WO2021173184A1 - Procédé de préparation d'une combinaison de bêta-endorphine et d'hormone adrénocorticotropique - Google Patents

Procédé de préparation d'une combinaison de bêta-endorphine et d'hormone adrénocorticotropique Download PDF

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WO2021173184A1
WO2021173184A1 PCT/US2020/048813 US2020048813W WO2021173184A1 WO 2021173184 A1 WO2021173184 A1 WO 2021173184A1 US 2020048813 W US2020048813 W US 2020048813W WO 2021173184 A1 WO2021173184 A1 WO 2021173184A1
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acth
endorphin
disease
treatment
mice
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PCT/US2020/048813
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English (en)
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Charles Peter Lollo
Dennis J. Carlo
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Adamis Pharmaceuticals Corporation
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Priority claimed from PCT/US2020/022473 external-priority patent/WO2020186108A1/fr
Application filed by Adamis Pharmaceuticals Corporation filed Critical Adamis Pharmaceuticals Corporation
Publication of WO2021173184A1 publication Critical patent/WO2021173184A1/fr

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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • 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
    • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • A61K38/35—Corticotropin [ACTH]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

  • the present disclosure is directed to co-formulations of b-endorphin and adrenocorticotropic hormone (ACTH) as well as their use in methods of treating mammalian disease.
  • ACTH adrenocorticotropic hormone
  • Extracts from animal pituitary glands have been used since the 1950s to treat numerous disease indications including multiple sclerosis, systemic lupus erythematosus, proteinuria in nephrotic syndrome, polymyositis, symptomatic sarcoidosis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, severe acute and chronic allergic and inflammatory processes involving the eye, and infantile spasms.
  • These extract products contain hundreds of peptides that mostly derive from pro-opiomelanocortin (POMC).
  • POMC pro-opiomelanocortin
  • POMC is cleaved in vivo into several major peptides including adrenocorticotropic hormone (ACTH), melanocyte stimulating hormones (a, b, and y), Lipotropin (b and g), b-endorphin and Met-Enkephalin.
  • peptide extracts contain hundreds of peptide forms that are generated by post-translational modifications.
  • ACTH cortisol
  • corticosterone corticosterone
  • aldosterone synthetic analogues of ACTH have been marketed, such as tetracosactide or cosyntropin (e.g., Cortrosyn® by Amphastar; Synacthen® by Mallinckrodt), consisting of the first 24 amino acids of ACTH’s 39 amino acids.
  • synthetic analogues of ACTH such as tetracosactide or cosyntropin (e.g., Cortrosyn® by Amphastar; Synacthen® by Mallinckrodt), consisting of the first 24 amino acids of ACTH’s 39 amino acids.
  • compositions comprising b-endorphin and adrenocorticotropic hormone (ACTH) or analogues of one, the other, or both, thereof.
  • the b-endorphin or ACTH have the human sequence of SEQ ID NO: 1 and SEQ ID NO: 2, respectively.
  • the b- endorphin or ACTH have the bovine sequence of SEQ ID NO: 3 and SEQ ID NO: 4, respectively, or the porcine sequence of SEQ ID NO: 5 and SEQ ID NO: 6 or 7, respectively.
  • ACTH and b-endorphin are highly conserved and the native sequences from other species may be considered analogues of one or another of the sequences enumerated herein.
  • the analogue is a truncation of a natural sequence, for example, ACTH (1-24).
  • Still other analogues incorporate one or more D-amino acids, for example, amino acids 1 to 5 of the N-terminal residues.
  • compositions comprising b-endorphin ACTH or analogues thereof do not comprise any active peptides comprising amino acid sequences from other regions of POMC. In some embodiments, compositions comprising b-endorphin and ACTH or analogues thereof do not comprise any other active peptides derived from POMC. In some embodiments, compositions comprising b-endorphin and ACTH or analogues thereof do not comprise a-melanocyte-stimulating hormone (a-MSH), corticotropin-like intermediate lobe peptide (CLIP), b-lipotropin (b-LPH), b-MSH, y-MSH, or A/-POMC, or any combination thereof.
  • a-MSH corticotropin-like intermediate lobe peptide
  • CLIP corticotropin-like intermediate lobe peptide
  • b-LPH b-lipotropin
  • compositions are pharmaceutical co-formulations of b-endorphin and ACTH.
  • the formulation is a repository or depot-forming formulation, for example, an injectable gel.
  • the injectable gel comprises gelatin, for example, 16% gelatin.
  • the co-formulation is supplied in a vial. In other embodiments, the co-formulation is supplied in a pre-filled syringe.
  • Disclosed herein are methods of treating a disease, disorder, or condition comprising administering a co-formulation of b-endorphin and ACTH, use of b-endorphin and ACTH for treating a disease, use of b-endorphin and ACTH in the manufacture of a medicament for treating a disease, and b-endorphin and ACTH for use in treating a disease.
  • Some embodiments further comprise administration of a superoxide dismutase mimetic, for example Tempol (4-oxypiperidol).
  • the disease to be treated is an autoimmune disease, an inflammatory disorder, or an allergic disorder.
  • the disease to be treated is multiple sclerosis, systemic lupus erythematosus, proteinuria in nephrotic syndrome, polymyositis, symptomatic sarcoidosis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, or severe acute and chronic allergic or inflammatory processes involving the eye.
  • the disease to be treated is a neurologic or seizure disorder, including various types of childhood epilepsy, for example, infantile spasms (West syndrome), Lennox- Gastaut syndrome, Landau-Kleffner syndrome, and electrical status epilepticus in sleep.
  • Fig. 1 depicts the change in EAE severity (mean clinical score) over the course of the study for each of the four groups: Vehicle (diamond), ACTH + b-endorphin - Low dose (triangle), ACTH + b-endorphin - High dose (square), and prednisolone (reference treatment; x).
  • Vehicle diamond
  • ACTH + b-endorphin - Low dose triangle
  • ACTH + b-endorphin - High dose square
  • prednisolone reference treatment; x.
  • low dose was 32 pg ACTH, 16 pg b-endorphin
  • high dose was 64 pg ACTH, 32 pg b- endorphin.
  • Fig. 2 depicts the change in body weight over the course of the study for each of the four groups: Vehicle (diamond), ACTH + b-endorphin - Low dose (triangle), ACTH + b- endorphin - High dose (square), and prednisolone (reference treatment; x).
  • Vehicle diamond
  • ACTH + b-endorphin - Low dose triangle
  • ACTH + b- endorphin - High dose square
  • prednisolone reference treatment; x.
  • low dose was 32 pg ACTH, 16 pg b-endorphin
  • high dose was 64 pg ACTH, 32 pg b-endorphin.
  • Fig. 3 depicts the change in EAE severity (mean clinical score) over the course of the study for each of the four groups: Vehicle (diamond), ACTH + b-endorphin - Low dose (triangle), ACTH + b-endorphin - High dose (square), and FTY720 (reference treatment; x).
  • Vehicle diamond
  • ACTH + b-endorphin - Low dose triangle
  • ACTH + b-endorphin - High dose square
  • FTY720 reference treatment; x.
  • low dose was 53 pg ACTH, 27 pg b-endorphin
  • high dose was 128 pg ACTH, 64 pg b- endorphin.
  • Fig. 4 depicts the change in body weight over the course of the study for each of the four groups: Vehicle (diamond), ACTH + b-endorphin - Low dose (triangle), ACTH + b- endorphin - High dose (square), and FTY720 (reference treatment; x).
  • Vehicle diamond
  • ACTH + b-endorphin - Low dose triangle
  • ACTH + b- endorphin - High dose square
  • FTY720 reference treatment; x.
  • low dose was 53 pg ACTH, 27 pg b-endorphin
  • high dose was 128 pg ACTH, 64 pg b-endorphin.
  • FIG. 5 presents representative micrographs of sections of spines stained with H&E and anti-MBP (myelin basic protein) for each of the four groups: Vehicle, ACTH + b-endorphin - Low dose, ACTH + b-endorphin - High dose, and FTY720 (reference treatment).
  • low dose was 53 pg ACTH, 27 pg b-endorphin
  • high dose was 128 pg ACTH, 64 pg b- endorphin.
  • Fig. 6 depicts the change in EAE severity (mean clinical score) over the course of the study for each of the three groups: Vehicle (diamond), ACTH + b-endorphin (triangle), and FTY720 (reference treatment; square).
  • Vehicle diamond
  • ACTH + b-endorphin triangle
  • FTY720 reference treatment; square.
  • low dose was 53 pg ACTH, 27 pg b- endorphin
  • high dose was 128 pg ACTH, 64 pg b-endorphin.
  • Fig. 7 depicts the change in body weight over the course of the study for each of the three groups: Vehicle (diamond), ACTH + b-endorphin (triangle), and FTY720 (reference treatment; square).
  • Vehicle diamond
  • ACTH + b-endorphin triangle
  • FTY720 reference treatment; square
  • the test dose was 128 pg ACTH, 64 pg b-endorphin.
  • compositions and formulations comprising b-endorphin and adrenocorticotropic hormone (ACTH) or analogues of either or both thereof b-endorphin and ACTH are both naturally derived by proteolytic processing from proopiomelanocortin (POMC).
  • POMC proopiomelanocortin
  • Human POMC is a 241 amino acid polypeptide (SEQ ID NO: 10) which gives rise to multiple recognized peptides.
  • Residues 1-26 are a signal peptide; residues 27-102 are N- terminal peptide of proopiomelanocortin (NPP); residues 77-87 are g-melanocyte-stimulating hormone (g-MSH); residues 105-134 are a “potential peptide”; residues 138-176 are ACTH, also called corticotropin; residues 138-150 are a-MSH; residues 156-176 are corticotropin-like intermediate lobe peptide (CLIP); residues 179-267 are b-lipotropin (b-LPH); residues 179-234 are g-LPH; residues 217-234 are b-MSH; residues 237-267 are b-endorphin; and residues 237- 241 are met-enkephalin; as described at UniProtKB -
  • the N-terminal amino acid residue of ACTH is considered 1, so that ACTH is amino acid residues 1-39, a-MSH is 1-13, CLIP is 19-39, b- LPH is 42-130, g-LPH is 42-97, b-MSH is 80-97, b-endorphin is 100-130, Met-enkephalin is 100-104, g-endorphin is 100-116, and a-endorphin is 100-115, of SEQ ID NO:11.
  • SEQ ID NO: 11 is:
  • b-endorphin is a 31 amino acid peptide.
  • the sequences of human, bovine, porcine, and murine b-endorphin peptides are each presented in Table 1.
  • compositions and formulations may specifically include one or more of the above peptides (in combination or as alternatives), or an analogue thereof.
  • Other embodiments of the herein disclosed compositions and formulations specifically exclude one or more of the above peptides, or analogues thereof.
  • b-endorphin is concentrated in the anterior pituitary and pars intermedia, but also widely distributed throughout the body and has been detected in nervous tissue as well as adrenals, heart, liver, and placenta. Concomitant with its broad distribution, the physiological activity of b-endorphin directly or indirectly includes neurotransmitter functions, suppressive effects on respiration, analgesia, maintenance of cardiovascular homeostasis, and even regulation of T- and B-cell function in the immune system, b-endorphin’s activity is mediated through classical m, d and k opioid receptors and perhaps a more selective epsilon receptor, b- endorphin, like Met-enkephalin, contains the amino acid sequence YGG (residues 1-3) and binds to opioid receptors (m, d, and k) which mediate its physiologic functions.
  • b-endorphin analogues comprise the YGG subsequence.
  • YGG (residues 1-3) and QTPLV (residues 11-15) are important for binding to the human m opioid receptor
  • K9, QTPLV (residues 11-15), FK (residues 18-19), and K29 are important for binding to the human 5 opioid receptor
  • YGGF (residues 1-4), T8, K9, F18, I22, A26, Y27, K29 and E31 are important for binding to the human k opioid receptor, (individual conserved residues are denoted simply as the amino acid and the residue position, so that K9 indicates the lysine that is the ninth residue.)
  • Y27 and E31 are not conserved across species; apparently these substitutions can be tolerated, or the activities of the non-human b-endorphins in human systems are not crucially dependent on binding to the human k opioid receptor.
  • ACTH is a 39 amino acid peptide.
  • the sequences of human, bovine, porcine, and murine ACTH peptides are each presented in Table 2.
  • compositions and formulations may specifically include one or more of the above peptides that can be derived from POMC (in combination or as alternatives), or an analogue thereof.
  • Other embodiments of the herein disclosed compositions and formulations specifically exclude one or more of the above peptides that can be derived from POMC, or analogues thereof.
  • the disclosed compositions are substantially free of other peptides that can be derived from POMC.
  • peptides that can be derived from POMC refer to peptides that arise from specific proteolytic processing of POMC, for example, NPP, a-MSH, b-MSH, g-MSH, CLIP b-LPH, g-LPH, Met-enkephalin, g-endorphin, and a- endorphin, but does not refer to degradants of ACTH or b-endorphin.
  • ACTH and b-endorphin, or analogues thereof together make greater than 90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9% or 99.99% w/w of the peptides that can be derived from POMC that are present in a disclosed composition or formulation.
  • ACTH and b- endorphin, or analogues thereof together make greater than 90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9% or 99.99%, on a molar basis, of the peptides that can be derived from POMC that are present in a disclosed composition or formulation.
  • ACTH acts through the melanocortin receptor 2 (MC2R) which is mainly found in the zona fasiculata of the adrenal cortex. By binding to this receptor, ACTH stimulates production of glucocorticoids by adrenocortical cells. This binding is dependent on the KKRRP sequence (residues 15-19) in ACTH, which is not found in other peptides derived from POMC. MC2R is also found on white and brown adipocytes, consistent with ACTH’s observed role in glucose metabolism on osteoblasts, and in the skin. ACTH also contains the sequence HFRW (residues 6-9) which mediates binding to all five of the melanocortin receptors.
  • M2R melanocortin receptor 2
  • ACTH can have functions beyond steroidogenesis.
  • ACTH analogues comprise the KKRRP subsequence, the HFRW subsequence, or both.
  • ACTH and b-endorphin used to make the herein disclosed compositions and formulations can be obtained by any of several methods. Both of these peptides are small enough that it is commercially feasible to produce them by chemical synthesis using standard techniques. Chemical synthesis offers the advantages of using the human amino acid sequences, avoids exposure to enzymes that might further cleave the desired peptide, and obviates fears about adventitious infectious agents (be they prions, viruses, or bacteria) that can attend biologically sourced material.
  • the composition or formulation comprising ACTH and b-endorphin is substantially free of other peptides found in pituitary extract.
  • ACTH and b-endorphin, or analogues thereof, in a disclosed composition or formulation are greater than 90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9% or 99.99% (w/w) free of other peptides found in pituitary extract. In various embodiments, ACTH and b-endorphin, or analogues thereof, in a disclosed composition or formulation are greater than 90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9% or 99.99% free of other peptides found in pituitary extract on a molar basis.
  • ACTH and b-endorphin can also be made using recombinant DNA technology either individually or from a common precursor. Post-translational modification of the final peptide is not necessary, so they may be produced in bacterial or eukaryotic culture systems.
  • the primary translation product can typically have an initiator methionine, which can either be retained or be part of a sequence that can be subsequently cleaved.
  • polypeptides are subject to degradation through multiple mechanisms.
  • the presence of small amounts of degradants of ACTH or b-endorphin does not mean that a herein disclosed composition or formulation is not substantially free of other peptides found in pituitary extract or other peptides derived from POMC.
  • the total amount of degradants, or the amount of any single degradant, in a composition or formulation does not exceed a level considered acceptable for a human pharmaceutical product by a relevant regulatory authority.
  • analogue can refer to any variant that retains sufficient structure and relevant activity to be recognized as being related to the base peptide and to serve a similar function.
  • an analogue contains one or more amino acid substitutions, insertions or deletions.
  • an analogue is a truncated version of the base peptide.
  • additional amino acid sequences have been added to one or the other termini of the base peptide. Such additional sequences may aid in the purification of the peptide, or alter its bioavailability or half-life after administration.
  • the analogue can include non-amino acid additions to the peptide, for example, PEGylation.
  • compositions including pharmaceutical compositions, and formulations may contain water or other solvents, salts, buffers, stabilizers, anti-bacterial or anti fungal agents, or other excipients as are used in pharmaceutical products.
  • Excipients can include: phenol, for example, 0.5%; added cysteine £0.1%; NaOH or acetic acid to adjust pH; and water for injection.
  • pharmaceutical composition refers to a composition that is suitable for use as a drug product, including that it facially meets safety standards as would be required by regulatory authorities such as the Food and Drug Administration or corresponding agencies outside the U.S. This is not meant to necessarily imply any particular level of laboratory or clinical testing to demonstrate safety.
  • Some embodiments are repository (or depot) formulations of b-endorphin and ACTH. Such formulations release the peptides over time, prolonging their effective half-life and reducing the number of administrations needed in a course of treatment or other time interval.
  • the repository formulation contains gelatin, for example 13-19% gelatin, for example 16% gelatin, or any sub-range or individual value therein obtained by steps of 0.5%.
  • a copolymer such as poly(lactic-co-glycolic acid) (PLGA) could be used instead of gelatin.
  • PLGA poly(lactic-co-glycolic acid)
  • a similar half-life prolonging effect can be obtained by PEGylation of the peptide.
  • polyethylene glycol (PEG) is covalently attached to a terminal C residue added to the sequence of the peptide.
  • the ACTH and b-endorphin are co-formulated in a single composition.
  • the ACTH and b-endorphin are formulated separately in which case they may be administered according to the same schedule, or according to different schedules within a common time interval so that the effects of both overlap within that time interval.
  • the formulation is provided in a vial. In other embodiments the formulation is provided in a pre-filled syringe. In some embodiments the formulation contains 80 USP units of ACTH per ml_. One mg of ACTH corresponds to about 150 units, based on rat potency testing. In some embodiments, after prolonged use, dosage is tapered off in quantity and/or frequency to avoid adrenal insufficiency, or recurrent symptoms, which can occur upon sudden withdrawal of ACTH.
  • the mass ratio of ACTH to b-endorphin is in the range of 1:1 to 4:1. In some embodiments the mass ratio of ACTH to b-endorphin is 2:1. In some embodiments a dose contains approximately half the molar amount of b-endorphin as ACTH (a mass ratio of about 2.6:1). In another embodiment, the formulation contains 0.5 to 2 mg/ml_ of ACTH and 0.1 to 1 mg/ml_ of b-endorphin.
  • a dosage comprising 40-80 U of ACTH in a repository (or other extended half-life) formulation over a 24-72 hour period is appropriate.
  • an adult dosage comprises about 0.8-1.2, 0.9-1.1, or 1 mg of ACTH.
  • the combination of ACTH and b-endorphin is administered to resolve exacerbations of the disease, while in on other embodiments the combination is administered as a maintenance therapy.
  • the dosage for maintenance therapy is less than for treating acute exacerbations.
  • Drug dosages are commonly expressed in units of mg/kg or units/kg, or even simply in mg or units if the therapeutic window is wide enough, largely for convenience.
  • drug dosages expressed in units of mg/m 2 of body surface area can provide greater precision, as drug exposure scales more closely to the subject’s body surface area (BSA) than it does to body weight. This can be particularly useful in choosing pediatric dosages.
  • BSA body surface area
  • BSA (m 2 ) Vheight (cm) c weight (kg) /3600)
  • BSA (m 2 ) Vheight (cm) c weight (kg) /3600)
  • the dosage can be administered by subcutaneous or intramuscular injection and can be administered by a healthcare professional (for example, a doctor, a nurse, a physician’s assistant, or the like) or by a trained patient, a trained parent of a patient, or other trained non professional assistant.
  • administration is viewed as taking place under the direction of and at the behest of the prescribing physician.
  • administration is viewed as taking place at the behest of the recipient patient.
  • administration should be viewed as being carried out in order to receive the benefits attendant to the treatment.
  • treatment refers to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect is therapeutic, i.e. , the effect partially or completely cures a disease and/or adverse symptom attributable to the disease, or prevents or reduces the worsening thereof.
  • treatment is directed at resolving acute exacerbations or flare-ups of the disease.
  • treatment is maintenance therapy directed at preventing or mitigating exacerbations or progression of the disease.
  • the effect is prophylactic, i.e. the effect prevents or reduces the incidence or risk of developing the disease and/or an adverse symptom attributable to the disease.
  • a “clinically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic or prophylactic result.
  • the clinically effective amount may vary according to factors such as the disease state, age, sex, weight of the individual, etc. Dosage may be further adjusted based on an individual’s initial response to treatment. It is within the skill of a physician or pharmacologist to take such considerations into account, in combination with the disclosures and guidance provided herein, to determine the clinically effective amount for any person in need thereof,
  • the two peptides, b-endorphin and ACTH bind to all of the melanocortin and opioid receptors bound by any of the peptides derived from POMC, and thus can be used to replicate the activity profile of pituitary extracts.
  • the herein disclosed compositions and formulations of b-endorphin and ACTH can be used to treat a variety of diseases and disorders currently treated with an ACTH-containing pituitary extract, as described in subsequent paragraphs.
  • a combination of b-endorphin and ACTH can be equally or more effective than the pituitary extracts and provide a more completely defined medicament.
  • Acute exacerbations of multiple sclerosis can be treated. Treatment speeds resolution of the acute exacerbation, but has not been shown to impact the long-term course of the disease. However, the non-steroidogenic immune-modulating activities of ACTH support potential usefulness for long-term treatment of multiple sclerosis.
  • the present compositions and formulations of b-endorphin and ACTH can be useful for chronic treatment of multiple sclerosis in addition to treating acute exacerbations.
  • a dosage comprising 80-120 units of ACTH is administered daily by intramuscular or subcutaneous injection for 2-3 weeks, or until the exacerbation resolves.
  • Acute episodes or exacerbations of rheumatic disorders can be treated, such as psoriatic arthritis, rheumatoid arthritis, including juvenile rheumatoid arthritis, and ankylosing spondylitis.
  • treatment constitutes short-term adjuvant therapy, but in some cases low dose maintenance therapy can be undertaken.
  • Collagen disease such as systemic lupus erythematosus and systemic dermatomyositis (polymyositis) can be treated either to address exacerbations or as maintenance therapy.
  • ophthalmic disease severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa (for example eyelids, lacrimal glands, and tear ducts) can be treated.
  • Specific conditions treated can include keratitis, ulceris, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis, and anterior segment inflammation.
  • compositions and formulations can be used to induce diuresis or remission of proteinuria in the nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus.
  • compositions and formulations can also be used to treat dermatologic diseases, such as severe erythema multiforme and Stevens-Johnson syndrome; allergic conditions, such as serum sickness; and respiratory disease, such as symptomatic sarcoidosis.
  • dermatologic diseases such as severe erythema multiforme and Stevens-Johnson syndrome
  • allergic conditions such as serum sickness
  • respiratory disease such as symptomatic sarcoidosis.
  • compositions and formulations can also be used to treat infectious diseases, including viral diseases, particularly to prevent, reduce, mitigate, or eliminate severe or excessive, pathology-causing, immune responses provoked by the infection.
  • the severe or excessive immune response comprises an inflammatory reaction, such as inflammation of the lung.
  • inflammation of the lung is thromboinflammatory syndrome.
  • the severe or excessive immune response is cytokine release syndrome (cytokine storm).
  • the viral disease is COVID-19.
  • some embodiments are methods of treatment in which a composition or formulation comprising ACTH and b-endorphin, or analogues thereof, such as described herein above, are administered to a patient in need thereof.
  • the patient in need thereof has an autoimmune disease, an inflammatory disorder, or an allergic disorder.
  • the disease to be treated is multiple sclerosis, systemic lupus erythematosus, proteinuria in nephrotic syndrome, polymyositis, symptomatic sarcoidosis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, or severe acute and chronic allergic or inflammatory processes involving the eye.
  • the disease to be treated is a neurologic or seizure disorder, including various types of childhood epilepsy, for example, infantile spasms (West syndrome), Lennox-Gastaut syndrome, Landau-Kleffner syndrome, and electrical status epilepticus in sleep.
  • Corresponding embodiments include use of a composition or formulation comprising ACTH and b-endorphin, or analogues thereof, in the treatment of anyone of these diseases or conditions, and use of ACTH and b-endorphin, or analogues thereof, in the manufacture of a medicament for the treatment of anyone of these diseases or conditions.
  • composition or formulation comprising ACTH and b-endorphin, or analogues thereof is administered intramuscularly or subcutaneously. In various embodiments, the composition or formulation comprising ACTH and b-endorphin, or analogues thereof, is administered twice daily, daily, or every 2nd day.
  • administering occurs twice a day, daily, once every second day, or once every third day.
  • the patient in need thereof is additionally treated with a superoxide dismutase mimetic.
  • the superoxide dismutase mimetic is Tempol (4-oxypiperidol; 1-A-oxidanyl-2,2,6,6-tetramethylpiperidin-4-ol).
  • Tempol is in a separate composition than the ACTH and b-endorphin, or analogues thereof. This allows the Tempol to be administered according to a different schedule and/or different route of administration.
  • Tempol is administered orally.
  • Tempol is administered topically, sublingually, transrectally, intramuscularly, intravenously, or subcutaneously.
  • the dosage of Tempol is 0.01-1000 mg per day.
  • Tempol is included in the composition or formulation comprising ACTH and b-endorphin, or analogues thereof.
  • Embodiment 1 A pharmaceutical composition comprising, b-endorphin and adrenocorticotropic hormone (ACTH) or analogues thereof of either or both.
  • ACTH adrenocorticotropic hormone
  • Embodiment 2 A pharmaceutical composition comprising, two active agents, wherein the active agents consist of b-endorphin and ACTH or analogues thereof.
  • Embodiment 3 The pharmaceutical composition of Embodiment 1, which does not comprise any pro-opiomelanocortin (POMC)-derived peptides other than b-endorphin and ACTH.
  • POMC pro-opiomelanocortin
  • Embodiment 4 A repository formulation comprising the pharmaceutical composition of any one of Embodiments 1 to 3.
  • Embodiment 5 The repository formulation of Embodiment 4 comprising gelatin.
  • Embodiment 6 The repository formulation of Embodiment 5 comprising 15-17% gelatin.
  • Embodiment 7 The composition of any one of Embodiments 1-2, or the formulation of any one of claims 4-6, wherein the b-endorphin has the sequence of human b-endorphin (SEQ ID NO: 1).
  • Embodiment 8 The composition of any one of Embodiments 1-2, or the formulation of any one of claims 4-6, wherein the b-endorphin has the sequence of bovine b-endorphin (SEQ ID NO: 3).
  • Embodiment 9 The composition of any one of Embodiment s 1-2, or the formulation of any one of claims 4-6, wherein the b-endorphin has the sequence of porcine b-endorphin (SEQ ID NO: 5).
  • Embodiment 10 The composition of any one of Embodiment s 1-2, or the formulation of any one of claims 4-6, wherein the ACTH has the sequence of human ACTH (SEQ ID NO: 2).
  • Embodiment 11 The composition of any one of Embodiment s 1 -2, or the formulation of any one of claims 4-6, wherein the ACTH has the sequence of bovine ACTH (SEQ ID NO: 4).
  • Embodiment 12 The composition of any one of Embodiment s 1-2, or the formulation of any one of claims 4-6, wherein the ACTH has the sequence of porcine ACTH (SEQ ID NO: 6 or SEQ ID NO: 7).
  • Embodiment 13 A method of treating an inflammatory, autoimmune, allergic, or neurologic disease or disorder comprising administering the pharmaceutical composition or formulation of any one of Embodiments 1 to 12.
  • Embodiment 14 The method of Embodiment 13, wherein the neurologic disorder is infantile spasm, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, or electrical status epilepticus in sleep.
  • Embodiment 15 The method of Embodiment 13, wherein the inflammatory or autoimmune disease is multiple sclerosis.
  • Embodiment 16 The method of Embodiment 13, wherein the inflammatory or autoimmune disease is psoriatic arthritis; rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus or systemic dermatomyositis.
  • Embodiment 17 The method of Embodiment 13, wherein the inflammatory or allergic disorder is an ophthalmic disease.
  • Embodiment 18 The method of Embodiment 17, wherein the ophthalmic disease is keratitis, ulceris, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis, or anterior segment inflammation.
  • the ophthalmic disease is keratitis, ulceris, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis, or anterior segment inflammation.
  • Embodiment 19 The method of Embodiment 13, wherein the inflammatory or allergic disorder is edema, severe erythema multiforme, Stevens-Johnson syndrome, serum sickness, or symptomatic sarcoidosis.
  • Embodiment 20 The method of any one of Embodiments 13-19, further comprising administration of Tempol.
  • Embodiment 21 A syringe, pre-filled with the formulation of any one of Embodiments 4 to 12.
  • Embodiment 22 The use of the composition of any one of Embodiments 1-2, or the formulation of any one of claims 4-6, for the treatment an inflammatory, autoimmune, allergic, infectious, or neurologic disease or disorder.
  • Embodiment 23 A method of treating an inflammatory, autoimmune, allergic, infectious, or neurologic disease or disorder comprising administering a clinically effective amount of adrenocorticotropic hormone (ACTH) and b-endorphin, or analogues thereof of either or both, to a person in need thereof.
  • ACTH adrenocorticotropic hormone
  • b-endorphin or analogues thereof of either or both
  • Embodiment 24 The method of Embodiment 23, wherein the disease or disorder is infantile spasms, multiple sclerosis, a rheumatic disorder, a collagen disease, a dermatologic disease, an allergic disorder, an ophthalmic disease, a respiratory disease, or an edematous disorder.
  • the disease or disorder is infantile spasms, multiple sclerosis, a rheumatic disorder, a collagen disease, a dermatologic disease, an allergic disorder, an ophthalmic disease, a respiratory disease, or an edematous disorder.
  • Embodiment 25 The method of Embodiment 24, wherein the rheumatic disorder is rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.
  • Embodiment 26 The method of Embodiment 24, wherein the collagen disease is systemic lupus erythematosus, or systemic dermatomyositis. (Systemic dermatomyositis is also known as polymyositis).
  • Embodiment 27 The method of Embodiment 24, wherein the dermatologic disease is severe erythema multiforme or Stevens-Johnson syndrome.
  • Embodimetn 28 The method of Embodiment 24, wherein the allergic disorder is serum sickness.
  • Embodiment 29 The method of Embodiment 24, wherein the ophthalmic disease is a severe acute or chronic allergic or inflammatory process involving an eye or its adnexa.
  • Embodiment 30 The method of Embodiment 29, wherein the allergic or inflammatory process is keratitis, ulceris, iridocyclitis, diffuse posterior uveitis or choroiditis, optic neuritis, choriorentinitis, or anterior segment inflammation.
  • Embodiment 31 The method of Embodiment 24, wherein the respiratory disease is symptomatic sarcoidosis.
  • Embodiment 32 The method of Embodiment 24, wherein the edematous disorder is proteinuria in nephrotic syndrome.
  • Embodiment 33 The method of Embodiment 23, wherein the neurologic disease or disorder is childhood epilepsy, infantile spasms (West syndrome), Lennox-Gastaut syndrome, Landau-Kleffner syndrome, or electrical status epilepticus in sleep.
  • Embodiment 34 The method of any one of Embodiments 23-33, wherein treating comprises mitigating or resolving an acute exacerbation of the disease.
  • Embodiment 35 The method of any one of Embodiments 23-33, wherein treating comprises maintenance therapy, whereby incidences or severity of exacerbations of the disease is reduced.
  • Embodiment 36 The method of Embodiment 35, wherein the disease in relapsing- remitting multiple sclerosis and the incidence or severity of relapses is reduced.
  • Embodiment 37 The method of Embodiment 23, wherein the infectious disease is a viral disease comprising an excessive or severe immune response.
  • Embodiment 38 The method of Embodiment 27, wherein the infectious disease is COVID- 19.
  • Embodiment 39 The method of any one of Embodiments 23-33 or 37-38, wherein the treatment is prophylactic.
  • Embodiment 40 The method of Embodiment 39, wherein the disease or disorder has a recognizable prodrome.
  • Embodiment 41 The method of Embodiment 39, wherein the person in need thereof has an elevated risk of developing the disease or severe symptoms thereof.
  • Embodiment 42 The method of Embodiment 41 , wherein the risk is familial or environmental.
  • Embodiment 43 The method of Embodiment 23, wherein the person in need thereof has a family history of multiple sclerosis, and the treatment is prophylactic.
  • Embodiment 44 The method of any one of Embodiments 23-43 comprising administering 40-120 units of ACTH.
  • Embodiment 45 The method of any one of Embodiments 23-43, comprising administering 0.8-1.2 mg of ACTH.
  • Embodiment 46 The method of Embodiment 45, comprising administering about 1 mg of ACTH.
  • Embodiment 47 The method of one of Embodiments 23-46, wherein the mass ratio of ACTH ⁇ -endorphin is 2:1.
  • the Ts65Dn mouse was initially developed as a model of Down’s syndrome, but shows spontaneous spike-and-wave discharges (Cortez, M.A., et al., Pediatric Research 65(5):499-503 (2009).
  • Gamma-aminobutyric acid B (GABA B R) agonists such as baclofen and g-butyrolactone, induce acute epileptic extensor spasms (AEES) associated with epileptiform polyspike bursts and an electrodecremental response on the EEG.
  • GABA B R agonist- treated Ts65Dn mouse shows the unique clinical, electrographic, and pharmacologic signature of infantile spasms and represents a valid, acute model of this disorder.
  • Rodent (but not porcine) ACTH SEQ ID NO: 9 can significantly reduce AEES.
  • Cohorts of TS65Dn mice are administered a GABA b R agonist and treated with a vehicle control, murine ACTH 1-24 , murine ACTH 1-39 , murine b-endorphin (SEQ ID NO: 8), murine ACTH 1-24 plus b-endorphin, or murine ACTH 1-39 plus murine b-endorphin and evaluated for the reduction in the number of AEES and of electrodecremental response.
  • EAE Experimental autoimmune encephalitis
  • PPP 139-151 synthetic myelin basic protein 139-151 peptide
  • RR-EAE relapsing-remitting form of the disease
  • H.P. Acthar Gel ® Acthar
  • Acthar treatment also suppresses ex vivo myelin peptide induced CD4 + T cell proliferation (Cusick et al., Autoimmunity 48(4):222-230 (2015).
  • RR-EAE is induced according to standard protocol. Briefly, SJL/J mice are sensitized by subcutaneous injection of with PLP139-151 in complete Freund’s adjuvant (CFA), followed by intravenous injections of Bordetella pertussis toxin. The mice are then randomized into the following treatment arms using a repository formulation: vehicle control, ACTH, b-endorphin, and ACTH plus b-endorphin; with comparison of human sequence to either porcine or murine sequence. In separate studies treatment is begun immediately upon relapse and five days after the onset of relapse. The mice are monitored daily for weight and clinical signs.
  • CFA complete Freund’s adjuvant
  • Clinical scoring uses the scale: 0, no clinical signs; 1, loss of tail tonicity; 2, presents with mild hind leg paralysis with no obvious gait disturbance; 3, mild leg paralysis with gait disturbance and paralysis; 4, hind legs are paralyzed; and 5, moribund or dead. Histology is performed on spinal cords harvested after death by euthanasia and scored for inflammation and demyelination.
  • ACTH plus b-endorphin dampens RR-EAE and ameliorates inflammation and demyelination to a greater extent that ACTH alone.
  • EAE EAE was induced in SJL mice by PLP139-151/CFA immunization on Day 0. Treatment was late therapeutic, starting on Day 20 after immunization for each mouse. Mice were observed through the end of the study, Day 42 after immunization.
  • Four groups of 20 mice each received one of the following treatments: vehicle (a negative control); 10 mg/kg oral prednisolone daily (reference treatment); 32 pg ACTH +16 pg endorphin by subcutaneous injection, every 2nd day (low dose); or 64 pg ACTH +32 pg b-endorphin by subcutaneous injection, every 2nd day (high dose).
  • mice were injected subcutaneously at four sites in the back with emulsion containing PLPi39-i5i (native sequence) from HOOKE KITTM PLP139-151/CFA Emulsion, catalog number EK- 0120 (Hooke Laboratories, Lawrence MA). Two sites of injection were in the upper back approximately 1 cm caudal of the neck line. The other two sites were in the lower back approximately 2 cm cranial of the base of the tail. The injection volume was 0.05 mL at each site. Even without treatment, most mice recover spontaneously after the first wave of disease. In the SJL model, EAE develops 10-15 days after immunization in 90-100% of immunized mice.
  • the first wave of EAE lasts several days and most mice fully or almost fully recover from this first wave. After a disease-free period, which can last from one day to several months, most mice relapse. During the first 5-7 weeks after immunization, 50-100% of mice will develop a relapse. Each wave of paralysis results in body weight loss at onset, most of which is regained at recovery from the wave. The greatest weight loss is during the first wave of EAE. During the chronic phase of disease, the average EAE body weight is relatively stable, with normal slow increase with age. Since individual mice experience relapses at different times, only a few mice in each group are acutely sick at any given time after the first wave of EAE.
  • mice 100 EAE induced mice were initially considered a single group and were scored daily starting on Day 9 after immunization. On Day 20, mice were assigned to the experimental groups in a balanced manner to achieve groups with similar times of EAE onset, similar maximum EAE score and similar scores at the time of enrollment into treatment (see Table 3). The remaining mice, which developed EAE last, or which developed unusual signs of EAE such as head tilting, were not assigned to any treatment group.
  • Vehicle was 16% gelatin from porcine skin (Sigma G2500-100G) prepared by dissolution in 60 °C sterile water with pH adjusted with 1 N NaOH to be 6.3 to 6.6,
  • porcine ACTH and porcine b-endorphin were dissolved in vehicle by heating to 80-90 °C for 20 minutes and then cooling to 60-70 °C followed by addition of ACTH and b- endorphin powder to achieve a concentration of 0.64 and 0.32 mg/ml solution, respectively, and stirring at 50-70 °C for 20 minutes; pH was between 6 and /.
  • this solution was diluted 1:2 with vehicle.
  • Treatment started on the day of group assignment (Day 20 after immunization). This was the time of the expected end of the first wave of EAE and before relapses were expected to begin. Treatment continued through Day 41. EAE score was determined daily by a person unaware of both treatment and of previous scores for each mouse. Weight was measured 3 times a week. Five mice in each group were euthanized on day 30 and the fifteen remaining mice euthanized at the end of the study (Day 42). Histological and immunohistological analyses were performed on tissue collected from the euthanized mice.
  • the prednisolone treatment group exhibited a statistically significant loss of weight versus the vehicle control emphasizing the marginal value of this treatment and indicating that even the low dose treatment with ACTH and b-endorphin provided a real improvement (see figure 2). Additionally, there was a trend toward reduced incidence of relapse in both the high and low dose groups that was greater than for the prednisolone treatment.
  • prednisolone treatment showed only at best a trend to reduction of inflammation and demyelination (and a higher level of gliosis), with none of these values approaching statistical significance.
  • mice * Calculated for all mice in the group 1 1 That is, mice followed until Day 42
  • Example 3 showed ACTH and b-endorphin treatment of EAE produced strong efficacy in histologic analysis and suggested dose responsiveness for clinical readouts (particularly incidence of relapse).
  • the model was repeated, essentially as described in Example 3, using greater doses, specifically 53 pg of ACTH +27 pg of b-endorphin (low dose), and 128 pg of ACTH + 64 pg of b-endorphin (high dose).
  • FTY720 (fingolimod, an FDA-approved drug for the treatment of multiple sclerosis) was used as a reference (positive control) treatment instead of prednisolone, which had not shown strong efficacy in Example 3.
  • FTY720 is one of the most efficacious drugs in both EAE and MS. Immunization was on Day 0, treatment started on Day 20, and the mice were observed through Day 42. An overview of the treatment regimen is provided in Table 7.
  • EAE severity (mean clinical score) over the course of the study (see Fig. 3) shows a clear separation of vehicle from the three treatment groups starting at Day 27 as the mice in the vehicle group began to relapse.
  • Clinical results are summarized in Table 8. Readouts are End score, End body weight (% of starting weight), Incidence of relapse, and Mean maximal score (MMS) in the relapse period. All clinical readouts of efficacy were similar between the FTY720 and Test groups. Both test treatments treatment showed improvement over the vehicle control for all readouts, with statistical significance of p ⁇ 0.05 versus vehicle. Both test treatments allowed for modest weight gain during the trial (see Fig.
  • the reference treatment showed statistically significant improvement versus vehicle for all readouts except End weight.
  • Incidence of relapses is the primary and most important readout in this model. Both the High dose and Low dose test groups significantly reduced relapses, with the high dose completely preventing new relapses. It is rare to see any treatment other than FTY720 completely suppress relapses in this model.
  • One of the thirty mice in the High Dose group relapsed on the day treatment started, and it had substantially recovered by the end of the study.
  • One of the nine mice in the reference treatment (FTY720) group also relapsed on the day treatment started, and also had substantially recovered by the end of the study.
  • mice that relapsed as a proportion of surviving mice that developed the first wave of EAE **Calculated for all mice in the group
  • mice were injected subcutaneously at four sites in the back with 0.05 ml_ of the emulsion component of HOOKE KITTM PLP139-151/CFA Emulsion PTX (catalog number EK- 2120; Hooke Laboratories, Lawrence MA). Two sites of injection were in the upper back approximately 1 cm caudal of the neck line. The other two sites were in the lower back approximately 2 cm cranial of the base of the tail. Two hours later the pertussis toxin component of the kit was administered intraperitoneally. A 30 ng dose of PTX was used to attain optimal disease severity.
  • mice were administered vehicle or 128 pg ACTH + 64 pg b-endorphin by subcutaneous injection every 2nd day, as a negative control and test treatment, respectively.
  • reference treatment positive control mice received 3mg/kg FTY720 daily by oral administration. There were 12 mice in each of these three groups.
  • the vehicle and test treatment groups were dosed from Day 0 through Day 18 (the last dose in the test treatment group was 88 pg ACTH + 44 pg b-endorphin due to lab mishap).
  • the reference treatment group was dosed from Day 0 through Day 19. Clinical scoring was as presented in Table 4 (above) beginning on Day 7 and continuing through Day 20.
  • AE severity (mean clinical score) over the course of the study (see Fig. 6) shows a clear separation of vehicle from the two treatment groups starting at Day 10 as the mice in the vehicle group began to exhibit symptoms of the disease.
  • the clinical findings are summarized in Table 10. Change in body weight over the course of the study is shown in Fig. 7. FTY720 was efficacious (as expected for a positive control), with EAE incidence, onset, and MMS all significantly improved vs. vehicle. (End score for FTY720 was also statistically significant if the criterion for statistical significance is set at p ⁇ 0.10 instead of p ⁇ 0.05). These are typical results Table 10 - Statistical analysis of clinical findings
  • a patient with early symptoms COVID-19, or an asymptomatic patient with a positive SARS-CoV-2 infection test is administered a composition of ACTH and b-endorphin, with a mass ratio of ACTH ⁇ -endorphin of 2:1, by daily intramuscular or subcutaneous injection at a dosage of 80-120 units of ACTH. Treatment is continued for 2-3 weeks or until the patient tests negative for SARS-CoV-2 infection Severe inflammatory symptoms and cytokine release syndrome do not emerge, or are reduced in duration and/or severity as compared to untreated patients.
  • a patient with worsening symptoms of COVID-19 and a positive SARS-CoV-2 infection test is administered a composition of ACTH and b-endorphin, with a mass ratio of ACTH ⁇ -endorphin of 2:1, by once or twice daily intramuscular injection for a total daily dosage of 80-150 units ACTH/m 2 .
  • Treatment is continued until any symptoms of cytokine release syndrome or other inflammatory response abate.
  • the dosage may be tapered down as symptoms lessen according to the judgement of the treating physician.

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Abstract

La présente invention concerne des compositions de bêta-endorphine et d'hormone adrénocorticotropique (ACTH). Ces compositions sont utiles dans des procédés de traitement de maladies.
PCT/US2020/048813 2020-02-25 2020-08-31 Procédé de préparation d'une combinaison de bêta-endorphine et d'hormone adrénocorticotropique WO2021173184A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090004246A1 (en) * 2007-06-26 2009-01-01 David Aaron Woolfson Intravaginal drug delivery devices for the delivery of macromolecules and water-soluble drugs
US20120114706A1 (en) * 2008-05-08 2012-05-10 Dipak Kumar Sarkar Endorphin Therapy Compositions and Methods of Use Thereof
US20130115640A1 (en) * 2011-11-03 2013-05-09 James A. Tumlin ACTH for Treatment of Kidney Disease

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Publication number Priority date Publication date Assignee Title
US20090004246A1 (en) * 2007-06-26 2009-01-01 David Aaron Woolfson Intravaginal drug delivery devices for the delivery of macromolecules and water-soluble drugs
US20120114706A1 (en) * 2008-05-08 2012-05-10 Dipak Kumar Sarkar Endorphin Therapy Compositions and Methods of Use Thereof
US20130115640A1 (en) * 2011-11-03 2013-05-09 James A. Tumlin ACTH for Treatment of Kidney Disease

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