EP4366711A2 - Procédés d'induction de la satiété et de traitement de troubles métaboliques - Google Patents

Procédés d'induction de la satiété et de traitement de troubles métaboliques

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Publication number
EP4366711A2
EP4366711A2 EP22838447.5A EP22838447A EP4366711A2 EP 4366711 A2 EP4366711 A2 EP 4366711A2 EP 22838447 A EP22838447 A EP 22838447A EP 4366711 A2 EP4366711 A2 EP 4366711A2
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EP
European Patent Office
Prior art keywords
day
pyy
composition
analog
dose
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP22838447.5A
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German (de)
English (en)
Inventor
Thomas VASICEK
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Gila Therapeutics Inc
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Gila Therapeutics Inc
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Publication of EP4366711A2 publication Critical patent/EP4366711A2/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2264—Obesity-gene products, e.g. leptin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/23—Calcitonins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form

Definitions

  • the invention features a method for inducing satiety or treating a disease or disorder selected from a metabolic syndrome, obesity, an obesity-related disorder, diabetes, fatty liver disease, nonalcoholic steatohepatitis, chronic kidney disease, polycystic ovary syndrome, cardiovascular disease, obstructive sleep apnea, retinopathy, peripheral vascular disease, peripheral artery disease, and neuropathy (e.g., diabetic neuropathy) in a subject in need thereof.
  • a disease or disorder selected from a metabolic syndrome, obesity, an obesity-related disorder, diabetes, fatty liver disease, nonalcoholic steatohepatitis, chronic kidney disease, polycystic ovary syndrome, cardiovascular disease, obstructive sleep apnea, retinopathy, peripheral vascular disease, peripheral artery disease, and neuropathy (e.g., diabetic neuropathy) in a subject in need thereof.
  • the method includes administering to the subject a composition that includes an agent selected from Peptide YY (PYY), glucagon-like peptide 1 (GLP-1), leptin, amylin, insulin, and calcitonin, or an analog, variant, or biologically active fragment thereof.
  • PYY Peptide YY
  • GLP-1 glucagon-like peptide 1
  • leptin amylin
  • insulin insulin
  • calcitonin or an analog, variant, or biologically active fragment thereof.
  • the composition is administered intranasally, topically to the gastrointestinal (Gl) tract, or intrarectally.
  • the composition provides treatment without substantially changing the concentration of the agent in the blood of the subject.
  • the composition is administered intranasally.
  • the composition may be formulated, for example, as a spray, a semisolid, a particulate, or in a lipid-based carrier.
  • the composition is administered topically to the Gl tract.
  • the composition may be formulated, for example, as a Gl patch.
  • the composition is administered intrarectally.
  • the composition may be formulated, for example, as a suppository.
  • the dose of the agent is from 1 ng to 20 mg per 100 kg body weight.
  • the dose of the agent may be from 1 ng to 10 ng per 100 kg body weight, e.g., 1 ng, 2 ng, 3 ng, 4 ng, 5 ng, 6 ng, 7 ng, 8 ng, 9 ng, or 10 ng per 100 kg body weight, e.g., from 10 ng to 100 ng per 100 kg body weight, e.g., 20 ng, 30 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, or 100 ng per 100 kg body weight, e.g., from 100 ng to 1 pg per 100 kg body weight, e.g., 200 ng, 300 ng, 400 ng, 500 ng, 600 ng, 700 ng, 800 ng, 900 ng, or 1 pg per 100 kg body weight, e.g., from 1 pg to 10 pg per 100 kg, e.g., 2 pg, 3, pg, 4 pg, from
  • the composition includes PYY or an analog, variant, or biologically active fragment thereof.
  • the PYY fragment may be, for example, PYY(3-36).
  • the composition includes GLP-1 or an analog, variant, or biologically active fragment thereof.
  • the composition includes leptin or an analog, variant, or biologically active fragment thereof.
  • the composition includes amylin or an analog, variant, or biologically active fragment thereof.
  • the composition includes insulin or an analog, variant, or biologically active fragment thereof.
  • the composition does not include insulin or an analog, variant, or biologically active fragment thereof.
  • the composition includes calcitonin or an analog, variant, or biologically active fragment thereof.
  • the term “about” refers to a value that is within 10% above or below the value being described.
  • metabolic disorder refers to a human or animal condition or disease associated with and/or resulting from abnormal function or control of the metabolic system (e.g., obesity, diabetes, fatty liver disease, nonalcoholic steatohepatitis, polycystic ovary syndrome, elevated blood glucose levels, chronic kidney disease, cardiovascular disease, obstructive sleep apnea, retinopathy, neuropathy (e.g., diabetic neuropathy), peripheral artery disease, and/or peripheral vascular disease).
  • abnormal function or control of the metabolic system e.g., obesity, diabetes, fatty liver disease, nonalcoholic steatohepatitis, polycystic ovary syndrome, elevated blood glucose levels, chronic kidney disease, cardiovascular disease, obstructive sleep apnea, retinopathy, neuropathy (e.g., diabetic neuropathy), peripheral artery disease, and/or peripheral vascular disease).
  • disorder generally refers to disruption to regular bodily structure and function or a pathophysiological response to internal or external factors.
  • the term “subject,” refers to a human or non-human animal (e.g., a mammal).
  • the invention features methods for inducing satiety and treating a condition affecting metabolism, such as metabolic syndrome, diabetes, obesity, and obesity-related disorders.
  • a condition affecting metabolism such as metabolic syndrome, diabetes, obesity, and obesity-related disorders.
  • the invention is based, in part, upon the surprising discovery that administration of a metabolic hormone, such as PYY, via an intranasal, topical Gl, or intrarectal route can activate a neural receptor in the central nervous system to effectively treat the disease or disorder.
  • the composition can provide treatment to the subject without substantially changing the concentration of the agent in the blood of the subject.
  • these routes of administration avoid systemic administration, which are known to produce unwanted side effects, such as nausea, injection site pain, or malaise.
  • the metabolic hormone can target specific pleasure centers in the brain, activate critical brain regions, and avoid neural or non- neural targets that can cause clinical risk (e.g., toxicity) or side effects, such as nausea.
  • systemic administration of a metabolic hormone activates neural receptors in the hypothalamus, nucleus tractus solitarius (NTS), and area postrema
  • non-systemic routes of administration as described herein activates neural receptors in the hypothalamus and NTS, but substantially avoids the area postrema.
  • NTS nucleus tractus solitarius
  • the neural receptors and connections can sufficiently activate the pleasure centers in the CNS, which control satiety. Accordingly, activation of these pleasure centers may provide treatment for a metabolic disorder or a satiety disorder associated with dysregulated pleasure centers in the brain. The methods are described in more detail below.
  • the methods described herein include administration of a metabolic hormone or a biologically active fragment or variant thereof.
  • the metabolic hormone targets (e.g., binds, associates, or interacts with) a Y2 receptor in the nasal cavity, Gl tract, or rectum of a subject.
  • the metabolic hormone is PYY, PYY(3-36), leptin, amylin, insulin, calcitonin, or GLP-1 , or a variant, analog, or biologically active fragment thereof.
  • the dose of the metabolic hormone or a biologically active fragment, variant, or analog thereof is from 0.1 ng to 20 mg.
  • the dose of the agent may be from 0.1 ng to 1 ng, e.g., e.g., 0.2 ng, 0.3 ng, 0.4 ng, 0.5 ng, 0.6 ng, 0.7 ng, 0.8 ng, 0.9 ng, or 1 ng, e.g., 1 ng to 10 ng, e.g., 1 ng, 2 ng, 3 ng, 4 ng, 5 ng, 6 ng, 7 ng, 8 ng, 9 ng, or 10 ng, e.g., from 10 ng to 100 ng, e.g., 20 ng, 30 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, or 100 ng, e.g., from 100 ng to 1 pg, e.g., 200 ng
  • the metabolic hormone is PYY or an analog, variant, or biologically active fragment thereof.
  • PYY or its variant, analog, or biologically active fragment thereof has at least 70% (e.g., 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 1.
  • PYY has the amino acid sequence set forth in SEQ ID NO: 1.
  • the methods described herein include administration of PYY or variant, analog, or biologically active fragment thereof in a dose of from about 2.5 pg to about 2.5 mg. In some embodiments, the methods described herein include administration of PYY or variant, analog, or biologically active fragment thereof in a dose of from about 10 pg to about 1 mg.
  • the methods described herein include administration of PYY or variant, analog, or biologically active fragment thereof in a dose of from about 25 pg to about 250 pg (e.g., a dose of about 25 pg, 50 pg, 75 pg, 100 pg, 125 pg, 150 pg, 175 pg, 200 pg, 225 pg, or 250 pg).
  • the PYY fragment is PYY(3-36) or a variant, analog, or biologically active fragment thereof.
  • PYY(3-36) or its variant, analog, or biologically active fragment thereof has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 2.
  • PYY(3-36) has the amino acid sequence set forth in SEQ ID NO: 2.
  • the methods described herein include administration of PYY(3-36) or variant, analog, or biologically active fragment thereof in a dose of from about 2.5 pg to about 2.5 mg.
  • the methods described herein include administration of PYY(3-36) or variant, analog, or biologically active fragment thereof in a dose of from about 10 pg to about 1 mg. In some embodiments, the methods described herein include administration of PYY(3-36) or variant, analog, or biologically active fragment thereof in a dose of from about 25 gg to about 250 gg (e.g., a dose of about 25 gg, 50 gg, 75 gg, 100 gg, 125 gg, 150 gg, 175 gg, 200 gg, 225 gg, or 250 gg).
  • the PYY variant is [Pro34]PYY.
  • [Pro34]PYY or its variant, analog, or biologically active fragment thereof has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 11.
  • [Pro34]PYY has the amino acid sequence set forth in SEQ ID NO: 11.
  • the PYY analog is NNC065-1273, which contains the PYY(3-36) polypeptide with a beta-homo-arginine at position 35.
  • the PYY analog is NNC0165-1875.
  • the PYY analog is NNC0165-1562.
  • the PYY analog is described, e.g., in Lear et al. J. of Med.
  • the PYY analog is PYY-Ab and PYY conjugated to one or more PEG moieties, e.g., as described in Rangwala et al. Cell Metab. 29:837-843, 2019, which is hereby incorporated by reference in its entirety.
  • the PYY analog or variant is described, e.g., in US Pat. No.
  • the PYY(3-36) variant, analog, or biologically active fragment thereof is PYY(26-36), PYY(25-36), PYY(24-36), PYY(23-36), PYY(22-36), PYY(21-36), PYY(20-36), PYY(19-36), PYY(18-36), PYY(17-36), PYY(16-36), PYY(15-36), PYY(14-36), PYY(13-36), PYY(12-36), PYY(11-36), PYY(10-36), PYY(9-36), PYY(8-36), PYY(7-36), PYY(6-36), PYY(5-36), or PYY(4-36), as in Balasubramaniam et al., Pept Res 1 :32-35, 1998; Liu et al., J.
  • the PYY(3-36) variant, analog, or fragment thereof may be a fragment with a single point mutation e.g., single point mutation of PYY(25-36) such as [Lys 25 ] P P Y (25-36), [Thr 27 ]PPY(25-36), [Phe 21 ]PPY(25-36), [lle 28 ]PYY(25-36), [Val 28 ]PYY(25-36), [Gln 29 ]PYY(25-36), [lle 30 ]PYY(25-36), [Val 30 ]PYY(25-36), [lle 31 ]PYY(25-36), [Leu 31 ]PYY(25-36), [Ser 32 ]PYY(25-36), [Lys 33 ]PYY(25-36), [Asn 34 ]PYYY(25-36)
  • the PYY(3-36) variant, analog, or biologically active fragment thereof may be a fragment with a double point mutation e.g., double point mutation of PYY(25-36) such as [Lys25, Thr27]PPY(25-36), [Lys25, Phe27]PPY(25-36), [Lys25, Ne28]PPY(25-36), [Lys25, Val28]PPY(25-36), [Lys25, Gln29]PPY(25-36), [Lys 25 , lle 30 ]PPY(25-36), [Lys 25 , Val 30 ]PPY(25-36), [Lys 25 , Val 30 ]PPY(25-36), [Lys 25 ,lle 31 ]PPY(25-36), [Lys 25 , Leu 31 ]PPY(25-36), [Lys 25 , Ser 32 ]PPY(25-36), [Lys 25 , Ly
  • the metabolic hormone is leptin or an analog, variant, or biologically active fragment thereof.
  • leptin or its variant or biologically active fragment thereof has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 6.
  • leptin has the amino acid sequence set forth in SEQ ID NO: 6.
  • the analog of leptin is the recombinant analog metreleptin (MYALEPT®), which contains a polypeptide having the sequence set forth in SEQ ID NO: 9 and contains a disulfide bridge connecting amino acid residues 97 and 147.
  • the analog of leptin is a murine leptin analog, e.g.., as described in Peters et al. Endocrinol. 148: 2878-2885, 2007, which is hereby incorporated by reference in its entirety.
  • the methods described herein include administration of leptin or variant, analog, or biologically active fragment thereof in a dose of from about 2.5 pg to about 2.5 mg. In some embodiments, the methods described herein include administration of leptin or variant, analog, or biologically active fragment thereof in a dose of from about 10 pg to about 1 mg.
  • the methods described herein include administration of leptin or variant, analog, or biologically active fragment thereof in a dose of from about 25 pg to about 250 pg (e.g., a dose of about 25 pg, 50 pg, 75 pg, 100 pg, 125 pg, 150 pg, 175 pg, 200 pg, 225 pg, or 250 pg).
  • the metabolic hormone is amylin or a variant or biologically active fragment thereof.
  • amylin or its variant, analog, or biologically active fragment thereof has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 7.
  • amylin has the amino acid sequence set forth in SEQ ID NO: 7.
  • the variant of amylin is pramlintide (SYMLIN®), which contains a polypeptide having to the sequence set forth in SEQ ID NO: 8.
  • the methods described herein include administration of amylin or variant, analog, or biologically active fragment thereof in a dose of from about 2.5 gg to about 2.5 mg. In some embodiments, the methods described herein include administration of amylin or variant, analog, or biologically active fragment thereof in a dose of from about 10 gg to about 1 mg. In some embodiments, the methods described herein include administration of amylin or variant, analog, or biologically active fragment thereof in a dose of from about 25 gg to about 250 gg (e.g., a dose of about 25 gg, 50 gg, 75 gg, 100 gg, 125 gg, 150 gg, 175 gg, 200 gg, 225 gg, or 250 gg).
  • the metabolic hormone is GLP-1 or an analog, variant, or biologically active fragment thereof.
  • GLP-1 or variant, analog, or biologically active fragment thereof has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 3.
  • GLP-1 has the amino acid sequence set forth in SEQ ID NO: 3.
  • the GLP-1 fragment is GLP-1 (7-36) or variant, analog, or biologically active fragment thereof.
  • GLP-1 (7-36) or variant, analog, or biologically active fragment thereof has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 4.
  • GLP-1 (7-36) has the amino acid sequence set forth in SEQ ID NO: 4.
  • the GLP-1 fragment is GLP-1 (7-37) or variant, analog, or biologically active fragment thereof.
  • GLP-1 (7-37) or variant, analog, or biologically active fragment thereof has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%,
  • GLP-1 (7-37) has the amino acid sequence set forth in SEQ ID NO: 5.
  • the methods described herein include administration of GLP-1 or variant, analog, or biologically active fragment thereof in a dose of from about 2.5 gg to about 2.5 mg. In some embodiments, the methods described herein include administration of GLP-1 or variant, analog, or biologically active fragment thereof in a dose of from about 10 gg to about 1 mg.
  • the methods described herein include administration of GLP-1 or variant, analog, or biologically active fragment thereof in a dose of from about 25 gg to about 250 gg (e.g., a dose of about 25 gg, 50 gg, 75 gg, 100 gg, 125 gg, 150 gg, 175 gg, 200 gg, 225 gg, or 250 gg).
  • the metabolic hormone is calcitonin or an analog, variant, or biologically active fragment thereof.
  • calcitonin or variant, analog, or biologically active fragment thereof has at least 70% (e.g., 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 10.
  • calcitonin has the amino acid sequence set forth in SEQ ID NO: 10.
  • the methods described herein include administration of calcitonin or variant, analog, or biologically active fragment thereof in a dose of from about 2.5 gg to about 2.5 mg.
  • the methods described herein include administration of calcitonin or variant, analog, or biologically active fragment thereof in a dose of from about 10 gg to about 1 mg. In some embodiments, the methods described herein include administration of calcitonin or variant, analog, or biologically active fragment thereof in a dose of from about 25 gg to about 250 gg (e.g., a dose of about 25 gg, 50 gg, 75 gg, 100 gg, 125 gg, 150 gg, 175 gg, 200 gg, 225 gg, or 250 gg).
  • the metabolic hormone is insulin, or an analog (e.g., insulin aspart (NOVOLOG®), insulin glargine (LANTUS®), insulin lispro (LYUMJEVTM), insulin glulisine (APIDRA®), or insulin detemir (LEVEMIR®), insulin degludec (TRESIBA®), NPH insulin (HUMULIN® N or NOVOLIN®
  • insulin or a variant, analog, or biologically active fragment thereof has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 12.
  • insulin has the amino acid sequence set forth in SEQ ID NO: 12.
  • the analog of insulin is insulin aspart (NOVOLOG®), having an A chain with the sequence set forth in SEQ ID NO: 13 and a B chain with the sequence set forth in SEQ ID NO: 14.
  • the analog of insulin is insulin glargine (LANTUS®), having an A chain with sequence set forth in SEQ ID NO: 15 and a B chain with to the sequence set forth in SEQ ID NO: 16.
  • the analog of insulin is insulin lispro (LYUMJEVTM), having an A chain with the sequence set forth in SEQ ID NO: 17 and a B chain with to the sequence set forth in SEQ ID NO: 18.
  • the analog of insulin is insulin glulisine (APIDRA®), having an A chain with the sequence set forth in SEQ ID NO: 19 and a B chain with to the sequence set forth in SEQ ID NO: 20.
  • the analog of insulin is insulin detemir (LEVEMIR®), having an A chain with to the sequence set forth in SEQ ID NO: 21 and a B chain with to the sequence set forth in SEQ ID NO: 22.
  • the methods herein described include the administration (e.g., topical) of insulin or a variant, analog, or biologically active fragment thereof in a dose of from about 2.5 pg to about 2.5 mg. In some embodiments, the methods herein described include the administration (e.g., topical) of insulin or a variant, analog, or biologically active fragment thereof in a dose of from about 10 pg to about 1 mg.
  • the metabolic hormones or variants or biologically active fragments thereof described herein can be formulated as pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.
  • compositions described herein may be administered to a subject (e.g., a human) in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the compositions described herein may be administered, for example, by any route that allows the composition (e.g., the metabolic) to reach the target receptor without substantially changing the concentration of the metabolic hormone in the blood of the subject.
  • the composition may be administered, for example, intranasal, intrarectal, or topical Gl routes.
  • the compositions described herein are formulated for intranasal delivery.
  • the intranasal composition may be formulated, e.g., as a spray, a semisolid, a particular, or in a lipid- based carrier.
  • the formulation may be, e.g., a solution, a suspension, a powder, or a gel.
  • Suitable intranasal formulations are described, e.g., in Marx et al. Drug Discov Dev 299-320, 2015, which is hereby incorporated by reference in its entirety.
  • the compositions described herein are administered via inhalation, e.g., via nasal inhalation.
  • An inhalable composition described herein may be provided as a liquid dosage form or dry powder dosage form.
  • a dry powder composition may be, e.g., administered by inhalation as is or after reconstitution in a vehicle, e.g., saline (e.g., isotonic saline), phosphate-buffered saline, or water.
  • a vehicle e.g., saline (e.g., isotonic saline), phosphate-buffered saline, or water.
  • compositions described herein are formulated for topical administration to the Gl tract.
  • the topical composition may be formulated, e.g., as a Gl patch. Suitable Gl patch formulations are described, e.g., in Tao, et al Drug discovery Today 10:909-915, 2005, which is hereby incorporated by reference it its entirety.
  • the compositions described herein are formulated for intrarectal delivery.
  • the intrarectal composition may be formulated, e.g., as a suppository, an enema, an ointment, or a rectal foam. Suitable intrarectal formulations are described, e.g., in Hua Front. Pharmacol. 10: 1196, 2019, which is hereby incorporated by reference in its entirety.
  • Compositions for rectal administration may be in the form of suppositories containing a conventional suppository base, such as cocoa butter.
  • Solutions of a composition described herein can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2012, 22nd ed.) and in The United States Pharmacopeia: The National Formulary (USP 41 NF 36), published in 2018.
  • composition described herein may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the composition, chosen route of administration, and standard pharmaceutical practice.
  • the compositions include excipients that increase the time the metabolic hormone (e.g., PYY(3-36)) is in contact with the mucosa (e.g., nasal mucosa, Gl mucosa, or rectal mucosa).
  • the excipients may provide viscosity enhancement, encapsulation, and controlled release. Without being bound by theory, it is believed that increasing the contact time of the pharmaceutical formulation with the mucosa, leads to increased binding of the metabolic hormone to its receptor.
  • Suitable excipients for viscosity enhancement include rheology modifiers which also may be mucoadhesive such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, alginic acid, polyvinylpyrrolidone, and sodium carboxymethylcellulose.
  • Suitable excipients for modified release of the metabolic hormone in the mucosa include mucoadhesive permeation enhancers such as 23-lauryl ether, aprotinin, azone, benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrins, dextran sulfate, and lauric acid.
  • mucoadhesive polymers used for the compositions described herein include agarose, chitosan, gelatin, hyaluronic acid, gums (e.g. guar, hakea, xanthan, gellan, carrageenan, pectin, and sodium alginate), cellulose derivatives (e.g., CMC, thiolated CMC, sodium CMC, HEC, HPMC, MC, methylhydroxylethylcellulose), poly (acrylic acid)-based polymers (e.g., CP, PC, PAA, polyacrylates, poly(methylvinylether-co-methacrylic acid), poly(2- hydroxyethyl methacryalate), poly(alkylcyanoacryalate), poly(isohexylcyanocrylate), poly(isobutylcyanoacrylate), copolymer of acrylic acid and PEG, poly(N-2-hydroxypropyl methacrylamide), PHPMAm, polyoxyethylene
  • a composition containing a metabolic hormone as described herein can include one or more pharmaceutically acceptable excipients, such as propylene glycol, potassium sorbate, l-arginine, edetate disodium, monosodium phosphate, and polysorbate 20.
  • the compositions described herein can include co-solvent stabilizers like propylene glycol or other suitable co-solvent stabilizers (e.g., lower molecular weight polyethylene glycols (PEG) such as PEG 200 and 400, glycerin, and ethanol.
  • PEG lower molecular weight polyethylene glycols
  • compositions described herein include amino acid stabilizers like L-arginine or other suitable amino acid stabilizers (e.g., alanine, aspartic acid, glycine, lysine, proline, or methionine).
  • amino acid stabilizers like L-arginine or other suitable amino acid stabilizers (e.g., alanine, aspartic acid, glycine, lysine, proline, or methionine).
  • compositions described herein can include preservatives like potassium sorbate, or other suitable preservatives (e.g., ascorbic acid, benzyl alcohol, benzoic acid, citric acid, chlorobutanol, m-cresol, glutathione, methionine, methylparaben, propylparaben, sodium sulfite, parahydroxybenzoate esters (methylhydroxybenzoate and propylhydroxybenzoate), boric acid and borate salts, sorbic acid and other sorbate salts besides potassium, and phenolics).
  • preservatives like potassium sorbate, or other suitable preservatives (e.g., ascorbic acid, benzyl alcohol, benzoic acid, citric acid, chlorobutanol, m-cresol, glutathione, methionine, methylparaben, propylparaben, sodium sulfite, parahydroxybenzoate esters (methylhydroxybenzoate and propylhydroxybenzoate
  • compositions described herein can include antioxidants such as edetate disodium or another suitable antioxidant (e.g., sodium formaldehyde sulphoxylate, butylated hydroxyanisole, and butylated hydroxytoluene).
  • the compositions described herein include buffers (e.g., acetate, carbonate, citrate, citrate-phosphate, glycine, HEPES, histidine, maleate, phosphate, succinate, tartrate, and triethanolamine (Tris)).
  • the compositions described herein can include surfactants, such as polysorbate 20 or other suitable surfactants (e.g., Poloxamer 188/407, polysorbate 40 or 80, or sodium lauryl sulfate).
  • the pharmaceutical composition may be administered as in a unit dose form or as a dose per mass or weight of the patient from 0.01 ng/kg to 250 pg/kg (e.g., for a person of 75 kg body weight).
  • the dose of the metabolic hormone may be from 0.01 ng/kg to 0.1 ng/kg, e.g., 0.01 ng/kg, 0.02 ng/kg, 0.03 ng/kg, 0.04 ng/kg, 0.05 ng/kg, 0.06 ng/kg, 0.07 ng/kg, 0.08 ng/kg, 0.09 ng/kg, or 0.1 ng/kg, e.g., from 0.1 ng/kg to 1 ng/kg, e.g., 0.1 ng/kg, 0.2 ng/kg, 0.3 ng/kg, 0.4 ng/kg, 0.5 ng/kg, 0.6 ng/kg, 0.7 ng/kg, 0.8 ng/kg, 0.9 ng/kg, or 1
  • ng/kg 2 ng/kg, 3 ng/kg, 4 ng/kg, 5 ng/kg, 6 ng/kg, 7 ng/kg, 8 ng/kg, 9 ng/kg, or 10 ng/kg, e.g., from 10 ng/kg to 100 ng/kg, e.g., 10 ng/kg, 20 ng/kg, 30 ng/kg, 40 ng/kg, 50 ng/kg, 60 pg/kg, 70 ng/kg, 80 ng/kg, 90 ng/kg, or 100 ng/kg, e.g., from 100 ng/kg to 1 pg/kg, e.g., 100 ng/kg, 200 ng/kg, 300 ng/kg, 400 ng/kg, 500 ng/kg, 600 ng/kg, 700 ng/kg, 800 ng/kg, 900 ng/kg, or 1 pg/kg, e.g., from 1 pg/kg to 10 pg/
  • the dosage of a pharmaceutical composition or the active agent in a pharmaceutical composition may be in the range of from about 10 ng to about 200 pg per kg body weight, e.g., from about 100 ng to about 10 pg per kg body weight, or e.g., from about 100 ng to about 2.5 pg per kg body weight, e.g., a dose of about 100 ng, 200 ng, 300 ng, 400 ng, 500 ng, 600 ng, 700 ng, 800 ng, 900 ng, 1 pg, 2 pg, or 2.5 pg per kg body weight (e.g., for a person of 75 kg body weight).
  • the active agent e.g., metabolic hormone, e.g., PYY (e.g., PYY(3-36)
  • GLP-1 e.g., leptin, amylin, insulin, or calcitonin, or a variant, analog, or biologically active fragment thereof
  • a pharmaceutical composition may be
  • the dosage of an analog, variant, or biologically active fragment of the active agent may be administered as a molar equivalent amount of the active agent.
  • a metabolic hormone analog containing a posttranslational modification or a half-life extending moiety may require an increased (e.g., by 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, or more) dosage than the dosage of the corresponding metabolic hormone without the posttranslational modification or half-life extending moiety.
  • the pharmaceutical composition may also be administered as a dose per mass or weight of the patient per unit day (e.g., 0.01 ng/kg/day to 250 pg/kg/day).
  • the pharmaceutical composition is administered at a dose from 10 ng/kg/day to 200 pg/kg/day (e.g., from 50 ng/kg/day to 100 pg/kg/day, from 100 ng/kg/day to 50 pg/kg/day, from 500 ng/kg/day to 1 pg/kg/day).
  • the pharmaceutical composition is administered at a dose from 100 ng/kg/day to 10 pg/kg/day (e.g., 100 ng/kg/day, 110 ng/kg/day, 120 ng/kg/day, 130 ng/kg/day, 140 ng/kg/day, 150 ng/kg/day, 160 ng/kg/day, 170 ng/kg/day, 180 ng/kg/day, 190 ng/kg/day, 200 ng/kg/day, 210 ng/kg/day, 220 ng/kg/day, 230 ng/kg/day, 240 ng/kg/day, 250 ng/kg/day, 260 ng/kg/day, 270 ng/kg/day, 280 ng/kg/day, 290 ng/kg/day, 300 ng/kg/day, 310 ng/kg/day, 320 ng/kg/day, 330 ng/kg/day, 340 ng/kg/day, 350 ng/kg/day,
  • the pharmaceutical composition is administered at a dose from about 100 ng/kg/day to about 2.5 pg/kg/day (e.g., 100 ng/kg/day, 110 ng/kg/day, 120 ng/kg/day, 130 ng/kg/day, 140 ng/kg/day, 150 ng/kg/day, 160 ng/kg/day, 170 ng/kg/day, 180 ng/kg/day, 190 ng/kg/day, 200 ng/kg/day, 210 ng/kg/day, 220 ng/kg/day, 230 ng/kg/day, 240 ng/kg/day, 250 ng/kg/day, 260 ng/kg/day, 270 ng/kg/day, 280 ng/kg/day, 290 ng/kg/day, 300 ng/kg/day, 310 ng/kg/day, 320 ng/kg/day, 330 ng/kg/day, 340 ng/kg/day, 350
  • a dose
  • compositions e.g., a composition including a metabolic hormone
  • the dosage of the compositions described herein can vary depending on many factors, such as the pharmacodynamic properties of the metabolic hormone, the mode of administration, the age, health, and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment, and the type of concurrent treatment, if any, and the clearance rate of the composition in the animal to be treated.
  • the compositions described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response.
  • the dosage of a composition is a prophylactically or a therapeutically effective amount.
  • compositions may be continuously given or divided into dosages given per a given time frame.
  • the composition can be administered, for example, every hour, day, week, month, or year. In some embodiments, the composition may be administered continuously.
  • a rectal formulation or Gl patch may be present on the subject for a sustained amount of time (e.g., for at least 1 hour, 2 hours,
  • the pharmaceutical compositions described herein may be provided in a kit that includes the pharmaceutical composition (e.g., in a container) and instructions for use thereof.
  • the kit may contain one or more containers, in which each container contains a different composition of the invention.
  • the instructions enclosed with the kit may be used to instruct a user to perform a method as described herein.
  • the methods described herein include administration of a metabolic hormone (e.g., PYY, PYY(3- 36), leptin, amylin, insulin, GLP-1 , or an analog, variant, or biologically active fragment thereof locally to the rectum, nasal cavity, or Gl tract of a subject, wherein the local administration does not produce substantial change to the level of the metabolic hormone in the blood and/or plasma of the subject.
  • a metabolic hormone e.g., PYY, PYY(3- 36)
  • leptin e.g., amylin, insulin, GLP-1 , or an analog, variant, or biologically active fragment thereof locally to the rectum, nasal cavity, or Gl tract of a subject
  • the local administration does not produce substantial change to the level of the metabolic hormone in the blood and/or plasma of the subject.
  • the metabolic hormone level in the blood and/or plasma of the subject does not increase more than up to 10% (e.g., 9%, 8%, 7%, 6%,
  • the blood and/or plasma level of PYY(3-36) does not substantially surpass pre-prandial levels of from about 15 pmol/l to about 25 pmol/l as reported in Batterham et al, Cell Metabolism, 4:223-233, 2006, herein incorporated by reference, in its entirety, after administration (e.g., topical) of PYY(3-36).
  • the blood and/or plasma level of leptin does not substantially surpass pre-prandial levels of from about 5 ng/ml to about 35 ng/ml as reported in Considine et al, N. Engl. J. Med.
  • the blood and/or plasma level of amylin does not substantially surpass pre-prandial levels of about 20 pmol/l as reported in Cooper et al, Hypertension, 26:460-464, 1995, herein incorporated by reference in its entirety, after administration (e.g., topical) of amylin.
  • the methods described herein include the administration of a metabolic hormone for the induction of satiety and/or treatment of metabolic syndrome, diabetes, obesity, or any obesity-related disorder.
  • the subject in need of treatment has been diagnosed with or it is at risk of a metabolic syndrome, obesity, an obesity-related disorder, diabetes, fatty liver disease, nonalcoholic steatohepatitis, chronic kidney disease, polycystic ovary syndrome, cardiovascular disease, obstructive sleep apnea, retinopathy, peripheral vascular disease, peripheral artery disease, and neuropathy (e.g., diabetic neuropathy).
  • the methods are used for maintenance of weight or prevention of weight gain.

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  • Engineering & Computer Science (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Endocrinology (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des procédés pour induire la satiété et traiter des troubles métaboliques, le diabète, l'obésité et des états liés à l'obésité. Ces procédés comprennent l'administration d'une hormone métabolique par voie intranasale, gastro-intestinale ou intrarectale.
EP22838447.5A 2021-07-08 2022-07-08 Procédés d'induction de la satiété et de traitement de troubles métaboliques Pending EP4366711A2 (fr)

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PCT/US2022/036439 WO2023283393A2 (fr) 2021-07-08 2022-07-08 Procédés d'induction de la satiété et de traitement de troubles métaboliques

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7166575B2 (en) * 2002-12-17 2007-01-23 Nastech Pharmaceutical Company Inc. Compositions and methods for enhanced mucosal delivery of peptide YY and methods for treating and preventing obesity
CA2660029A1 (fr) * 2006-08-04 2008-02-07 Nastech Pharmaceutical Company Inc. Compositions pour administration intranasale d'insuline humaine et leurs utilisations

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