The complement cascade, an arm of the innate immune system consisting of a collection of small proteins with various functions in targeting pathogens, has been implicated in the pathology of a number of different neurological diseases, from autoimmune diseases like myasthenia gravis (MG) to neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), says GlobalData. The leading data and analytics company notes that inhibiting the complement cascade and associated auto-inflammation is a neuroimmunological strategy of growing importance across a wide range of neurological conditions, many of which have significant need for new, more effective treatment options.

Along with two marketed agents, AstraZeneca’s Soliris (approved for MG, neuromyelitis optica spectrum disorder [NMOSD], and two non-neurological indications) and Ultomiris (approved for MG, along with two non-neurological indications), GlobalData has identified 28 pipeline agents in clinical or preclinical phases of development for neurological conditions. With impressive efficacy seen in clinical trials for both approved and late-stage agents, GlobalData expects complement inhibitors to have a significant impact on the neurology market going forward.

Rose Joachim, Associate Director of Neurology at GlobalData, comments: “Complement-mediated injury is an important part of MG pathology, evidenced by both marketed products, Soliris and Ultomiris, having their first neurology-specific approvals in this indication. On top of these approved agents, there are currently eleven additional complement-targeting drugs in development for this disease. AD is the indication with the next highest number of complement inhibitors in development, albeit most are in preclinical/discovery stages of development. After AD, Guillain-Barre syndrome (GBS), NMOSD, and ALS are all crucial areas for pipeline development of complement inhibitors. This mechanism of action is certainly one to watch in these indications.”

Complement-targeting products currently in Phase III development include Soliris for GBS, Ultomiris for NMOSD, UCB’s zilucoplan for ALS, and Regeneron Pharmaceutical’s pozelimab for MG.

The majority (40%) of complement-targeting agents in development and 100% of Phase III products target one particular protein involved in the complement cascade, complement factor C5. C5, is important in driving auto-inflammatory pathology as its cleavage leads to the production of C5a, a potent chemotactic agent for white blood cells and anaphylatoxin, and C5b, which serves as part of the membrane attack complex, whereby cytotoxic pores are formed across cell membranes. While this innate immune pathway is useful in killing bacterial cells, when directed toward self, it can cause severe damage to neural cells.

Joachim concludes: “With promising clinical trial data and a consistently broadening pipeline, targeting the complement cascade is a neuroimmunological strategy of growing importance across a wide range of neurological conditions. GlobalData expects this class of drugs to become a crucial component of the neurology market going forward.”