Small-molecule factor D inhibitors selectively block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome

Abstract

Paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome are diseases of excess activation of the alternative pathway of complement that are treated with eculizumab, a humanized monoclonal antibody against the terminal complement component C5. Eculizumab must be administered intravenously, and moreover some patients with paroxysmal nocturnal hemoglobinuria on eculizumab have symptomatic extravascular hemolysis, indicating an unmet need for additional therapeutic approaches. We report the activity of two novel small-molecule inhibitors of the alternative pathway component Factor D using in vitro correlates of both paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Both compounds bind human Factor D with high affinity and effectively inhibit its proteolytic activity against purified Factor B in complex with C3b. When tested using the traditional Ham test with cells from paroxysmal nocturnal hemoglobinuria patients, the Factor D inhibitors significantly reduced complement-mediated hemolysis at concentrations as low as 0.01 μM. Additionally the compound ACH-4471 significantly decreased C3 fragment deposition on paroxysmal nocturnal hemoglobinuria erythrocytes, indicating a reduced potential relative to eculizumab for extravascular hemolysis. Using the recently described modified Ham test with serum from patients with atypical hemolytic uremic syndrome, the compounds reduced the alternative pathway-mediated killing of PIGA-null reagent cells, thus establishing their potential utility for this disease of alternative pathway of complement dysregulation and validating the modified Ham test as a system for pre-clinical drug development for atypical hemolytic uremic syndrome. Finally, ACH-4471 blocked alternative pathway activity when administered orally to cynomolgus monkeys. In conclusion, the small-molecule Factor D inhibitors show potential as oral therapeutics for human diseases driven by the alternative pathway of complement, including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.

Endothelial Microparticles and Systemic Complement Activation in Patients With Chronic Kidney Disease

“…Even when complement activation is initiated by immune complexes or immunoglobulin bound to self antigens, amplification through the alternative pathway is an important cause of inflammation and tissue damage. Increased levels of microparticle‐associated factor D in patients with CKD could exacerbate the inflammatory process 49. Conversely, alternative pathway–mediated diseases, such as atypical hemolytic uremic syndrome, are frequently associated with defects in regulation of the alternative pathway that could further amplify factor D–mediated complement activation in patients with CKD 50.…”

The renaissance of complement therapeutics

“…Novartis has developed small-molecule FD inhibitors inspired by kallikrein blockers that bind to the catalytic site of FD, are orally bioavailable and appear to distribute into ocular tissue, with potential implications for AMD therapy 122,123 . Similarly, Achillion has introduced small FD inhibitors, one of which, ACH-4471, has been assessed in preclinical PNH and aHUS models 124 and is currently being evaluated in phase II clinical trials in an orally administered form 125 . Programmes for ACH-4471 in C3G and for next- generation FD inhibitors (such as ACH-5228) for oral and/or ophthalmic use are in the Achillion pipeline 126 .…”

Hematopoietic stem cell transplant-associated thrombotic microangiopathy: current paradigm and novel therapies

“…79 ACH-4471 is the first oral complement inhibitor with promising therapeutic results in in vitro models of diseases with excessive activation of alternate complement pathway such as paroxysmal nocturnal hematuria and aHUS. 80 New-generation Compstatin analogs such as Cp40 and PEG-Cp40 provide a more comprehensive and effective blockade compared with eculizumab as it also blocks C3-mediated hemolysis and opsonization. 81 LFG316, a fully human monoclonal antibody against C5, is in phase 2 clinical trial in patients with TA-TMA (Clinical trial ID NCT02763644).…”