosed at 10 mg/kg/day by oral gavage (open circles) and control (solid circles), for each of (A) HMC-C-02-A, (B) HMC-C-01-A, (C) HMC-N-02-A, (D) HMC-N-01 -A, (E) NASMP-01-A, (F) CHMSA-01-A, (G) CHMSA-03-A.
  • FIG. 8 Graphs showing the average bone resorption counts in mice with collagen-induced arthritis treated with (A) vehicle control, 3 mg/kg/day etanercept, or 10 mg/kg/day of either HMC-C-01-A, HMC-C-01-B, or HMC-N-01-B and (B) vehicle control, or 10 mg/kg/day of either ABD900, NASMP-01 , CHMSA-03-A, or NASMP-06.
  • MCIM compounds of the invention protect against bone resorption in mice suffering from collagen-induced arthritis at levels comparable or exceeding approved treatment etanercept. Data are mean ⁇ s.e.m.. ** p ⁇ 0.01 *** p ⁇ 0.005 vs vehicle ⁇ p ⁇ 0.005 vs etanercept.
  • Figure 9 Graphs showing the (A) average osteoid counts in mice with collagen-induced arthritis treated with vehicle control, 3 mg/kg/day etanercept, or 10 mg/kg/day of either HMC-C-01-A, HMC-C-01-B, or HMC-N-01-B, and (B) average osteoid zones in mice with collagen-induced arthritis treated with vehicle control, or 10 mg/kg/day of either ABD900, NASMP-01 ,CHMSA-03-A, or NASMP- 06.
  • MCIM compounds of the invention promote the formation of osteoid, an indicator of bone formation, in mice with established collagen-induced arthritis.
  • the new bone formation in animals with existing bone erosion indicates a repair effect, occurring to a much greater extent than seen with the approved therapeutic drug etanercept.
  • Data are mean ⁇ s.e.m.. ** p ⁇ 0.01 *** p ⁇ 0.005 vs vehicle ⁇ p ⁇ 0.005 vs etanercept.
  • FIG. 10 Histological sections (160x magnification, stained with toluidine blue) of limbs from mice with collagen-induced arthritis treated with either vehicle control (top panels), 10 mg/kg/day MCIM compound (middle panels) or 3 mg/kg/day etanercept (bottom panels).
  • MCIM compounds of the invention promote bone formation in established arthritis, indicating an adaptive repair response.
  • Top panel shows bone from collagen-induced arthritic mice treated with vehicle showing no clear signs of bone formation.
  • Middle panel shows bone from collagen-induced arthritis mice which have clear indications of osteoid (new bone) formation in a structured manner as indicated by the black arrows. In contrast, mice treated with etanercept show only low levels of reactive and sporadic new bone formation.
  • FIG. 11 Graph showing the relative inflammatory (left two bars) and osteoid (right two bars) scores in mice with collagen-induced arthritis treated with either vehicle control or a very low dose MCIM compound at 0.03 mg/kg per day for 14 days.
  • MCIM compounds of the invention promote adaptive responses leading to repair (osteoid formation) in mice with established collagen-induced arthritis at doses which don’t control inflammation, showing that the response is not a consequence of control of inflammation, but an independent, adaptive response.
  • Data are mean ⁇ s.e.m.. *** p ⁇ 0.005 vs vehicle.
  • FIG. 12 Graphs showing the mean change in (A) synovitis score (B) cartilage damage, (C) bone resorption and (D) bone pathology in mice with collagen-induced arthritis treated with either 1 mg/kg/day etanercept, 0.03 mg/kg/day MCIM compound or a combination of 1 mg/kg/day etanercept and 0.03 mg/kg/day MCIM compound.
  • Mean changes were calculated relative to mice with collagen- induced arthritis treated with vehicle control. Data are mean ⁇ s.e.m.. * p ⁇ 0.05 ** p ⁇ 0.01 vs vehicle.
  • Figure 13 Graph showing the mean change in osteoid score in mice with collagen-induced arthritis treated with either 3 mg/kg/day etanercept (black bar), 0.03 mg/kg/day MCIM compound (white bar) or a combination of 3 mg/kg/day etanercept and 0.03 mg/kg/day (grey bar). Mean changes were calculated relative to mice with collagen-induced arthritis treated with vehicle control. Data are mean fold increase above vehicle control.
  • Figure 14 A graph showing a comparison of disease activity index in mice with DSS-induced colitis treated with vehicle control, sulfasalazine, etanercept and MCIM compound.
  • MCIM compounds of the invention reduce the severity of symptoms of mice with DSS-induced colitis compared to mice treated with vehicle control, sulfasalazine or etanercept.
  • Data are mean ⁇ s.e.m.. * p ⁇ 0.05, *** p ⁇ 0.005 vs vehicle, ⁇ p ⁇ 0.005 vs sulfasalazine, aaa p ⁇ 0.005 vs etanercept.
  • FIG. 15 Two graphs showing a comparison of mucosal erosion in mice with DSS-induced colitis treated with (A) vehicle control, sulfasalazine or ABD900 and (B) vehicle control, sulfasalazine or HMC-C-01-A.
  • MCIM compounds of the invention inhibit mucosal erosion to a greater extent in mice with established DSS-induced colitis compared to mice treated with vehicle control, Sulfasalazine (A), or Etanercept (B).
  • Data are mean ⁇ s.e.m.. * p ⁇ 0.05 vs vehicle ⁇ p ⁇ 0.05 vs sulfasalazine.
  • FIG. 16 Two graphs showing a comparison of glandular loss in mice with DSS-induced colitis treated with (A) vehicle control, sulfasalazine or ABD900 and (B) vehicle control, sulfasalazine or HMC-C-01-A.
  • MCIM compounds of the invention reduce glandular loss to a greater extent in mice with established DSS-induced colitis compared to mice treated with vehicle control, Sulfasalazine (A) or Etanercept (B).
  • Data are mean ⁇ s.e.m.. ** p ⁇ 0.01 vs vehicle, ⁇ p ⁇ 0.05 vs sulfasalazine.
  • FIG. 17 Two graphs showing a comparison of epithelial hyperplasia in mice with DSS-induced colitis treated with (A) vehicle control, sulfasalazine or ABD900 and (B) vehicle control, sulfasalazine or HMC-C-01-A.
  • MCIM compounds of the invention can promote epithelial hyperplasia in mice with established DSS-induced colitis at a comparable level compared to mice treated with Sulfasalazine
  • mice treated with Etanercept (A) but to a greater extent than mice treated with Etanercept (B). Data are mean ⁇ s.e.m.. * p ⁇ 0.05 vs vehicle.
  • FIG. 18 Two graphs showing a comparison of fibroplasia, which is indicative of tissue or wound repair, in mice with DSS-induced colitis treated with (A) vehicle control, sulfasalazine or ABD900 and
  • MCIM compounds of the invention promote increased ‘healthy’ fibroplasia in mice with established DSS-induced colitis compared to mice treated with vehicle control, Sulfasalazine (A) or Etanercept (B).
  • Data are mean ⁇ s.e.m.. *** p ⁇ 0.005 vs vehicle, ⁇ p ⁇ 0.005 vs sulfasalazine, aaa p ⁇ 0.005 vs etanercept.
  • FIG. 19 Histological sections from mice with DSS-induced colitis treated with either vehicle control (top panels), etanercept (middle panels) or an HMC-C-01-A (bottom panels). Ulceration, loss of architecture, oedema/inflammation and erosion is seen in the vehicle control (arrows).
  • the positive control, etanercept shows general conservation of tissue architecture but with underlying inflammation and oedema (arrows).
  • the MCIM of the invention shows a general conservation of architecture, with no inflammation or oedema and with radial distribution of repair (arrows).
  • Figure 20 Homology model of the complete Complex I constructed from publicly available structures for 5 different organisms. The putative targets were resolved in all 5 structures.
  • FIG. 21 In silica homology model of NDUFS2. Druggability assessment was performed using SiteMap and identified two binding pockets in the Complex I subunit NDUFS2 (spheres).
  • FIG 22 In silica SiteFinder model of NDUFS2 when in Complex I. A narrow channel was identified for Q10 and drug-like compound binding in the Q-tunnel. Spheres are used to illustrate the space/channels around NDUFS2 when in the Complex I structure.
  • FIG 23 In silica model of a MCIM compound of the invention docked in the Q-site of Complex I. This model reveals interactions between a Complex I inhibitor of the invention and NDUFS2 and additional interactions with the neighbouring Complex I subunit NDUFS7.
  • Figure 24 3D representation of a pharmacophore model built from in silica modelling of drug docking in Complex I.
  • FIG. 25 Overlay of a MCIM compound of the invention on the ligand-protein pharmacophore model illustrating successful docking of the MCIM compound of the invention in the Q-tunnel of Complex I.
  • FIG. 26 Overlay of a MCIM compound of the invention, CHMSA-02-A, on the ligand-protein pharmacophore model (top panel) and the chemical structure of CHMSA-02-A (bottom panel). This illustrates successful docking of CHMSA-02-A in the Q-tunnel of Complex I.
  • FIG. 27 Graph showing the quantitative structure-activity relationship (QSAR) model used to identify further Complex I binders of the invention and to predict their activity in vivo.
  • QSAR quantitative structure-activity relationship
  • Predicted pAct of Complex I binders of the invention correlates well with their experimentally validated pAct, with a coefficient of determination (R 2 ) value of 0.8322 demonstrating that this QSAR model can be used to accurately identify Complex I binders of the invention.
  • the present disclosure provides a pharmaceutical combination and a pharmaceutical composition comprising an MCIM compound and a TNF inhibitor compound.
  • the combination or composition may be for use as a medicament.
  • the present disclosure also provides a composition comprising an MCIM compound for use in a method of treating or preventing an inflammatory and/or progressive disease, wherein the method further comprises administering a TNF inhibitor compound.
  • a pharmaceutical composition comprising a TNF inhibitor compound for use in a method of treating or preventing an inflammatory and/or progressive disease, wherein the method further comprises administering an MCIM compound.
  • a pharmaceutical composition comprising an MCIM compound and a TNF inhibitor compound for use in a method of treating or preventing an inflammatory and/or progressive disease.
  • an MCIM compound in the manufacture of a medicament for use in a method of treatment, for example for use in a method of treating or preventing an inflammatory and/or progressive disease, wherein the method further comprises administering a TNF inhibitor compound.
  • a TNF inhibitor compound in the manufacture of a medicament for use in a method of treatment, for example for use in a method of treating or preventing an inflammatory and/or progressive disease, wherein the method further comprises administering an MCIM compound.
  • a method of treating or preventing an inflammatory and/or progressive disease comprising administering a therapeutically- or prophylactically-effective amount of (i) an MCIM compound and (ii) a TNF inhibitor compound to a subject in need of treatment.
  • the present disclosure also provides an MCIM compound and TNF inhibitor compound (e.g. in the form of a pharmaceutical combination or pharmaceutical composition comprising an MCIM compound and TNF inhibitor compound) for use in a method of treating or preventing an inflammatory and/or progressive disease. Also provided is the use of an MCIM compound and a TNF inhibitor compound (e.g. in the form of a pharmaceutical combination or pharmaceutical composition comprising an MCIM compound and a TNF inhibitor compound) in the manufacture of a medicament for use in a method of treating or preventing an inflammatory and/or progressive disease.
  • a therapeutically- or prophylactically-effective amount of an MCIM compound and TNF inhibitor compound e.g. in the form of a pharmaceutical combination or pharmaceutical composition comprising an MCIM compound and TNF inhibitor compound
  • the MCIM compound and the TNF inhibitor compound may be provided as a combination therapy.
  • the MCIM compound and the TNF inhibitor compound may be administered simultaneously or sequentially.
  • Simultaneous administration refers to administration of the two or more agents together, for example as a pharmaceutical composition containing both agents (i.e. as a combined preparation), or immediately after one another (e.g. within 1 , 4, 6, 8 or 12 hours), and optionally via the same route of administration, e.g. to the same artery, vein or other blood vessel.
  • Sequential administration refers to administration of one of the agents followed after a given time interval by separate administration of another agent. It is not required that the agents are administered by the same route, although this is the case in some embodiments.
  • the time interval may be any time interval.
  • an MCIM compound in the manufacture of a medicament for use in treating or preventing inflammatory and/or progressive disease, wherein treating or preventing the inflammatory and/or progressive disease further comprises administering a TNF inhibitor compound.
  • the present disclosure further provides a pharmaceutical composition comprising an MCIM compound for use in a method of treatment, wherein the method comprises administering a TNF inhibitor compound.
  • the present disclosure further provides a pharmaceutical composition comprising an MCIM compound as disclosed herein for use in a method of treatment, wherein the method further comprises administering a TNF inhibitor compound, wherein the TNF inhibitor compound comprises an antibody or a fusion protein.
  • the present disclosure further provides a pharmaceutical composition comprising an MCIM compound for use in a method of treatment, wherein the method further comprises administering etanercept, infliximab, adalimumab, golimumab, or certolizumab.
  • the present disclosure further provides a pharmaceutical composition comprising a TNF inhibitor compound for use in medicine, wherein the method further comprises administering an MCIM compound as disclosed herein.
  • the present disclosure further provides a pharmaceutical composition comprising a TNF inhibitor compound, wherein the TNF inhibitor compound comprises an antibody or a fusion protein for use in medicine, wherein the use further comprises administering an MCIM compound as disclosed herein.
  • the present disclosure further provides a pharmaceutical composition comprising etanercept, infliximab, adalimumab, golimumab, or certolizumab for use in medicine, wherein the method further comprises administering an MCIM compound as disclosed herein.
  • the present disclosure further provides a pharmaceutical composition comprising an MCIM compound as disclosed herein and a TNF inhibitor compound for use in medicine.
  • the present disclosure further provides a pharmaceutical composition comprising an MCIM compound as disclosed herein and etanercept, infliximab, adalimumab, golimumab, or certolizumab for use in medicine.
  • a pharmacophore is used herein as defined in Wermuth, C.G., Ganellin, C.R., Lindberg, P., Mitscher, L.A.; Glossary of Terms Used in Medicinal Chemistry (IUPAC Recommendations 1998); Pure & Appl. Chem. 70:5 (1998) 1129-1143:
  • a pharmacophore is an ensemble of aromatic steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response.
  • the ensemble of aromatic steric and electronic features represent so-called “pharmacophoric features”.
  • Typical pharmacophoric features include, for example, hydrogen bond donor, hydrogen bond acceptor, hydrophobic, aromatic, and positively and negatively ionized areas.
  • pharmacophore model relates to a pharmacophore hypothesis for the binding interactions in a particular active site.
  • a pharmacophore model is made up of a set of annotation points which are interrelated in 3D space.
  • the annotation points show the location and type of biologically important atoms and groups, i.e., each annotation point relates to a pharmacophore feature of the model.
  • Each annotation point is associated with a radius that describes the permissible variation in 3D space for the location of the given pharmacophoric feature.
  • the phrase “conform to a pharmacophore model” means that a compound described herein binds to the target binding site (i.e., the NDUSF2 and/or NDUSF7 binding site) in a 3D conformation (i.e., “pose”) whereby, 4 or more of the annotation points of the pharmacophore model described herein are occupied by corresponding features of the MCIM compound described herein, as determined the unified annotation scheme in Molecular Operating Environment (MOE), 2022.02 Chemical Computing Group ULC, 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7, 2022.
  • MOE Molecular Operating Environment
  • the annotation points of the pharmacophore model described herein are occupied by corresponding features of the MCIM compound described herein.
  • five or more, six or more, seven or more, eight or more, or all nine of the annotation points of the pharmacophore model described herein are occupied by corresponding features of the MCIM compound described herein.
  • the conformance of a compound described herein with the pharmacophore features is as determined using the unified annotation scheme in Molecular Operating Environment (MOE), 2022.02 Chemical Computing Group ULC, 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7, 2022
  • Annotation points can be broadly divided into three categories: atom, projected, and centroid. Annotation points are determined for a given compound by the unified annotation scheme in Molecular Operating Environment (MOE), 2022.02 Chemical Computing Group ULC, 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7, 2022.
  • MOE Molecular Operating Environment
  • Atom annotations are located directly on an atom of a molecule and typically indicate a function related to protein-ligand binding.
  • Don annotates an H-bond donor heavy atom.
  • a Don annotation is added to all oxygen and nitrogen atoms with at least one (possibly implicit) hydrogen attached.
  • O, S, and N elements can be hydrogen bond acceptors provided that they conform to the following rules:
  • Nitrogen atoms are acceptors and given Acc annotations provided that they are not buried.
  • Oxygen atoms are acceptors and are given Acc annotations provided that they are not buried and provided that they are not in certain exception groups.
  • Projected annotations are (typically) located along implicit lone pair or implicit hydrogen directions and are used to annotate the location of possible hydrogen bond or metal ligation partners, or possible R-group atom locations.
  • Projected Don2 annotations are added according to the hybridization and the heavy atom coordination of the donor. In the following table the d denotes a Don2 feature.
  • Hydrogen bond Acc2 projected annotations are added to those heavy atoms that qualify as H-bond acceptors (see above) and are given Acc annotations.
  • the Acc2 projected annotations are added in the same locations as those for the Don2 projected annotations and according to the same rules. (That is, the donors and the acceptors are projected using the same angles and the same distances.)
  • An atom that is both a Don and an Acc will be annotated with “Don2&Acc2” projected annotations.
  • Projected annotations such as Don2, and Acc2 are located at potential heavy atom positions.
  • Don2 indicates a potential hydrogen bond partner heavy atom.
  • this partner atom cannot have too much overlap with any of the atoms of the molecule generating the projected annotation. This condition depends on the particular conformation of a molecule and cannot be reliably predicted by topological means. Consequently, a solvent exposure test must be applied to validate any hits resulting from a Pharmacophore Search, i.e., a test to verify that applicable projected features are not covered by other parts of the conformation (that would prevent the putative projection atom from occupying the intended position). Centroid
  • Centroid annotations are located at the geometric center of a subset of the atoms of a molecule.
  • Aro annotation centroids are used for aromatic and pseudo aromatic rings.
  • the Aro annotation centroid is placed at the centroid of each aromatic ring (e.g. two centroids in naphthalene).
  • aromaticity is generous (a Daylight-style definition) in which each ring is treated in isolation and a Huckel 4n+2 rule is applied.
  • N X nitrogens count 1 and >N- nitrogens and -O- oxygens count 2 electrons.
  • Hydrophobic atoms are annotated with HydA and hydrophobic centroids are annotated with Hyd.
  • Hydrophobic groups are determined by graph theoretic algorithms.
  • Nitro nitrogen atoms (not in nitrate anions) are hydrophobic.
  • Halogens are hydrophobic.
  • Carbon atoms are hydrophobic except a) aliphatic carbons ir bonded to non-carbon atoms; or b) IT carbon atoms adjacent to univalent oxygen; or c) aromatic carbon adjacent to aromatic oxygen in 5-rings; or d) carbon atoms adjacent to two or more ⁇ N,O ⁇ atoms; or e) anionic carbons in c1cccc1 ;
  • the assignment of hydrophobic annotations proceeds by first applying the preceding hydrophobic atom typing rules but leaving out fluorine atoms on the grounds that they are small and should not affect annotation placement.
  • the Unified scheme provides an atom-centered hydrophobic annotation, HydA and a centroid hydrophobic feature Hyd.
  • the HydA annotation is used for hydrophobic atoms that are deemed to have sufficiently high (potential) exposure to a potential receptor. This means that, for example, sp3 carbons with 4 heavy neighbors are not marked (since they are buried) and aromatic carbons with two heavy neighbors and two ortho substituents are not annotated.
  • the Hyd annotations are assigned by a procedure that groups connected hydrophobic atoms and assigns centroids weighted by an estimate of the likely exposed surface area of each hydrophobic atom; that is, the Hyd centroid will be placed closer to more exposed hydrophobic atoms in a hydrophobic group.
  • Rings Find all 5-, 6-, 7-, and 8-member rings that are not composed of smaller rings. For each such ring, extract each contiguous stretch of hydrophobic atoms with at least three atoms that have a sufficiently high total exposed surface area, and generate a surface area weighted centroid annotation. Remove all annotated ring atoms from further consideration.
  • the MCIM compounds described herein conform to a pharmacophore model as described herein.
  • the MCIM compounds for use in combination with a TNF inhibitor compound e.g. Adalimumab, Etanercept, Infliximab, and/or Certolizumab
  • a TNF inhibitor compound e.g. Adalimumab, Etanercept, Infliximab, and/or Certolizumab
  • MCIM mitochondrial Complex I modulator
  • the disease may be a chronic progressive disease associated with fibrosis of the affected tissue(s), such as: interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF); pulmonary fibrosis; liver fibrosis; nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD); kidney fibrosis; chronic kidney disease (CKD); cardiac fibrosis; ischaemia reperfusion injury; heart failure with reduced ejection fraction, heart failure with preserved ejection fraction; myelofibrosis; retroperitoneal fibrosis; atherosclerosis; myocardial infarction; stroke; neurodegenerative disease; multiple sclerosis; fronto-temporal dementia (FTD); amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD); osteoporosis, osteopenia; osteoarthritis; endometriosis; bone loss associated with endometriosis; neoplasia of bones (including, e.g.
  • the disease may be an autoimmune disease, such as: rheumatoid arthritis (RA); psoriatic arthritis; ankylosing spondylitis; spondyloarthritis; reactive arthritis; infectious arthritis; systemic lupus erythematosus; scleroderma; juvenile idiopathic arthritis; psoriasis; systemic lupus erythematosus; lupus nephritis; uveitis; systemic sclerosis; scleroderma; hepatitis; Sjogren's syndrome; inflammatory bowel disease; ulcerative colitis; Crohn’s disease; multiple sclerosis; atherosclerosis; chronic obstructive pulmonary disease (COPD); uveitis; allergic disease (including, e.g., atopy, allergic rhinitis, atopic dermatitis, anaphylaxis, allergic bronchopulmonary aspergillosis, allergic gastroenteritis,
  • Disease control may be achieved by treatment with the compositions of the invention.
  • Disease control can comprise inhibition of disease progression and/or control of disease symptoms.
  • Inhibition of disease progression includes prevention of disease progression and slowing down disease progression. Standard methods in the art may be employed to determine disease progression.
  • Chronic autoimmune diseases are amenable to treatment with a combination of the Complex I modulator (MCIM) compound as described herein with a TNF inhibitor compound.
  • MCIM Complex I modulator
  • diseases include RA, IBD, Ulcerative colitis (UC), Psoriatic arthritis (PsA), and psoriasis.
  • the MCIM compound can elicit tissue repair and disease regression.
  • a histopathological assessment can be used to determine the effect of the MCIM compound and the MCIM compound in combination with a TNF inhibitor compound on arthritis: For this assessment of arthritis, the following signs are monitored in digits or limbs of each subject three times per week and summed to generate the Arthritic Index (Al). (The maximum Al for one animal is 16):
  • the MCIM compound in combination with a TNF inhibitor compound reduces the average score compared with subject treated with a negative control, MCIM compound alone and/or a TNF inhibitor compound alone.
  • ACR/EULAR 2010 scoring criteria ACR/EULAR score
  • DAS28 score Disease activity score at 28 joints
  • HAQ-DI score health assessment questionnaire disability index
  • CDAI score clinical disease activity index
  • SDAI score Standard disease activity index
  • EULAR score European league against rheumatism response criteria
  • mTSS score ModemTSS score
  • RAPID3 score Routine assessment of patient index data 3 score
  • inhibition of disease progression may be determined by comparing the Al score, ACR/EULAR score, DAS38 score, HAQ-DI score, CDAI score, SDAI score, ACR20/50/70 score, EULAR score, mTSS score, and/or RAPID3 score of a subject before, during and/or after receiving treatment with an MCIM compound and a TNF inhibitor compound. Inhibition of disease progression may be indicated by the Al score, ACR/EULAR score, DAS38 score, HAQ-DI score, CDAI score, SDAI score, ACR20/50/70 score, EULAR score, mTSS score, and/or RAPID3 score being stable (i.e. not changing) over time following treatment.
  • Inhibition of disease progression may be indicated by the Al score, ACR/EULAR score, DAS38 score, HAQ-DI score, CDAI score, SDAI score, ACR20/50/70 score, EULAR score, mTSS score, and/or RAPID3 score progressing or increasing at a slower rate following treatment.
  • Disease control in Arthritis may be determined by any suitable method known in the art.
  • the MCIM compound in combination with the TNF inhibitor compound is for use in the treatment of arthritis to reduce the average arthritic score (e.g, Al score, ACR/EULAR score, DAS38 score, HAQ-DI score, CDAI score, SDAI score, ACR20/50/70 score, EULAR score, mTSS score, and/or RAPID3 score) compared to administration of MCIM compound or TNF inhibitor compound alone.
  • average arthritic score e.g, Al score, ACR/EULAR score, DAS38 score, HAQ-DI score, CDAI score, SDAI score, ACR20/50/70 score, EULAR score, mTSS score, and/or RAPID3 score
  • the MCIM compound in combination with a TNF inhibitor compound reduces the Al score, ACR/EULAR score, DAS38 score, HAQ-DI score, CDAI score, SDAI score, ACR20/50/70 score, EULAR score, mTSS score, and/or RAPID3 score in a subject by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • repair/healing can be clinically assessed using gut transit time, occult blood, endoscopy, histopathology, electrolytes and/or by measuring biomarkers such as pANCA, ASCA, GP2, CUZD1 , CHI3L1 , GM-CSF, ACA, PS/PT, ALCA, ACCA, AMCA, OmpC, I2, CBirl , Laminarin, Chitin, IFI16, IL- 1 p, IL-6, IL-8, IL-9, IFN-y, TNF, CCL2, IL-22, IL-2, and/or IL-6, as disclosed in Chen et al (2020) which is incorporated herein in its entirety by reference.
  • biomarkers such as pANCA, ASCA, GP2, CUZD1 , CHI3L1 , GM-CSF, ACA, PS/PT, ALCA, ACCA, AMCA, OmpC, I2, CBirl ,
  • a histopathological assessment can be used to determine the effect of the MCIM compound and the MCIM compound in combination with a TNF inhibitor compound on IBD: lleo-caecal issue sections can be stained with Haematoxylin and Eosin (H&E) and parameters of inflammation, mucosal erosion, epithelial hyperplasia, epithelial metaplasia, mucus cell metaplasia, and fibroplasia are assessed on a scale of 0-5 as follows:
  • the MCIM compound in combination with the TNF inhibitor compound reduces the average score compared with a subject treated with a negative control, MCIM compound alone and/or a TNF inhibitor compound alone.
  • the MCIM compound in combination with the TNF inhibitor compound is for use in the treatment of IBD to reduce the average IBD score compared to administration of MCIM or TNF inhibitor compound alone.
  • the average score is reduced by at least 1 , at least 2, at least 3, at least 4, or 5.
  • Disease control may be achieved by treatment with an MCIM compound and a TNF inhibitor compound.
  • Disease control can comprise inhibition of disease progression, control of disease symptoms and/or supporting tissue repair. Inhibition of disease progression includes prevention of disease progression and slowing down disease progression. Standard methods in the art may be employed to determine disease progression.
  • Inhibition of disease progression may be determined by the histopathological methods described above, or any other suitable method known in the art. For example, inhibition of disease progression may be determined by comparing histopathological results from a subject before and after treatment with the compositions disclosed herein. Inhibition of disease progression may be indicated by the histopathological score being stable (i.e. not changing) over time following treatment. Inhibition of disease progression may be indicated by the histopathological score progressing at a slower rate following treatment compared to disease progression before treatment.
  • the TNF inhibitor compound comprises an antibody or a fusion protein, optionally wherein the TNF inhibitor compound is selected from etanercept, infliximab, adalimumab, golimumab, or certolizumab, or a combination of any of the foregoing, and the inflammatory and/or progressive disease is RA.
  • the TNF inhibitor compound comprises an antibody or a fusion protein, optionally wherein the TNF inhibitor compound is selected from etanercept, infliximab, adalimumab, golimumab, or certolizumab, or any combination of the foregoing, and the inflammatory and/or progressive disease is an inflammatory bowel disease, such as Crohn’s disease and ulcerative colitis.
  • the TNF inhibitor compound comprises an antibody or a fusion protein, optionally wherein the TNF inhibitor compound is selected from etanercept, infliximab, adalimumab, golimumab, or certolizumab, or a combination of any of the foregoing, and the inflammatory and/or progressive disease is lupus erythematosus.
  • the TNF inhibitor compound comprises an antibody or a fusion protein, optionally wherein the TNF inhibitor compound is selected from etanercept, infliximab, adalimumab, golimumab, or certolizumab, or a combination of any of the foregoing, and the inflammatory and/or progressive disease is psoriatic arthritis.
  • the TNF inhibitor compound comprises an antibody or a fusion protein, optionally wherein the TNF inhibitor compound is selected from etanercept, infliximab, adalimumab, golimumab, or certolizumab, or a combination thereof, and the inflammatory and/or progressive disease is reactive arthritis.
  • tissue repair, disease regression, disease control (which includes, for example, preventing or slowing disease progression), increase in reparative cells, decrease in destructive cells and/or reduction in cytokine production from peripheral mononuclear cells or lymphoid cells (such as T-, B- or NK-cells) can be determined as defined herein.
  • the MCIM compound reduces the levels of inflammatory mediators such as TNFa, eSEL, CD38, CD40, CD69, slgG, slL-17A, slL-17F, slL-2 and/or slL-6 that are produced by a target cell.
  • the MCIM compound reduces the levels of collagen type I and/or MMP1 , and/or increases collagen type IV production. In some embodiments, the MCIM compound increases ETC efficiency, without an increase in biomass. In some embodiments, the MCIM compound decreases ETC efficiency. In some embodiments, the MCIM compound reduces cellular proliferation without reducing ATP concentration/cell and viability, dependent on the environmental composition such as in the absence of pyruvate. In some embodiments, the MCIM compound induces an adaptive/repair response under conditions of metabolic stress conditions.
  • the MCIM compound modulates Complex I activity and attenuates high energy processes such as proliferation and/or differentiation and concurrently induces an adaptive/repair response by increasing the production of pro-angiogenic/repair factors such as VEGF to restore tissue metabolic homeostasis, particularly under metabolic stress conditions.
  • the MCIM compound reduced cell viability, particularly in cell types which are heavily dependent on Complex I metabolism and lack the metabolic flexibility to adapt.
  • lung fibroblasts are used as a target cell to determine the effect of the MCIM compound.
  • cellular adaptation may be determined in human primary lung fibroblasts, e.g. by measuring vascular endothelial growth factor (VEGF) secretion.
  • VEGF vascular endothelial growth factor
  • VEGF can be induced in a cell that is not receiving enough oxygen or nutrients to support ATP production. This can indicate how metabolic signalling pathways interact and integrate with angiogenic signalling events and repair).
  • VEGF secretion can be measured by plating primary human lung fibroblasts at 2 x 10 3 cells/well in 96-well plates in 100 pL DMEM complete medium with: 1 g/L glucose and 110 mg/L pyruvate; or 1 g/L glucose without pyruvate (each supplemented with 1 % penicillinstreptomycin and 10% heat inactivated foetal bovine serum), and incubating in a humidified 37°C incubator with 5% CO2 for 24 hours.
  • the test compound is prepared as a 10x final concentration solution in culture medium and added to final concentrations before further incubating the cells at 37°C / 5% CO2 for 24 hours.
  • VEGF secretion is measured in the cell supernatants using Quantikine® ELISA Human VEGF kits according to the manufacturer’s instructions. Absorbance at 450 nm is measured on a BMG Plate reader (CLARIOstar plus) using pathlength correction. Background absorbance is measured at 540 nm.
  • treatment with the test compound results in an increase in VEGF secretion in the absence of pyruvate, but not in the presence of pyruvate as a metabolic substrate for the cell. This indicates the induction of an adaptive/repair response under conditions of metabolic stress conditions via the attenuation of highly energy-consuming processes such as proliferation and concurrent production of pro-angiogenic/repair factors such as VEGF to restore tissue metabolic homeostasis.
  • a histopathological assessment can be used to determine the effect of the MCIM compound and the MCIM compound in combination with a TNF inhibitor compound on IBD: lleo-caecal issue sections can be stained with Haematoxylin and Eosin (H&E) and parameters of inflammation, mucosal erosion, epithelial hyperplasia, epithelial metaplasia, mucus cell metaplasia, and fibroplasia are assessed on a scale of 0-5 as follows:
  • the MCIM compound in combination with the TNF inhibitor compound reduces the average score compared with a subject treated with a negative control, MCIM compound alone and/or a TNF inhibitor compound alone.
  • Disease control may be achieved by treatment with the compositions of the invention.
  • Disease control can comprise inhibition of disease progression, control of disease symptoms and/or supporting tissue repair.
  • Inhibition of disease progression includes prevention of disease progression and slowing down disease progression. Standard methods in the art may be employed to determine disease progression.
  • Inhibition of disease progression may be determined by the histopathological methods described above, or any other suitable method known in the art. For example, inhibition of disease progression may be determined by comparing histopathological results from a subject before and after treatment with the composition of the invention. Inhibition of disease progression may be indicated by the histopathological score being stable (i.e. not changing) over time following treatment. Inhibition of disease progression may be indicated by the histopathological score progressing at a slower rate following treatment compared to disease progression before treatment.
  • a histopathological assessment can be used to determine the effect of the MCIM compound and the MCIM compound in combination with a TNF inhibitor compound on arthritis: For this assessment of arthritis, the following signs are monitored in digits or limbs of each subject three times per week and summed to generate the Arthritic Index (Al). (The maximum Al for one animal is 16):
  • the MCIM compound in combination with a TNF inhibitor compound reduces the average score compared with subject treated with a negative control, MCIM compound alone and/or a TNF inhibitor compound alone.
  • inhibition of disease progression may be indicated by a stable Arthritic Index (Al) score, or any other suitable method known in the art.
  • Al Arthritic Index
  • inhibition of disease progression may be determined by comparing the Al score from a subject before and after treatment with the composition of the invention. Inhibition of disease progression may be indicated b the Al score being stable (i.e. not changing) over time following treatment. Inhibition of disease progression may be indicated by the Al score progressing or increasing at a slower rate following treatment.
  • Disease control in Arthritis may be determined by any suitable method known in the art.
  • tissue repair, disease regression, disease control, increase in reparative cells, decrease in destructive cells and/or reduction in cytokine production from pro-inflammatory myeloid cells can be determined as defined herein.
  • the combination therapy reduces the levels of inflammatory mediators such as TNFa, eSEL, CD38, CD40, CD69, slgG, slL-17A, si L-17F, slL-2 and/or slL-6 that are produced by a target cell.
  • the combination therapy increases Coll IV expression.
  • the combination therapy increases ETC efficiency, without an increase in biomass.
  • the combination therapy reduces cellular proliferation without reducing ATP concentration/cell and viability, in the absence of pyruvate.
  • the combination therapy induces an adaptive/repair response under conditions of metabolic stress conditions, reducing cell death.
  • the MBS compound modulates Complex I activity and attenuates high energy processes such as proliferation and concurrently induces an adaptive/repair response by increasing the production of pro-angiogenic/repair factors such as VEGF to restore tissue metabolic homeostasis, particularly under metabolic stress conditions.
  • pro-angiogenic/repair factors such as VEGF
  • a pharmaceutical combination as disclosed herein refers to a combination comprising two or more active compounds.
  • a pharmaceutical combination may comprise two or more compositions each comprising at least one active compound.
  • the two or more compositions may be administered separately, sequentially or simultaneously.
  • the pharmaceutical combination may comprise a first composition comprising an MCIM compound, such as HMC-C-01-A, and a second composition comprising a TNF inhibitor compound, such as an antibody or a fusion protein, optionally wherein the TNF inhibitor compound is selected from etanercept, infliximab, adalimumab, golimumab, or certolizumab, or any combination of the foregoing.
  • the first and second composition may be administered separately, sequentially or simultaneously.
  • a pharmaceutical combination may comprise a single composition comprising two or more active compounds.
  • the combination may comprise a single composition comprising an MCIM compound and a TNF inhibitor compound.
  • the MCIM compound comprises HMC-C-01-A.
  • the TNF inhibitor compound comprises one or more compounds selected from an antibody or a fusion protein, optionally wherein the TNF inhibitor compound is selected from etanercept, infliximab, adalimumab, golimumab, or certolizumab, or any combination of the foregoing.
  • the composition comprises the MCIM compound HMC-C-01-A and a TNF inhibitor compound selected from an antibody or a fusion protein, optionally wherein the TNF inhibitor compound is selected from etanercept, infliximab, adalimumab, golimumab, or certolizumab, or a combination thereof.
  • Medicaments and pharmaceutical compositions according to the aspects disclosed herein may be formulated for administration by a number of routes, including but not limited to, parenteral i.e. nonoral route (for example, by injection: sub-cutaneous, intravenous, intra-arterial, intramuscular, or intratumoural; by topical or intradermal; by inhalation or intranasal; or by rectal), and peroral i.e. oral route.
  • the medicaments and compositions may be formulated in a solid, semi-solid, or liquid dosage form.
  • the pharmaceutical compositions according to this invention may be delivered by a route which facilitates exposure in the systemic circulation or by a route or method which gives rise to localised, targeted, delivery of the active compounds to a selected region in the body.
  • compositions according to this invention may also be administered to humans or animals. Administration is preferably in a "therapeutically effective amount", this being sufficient to show benefit to the individual.
  • the actual amount administered, and rate and time-course of administration, will depend on the nature and severity of the disease being treated.
  • the rate of release of the active compounds from the pharmaceutical composition may be immediate, sustained, extended, controlled, pulsatile or follow a pattern that is optimal for the intended therapeutic application.
  • the frequency of dosing can be fixed or variable depending on the rate of drug release, the required level in the systemic circulation or at the target site to provide the desired therapeutic effect. Prescription of treatment, e.g.
  • the disclosure provides pharmaceutical combinations comprising a MCIM compound and a TNF inhibitor compound.
  • the combination may comprise a single composition comprising the MCIM compound and the TNF inhibitor compound.
  • the pharmaceutical combination may comprise a first composition comprising a MCIM compound and a second composition comprising a TNF inhibitor compound.
  • the combination comprises a first composition comprising a MCIM compound and a second compositions comprising two or more TNF inhibitor compounds.
  • the two or more TNF inhibitor compounds may be formulated as individual compositions comprising a single TNF inhibitor compound.
  • compositions may be prepared using a pharmaceutically acceptable “carrier” composed of materials that are considered safe and effective.
  • “Pharmaceutically acceptable” refers to molecular entities and compositions that are "generally regarded as safe", e.g., that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset and the like, when administered to a human.
  • this term refers to molecular entities and compositions approved by a regulatory agency of the US federal or a state government, as the GRAS list under section 204(s) and 409 of the Federal Food, Drug and Cosmetic Act, that is subject to premarket review and approval by the FDA or similar lists, the U.S. Pharmacopeia or another generally recognised pharmacopeia for use in animals, and more particularly in humans.
  • carrier refers to diluents, binders, lubricants and disintegrants. Those with skill in the art are familiar with such pharmaceutical carriers and methods of compounding pharmaceutical compositions using such carriers.
  • the pharmaceutical compositions when formulated as a solid dosage form, may further be uncoated or coated with an outer layer to impart aesthetic features, physical protection, enhance the physical and/or chemical stability of the active compounds or other constituents of the pharmaceutical compositions, and/or alter the rate of dissolution and release of the active compounds from the pharmaceutical compositions.
  • the pharmaceutical compositions when formulated as a parenteral injectable dosage form, may additionally contain aqueous or non-aqueous solvents, co-solvent mixtures, buffering agents, surfactants, tonicity modifying agents, chelating agents, pH modifiers, viscosity modifiers, and/or suspending agents.
  • the pharmaceutical compositions when formulated as a parenteral dosage form for inhalation, may additionally contain particle carriers for the pulmonary delivery of the active compounds, absorption penetration enhancers, and/or propellants, dependent on the inhalation delivery device to be used.
  • Those with skill in the art are familiar with such pharmaceutical carriers, excipients therein, and methods of compounding these excipients into pharmaceutical compositions. Suitable excipients for use in the pharmaceutical compositions can be found in standard pharmaceutical texts, for example, Handbook of Pharmaceutical Excipients, 9th edition, Pharmaceutical Press, American Pharmaceutical Association, 2020.
  • compositions provided herein may include one or more excipients, e.g., solvents, solubility enhancers, suspending agents, buffering agents, isotonicity agents, antioxidants or antimicrobial preservatives.
  • excipients e.g., solvents, solubility enhancers, suspending agents, buffering agents, isotonicity agents, antioxidants or antimicrobial preservatives.
  • the excipients of the compositions will not adversely affect the stability, bioavailability, safety, and/or efficacy of the active ingredients, i.e. the MCIM compound and/or the TNF inhibitor compound used in the composition.
  • Excipients may be selected from the group consisting of buffering agents, solubilizing agents, tonicity agents, chelating agents, antioxidants, antimicrobial agents, and preservatives.
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a dihydrate, a tri-hydrate, etc.
  • a reference to a particular compound also includes the solvate forms thereof.
  • a corresponding salt of the active compound(s) for example, a pharmaceutically-acceptable salt of an MCIM compound, for example HMC-C-01-A, or a TNF inhibitor compound.
  • a pharmaceutically-acceptable salt of an MCIM compound for example HMC-C-01-A
  • TNF inhibitor compound for example, HMC-C-01-A
  • pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1- 19.
  • a salt may be formed with a suitable cation.
  • a salt may be formed with a suitable anion.
  • a reference to a particular compound also include salt forms thereof.
  • compositions according to this invention include, but are not limited to, dosage forms wherein the active compounds are co-formulated uniformly in a common excipient base, such as a conventional single-layer tablet or conventional powder-in-capsule for oral administration; a solution, suspension or dispersed system for parenteral administration; a lotion, cream, ointment for topical administration; a transdermal patch, microneedle or autoinjector system for transdermal administration; a dry powder, solution or suspension for inhalation administration; and a solution or suspension for intranasal administration.
  • a common excipient base such as a conventional single-layer tablet or conventional powder-in-capsule for oral administration
  • a solution, suspension or dispersed system for parenteral administration such as a lotion, cream, ointment for topical administration
  • a transdermal patch, microneedle or autoinjector system for transdermal administration
  • a dry powder, solution or suspension for inhalation administration such as a dry powder, solution or suspension for in
  • compositions particularly useful for solid dosage forms for oral administration, are provided according to this invention wherein the active compounds are physically separated within a single pharmaceutical composition to avoid the potential for physical and chemical interactions and incompatibilities.
  • Such pharmaceutical compositions include, but are not limited to, a bi-/multi-layer tablet, wherein the formulation of each layer is optimised for each active compound, which can be combined in a single pharmaceutical composition by conventional tablet compression.
  • Such pharmaceutical compositions may also include a single-layer or bi-/multi-layer tablet wherein one of the active compounds is contained within a layer that is coated on the outside of the singlelayer or bi-/multi-layer compressed tablet core, thus, providing a physical separation of the active compounds and their associated excipient systems.
  • a further alternative pharmaceutical composition according to this invention is a multi-particulate capsule, wherein the formulation of each active compound in a particulate/granular form can be optimised, then combined and encapsulated into a conventional capsule as a single pharmaceutical composition.
  • BioMAP® A high-throughput integrative biology platform (BioMAP ®) was used to profile the effect of MCIM compounds on multiple disease-associated regulatory pathways.
  • BioMAP® has been developed as a method to assess efficacy, safety and the mechanism of action of drugs in multiple human cell types stimulated with inflammatory challenges as described in US6656695, which is incorporated herein in its entirety.
  • the BioMAP system reflects human disease pathology and has the ability to detect and distinguish the effects of approved drugs and investigational human therapeutic compounds. BioMAP technology enables rapid determination of efficacy, side effects and mechanism of action of drug candidates.
  • BioMAP® provides an unbiased, target-agnostic and data-driven approach to understanding compound or combination therapy impact on human disease models and translational biomarkers.
  • the system is validated with clinically approved drugs and known test agents.
  • the principle of the assay is to test compounds in human primary cell-based disease systems, and compare the data with a Reference Database of over 4,500 compounds.
  • the profile of a compound can be compared against a reference compound to see if the biological activity of the test item is differentiated from the reference.
  • MCIM compounds The activity of MCIM compounds was determined in three BioMAP systems; Fibrosis panel, Autoimmune panel HDFSAg and Diversity Plus.
  • BioMAP® panels consist of human primary cell-based systems designed to model different aspects of the human body in an in vitro format.
  • the 12 cell assays utilised in the Diversity PLUS panel allow characterisation of test agent responses in an unbiased way across a broad set of systems modelling various human disease states compared to historical controls.
  • BioMAP® panels are constructed with primary cell types from healthy human donors, with stimuli (such as cytokines or growth factors) added to capture relevant signalling networks that naturally occur in human tissue or pathological conditions.
  • MCIM Compounds were tested in these assays at four concentrations: 4000 nM, 1300 nM, 400 nM & 150 nM.
  • Human blood derived CD14 + monocytes were differentiated into macrophages in vitro before being added to the LPS system (Eurofins DiscoverX Corporation).
  • the human cell types and stimuli used in each assay system were as follows: 3 C system [human umbilical vein endothelial cells (HUVEC) + (IL-1 p, TNFa and IFNy)], 4H system [HUVEC + (IL-4 and histamine)], lipopolysaccharide (LPS) system [peripheral blood monocyte cells (PBMC) and HUVEC + LPS (TLR4 ligand)], Sag system [peripheral blood mononuclear cells, PBMC and HUVEC + TCR ligands], HDFSAg system [peripheral blood mononuclear cells, PBMC and human neonatal dermal fibroblasts + TCR ligands], BT system [CD19 + B cells and PBMC + (a-IgM and TCR ligands)], BF4T system [bronchial epithelial cells and human neonatal dermal fibroblasts, HDFn, + (TNFa and IL-4)], BE
  • Assays were derived from either single cell types or co-culture systems. Adherent cell types were cultured in 96 or 384-well plates until confluence, followed by the addition of PBMC (Sag and LPS systems).
  • the BT system consisted of CD19 + B cells co-cultured with PBMC and stimulated with a BCR activator and low levels of TCR stimulation.
  • Test agents prepared in either DMSO (small molecules; final concentration ⁇ 0.1 %) or PBS (biologies) were added at the indicated concentrations 1 h before stimulation, and cells remained in culture for 24 h or as otherwise indicated [48 h, MyoF system; 72 h, BT system (soluble readouts); 168 h, BT system (secreted IgG)].
  • Each assay plate contained negative controls (e.g., non-stimulated conditions) and vehicle controls (e.g., 0.1 % DMSO) appropriate for each system.
  • Direct ELISA was used to measure biomarker levels of cell-associated and cell membrane targets. Soluble factors from supernatants were quantified using either HTRF® detection, bead-based multiplex immunoassay, or capture ELISA. Overt adverse effects of (compounds) on cell proliferation and viability (cytotoxicity) were detected by sulforhodamine B (SRB) staining for adherent cells, and alamarBlue® reduction for cells in suspension.
  • SRB sulforhodamine B
  • Biomarker measurements in treated samples were divided by the average of the control samples (at least 6 vehicle controls from the same plate) to generate a ratio that was then Iog10 transformed.
  • Significance prediction envelopes were calculated using proprietary historical vehicle control data at a 95% confidence interval.
  • Biomarker activities were annotated when two or more consecutive concentrations change in the same direction relative to vehicle controls were outside of the significance envelope and had at least one concentration with an effect size > 20% (Iog10 ratio> 0.1).
  • Biomarker key activities were described as modulated if these activities increase in some systems but decrease in others.
  • Cytotoxic conditions were noted when total protein levels decreased by more than 50% (Iog10 ratio of SRB or alamarBlue® levels ⁇ -0.3) and were indicated by a thin black arrow above the X-axis. A compound was considered to have broad cytotoxicity when cytotoxicity was detected in 3 or more systems. Concentrations of test agents with detectable broad cytotoxicity were excluded from biomarker activity annotation and downstream benchmarking, similarity search and cluster analysis. Antiproliferative effects were defined by an SRB or alamar Blue® Iog10 ratio value ⁇ -0.1 from cells plated at a lower density and were indicated by grey arrows above the X-axis. Cytotoxicity and antiproliferative arrows only require one concentration to meet the indicated threshold for profile annotation.
  • Figure 2 shows the BioMAP profile of several MCIM compounds.
  • ABD599 tested in the full bioMAP profile shows decreased inflammation and immune modulation, and tissue remodelling with increased collagen IV levels.
  • HMC-C-01-A shows anti-inflammatory and immune modulation activity in the BT and Sag systems and
  • C HMC-C-01-A in the fibrosis panels increases Collagen type IV.
  • Figure 3 shows the BioMAP profile of three anti-TNF compounds in the HDFSAg inflammation system.
  • A adalimumab, a humanised monoclonal antibody against TNF approved for the treatment of Crohn’s disease, psoriatic arthritis, plaque psoriasis, rheumatoid arthritis and ulcerative colitis and etanercept, a biologic fusion protein that blocks TNF approved for the treatment of rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, juvenile idiopathic arthritis and ankylosing spondylitis shows anti-inflammatory activity and reduced tissue remodelling.
  • infliximab a chimeric monoclonal antibody against TNF approved for the treatment of psoriarsis, Crohn’s disease, ankylosing spondylitis, psoriatic arthritis and ulcerative colitis shows anti-inflammatory activity and reduced tissue remodelling.
  • Table I shows the bioMAP activities of the compounds and known TNF inhibitors.
  • MCIM compounds have a distinct phenotypic profile with multi-modal actions; having specific effects in different cell types following stimulation with different inflammatory mediators.
  • MCIM compounds modulated immune activities with reduced the levels of inflammatory mediators such as TNFa, eSEL, CD38, CD40, CD69, slgG, slL-17A, slL-17F, slL-2 and slL-6, in common with TNF inhibitors.
  • TNFa eSEL
  • CD38 CD40
  • CD69 slgG
  • slL-17A slL-17A
  • slL-17F slL-2 and slL-6
  • Coll IV a critical basement membrane collagen which is involved in tissue repair and remodelling activities. This activity was differentiated compared with TNF inhibitors.
  • MCIM compounds have a distinct phenotypic profile with multi-modal actions, having specific effects in different cell types following stimulation with different inflammatory mediators.
  • the MCIM compounds modulate immune activities by reducing the levels of inflammatory mediators such as TNFa, e-Selectin, CD38, CD40, CD69, slgG, slL-17A, slL-17F, slL-2 and slL-6.
  • the MCIM compounds show potential for tissue remodelling as indicated by the decrease in Col I and MMP1.
  • the MCIM compounds increase production of Coll IV, a critical basement membrane collagen which is involved in tissue repair and remodelling activities. This activity was differentiated compared with TNF inhibitors.
  • the ability of mitochondria to undergo fusion and fission processes is essential to mitochondrial function and cellular health.
  • Qualitative and/or quantitative changes in the mitochondrial reticulum are also observed under pathological conditions that are caused by inherited mutations in mitochondrial DNA or in nuclear OXPHOS genes and suggest a tight relationship between mitochondrial structure and function.
  • several lines of evidence suggest that the damage response of injured cells can be ameliorated by the presence of healthy mitochondria (Jin,et al, 2019, which is hereby incorporated by reference in its entirety). Studying mitochondrial form and function may therefore yield important insights into the potential of cells and tissues to recover from damage.
  • Osteoclasts are a highly energetic cell type sensitive to changes in mitochondrial metabolism that are suitable for evaluating such relationships.
  • Peripheral blood mononuclear cells were isolated from human whole blood by differential centrifugation over Ficoll-Paque PLUS (GE Healthcare Biosciences). CD14+ monocytes were purified from the freshly isolated PBMCs using the CD14+ selection kit (StemCells. UK) by positive magnetic selection according to manufacturer’s instructions.
  • Cells were differentiated to osteoclasts by adding 1x10 6 ml-1 cells in complete minimum essential medium-alpha supplemented with 10% heat inactivated fetal bovine serum (FBS, lnvitrogen,UK),2mM glutamine (lnvitrogen,UK) 20U ml-1 penicillin, 100ug/ml streptomycin (Sigma ALdrich, UK) along with 25ng ml-1 recombinant human M- CSF (Peprotech, UK) and 25 ng ml-1 RANKL for 6 days. On th e 6th day, the cells were treated with test compound (final concentration 0.03-1 uM, 0,05 % DMSO) or a control, rotenone (100 nM).
  • test compound final concentration 0.03-1 uM, 0,05 % DMSO
  • rotenone 100 nM
  • Adherent cells were fixed in 2.5% glutaraldehyde in 0.1 M cacodylate buffer, pH 7.4, for 1 h, post fixed with 1% osmium tetroxide (Electron Microscopy Science), dehydrated in a graded series of ethanol, and embedded in Epon (Electron Microscopy Science).
  • the embedded samples were sectioned by an ultramicrotome (Ultracut E, Richert-Jung, Leica Microsystem). Thin sections (90 nm thick) were collected on 300 mesh nickel grids and stained with uranyl acetate (Electron Microscopy Science) and lead citrate. Samples were observed by using a Zeiss EM 109 apparatus (Zeiss). Images were captured using a Nikon digital camera Dmx 170 1200F and ACT-1 software.
  • Control cells show a heterogenous and dynamic population of mitochondria with a good balance of fusion and fission (mitochondria (M) and endoplasmic reticulum (ER)).
  • M mitochondria
  • ER endoplasmic reticulum
  • B cells treated with the archetypal Complex I inhibitor, rotenone show increased numbers of abnormal mitochondria which were more rounded and had condensed cristae with evidence of fragmentation, and evidence of lysosomes (L) close by.
  • C 0.03 pM ABD900 showed increased tubular mitochondrial with evidence of extrusion budding, consistent with an adaptive change in mitochondrial structure to increase mitochondrial area without an overt increase in organelle biomass.
  • Dumbbell morphology consistent with the formation of electron transport chain (ETC) super-complexes, were also observed.
  • D 0.1 pM ABD900 showed a similar profile with evidence of cristae refraction.
  • E 0.3 pM ABD900 shows filamentous extensions in many mitochondria consistent with an attempt to enlarge cristae volume.
  • F 1 pM ABD900 shows a heterogenous mitochondrial population with rounded morphology and condensed cristae.
  • the MCIM compounds of the invention elicit a mitochondrial phenotype consistent with differentiation based on maturity. For example, older mitochondria, which are usually cleared by mitophagy, are retained as part of an integrated stress response. To increase ETC efficiency, without an overt increase in biomass, structural adaptation occurs to maintain cellular free energy.
  • EXAMPLE 3 Cellular metabolism and viability The in vitro effects of test compounds on cellular metabolism and viability were determined by incubation with human primary lung fibroblasts followed by measurement of cellular ATP concentrations and cell counts.
  • ATP is an organic compound which can be produced by several cellular processes such as glycolysis and oxidative phosphorylation. However, if levels of oxygen, or substrates to fuel oxidative phosphorylation are insufficient, cells can reprogramme their metabolism towards glycolysis or other pathways to maintain their availability of ATP. Depending on the environment of the cell, such changes in metabolism may be accompanied by adaptive changes in gene expression. For example, under certain culture conditions, cells may upregulate an ‘adaptive response’ gene known as vascular endothelial growth factor (VEGF); VEGF encodes a proangiogenic protein (VEGF), whose function to induce new blood vessel formation to seek out new sources of oxygen and nutrients. This is critical to eliciting a functional repair response. By modulating the activity of Complex I, the MCIM compounds of the invention modulate ATP production, and thereby induce a cellular adaptation response.
  • VEGF vascular endothelial growth factor
  • HEF human primary lung fibroblasts
  • Human primary lung fibroblasts were plated at a concentration of 2 x 10 3 cells/well in 96-well plates in 100 pL DMEM complete media (5.5 mM glucose, 2 mM L-glutamine, and 1 mM pyruvate) containing 1% penicillin-streptomycin and 10% heat inactivated foetal bovine serum. Cells were incubated at 37°C / 5% CO 2 overnight to allow cell attachment.
  • VEGF secretion was measured from cell culture supernatants; 72 hours post treatment, cells were assayed for nucleus counts and ATP generation.
  • the cells were washed twice with TBS-T, and cells were counted in 100 pL PBS solution using an I mageXpress Pico system with stitched plate acquisition (4x magnification), DAPI channel (50ms exposure, -3 digital confocal setting).
  • ATPIite 1step Luminescence Assay System 50 pL of reconstituted ATPIite substrate solution (ATPIite 1step Luminescence Assay System, Perkin Elmer) was added to the cells. After a 5-minute incubation at room temperature on a plate shaker, luminescence was measured on a BMG Plate reader (PHERAstar) using LUM plus module, gain 3000, CR 96/384 aperture spoon (type A3).
  • IC50 half-maximal inhibitory concentration
  • VEGF secretion was measured following the Quantikine® ELISA Human VEGF kit manufacturer instructions. Absorbance at 450 nm was measured on a BMG Plate reader (CLARIOstar plus) using pathlength correction. Background absorbance was measured at 540 nm.
  • Data were normalised to a VEGF standard curve and expressed as the average of the control wells in pg/mL. Data were plotted and the IC50 for the effect on VEGF secretion was calculated by fitting the data to a four-parameter IC50 equation using GraphPad Prism software (v9).
  • Figure 5A consists of 3 panels showing intracellular ATP (left panel), nucleus counts (middle panel) and ATP readout per cell (right panel) after 72 hrs incubation with MCIM compound.
  • cells cultured in glucose-supplemented media squares
  • cells cultured in media supplemented with glucose and glutamine open circles
  • intracellular ATP levels and nucleus counts given vehicle compared to cells cultured with glucose alone.
  • Treatment of cells cultured in medium supplemented with glucose and glutamine with the MCIM compound reduced intracellular ATP levels and nucleus counts, in a concentration-dependent manner, with no effect on ATP levels per cell.
  • results show that treatment with MCIM compounds of the invention induces an adaptive response to enable cells to maintain their supply of ATP.
  • cells When cells are treated with MCIM compound, they attempt to restore tissue homeostasis by reducing energy-intensive activities such as proliferation and increasing production of growth factors such as VEGF. This occurs without any effect on cell viability.
  • Human primary lung fibroblasts were plated at a concentration of 5 x 10 3 cells/well in 96well plates in 100 pL DMEM complete media (5.5 mM glucose, 2 mM L-glutamine, and 1 mM pyruvate) containing 1% penicillin-streptomycin and 10% heat-inactivated foetal bovine serum. Cells were incubated overnight at 37°C / 5% CO 2 to allow cell attachment.
  • the cells were washed twice with TBS-T, and cells were counted in 100 pL PBS solution using an I mageXpress Pico system with stitched plate acquisition (4x magnification), DAPI channel (50 ms exposure, -3 digital confocal setting).
  • BrdU can be utilised to measure DNA replication.
  • BrdU can be incorporated into the newly synthesized DNA in place of thymidine.
  • FIG. 6 The results are shown in Figure 6.
  • the figure shows 4 panels: cell proliferation inhibition measured by BrdU incorporation (A) and nucleus counts (B), and effects of compound washout on cell proliferation by BrdU incorporation (C) and nucleus counts (D) at the highest tested concentration.
  • ABD900 is shown in filled circles (•)
  • rotenone is shown in grey squares ( ⁇ )
  • IACS-010759 in open circles (O).
  • FIG. 6-D cells without washout are shown in solid black (IACS-010759) and grey (Rotenone) fill, and washout in open black (IACS-010759) and grey (rotenone) bars.
  • washout cells are shown with an open fill pattern and cells not washed out are shown in a checkerboard fill.
  • Data are mean ⁇ s.e.m..
  • the results show that typical Complex I inhibitors such as IACS-010759 and rotenone reduce cell proliferation (BRdU incorporation and nucleus counts) when cells are cultured in pyruvate-restricted conditions.
  • Complex 1 inhibitors such as IACS-010759 and rotenone
  • the MCIM compound there is a recovery in the proliferative capacity (BrdU incorporation and nucleus counts) of the cells after the compound is washed out.
  • the data together show that the MCIM compounds of the invention display different cellular effects to the known, archetypal, inhibitors of Complex I.
  • CFA Complete Freund’s adjuvant
  • IFA Incomplete Freund’s adjuvant
  • Figure 7 shows seven graphs, each of average arthritic index as a function of time (dosing day) for test compound dosed at 10 mg/kg/day by oral gavage (open circles (O)) and control (solid circles (•)), for each of: (A) HMC-C-02-A, (B) HMC-C-01-A, (C) HMC-N-02-A, (D) HMC-N-01-A, (E) NASMP- 01-A, (F) CHMSA-01-A, (G) CHMSA-03-A.
  • Animals were sorted into treatment groups with a mean arthritic index of 2.5 and then dosed once daily for 14 days with compound by oral gavage. On Day 14, animals were sacrificed, and limbs were fixed in 10% neutral buffered formalin. The fixed limbs were processed into paraffin blocks and sectioned, and then stained using Toluidine Blue.
  • bone resorption was assessed by a direct count per bone of areas showing evident Howship’s lacunae or active osteolytic foci.
  • a total count of cancellous bone osteoid zones was performed.
  • Figure 8 and 9 shows a decrease in bone resorption with approved drugs, etanercept (Figure 8A) and tofacitinib (Figure 8C) and various MCIM compounds (Figure 8A and B).
  • Figure 9A shows a modest increase in bone formation in mice treated with etanercept compared to vehicle control.
  • mice treated with HMC-C-01-A, HMC-C-01-B, and HMC-N-01-B have significantly increased bone formation compared to vehicle control and etanercept (Figure 9A).
  • Figure 10 shows the appearance of the osteoid/new bone formed in response to treatment with vehicle (top panel), an approved disease modifying anti-rheumatic drug (etanercept; bottom panel) and compound HMC-C-01-A (middle panel).
  • Figure 10, middle panel demonstrates the new bone formed in response to treatment with HMC-C-01-A has a regular appearance with conservation of the tide-mark (arrows). This indicates that the bone formed is responsive to pressure and has structural integrity in contrast to the reactive and sporadic deposits generated with etanercept (bottom panel) or tofacitinib (data not shown).
  • Figure 11 shows that improvements in osteoid are achieved in mice treated with HMC-C-01 without control of inflammation. This indicates a direct remodelling effect that is not dependant on control of inflammation.
  • Figures 7-11 show the effects of the MCIM compounds in a model of joint inflammation and bone loss.
  • the results show that the MCIM compounds alone reduce total bone resorption, and local focal areas of bone resorption as well as, or better than, anti-biologic drugs such as etanercept or Janus kinase (JAK) inhibitors such as tofacitinib.
  • the MCIM compounds trigger an adaptive repair response resulting in an increase in new bone deposition (osteoid), both in terms of osteoid counts and the areas of osteoid formation.
  • the new bone formed in response to treatment with the MCIM compounds has a regular appearance with conservation of the tide-mark. This indicates that the bone formed is responsive to pressure and has structural integrity in contrast to the reactive and sporadic deposits generated with etanercept.
  • the above data indicate that the MCIM compounds show excellent oral in vivo activity in preventing the progression of bone loss in established, severe arthritis, but importantly that they increase bone formation, indicating repair, in established arthritis.
  • Figure 12 shows 4 graphs demonstrating the anti-arthritic effects of TNF inhibitor compound etanercept, the MCIM compound HMC-C-01 , and the combination of etanercept and HMC-C-01 on (A) synovitis, (B) cartilage damage, (C) bone resorption, and (D) overall mean change in bone pathology.
  • Figure 13 shows 1 graph demonstrating the effects of TNF inhibitor compound etanercept, the MCIM compound HMC-C-01 , and the combination of etanercept and HMC-C-01 on osteoid, or new bone formation.
  • HMC-C-01 have an additive effect on synovitis, bone resorption and cartilage damage.
  • the combination of HMC-C-01 and etanercept reduces overall bone pathology to a greater extent than either agent alone, with a synergistic effect observed when used in combination compared to either compound alone ( Figure 11 D).
  • HMC-C- 01 shows a strong effect on osteoid formation when given alone, an indicator of its pro-repair phenotype.
  • the TNF inhibitor compound etanercept shows limited effects on osteoid formation.
  • the combination of HMC-C-01 and etanercept improves overall bone osteoid formation to a greater extent than either agent alone.
  • the effect of the MCIM and TNF inhibitor combination in reducing bone pathology is thought to be due to the remodelling and repair activities of the MCIM compound, augmenting control of pathology over what can be achieved simply through control of synovitis.
  • DSS-induced colitis is a widely used model of IBD (Chassaing et al, 2015, which is hereby incorporated by reference in its entirety). Eight- to nine-week-old female C57BI/6 mice were used for all procedures. Animals were housed in groups of 10 and were maintained at 21 °C ⁇ 2°C on a 12-hour light/dark cycle with food and water ad libitum. Dextran sulphate (DSS) was prepared by dissolving DSS in water to a final concentration of 1 .5%.
  • mice All mice were given ad libitum access to the DSS-containing water for 6 hours prior to dosing with vehicle control, 300 mg/kg sulfadiazine, 3 mg/kg etanercept or 10 mg/kg MCIM test compound by oral gavage, once daily for 8 days. The mice started to develop signs and symptoms of colitis within 1 day.
  • mice For assessment of colitis, mouse body weight, stool consistency and presence/absence of blood in stool were monitored. Depending on the severity of the change in each of these observed parameters, the mice were assigned a score based on the criteria in Table 5. The disease scores were summed to generate the Disease Activity Index (DAI) (the maximum DAI for one animal is 9). The data are presented as mean s.e.m. across the group, and statistical analysis was performed using a two-way ANOVA with multiple comparisons (GraphPad Prism v 9.2.0). *p ⁇ 0.05, ***p ⁇ 0.005 vs vehicle, ⁇ p ⁇ 0.005 vs sulfasalazine, aaa p ⁇ 0.005 vs etanercept.
  • DAI Disease Activity Index
  • Figure 14 shows the mean disease activity index for mice with DSS-induced colitis following treatment with vehicle, 300 mg/kg/d sulfasalazine, 3 mg/kg/d etanercept or 10 mg/kg/d MCIM compound, HMC- C-01-A.
  • H&E Haematoxylin and Eosin
  • Figure 14 shows one graph, showing the average disease activity index for vehicle control, 300 mg/kg/day sulfasalazine, 3 mg/kg/day etanercept and 10 mg/kg/day HMC-C-01-A.
  • Figure 15 shows two graphs, each of average mucosal erosion score for (A) vehicle control, 300 mg/kg/day sulfasalazine and 10 mg/kg/day ABD900and (B) vehicle control, 3 mg/kg/day etanercept and 10 mg/kg/day HMC-C-01-A.
  • Figure 16 shows two graphs, each of average glandular loss score for each of: (A) vehicle control, 300 mg/kg/day sulfasalazine and 10 mg/kg/day ABD900 and (B) vehicle control, 3 mg/kg/day etanercept and 10 mg/kg/day HMC-C-01-A.
  • Figure 17 shows 2 graphs, each of average epithelial hyperplasia score for each of: (A) vehicle control, 300 mg/kg/day sulfasalazine and 10 mg/kg/day ABD900 and (B) vehicle control, 3 mg/kg/day etanercept and 10 mg/kg/day HMC-C-01-A.
  • Figure 18 shows 2 graphs, each of average fibroplasia score for each of: (A) vehicle control, 300 mg/kg/day sulfasalazine and 10 mg/kg/day ABD900, (B) vehicle control, 3 mg/kg/day etanercept and 10 mg/kg/day HMC-C-01-A.
  • Figure 19 shows representative histological cross sections of colon taken from mice with DSS- induced colitis treated with vehicle, 3 mg/kg/day etanercept or 10 mg/kg/day HMC-C-01-A, respectively.
  • vehicle treated mice there is clear ulceration (top right panel, arrow) and a general loss of tissue architecture of the colon as demonstrated by visible oedema/inflammation and erosion (top left panel, arrow).
  • Mice treated with etanercept display a general conservation of tissue architecture but still display a moderate degree of inflammation and oedema (middle panels, arrows).
  • the colon of mice treated with HMC-C-01-A have conserved tissue architecture and no visible signs of inflammation or oedema.
  • HMC-C-01 -A stimulates an adaptive repair of the colon which is not seen with Etanercept treatment (bottom panel, arrows).
  • the histological section from mice treated with HMC-C-01 -A demonstrates that this reaction is organised and localised within the lamina intestinal and aligned along the basal layer, with expansion/maintenance of basement membrane and maintenance of crypt architecture.
  • HMC-C-01-A and ABD900 compounds have excellent activity in preventing the progression of established colitis and can stimulate repair of damaged tissues.
  • Administration of MCIM compounds inhibited the key histological outcome of mucosal erosion/ ulceration, as shown in Figure 15. Importantly, administration also increased hyperplasia of epithelium, suggesting induction of a repair response. This is supported by the unique finding of fibroplasia in the MCIM compound treated groups ( Figure 17A and 17B).
  • Figures 14 to 19 show the effects of the MCIM compounds in a model of gastrointestinal disease.
  • the results show that the MCIM compounds reduce disease signs and symptoms and protect the underlying tissue damage to a greater extent than approved drugs, sulfasalazine or anti- TNF biologic, etanercept, and that the MCIM compounds promote repair responses of epithelial hyperplasia, mucus cell metaplasia and fibroplasia to a greater extent than sulfasalazine and etanercept.
  • EXAMPLE 7 Cellular thermal shift assay (CETSA) and multiplexes Quantitative mass spectrometry
  • MCIM compounds can affect mitochondrial morphology and modulate cellular metabolism it was next investigated whether the reparative properties of the MCIM compounds could be attributed to binding to/modulation of mitochondrial proteins and/or complexes. To this end, MCIM compounds were assessed using a cellular thermal shift assay (CETSA) coupled with quantitative mass spectroscopy (MS) to determine what pathways are modulated by the MCIM compounds.
  • CETSA cellular thermal shift assay
  • MS quantitative mass spectroscopy
  • Thp-1 cells were incubated in the presence of 2 pM MCIM compound (ABD900) or DMSO (vehicle control) for 4 hours. Following the incubation period, samples were heated to one of the following temperatures: 40.0, 42.9, 46.0, 49.6, 53.2, 56.8, 60.8, 64.0, 67.1 , 70.0°C. Each test condition was performed in duplicate.
  • LC-MS/MS Liquid Chromatography with tandem mass spectrometry
  • 105 proteins were identified as showing a thermal shift when incubated with the MCIM compound indicating that they were either stabilised or destabilised. Of these 105 proteins, 73 were classified as high confidence and 32 as medium confidence hits.
  • EXAMPLE 8 Photoaffinity labelling (PAL) and Quantitative stable isotope labelling by amino acids in cell culture (SI LAC)
  • the homology modelling revealed a lid pocket in the NDUFS2 subunit of Complex I which is in contact with the Q-tunnel.
  • the lid pocket was seen to be in an “open” conformation while in the remaining model it was in a “closed” conformation.
  • a homology model of the “open” confirmation was constructed and then SiteFinder was used to map NDUFS2 in the open and closed conformations.
  • SiteFinder Halgren T. A., 2009
  • This model identified two binding sites on NDUFS2.
  • the first binding site (“Pocket A”) is located on the lid pocket in the open conformation and is represented on Figure 19 by a cluster of spheres. Pocket A has a percentage buried non-polar available surface area of 72%.
  • the second binding site (“Pocket B”) is located at the “back” of the mitochondrial Complex I, relative to the position of the mitochondrial Complex I subunits NDUFS7 and ND1 and is represented by a second cluster of spheres. Pocket B has a percentage buried non-polar available surface area of 71%.
  • Example 10 Virtual Screening to assess structure-activity relationship against the NDUFS2 pocket
  • Example 9 As discussed in Example 9, is has been determined that the optimal binding site for MCIM compounds is in the lid pocket of NDUFS2 which is in close proximity to the Q-tunnel. From the data in Example 9, a ligand-protein pharmacophore model was built which identified 9 pharmacophoric features (Figure 24 and Tables 7A to 7C).
  • Table 7-A describes the relationship between the type of pharmacophoric feature and the permissible variation in 3D space for the location of the given pharmacophoric feature.
  • Table 7-B shows a distance matrix describing the 3D relationship between the centre of each pharmacophoric feature.
  • Table 7-C describes the angle between each triplet combination of pharmacophoric features, wherein column “Y” describes the vertex of each angle.
  • 117 compounds were assessed for their ability to dock in the predicted binding site using the pharmacophore model described above. To be treated as a successful docking in the predicted binding site, it is required that a molecule hits at least 4 features of the pharmacophore model shown in Figure 22 and has a half-maximal inhibitory concentration (IC50) ⁇ 1 pM.
  • IC50 half-maximal inhibitory concentration
  • Figure 25 shows a MCIM compound that conforms to the pharmacophore model and satisfies 7 out of the 9 annotation points determined to be important for binding to Complex I. Surprisingly, it was also found that out of the 117 compounds assessed for their ability to bind in the pharmacophore model, only 13 compounds had an IC50 > 1 pM, which indicates that these compounds would fail to dock in the predicted binding sites. The remaining 104 compounds hit at least 4 of the pharmacophore features and are predicted to have an IC50 ⁇ 1 pM.
  • Figure 26 shows representative compound CHMSA-02-A, which fulfils the pharmacophore model and is predicted to have a pAct (-Log(IC5o) of ⁇ 7.
  • the 3D model of the entire Complex 1 described in Example 9 was validated by docking Q10 and active MCIM compounds. This allowed establishment of the bioactive conformation of the MCIM compounds when docked in the Q-tunnel of Complex I. This further allowed a structure-based hypothesis to be generated and to rationalise the structure-activity relationship (SAR) of the compounds and to build the pharmacophore model described in Example 10 and a QSAR model ( Figure 27) for activity prediction.
  • the QSAR model is a linear regression model which includes docking scores and parameters related to ligand energies and electrostatics.
  • a library of compounds was screened against the pharmacophore model described in Example 10.
  • the model identified 37.6 million compounds from the library of compounds which generally hit 3-6 of the pharmacophore features. Of these 37.6 million compounds, those up to a molecular weight of -350 Da were then virtually docked in the 3D Complex I model without imposing pharmacophore constraints. 67,000 compounds were predicted to dock in Complex I and were retained for further screening.
  • TNF-a Tumor Necrosis Factor Alpha

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Abstract

L'invention concerne des polythérapies comprenant des composés inhibiteurs de TNF et des composés modulateurs du complexe mitochondrial I (MCIM), qui trouvent une utilité dans le domaine médical des troubles inflammatoires et progressifs tels que la polyarthrite rhumatoïde, les MICI, la fibrose pulmonaire idiopathique, la maladie pulmonaire interstitielle et la SEP.
PCT/EP2024/065836 2023-06-08 2024-06-07 Polythérapies à base d'inhibiteur de tnf Ceased WO2024252010A1 (fr)

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WO2025099187A1 (fr) * 2023-11-07 2025-05-15 Istesso 2 Ltd Polythérapies antirhumatismales modifiant la maladie
EP4647071A1 (fr) * 2024-05-10 2025-11-12 Istesso Therapeutics Limited Réparation clinique de l'arthrite
WO2026033048A1 (fr) * 2024-08-06 2026-02-12 Istesso 2 Ltd Associations comprenant des inhibiteurs de nf-kb et des modulateurs de mcim

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025099187A1 (fr) * 2023-11-07 2025-05-15 Istesso 2 Ltd Polythérapies antirhumatismales modifiant la maladie
EP4647071A1 (fr) * 2024-05-10 2025-11-12 Istesso Therapeutics Limited Réparation clinique de l'arthrite
WO2025233526A1 (fr) * 2024-05-10 2025-11-13 Istesso Therapeutics Limited Modulateur du complexe mitochondrial i destiné à être utilisé dans le traitement de l'arthrite
WO2026033048A1 (fr) * 2024-08-06 2026-02-12 Istesso 2 Ltd Associations comprenant des inhibiteurs de nf-kb et des modulateurs de mcim

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