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New molecules controlling endothelial barrier

Introduction

Acute lung injury (ALI) and its hypoxemic form, acute respiratory distress syndrome (ARDS), has no approved pharma cological treatment and is a condition with high mortality. Vascular leakage is one of the early events of ALI/ARDS. CD73 activity (ecto5'-nucleotidase) maintains the endothelial barrier function of lung capillaries via its enzymatic endproduct adenosine. Interferon-beta (IFNβ) increases synthesis of CD73 and has been effective in a mouse model of ALI [1].

Methods

Therefore we conducted a phase I/II trial [2], in which intravenously administered human recombinant IFNβ1a (FP-1201) was used in the study, which consisted of dose escalation (phase I) and expansion (phase II) parts to test the FP-1201 safety, tolerability and efficacy in ALI/ARDS patients. CD73, MxA (a marker for IFN β response) and other biomarkers were measured to follow pharmacokinetics/ dynamics of the intravenously administered FP-1201 and therapeutic efficacy.

Results

The optimal tolerated dose of FP-1201 (10 μg/day for 6 days) resulted in maximal MxA stimulation. Also soluble CD73 values increased, while IL-6 decreased in sera of the FP-1201-treated ALI/ARDS patients. The overall mortality of the 37 patients treated with FP-1201 was only 8.1%, fourfold to fivefold less than the expected rate based on APACHE II score values of 21.9. The control group (n = 59), which was eligible for the trial but not possible to recruit, had mortality of 32.2% (P = 0.01) and APACHE II score 23.0.

Conclusion

Restriction of vascular leakage with FP-1201 seems to significantly benefit ALI/ARDS patients. Our results suggest that FP1201 could be the first effective, mechanistically targeted, disease-specific pharmacotherapy for patients with ARDS. However, these findings warrant conduction of a large multicenter study to establish safe and effective FP-1201 treatment of ARDS.

References

  1. 1.

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  2. 2.

    Bellingan G, et al: Lancet Respir Med. 2014, 2: 98-107. 10.1016/S2213-2600(13)70259-5.

    CAS  Article  PubMed  Google Scholar 

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Jalkanen, S. New molecules controlling endothelial barrier. Crit Care 19, P234 (2015). https://doi.org/10.1186/cc14314

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Keywords

  • Adenosine
  • Multicenter Study
  • Therapeutic Efficacy
  • Acute Lung Injury
  • Early Event