Our immune system consists of a complex network of cells and molecules working together to defend the body from invading external pathogens. When our body is challenged by a pathogen, such as a virus, bacteria, or toxic chemical, the immune system immediately reacts through the development of an inflammatory response.
Neutrophils, a type of white blood cell, play a master role in regulating inflammatory responses, since they are primarily recruited to recognize and clear pathogenic elements through various mechanisms. One of the most effective neutrophil-mediated self-defense strategies is the production of Neutrophil Extracellular Traps (NETosis). This mechanism entraps pathogens in a biological trap or net, followed by ingestion and clearance. Without this response, we would be highly vulnerable to any pathogenic threat. That said, the equilibrium between NETosis and inflammation must be finely tuned to avoid an overreactive response that may cause excessive inflammation and potentially harm our healthy tissues.
A novel approach to inflammation
Interleukin 8 (IL-8, more recently referred to as CXCL-8) is an inflammatory signaling molecule, notably involved in neutrophil recruitment and activation of NETosis during the inflammatory response. In particular, high IL-8 gene expression or protein levels (in serum or tissues from patients) have been associated with pathogenic inflammatory signaling and disease progression. Based on this background, Dompé focused on designing a molecule able to modulate the immune response triggered by Il-8 signaling. Through a comprehensive analysis of putative targets, our research team selected the antagonists of IL8-receptors, CXCR1 and CXCR2, as the most effective candidates for regulating this inflammatory signaling. Therefore, we designed Reparixin, a non-competitive allosteric antagonist, that may be capable of inhibiting IL-8-activated signaling without altering IL-8/CXCR1/2 binding and physiological turnover, which remain critical for a normal immune response.
Our hypothesis has been tested and confirmed in preclinical studies. As a first challenge for demonstrating efficacy and safety of Reparixin, we evaluated the immunomodulatory potential of the molecule in lung transplantation and COVID-19.
What are CAP and acute ARDS?
Community-acquired pneumonia (CAP) is one of the most common infectious cause of hospitalization and death worldwide, which may lead to acute respiratory distress syndrome (ARDS) is a very critical condition with an estimated 60% of patients who survive.
When the COVID-19 pandemic started in early 2020, some patients were admitted to hospitals with acute respiratory distress syndrome (ARDS). This pulmonary condition was known to scientists long before the pandemic began and can rapidly progress into life-threatening acute lung injury. ARDS is characterized by widespread lung inflammation triggered by various events, such as illness or trauma. When people experience ARDS, excessive fluid accumulates in the lungs, reducing the oxygen in the blood to be distributed to peripheral organs.
As a pharmaceutical company, we joined healthcare institutions and organizations to respond to the high medical needs of the moment by investigating the therapeutic potential of Reparixin in severe pneumonia and respiratory failure.
Reparixin targets a pathogenic mechanism different from those targeted by current therapies, for instance, antibiotics or antiviral medication. Indeed, Reparixin-mediated treatment is been investigated to be a synergic therapeutic action with standard and supportive treatment to enhance recovery from acute lung injury complications, compared to standard treatment alone.
Commitment to developing treatments for the future
While vaccines have helped to mitigate the severity of COVID-19, the in-hospital treatments available for the vast majority of acute lung injury conditions remain limited. Therefore, Dompé has chosen to focus on a clinical development program to help patients affected by respiratory failure and acute lung injury.
To date, Reparixin displayed high tolerability in clinical trials with hospitalized patients suffering from severe COVID-19 pneumonia. Reparixin was administered via oral tablets and results obtained in COVID-19 have informed the design of a Phase 3 study in patients with pneumonia (including patients with COVID-19) and a Phase 2 study in patients with ARDS, which are currently both ongoing.
Dompé will continue to exploit the potential of Reparixin to reduce respiratory complications in life-threatening lung diseases, and its therapeutic potential in other conditions.