Investigators have identified a novel strategy for treating paroxysmal nocturnal hemoglobinuria (PNH), according to a paper published in Blood.
In patients with PNH, defective expression of regulatory proteins on the surface of red blood cells leaves the cells vulnerable to attack by the complement immune system.
This can lead to hemolysis, which results in severe anemia and contributes to a high risk of thrombosis.
Eculizumab is the only approved therapeutic for PNH. The drug reduces hemolysis and can provide patients with relief from blood transfusions.
However, eculizumab is costly (currently more than $400,000 per year per patient), and one third of PNH patients who receive eculizumab continue to require blood transfusions to manage their anemia.
Investigators previously discovered that this non-response is due to fragments of complement C3 proteins on the surface of red blood cells, which are eventually attacked by immune cells.
Therefore, John Lambris, PhD, of the University of Pennsylvania, and his colleagues hypothesized that using small molecules to inhibit the complement cascade at the level of C3 proteins might be an effective strategy for treating PNH.
The team thought this method would prevent both hemolysis and immune cell recognition, and it might be more cost-effective than the current antibody-based treatment.
So they investigated the effect of a C3 inhibitor called Cp40 and its long-acting form, PEG-Cp40, on self-attack and resulting hemolysis using human PNH cells. Both compounds effectively inhibited hemolysis and efficiently prevented deposition of C3 fragments on PNH red blood cells.
In non-human primates, a single injection of PEG-Cp40 had an elimination half-life of more than 5 days. However, the investigators found evidence to suggest the drug may affect plasma levels of C3.
“We think these 2 compounds are excellent and potentially cost-effective candidates for further clinical investigation,” Dr Lambris said.
He hopes the compounds will be tested in clinical trials by 2015. Dr Lambris and his colleague, Daniel Ricklin, PhD, are the inventors of patents and patent applications owned by the University of Pennsylvania that describe the use of complement inhibitors for therapeutic purposes.
And Dr Lambris is a founder and equity holder of Amyndas Pharmaceuticals, which has exclusively licensed the Cp40 and PEG-Cp40 technologies from the university and is developing complement inhibitors for clinical applications.
