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WO2018211111A1 - Agonistes doubles de l'amyline et du récepteur de la calcitonine destinés au traitement de maladies et de troubles - Google Patents

Agonistes doubles de l'amyline et du récepteur de la calcitonine destinés au traitement de maladies et de troubles Download PDF

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Publication number
WO2018211111A1
WO2018211111A1 PCT/EP2018/063202 EP2018063202W WO2018211111A1 WO 2018211111 A1 WO2018211111 A1 WO 2018211111A1 EP 2018063202 W EP2018063202 W EP 2018063202W WO 2018211111 A1 WO2018211111 A1 WO 2018211111A1
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WIPO (PCT)
Prior art keywords
peptide
seq
kbp
amino acid
residue
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PCT/EP2018/063202
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English (en)
Inventor
Kim Henriksen
Kim V. ANDREASSEN
Morten Karsdal
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Keybioscience Ag
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Publication of WO2018211111A1 publication Critical patent/WO2018211111A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/585—Calcitonins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to novel dual amylin and calcitonin receptor agonists, specifically calcitonin-like amylinomimetic therapeutic agents, and extends to their use as medicaments in the treatment of various diseases and disorders, including, but not limited to diabetes (Type I and Type II), obesity, excess bodyweight, excessive food
  • NASH steatohepatitis
  • alcoholic and non-alcoholic fatty liver disease producing a decrease in liver triglycerides, reducing fat accumulation in the liver of a subject, the regulation of blood glucose levels, the regulation of
  • T2DM type 2 diabetes mellitus
  • T2DM is a heterogeneous disease characterized by
  • T2DM abnormalities in carbohydrate and fat metabolism.
  • the causes of T2DM are multi-factorial and include both genetic and environmental elements that affect ⁇ -cell function and insulin sensitivity in tissues such as muscle, liver, pancreas and adipose tissue.
  • impaired insulin secretion is observed and paralleled by a progressive decline in ⁇ -cell function and chronic insulin resistance.
  • the inability of the endocrine pancreas to compensate for peripheral insulin resistance leads to hyperglycaemia and onset of clinical diabetes.
  • Tissue resistance to insulin- mediated glucose uptake is now recognized as a major pathophysiologic determinant of T2DM.
  • a success criterion for an optimal T2DM intervention is the lowering of blood glucose levels, which can be both chronic lowering of blood glucose levels and increased ability to tolerate high glucose levels after food intake, described by lower peak glucose levels and faster clearance. Both of these situations exert less strain on ⁇ -cell insulin output and function.
  • Type I diabetes is characterised by a loss of the ability to produce insulin in response to food intake and hence an inability to regulate blood glucose to a normal physiological level.
  • the physical structure of bone may be compromised by a variety of factors, including disease and injury.
  • One of the most common bone diseases is osteoporosis, which is
  • Osteoporosis develops when there is an imbalance such that the rate of bone resorption exceeds the rate of bone formation.
  • Inflammatory or degenerative diseases including myeloma
  • OA osteoarthritis
  • RA rheumatoid arthritis
  • JRA juvenile rheumatoid arthritis
  • AS ankylosing spondylitis
  • MS multiple sclerosis
  • Subchondral bone just beneath the cartilage may also degrade.
  • Administering an effective amount of an anti-resorptive agent, such as calcitonin, may prevent resorption of bone.
  • Calcitonins are highly conserved over a wide range of species. Full-length native calcitonin is 32 amino acids in length. The sequences of examples of natural calcitonins are set out below:
  • Canine-1 CSNLSTCVLGTYSKDLNNFHTFSGIGFGAETP (SEQ ID NO: 7)
  • Canine-2 CSNLSTCVLGTYTQDLNKFHTFPQTAIGVGAP (SEQ ID NO: 8)
  • amylin receptor activation profile of dual amylin-calcitonin receptor agonists hence, an amylinomimetic with a higher potency as well as protracted and improved in vivo action could improve this class of ligands and further enhance the efficacy of this class of therapeutic agents.
  • the inventors of the present invention therefore aimed to produce calcitonin-like amylinomimetic dual amylin- calcitonin receptor agonists with improved therapeutic properties .
  • the invention relates to a peptide, wherein the peptide is a 33mer peptide in accordance with formula (I) :
  • each of Xi to X 4 is any amino acid, with the proviso that at least one of Xi to X 4 is a basic amino acid residue, and/or at least two of Xi to X 4 are independently a polar amino acid residue or a basic amino acid residue, and/or at least one of Xi to X4 is a Gly residue, and wherein none of Xi to X4 is an acidic residue;
  • X 5 is D or N
  • Z is selected from SQDLHRLSNNFGA (SEQ ID NO: 15), SQDLHRLQTYGAI (SEQ ID NO: 16) or ANFLVHSSNNFGA (SEQ ID NO: 17) .
  • At least one of Xi or X 4 is a basic amino acid residue.
  • at least one of Xi or X 4 is a basic amino acid residue, and at least one more of Xi to X4 are independently a polar amino acid residue or a basic amino acid residue, and none of Xi to X4 is an acidic residue.
  • At least three of Xi to X4 are
  • all of Xi to X4 are independently a polar amino acid residue or a basic amino acid residue, and none of Xi to X4 is an acidic residue.
  • all of Xi to X4 are independently a polar amino acid residue or a basic amino acid residue, at least three of Xi to X4 are basic amino acid residues, and none of Xi to X4 is an acidic residue .
  • the basic amino acid residues may be any natural or unnatural amino acid residues with basic side chains, and may be selected from, but are not limited to, Arg, His or Lys .
  • the polar amino acid residues may be any natural or unnatural amino acid residues with polar uncharged side chains, and may be selected from, but are not limited to, Ser, Thr, Asn, Gin or Cys .
  • the term "acidic residue” refers to any natural or unnatural amino acid residue that has an acidic side chain, such as, for example, Glu or Asp.
  • Xi is selected from Asn, Phe, Val, Gly, lie, Leu, Lys, His or Arg;
  • X2 is selected from Ala, Asn, His, Leu, Ser, Thr, Gly or
  • X 3 is selected from Ala, Phe, lie, Ser, Pro, Thr, Gly or Lys; and/or
  • X 4 is selected from lie, Leu, Gly, His, Arg, Asn, Ser,
  • At least one of Xi or X 4 is a basic amino acid residue, and/or at least two of Xi to X4 are independently a polar amino acid residue or a basic amino acid residue, and/or at least one of Xi to X 4 is a Gly residue .
  • Xi is selected from Asn, Gly, lie, His or Arg;
  • X2 is selected from Asn, Leu, Thr, Gly or Lys;
  • X 3 is selected from Phe, Pro, lie, Ser, Thr, Gly or Lys; and/or
  • X 4 is selected from Gly, His, Asn, Ser, Lys, Thr or Gin; with proviso that at least one of Xi or X 4 is a basic amino acid residue, and/or at least two of Xi to X 4 are independently a polar amino acid residue and/or a basic amino acid residue, and/or at least one of Xi to X 4 is a Gly residue .
  • the peptide of the invention is selected from the group consisting of:
  • KBP-084 CSNLSTCMLGRLSQDLHRLQTYPKHSSTDVGANAP KBP-086 CSNLSTCMLGRLSQDLHRLQTYPKHSSNTDVGANAP
  • SEQ ID NO: 20 KBP-108 CSNLSTCMLGRLSQDLHRLSNNFGAILSSTNVGANAP
  • SEQ ID NO: 21 KBP-109 CSNLSTCMLGRLSQDLHRLQTYGAILSPKTDVGANAP
  • KBP-110 CSNLSTCMLGRLANFLVHSSNNFGAILPKTDVGANAP KBP-116 CSNLSTCMLGRLSQDLHRLQTYPKGAILTDVGANAP
  • KBP-116 CSNLSTCMLGRLSQDLHRLQTYPKGAILTDVGANAP KBP-117 CSNLSTCMLGRLSQDLHRLQTYPKILSSTDVGANAP
  • SEQ ID NO: 25 KBP-118 CSNLSTCMLGRLSQDLHRLQTYPKFGAITDVGANAP
  • the peptide of the invention is selected from the group consisting of:
  • the methionine residue at position 8 of the peptides of the invention may be substituted with valine.
  • the methionine residue at position 8 of the peptides of the invention may be substituted with 2-aminoisobutyric acid (CAS No. 62-57-7) .
  • Peptides of the invention in accordance with formulae (I) -(III), supra, may comprise one or more of the following conservative substitutions:
  • SQDLHRLQTYGAI (SEQ ID NO: 16), may comprise one or more of the following conservative substitutions:
  • the peptides of the invention may be acylated at its N- terminal or otherwise modified to reduce the positive charge of the first amino acid and independently of that may be amidated at its C-terminal.
  • the peptide may be formulated for administration as a pharmaceutical and may be formulated for enteral or
  • Preferred formulations are injectable, preferably for subcutaneous injection, however the peptide may be formulated with a carrier for oral
  • Suitable carriers include ones that comprise 5-CNAC, SNAD, or S AC .
  • the peptide is formulated in a pharmaceutical composition for oral administration comprising coated citric acid particles, and wherein the coated citric acid particles increase the oral bioavailability of the peptide.
  • the invention includes a peptide of the invention for use as a medicament.
  • the peptide may be for use in treating diabetes (Type I and/or Type II), excess bodyweight, obesity, excessive food consumption, metabolic syndrome, rheumatoid arthritis, non-alcoholic steatohepatitis (NASH) , non- alcoholic fatty liver disease, alcoholic fatty liver disease, osteoporosis, or osteoarthritis, poorly regulated blood glucose levels, poorly regulated response to glucose
  • the peptides may be used to lower an undesirably high fasting blood glucose level or to lower an undesirably high HbAlc or to reduce an undesirably high response to a glucose tolerance test.
  • the peptides of the invention may be used for producing a decrease in liver triglycerides and/or for reducing fat accumulation in the liver of a subject.
  • the peptides of the invention may be produced using any suitable method known in the art for generating peptides, such as synthetic (chemical) and recombinant technologies.
  • the peptides are produced using a synthetic method. Synthetic peptide synthesis is well known in the art, and includes (but is not limited to) solid phase peptide synthesis employing various protecting group strategies (e.g. using Fmoc, Boc, Bzl, tBu, etc.) .
  • the N-terminal side of the peptides discussed supra is modified to reduce the positive charge of the first amino acid.
  • an acetyl, propionyl, or succinyl group may be substituted on cysteine-1.
  • Alternative ways of reducing positive charge include, but are not limited to, polyethylene glycol-based PEGylation, or the addition of another amino acid such as glutamic acid or aspartic acid at the N-terminus.
  • other amino acids may be added to the N-terminus of peptides discussed supra
  • cysteines having a plurality of cysteine residues frequently form a disulfide bridge between two such cysteine residues. All such peptides set forth herein are defined as optionally including one or more such disulphide bridges, particularly at the Cysl-Cys7 locations. Mimicking this, the cysteines at positions 1 and 7 may jointly be replaced by an - aminosuberic acid linkage. Alternatively, the cysteines at positions 1 or 7 may independently be replaced by an - aminosuberic acid linkage.
  • peptides of the present disclosure may exist in free acid form, it is preferred that the C-terminal amino acid be amidated. Applicants expect that such amidation may contribute to the effectiveness and/or bioavailability of the peptide.
  • Synthetic chemical methods may be employed for amidating the C-terminal amino acid.
  • Another technique for manufacturing amidated versions of the peptides of the present disclosure is to react precursors (having glycine in place of the C-terminal amino group of the desired amidated product) in the presence of peptidylglycine alpha-amidating monooxygenase in accordance with known techniques wherein the precursors are converted to amidated products in reactions described, for example, in US4708934 and EP0308067 and
  • the production of the preferred amidated peptides may proceed, for example, by producing glycine-extended precursor in E. coli as a soluble fusion protein with glutathione-S- transferase, or by direct expression of the precursor in accordance with the technique described in US6103495.
  • a glycine extended precursor has a molecular structure that is identical to the desired amidated product except at the C- terminus (where the product terminates --X--N3 ⁇ 4, while the precursor terminates --X-gly, X being the C-terminal amino acid residue of the product) .
  • An alpha-amidating enzyme described in the publications above catalyzes conversion of precursors to product. That enzyme is preferably
  • Free acid forms of peptide active agents of the present disclosure may be produced in like manner, except without including a C-terminal glycine on the "precursor", which precursor is instead the final peptide product and does not require the amidation step. Except where otherwise stated, the preferred dosage of the peptide of the present disclosure is identical for both therapeutic and prophylactic purposes. Desired dosages are discussed in more detail, infra, and differ depending on mode of administration.
  • dosages herein refer to weight of active compounds (i.e. peptides of the invention) unaffected by or discounting pharmaceutical excipients, diluents, carriers or other ingredients, although such additional ingredients are
  • any dosage form (capsule, tablet, injection or the like) commonly used in the pharmaceutical industry for delivery of peptide active agents is appropriate for use herein, and the terms "excipient”, “diluent”, or “carrier” includes such non-active ingredients as are
  • a preferred oral dosage form is discussed in more detail, infra, but is not to be considered the exclusive mode of administering the active agents of the present disclosure.
  • the peptides of the present disclosure can be any amino acid sequence having the same or different amino acids.
  • the peptides of the present disclosure can be any amino acid sequence having the same or different amino acids.
  • the term "patient” means any organism belonging to the kingdom Animalia. In an
  • the term "patient” refers to vertebrates, more preferably, mammals including humans.
  • the present disclosure includes the use of the peptides in a method of treatment of type I diabetes, Type II diabetes or metabolic syndrome, obesity, or of appetite suppression, or for mitigating insulin resistance, or for reducing an undesirably high fasting serum glucose level, or for reducing an undesirably high peak serum glucose level, or for reducing an undesirably high peak serum insulin level, or for reducing an undesirably large response to a glucose tolerance test, or for treating osteoporosis, or for treating osteoarthritis, or for treating non-alcoholic steatohepatitis (NASH) , or for treating alcoholic or non- alcoholic fatty liver disease, or for producing a decrease in liver triglycerides, or for reducing fat accumulation in the liver of a subject.
  • NASH non-alcoholic steatohepatitis
  • a patient in need of treatment or prevention regimens set forth herein include patients whose body weight exceeds recognized norms or who, due to heredity, environmental factors or other recognized risk factor, are at higher risk than the general population of becoming
  • the peptides of the invention may be used to treat diabetes where weight control is an aspect of the treatment.
  • the method includes enteral
  • the method includes parenteral
  • parenteral administration including intraperitoneal, subcutaneous, intravenous, intradermal or intramuscular injection
  • parenteral administration including intraperitoneal, subcutaneous, intravenous, intradermal or intramuscular injection
  • solutions of a peptide of the present disclosure in either sesame or peanut oil or in aqueous propylene glycol may be employed, for example.
  • the aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic.
  • These aqueous solutions are suitable for intravenous injection purposes.
  • the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes.
  • the preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • suitable preparations include solutions, preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories.
  • Peptides may be formulated in sterile form in multiple or single dose formats such as being dispersed in a fluid carrier such as sterile physiological saline saline dextrose solutions commonly used with inj ectables .
  • Said method may include a preliminary step of
  • the active compound is preferably administered once daily or more such as at least twice per day, e.g. from 2-4 times per day.
  • Formulations of the active compound may contain a unit dosage appropriate for such an administration schedule.
  • the active compounds may be administered with a view to controlling the weight of a patient undergoing treatment for diabetes or metabolic syndrome.
  • Oral enteral formulations are for ingestion by
  • swallowing for subsequent release in the intestine below the stomach, and hence delivery via the portal vein to the liver, as opposed to formulations to be held in the mouth to allow transfer to the bloodstream via the sublingual or buccal routes .
  • Suitable dosage forms for use in the present disclosure include tablets, mini-tablets, capsules, granules, pellets, powders, effervescent solids and chewable solid formulations.
  • Such formulations may include gelatin which is preferably hydrolysed gelatin or low molecular weight gelatin.
  • Such formulations may be obtainable by freeze drying a homogeneous aqueous solution comprising a peptide of the invention and hydrolysed gelatin or low molecular weight gelatin and further processing the resulting solid material into said oral pharmaceutical formulation, and wherein the gelatin may have a mean molecular weight from 1000 to 15000 Daltons.
  • Such formulations may include a protective carrier compound such as 5-CNAC or others as disclosed herein.
  • compositions for use in the present disclosure may take the form of syrups, elixirs or the like and
  • Oral delivery is generally the delivery route of choice since it is convenient, relatively easy and generally painless, resulting in greater patient compliance relative to other modes of delivery.
  • biological, chemical and physical barriers such as varying pH in the gastrointestinal tract, powerful digestive enzymes, and active agent impermeable gastrointestinal membranes, makes oral delivery of calcitonin like peptides to mammals problematic, e.g. the oral delivery of calcitonins, which are long-chain polypeptide hormones secreted by the
  • a peptide of the present invention is administered at adequate dosage to maintain serum levels of the mimetic in patients between 5 picograms and 500 nanograms per milliliter, preferably between 50 picograms and 250 nanograms, e.g. between 1 and 100 nanograms per milliliter.
  • the serum levels may be measured by any suitable techniques known in the art, such as radioimmunoassay or mass
  • the attending physician may monitor patient response, and may then alter the dosage somewhat to account for individual patient metabolism and response.
  • the disclosure also includes, for example, dividing the required amount of the peptide among two or more tablets or capsules which may be administered together such that they together provide the necessary amount of all ingredients.
  • “Pharmaceutical composition,” as used herein includes but is not limited to a complete dosage appropriate to a particular administration to a patient regardless of whether one or more tablets or capsules (or other dosage forms) are recommended at a given administration.
  • a peptide of the present invention may be formulated for oral administration using the methods employed in the Unigene Enteripep® products. These may include the methods as described in US Patent No. 5,912,014, US Patent No.
  • it may include the use of conjugation of the compound to a membrane translocator such as the protein transduction domain of the HIV TAT protein, co-formulation with one or more protease inhibitors, and/or a pH lowering agent which may be coated and/or an acid resistant protective vehicle and/or an absorption enhancer which may be a
  • a peptide of the present invention is preferably formulated for oral delivery in a manner known in U.S. Patent Publication No. 2009/0317462.
  • a peptide of the present invention may be formulated for enteral, especially oral, administration by admixture with a suitable carrier compound.
  • suitable carrier compounds include those described in US Patent No. 5,773,647 and US Patent No. 5866536 and amongst these, 5-CNAC (N- (5- chlorosalicyloyl) -8-aminocaprylic acid, commonly as its disodium salt) is particularly effective.
  • a pharmaceutical composition of the present disclosure comprises a delivery effective amount of carrier such as 5- CNAC, i.e. an amount sufficient to deliver the compound for the desired effect.
  • the carrier such as 5-CNAC is present in an amount of 2.5% to 99.4% by weight, more
  • R 1 , R 2 , R 3 , and R 4 are independently hydrogen, -OH, -NR 6 R 7 , halogen, C1-C4 alkyl, or C1-C4 alkoxy;
  • R 5 is a substituted or unsubstituted C2-C16 alkylene,
  • calcitonins e.g. salmon calcitonin
  • active agents such as calcitonins, e.g. salmon calcitonin, and these may be used in the present disclosure.
  • micronised 5-CNAC may be generally as described in
  • the compound may be formulated for oral administration using the methods employed in the Capsitonin product of Bone Medical Limited. These may include the methods incorporated in Axcess formulations. More particularly, the active ingredient may be encapsulated in an enteric capsule capable of withstanding transit through the stomach. This may contain the active compound together with a hydrophilic aromatic alcohol absorption enhancer, for instance as described in WO02/028436. In a known manner the enteric coating may become permeable in a pH sensitive manner, e.g. at a pH of from 3 to 7. WO2004/091584 also describes suitable formulation methods using aromatic alcohol absorption
  • the compound may be formulated using the methods seen in the Oramed products, which may include formulation with omega-3 fatty acid as seen in WO2007/029238 or as described in US5, 102, 666.
  • solvates e.g. alcohol solvates
  • hydrates of these carriers or delivery agents may be used.
  • Oral administration of the pharmaceutical compositions according to the disclosure can be accomplished regularly, e.g. once or more on a daily or weekly basis; intermittently, e.g. irregularly during a day or week; or cyclically, e.g. regularly for a period of days or weeks followed by a period without administration.
  • compositions of the presently disclosed embodiments can be any known form, e.g. liquid or solid dosage forms.
  • the liquid dosage forms include solution emulsions, suspensions, syrups and elixirs.
  • the liquid formulations may also include inert excipients commonly used in the art such as, solubilizing agents e.g. ethanol; oils such as cottonseed, castor and sesame oils; wetting agents; emulsifying agents; suspending agents; sweeteners;
  • the solid dosage forms include capsules, soft-gel capsules, tablets, caplets, powders, granules or other solid oral dosage forms, all of which can be prepared by methods well known in the art.
  • the pharmaceutical compositions may additionally comprise
  • additives in amounts customarily employed including, but not limited to, a pH adjuster, a preservative, a flavorant, a taste-masking agent, a fragrance, a humectant, a tonicifier, a colorant, a surfactant, a plasticizer, a lubricant such as magnesium stearate, a flow aid, a compression aid, a
  • solubilizer an excipient, a diluent such as microcrystalline cellulose, e.g. Avicel PH 102 supplied by FMC corporation, or any combination thereof.
  • diluent such as microcrystalline cellulose, e.g. Avicel PH 102 supplied by FMC corporation, or any combination thereof.
  • Other additives may include
  • the composition may also include one or more enzyme inhibitors, such as actinonin or epiactinonin and derivatives thereof; aprotinin, Trasylol and Bowman-Birk inhibitor.
  • a transport inhibitor i.e. a [rho]- glycoprotein such as Ketoprofin, may be present in the compositions of the present disclosure.
  • compositions of the instant disclosure can be prepared by conventional methods e.g. by blending a mixture of the active compound, the carrier such as 5-CNAC, and any other ingredients, kneading, and filling into capsules or, instead of filling into capsules, molding followed by further tableting or compression-molding to give tablets.
  • the carrier such as 5-CNAC
  • any other ingredients kneading, and filling into capsules or, instead of filling into capsules, molding followed by further tableting or compression-molding to give tablets.
  • a solid dispersion may be formed by known methods followed by further processing to form a tablet or capsule.
  • compositions of the instant disclosure are homogeneously or uniformly mixed throughout the solid dosage form.
  • the active compound may be formulated as a conjugate with said carrier, which may be an oligomer as described in US2003/0069170, e.g.
  • conjugates may be administered in combination with a fatty acid and a bile salt as described there.
  • Conujugates with polyethylene glycol (PEG) may be used, as described for instance in Mansoor et al .
  • active compounds may be admixed with nitroso-N-acetyl-D, L-penicillamine (SNAP) and Carbopol solution or with taurocholate and Carbapol solution to form a mucoadhesive emulsion.
  • the active compound may be formulated by loading into chitosan nanocapsules as disclosed in Prego et al (optionally PEG modified as in Prego Prego C, Torres D, Fernandez-Megia E, Novoa-Carballal R, Quinoa E, Alonso MJ.) or chitosan or PEG coated lipid nanoparticles as disclosed in Garcia-Fuentes et al .
  • Chitosan nanoparticles for this purpose may be iminothiolane modified as described in Guggi et al . They may be formulated in water/oil/water emulsions as described in Dogru et al .
  • the bioavailability of active compounds may be increased by the use of taurodeoxycholate or lauroyl
  • nanoparticles as carriers are discussed in de la Fuente et al and may be used in the present
  • TPE transient permeability enhancer
  • GI hostile gastrointestinal
  • the active compound may be formulated in seamless micro ⁇ spheres as described in WO2004/084870 where the active pharmaceutical ingredient is solubilised as an emulsion, microemulsion or suspension formulated into mini-spheres; and variably coated either by conventional or novel coating technologies.
  • the result is an encapsulated drug in "pre- solubilised” form which when administered orally provides for predetermined instant or sustained release of the active drug to specific locations and at specific rates along the
  • pre-solubilization of the drug enhances the predictability of its kinetic profile while simultaneously enhancing permeability and drug
  • the active molecule administered with this technology is protected inside the nanocapsules since they are stable against the action of the gastric fluid.
  • the mucoadhesive properties of the system enhances the time of adhesion to the intestine walls (it has been verified that there is a delay in the gastrointestinal transit of these systems) facilitating a more effective absorption of the active molecule.
  • Methods developed by TSR1 Inc. may be used. These include Hydrophilic Solubilization Technology (HST) in which gelatin, a naturally derived collagen extract carrying both positive and negative charges, coats the particles of the active ingredient contained in lecithin micelles and prevents their aggregation or clumping. This results in an improved wettability of hydrophobic drug particles through polar interactions.
  • the amphiphilic lecithin reduces surface tension between the dissolution fluid and the
  • the active ingredient may be formulated with
  • an absorption enhancer which may be a medium chain fatty acid or a medium chain fatty acid derivative as described in US2007/0238707 or a membrane translocating peptide as described in US7268214.
  • GIRESTM technology which consists of a controlled-release dosage form inside an inflatable pouch, which is placed in a drug capsule for oral administration. Upon dissolution of the capsule, a gas-generating system inflates the pouch in the stomach. In clinical trials the pouch has been shown to be retained in the stomach for 16-24 hours.
  • the active may be conjugated to a
  • the active may be conjugated covalently with a monodisperse, short-chain methoxy polyethylene glycol glycolipids
  • HDV hepatic-directed vesicle
  • An HDV may consist of liposomes ( ⁇ 150 nm diameter) encapsulating the active, which also contain a hepatocyte-targeting molecule in their lipid bilayer.
  • the targeting molecule directs the delivery of the encapsulated active to the liver cells and therefore relatively minute amounts of active are required for effect.
  • the active may be incorporated into a composition containing additionally a substantially non-aqueous
  • hydrophilic medium comprising an alcohol and a cosolvent, in association with a medium chain partial glyceride, optionally in admixture with a long-chain PEG species as described in US2002/0115592 in relation to insulin.
  • the active may be incorporated into an erodible matrix formed from a hydrogel blended with a hydrophobic polymer as described in US Patent No. 7189414.
  • Suitable oral dosage levels for adult humans to be treated may be in the range of 0.05 to 5mg, preferably about 0.1 to 2.5mg .
  • the frequency of dosage treatment of patients may be from 1 to six times daily, for instance from two to four times daily. Treatment will desirably be maintained over a prolonged period of at least 6 weeks, preferably at least 6 months, preferably at least a year, and optionally for life. Combination treatments for relevant conditions may be carried out using a composition according to the present disclosure and separate administration of one or more other therapeutics. Alternatively, the composition according to the present disclosure may incorporate one or more other therapeutics for combined administration.
  • compositions include combinations of an active compound as described with insulin, GLP-2, GLP-1, GIP, or amylin, or generally with other anti-diabetics.
  • an active compound as described with insulin, GLP-2, GLP-1, GIP, or amylin, or generally with other anti-diabetics.
  • therapies including co-formulations may be made with insulin sensitizers including biguanides such as Metformin, Buformin and Phenformin, TZD' s (PPAR) such as Balaglitazone,
  • biguanides such as Metformin, Buformin and Phenformin
  • TZD' s such as Balaglitazone
  • Pioglitazone Rivoglitazone, Rosiglitazone and Troglitazone, dual PPAR agonists such as Aleglitazar, Muraglitazar and
  • Tesaglitazar, or secretagogues including sulphonylureas such as Carbutamide, Chloropropamide, Gliclazide, Tolbutamide, Tolazamide, Glipizide, Glibenclamide, Glyburide, Gliquidone, Glyclopyramide and Glimepriride, Meglitinides/glinides (K+) such as Nateglinide, Repaglinide and Mitiglinide, GLP-1 analogs such as Exenatide, Liraglutide and Albiglutide, DPP-4 inhibitors such as Alogliptin, Linagliptin, Saxagliptin, Sitagliptin and Vildagliptin, insulin analogs or special formulations such as (fast acting) Insulin lispro, Insulin aspart, Insulin glulisine, (long acting) Insulin glargine,
  • Insulin detemir inhalable insulin - Exubra and NPH insulin, and others including alpha-glucosidase inhibitors such as Acarbose, Miglitol and Voglibose, amylin analogues such as Pramlintide, SGLT2 inhibitors such as Dapagliflozin,
  • Leptin resistance is a well- established component of type 2 diabetes; however, injections of leptin have so far failed to improve upon this condition. In contrast, there is evidence supporting that amylin, and thereby molecules with amylin-like abilities, are able to improve leptin sensitivity.
  • Amylin/leptin combination has shown a synergistic effect on body weight and food intake, and also insulin resistance [Kusakabe T et al] .
  • a further preferred combination therapy includes co- formulation or co-administration of the peptides of the invention with one or more weight loss drugs.
  • weight loss drugs include, but are not limited to, lipase inhibitors (e.g. pancreatic lipase inhibitors, such as Orlistat) , appetite suppressing amphetamine derivatives (e.g.
  • Phentermine Phentermine
  • Topiramate Qysmia® ( Phentermine/Topiramate combination)
  • 5-HT 2 c receptor agonists e.g. Locaserin
  • Contrave® glucagon-like peptide-1 [GLP-1] analogues and derivatives (e.g.
  • SR sarco/endoplasmic reticulum
  • SERCA Ca 2+ ATPase
  • FGF-21 Fibroblast growth factor 21 [FGF-21] receptor agonists
  • ⁇ 3 adreno receptor agonists e.g. Mirabegron
  • Such combinations may be used to treat an overweight condition, such as obesity.
  • Figure 1 Amino acid sequences of the peptides of the
  • Figure 2 ⁇ -arrestin recruitment dose response by KBP-101 to KBP-113 as a function of calcitonin receptor activation. Dose range is 1 ⁇ to 15 pM and data is shown as fold of vehicle.
  • Figure 3 ⁇ -arrestin recruitment dose response by KBP-101 to KBP-113 as a function of amylin receptor activation. Dose range is 1 ⁇ to 15 pM and data is shown as fold of vehicle.
  • Figure 5 ⁇ -arrestin recruitment dose response by KBP-079 to KBP-086 as a function of calcitonin receptor activation. Dose range is 100 nM to 32 pM and data is shown as fold of
  • Figure 6 ⁇ -arrestin recruitment dose response by KBP-079 to KBP-086 as a function of amylin receptor activation. Dose range is 100 nM to 32 pM and data is shown as fold of
  • Figure 8 Protracted attenuation of food intake in SD rats by KBP-101 to KBP-113. After single s.c dose of 2.5 yg/kg of KBP or 5 yg/kg rat amylin, food intake was monitored in intervals of 0-4h and 4-24h to assess the protracted action of
  • Figure 10 ⁇ -arrestin recruitment dose response by KBP-116 to KBP-135 as a function of calcitonin receptor activation. Dose range is 100 nM to 32 pM and data is shown as fold of vehicle .
  • Figure 11 ⁇ -arrestin recruitment dose response by KBP-116 to KBP-135 as a function of amylin receptor activation. Dose range is 100 nM to 32 pM and data is shown as fold of vehicle.
  • Figure 13 Protracted attenuation of food intake in SD rats by KBP-116 to KBP-135. After single s.c dose of 5.0 yg/kg of
  • parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.
  • CTR Calcitonin Receptor
  • Amylin Receptor (AMY-R) : CHO-K1 CALCR + RAMP3 from DiscoveRx (Cat. No.: 93-0268C2).
  • CTR and AMY-R cells were treated at the indicated timepoints with increasing doses of KBPs identified in Table 2 (1000, 250, 62.5, 15.6, 3.9, 1.0, 0.24, 0.06, 0.02 nM and vehicle)
  • KBP-082 CSNLSTCMLGRLSQDLHRLQTYPKHSTDVGANAP (SEQ ID NO: 43)
  • KBP-083 CSNLSTCMLGRLSQDLHRLQTYPKAILTDVGANAP (SEQ ID NO: 44)
  • KBP-084 CSNLSTCMLGRLSQDLHRLQTYPKHSSTDVGANAP (SEQ ID NO: 19)
  • KBP- 085 CSNLSTCMLGRLSQDLHRLQTYPKAILSTDVGANAP (SEQ ID NO: 45)
  • KBP- 133 CSNLSTCMLGRLSQDLHRLQTYPKEEEETDVGANAP (SEQ ID NO: 58) KBP-134 CSNLSTCMLGRLSQDLHRLQTYPKHKKNTDVGANAP (SEQ ID NO: 39) KBP-135 CSNLSTCMLGRLSQDLHRLQTYPKHKKHTDVGANAP (SEQ ID NO: 40)
  • Example 1 ⁇ -Arrestin Assay PathHunter ⁇ -Arrestin GPCR assays are whole cell, functional assays that directly measure the ability of a ligand to activate a GPCR by detecting the interaction of ⁇ - Arrestin with the activated GPCR. Because ⁇ -arrestin
  • the GPCR is fused in frame with the small enzyme fragment ProLinkTM and co-expressed in cells stably expressing a fusion protein of ⁇ -Arrestin and the larger, N-terminal deletion mutant of ⁇ -gal (called enzyme acceptor or EA) .
  • EA enzyme acceptor
  • the assay was performed in white 384 well plates
  • KBP-101 to KBP-112 are quite similar in activity with the exception of KBP-113 which resembles endogenous amylin the most by far.
  • KBP-108, KBP-109, KBP-110 and KBP-112 show a superior ability to activate and maintain activation of the CTR as illustrated in Figure 4, where the individual ligands are plotted at one given concentration and as a function of time.
  • KBP-108, KBP-109, KBP-110 and KBP- 112 are superior to the other peptides in terms of protracted calcitonin receptor activation.
  • KBP-107 and KBP- 111 have a prolonged, albeit slightly attenuated response and KBP-113 and rat amylin have no prolonged response at all, which is also a hallmark characteristic of endogenous
  • CTR CTR: U20S-CALCR from DiscoveRx (Cat. No.: 93-0566C3) cell line, and as opposed to the classical 3 hour output, ⁇ - arrestin accumulation was conducted over 24, 48 and 72 hour and then analyzed.
  • KBP-108 scored the best EC50 followed by KBP-112 and KBP-110,
  • KBP-116 to KBP-135 Another important trait of this class of molecules is the ability to activate the amylin receptor, and as seen in Figure 6. Most of the KBPs are fully capable of activating this receptor and are comparable in activity. KBP-116 to KBP-135
  • KBP-101 to KBP-113 Rats were single caged four days prior to individual tests. They were randomized by weight into eight groups
  • Rats were single caged four days prior to individual tests. They were randomized by weight into seven groups (Vehicle (0.9% NaCl) , KBPs (doses: 750 pmol/kg) . They were fasted overnight and then treated with a single dose of peptide or vehicle in the morning using subcutaneous administration. The food intake was monitored in the
  • Rats were single caged four days prior to individual tests. They were randomized by weight into seven groups (Vehicle (0.9% NaCl) , KBPs (doses: 1500 pmol/kg (5.30 yg/kg) ) . They were fasted overnight and then treated with a single dose of peptide or vehicle in the morning using subcutaneous administration. The food intake was monitored in the following intervals (0-4hours and 4-24 hours) .
  • KBP-116 to KBP-123 This series was designed to focus on exploring the "FGAILSST” amylin inserts (expanding upon the "AILS” insert as per KBP-085) . As seen in Figure 13A, all peptides led to a -50% reduction in food intake within both the 0-4 hours and 4-24 hour intervals. Substituting amino acid conservatively in the "AILS" domain provided similar results (KBP-120, 121, 122) .
  • KBP-124 to KBP-131 This series was designed to focus on the "LVHSSNNF” amylin inserts (expanding upon the "HSSN” insert as per KBP-085) . As seen in Figure 13B, all peptides led to a -50% reduction in food intake in 0-4 hour interval.
  • KBP-129, 130, 131 a marked attenuation in the 4-24 hour interval by three of four peptides tested (KBP-129, 130, 131) was observed.
  • KBP-128 demonstrated a -50% attenuation of food intake
  • KBP-129, KBP-130 and KBP-131 demonstrated a >75% attenuation of food intake in the 4-24 hour interval.
  • KBP-129 and KBP-131 both demonstrated a 43% and
  • the lead candidates are KBP-080, 084, 086, 108, 109, 110, 117, 120, 123, 125, 129, 130, 131, 134 and 135 which have the best performance in the screening.

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Abstract

La présente invention concerne de nouveaux agonistes doubles de l'amyline et du récepteur de la calcitonine, plus particulièrement des agents thérapeutiques amylinomimétiques de type calcitonine, et étend leur utilisation en tant que médicaments dans le traitement de diverses maladies et divers troubles, tels que le diabète (type I et type II), l'obésité, le surpoids, la consommation excessive d'aliments et le syndrome métabolique, la stéatohépatite non alcoolique (NASH), la stéatose hépatique alcoolique et non alcoolique, la production d'une diminution des triglycérides du foie, la réduction de l'accumulation de graisse dans le foie d'un sujet, la régulation des taux de glucose sanguin, la régulation de la réponse aux tests de tolérance au glucose, la régulation de l'ingestion d'aliments, le traitement de l'ostéoporose et le traitement de l'arthrose.
PCT/EP2018/063202 2017-05-18 2018-05-18 Agonistes doubles de l'amyline et du récepteur de la calcitonine destinés au traitement de maladies et de troubles WO2018211111A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11274158B2 (en) 2018-01-30 2022-03-15 Flagship Pioneering Innovations V, Inc. Methods and compositions for treating inflammatory or autoimmune diseases or conditions using calcitonin receptor activators
JP7569487B2 (ja) 2020-12-18 2024-10-18 イーライ リリー アンド カンパニー 二重アミリン及びカルシトニン受容体アゴニスト、並びにその使用

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11274158B2 (en) 2018-01-30 2022-03-15 Flagship Pioneering Innovations V, Inc. Methods and compositions for treating inflammatory or autoimmune diseases or conditions using calcitonin receptor activators
JP7569487B2 (ja) 2020-12-18 2024-10-18 イーライ リリー アンド カンパニー 二重アミリン及びカルシトニン受容体アゴニスト、並びにその使用

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