WO2019072411A1 - Application d'érythropoïétine (epo) dans une thérapie de lésion de la moelle épinière (lme) - Google Patents

Application d'érythropoïétine (epo) dans une thérapie de lésion de la moelle épinière (lme) Download PDF

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Publication number
WO2019072411A1
WO2019072411A1 PCT/EP2018/000466 EP2018000466W WO2019072411A1 WO 2019072411 A1 WO2019072411 A1 WO 2019072411A1 EP 2018000466 W EP2018000466 W EP 2018000466W WO 2019072411 A1 WO2019072411 A1 WO 2019072411A1
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Prior art keywords
epo
treatment
spinal cord
sci
treatment according
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PCT/EP2018/000466
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English (en)
Inventor
Augustinus Bader
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Augustinus Bader
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Publication of WO2019072411A1 publication Critical patent/WO2019072411A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1816—Erythropoietin [EPO]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • EPO Erythropoietin
  • SCI spinal cord injury
  • the invention relates to the therapy of dysfunctions, disorders, and destructions which occur in consequence of a spinal cord injury (SCI) event in a patient, preferably in cases where standard treatment with steroids is not or not more effective.
  • SCI spinal cord injury
  • the invention relates, above all, to the treatment of such secondary pathologic events after SCI by means of erythropoietin or erythropoietin derivatives (EPO).
  • the invention relates, above all, to the treatment of SIC patients suffering not completely from paresis by means of EPO applied to said patient by a two-step administration setting: unique intrathecal injection of EPO followed by several subcutaneous or systemic application of EPO in combination with other agents promoting regeneration of neuronal and vascular tissue.
  • Mature EPO is a glycoprotein hormone which consists of 165 amino acids with a molecular weight of 30.4 kDa. Human EPO is synthesized by peritubular capillary endothelial cells in adults and by hepatic cells in the fetus; a small amount is synthesized in the adult liver, too.
  • EPO has been originally characterized as a principal regulator of erythropoiesis by inhibition of apoptosis and stimulation of proliferation and differentiation of erythroid precursor cells [28]. Several evidences suggest its potential role other than erythropoiesis. EPO is a promising neuroprotective agent with anti-apoptotic properties. It can block the axonopathy development, too.
  • EPO exerts its effects by binding to the erythropoietin receptor (EPOR). EPO specific receptors are expressed in different tissues. High levels of basal EPOR expression have been found in the spinal cord's neurons and glial cells, for-skin cells. EPOR belongs to the cytokine receptor type 1 super family. Different mechanisms imply its neuroprotective effects including the activation of survival kinase pathways of transcription factors like nuclear factor kappa B which increase the neurotrophin expression, anti-apoptotic setting establishment, calcium channels activation, antioxidant enzymes in neurons production and angio-genesis promotion. Several studies reported that EPO and EPOR have an essential role in neurogenesis.
  • G-CSF is a hormone that induces the production of granulocytes. Different studies indicate that G-CSF also has neuroprotective abilities and may reduce secondary injury aftereffects following acute SCI. It is assumed that G-CSF affects a better functional recovery than the application of steroids, such as methylprednisolone. Vitamin C (ascorbic acid) is a biologically well-tolerated compound revealing antioxidant properties in biological systems. It can scavenge free radicals and avoid tissue damage as it occurs as secondary effect in SCI. Different studies in the art showed that high-dose intraperitoneal administration of vitamin C can reduce secondary-injury-induced tissue necrosis and improve functional recovery in a rat model. Spinal cord injury (SCI) is a rare disease with an incidence about 40 cases per million population in the USA. The most common reasons are traffic accidents, falls, violence and sports. Patients recover mostly in the first 90 days after the injury but often have motor or sensory disorders.
  • SCI Spinal cord injury
  • SCI creates more complications such as neurogenic bladder dysfunction and central neuropathic pain in addition to paralysis and numbness.
  • Traumatic spinal cord injury is defined as an acute injury of the spinal cord which results in a varying degree of paralysis and/or sensory disorder. Based on pathophysiological changes the early acute phase is defined to be 2 - 48 h after the injury, the subacute phase from 2 days to 2 weeks, and the intermediate phase from 2 weeks to 6 months. Based on timing of surgery studies it was found that early decompression of the neuronal environment of the respective area of the spine either ⁇ 24 h or ⁇ 72 h resulted in statistically better outcomes compared to delayed decompression.
  • An acute traumatic SCI starts with an abrupt, injury to the spine leading to fractures or dislocations of vertebrae. Displaced bone fragments and disc material causes the immediate injury leading to irreversible damage of axons and broken neural cell membranes
  • Acute SCI involves a combination of primary mechanical and secondary cellular injury leading to neural tissue destruction.
  • Primary mechanisms refer to the initial rapid spinal cord compression and trauma induced by a fracture or shearing force.
  • Primary trauma to the cord is irreversible, and initiates a cascade of pathologic and molecular changes that contribute to secondary injury.
  • Secondary injury mechanisms include hemorrhage, vasospasm, ischemia, edema, excitotoxicity, inflammation, and apoptosis.
  • the spinal cord is affected by both the immediate physical effects of trauma, and secondary0 pathologic processes. Especially ischemia and edema may worsen the injury during the first few hours after an injury. After a traumatic SCI, the number of complications during the acute phase hospitalization, depends on the timing of surgery, with less complications when surgery is performed soon after the injury.
  • NASCIS trials II and III The National Acute Spinal Cord Injury Studies (NASCIS trials II and III) have shown that patients treated with the steroid methylprednisolone within 8 hours of acute SCI exhibit improved neurologic outcomes at 1 year compared to placebo.
  • methylprednisolone0 has been established as the only standard of care for acute SCI, recent evidence suggests that there is no benefit in both short-term and long-term results and that the risks of high doses of methylprednisolone outweigh the benefits.
  • SIC events the patient cannot be treated within a few hours with steroids after the injury occurred. Thus, the steroids are not more effective at a later stage to improve or prevent secondary neuronal and other pathologic complications.
  • a two-step administration therapy based on a first administration step, comprising intrathecal / intradural injection of EPO, or topical positioning of EPO in or on top or proximity of the dura mater, or injection of EPO into the peripheral soft tissue surrounding the lesion of the spinal cord.
  • a therapy is provided comprising
  • a first administration step comprising intrathecal injection of EPO, or topical positioning of EPO in or on top or proximity of the dura mater, and additionally
  • a second administration step comprising applying for a period of several weeks and months systemically or subcutaneously EPO in combination with G-CSF or GM-CSF and optionally an antioxidant such as vitamin C and / or vitamin A, ideally both applied together, is suitable to treat spinal cord injuries.
  • the proposed treatment according to the invention is principally applicable during all phases of the injury described here, preferably after surgery.
  • the intrathecal or intradural administration of EPO preferably within 72, more preferably within 48 hours after the injury impact is of great importance for the treatment of SCI and affects improvements of neuronal/muscle functions independent on the starting conditions including surgical decompression of the spinal cord or not.
  • administration and timing regimen injury impact -> surgery or not - start of EPO injection -> optionally systemic or subcutaneous EPO plus G- SCF/GM-CSF (optionally) plus vitamin C/A) recovery and regeneration of muscle and nerve functions affected by the injury can be obtained between 20 and 100%.
  • the second administration step further comprises systemic or subcutaneous application of EPO, G-CSF and vitamin C in doses indicated above and below.
  • EPO EPO
  • G-CSF G-CSF
  • vitamin C vitamin C
  • co-agents improving the regeneration of neuronal functions such as vitamin E and vitamins of the B series, and combinations thereof are beneficial as well.
  • the improvement or the prevention of said complications, dysfunctions, disorders or destructions are distinctive the less paralysis is, caused by the impact.
  • the improvement or prevention is significantly distinctive in cases where the patient suffers from a paresis, even a tetraparesis and the spinal cord injury event did not cause complete paralysis.
  • An improvement according to the invention means an objective and/or patient-subjective abatement or clearance of one or more specific disorders or symptoms, such as muscle functions hus, it could be shown by the inventors that above all the muscle functions of SCI patients treated with EPO by means of the two step administration approach as claimed can be regenerated by 20 to 100% preferably by 50 to 85% at the end of the administration period.
  • the suggested treatment is effective when the standard treatment of such events with steroids is not or not more effective.
  • the proposed treatment according to the invention is preferably used in all cases, where the standard treatment of the art by means of steroids, such as methylprednisolone is not or not more effective, which is empirically the case after 6 to 12 hours, preferably 8 - 10 hours after the impact.
  • the dose range of EPO varies between 4.000 and 10.000 IU EPO (40 IU - 130 IU / kg BW), preferably between 6.000 and 8.000 IU EPO ( 80 - 100 IU / kg BW) dependent on the severity of the injury. In many cases, a dose of 100 IU / kg BW effects a measurable improvement.
  • systemic and / or subcutaneous administration of EPO is started, wherein the preferable dose is in the range as indicated above.
  • EPO is applied to the patient in combination with G-CSF and optionally vitamin C.
  • the compounds may be administered simultaneously or in immediate sequence.
  • the dose of G-CSF (or GM-CSF) applicable according to this invention varies between 1 and 7 g / kg BW, preferably 5 ⁇ / kg BW.
  • the dose of vitamin C applicable according to this invention may vary between 0.2g and 2.0 g, preferably 200 mg - 1000 mg, preferably by i.v. administration.
  • the sole systemic/subcutaneous administration of EPO plus G-CSF plus vitamin C without preceding intrathecal administration of EPO is not sufficiently effective as compared to the full administration setting according to the invention.
  • 75 - 100 % recovery of the muscle / neuronal functions can be obtained if the full therapy regimen is applied (intrathecal administration of EPO plus combination therapy of EPO together with G-CSF and vitamin C dependent on the timing after the injury impact.
  • the best recovery values can be obtained when the therapy starts during surgery or within 72h, preferably within 24h after surgery and where the surgery was achieved preferably within 48h after the impact of injury).
  • the muscles of the right side of his body were weaker than the left side.
  • the right hip flexors were not affected as much as the muscles in the other segments below C5.
  • the anal sphincter was floppy but could be activated to a minor degree from the right side.
  • Clinical testing on the muscle strength showed that the patient had spared muscle movement below the level of the injury and could not move against gravity on one half of his body. The other half was not effected in this way.
  • ASIA American Spinal Injury Association
  • the patient has to be checked for injuries of the vertebrae, the spinal cord and the soft tissue of his dorsum. Fractures can be assessed using X-ray or computed tomography (CT) of the spine.
  • CT imaging should be preferred if avail-able because it is not possible to display the complete spine using X-ray. Especially the cervicothoracic junction is often superimposed by the shoulders.
  • the biggest advantage of the CT is the possibility to create multiplanar reconstructions of different planes of the spine.
  • Magnetic resonance imaging (MRI) is necessary to evaluate whether the patient has a direct or indirect (swelling/edema/bleeding) injury of the spinal cord or soft tissue injury.
  • MRI Magnetic resonance imaging
  • a CT which showed an avulsion of the anterior inferior margin of the 6th cervical vertebra. Additionally there were fractures of the transverse processes of the 6th and 7th cervical vertebra, the 1 st thoracic vertebra and rib fractures from the 4 th to the 8 th rib on the left side.
  • the patient received no methylprednisolone because he arrived more than 8 hours after the injury happened.
  • EPO erythropoietin
  • SCIs The main problem of SCIs is the secondary injury caused by inflammation and swelling of the spinal cord. To avoid this, the patient was experimentally treated with EPO intrathecal and EPO, G-CSF and vitamin C subcutaneous after his initial spinal cord relief surgery. These drugs were thought to be able to relieve said secondary reactions but were never applied for this indication in human before.
  • MRI images of the patient's spinal cord before and after the treatment according to the invention were made based on three patterns of MRI in SCI patients (hemorrhage, edema and contusion) correlating them with the neurological status at the time of discharge including other patterns of cord transection and spinal cord compression in order to get a good prognostic value for neurological recovery and functional ambulation of the patient.
  • the inventors observed a significant recovery of neurological damage such as cord hemorrhage, swelling, soft tissue and ligament injury, blood clots or herniated disc, as it could be seen by MRI (Fig. 1 ), and by muscle function measurements (Tables 1 - 5)
  • the muscle function of the patient started to increase within the first 30 days, which seems to be normal in patients with incomplete paresis and spinal cord lesions. It is noteworthy that the patient almost completely recovered within the first 90 days after the injury. Only his bladder function was still affected from a functional disorder. This suggests that the experimental drug therapy can avoid secondary injury and supports the healing processes (e.g. by induction of angiogenesis). This therapy may be considered in patients with SCI without any other therapeutic option.
  • Muscle function grading 0, total paralysis; 1 , palpable contraction; 2, active movement with full range of motion (ROM) with gravity eliminated; 3, active movement with full ROM against gravity; 4, active movement with full ROM against moderate resistance; 5, active movement with full ROM against full resistance.
  • Finger flexors distal phalanx of
  • Th1 Finger abductors (little finger) 0/5 3/5
  • Finger flexors distal phalanx of
  • Th1 Finger abductors (little finger) 0/5 3/5
  • Finger flexors distal phalanx of
  • Th1 Finger abductors (little finger) 0/5 3/5
  • Finger flexors distal phalanx of
  • Finger flexors distal phalanx of
  • Dog “A” suffered from a grade 5 paresis without deep pain caused by an injury in the thoraco-lumbo-sacral spinal cord. The animal was not able to stand up and / or to walk. The animal obtained an intrathecal injection of EPO (80 IU/ kg BW) into the peripheral soft tissue surrounding the lesion 8h after the injury impact. No surgery was carried out.
  • EPO 80 IU/ kg BW
  • EPO and vitamin C were administered subcutaneously in doses specified above once a day for 1 week.
  • Dog “B” suffered from a grade 5 paresis obviously with some pain caused by an injury in the thoraco-lumbo-sacral spinal cord as well.
  • the animal was not able to stand up and / or to walk and had a bad general condition: The surgical decompression of the injured position was achieved approximately 24 h after the injury.
  • Intraoperative injection of EPO (100 IU / Kg BW, intradural) and additionally injection of 100 IU EPO into the peripheral soft tissue of the lesion area was achieved. No further EPO or co-agent was applied during the post-operative phase.
  • Dog “C” suffered also from a grade 5 paresis obviously with no pain caused by an injury in the thoraco-lumbo-sacral spinal cord as well. The animal was not able to stand up and / or to walk and had a bad general condition too.
  • the surgical decompression of the injured position was achieved ca. 30h after the injury.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Vascular Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne la thérapie de dysfonctionnements, de troubles et de destructions qui surviennent en conséquence d'un événement de lésion de la moelle épinière (LME) chez un patient, de préférence dans des cas où un traitement standard avec des stéroïdes n'est pas ou pas plus efficace. L'invention concerne, surtout, le traitement de tels événements pathologiques secondaires après une LME au moyen d'érythropoïétine ou de dérivés d'érythropoïétine (EPO) en combinaison avec d'autres médicaments selon un réglage et une gestion de thérapie spécifiques, le traitement pouvant être appliqué sans ou pendant ou après une chirurgie de la moelle épinière.
PCT/EP2018/000466 2017-10-10 2018-10-09 Application d'érythropoïétine (epo) dans une thérapie de lésion de la moelle épinière (lme) WO2019072411A1 (fr)

Applications Claiming Priority (2)

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EP17001664 2017-10-10
EP17001664.6 2017-10-10

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WO2019072411A1 true WO2019072411A1 (fr) 2019-04-18

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005117927A2 (fr) * 2004-05-20 2005-12-15 The Kenneth S. Warren Institute, Inc. Cytokines protegeant les tissus pour la protection, la restauration et l'augmentation des cellules receptives, des tissus et des organes par une fenetre therapeutique etendue

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005117927A2 (fr) * 2004-05-20 2005-12-15 The Kenneth S. Warren Institute, Inc. Cytokines protegeant les tissus pour la protection, la restauration et l'augmentation des cellules receptives, des tissus et des organes par une fenetre therapeutique etendue

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
KAMIYA KOSHIRO ET AL: "Neuroprotective therapy with granulocyte colony-stimulating factor in acute spinal cord injury: a comparison with high-dose methylprednisolone as a historical control", EUROPEAN SPINE JOURNAL, SPRINGER VERLAG, BERLIN, DE, vol. 24, no. 5, 25 June 2014 (2014-06-25), pages 963 - 967, XP035494571, ISSN: 0940-6719, [retrieved on 20140625], DOI: 10.1007/S00586-014-3373-0 *
M YAN ET AL: "High-dose ascorbic acid administration improves functional recovery in rats with spinal cord contusion injury", SPINAL CORD, vol. 52, no. 11, 1 November 2014 (2014-11-01), GB, pages 803 - 808, XP055533373, ISSN: 1362-4393, DOI: 10.1038/sc.2014.135 *
MOFIDI A ET AL: "The use of erythropoietin and its derivatives to treat Spinal Cord injury", MINI REVIEWS IN MEDICINAL CHEMI, BENTHAM SCIENCE PUBL, NL, vol. 11, no. 9, 1 January 2011 (2011-01-01), pages 763 - 770, XP009154910, ISSN: 1389-5575 *
MOFIDI, MINI REV MED CHEM., vol. 11, no. 9, August 2011 (2011-08-01), pages 763 - 70
SANLI A M ET AL: "Effect of granulocyte-colony stimulating factor on spinal cord tissue after experimental contusion injury", JOURNAL OF CLINICAL NEUROSCIENCE, CHURCHILL LIVINGSTONE, GB, vol. 17, no. 12, 1 December 2010 (2010-12-01), pages 1548 - 1552, XP027442024, ISSN: 0967-5868, [retrieved on 20101029], DOI: 10.1016/J.JOCN.2010.03.043 *
VASILEIOS A KONTOGEORGAKOS ET AL: "The efficacy of erythropoietin on acute spinal cord injury. An experimental study on a rat model", ARCHIVES OF ORTHOPAEDIC AND TRAUMA SURGERY ; INCLUDING ARTHROSCOPY AND SPORTS MEDICINE, SPRINGER, BERLIN, DE, vol. 129, no. 2, 29 February 2008 (2008-02-29), pages 189 - 194, XP019713438, ISSN: 1434-3916 *

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