Preliminary Promise of the Alternative Complement Pathway Inhibition in IgA Nephropathy Research

The alternative complement pathway has received universal recognition since it was discovered by Pillemer and colleagues in 1954. As one of the three complement pathways conditioning and killing pathogens, the alternative pathway acts an important role in the body's defense mechanism while independent of the immune responses.

It doesn't require specific antigen-antibody interactions but specific types of compounds for auto-activation. The alternative pathway activated by viruses, fungi, bacteria, polysaccharides, parasites, cobra venom, and immunoglobulin A takes the main responsibility of defending the body against infections, especially in an early period when specific antibodies have not been produced.

However, its ability to spontaneously activate sometimes could be a shortcoming in that the C3 convertase amplification loop in the alternative pathway could cause unwanted inflammation and damage. As a result, the regulation and inhibition of the alternative complement pathway are necessary treatments in certain conditions.

A recent phase 2, dose-ranging research unveils that the complement inhibitor of the alternative complement pathway that drives the pathogenesis of primary glomerulonephritis, iptacopan (LNP023, Novartis), is anticipated to be the first targeted therapy for the treatment of IgA nephropathy.

IgA nephropathy (IgAN), also known as Berger's disease, is a kidney disease that occurs when IgA deposits produced by the immune system to protect the body from foreign substance invasion are accumulated in the kidneys, causing inflammation that damages the kidney tissues. This common form of glomerulonephritis is tricky to treat because asymptomatic individuals and patients with rapidly progressive kidney failure present quite different symptoms.

Complement-driven renal diseases, including IgAN, are devastating and mostly affect young adults, imposing a high disease burden. Therefore, a new treatment for the glomerular disease is more than exciting on the condition that it has been few and far over the past decades.

The discovery of the new drug iptacopan exhibits preliminary promise for the treatment of IgA nephropathy. The research has proven that usage of this complement inhibitor for 90 days results in a significant and dose-dependent reduction in proteinuria and a trend towards stabilization of kidney function. It's meaningful as such an early reduction in proteinuria is a key marker of drug efficacy in IgA nephropathy

"These efficacy data along with the safety profile seen after 90 days of treatment offer hope that inhibition of the alternative complement pathway with iptacopan may be an effective way to delay IgAN disease progression." Jonathan Barratt, MD, PhD, of John Walls Renal Unit of Leicester General Hospital, lead study author and professor of renal medicine at the University of Leicester, UK, told a press briefing.

Nevertheless, researchers also cautioned that the reduction in proteinuria in this early stage trial is a surrogate outcome compared with the decrease of the time to end-stage kidney disease (ESKD), for which the development of iptacopan with the Phase III IgAN trial APPLAUSE is already underway.

Besides complement inhibitors, the field of complement-directed drug discovery and development, as well as complement technology are experiencing a highly successful and inspiring period. Many life science enterprises like Creative Biolabs and institutions are dedicated to accelerating the development of complement therapeutics, ranging from therapeutic antibodies, serine protease inhibitors, soluble complement regulators, complement component inhibitors, anaphylatoxin receptor antagonists, and other small molecules.

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