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JP-7855526-B2 - B-Beta-15-42 for treating viral endotheliitis

JP7855526B2JP 7855526 B2JP7855526 B2JP 7855526B2JP-7855526-B2

Inventors

  • ザカロウスキー，カイ
  • ウルフロス，ペトラ
  • メイボム，パトリック

Assignees

  • エフフォー ファルマ ゲーエムベーハー

Dates

Publication Date
20260508
Application Date
20210519
Priority Date
20200519

Claims (12)

  1. A composition for use in the treatment of inflammatory endothelial disorders and/or complications resulting from a viral infection in a subject, wherein the composition comprises fibrin-derived peptide B beta 15-42 and/or at least one functional derivative thereof or a physiologically acceptable salt thereof, the treatment comprising the step of administering the composition to the subject in a therapeutically effective amount, the viral infection in the subject being caused by a virus of the family Coronavirus, the functional derivative being a peptide having at most three amino acid substitutions, deletions and/or additions compared to the amino acid sequence of SEQ ID NO: 1, and the fibrin-derived peptide B beta 15-42 comprising the amino acid sequence GHRPLDKKREEAPSLRPAPPPISGGGYR (SEQ ID NO: 1) .
  2. The composition for use according to claim 1, wherein the functional derivative is a peptide having at most two or at most one amino acid substitutions, deletions, and/or additions compared to the amino acid sequence of SEQ ID NO : 1, and the substitutions, deletions, and/or additions do not affect the positions of the first four amino acids of SEQ ID NO: 1 .
  3. The composition for use according to claim 1 or 2 , wherein the viral infection is caused by a virus that infects endothelial cells.
  4. The composition for use according to any one of claims 1 to 3 , wherein the inflammatory impairment of the endothelium is related to the accumulation of inflammatory cells associated with the endothelium in the subject.
  5. The composition for use according to any one of claims 1 to 4 , wherein the subject suffers from one or more disorders that increase the risk of a poor prognosis, selected from the group consisting of immunosuppression, chronic lung disease, hypertension, obesity, and diabetes.
  6. The composition for use according to claim 5, wherein the chronic lung disease is asthma, chronic obstructive pulmonary disease, cystic fibrosis, interstitial lung disease, bronchitis, sarcoidosis, idiopathic pulmonary fibrosis, bronchiectasis, acute respiratory distress syndrome, or acute lung injury.
  7. A composition for use according to any one of claims 1 to 6, wherein the viral infection is caused by HCoV-229E, HCoV-OC43 (HCoV-OC43), Middle East Respiratory Syndrome-related Coronavirus (MERS)-CoV, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), or SARS-CoV- 2 .
  8. A composition for use according to any one of claims 1 to 7, wherein the fibrin-derived peptide B beta 15-42 and/or at least one functional derivative thereof or a physiologically acceptable salt thereof is administered to a subject in a daily dose of 100 mg to 1000 mg, 150 mg to 800 mg, 200 mg to 600 mg, 300 mg to 500 mg, 300 mg, 400 mg, 500 mg, or 600 mg.
  9. The composition for use according to any one of claims 1 to 8 , wherein the composition is administered to the subject by intravenous (bolus) injection or intravenous infusion.
  10. The composition for use according to any one of claims 1 to 9 , wherein the treatment comprises a therapy lasting 1 to 10 days or 3 to 7 days.
  11. A composition for use according to any one of claims 1 to 10, wherein the fibrin-derived peptide B beta 15-42 and/or at least one functional derivative thereof or a physiologically acceptable salt thereof is administered in doses of 0.1 mg/kg body weight to 50 mg/kg body weight, 0.5 to 20 mg/kg body weight, or 0.7 to 17.5 mg/kg body weight.
  12. The composition for use according to any one of claims 1 to 11 , wherein the composition is formulated as a pharmaceutical composition together with a pharmaceutically acceptable carrier and/or excipient.

Description

This invention is based on fibrin-derived peptides, which are therapeutic compounds for treating inflammatory complications of viral diseases, such as diffuse inflammation of the endothelium, also known as systemic endotheliitis or vasculitis, and related disorders. The use of specific fibrin-derived peptides and analogues of these compounds has resulted in remarkably effective patient recovery. In December 2019, a cluster of viral pneumonia cases associated with a novel coronavirus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) emerged in China [1]. The clinical range of this new disease is highly variable, with symptoms ranging from asymptomatic infection to severe, progressive illness leading to respiratory failure or even death [2]. Critical patients, accounting for approximately 2–9% of all infected individuals, progress from pneumonia and hypoxemia to multi-organ failure, with limited acute treatment options [3]. Gathering and disseminating information on potential experimental treatment options for this novel viral infection, for which no specific therapies beyond supportive care are available, is essential to enabling rapid response. Currently, while many drugs demonstrate in vitro activity against different coronaviruses, there is no clinical evidence to support the efficacy and safety of any drug against any human coronavirus, including SARS-CoV-2 [4]. However, numerous off-label and humanitarian-use therapies demonstrating antiviral or anti-inflammatory properties in vitro have been tested worldwide, including chloroquine, hydroxychloroquine, azithromycin, lopinavir, ritonavir, favipiravir, remdesivir, ribavirin, interferon, steroids, and anti-IL-6 inhibitors. Nevertheless, no proven effective therapies have been reported to date [5,6]. Low kinase inhibitors have been proposed for the treatment of SARS-CoV-2-induced acute respiratory distress syndrome [7]. In particular, the associated increase in angiotensin-converting enzyme 2 (ACE2) with low kinase inhibition has been described [7]. Therefore, the reuse of drugs that are already available, clinically safe, have been tested for adverse reactions, and (ideally) are approved may be essential for the rapid treatment of COVID-19 and/or other viral diseases, or the inflammatory complications they cause, in infected patients. FX-06 (or "FX06") is a peptide (amino acids 15-42) derived from the naturally occurring Bβ polypeptide chain of human fibrin, which binds to the transmembrane adhesion receptor vascular endothelial (VE) cadherin. Fibrin is an insoluble plasma protein produced by thrombin-mediated proteolytic cleavage from the soluble parent protein fibrinogen, a protein complex composed of three pairs of polypeptide chains: Aα, Bβ, and γ. The proteolytic conversion of fibrinogen to fibrin releases two fibrinopeptides, A and B, derived from the Aα and Bβ polypeptide chains, respectively. Cleavage of fibrinopeptide B from the Bβ chain exposes amino acids 15-42 on the Bβ polypeptide chain of fibrinogen, thereby enabling fibrin and its degradation products to bind to VE cadherin. Despite being naturally occurring in the blood, the Bβ15-42 peptide exhibits lower affinity for VE-cadherin binding compared to the endogenous pro-inflammatory fibrin E1 fragment. However, application of Bβ15-42 at hyperphysiological doses has been demonstrated to reduce leukocyte migration across the endothelial barrier, an effect associated with a reduction in infarct size in animal models of acute myocardial infarction. This finding led to the development of FX-06, which is involved in the administration of Bβ15-42 at hyperphysiological doses. In addition to binding to VE-cadherin, FX-06 induces VE-cadherin-mediated intracellular signaling events in endothelial cells, stabilizing the actin cytoskeleton and adhesion junctions. VE-cadherin signaling induced by FX-06 can maintain endothelial barrier function, thereby reducing capillary leakage; therefore, FX-06 is also considered to have potential therapeutic benefits in the treatment of diseases associated with endothelial barrier breakdown. At the time of its release, FX-06 had completed a Phase 2 trial for the prevention of ischemia/reperfusion injury (ClinicalTrials.gov identifier: NCT00326976; FIRE) and was undergoing preclinical evaluation for the treatment of capillary leak syndrome. During the 2014 Ebola virus outbreak, FX06 treatment was used empirically as a treatment in patients with severe Ebola virus disease [8]. FX06 binds to endothelial cells and prevents leukocyte migration through endothelial cell gap junctions [9], thus maintaining endothelial integrity. FX06 is known for its anti-inflammatory properties [10,11] and has already been investigated in clinical trials, demonstrating a well-tolerated and compelling efficacy with a favorable safety profile [12]. The treatment of dengue shock syndrome induced by the dengue virus with FX06 is described, and FX06 was found to help maintain the