WO2022234101A1 - Défibrotide pour le traitement et la prévention du syndrome de détresse respiratoire aiguë - Google Patents

Défibrotide pour le traitement et la prévention du syndrome de détresse respiratoire aiguë Download PDF

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WO2022234101A1
WO2022234101A1 PCT/EP2022/062310 EP2022062310W WO2022234101A1 WO 2022234101 A1 WO2022234101 A1 WO 2022234101A1 EP 2022062310 W EP2022062310 W EP 2022062310W WO 2022234101 A1 WO2022234101 A1 WO 2022234101A1
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defibrotide
administered
ards
patient
days
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PCT/EP2022/062310
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English (en)
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Yasuhiro Oki
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Jazz Pharmaceuticals Ireland Limited
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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions

Definitions

  • the present disclosure is directed to methods of administering defibrotide to prevent and/or treat acute respiratory distress syndrome (ARDS).
  • ARDS acute respiratory distress syndrome
  • ARDS Acute respiratory distress syndrome
  • ARDS is a severe and often life-threatening complication of several systemic disorders and direct injury to the lungs. It is associated with a high mortality rate, primarily as a consequence of multiple organ failure (Frutos-Vivar et al., Curr Opin Crit Care 2004, 10:1-6).
  • ARDS occurs when fluid builds up in the alveoli of the lungs. More fluid in the lungs means less oxygen reaching the bloodstream, which deprives organs of the oxygen they need to function.
  • ARDS typically occurs in people who are already critically ill or who have significant injuries (e.g. from trauma or aspiration) or infections including sepsis, pancreatitis, and/or pneumonia.
  • ARDS Symptoms of ARDS includes severe shortness of breath, labored and unusually rapid breathing, low blood pressure, and confusion and extreme tiredness, which usually develops within a few hours to a few days after an original disease or trauma.
  • the primary treatment of ARDS involves mechanical ventilation together with treatments directed at the underlying cause (Fan et al., (20 February 2018) JAMA. 319 (7): 698-710). Ventilation strategies include using low volumes and low pressures. If oxygenation remains insufficient, lung recruitment maneuvers and neuromuscular blockers may be used. If this is insufficient, extracorporeal membrane oxygenation (ECMO) may be an option.
  • ECMO extracorporeal membrane oxygenation
  • Defibrotide (Defitelio®, jazz Pharmaceuticals) is approved for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).
  • VOD hepatic veno-occlusive disease
  • SOS sinusoidal obstruction syndrome
  • HSCT hematopoietic stem-cell transplantation
  • Defibrotide reduces endothelial cell (EC) activation and damage by mechanisms that are antithrombotic, fibrinolytic, anti-adhesive, and anti inflammatory; thereby restoring the thrombotic-fibrinolytic balance and preserving endothelial homeostasis (Coccheri 1988; Celia 2001; Falanga 2003; Corbacioglu 2004; Benimetskaya 2008; Echart 2009; Palmer 1993; Pescador 2013; Richardson 2018). Defibrotide has been shown to modulate endothelial cell injury in the lung in mouse models of acute lung injury or idiopathic pulmonary syndrome following allogeneic blood and marrow transplantation.
  • mice treated with defibrotide had reduced mRNA levels of TNFa, IL-6, Ang-2, E-selectin, and P-selection (Klein 2020).
  • the present invention identifies that through its modulation of multiple pathways to restore the thrombotic-fibrinolytic balance and preserve endothelial homeostasis, defibrotide will attenuate the progression and promote the improvement of ARDS.
  • the present disclosure provides methods of preventing or treating acute respiratory distress syndrome (ARDS) in a patient comprising administering a therapeutically effective amount of defibrotide.
  • ARDS acute respiratory distress syndrome
  • the present disclosure provides methods of decreasing serum biomarker levels associated with the development of acute respiratory distress syndrome (ARDS), in a patient comprising administering a therapeutically effective amount of defibrotide.
  • the defibrotide is administered to the patient until the serum biomarker levels decrease to levels observed in patients who do not develop acute respiratory distress syndrome (ARDS).
  • the defibrotide is administered to the patient until the serum biomarker levels decrease to levels observed in the same patient before treatment or an uninfected patient.
  • the defibrotide is administered before the development of acute respiratory distress syndrome (ARDS) or symptoms thereof. In some embodiments, the defibrotide is administered after the development of acute respiratory distress syndrome (ARDS), or symptoms thereof. In some embodiments, the defibrotide is administered to patients at risk of developing acute respiratory distress syndrome (ARDS) after administration of another therapy.
  • ARDS acute respiratory distress syndrome
  • the defibrotide is administered after the development of acute respiratory distress syndrome (ARDS) or symptoms thereof and administration continues until symptoms improve.
  • ARDS acute respiratory distress syndrome
  • the defibrotide is administered at a dose between 1 mg/kg and 40 mg/kg. In some embodiments, the defibrotide is administered at a dose of 6.25 mg/kg.
  • the defibrotide is administered once a day. In some embodiments, the defibrotide is administered in multiple doses per day. In some embodiments, the defibrotide is administered in two to ten doses per day. In some embodiments, the defibrotide is administered four times a day. In some embodiments, the defibrotide is administered every six hours. In some embodiments, the defibrotide is administered by continuous infusion.
  • the defibrotide is administered intravenously, every six hours at a dose of 6.25 mg/kg.
  • Defibrotide is approved as Defitelio® (Gentium S.r.l; jazz Pharmaceuticals) for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).
  • VOD hepatic veno-occlusive disease
  • SOS sinusoidal obstruction syndrome
  • HSCT hematopoietic stem-cell transplantation
  • Defibrotide reduces endothelial cell (EC) activation and damage by mechanisms that are antithrombotic, fibrinolytic, anti-adhesive, and anti-inflammatory; thereby restoring the thrombotic-fibrinolytic balance and preserving endothelial homeostasis (Coccheri 1988; Celia 2001; Falanga 2003; Corbacioglu 2004; Benimetskaya 2008; Echart 2009; Palmer 1993; Pescador 2013; Richardson 2018).
  • EC endothelial cell
  • defibrotide increases systemic tissue factor pathway inhibitor (TFPI), tissue plasminogen activator (t-PA) expression, and thrombomodulin expression; decreases von Willebrand factor (vWF) and plasminogen activator inhibitor- 1 (PAI-1) expression; and enhances enzymatic activity of plasmin to hydrolyse fibrin clots (Celia 2001; Coccheri 1988; Coccheri and Nazzari 1996; Cohen 1989; Zhou 1994; Falanga 2003; Echart 2009; Umemura 2016; Kaleelrahman 2003).
  • TFPI tissue factor pathway inhibitor
  • t-PA tissue plasminogen activator
  • PAI-1 plasminogen activator inhibitor- 1
  • defibrotide inhibits leukocyte adhesion to endothelium by suppressing P-selectin and vascular cell adhesion molecule-1 (VCAM)-l and interfering with lymphocyte function-associated antigen 1 -intercell adhesion molecule (LFA-l-ICAM)- mediated leukocyte transmigration.
  • VCAM vascular cell adhesion molecule-1
  • LFA-l-ICAM lymphocyte function-associated antigen 1 -intercell adhesion molecule
  • Platelet adhesion is inhibited via increases in nitric oxide (NO), prostaglandin 12 (PGI2), and prostaglandin E2 (PGE2) (Biagi 1991; Ferraresso 1993; Palomo 2016).
  • defibrotide In vitro, defibrotide demonstrates anti-inflammatory effects that attenuate the release and production of reactive oxygen species and inflammatory mediators such as interleukin (IL)-l, IL-6, thromboxane A2, leukotriene B4, and tumor necrosis factor-a (TNF- a) (Ferraresso 1993; Bracht and Schror 1994; Palomo 2011; Yakushijin 2019). Additionally, defibrotide inhibits the expression of heparanase, thereby contributing to extracellular matrix integrity (Eissner 2002; Barash 2018).
  • IL interleukin
  • IL-6 interleukin-6
  • thromboxane A2 thromboxane A2
  • leukotriene B4 and tumor necrosis factor-a
  • TNF- a tumor necrosis factor-a
  • defibrotide prevents pulmonary microthrombi, decreases pulmonary endothelial production of inflammatory cytokines, promotes vaso-dilation (increased production of NO, prostanoids), inhibits platelet activation (reduction in vWF), and/or regulates the fibrinolytic pathway (reduction in PAI-1), to lead to improvement in oxygenation and promote the resolution of ARDS.
  • defibrotide identifies a polydeoxyribonucleotide that is obtained by extraction from animal and/or vegetable tissues but which may also be produced synthetically; the polydeoxyribonucleotide is normally used in the form of an alkali-metal salt, generally a sodium salt, and generally has a molecular weight of 13 to 30 kDa (CAS Registry Number: 83712-60-1).
  • defibrotide is obtained according to U.S. Pat. No. 4,985,552 and U.S. Pat. No. 5,223,609 and/or presents the physical/chemical characteristics described in the same U.S. Pat. No. 4,985,552 and U.S. Pat. No.
  • the term “subject” is used interchangeably herein with “patient” to refer to an individual to be treated.
  • the subject is a mammal (e.g., human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc.).
  • the subject can be a clinical patient, a clinical trial volunteer, an experimental animal, etc.
  • the subject can be suspected of having or at risk for having a condition or be diagnosed with a condition that leads to ARDS.
  • the subject can also be suspected of having or at risk for having ARDS.
  • the subject to be treated according to this invention is a human.
  • Subjects to be treated by the methods of the disclosed embodiments include both human subjects and animal subjects (e.g., dog, cat, monkey, chimpanzee, and/or the like) for veterinary purposes.
  • the subjects may be male or female and may be any suitable age, e.g, neonatal, infant, juvenile, adolescent, adult, or geriatric.
  • the subjects are preferably mammalian.
  • treating means one or more of relieving, alleviating, delaying, reducing, improving, or managing at least one symptom of a condition in a subject.
  • the term “treating” may also mean one or more of arresting, delaying the onset (i.e., the period prior to clinical manifestation of the condition) or reducing the risk of developing or worsening a condition.
  • a “therapeutically effective amount”, as used herein refers to an amount that is sufficient to achieve a desired therapeutic effect.
  • a therapeutically effective amount can refer to an amount that is sufficient to improve at least one sign or symptom of ARDS.
  • the terms “about” and/or “approximately” may be used in conjunction with numerical values and/or ranges.
  • the term “about” is understood to mean those values near to a recited value.
  • “about 1200 [units]” may mean within ⁇ 10% of 1200, within ⁇ 10%, ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 7%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, ⁇ 1%, less than ⁇ 1%, or any other value or range of values therein.
  • the phrases “less than about [a value]” or “greater than about [a value]” should be understood in view of the definition of the term “about” provided herein.
  • the terms “about” and “approximately” may be used interchangeably.
  • excipient refers to any substance that may be formulated with defibrotide and may be included for the purpose of enhancement of the defibrotide in the final dosage form, such as facilitating its bioavailability, reducing viscosity and/or osmolality, enhancing solubility of the composition or to enhance long-term stability. Excipients can also be useful in the manufacturing process, to aid in the handling of the active substance. The selection of appropriate excipients also depends upon the route of administration and the dosage form, as well as the active ingredient and other factors.
  • defibrotide may be combined with any excipient(s) known in the art that allows tailoring its performance during manufacturing or administration as well as its in vitro and in vivo performance. Many of these excipients may be utilized to tailor the pharmacokinetic profiles of defibrotide formulations.
  • formulation refers to compositions for therapeutic use, including, for example, a stable and pharmaceutically acceptable preparation of a pharmaceutical composition or formulation disclosed herein.
  • the term, “high concentration formulation” or “high concentration liquid formulation” or “HCLF” as used herein, refers to those formulations where the concentration of the nucleic acid is about 80 mg/mL or higher; or about 85 mg/mL or higher.
  • the defibrotide is a high concentration, low viscosity defibrotide formulation.
  • the high concentration, low viscosity defibrotide formulation is one disclosed in U.S. Application No. 16/105,319 filed August 3, 2018 the contents of which are incorporated herein for all purposes.
  • high concentration defibrotide formulations refers to those formulations where the defibrotide concentration is about 80 mg/mL or higher, or about 85 mg/mL or higher.
  • PK pharmacokinetic
  • Cmax maximum concentration
  • AUC area under the curve
  • Tmax time to maximum concentration of said agent
  • compositions of the disclosure refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to an animal and/or human.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
  • parenteral refers to any non-oral means of administration. It includes intravenous (i.v. or IV) infusion, IV bolus injection, subcutaneous (s.c. or SC) and intramuscular (i.m. or IM) injection.
  • defibrotide is administered intraveneously.
  • defibrotide is administered subcutaneously. Defibrotide which may be administered subcutaneously may require less frequent dosing than defibrotide products currently on the market are provided.
  • a device used to administer defibrotide is one disclosed in PCT Application No. PCT/US2019/064901 filed December 6, 2019 the contents of which are incorporated herein for all purposes.
  • a device used to administer defibrotide is one disclosed in U.S. Application No. 62/802,099 filed February 6, 2019 or U.S. Application No. 62/983,023 filed February 28, 2020, the contents of both which are incorporated herein for all purposes.
  • Defibrotide (CAS number 83712-60-1) is a substance derived from materials of natural origin.
  • Defibrotide a nucleic acid salt, is a highly complex mixture of random sequences, predominantly single-stranded polydeoxyribonucleotides (predominantly single stranded and approximately 10% double stranded) derived from animal mucosal DNA
  • Defibrotide has pleotropic biologic effect leading to the stabilization of endothelial cells, and in particular, defibrotide has protective effects on vascular endothelial cells, particularly those of small vessels and has antithrombotic, anti-inflammatory and antiischemic properties.
  • Defibrotide has a diverse size range and is known to have a mean molecular weight (MW) between 13 and 20 kDa.
  • Defibrotide can be obtained according to U.S. Pat. No. 4,985,552 and U.S. Pat. No. 5,223,609 and/or presents the physical/chemical characteristics described in the same U.S. Pat. No. 4,985,552 and U.S. Pat. No. 5,223,609, each of which is incorporated herein by reference.
  • Synthetic defibrotide, presented as phosphodiester oligonucleotides that mimic the therapeutic action of defibrotide are described in US20110092576 which is incorporated herein by reference in its entirety.
  • Defibrotide has numerous therapeutic applications, including use as an anti -thrombotic agent (U.S. Patent No. 3,829,567), treatment of peripheral arteriopathies (U.S. Patent 5,081,109), treatment of acute renal insufficiency (U.S. Pat. No. 4,694,134), treatment of acute myocardial ischaemia (U.S. Pat. No. 4,693,995), topical treatments (U.S. Patent No. 5,116,617) among other uses described in U.S. Patent Nos.
  • defibrotide has been used for the treatment and prevention of sinusoidal obstruction syndrome/veno-occlusive disease (EU clinical trial EudraCT:2004- 000592-33, US clinical trial 2005-01 (ClinicalTrials.gov identifier: NCT00358501).
  • Defitelio® is prepared as an intravenous infusion by a dilution in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP. Intravenous preparation is used within 4 hours if stored at room temperature or within 24 hours if stored under refrigeration. It is administered for a total of 8 hours over 4 intravenous infusions.
  • defibrotide is administered as a “high concentration formulation” (HCLF).
  • concentration of the nucleic acid in the HCLF is about 80 mg/mL or higher; or about 85 mg/mL or higher.
  • the defibrotide is a high concentration, low viscosity defibrotide formulation.
  • the high concentration, low viscosity defibrotide formulation is one disclosed in U.S. Application No. 16/105,319 filed August 3, 2018 the contents of which are incorporated herein for all purposes.
  • defibrotide may be administered to a patient diagnosed as having been infected with SARS-CoV-2. In some embodiments, defibrotide may be administered to a patient displaying one or more symptoms of SARS-CoV-2 infection. In some embodiments, defibrotide may be administered to a patient suspected of being infected with SARS-CoV-2. In some embodiments, defibrotide may be administered to a patient diagnosed with COVID- 19. In some embodiments, defibrotide may be administered to a patient displaying one or more symptoms of COVID-19. In some embodiments, defibrotide may be administered to an asymptomatic patient infected with SARS-CoV-2.
  • defibrotide may be administered to a patient presenting with low oxygen saturation levels. In some embodiments, defibrotide may be administered to a patient requiring oxygen therapy. In some embodiments, defibrotide may be administered to a patient requiring assistance breathing. In some embodiments, defibrotide may be administered to a patient who is on, or about to be placed on, a ventilator. In some embodiments, defibrotide is administered to a patient that has received treatment with a ventilator. In some embodiments, defibrotide is administered to prevent, ameliorate, delay, or treat ARDS or other inflammatory respiratory distress in a patient who is on, or about to go on, a ventilator.
  • defibrotide is administered to prevent, ameliorate, delay, or treat ARDS in a patient who is suffering from an infection. In some embodiments, defibrotide is administered to prevent, ameliorate, delay, or treat ARDS or other inflammatory respiratory distress in a patient who is suffering from sepsis. In some embodiments, defibrotide is administered to prevent, ameliorate, delay, or treat ARDS or other inflammatory respiratory distress in a patient who is suffering from pancreatitis. In some embodiments, defibrotide is administered to prevent, ameliorate, delay, or treat ARDS or other inflammatory respiratory distress in a patient who is suffering from pneumonia.
  • defibrotide is administered to prevent, ameliorate, delay, or treat ARDS in a patient who is suffering from an infection caused by one or more viruses. In some embodiments, defibrotide is administered to prevent, ameliorate, delay, or treat ARDS or other inflammatory respiratory distress in a patient who is suffering from an infection caused by one or more coronaviruses.
  • defibrotide is administered to prevent, ameliorate, delay, or treat ARDS or other inflammatory respiratory distress in a patient who is suffering from lung trauma. In some embodiments, defibrotide is administered to prevent, ameliorate, delay, or treat ARDS or other inflammatory respiratory distress in a patient who is suffering from lung injury.
  • the defibrotide may be administered as often and as for long as required. In some embodiments, the defibrotide is administered 1-120 times. In some embodiments, the defibrotide is administered for about one day, about two days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, or about 30 days or more.
  • the defibrotide may be administered daily, weekly, or monthly. In some embodiments, the defibrotide is administered every day for about one week, about two weeks, about three weeks, or about four weeks.
  • administration of defibrotide decreases the amount of one or more serum biomarkers associated with the development of ARDS.
  • the one or more serum biomarkers include, but are not limited to, RAGE, Ang-2, SP-D, IL-8, Fas, Fas ligand, PCP I, PCP III, octane, acetaldehyde, and 3-methylheptane.
  • a defibrotide treatment period may vary on a patient- by-patient basis. In some embodiments, a defibrotide treatment period may vary depending on the assessed likelihood of ARDS. In some embodiments, a defibrotide treatment period is determined by monitoring signs and symptoms of ARDS. For example, if the signs and symptoms of ARDS are still present after an initial treatment period, defibrotide treatment is continued until resolution of ARDS.
  • a defibrotide treatment period may vary on a patient- by-patient basis.
  • a defibrotide treatment period is determined by monitoring signs and symptoms of ARDS or consequences thereof. For example, if the signs and symptoms of ARDS or consequences thereof are still present after an initial treatment period, defibrotide treatment is continued until resolution of ARDS or consequences thereof.
  • a treatment period lasts from about 1 day to about 1 year, for example about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or more, including all values and ranges in between thereof.
  • a treatment period lasts 1 week.
  • defibrotide dosing may be determined by a variety of factors that will be readily apparent to a skilled artisan.
  • a dose is based on patient’s baseline body weight.
  • defibrotide is administered in an amount of about 1 to about 100 mg/kg of body weight per day.
  • defibrotide is administered in an amount of about 1 mg/kg, about 1.25 mg/kg, about 1.50 mg/kg, about 1.75 mg/kg, about 2 mg/kg, about 2.25 mg/kg, about 2.50 mg/kg, about 2.75 mg/kg, about 3 mg/kg, about 3.25 mg/kg, about 3.50 mg/kg, about 3.75 mg/kg, about 4.25 mg/kg, about 4.50 mg/kg, about 4.75 mg/kg, about 5 mg/kg, about 5.25 mg/kg, about 5.50 mg/kg, about 5.75 mg/kg, about 6 mg/kg, about 6.25 mg/kg, about 6.50 mg/kg, about 6.75 mg/kg, about 7 mg/kg, about 7.25 mg/kg, about 7.50 mg/kg, about 7.75 mg/kg, about 8 mg/kg, about 8.25 mg/kg, about 8.50 mg/kg, about 8.75 mg/kg, about 9 mg/kg, about 9.25 mg/kg, about 9.50 mg/kg, about 9.75 mg/kg, about 10 mg/kg,
  • defibrotide is administered in an amount of about 25 mg per kilogram of body weight per day. In some embodiments, doses based on the patient’s body weight were rounded to the nearest 10 mg for patients over 35 kg. In some embodiments, doses based on the patient’s body weight were rounded to the nearest 5 mg for patients under 35 kg. In some embodiments, the dose is 25 mg/kg/day. In some embodiments, the dose is 25 mg/kg/dose. In some embodiments, the dose is 2.5 mg/kg/dose. In some embodiments, the dose is 6.25 mg/kg/dose. In some embodiments, defibrotide is administered as a high concentration low viscosity formulation, as described in WO 2019/028340 the contents of which are incorporated by reference in their entirety for all purposes.
  • the defibrotide may be administered as a single daily dose or in multiple doses per day. In some embodiments, defibrotide is administered once a day. In some embodiments, defibrotide is administered in multiple doses per day. For example, defibrotide may be administered in 2, 3, 4, 5, 6, 7, 8, 9, or in 10 doses per day. In some embodiments, defibrotide is administered in four doses per day. In some embodiments, defibrotide is administered in four doses per day every 6 hours. In some embodiments, defibrotide is administered by continuous infusion.
  • the different doses of defibrotide are administered from about 30 minutes to about 12 hours apart.
  • defibrotide is administered about every 30 minutes, about every 40 minutes, about every 50 minutes, about every 60 minutes, about every 70 minutes, about every
  • defibrotide when defibrotide is administered in multiple doses per day, the different doses of defibrotide are administered about 6 hours apart.
  • the defibrotide may be administered daily, weekly, or monthly. In some embodiments, the defibrotide is administered every day for about one week, about two weeks, about three weeks, or about four weeks, or more. In some embodiments, defibrotide administration occurs on consecutive days. In some embodiments, defibrotide administration occurs on discontinuous days.
  • defibrotide administration occurs on consecutive days. In some embodiments, defibrotide administration occurs on discontinuous days.
  • the dosing schedule for defibrotide is summarized in Example 1
  • the one or more administrations of defibrotide are administered to treat symptoms of ARDS or other inflammatory respiratory distress.
  • the defibrotide is administered until symptoms improve.
  • the defibrotide is administered until symptoms are eradicated.
  • the defibrotide is administered until ARDS, other inflammatory respiratory distress, or related disorder is cured.
  • defibrotide is administered prophylactically.
  • one or more administrations of defibrotide are administered prophylactically to a patient determined to be at high-risk of developing ARDS, other inflammatory respiratory distress, or a related disorder.
  • the one or more administrations of the defibrotide begins before the patient develops ARDS, other inflammatory respiratory distress, or a related disorder.
  • the one or more administrations of the defibrotide begins before the patient starts showing symptoms of ARDS, other inflammatory respiratory distress, or a related disorder.
  • the one or more administrations of the defibrotide begins after the patient shows an altered level of a biomarker associated with the development of ARDS, other inflammatory respiratory distress, or a related disorder.
  • prophylactic administration of defibrotide prevents the development of ARDS, other inflammatory respiratory distress, or a related disorder.
  • prophylactic administration of defibrotide delays the development of ARDS, other inflammatory respiratory distress, or a related disorder.
  • prophylactic administration of defibrotide delays or ameliorates the development of one or more symptoms of ARDS, other inflammatory respiratory distress, or a related disorder.
  • the one or more defibrotide treatments may begin before the patient is diagnosed with ARDS, other inflammatory respiratory distress, or a related disorder. In some embodiments, the one or more defibrotide treatments may begin on the same day as the patient was diagnosed with ARDS, other inflammatory respiratory distress, or a related disorder or, for a variety of reason which are readily apparent to a skilled artisan, they may begin on a day after the patient was diagnosed with ARDS, other inflammatory respiratory distress, or a related disorder. For example, the defibrotide treatments may begin on days 0, 1,
  • the one or more administrations of the defibrotide begins on the same day that the patient diagnosed as having ARDS, other inflammatory respiratory distress, or a related disorder (i.e., day 0). In other embodiment, the one or more administrations of the defibrotide begins on 1, 2, 3, 4, 5, 6, or 7 days after the patient diagnosed as having ARDS, other inflammatory respiratory distress, or a related disorder. In some embodiments, the one or more administrations of defibrotide begin 1 day after the patient was diagnosed as having ARDS, other inflammatory respiratory distress, or a related disorder.
  • the timing of the administration of the defibrotide may depend on the particular patient (e.g. whether the patient is at high-risk of developing ARDS, other inflammatory respiratory distress, or a related disorder) and any additional therapies to be administered or co administered.
  • the defibrotide treatment period may vary on a patient-by-patient basis.
  • the defibrotide treatment period is determined by monitoring signs and symptoms of ARDS, other inflammatory respiratory distress, or a related disorder. For example, if the signs and symptoms of ARDS, other inflammatory respiratory distress, or a related disorder are still present after an initial treatment period, defibrotide treatment is continued until resolution of ARDS, other inflammatory respiratory distress, or a related disorder.
  • a patient is administered defibrotide intravenously in an amount of about 2.5 mg per kilogram of body weight about every 6 hours. Accordingly, in some embodiments, a patient is administered defibrotide intravenously in an amount of about 6.25 mg per kilogram of body weight about every 6 hours.
  • the defibrotide may be administered by any suitable route, including without limitation parenteral (e.g., intravenous, subcutaneous, intrasternal, intramuscular, or infusion techniques), oral, sublingual, buccal, intranasal, pulmonary, topical, transdermal, intradermal, mucosal, ocular, otic, rectal, vaginal, intragastric, intrasynovial, and intra- articular routes.
  • defibrotide is administered intravenously.
  • defibrotide is administered via intravenous infusion.
  • defibrotide is administered by constant intravenous infusion over a 2-hour period.
  • the defibrotide is diluted prior to infusion.
  • the diluted defibrotide solution is administered using an infusion set equipped with a filter (e.g., a 0.2 micron in-line filter).
  • a filter e.g., a 0.2 micron in-line filter.
  • the intravenous administration line e.g., peripheral or central
  • is flushed immediately before and after administration e.g., with 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP).
  • the defibrotide is administered subcutaneously.
  • the defibrotide is administered subcutaneously by means of a device that is commercially available such as, for example, the FREEDOM60® pump or similar (RMSTM Medical Products).
  • the defibrotide is administered subcutaneously using an automated injection device.
  • Subcutaneous administration of a high concentration low viscosity defibrotide formulation via an automated injection device may offer significant reduction of the time for clinical administration and enable outpatient dosing of the product for as long as needed.
  • the use of an automated injection device improves convenience and allows faster administration by health-care professionals (HCP), care-givers, or even self administration by the patients.
  • HCP health-care professionals
  • care-givers or even self administration by the patients.
  • the route of administration affects the efficacy and/or longevity of the formulations of the present disclosure.
  • subcutaneous, intramuscular and/or intraperitoneal administration is associated with an extended systemic half-life compared to the same formulation administered intravenously.
  • subcutaneous administration of the formulation provides lower peak-to-trough ratios of plasma concentrations compared to the same formulation administered intravenously.
  • subcutaneous administration provides improved efficacy and/or improves the safety profile of the formulation compared to the same formulation administrated intravenously.
  • Devices for subcutaneous administration may be prefilled, with for example a predefined adult or pediatric dose, or may be used to administer a weight-based dose specific for individual patients.
  • the patient determines the dose and administers it.
  • formulations of the disclosure are administered subcutaneously in less than about two hours, less than about one hour, or less than about 30 minutes. In some specific embodiments, formulations of the disclosure are delivered subcutaneously over about 5 minutes to about 1 hour, about 10 minutes to about 1 hour or about 15 minutes to about 45 minutes.
  • subcutaneous administration of the low-viscosity formulations of the present disclosure allows for less-frequent administration and/or lower doses. In some embodiments, subcutaneous administration of the low-viscosity formulation of the present disclosure allows for reduced administration volume.
  • a patient is from about 0 years of age to about 16 years of age, including all ranges and subranges therein.
  • a patient is from about 0 months, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 14 years, 15 years, to about 16 years of age.
  • a patient is from about 0 months to about 23 months of age. In some embodiments, a patient is from about 2 years to about 11 years of age. In some embodiments, a patient is from about 12 years to about 16 years of age. In accordance with some embodiments of the present disclosure, a patient may be a pediatric patient or adult. A pediatric patient is from about 0 years of age to about 16 years of age, including all ranges and subranges therein.
  • a pediatric patient is from about 0 months, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 14 years, 15 years, to about 16 years of age.
  • a patient is from about 0 months to about 23 months of age.
  • a patient is from about 2 years to about 11 years of age.
  • a patient is from about 12 years to about 16 years of age. [0062] In some embodiments, a patient is an adult patient. An adult patient is older than 16 years of age. In some embodiments, the adult patient is 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,
  • an adult patient is between 16 and 30 years of age, including all values and ranges in between. In some embodiments, an adult patient is between 31 and 40 years of age, including all values and ranges in between. In some embodiments, an adult patient is between 41 and 50 years of age, including all values and ranges in between. In some embodiments, an adult patient is between 51 and 60 years of age, including all values and ranges in between. In some embodiments, an adult patient is between 61 and 70 years of age, including all values and ranges in between. In some embodiments, an adult patient is between 71 and 80 years of age, including all values and ranges in between.
  • an adult patient is between 81 and 90 years of age, including all values and ranges in between. In some embodiments, an adult patient is between 91 and 100 years of age, including all values and ranges in between. In some embodiments, a patient older than 60 years old is considered to be at higher risk of developing ARDS, other inflammatory lung disorders, or related conditions.
  • the patient is considered at risk of developing ARDS, other inflammatory lung distress, or related conditions if the patient presents with one or more comorbidities.
  • the one or more comorbidities include, but are not limited to, obesity, hypertension, diabetes, an autoimmune disorder (e.g. rheumatoid arthritis), heart disease, heart failure, atherosclerosis, cancer (e.g. lung cancer), a history of smoking or exposure to other lung-damaging agents), liver disease, alcoholism, other pulmonary infection, and chronic kidney disease.
  • the patient presents with elevated markers of cardiac injury or dysfunction.
  • one or more factors increasing patient risk of developing severe COVID-19 is race and/or socioeconomic status.
  • Example 1-Defibrotide to treat acute respiratory distress syndrome (ARDS) [0066] Study: to Evaluate the Safety and Efficacy of Defibrotide in the treatment of acute respiratory distress syndrome (ARDS)
  • the target patient population is subjects with ARDS and between 60-150 patients will be treated.
  • the study design is as follows:
  • the Primary endpoint 28 or 30-day mortality (target 19%, reduction from reference value 38%).
  • Time to clinical improvement defined as a decrease of 2 categories on a 7-category ordinal scale
  • TEAEs treatment-emergent adverse events
  • Exploratory endpoints Biomarker analysis before and after defibrotide.
  • Bayesian optimal interval (BOIN) design is used to find the RP2D.
  • Final sample size determined based on statistical methodology and desired alpha and power levels.
  • Subject is > 1 year of age at signing of informed consent.
  • Subject is currently receiving dialysis or expected to receive dialysis.
  • Subject has clinically significant active bleeding, history of intracranial bleeding, or is at risk for intracranial bleeding as determined by the Investigator.
  • Subject in the opinion of the Investigator, may not be able to comply with the study protocol, including appropriate supportive care, follow-up, research tests, and safety monitoring requirements.
  • Subject has a serious underlying medical condition, as judged by the Investigator, that is likely to interfere with the conduct of this study.
  • Subject is pregnant or lactating and does not agree to stop breastfeeding.
  • Subject has a known history of hypersensitivity to defibrotide or any of the excipients.
  • Test Product Defibrotide (Defitelio®) Intravenous solution 200 mg/2.5 mL (80 mg/mL) vial.
  • Dose and Mode of Administration Eligible subjects will receive defibrotide (6.25 mg/kg/dose or 2.5mg/kg/dose) infused intravenously over 2 hours ( ⁇ 30 min). Defibrotide will be administered every 6 hours (4 times a day) over 14 days. Each defibrotide dose (infused over a 2 hour ⁇ 30 min infusion period) may be administered within ⁇ 1 hour of the scheduled dosing time provided that there is at least a 2-hour window between the end of an infusion and the start of the next infusion. Standard treatment duration for 14 days.
  • Part 2 of the study The primary objective of the study is to assess the efficacy of defibrotide for the treatment of ARDS. The primary endpoint is the mortality rate at Day 28 or 30.
  • Defibrotide prevents the activation of macrovascular and microvascular endothelia caused by soluble factors released to blood by autologous hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2011;17(4):497-506. Palomo M, Mir E, Rovira M, et al. What is going on between defibrotide and endothelial cells? Snapshots reveal the hot spots of their romance. Blood, The Journal of the American Society of Hematology. 2016 Mar 31 ; 127(13): 1719-27. Pescador R, Capuzzi L, Mantovani M, et al. Defibrotide: properties and clinical use of an old/new drug. Vascul Pharmacol. 2013;59(l-2): 1-10.

Abstract

La présente invention concerne des procédés de prévention, de réduction des effets ou de traitement du syndrome de détresse respiratoire aiguë (SDRA), comprenant l'administration de défibrotide.
PCT/EP2022/062310 2021-05-06 2022-05-06 Défibrotide pour le traitement et la prévention du syndrome de détresse respiratoire aiguë WO2022234101A1 (fr)

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