An optimal treatment regimen for patients with C3 glomerulopathy (C3G) has not been established, and no therapies are currently US Food and Drug Administration (FDA) approved for C3G. An important treatment goal is a reduction in urine protein to creatinine ratio to improve renal survival.

C3G is like other glomerular diseases in that patients experience hypertension and marked proteinuria, among other clinical findings that are associated with glomerular disease. Therefore, our initial focus, which we classify generally as supportive care, is directed at those manifestations. Once we have a confirmed C3G diagnosis, we quickly address hypertension and proteinuria using drugs such as ARBs or ACE inhibitors. These agents are what we would consider to be supportive measures because we use them in all patients who have glomerular disease. Along with supportive care, we recommend lifestyle modifications, such as reducing sodium and protein intake.

If a patient continues to have proteinuria that is greater than 1 g per day despite supportive care measures, then the Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Glomerular Diseases recommends starting nonspecific treatment, if you will, with mycophenolate mofetil and glucocorticoids, followed by eculizumab if these agents do not work. With each incremental nonspecific therapy, we are capturing a few additional patients who are responding. So, it is important to go through the sequence of therapies and see if you can get a patient’s disease to respond. Unfortunately, up to 50% of patients with C3G go on to develop end-stage renal disease by 10 years despite treatment, and that really is the reason we must press further and find something better to treat this group of patients.

We want to try targeting the alternative complement pathway as opposed to the terminal pathway with agents such as eculizumab or ravulizumab. The 2 leading agents that target the alternative pathway (ie, iptacopan and pegcetacoplan) have completed phase 2 trials in C3G. The data from these trials suggest that blocking the alternative pathway provides additional benefits in patients who are already on mycophenolate mofetil and steroids, with some patients experiencing a further reduction in proteinuria.

The phase 3 placebo-controlled APPEAR-C3G trial evaluating iptacopan has finished recruitment, and all patients have made it through 6 months of study. Those data will be available very soon, and we will be able to see whether the phase 3 data recapitulate what was reported in the phase 2 trial on iptacopan by Wong et al. The phase 3 VALIANT trial evaluating pegcetacoplan is also ongoing, although it has not reached the 6-month point. These agents appear promising for all patients with C3G who currently do not have a therapeutic agent that works for them.