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WO2021185832A1 - Nouveau traitement thérapeutique - Google Patents

Nouveau traitement thérapeutique Download PDF

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Publication number
WO2021185832A1
WO2021185832A1 PCT/EP2021/056678 EP2021056678W WO2021185832A1 WO 2021185832 A1 WO2021185832 A1 WO 2021185832A1 EP 2021056678 W EP2021056678 W EP 2021056678W WO 2021185832 A1 WO2021185832 A1 WO 2021185832A1
Authority
WO
WIPO (PCT)
Prior art keywords
emapalumab
treatment
use according
daily dose
administration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2021/056678
Other languages
English (en)
Inventor
Christina DE MIN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Swedish Orphan Biovitrum AG
Original Assignee
Swedish Orphan Biovitrum AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Swedish Orphan Biovitrum AG filed Critical Swedish Orphan Biovitrum AG
Publication of WO2021185832A1 publication Critical patent/WO2021185832A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/249—Interferons
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • a dose, such as a daily dose, of emapalumab may be administered as a single injection.
  • Emapalumab may be administered by intravenous (i.v.) infusion.
  • the treatment with emapalumab may also comprise treatment with a further therapeutic agent.
  • the further therapeutic agent may be selected from the group consisting of: anti-inflammatory agents, antibiotics, anti-fungal agents, anti-viral agents.
  • the anti- inflammatory agent may be methylprednisolone.
  • Methylprednisolone may be adiministered at a daily dose of at least 15 mg, such as at least 30 mg, such as at least 60 mg.
  • the treatment may involve administration of a daily dose of 30 mg or 60 mg of methylprednisolone for at least 3 days, such as at least 5 days.
  • a daily dose of methylprednisolone is distributed over three administration occasions.
  • methylprednisolone may be administered at a daily dose of 60 mg, distributed over three administration occasions, on day 1 to day 5 of a treatment period.
  • methyl prednisolone may be administered at a daily dose of 30 mg, distributed over three administration occasions, on day 6 to day 10 of a treatment period.
  • methylprednisolone may be administered at a daily dose of 15 mg, distributed over three administration occasions, on day 11 to day 14 of a treatment period.
  • the treatment is treatment of at least one of respiratory distress an hyperinflammation.
  • the subject to be treated may exhibit signs of at least one of respiratory distress and hyperinflammation.
  • Signs of respiratory distress may comprise one or more of: Pa02/Fi02 ⁇ 300 mmHg and >200 mmHg, RR > 30 breaths/min, Sp02 ⁇ 93% in air at rest.
  • Signs of hyperinflammation may comprise one or more of: Ferritin >500 ng/mL, LDH >300 U/L, D-dimers >1000 ng/mL.
  • the treatment does not include concomitant administration of one or more of the following agents: tocilizumab, canakinumab, TNF inhibitors, JAK inhibitors, hydroxychloroquine.
  • an injectable pharmaceutical formulation for use in treatment of SARS-CoV-2 as described herein comprising per mL: 5 mg or 25 mg of a fully human anti-interferon gamma (IFND) monoclonal antibody, in particular emapalumab; 1.55 mg L-histidine, 3.14 mg L-histidine monohydrochloride, monohydrate, 7.31 mg sodium chloride (NaCI), and 0.05 mg Polysorbate 80, where the pH is between 5.8 and 6.2.
  • IFND fully human anti-interferon gamma
  • the following clinical study protocol synopsis describes a phase 2/3, randomized, open-label, parallel group, 3-arm, multicenter study to investigate the efficacy and safety of intravenous administrations of anakinra, an interleukin-1 (IL-1) receptor antagonist, and emapalumab, an anti interferon gamma (anti-IFNy) monoclonal antibody, versus standard of care in reducing hyper-inflammation and respiratory distress in patients with SARS- CoV-2 infection.
  • IL-1 interleukin-1
  • emapalumab an anti interferon gamma (anti-IFNy) monoclonal antibody
  • Presence of respiratory distress defined as: o Pa02/Fi02 ⁇ 300 mm Fig and >200 mm Fig or o RR > 30 breaths/m in or o Sp02 ⁇ 93% in air at rest Note: Patients in CPAP are eligible.
  • Impairment of cardiac function defined as poorly controlled heart diseases, such as NYHA class II (mild*) and above, cardiac insufficiency, unstable angina pectoris, myocardial infarction within 1 year before enrollment, supraventricular or respiratory insufficiency or evidence of rapid worsening (respiratory distress requiring mechanical ventilation or presence of shock or presence of concomitant organ failure requiring ICU admission)
  • Impairment of cardiac function defined as poorly controlled heart diseases, such as NYHA class II (mild*) and above, cardiac insufficiency, unstable angina pectoris, myocardial infarction within 1 year before enrollment, supraventricular or ventricular arrhythmia need treatment or intervention.
  • Anakinra is the recombinant form of the IL-1 human receptor antagonist (IL- 1ra).
  • Emapalumab is a fully human lgG1 monoclonal antibody (mAb) neutralizing human IFNy.
  • Anakinra will be administered at a total dose of 400 mg per day, divided in 4 i.v. doses of 100 mg every 6 hours. Anakinra treatment will continue for 14 days i.e. , days 1 to 14.
  • Emapalumab will be administered at the initial dose of 6 mg/kg by i.v. infusion i.e., Day 1. Emapalumab treatment will be continued at the dose of 3 mg/kg, every 3 days for a total of 4 additional infusions i.e., Days 4, 7, 10 and 13.
  • methylprednisolone will be given at 20 mg x 3/day for 5 days, then 10 mg x 3/day for 5 days, then 5 mg x 3/day for 4 days. Concomitant use of tocilizumab, canakinumab, TNF inhibitors, JAK inhibitors and hydroxychloroquine is not allowed.
  • Antimicrobial therapy and prophylaxis are not limited.
  • Analgesic treatment transfusion of blood products, electrolyte and glucose infusions, i.v. parenteral nutrition, inotropic support, antibiotics, anti-fungal and anti-viral treatments, ultrafiltration or hemodialysis, as well as general supportive care are permitted.
  • Study duration and study end definition The study consists of screening, a 2-week treatment period and an 8-week follow-up period.
  • the 2-week treatment period is open, and the patients will be randomized to treatment with emapalumab, anakinra or standard of care in a 1 : 1 : 1 ratio.
  • the primary endpoint will be evaluated at Day 15.
  • a follow-up by visit or phone call will be performed 4 and 8 weeks after the end of the treatment period (Weeks 6 and 10).
  • the study duration for an individual patient will not exceed 10 weeks.
  • the end of the study is defined as last patient last follow-up visit/phone call (LPLV).
  • Rate of treatment success defined as the percentage of patients not requiring any of the followings: o Invasive mechanical ventilation or o Extracorporeal membrane oxygenation (ECMO) or o Continuous positive airway pressure (CPAP)
  • Table 1 The clinical and laboratory parameters to be collected at given time points are indicated in Table 1 (Schedule of Events). This schedule also includes information on the patient ' s demographics, medical history and prior medication. High resolution CT scan is required at screening (within 72 hours prior to start of treatment) to document the presence of pulmonitis. All parameters indicated in the Schedule of Events will be assessed at the study site. Statistics
  • Each of the study drug treatment arms is compared independently to standard of care.
  • Stage 1 the success rates are compared between each of the two treatment arms and standard of care. There is the potential to stop for futility or for efficacy of emapalumab or anakinra. Note: these rules are binding. If the trial continues beyond Stage 1 , the groups will be compared to standard of care at the end of Stage 2 for efficacy.
  • the overall one-sided significance level for efficacy for either emapalumab or anakinra is 0.097 (9.7%) to allow the initial acceptance of a potentially valuable new treatment.
  • the design has a total sample size of 54, 27 recruited in Stage 1 and 27 recruited in Stage 2 with equal 1:1:1 randomisation.
  • This design has acceptable properties in terms of the false positive potential, controlling the overall type I error at 7.9% for each of the 2 comparisons.
  • the power of this design for each of those comparisons is 74% under the assumption that the true success rates are 50% in the SoC group increasing to 80% in the emapalumab or anakinra groups.
  • the calculations on the operating characteristics of this design have been undertaken using PASS, Version 14: Group-Sequential Tests for Two Proportions (Simulation).
  • the value for the type I error has been chosen in recognition of the urgent unmet medical need to allow the identification of a signal, at least, from a statistical perspective. Having seen a statistical signal, it is then a matter of evaluating whether the observed treatment differences represent clinically relevant effects that can satisfy that unmet need. In case indications of efficacy require to be confirmed, additional patients may be added into this study. In case the outcome is statistically convincing, i.e. statistically significant on a 5% level in the stage 2 analysis, efficacy will be considered confirmed and the results will, where warranted, be used to seek regulatory approvals.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Virology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne l'émapalumab, un anticorps monoclonal anti-interféron IgGI entièrement humain (IFNy), destiné à être utilisé dans le traitement d'une infection par le SARS-CoV-2, en particulier pour traiter ou soulager des symptômes de la détresse respiratoire et/ou de l'hyperinflammation chez un patient. Le traitement comprend l'administration d'émapalumab à une dose quotidienne d'au moins 3 mg/kg tous les trois jours pendant une période de traitement de 14 jours par exemple. Une dose initiale peut comprendre l'administration de 6 mg/kg d'émapalumab.
PCT/EP2021/056678 2020-03-16 2021-03-16 Nouveau traitement thérapeutique Ceased WO2021185832A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP20163459.9 2020-03-16
EP20163459 2020-03-16

Publications (1)

Publication Number Publication Date
WO2021185832A1 true WO2021185832A1 (fr) 2021-09-23

Family

ID=69845109

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2021/056678 Ceased WO2021185832A1 (fr) 2020-03-16 2021-03-16 Nouveau traitement thérapeutique

Country Status (1)

Country Link
WO (1) WO2021185832A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006109191A2 (fr) 2005-01-27 2006-10-19 Novimmune S.A. Anticorps anti-interferon gamma et leurs procedes d'utilisation
WO2016177913A1 (fr) 2015-05-07 2016-11-10 Novimmune Sa Méthodes et compositions de diagnostic et de traitement de troubles chez des patients présentant des niveaux élevés de cxcl9 et d'autres biomarqueurs
WO2018078442A2 (fr) 2016-10-24 2018-05-03 Novimmone Sa Procédés, compositions et schémas posologiques pour traiter ou prévenir des indications associées à l'interféron gamma

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006109191A2 (fr) 2005-01-27 2006-10-19 Novimmune S.A. Anticorps anti-interferon gamma et leurs procedes d'utilisation
WO2016177913A1 (fr) 2015-05-07 2016-11-10 Novimmune Sa Méthodes et compositions de diagnostic et de traitement de troubles chez des patients présentant des niveaux élevés de cxcl9 et d'autres biomarqueurs
WO2018078442A2 (fr) 2016-10-24 2018-05-03 Novimmone Sa Procédés, compositions et schémas posologiques pour traiter ou prévenir des indications associées à l'interféron gamma

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Efficacy and Safety of Emapalumab and Anakinra in Reducing Hyperinflammation and Respiratory Distress in Patients With COVID-19 Infection. - Full Text View - ClinicalTrials.gov", 27 March 2020 (2020-03-27), XP055720655, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/show/NCT04324021> [retrieved on 20200806] *
ANONYMOUS: "GAMIFANTTM (emapalumab-lzsg)", 1 November 2018 (2018-11-01), XP055808527, Retrieved from the Internet <URL:https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761107lbl.pdf> [retrieved on 20210528] *
DANA T. LOUNDER ET AL: "Treatment of refractory hemophagocytic lymphohistiocytosis with emapalumab despite severe concurrent infections", BLOOD ADVANCES, vol. 3, no. 1, 8 January 2019 (2019-01-08), pages 47 - 50, XP055720674, ISSN: 2473-9529, DOI: 10.1182/bloodadvances.2018025858 *
FABRIZIO DE BENEDETTI ET AL: "EMAPALUMAB, AN INTERFERON GAMMA (IFN-gamma)-BLOCKING MONOCLONAL ANTIBODY, IN PATIENTS WITH MACROPHAGE ACTIVATION SYNDROME (MAS) COMPLICATING SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS (SJIA)", ORAL PRESENTATIONS, 1 June 2019 (2019-06-01), pages 178.1 - 178, XP055720714, DOI: 10.1136/annrheumdis-2019-eular.3341 *
GIUSI PRENCIPE ET AL: "Neutralization of IFN-[gamma] reverts clinical and laboratory features in a mouse model of macrophage activation syndrome", JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 141, no. 4, 1 April 2018 (2018-04-01), AMSTERDAM, NL, pages 1439 - 1449, XP055720659, ISSN: 0091-6749, DOI: 10.1016/j.jaci.2017.07.021 *
HUANG CHAOLIN ET AL: "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China", THE LANCET, ELSEVIER, AMSTERDAM, NL, vol. 395, no. 10223, 24 January 2020 (2020-01-24), pages 497 - 506, XP086050317, ISSN: 0140-6736, [retrieved on 20200124], DOI: 10.1016/S0140-6736(20)30183-5 *
KAO-JEAN HUANG ET AL: "An interferon-gamma-related cytokine storm in SARS patients", JOURNAL OF MEDICAL VIROLOGY, vol. 75, no. 2, 1 January 2004 (2004-01-01), pages 185 - 194, XP055183753, ISSN: 0146-6615, DOI: 10.1002/jmv.20255 *
RANDY CRON ET AL: "Coronavirus: Cytokine storm syndrome treatments for Covid-19 patients may cut death rates", 12 March 2020 (2020-03-12), XP055720657, Retrieved from the Internet <URL:https://www.vox.com/2020/3/12/21176783/coronavirus-covid-19-deaths-china-treatment-cytokine-storm-syndrome> [retrieved on 20200806] *
YE YI ET AL: "COVID-19: what has been learned and to be learned about the novel coronavirus disease", INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES, vol. 16, no. 10, 15 March 2020 (2020-03-15), Australia, pages 1753 - 1766, XP055720809, ISSN: 1449-2288, DOI: 10.7150/ijbs.45134 *

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