Inhibition of Complement Pathway by Small Molecule Factor D Inhibitors in PNH and aHUS: A Therapeutic Breakthrough

The abstract discusses the role of Factor D, a serine protease involved in the alternative pathway of complement (APC), as a potential therapeutic target for conditions such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). It highlights that eculizumab, the current treatment for these diseases, requires intravenous administration and has limitations. The study introduces a modified Ham test as an in vitro model for aHUS and presents three small molecule inhibitors of Factor D (ACH-3856, ACH-4100, ACH-4471), which are being developed for oral administration.

The methodology involved testing these inhibitors on blood samples from PNH and aHUS patients, using various assays to evaluate binding affinity, protease inhibition, and the impact on hemolysis and C3 fragment deposition. The modified Ham test was used to assess the effect of these inhibitors on complement-mediated cell killing in aHUS.

The results showed that all three molecules had high binding affinity to human Factor D and inhibited its proteolytic activity in a dose-dependent manner. They also reduced hemolysis in rabbit erythrocytes and significantly decreased cell killing in the modified Ham test at low concentrations.

The conclusion emphasizes that these Factor D inhibitors could be the first oral complement inhibitors, effectively blocking hemolysis in PNH and reducing C3 fragment accumulation. The modified Ham test is validated as a preclinical model for testing complement inhibitors in aHUS.

Disclosures mention employment relationships with Achillion Pharmaceuticals for several authors and a board membership or advisory committee role with Alexion Pharmaceuticals for one author.