ALX-009 is a first-in class orphan drug candidate for Cystic Fibrosis (CF) patients.
It consists in the combination of two endogenous substances, hypothiocyanite (OSCN-) and lactoferrin, exhibiting antimicrobial properties compensating the defective innate immune system in CF patients. ALX-009 is presented as a solution for inhalation for the symptomatic treatment of lung infections.
ALX-009 scientific and medical rationale.The genetic causes of CF are linked to the mutation of a single gene, the cftr (cystic fibrosis transmembrane conductance regulator) gene. This gene codes for the CFTR membrane proteins involved in the ion exchange between the cell and the lumen. In the lung, ionic equilibrium is important to preserve the protective action of the Airway Surface Liquid (ASL) and mucus. However, in CF patients, ASL, mucus volumes and compositions are modified. The ASL normally contains bactericidal/bacteriostatic products in solution that are less or not present in the ASL of CF patients. In addition, the volume of the ASL of CF patients is reduced with increased salt content; both factors dehydrate the mucus that becomes thick and accumulates at the surface of cells.Impaired OSCN- and lactoferrin in CF patients lungs’ defenseOSCN- and lactoferrin are among the bactericidal compounds that are deficient in the ASL of CF patients. OSCN- is a potent large spectrum antimicrobial compound whereas lactoferrin is a multifunctional protein that inactivates/kills bacteria.
Presence of OSCN- is significantly influenced by the CFTR function. Indeed, the precursor molecule SCN- transits by the CFTR channel to the ASL where it reacts with H2O2 via a lactoperoxidase enzymatic reaction to produce OSCN-. However, in CF patients, the SCN- traffic via the CFTR channel is inefficient and the secretion of lactoperoxidase seems also impaired by the obstruction of goblet cells by the thick mucus covering the CF lung epithelia. OSCN- production is then compromised. Lactoferrin secretion is also blocked by the mucus, reducing even more the natural ASL defense capacity.
OSCN- is a highly reactive compound that oxidizes free thiol radicals of proteins to created disulfide bonds that perturb the bacterial physiology. Lactoferrin may act by direct interaction with bacterial cell membranes by depriving bacteria of iron due to its iron chelator activity. By providing both molecules, ALX-009, a fixed combination of OSCN- and lactoferrin, will contribute to restore the natural capacity of the lung to fight against infections.ALX-009 (OSCN-/bLF) – a therapeutic option to fight broader bacterial infectionsTests performed by Alaxia or in collaboration with Queen’s University Belfast or Colorado State UniversityAchromobacter spp, Pseudomonas aeruginosa, Burkholderia cepacia complex, Stenotrophomonas maltophilia, Burkholderia pseudomallei
In contrast with antibiotics, ALX-009 activity is not altered by complex structures such as biofilm and/or sputum that are present in lung infections
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