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Definitions

• the present invention relates to the screening, diagnosis, prognostic evaluation, and treatment or prevention of age associated inflammation, chronic inflammation, and inflammatory diseases.
• the present invention relates to methods, agents and compositions for treating inflammatory diseases (e.g. rheumatoid arthritis or spondyloarthritis) or patients with inflammatory peripheral GnRH with GnRH antagonists, including drugs that lower the effects of GnRH or GnRH inhibitors.
• Ageing is among the largest known risk factors for human diseases. Roughly 100,000 people die each day of age-related causes. Between 2000 and 2050, the proportion of the number of people aged 60 years and over is expected to increase from 605 million to 2 billion.
• Chronic inflammation is associated with normal and pathological ageing. Systemic chronic inflammation can accelerate ageing (Jurk D, et al., Nat Comm, 2014; doi: 10.1038/ncomms5172). Many age-related diseases and ageing itself are closely associated with low-level chronic inflammation (Chung HY, et al, Ageing Res Rev 2009; 8: 18-30).
• Inflammatory markers are significant predictors of mortality in older humans. This proinflammatory status of the elderly underlies biological mechanisms responsible for the decline of physical function decline and age-related diseases such as Alzheimer's disease and
• Atherosclerosis that are initiated or worsened by systemic inflammation. Understanding of the ageing process should have a prominent role in new strategies for extending the health of the older population.
• Inflammatory diseases themselves accelerate the ageing process due to systemic chronic inflammation. Many of these diseases, such as rheumatoid arthritis and multiple sclerosis accelerate cardiovascular disease and osteoporosis, both of which are examples of age-related conditions. Indeed, inflammatory diseases have on average a 10 year premature mortality largely due to increased cardiovascular disease.
• Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks the joints producing an inflammatory synovitis that progresses to cartilage and bone destruction. Rheumatoid arthritis can also produce diffuse inflammation in the lungs, pericardium, pleura and sclera, and also nodular lesions, most common in subcutaneous tissue under the skin. Although the cause of rheumatoid arthritis is unknown, autoimmunity plays a role in its chronicity and progression.
• rheumatoid arthritis Current treatments for rheumatoid arthritis include: corticosteroids, methotrexate, tumour necrosis factors inhibitors such as etanercept (Embrel®), adalimubab (Humira®), and infliximab (Remicade®), and other immunomodulatory and cytotoxic agents. Whilst these treatments can be effective many require close supervision because of hazardous side-effects. Response to treatment with these agents is variable and some patients will experience pain and joint degeneration. Thus there is a need for additional treatments for rheumatoid arthritis and related diseases. Other inflammatory diseases have no disease modifying therapies available, such as progressive multiple sclerosis.
• the present invention relates to the screening, diagnosis, prognostic evaluation, and treatment or prevention of inflammatory conditions including age associated inflammation, chronic inflammation, and inflammatory diseases.
• the present invention relates to methods of treating inflammatory diseases (e.g. rheumatoid arthritis or spondylarthritis) or patients with inflammatory peripheral GnRH with GnRH antagonists or drugs that lower the effects of GnRH.
• inflammatory diseases e.g. rheumatoid arthritis or spondylarthritis
• GnRH antagonists or drugs that lower the effects of GnRH.
• Inflammatory conditions generally require or benefit from long term treatment.
• a first aspect of the invention provides a GnRH antagonist for use in the treatment or prevention of an inflammatory condition in a subject, selected from an inflammatory condition in a subject, selected from an
• GnRH antagonist is for long-term administration to said subject for a period of at least 12 weeks.
• composition comprising a
• this aspect of the invention provides a pharmaceutical composition comprising a
• GnRH antagonist for use in the treatment or prevention of an inflammatory condition in a subject, selected from an inflammatory disease, chronic inflammation, age-related inflammation or inflammatory peripheral GnRH, wherein said composition is for long-term administration to said subject for a period of at least 12 weeks.
• the invention provides use of a GnRH antagonist for the manufacture of a medicament for use in the treatment or prevention of an inflammatory condition in a subject, selected from an inflammatory disease, chronic inflammation, age-related inflammation or inflammatory peripheral GnRH, wherein said GnRH antagonist is for long-term administration to said subject for a period of at least 12 weeks.
• the invention also provides a method of treating or preventing an inflammatory condition in a subject, selected from an inflammatory disease, chronic
• said method comprising administering a GnRH antagonist to said subject, wherein said GnRH antagonist is administered long-term to said subject for a period of at least 12 weeks.
• Embodiments of the present invention provide methods, and uses based thereon, for the screening, diagnosis, prognostic evaluation, and treatment or prevention of age associated inflammation, chronic inflammation, inflammatory peripheral GnRH and inflammatory diseases, comprising administering a GnRH antagonist to the subject, as well as agents and compositions for such treatment.
• the present invention is not limited to a particular inflammatory disease.
• Examples include, but are not limited to, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, spondylo arthritis, psoriasis, systemic sclerosis
• the inflammatory conditions do not include systemic lupus erythematosus.
• Patients with peripheral GnRH include, but are not limited to, those with age associated inflammation, chronic inflammation, autoimmune disease, cardiovascular disease, osteoporosis, Alzheimer's disease, cataracts, cancers, cancer associated inflammation, postpartum and gonadal failure (including natural and surgical menopause, polycystic ovarian syndrome and Turner's syndrome).
• subjects with peripheral GnRH do not necessarily have an inflammatory disease and may be healthy.
• “Peripheral GnRH” and more particularly "inflammatory peripheral GnRH” are defined further below.
• the present invention is not limited to a particular GnRH antagonist.
• GnRH antagonists include, but are not limited to, cetrorelix, ganirelix, abarelix, degarelix, detirelix, iturelix, ozarelix, prazarelix, ramorelix, elagolix, relugolix, ASP 1707, teverelix, D17DT GnRH vaccination, or spiroindoline derivatives as gonadotropin- releasing hormone receptor antagonists.
• the GnRH antangonist is ASP 1707.
• the GnRH antagonist is administered in one or more repeated doses (e.g. several times daily, daily, weekly, monthly, or other interval) for a period of time.
• the GnRH antagonist is administered for a period of at least 12 weeks, (e.g. at least three months, at least 6 months, at least 1 year, at least 3 years, at least 5 years, or at least 10 years, or longer).
• the GnRH antagonist may be administered for a shorter period (e.g. at least one week, at least two weeks, at least one month, at least two months), In some
• the GnRH antagonist is administered at a dose of 0.1 mg to 1000 mg (e.g. 0.1, 0.25, 0.5, 1.0, 5.0, 10, 25, 50, 100, 200, 300, 400, 500, 750, or 1000 mg) In some embodiments, the GnRH antagonist is administered multiple times per day, daily, weekly, or monthly. In some embodiments, the GnRH antagonist is administered with an initial loading dose between 20 mg to lOOOmg (e.g. 20, 30, 40, 50, 60, 100, 200, 300, 400, 500, or lOOOmg) followed by a lower maintenance dose administered multiple times per day, daily, weekly, or monthly, or at least every 2-12 months.
• lOOOmg e.g. 20, 30, 40, 50, 60, 100, 200, 300, 400, 500, or lOOOmg
• a long acting GnRH antagonist such as Degarelix, Ozarelix or Abarelix is administered weekly, or every 2-4 week intervals, or monthly intervals or every 2-6 month intervals, or yearly, lOmg to lOOOmg, in some embodiments, with an initial loading dose of the long acting GnRH antagonist between 20mg to lOOOmg. Further doses and dosage regimes are discussed below.
• short acting GnRH antagonists such as Cetrorelix or Ganirelix
• oral GnRH antagonists such as nonpeptide oral GnRH
• spiroindoline derivatives as gonadotropin- releasing hormone receptor antagonists, Relugolix, Elagolix, or ASP 1707 is administered up to 6 times daily, e.g. 2, 3 or 4 to 6 times daily, or daily, or 2-6 times weekly or weekly at a dose of O. lmg to 3g (e.g. 0.1, 0,25, 0.5, 1.0,
• the present invention combats inflammatory or age-associated bio-markers such as TNF-a, IL-1, IL-6 or IGF-1, an amount dependent on their age and sex in the form of a medicament.
• Certain embodiments provide for the treatment or prevention of osteoporosis and/or increasing bone mineral density in a subject, by administering a GnRH antagonist to the subject, or administering a GnRH antagonist, with titrated oestrogen or testosterone to baseline or higher levels, or with an osteoporosis drug.
• Some embodiments provide for treating or preventing age associated inflammation, chronic inflammation or cardiovascular disease, or decreasing the risk of cardiovascular disease, or decreasing a patient's risk for developing coronary heart disease or having a cardiovascular event, including a recurrent cardiovascular event, e.g. by decreasing HBAlc or fasting blood glucose levels, decreasing blood pressure, decreasing chronic inflammation, or increasing HDL levels or decreasing LDL levels in a subject, by administering a GnRH antagonist to the subject, or administering a GnRH antagonist, with titrated oestrogen, or testosterone to baseline or higher levels, or with a drug to treat cardiovascular disease.
• a recurrent cardiovascular event e.g. by decreasing HBAlc or fasting blood glucose levels, decreasing blood pressure, decreasing chronic inflammation, or increasing HDL levels or decreasing LDL levels in a subject, by administering a GnRH antagonist to the subject, or administering a GnRH antagonist, with titrated oestrogen, or testosterone to baseline or higher levels, or with a drug to treat cardiovascular
• the present invention further provides for the use of a GnRH antagonist in the treatment of an autoimmune disease in a subject in need thereof.
• Some embodiments provide for decreasing a patient's risk for developing metabolic syndrome or developing type II diabetes, including decreasing HbAlC or fasting glucose in a subject by administering a GnRH antagonist to the subject.
• Additional embodiments provide for treating systemic sclerosis (scleroderma) in a subject, by administering a GnRH antagonist to the subject.
• Certain embodiments provide for treating multiple sclerosis in a subject, by administering a GnRH antagonist to the subject.
• Additional embodiments provide for treating inflammatory bowel disease in a subject, by administering a GnRH antagonist to the subject.
• the present invention provides for the use of a GnRH antagonist in the treatment of ankylosing spondylitis.
• the present invention provides for the use of a GnRH antagonist in the treatment of spondyloarthritis. In some embodiments, the present invention provides the use of a GnRH antagonist in the treatment of nephritis.
• the present invention provides the use of a GnRH antagonist in the treatment of cancer inflammation.
• the GnRH antagonist may be used for decreasing HBAlc, decreasing blood pressure, or increasing HDL levels in a subject.
• the present invention provides methods and uses of a GnRH antagonist to lower the levels of cytokines and/or chemokines in a subject.
• the proinflammatory cytokines are TNFa, IFNg, IL-lb and/or IL-2.
• the present invention provides the use of a GnRH antagonist to lower the levels of acute phase proteins such as CRP or high sensitivity CRP or the levels of auto-antibodies such as antibodies e.g. cyclic citrullinated peptide (CCP).
• autoimmune or inflammatory disease comprising: a) identifying subjects that exhibit one or more of: are negative for anti-cyclic citrullinated peptide (CCP) antibodies; are non-responders to anti-TNF therapy or disease-modifying anti-rheumatic drugs (DMARDs); and b)
• the present invention provides for the use of combination therapy, particularly titrated oestrogen or testosterone therapy to baseline or higher levels, or a disease modifying drug, or stable or tapered prednisolone , or local topical treatment, or a biologic drug, with a GnRH antagonist in the prevention or treatment of an inflammatory condition selected from age associated inflammation, chronic inflammation, inflammatory peripheral GnRH and inflammatory diseases.
• the present invention further provides an agent, e.g. a GnRH antagonist, particularly a conjugate comprising a GnRH antagonist linked to a polymer, and pharmaceutical compositions comprising said agent, as described further herein.
• an agent e.g. a GnRH antagonist, particularly a conjugate comprising a GnRH antagonist linked to a polymer, and pharmaceutical compositions comprising said agent, as described further herein.
• the present invention also provides for the use of said agents and compositions in therapy, particularly in the uses and methods described herein.
• Figs. 1A, IB and 1C show images of arthritis in the foot of patient 1 before and during treatment with degarelix.
• Fig. 2 shows ultrasound pictures of patient 5.
• Fig. 2A shows white area highlighted by arrow, is power Doppler denoting inflammatory activity in shoulder.
• Fig. 2B shows no power Doppler in same shoulder.
• Fig. 2C shows white area highlighted by arrow, is power Doppler denoting inflammatory activity in right MCP 4 (finger joint) right side.
• Fig. 2D shows no power Doppler in right MCP4 joint.
• Fig. 2E shows white area highlighted by arrow, is power Doppler denoting inflammatory activity in right MCP 4 (finger joint) left side.
• Fig. 2F shows no power Doppler in MCP 4 left side, and decreased joint fluid (oval).
• Fig. 3 shows patient 6 before (FIG. 3A) and after (FIG. 3B) degarelix treatment.
• Fig. 4 shows ultrasounds of patient 6.
• the first ultrasound shows a large effusion (swelling indicated by black area) over the right wrist.
• the second ultrasound shows the same area by 3.5 weeks.
• the effusion on the right is much smaller, and no longer painful.
• Fig. 5 shows disease activity variables of Patient 2 whilst being treated with degarelix.
• Fig. 6 shows A and C, foot ulcers in a lupus patient prior to degarelix treatment and B and D, after degarelix treatment.
• Fig. 7 shows hand ulcers in a lupus patient before A and after B degarelix treatment.
• Fig. 8 shows photographs of foot swelling in a patient with lupus after 8 weeks of treatment with degarelix.
• Fig. 9 shows hip bone mineral density in patient 1.
• Fig. 10 shows hip bone mineral density in patient 2.
• Fig. 11 shows a photograph of a baseline of a patient with systemic sclerosis prior to treatment. 5 Digital ulcers/Pitting scars on finger pulpa and a fingertip pain score 100mm (0- 100mm) was observed.
• Fig. 12 shows a photograph of the same patient as figure 12 after 6 weeks of treatment.
• the fingers are almost cleared of digital ulcers/pitting scars on finger pulpa and the fingertip pain score is 30 (0-100mm).
• Fig. 13 shows the synergistic effect of methotrexate and GnRH antagonist in rheumatoid arthritis.
• Fig. 14 shows a graph depicting the association of GnRH and TNF-alpha in the periphery of patients with rheumatoid arthritis.
• GnRH antagonist refers to an agent or drug that decreases, blocks, inhibits, abrogates, or interferes with GnRH activity in vivo.
• GnRH antagonists prevent or inhibit GnRH synthesis, and/or GnRH release, and/or GnRH function or activity. They may inhibit the action of GnRH by inhibiting binding of GnRH at its receptor, and may act at the GnRH receptor or at the GnRH molecule.
• GnRH antagonist thus includes compounds such as GnRH inhibitors, GnRH vaccinations such as GnRH-DT vaccinations consisting of the GnRH decapeptide linked to diphtheria toxoid, GnRH receptor antagonists, e.g. selective immune cell (e.g. T cell, B cell or macrophage cell) GnRH receptor antagonists, anti-GnRH antibodies, e.g.
• GnRH monoclonal antibodies against GnRH, circulating GnRH receptor fusion proteins, spiroindoline derivatives as gonadotropin- releasing hormone receptor antagonists, non-peptide oral GnRH antagonists, as well as agents which act to inhibit GnRH production and/or action by other mechanisms, for example by downregulating GnRH production due to negative feedback mechanisms, e.g. kisspeptin antagonists, estrogen compounds, testosterone compounds, luteinizing hormone (LH) compounds or follicle- stimulating hormone (FSH) compounds, hypothalamic hormones or neuropeptides.
• kisspeptin antagonists e.g. kisspeptin antagonists, estrogen compounds, testosterone compounds, luteinizing hormone (LH) compounds or follicle- stimulating hormone (FSH) compounds, hypothalamic hormones or neuropeptides.
• LH luteinizing hormone
• FSH follicle- stimulating hormone
• An oestrogen, testosterone, LH or FSH compound may be any compound or molecule or preparation which has oestrogen, testosterone, LH or FSH activity, including in particular oestrogen, testosterone, LH or FSH, or any preparation containing a said hormone, or a derivative of any said hormone.
• GnRH antagonists which may be used according to the invention are discussed further below.
• the GnRH antagonist acts to inhibit GnRH activity, e.g. by acting on or at the GnRH receptor or on GnRH itself (e.g. by binding to the receptor or GnRH).
• a suitable GnRH antagonist prevents or inhibits GnRH receptor signaling.
• a suitable 'GnRH antagonist' may be too large to cross the blood brain barrier.
• Such antagonist may take the form of a conjugate of a GnRH antagonist with a polymeric partner, e.g. a polymer such as a polypeptide (e.g. a protein such albumin), polysaccharide, or other polymer, such as polyethylene glycol (PEG) e.g. pegylated GnRH inhibitors, or GnRH inhibitors fused to proteins such as albumin.
• a polymer is defined broadly herein to include any compound having a multiplicity of repeating monomer units or residues and includes oligomers.
• a "multiplicity" may be 2 or more, e.g.
• a polypeptide may accordingly include longer polypeptide sequences such as proteins as well as shorter peptides.
• Conjugates of a drug molecule/active agent with a polymer molecule are widely used and reported for drug delivery, as indeed is the use of polymers in formulation of drug delivery systems.
• the polymer may be water-soluble.
• the physical and chemical properties of the polymers typically used in polymer-drug conjugates are specially synthesized to flow through the kidneys and liver without getting filtered out, allowing the drugs to be used more effectively.
• the polymer may be degraded e.g. through enzymes and acidity.
• Polymers may be synthesized to be sensitive to specific enzymes that are very apparent with diseased tissue. The drugs remain attached to the polymer and are not activated until the enzymes associated with the diseased tissue are present. This process significantly minimizes damage to healthy tissue.
• Any such polymer as is typically used in such drug delivery formulations or conjugates may be used to prepare a conjugate of a polymer with a GnRH antagonist according to the present invention.
• examples include but are not limited to poly(ethylene glycol) (PEG), N-(2- hydroxypropyl)methacrylamide (HPMA), and poly(lactide-co-glycolide) (PLGA) copolymers.
• the polymer of the conjugate may act, or serve, to inhibit passage of the antagonist across the blood brain barrier.
• the term "inhibit”, whether in this or any other context, includes reducing as well as preventing.
• GnRH antagonists include but not limited to peptide or polypeptide/protein-based antagonists and non-peptide small molecule organic compounds in a number of different chemical classes.
• a "small molecule" antagonist is defined herein as a non-peptide compound of size less than 2000 Da, more particularly less than 1500 or 1000 Da. Examples include relugolix, elagolix, spiroindoline derivatives and ASP 1707.
• a "peptide GnRH antagonist” is typically an analogue of the GnRH decapeptide, and may comprise one or more amino acid modifications and/or substitutions.
• a peptide GnRH antagonist may thus comprise a peptide chain, and may comprise one or more non-native or modified amino acids. Typically such an antagonist is 9 or 10 amino acids long, but may be shorter or longer.
• a number of such antagonists are known as described further below (e.g. degarelix, abarelix, ozarelix, cetrorelix, ganirelix).
• the antagonists may be long acting or short-acting.
• a "long acting" antagonist may be defined as having a prolonged duration of action when administered to a subject in a single dose, e.g. at least 7, 12, 14, 15, 20, 30, 40, or 60 days, or at least 2, 4, 6, or 8 months.
• Exemplary long acting antagonists include the peptide antagonists degarelix, abarelix and ozarelix.
• a “short acting" antagonist may have a duration of action of less than 7 days when administered to a subject in a single dose, more particularly less than, 6, 5, 4, 3, 2 days or 1 day.
• Exemplary short-acting GnRH antagonists include peptide antagonists such as cetrorelix and ganirelix, as well as non-peptide small molecule antagonists such as relugolix, elagolix, spiroindoline derivatives and ASP 1707.
• a prolonged duration of action may also be achieved by formulating the antagonist as a sustained release or "depot" preparation or conjugate, e.g. with a protein such as albumin or salts and esters of acid derivatives, according to principles and procedures known in the art.
• the term "subject" refers to any animal (e.g.
• a mammal including, but not limited to, humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment.
• the terms “subject” and “patient” are used interchangeably herein in reference to a human subject.
• non-human animals refers to all non-human animals including, but not limited to, vertebrates such as rodents, non-human primates, ovines, bovines, ruminants, lagomorphs, porcines, caprines, equines, canines, felines, aves, etc.
• sample is used in its broadest sense. In one sense, it is meant to include a specimen or culture obtained from any source, as well as biological and
• Biological samples may be obtained from animals (including humans) and encompass fluids, solids, tissues, and gases. Biological samples include blood products, such as plasma, serum and the like. Environmental samples include environmental material such as surface matter, soil, water, crystals and industrial samples. Such examples are not however to be construed as limiting the sample types applicable to the present invention.
• drug is meant to include any molecule, molecular complex, prodrug, or substance administered to an organism for diagnostic or therapeutic purposes, including medical imaging, monitoring, contraceptive, cosmetic, nutraceutical, pharmaceutical and prophylactic applications.
• drug is further meant to include any such molecule, molecular complex or substance that is chemically modified and/or operatively attached to a biologic or biocompatible structure.
• the term “purified” or “to purify” or “compositional purity” refers to the removal of components (e.g. contaminants) from a sample or the level of components (e.g.
• test compound and “candidate compound” refer to any chemical entity, pharmaceutical, drug, and the like that is a candidate for use to treat or prevent a disease, illness, sickness, or disorder of bodily function (e.g. cancer).
• Test compounds comprise both known and potential therapeutic compounds.
• a test compound can be determined to be therapeutic by screening using screening methods known in the art.
• peripheral GnRH or "inflammatory peripheral GnRH” mean that the subject has a GnRH level in the periphery of the body, that is outside the brain, which is elevated, or particularly elevated as compared with a reference subject does not have peripheral GnRH, or as compared to a normal reference peripheral GnRH (e.g. 0 to 160 pg/ml). Elevated peripheral levels of GnRH may be associated with inflammation or with an inflammatory condition (e.g. they may be indicative of an inflammatory condition, or may predispose to or cause or lead or contribute to an inflammatory condition), in particular with age-related inflammation, as part of the expected ageing process. Accordingly, increased levels of peripheral GnRH are proposed to be inflammatory (hence the use of the term "inflammatory peripheral GnRH").
• a subject with peripheral GnRH may have a low level systemic inflammation (that is a generalised
• the subject may be healthy. More particularly, such a subject may have a level of peripheral GnRH which is 160 pg/ml or above, e.g. in the plasma or serum.
• the GnRH may be secreted by immune cells, specifically peripheral immune cells, for example T-cells.
• the GnRH may act upon the T- cells in a cytokine-like way, stimulating T-cell proliferation and maturation.
• GnRH may also act on B cells.
• a GnRH antagonist may act to combat peripheral inflammation by inhibiting the action of GnRH on immune cells, e.g. T and/or B cells, e.g. by inhibiting the effect of GnRH on GnRH receptors on such cells.
• Chronic inflammation means an inflammation (e.g. an inflammatory condition) that is of persistent or prolonged duration in the body of a subject. Generally speaking this means an inflammatory response or condition of duration of 20, 25 or 30 days or more or 1 month or more, more particular of at least 2 or 3 months. Chronic inflammation leads to a progressive shift in the type of cells present at the site of inflammation. Chronic inflammation may occur as a result of persistent or prolonged injury or infection, prolonged exposure to toxic substances or by autoimmune responses or conditions. Chronic inflammation may be a factor in the development of a number of diseases or disorders, including particularly degenerative diseases, or diseases or conditions associated with loss of youthful function or ageing (e.g. as discussed above).
• Systemic inflammation is inflammation which is not confined to a particular tissue or site or location in the body. The inflammation may be generalised throughout the body. Systemic inflammation typically involves the endothelium and other organ systems.
• Low-level inflammation (which term is used herein as synonymous with “low-grade inflammation”) is characterised by a 2- to threefold increase in the systemic concentrations of cytokines such as TNF-alpha IL-6 and CRP, e.g. as measured in the plasma or serum. The increase may be relative to, or as compared with, normal concentrations or reference
• concentrations for example concentrations as determined in a particular reference cohort or population of subjects, e.g. young subjects (e.g. young adults) or healthy subjects, for example subjects who are not suffering from any disease or condition, including any inflammatory disease, or who do not have inflammation.
• the increase may also be relative to the level of concentration in a subject prior to development of the inflammation.
• Low- level inflammation may be observed in the absence of overt signs or symptoms of disease. Thus, low-level inflammation may be sub-clinical inflammation.
• a subject with low-level inflammation may not have a clinically diagnosed condition or disease, but may exhibit certain signs or symptoms of an inflammatory response or inflammatory condition. In other words, there may be signs or symptoms of the effect of inflammation in the body, but this may not yet have progressed to an overt or recognised disease.
• Low-level inflammation may be peripheral inflammation, that is more particularly inflammation associated with peripheral GnRH, as discussed above.
• Age-related inflammation is an inflammation, typically a chronic, particularly a chronic systemic inflammation which occurs with increasing age. Such inflammation may be observed above the age of 30, 35 or 40 but typically is seen in subjects aged 45, 50, 55 or 60 or more. In many cases this may be a low level inflammation.
• Cancer inflammation is inflammation that occurs in the context of cancer and may alternatively be defined as “cancer-associated inflammation”. Inflammation has been identified as a hallmark of cancer and may be necessary for tumorgenesis and maintenance of the cancer state. Cancer symptoms are associated with inflammation. Thus a subject with cancer may have or exhibit inflammation, which can be a low-level or peripheral inflammation as discussed above, and in particular a a chronic or systemic inflammation as discussed above.
• Long-term administration means that the GnRH antagonist is administered for a period of at least 12 weeks. This includes that the GnRH antagonist is administered such that it is effective over, or for, a period of at least 12 weeks and does not necessarily imply that the administration itself takes place for 12 weeks, for example if sustained release compositions or long acting antagonists are used. Thus, the subject is treated for a period of at least 12 weeks. In many cases, long-term administration is for at least 4, 5, 6, 7, 8, 9 months or more, or for at least 1, 2, 3, 5, 7 or 10 years, or more.
• a "biologic" drug or agent for example as typically used to treat an inflammatory disease such as rheumatoid arthritis, is any agent which is derived from, based on, or comprises a biological molecule. Typically, this may be an antibody, which term includes monoclonal and polyclonal antibodies, antibody fragments, and antibody derivatives such as e.g. chimeric humanised antibodies or single chain antibodies etc., or a another protein such as a receptor or receptor chain, domain or fragment.
• the present invention relates to screening, diagnosis, prognostic evaluation, and treatment or prevention of an inflammatory condition selected from age associated inflammation, chronic inflammation, and inflammatory diseases.
• the present invention relates to methods of treating inflammatory diseases (e.g., rheumatoid arthritis or spondyloarthritis) or patients with inflammatory peripheral GnRH with drugs that lower the effects of GnRH or GnRH inhibitors.
• hypothalamic-pituitary-gonadal (HPG) axis The stimulation of the hypothalamic-pituitary-gonadal (HPG) axis is related to systemic aging and lifespan. It has been shown that age-related hypothalamic changes occur
• GnRH pulse amplitude is increased and particularly erratic during the menopausal transition, when the risk for cardiovascular disease and osteoporosis is accelerated in females. Therefore, one may speculate that the pronounced rapid changes in GnRH and gonadotropin levels might be of particular importance in not only the pathogenesis of autoimmune diseases, where early menopause has been shown to be a risk factor, but also in the pathogenesis of cardiovascular disease and osteoporosis. This is also the time of the greatest and most erratic GnRH pulse amplitude as well as the greatest rate of unfavourable changes in lipid markers, and the greatest rate of bone mineral density loss in females.
• GnRH is transported in a unique hypothalamic portal system and is rapidly degraded after reaching the pituitary. It has been suggested that the isolated hypophyseal portal system may not only have evolved solely as a means to deliver hypothalamic peptides to the pituitary, but also as a way to prevent their delivery to extra-pituitary targets. This is in accordance with a detrimental inflammatory GnRH.
• TNF- a is acutely reduced by GnRH antagonists, as indicated in the AGRA study, does not show that GnRH antagonism is beneficial in rheumatoid arthritis or other inflammatory diseases using long term therapy.
• GnRH antagonism is beneficial in rheumatoid arthritis or other inflammatory diseases using long term therapy.
• a person skilled in the art would look for further data on the long term safety of GnRH antagonism in premenopausal females, postmenopausal females, and males. Degarelix, a depot GnRH antagonist, has only been tested in males over long term.
• Cetrorelix is actually contraindicated in postmenopausal females.
• the present disclosure in some embodiments, encompasses the long term use of GnRH antagonists in males, postmenopausal females, as well as premenopausal females.
• beneficial uses of medicines in rheumatoid arthritis over short term include high dose non-steroidal antiinflammatory drugs or high dose intravenous steroids. These are treatments that must not be used over long term due to serious side effects. Side effects of GnRH antagonist therapy are believed to be osteoporosis and cardiovascular disease.
• GnRH antagonists which inhibit oestrogen, are expected to reduce bone density and contribute to cardiovascular disease.
• the AGRA study showed some short term anti- inflammatory effects in rheumatoid arthritis.
• the long term data with Degarelix, Cetrorelix and Ganirelix treatment in patients shows surprising unlikely improvements in severely ill patients.
• the mean disease activity score of the AGRA patients was 5.0, whereas the mean Degarelix disease activity score was 7.3 (scale 1.3-8.8 , with higher numbers denoting greater disease activity); this supports a substantially greater disease activity in the Degarelix patients compared to patients in the AGRA study. Due to these baseline differences, the effects of Degarelix are surprising compared to the short term study.
• Cetrorelix is used to treat hormone-sensitive cancers of the prostate and breast, and some benign gynaecological disorders. In addition, it is used in assisted reproduction to inhibit premature LH surges. The drug blocks the action of GnRH upon the pituitary, thus rapidly suppressing the production and action of LH and FSH. Both Cetrorelix and Ganirelix are administered as 0.25mg daily s.c. injections. Degarelix is a depot monthly GnRH antagonist injection licensed for prostate cancer in males with a loading dose of 240mg, and 80mg monthly injections thereafter. The present disclosure provides different dosing schedules for patients with chronic inflammation.
• LH levels stay low throughout long term therapy.
• the present disclosure provides the unexpected result that rheumatoid arthritis patients and other subjects with an inflammatory condition can be treated safely with a GnRH antagonist over the long term.
• Experiments described herein provide an example of a patient (patient 6 in Example 1) who did not improve in the short term study of 5 days, but improved surprisingly with long term treatment.
• the definition of long term treatment is treatment over 12 weeks according to FDA guidelines (Guidance for Industry Rheumatoid Arthritis: Developing Drug Products for Treatment May 2013).
• the disclosure also shows that long term therapy is safe and effective in postmenopausal females (previously contraindicated), premenopausal females, and males, without contributing to increased cardiovascular disease or osteoporosis as demonstrated by bone scans, laboratory variables and blood pressure, sometimes in combination with individual titration to baseline or higher levels of oestradiol or testosterone.
• the disclosure further shows that stably low levels of LH contribute to continued improvements in rheumatoid arthritis.
• Rheumatoid arthritis may develop, flare, or subside during hormonal changes in the HPG axis; for example, during pregnancy, postpartum, menopause, or aromatase inhibition therapy.
• gonadal hormones of the HPG axis such as oestrogen and testosterone in rheumatoid arthritis; but the results have been inconclusive.
• Hypothalamic and pituitary hormones of the HPG axis control gonadal hormones.
• Gonadal hormones in both sexes are stimulated by pituitary LH and FSH.
• LH and FSH secretion are stimulated by the hypothalamic GnRH.
• GnRH, LH, and FSH have important physiological roles in both male and female reproduction. Therefore, these hormones may be involved in pathological processes in males as well as females.
• GnRH-antagonism produced sustained long term anti- inflammatory effects in rheumatoid arthritis patients. Further experiments demonstrated that GnRH antagonists can be used to lower the amount of cytokines such as TNF-a, IL- ⁇ , IL-10, and IL-2.
• embodiments of the present invention provide methods and uses of treating an autoimmune or inflammatory disease, comprising administering a GnRH antagonist to the subjects.
• the subjects are patients suffering rheumatoid arthritis. In some embodiments, subjects to be treated do not respond to methotrexate. In some embodiments, subjects to be treated do not respond to anti-TNF treatment. In some embodiments, the subjects to be treated do not respond to biologies as described above.
• subjects are women (e.g. postmenopausal women or women over age 40).
• women are treated with a GnRH antagonist at a specific point in the menstrual cycle (e.g. midcyle when LH and FSH levels reach a high point). While not limited to a particular mechanism, it is contemplated that such treatment prevents premenstrual flare ups of RA symptoms.
• subjects are men over age 40 (e.g. over age 50, 60, or
• the patient population is defined as negative for CCP antibodies. In some embodiments, the patient population is defined as DMARD and/or TNF non responders.
• GnRH antagonists find use in the treatment and prevention of systemic lupus erythematosus, nephritis including lupus nephritis, ankylosing spondylitis, multiple sclerosis, scleroderma, psoriasis, inflammatory bowel disease, osteoporosis (e.g. by increasing bone mineral density), and cardiovascular disease (e.g. by decreasing HBAlc, decreasing blood pressure, or increasing HDL levels).
• the risk of cardiovascular disease is estimated in a variety of ways by a number of prognostic indicators.
• the Framingham Risk Score is based on data obtained from the Framingham Heart Study and is used to estimate the 10-year cardiovascular risk of an individual.
• the Framingham Risk Score is a calculated estimated risk for developing fatal or non-fatal cardiovascular event based on a composite score based on a pre-existing risk factors, including: age, gender, systolic blood pressure level (+/- treatment), HDL cholesterol level, and smoker status.
• a patient's risk score gives an indication of the likely benefits of prevention and also can be a useful metric to determine the effects of treatments.
• the present invention is not limited to a particular GnRH antagonist or agent that alters the biological activity of GnRH.
• GnRH antagonist or agent that alters the biological activity of GnRH. Examples include, but are not limited to, cetrorelix, elagolix, ganirelix, abarelix, degarelix, detirelix, iturelix, ozarelix, prazarelix, ramorelix, teverelix, elagolix, relogolix, or ASP 1707.
• the present invention applies to any drug that prevents or inhibits GnRH receptor signaling.
• GnRH inhibitors GnRH vaccines such as GnRH -DT the GnRH decapeptide linked to diphtheria toxoid, selective immune cell GnRH receptor antagonists, anti-GnRH antibodies, monoclonal antibodies against GnRH, circulating GnRH receptor fusion proteins, spiroindoline derivatives as gonadotropin- releasing hormone receptor antagonists, non-peptide oral GnRH antagonists, kisspeptin antagonists, estrogen compounds, testosterone compounds, LH compounds or FSH compounds, hypothalamic hormones or neuropeptides.
• a suitable GnRH antagonist also prevents or inhibits GnRH receptor signaling.
• the antagonists may be used singly or in any combination.
• GnRH antagonists As mentioned above, a wide variety of different GnRH antagonists are known and have been described in the literature, including both peptide and nonpeptide antagonists, the latter including antagonists in a large and varied range of different chemical classes. With regard to non-peptide small molecule GnRH antagonists reference may be made to the reviews by Heitman and Ijzerman, 2008, Med. Res. Rev., 28 (6), 975-1011 and Zhu and Chen, 2004, Expert Opin. Ther. Patents, 14 (2), 187-199, which reviews and the reference documents cited therein are all incorporated herein by reference.
• GnRH antagonists Any of the GnRH antagonists known and described in the literature may be used.
• Known peptide antagonists include acetyl-P-[2-naphthyl]-D-Ala-D-p-chloro-Phe-P-[3-pyridyl]-D-Ala- Ser-Ne- [Nicotinoyl] -Lys-Ne- ⁇ Nicotinoyl] -D-Lys-Leu-Ne- [isopropyl] -Lys-Pro-D- Ala-NH 2 (Antide), acetyl D2Nal 1, D4ClPhe2, D3Pal3, Arg5, Dglu6 (AA) (also known as NalGlu), acetyl-D2NaI,D4CIPhe-D3Pal-Ser-Aph(Ac)-D-Aph(Ac)-Leu-Lys(lpr)
• GnRH antagonists useful in the present invention may have a binding affinity that parallels the antagonistic properties and can be linear or cyclized
• GnRH antagonists are also described in e.g. US 5,470,947, WO 89/01944; US 5,413,990; US 5,300,492; US 5,371,070, US 5,296,468; US 5,171,835; US 5,003,011; US 4,431,635; US 4,992,421; US 4,851,385; US 4,801,5; and US 4,689,396.
• the gonadotropin releasing hormone antagonist is a peptide, characterized by the structure: Ac-D-Nal-4-Cl-Phe-D-Pal-Ser-Tyr-D-Pal(N— O-Leu-Lys(iPr)- Pro-D-Ala-NH 2 , or in another embodiment comprising a structure of Ac-D-Nal-4-Cl-D-Phe-D- Pal-Ser-Tyr-D-Pal(CH2-COO-)-Leu-Lys(iPr)-Pro-Ala-NH 2 , or in another embodiment, Ac-Sar- 4-Cl-D-Phe-D-Nal-Ser-Tyr-D-Pal(Bzl)-Leu-Lys(iPr)-Pro-Ala-NH 2 or a pharmaceutically acceptable sale thereof.
• US 5,516,887 describes antarelix D-4CIPhe 2 , D3 Pal 3 , D-N e -carbamoyl Lys 6 , Ilys 8 , D-Ala 10 ]-GnRH.
• US 5,296,468 discloses the design and synthesis of a number of GnRH antagonists wherein the side chains of selected residues are reacted to create
• cyanoguanidino moieties some of which subsequently spontaneously convert to a desired heterocycle, e.g. a 3-amino-l,2,4-triazole(atz).
• cyanoguanidino moieties are built upon the omega-amino group in an amino acid side chain, such as lysine, ornithine, 4-amino
• GnRH antagonists having such significantly modified or unnatural amino acids in the 5- and 6-positions exhibit good biological potency, and those build upon Aph are generally considered to be particularly potent.
• Azaline B i.e. D-4ClPhe 2 , D-3 Pal 3 , 4Aph(atz) 5 , D- 4Aph(atz) 6 , ILys 8 , D-Ala 10 ]-GnRH.
• US 5,506,207 discloses GnRH antagonists with acylated, amino-substituted phenylalanine side chains of residues in the 5- and 6-positions; one such decapeptide is Acyline, D-4CIPen 2 , D-3 Pal 3 , 4Aph(Ac) 5 , D-4Aph(Ac) 6 , ILys 8 , D- Ala 10 ]-GnRH.
• Peptide antagonists generally may be subject to degradation in the GI tract and so tend to be administered parenterally, typically by injection, e.g. subcutaneously or intramuscularly.
• small molecule-peptide GnRH antagonists at least 14 different chemical classes of compounds have been reported. Many such antagonists have the advantage that they may be administered orally.
• the chemical classes include thieno[2,3-d]pyridin-4-one derivatives, quinolin-2-one derivatives, indole derivatives, pyrrolo [ 1 ,2-a]pyrimid-7-one derivatives, imidazolo[l,l-a] pyramidin-5-one derivatives, thieno[2,3-d]pyrimidin-2,4-dione derivatives, furamide derivatives, pyrimidin-2,4-dione derivatives, benzimidazole derivatives, 1,3,5-triazine- 2,4,6-trione derivatives, thiazolino[3,2-c] pyramidin-5,7-diones and oxazole derivatives thereof, tetrahydropyrido[4,3,d]pyrimidin-2,4-dione derivatives, tetrahydropyrrolo[3,2-c] pyridines, thieno[2,3-b]pyrolle derivatives, 3-pyrazinone, pyrid-2
• 1,3-dihydrobenzimidazole derivatives imidazo[l,2- ajpyridines, bicyclic pyrrolidines, qujnolines, imidazo[4,5-c]pyridines, benzimidazoles, benzoxazoles, benzothiazoles, quinazoline-2,4-diones, tricyclic pyrrolidines, 1,2,3,4-tetrahydro carbazoles.
• certain spiroindoline derivatives have been found to have GnRH antagonists activity. GnRH receptor antagonists have thus been described with a wide range of diverse chemical structures. Spiroindoline GnRH antagonists are described in WO2014166958 (Bayer), which is incorporated herein by reference. Representative examples of such
• spiroindoline compounds include compounds of the following Formula 1
• GnRH antagonists may be obtained commercially.
• Degarelix is marketed under the name Firmagon by Ferring. Ganirelix is described in US 5,767,082, and US 6,653,286 and is available from Merck/MSD.
• Cetrorelix is available from Merck Serono. Relugolix is available from Takeda.
• Elagolix is available from Abbvie/Neurocrine Biosciences Inc.
• ASP 1707, a benzimidazoylidene propane- 1 ,3-dione derivative and other propane- 1 ,3-dione derivatives are described in WO 2005/118556, US 8,076,367 and US 7,569,688.
• ASP1707 is available from Astellas.
• Spiroindoline derivatives are available from Bayer.
• a GnRH-DT vaccine is available from GSK.
• Various pyrazole and pyrrole compounds are available from AstraZeneca.
• a suitable 'GnRH antagonist' may be too large to cross the blood brain barrier (BBB).
• BBB blood brain barrier
• large antagonists may be provided by coupling or conjugating a GnRH receptor antagonist to a polymer, including particularly a polymer selected from a polypeptide, a polysaccharide, a polyethylene glycol or HPMA or a PLGA copolymer.
• the polypeptide may typically be a protein such as albumin, or the Fc part of an antibody.
• the polysaccharide may for example be a dextran etc.
• a non-BBB crossing GnRH antagonist may include pegylated GnRH inhibitors, or GnRH inhibitors fused to proteins such as albumin.
• any of the GnRH antagonists described above may be coupled to a polymer, including particularly peptide antagonists such as degoralix, cetrorelix or ganirelix, or small molecule non-peptide antagonists such as elagolix, relugolix, ASP1707, or a spiroindoline derivative.
• peptide antagonists such as degoralix, cetrorelix or ganirelix, or small molecule non-peptide antagonists such as elagolix, relugolix, ASP1707, or a spiroindoline derivative.
• conjugates represent a novel aspect of the present invention. Accordingly, in a further aspect the present invention provides a conjugate comprising a GnRH antagonist linked to a polymer, more particularly a polymer which serves (more particularly specifically serves) to inhibit passage of the GnRH antagonists across the BBB.
• a conjugate may be used for the treatment or prevention of any inflammatory condition, as defined and discussed above.
• the invention accordingly provides such a conjugate for use in therapy.
• the invention provides a pharmaceutical composition containing a conjugate of the invention as herein defined, together with at least one pharmaceutically acceptable carrier or excipient.
• GnRH conjugates may readily be prepared using well known procedures and reagents, as described in the art.
• a variety of different methods and reagents for linking peptides or non-peptide small organic molecules to polymers such as proteins or other polypeptides, polysaccharides or polyethylene glycol are available and would be known to the person skilled in this art.
• the GnRH antagonists may be linked directly or indirectly, e.g. via a spacer or linker group, to the polymer.
• the conjugates of the invention have particular utility in long term treatment of an inflammatory condition, but are not limited to such use. In a particular embodiment they have utility in the treatment of chronic inflammation, age-related inflammation or inflammatory peripheral GnRH.
• such conjugates are advantageous in that by not being able to cross the BBB, they do not act centrally (in other words they are inhibited from acting at central GnRH receptors, that is GnRH receptors on the pituitary). In this way undesirable side-effects may be avoided, and in particular side-effects comprising or involving inhibition of sex hormone (e.g. oestrogen or testosterone) production and/or action.
• sex hormone e.g. oestrogen or testosterone
• GnRH antagonists should only work centrally on pituitary gonadotropes.
• the present disclosure describes the treatment of inflammatory peripheral GnRH, that contributes to chronic
• GnRH inhibition is possible through drugs that lower the peripheral effects of GnRH without crossing the BBB.
• Such compounds would have to be larger than the currently available GnRH antagonists which do cross the BBB.
• Examples include, but are not limited to, a larger GnRH antagonist such as a GnRH antagonist attached to albumin, or a pergylated GnRH antagonist, which are producible by persons skilled in the art.
• the same may be applied to other hormones, peptides, or substances that are involved in the regulation of GnRH including, but not limited to, kisspeptin.
• the present invention further provides the use of a GnRH antagonist in the treatment of an autoimmune disease in a subject.
• the present invention is not limited to the treatment of a particular autoimmune or inflammatory disease.
• the disease is rheumatoid arthritis.
• inflammatory diseases include but are not limited to arthritis, inflammatory bowel disease, psoriatic arthritis, osteoarthritis, degenerative arthritis, polymyalgia rheumatic, ankylosing spondylitis, reactive arthritis, gout, pseudogout, inflammatory joint disease, systemic lupus erythematosus, polymyositis, and fibromyalgia.
• arthritis Additional types include achilles tendinitis, achondroplasia, acromegalic arthropathy, adhesive capsulitis, adult onset Still's disease, anserine bursitis, avascular necrosis, Behcet's syndrome, bicipital tendinitis, Blount's disease, brucellar spondylitis, bursitis, calcaneal bursitis, calcium pyrophosphate dihydrate deposition disease (CPPD), crystal deposition disease, Caplan's syndrome, carpal tunnel syndrome, chondrocalcinosis, chondromalacia patellae, chronic synovitis, chronic recurrent multifocal osteomyelitis, Churg-Strauss syndrome, Cogan's syndrome, corticosteroid- induced osteoporosis, costostemal syndrome, CREST syndrome, cryoglobulinemia, degenerative joint disease, dermatomyositis, diabetic finger sclerosis, diffuse idiopathic skeletal hyperosto
• mucopolysaccharidosis multicentric reticulohistiocytosis, multiple epiphyseal dysplasia, mycoplasmal arthritis, myofascial pain syndrome, neonatal lupus, neuropathic arthropathy, nodular panniculitis, ochronosis, olecranon bursitis, Osgood-Schlatter's disease, osteoarthritis, osteochondromatosis, osteogenesis imperfecta, osteomalacia, osteomyelitis, osteonecrosis, osteoporosis, overlap syndrome, pachydermoperiostosis Paget' s disease of bone, palindromic rheumatism, patello femoral pain syndrome, Pellegrini-Stieda syndrome, pigmented villonodular synovitis, piriformis syndrome, plantar fasciitis, polyarteritis nodos, Polymyalgia rheumatic, polymyositis, popliteal cyst
• the GnRH or gonadotropin antagonist is administered in combination with an additional treatment i.e. additional active agent (e.g. treatments or agents known to be useful or effective in the treatment of autoimmune or inflammatory disease such as rheumatoid arthritis).
• additional active agent may accordingly be a disease-modifying drug and in particular a disease-modifying drug for use in treating or preventing inflammation or an inflammatory condition as defined herein.
• diseases-modifying antirheumatic drugs e.g. leflunomide, methotrexate, sulfasalazine, hydroxychloroquine
• disease-modifying agents for use in treating multiple sclerosis e.g.
• Famprydine biologic agents
• biologic agents e.g. rituximab, infliximab, etanercept, adalimumab, golimumab, tofacitinib, anakinra, abatacept
• nonsteroidal anti-inflammatory drugs e.g. ibuprofen, celecoxib, ketoprofen, naproxen, piroxicam, diclofenac
• analgesics e.g. acetaminophen, tramadol
• steroids and glucocorticoids e.g. prednisone, methylprednisone
• therapies for osteoporosis such as Fosamax or Zolendronic acid.
• the invention also provides a GnRH antagonist for use in the treatment or prevention of an inflammatory condition in a subject, selected from an inflammatory disease, chronic inflammation, age-related information or inflammatory peripheral GnRH, wherein said GnRH antagonist is for co-administration to said subject together with a further active agent, and in particular wherein said further active agent is a disease-modifying drug, or a sex hormone or an agent which regulates sex hormone production and/or activity (e.g. an agent useful in sex hormone substitution therapy).
• a GnRH antagonist for use in the treatment or prevention of an inflammatory condition in a subject, selected from an inflammatory disease, chronic inflammation, age-related information or inflammatory peripheral GnRH, wherein said GnRH antagonist is for co-administration to said subject together with a further active agent, and in particular wherein said further active agent is a disease-modifying drug, or a sex hormone or an agent which regulates sex hormone production and/or activity (e.g. an agent useful in sex
• a sex hormone may be oestrogen or testosterone or an oestrogen or testosterone derivative.
• oestrogen or testosterone derivatives are widely described in the art and available commercially.
• agents useful in sex hormone substitution therapy are also well known in the art and widely available, and include for example LH or FSH or LH or FSH derivatives or analogues.
• the further active agent may be useful in, or effective for, the treatment of an inflammatory condition, e.g. an inflammatory disease including an inflammatory disease as defined herein.
• the further active agent may be as described above.
• the GnRH antagonist may be for long-term administration.
• kits or combined/combination products containing or comprising a GnRH antagonist and an additional active agent.
• kits or combined/combination products are for use in treating or preventing an inflammatory condition as defined herein.
• the GnRH antagonist and additional active agent may be formulated for administration together, e.g. in a single pharmaceutical composition, or they may be formulated for separate, e.g. sequential or simultaneous, or substantially simultaneous, administration.
• the kit or combined/combination product may comprise separate containers, each containing a GnRH antagonist and a further active agent.
• the GnRH antagonist and the additional active agent may be administered by the same route or by different routes.
• the GnRH antagonist may be administered parenterally, e.g. by injection (e.g. subcutaneous or intramuscular injection) and the additional active agent may be administered orally.
• both the components may be administered orally, or both may be administered parenterally e.g. by injection.
• the invention provides a product (e.g. a kit) comprising a GnRH antagonist and an additional active agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of an inflammatory condition in a subject, selected from an inflammatory disease, chronic inflammation, age-related inflammation or inflammatory peripheral GnRH, wherein said additional agent is useful in the treatment of said inflammatory condition.
• a product e.g. a kit
• an additional active agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of an inflammatory condition in a subject, selected from an inflammatory disease, chronic inflammation, age-related inflammation or inflammatory peripheral GnRH, wherein said additional agent is useful in the treatment of said inflammatory condition.
• said GnRH antagonist and additional active agent are for long-term administration to said subject for a period of at least 12 weeks.
• GnRH antagonists when administered with an additional active agent may exhibit synergy. There may be an additional, e.g. greater than cumulative, effect when the additional active agent is co-administered with a GnRH antagonist. In other embodiments, the clinical benefit experienced by the subject may be improved or augmented in any way, when the GnRH antagonist is co-administered with the additional active agent. Synergistic combinations of a GnRH antagonist and an additional active agent represent one preferred embodiment of the invention.
• the additional agent can be an agent effective in treating arthritis (e.g. TNF-a inhibitors such as anti-TNF a monoclonal antibodies (such as REMICADE®, CDP-870 and HUMIRATM (adalimumab) and TNF receptor- immunoglobulin fusion molecules (such as ENBREL®)(entanercept), IL-1 inhibitors, receptor antagonists or soluble IL-1R a (e.g. TNF-a inhibitors such as anti-TNF a monoclonal antibodies (such as REMICADE®, CDP-870 and HUMIRATM (adalimumab) and TNF receptor- immunoglobulin fusion molecules (such as ENBREL®)(entanercept), IL-1 inhibitors, receptor antagonists or soluble IL-1R a (e.g.
• TNF-a inhibitors such as anti-TNF a monoclonal antibodies (such as REMICADE®, CDP-870 and HUMIRATM (adalimumab) and TNF
• KJNERETTM or ICE inhibitors nonsteroidal antiinflammatory agents
• NSAIDS nonsteroidal antiinflammatory agents
• piroxicam diclofenac, naproxen, flurbiprofen, fenoprofen, ketoprofen ibuprofen, fenamates, mefenamic acid, indomethacin, sulindac, apazone,
• COX-2 inhibitors such as CELEBREX® (celecoxib), VIOXX® (rofecoxib), BEXTRA® (valdecoxib) and etoricoxib, (preferably MMP-13 selective inhibitors), NEUROTIN®, pregabalin, sulfasalazine, low dose methotrexate, leflunomide, hydroxychloroquine, d-penicillamine, auranofm, parenteral or oral gold), rituximab, roactemera, or orencia.
• the additional agents to be co-administered can be any of the well-known agents in the art, including, but not limited to, those that are currently in clinical use.
• the GnRH antagonist is administered in combination with hormone substitution therapy (e.g. testosterone, such as Testogel 50mg every 1-5 days, oestrogen, such as Activelle lmg/0.5mg every 1-5 days, luteinizing hormone, such as 75IE lutropin alfa daily, or every 2-5 days, or follicle stimulating hormone, such as 75-150IE follitropin alfa daily, or every 2-5 days.
• hormone substitution therapy e.g. testosterone, such as Testogel 50mg every 1-5 days, oestrogen, such as Activelle lmg/0.5mg every 1-5 days, luteinizing hormone, such as 75IE lutropin alfa daily, or every 2-5 days, or follicle stimulating hormone, such as 75-150IE follitropin alfa daily, or every 2-5 days.
• the patients receive oestrogen or testosterone supplement daily or every 2-6 days or weekly, in addition to GnRH antagonist.
• the physician titrates the dose of oestrogen or testosterone to the patient's baseline or higher levels.
• the dose of the sex hormone or other agent is titrated to achieve a desired or selected oestrogen or testosterone level in the subject, for example a level which is substantially equal to or higher than a baseline level, or in some cases lower than a baseline level.
• a baseline level may be the level of the subject prior to administration of the GnRH antagonist, or it may be a reference baseline level, for example a level of oestrogen or testosterone which is a normal level or which is a typical level for that subject (e.g. an age- and/or sex-matched subject or a healthy subject of the appropriate gender).
• An appropriate or desired level may be selected according to need or circumstance, for example based on the age, sex and/or clinical condition of the patient. Thus, for example, as a patient ages a lower level may be appropriate, particularly over a long course of treatment over many years.
• the desired or appropriate level may change.
• the GnRH antagonist is continually administered, or given as a vaccination with booster doses, or administered in one or more repeated doses (e.g. up to 6 times daily, e.g. 2, 3 or 4 to 6 times daily, daily, weekly, monthly, or other interval) for a period of time (e.g. at least three months, at least 6 months, at least 9 month, at least 12 months or longer).
• a period of time e.g. at least three months, at least 6 months, at least 9 month, at least 12 months or longer.
• the GnRH antagonist may be administered for at least 1, 2, 3, 5, 6, 7, 8, 9, 10 or 20 years or longer.
• short acting or long acting formulations are utilized.
• the GnRH antagonist may be administered by any convenient or desired route, including both parenterally or enterally.
• the GnRH antagonist is administered subcutaneously, intramuscularly, intravenously, dermally, orally, infusion pump, or
• GnRH antagonists are administered up to 6 times daily or weekly or every 2-4 week intervals, or monthly intervals or every 2-6 month intervals, or yearly, 0.1 mg to 3000 mg, e.g. 10 mg to 1000 mg. In some embodiments with an initial loading dose between 20 mg to lOOOmg.
• a long acting GnRH antagonist e.g Degarelix, Ozarelix or
• Abarelix is administered weekly, or every 2-4 week intervals, or monthly intervals or every 2-6 month intervals, or yearly, lOmg to lOOOmg. In some embodiments, with an initial loading dose of the long acting GnRH antagonist between 20mg to lOOOmg.
• a long-acting antagonist (which may be a long-acting peptide antagonist, e.g. degarelix, or a sustained release preparation of a GnRH antagonist) is administered at an initial loading dose of 20 to 100 mg, followed by a maintenance dose of 40- lOOOmg every 10-14 days, e.g. every 2 weeks.
• the maintenance dose may be 60- 1000, 80-1000, 100-1000, 60-800, 60-500, 80-800, 80-500, 100-800, 100-500, 80-400, 80-320, 60-400, 60-320, 60-160, 80-160, 60-150, 80-150 mg or any range between any of the above- mentioned integers.
• maintenance dose may be administered every 5 to 10 days, e.g. every 7 days or every week.
• the maintenance dose may be in the range as indicated above or may be 30-1000, 30-800, 30-500, 30-400, 30-320, 30-320, 30-200, 30-150mg, or it may be 40 or 50mg to any one of 1000, 800, 500, 400, 320, 300, 250, 200, 180, 160 or 150 mg.
• short acting GnRH antagonists e.g. peptide antagonists such as Cetrorelix or Ganirelix are administered up to 6 times daily (e.g. 2, 3 or 4 to 6 times daily) or daily or 2-6 times weekly or weekly or every 2-4 weeks, e.g. at a dose of 0.
• the antagonist may be administered at a dose of any one of 0.1 , 0.5, 0.75, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or lOmg to any one of 20, 30, 40, 50, 60, 70, 80, 90 or 100 mg.
• an oral GnRH antagonist such as nonpeptide oral GnRH antagonists, spiroindoline derivatives as GnRH antagonists, Relugolix, Elagolix, or ASP 1707 is administered up to 6 times daily (e.g. 2, 3 or 4 to 6 times daily), or daily, or 2-6 times weekly or weekly, e.g at a dose of O. lmg to 3g.
• Elagolix may be administered at a dose of lOto 2000 mg/day, e.g. 200 to
• Relugolix may be administered at a dose of 10 to 1000 mg/day, e.g. a 20-100, 50-200, 100-500, 500-1000 mg/day, e.g.400 mg/day.
• ASP1707 may be administered at a dose of 0.5-50 mg/day, e.g. 1-20, 1-15, 1-10, 2-10, 3-
• a spiroindoline derivative may be administered at a dose of 0.1 to 1000 mg/day, e.g. 0.1 to 10, 0.5 to 150, 150 to 500, 550 to 750 e.g. 200 mg/day.
• GnRH antagonist may be administered at a higher dose than is presently proposed for uses of GnRH antagonists in the art, particularly where such
• antagonists are used for treating hormone-related problems, e.g. prostate cancer, fibroids or endometriosis, or for fertility treatment.
• hormone-related problems e.g. prostate cancer, fibroids or endometriosis, or for fertility treatment.
• doses or concentrations may be 3 or 4 times higher than typical, conventional or normal doses or concentrations, e.g. doses or concentrations for such treatments.
• the GnRH antagonists are proposed according to the invention described above for administration on a long-term basis, that is for at least 12 weeks.
• 'healthy' people or 'unhealthy' people are identified with increased levels of peripheral GnRH using ELISA GnRH detection kits, PET scans for the detection of GnRH activity, tissue staining, or otherwise i.e. screened, diagnosed, or
• peripheral GnRH a drug to lower the effects of peripheral GnRH.
• the detrimental effects of peripherally detectable GnRH are expected to decrease with treatment which decreases the effects of GnRH over time. It may be necessary to individually titrate levels of altered downstream hormones, for example oestrogen or testosterone.
• the detection of peripheral GnRH will be positively associated with the amount of systemic inflammation or the rate of increase of systemic inflammation. This is a method for the prognostic evaluation for disease(s) caused by inflammation.
• GnRH is thought to be only detectable in the brain. GnRH is rapidly degraded after reaching the pituitary. It has been suggested that the isolated hypophyseal portal system may not only have evolved solely as a means to deliver hypothalamic peptides such as GnRH to the pituitary, but also as a way to prevent their delivery to extra-pituitary targets resulting in unfavorable outcomes, such as systemic inflammation or age associated inflammation. Through the detection of GnRH activity outside the brain, people can be screened, diagnosed, evaluated, and treated for age associated inflammation, chronic inflammation or inflammatory diseases.
• the present invention in a further aspect provides a GnRH antagonist for use in the treatment or prevention of peripheral inflammation, or systemic inflammation, or chronic low level inflammation (particularly chronic systemic low level inflammation), including age-related inflammation (e.g. low level age-related inflammation).
• a GnRH antagonist for use in the treatment or prevention of peripheral inflammation, or systemic inflammation, or chronic low level inflammation (particularly chronic systemic low level inflammation), including age-related inflammation (e.g. low level age-related inflammation).
• the invention provides a GnRH antagonist for use in the treatment or prevention of inflammatory peripheral GnRH. More particularly, the subject has a peripheral GnRH level of 160pg/ml or more, e.g. as measured in plasma or serum. In other embodiments, the subject may have a peripheral GnRH level of at least 120% of the concentration of healthy control subject(s), 100, 200, 320, 350, 370, 380, 400, 420, 450, 470, 480 or 500 pg/ml or more.
• the GnRH antagonist is preferably administered long term for at least 12 weeks.
• Peripheral GnRH may be measured or determined in a sample of any body tissue or fluid taken from the subject at or from a site or location outside of the brain (i.e. from the periphery of the body). Conveniently, the GnRH may be determined in a blood or a blood-derived sample, particularly serum or plasma, but this can be in any other blood-derived preparation. Other representative samples include vascular tissue and synovial fluid. The GnRH may be determined or measured by any method or technique known in the art. Conveniently an immunoassay may be used.
• an immunoassay may be performed using an antibody (or antibody fragment or antibody derivative etc.) which binds specifically to GnRH, and the binding of the antibody to GnRH is detected or determined, e.g. an ELISA, and kits for performing such assays are commercially available.
• GnRH may be detected with histochemical and/or histological techniques e.g. immunohistochemical techniques.
• peripheral GnRH may be determined by assays or methods carried out in in vivo on the body, e.g. by imaging techniques.
• a PET scan may be performed for GnRH activity, e.g. using a GnRH antagonist radio labelled with positron emitting nuclides for visualising GnRH receptors.
• the subject may be a subject who does not have or exhibit any signs or symptoms of an inflammatory disease. Accordingly, in particular embodiments the subject may have a sub-clinical inflammatory condition, or may be without overt symptoms of disease, or overt clinical symptoms of disease, or may be healthy. Thus, as noted above, the subject may have normal blood pressure, and/or normal cholesterol, and/or normal high sensitivity CRP, and/or normal blood lipids (e.g. triglycerides) etc. The subject may have a normal weight, or normal BMI parameters. In other embodiments the subject may be overweight or obese or have increased BMI parameters etc. In other embodiments, the subject may, as noted above, have low level inflammation, or chronic systemic inflammation, or age- related inflammation.
• a sub-clinical inflammatory condition or may be without overt symptoms of disease, or overt clinical symptoms of disease, or may be healthy.
• the subject may have normal blood pressure, and/or normal cholesterol, and/or normal high sensitivity CRP, and/or normal blood lipids (e.
• the treatment of inflammatory peripheral GnRH, or indeed any inflammatory condition, may involve a combination therapy as discussed above, and in particular a combination therapy with a sex hormone or other agent effective for hormone substitution therapy, and in particular the sex hormone or other agent may be titrated to baseline level or higher, as described above.
• a method of the invention may accordingly involve determining a level of peripheral GnRH in a subject, and if said level is higher than that of a young healthy adult or 160pg/ml or above, administering a GnRH antagonist.
• the step of determining the peripheral GnRH level may involve monitoring the peripheral GnRH level in a subject over a period of time, e.g. over 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 18, 20 weeks or more, for example over 1, 2, 3, 4, 5, 6, 7, 8, 9 months or more, or 1, 2 or 3 years or more.
• the GnRH antagonist may be administered to a subject in whom the level of peripheral GnRH has been determined, in particular pre-determined, and in particular in a subject who has been monitored for peripheral GnRH levels.
• the uses of the invention may thus combine a step of determining or screening for peripheral GnRH levels and a step of administering a GnRH antagonist if the peripheral GnRH level exceeds a particular threshold or cut-off value (e.g. of 1600pg/ml).
• the invention provides a method for detecting or determining an inflammatory condition in a subject, said method comprising determining the level of peripheral GnRH in said subject.
• a method may, as discussed above, be performed on a sample of a body tissue or fluid e.g. serum or plasma.
• an in vivo method e.g. imaging or scanning may be used.
• the presence of an inflammatory condition is detected or determined if said level of peripheral GnRH is 160 pg/ml or more.
• the subject may have low- level inflammation, or chronic systemic inflammation, or age-related inflammation.
• the subject may be healthy or may have no signs or symptoms of an inflammatory disorder, as discussed above.
• the invention also provides an agent capable of disclosing GnRH level and/or activity for detecting or determining in vivo an inflammatory condition in a subject
• the invention may provide a diagnostic method or use practiced on the body of the subject, i.e, agent for use in diagnosing an inflammatory condition in a subject.
• agent may be a GnRH antgonist, or a molecule capable of binding to the GnRH receptor or to GnRH (e.g. an affinity binding partner for GnRH or for the GnRH receptor, such as antibody or fragment or derivative thereof), which antagonist or molecule is provided with a label, particularly a detectable label, e.g. a radiolabel or positron-emitting nuclide or some other signal-giving label.
• a detectable label e.g. a radiolabel or positron-emitting nuclide or some other signal-giving label.
• Example 1 is provided in order to demonstrate and further illustrate certain preferred embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof.
• Example 1 is provided in order to demonstrate and further illustrate certain preferred embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof.
• ESR erythrocyte sedimentation rate
• CRP C-reactive protein
• CK creatinine kinase
• Hb Hemoglobin
• LH luteinizing hormone
• FSH follicle-stimulating hormone
• CCP cyclic citrullinated peptide
• HbAlC glycated hemoglobin: ACTH, adrenocorticotrophic hormone
• the figures show differences before and after treatment with Degarelix. Patients have not increased their concomittant stable medications, and they have not intraarticular, intramuscular or intravenous cortisone therapy.
• FIGS 1A, IB and 1C show images of arthritis in the foot of patient 1 before and during treatment with Degarelix.
• Figure 2 shows ultrasound pictures of patient 5.
• Figure 2A shows white area highlighted by arrow, is power Doppler denoting inflammatory activity in shoulder.
• Figure 2 B shows no power Doppler in same shoulder.
• Figure 2C shows white area highlighted by arrow, is power
• FIG. 2D shows no power Doppler in right MCP4 joint.
• Figure 2 E shows white area highlighted by arrow, is power Doppler denoting inflammatory activity in right MCP 4 (finger joint) left side.
• Figure 2 F shows no power Doppler in MCP 4 left side, and decreased joint fluid (oval).
• Figure 3 shows patient 6 before and after Degarelix treatment.
• Figure 4 shows ultrasounds of patient 6.
• the first ultrasound shows a large effusion (swelling indicated by black area) over the right wrist.
• the second ultrasound shows the same area by 3.5 weeks.
• the effusion on the right is much smaller, and no longer painful.
• She halved her long term stable prednisolone dose from lOmg til 5 mg within days of the first Degarelix injection (without informing the physician).
• She has reduced two shoe sizes, bought new shoes, and also halved her morphine and diuretic intake ('Oxycodone/Oxynorm' and 'Butemanide/Burinex' tablets).
• FIGS 5A-F shows disease activity variables of Patient 2 whilst being treated with degarelix.
• This example described the treatment of Lupus with a GnRH antagonist.
• the patient has a medical history of a multimorbid patient.
• Systemic lupus erythematosus (SLE) was diagnosed in 1988 based on Raynauds, skin changes, arthralgia, high titre lupus anticoagulant, ANA, SSA, and SSB.
• Chilblain type changes in hands and feet ( Figures 6-8).
• He has previously tried methotrexate, azathioprine, and mycophenolate mofetil, which were not effective in reducing the pain in his extremities, and gave intolerable side effects such as mouth ulcers.
• He has had a pacemaker since 1986, AV block II.
• the patient had kidney failure since 2012, required dialysis, stabilized creatinine around 150, osteoporosis, COPD, and is a smoker.
• the patient has had severe pain in his hands and feet for the last 10 years, especially under the soles of his feet. Has had continuous small ulcerations on his toes and hands, and pigmented skin. This pain was debilitating, and reduced his daily function. He walked with difficulty, and had atrophic musculature in both his lower extremities. He had ataxi in his lower extremities, especially left side, and minimal patellar and achilles reflexes. He was unbalanced, experienced numbness, and parasthesias, all documented in his medical journal from the neurology outpatients clinic April 2014. His electromyography findings from 2010 support a diagnosis of thin fiber neuropathy related to lupus. Due to his painful condition, he has been followed up by a pain clinic.
• amitriptyline 25mg in March 2014 for his painful condition. This had no effect on his pain.
• the amitriptyline was increased to 50mg with no effect. This was soon after increased to 150mg daily with no effect.
• GnRH antagonists have shown anti-inflammatory effects and therefore we considered that degarelix, a depot GnRH antagonist, may have a therapeutic effect in lupus.
• the example describes the treatment of ankylosing spondylitis with a GnRH antagonist.
• BASDAI Breast Ankylosing Spondylitis Disease Activity Indexl
• BASDAl 50% improvement is defined as a major clinical response. He has also achieved an ASAS 80 (Ankylosing Spondylitis Assessment Group of at least 80% improvement) response. For comparison, approximately 50-60% of patients achieve a BASDAl 50 by 12 weeks on TNF inhibitors (4). His ESR has decreased from 46mm to 23mm, which is his lowest ESR reading in 19 years.
• This example describes improvement in bone mineral density in patients taking a GnRH antagonist.
• Bone mineral density was measured in Patients 1 and 2 (See Example 1 for patient information).
• Figure 9 shows that patient 1 shows an improvement in her bone mineral density in her hips for the first time in 3.5 years. She was not taking any therapies for osteoporosis during this period. This was unexpected as the summary of product characteristics states that a decrease in bone mineral density is expected under GnRH antagonist treatment. However, our data indicates the opposite. Despite having low oestrogen, using concomitant prednisolone and longstanding rheumatoid arthritis (all of which are independent risk factors for osteoporosis), her bone mineral density improved during GnRH antagonist treatment.
• Figure 10 shows an improvement in her bone mineral density in the hips of patient 2 for the first time in 4.5 years. This was unexpected as the summary of product characteristics states that a decrease in bone mineral density is expected under GnRH antagonist treatment. Despite using having low oestrogen, using concomitant prednisolone and longstanding rheumatoid arthritis (all of which are independent risk factors for osteoporosis), her bone mineral density improved during GnRH antagonist treatment.
• diabetes may occur, therefore diabetic patients may require more frequent monitoring of blood glucose ⁇ and therefore HBAlc) when receiving androgen deprivation therapy.
• Cardiovascular disease such as stroke and myocardial infarction has been reported in the medical literature in patients with androgen deprivation therapy. Therefore, all
• cardiovascular risk factors should be taken into account.
• HBAlc contributes to CVD (normal reference range 4.3-6.1%) At baseline 6.4%, high.
• HBAlc had normalized to 6.1%. This continues to be normal, and at 8 months is 5.7%.
• Her fasting glucose was 6.6mmol/L in September 2014, by October 2014 this was reduced to 6.3mmol/L.
• High blood pressure contributes to CVD at baseline 151/90 (measured at several times prior to baseline with repeatedly high blood pressure). Blood pressure by 6 months 120/71, and this continues to be normal. At her last check up at 8 months, her blood pressure was 118/78.
• High HBAlc contributes to CVD (normal reference range 4.3-6.1%).
• HBAlc was 6.9%>, high.
• His hospital records from a nearby hospital stated that his fasting glucose was high at 8.5mmol/l (reference range 4.0- 6.0) in December 2013, and by April 2014 this was higher at 8.9. They asked the patient's family doctor to initiate treatment due to the development of diabetes type II. His fasting glucose had reduced to 6.6mmol/l by 3 months after starting Degarelix, and by 4 months has now normalised to 6.0 mmol/L. No other abnormalities baseline for assessment
• Low HDL contributes to CVD (normal reference range 1.0-2.7mmol/L).
• Mora et al investigated the link between cholesterol and cardiovascular events in women and found baseline HDL level was consistently and inversely associated with incident coronary and CVD events.- A low HDL cholesterol level is thought to accelerate the development of atherosclerosis because of impaired reverse cholesterol transport and possibly because of the absence of other protective effects of HDL, such as decreased oxidation of other lipoproteins.
• HBA1C blood pressure, lipids
• the assessment of disease activity presents challenges to clinicians.
• Fecal calprotectin has been shown to be useful in the diagnosis of IBD, correlates with mucosal disease activity, and can help to predict response to treatment or relapse. Fecal calprotectin levels are elevated in patients with both Crohn's disease and ulcerative colitis 1-2. There have been several studies looking at the use of fecal calprotectin to predict or monitor response to treatment, o In a study looking at 11 patients with relapsing IBD, fecal calprotectin was
• infliximab infusion (anti-tumour necrosis factor-a)8.
• a level of ⁇ 50mg/kg is considered normal or remission
• This patient gave three fecal samples in total.
• the Mayo non-invasive colitis assessment of response score can be used to assess treatment effect of IBD in clinical trials9-l 1. This score has been shown to correlate well with the total Mayo score 12. Both the partial Mayo and total Mayo score are used to assess disease activity in clinical trialsl3. The partial Mayo score also had good discriminatory value between subjects in remission and those with active disease 14. A clinical response has been defined as a 3 point or greater change in the partial Mayo scorel5.
• This patient had a partial Mayo score of 3 at baseline; and 0 at 12 weeks. A score of 0 is clinical remission. This is supported by his high fecal calprotectin score around baseline, reduced fecal calprotectin level at 4 weeks and further reduced calprotectin level by 12 weeks.
• This example demonstrates GnRH antagonist treatment in a patient with colitis improved his disease activity, as well as normalizing his fecal calprotectin levels.
• GnRH antagonists are beneficial in IBD's in general.
• Psoriasis Area Severity Index (PASI 1) score of 53.6.
• the PASI score is a standardized score for assessing disease activity in psoriasis.
• Testogel containing 50mg of testosterone, first daily; thereafter every 3 days to maintain testosterone levels within the normal range.
• his testosterone levels were normalized at 9nmol/L (under testosterone substitution and a GnRH antagonist.
• This patient had a serum uric acid (reference range 230-480umol/L) of 485 umol/L at baseline; and this was normalized by 8 weeks at a level of 432umol/L.
• Lithium induced psoriasis is particularly resistant to therapy. There are very few trials of lithium induced psoriasis. One trial examined 15 patients with psoriasis who were taking lithium. Their psoriasis was mild, with a median pretreatment PASI score of 4.9. After 10 weeks of inositol therapy, their median PASI score was reduced by 1.7 points, or by 35% 4.
• This example demonstrates improved signs and symptoms in a patient with psoriasis treated with a GnRH antagonist treatment.
• This example also demonstrates the effective combination of a GnRH antagonist with gonadal hormone replacement, in this case testosterone replacement, in an inflammatory disease.
• This example demonstrates improved signs and symptoms in a patient with systemic sclerosis treated with a GnRH antagonist.
• DAS Disease activity score
• a DAS reduction of 0.6 units is defined as a clinical response to treatment.
• Her rheumatoid factor level has also decreased from 137kIU/L to 111 klU/L.
• BASDAl Breast Ankylosing Spondylitis Disease Activity Index 1
• BASDAl Basal Ankylosing Spondylitis Disease Activity Index 1
• This is a composite index that evaluates fatigue, axial and peripheral pain, stiffness and enthesopathy.
• His BASDAl was at 3.8 at baseline.
• Degarelix 240mg sc In October 2014 he received his first dose of Degarelix 240mg sc.
• his BASDAl had reduced to 2.9, and by 8 weeks it had reduced to 1.3, remission.
• his BASDAl continues to be low at 1.5.
• This example demonstrates improved signs and symptoms in a patient with spondyloarthritis treated with a GnRH antagonist.
• MS multiple sclerosis
• help/physiotherapist's help to perform these activities She climbed onto a step unaided at her 6 week checkup. The improvement started at around 4 weeks after the initiation of therapy, and continued to improve further by 6 weeks.
• Patient-reported outcomes are of increasing importance in trials of progressive multiple sclerosis. 2 The most frequently used global patient-reported outcome in multiple sclerosis is the MSIS-29. 3 This has been correlated with clinical and imaging metrics specifically in progressive forms of the disease. 4 According to a recent review, 2 patient reported outcomes in trials of progressive multiple sclerosis can be used to validate MRI or clinical metrics, and increased use of patient-reported outcomes in trials of progressive multiple sclerosis will expected to help satisfy regulators' requirements that treatments show relevant benefit for patients. • At baseline, she scored 121 on the MSIS-29. By 6 weeks, her score was reduced to 110. A clinically significant minimal difference is a score change of 8. Therefore this reduction of 11 in her score is considered clinically significant. 5
• MSWS-12 Multiple Sclerosis Walking Scale -12
• the MSWS-12 6 was designed as a disease-specific patient-based instrument for use in clinical trials and clinical practice, to capture the complex impact of MS on walking ability.
• the MSWS-12 has been extensively evaluated in MS, with demonstration of internal consistency, high reliability and validity, and good generalizability. 7 ' 8
• the MSWS-12 was shown to be more responsive than other walking based measures, including the EDSS and the timed 25 foot walk (T25FW).
• the MFIS-5 is a modified form of the Fatigue Impact Scale 10 based on items derived from interviews with MS patients concerning how fatigue impacts their lives. This instrument provides an assessment of the effects of fatigue in terms of physical, cognitive, and psychosocial functioning.
• T25FW is another common endpoint in trials. At baseline, she used 16.7 seconds to walk 25 feet, and by 6 weeks she used 15.2 seconds. This improvement in walking speed supports the patient's reported improved outcomes.
• Examples 13 and 14 describe the treatment of RA using particularly different dosing schedules.
• DAS Disease activity score
• ⁇ A DAS reduction of 0.6 units is defined as a clinical response to treatment (1).
• Her ESR has decreased from 62mm to 38mm, with a decrease in her CRP from 87 mg/L to 67mg/L.
• DAS Disease activity score
• a DAS reduction of 0.6 units is defined as a clinical response to treatment (1).
• Her ESR decreased from 28mm to 19mm, with a normalization of her CRP from
• her anti-cyclic citrullinated peptide (CCP) antibodies from 27u/mL. to 14 u/mL.
• Her rheumatoid factor level has also decreased from 113 klU/L to 75 klU/L.
• DAS Disease activity score
• ⁇ A DAS reduction of 0.6 units is defined as a clinical response to treatment (1).
• DAS Disease activity score
• a DAS reduction of 0.6 units is defined as a clinical response to treatment (1).
• Relugolix a GnRH antagonist, improves signs and symptoms in a patient with rheumatoid arthritis.
• DAS Disease activity score
• a DAS reduction of 0.6 units is defined as a clinical response to treatment (1).
• This example demonstrates how ASP 1707, a GnRH antagonist, improves signs and symptoms in a patient with rheumatoid arthritis shown with international response criteria.
• a randomized controlled trial is carried out to ascertain whether inhibiting the effects of GnRH reduces fracture rates, vascular events, myocardial infarctions, and all-cause mortality, with or without gonadal hormone replacement.
• GnRH GnRH
• 160pg/mL are allocated to three groups: to either daily oral 5500mg Elagolix, oral 5500mg Elagolix combined with oestrogen (for example, Activelle lmg/0.5mg women or the amount required to titrate to age/sex pre-chosen levels) or testosterone (for example, Testogel 50mg every 2-3 days for men or the amount required to titrate to age/sex pre-chosen levels) or placebo.
• oestrogen for example, Activelle lmg/0.5mg women or the amount required to titrate to age/sex pre-chosen levels
• testosterone for example, Testogel 50mg every 2-3 days for men or the amount required to titrate to age/sex pre-chosen levels
• Additional analyses include evaluations of total mortality; the number needed to treat (NNT) to prevent 1 vascular event; whether any observed effect is attributable to LDL reduction, to CRP reduction, or to a combination of both lipid- lowering and antiinflammatory effects.
• mice An animal study is conducted with 40 fertile female mice aged approximately 6-20 months in a control group (group 1) receiving placebo, 40 age and sex matched mice receiving a drug that reduces the activity of GnRH (group 2), such as Cetrorelix 0.5mg/kg daily, and 40 age and sex matched mice receiving the same GnRH inhibitor as group 2, but with the additional replacement of gonadal hormone (oestrogen) to age adjusted pre-chosen levels. All mice are followed prospectively, and evaluated for systemic inflammation markers, atherosclerosis, osteoporosis, LDL, and age at death.
• group 2 a drug that reduces the activity of GnRH
• group 2 such as Cetrorelix 0.5mg/kg daily
• oestrogen gonadal hormone
• mice Male mice with 40 male mice in each group, aged approximately 6-20 months, replacing the gonadal hormone testosterone to pre-chosen levels in group 3.
• Mice treated with a drug that reduces the activity of GnRH, such as Cetrorelix 0.5mg/kg daily with or without the replacement of gonadal hormone (preferably with) reach a higher age at death compared with mice in the placebo groups.
• These mice also show less atherosclerosis, osteoporosis and systemic inflammation than mice in the placebo groups.
• This example demonstrates how a drug to lower the effects of GnRH, such as Cetrorelix can be given to prevent and/or treat age related inflammation.
• GnRH Gonadotropin-releasing hormone
• PINP procollagen type 1 amino -terminal propeptide
• ⁇ In order to treat the secondary inflammation as a result of his knee osteoarthritis, he is offered intra-articular GnRH antagonist treatment, for example Cetrorelix lmg injected into both knees. Subcutaneous Cetrorelix for injection can be used.
• DAS Disease activity score
• a DAS reduction of 0.6 units is defined as a clinical response to treatment (1).
• This example demonstrates how spiroindoline derivatives as GnRH antagonists, can improve signs and symptoms in a patient with rheumatoid arthritis shown with international response criteria.
• DAS Disease activity score
• a DAS reduction of 0.6 units can be defined as a clinical response to treatment (1).
• This example demonstrates how ASP 1707, a GnRH antagonist, improves signs and symptoms in a patient with rheumatoid arthritis shown with international response criteria.
• This example shows that patients with inflammatory diseases may have higher peripheral GnRH levels than healthy controls, and this example shows how assessing peripheral levels of GnRH can be used to generally used to diagnose inflammatory diseases and evaluate treatment effect/prognostic evaluation.
• the chemically active or activated derivatives of the PEG polymer are prepared to attach the PEG to the desired molecule, the GnRH antagonist or drug to lower GnRH activity.
• the overall PEGylation process is either a solution phase batch process or an on-column fed-batch process. During the simple and commonly adopted batch process reagents are mixed together in a suitable buffer solution, preferably at a temperature between 4 and 6 °C.
• the choice of the suitable functional group for the PEG derivative is based on the type of available reactive group on the molecule that is coupled to the PEG.
• typical reactive amino acids include lysine, cysteine, histidine, arginine, aspartic acid, glutamic acid, serine, threonine, tyrosine.
• the N-terminal amino group and the C-terminal carboxylic acid can also be used as a site specific site by conjugation with aldehyde functional polymers.
• PEG derivatives the PEG polymer reacts with a group that is reactive with hydroxyl groups, typically anhydrides, acid chlorides,
• Heterobifunctional PEGs are very useful in linking two entities, where a hydrophilic, flexible and biocompatible spacer is needed.
• Preferred end groups for heterobifunctional PEGs are maleimide, vinyl sulfones, pyridyl disulfide, amine, carboxylic acids and NHS esters.
• Third generation pegylation agents where the shape of the polymer has been branched, Y shaped or comb shaped are available which show reduced viscosity and lack of organ accumulation. These compounds are tested in animal studies, showing that they do not cross the blood brain barrier due to their physically large size. Some of these compounds can have extended half lives. They do not act upon the pituitary GnRH receptors.
• Mice are immunized to stimulate anti-GnRH antibody production.
• Antibody forming cells are isolated from the spleen. Tumor cells are grown in tissue culture. Antibody- forming cells that are isolated from the spleen are fused with cultivated tumor cells to form hybridomas. Hybridomas are screened for antibody production. Antibody producing hybridomas are cloned. Monoclonal antibodies are isolated for cultivation. The monoclonal antibody works by binding with high affinity to peripheral GnRH, preventing the binding of GnRH to its receptor. The antibody is a large molecule that is unable to pass the BBB therefore central GnRH receptors remain unaffected, thereby the reproductive hypothalamic pituitary gonadal axis is unaffected.
• Inflammation and cancer are linked inextricably. Inflammation has been described as the 7 th hallmark of cancer. The majority of cancer related symptoms are associated with inflammation. Patient History
• inflammation such as pain, anorexia and fatigue.
• This example demonstrates how a GnRH antagonist may be given to treat an inflammatory bowel disease.

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