Compound class: Endogenous peptide in human, mouse or rat

Comment: The three principal activation pathways of the complement system (the classical, lectin and alternative pathways) converge on complement peptide C3, making it a central target for drug development in the search for immune system modulators for the treatment of complement-mediated disorders. Excessive or uncontrolled activation of the complement system plays a key role in a wide range of autoimmune and inflammatory diseases. Pharmacological inhibition of C3 activation can modify all outcomes of complement cascade activation (opsonization, inflammation and membrane attack complex formation), irrespective of which complement pathway is activated.

C3 inhibitors in development, include compstatin derivatives. Examples include Apellis Pharmaceuticals' peptide drug candidates which act as C3 inhibitors to effect disease control and disease modification, in conditions including paroxysmal nocturnal hemoglobinuria (PNH), age-related macular degeneration (AMD) and chronic obstructive pulmonary disease (COPD). APL-1 (previously POT-4), a short-acting inhibitor has completed Phase 1 in AMD and has potential for COPD (inhaled administration). APL-2 (INN pegcetacoplan; FDA approved 2021 as Empaveli®) is PEGylated APL-1 formulated for subcutaneous (PNH) and intravitreal administration (AMD). Pegcetacoplan was the first C3-targeted PNH therapy to be approved in the USA. APL-9 (a second generation derivative of APL-2) was tested in clinical trial for potential to treat SARS-CoV-2-induced mild-moderate ARDS (NCT04402060), but the program was terminated in early 2021 when an interim data review showed that APL-9 therapy did not significantly reduce mortality.

AMY-101 (a next-generation proprietary compstatin from Amyndas Pharmaceuticals) [1] has been granted Orphan Designation by both the EMA and US FDA for the treatment of C3 glomerulopathy (C3G). This candidate has been entered into clinical trials that aim to determine its ability to combat the inflammatory damage (to lung and other organs) in patients with severe COVID-19 (Phase 2 NCT04395456) [2]. Peptide Cp40 has shown effective C3 inhibition in C3G in vitro [5].

Species: Human