Oral treatment effective for most with C3G, but responses vary

The approved therapy Fabhalta (iptacopan) is effective at reducing urine protein content for most people with hard-to-treat C3 glomerulopathy (C3G), a real-world study showed.

Although Fabhalta was effective for most patients, the researchers noted that individual responses varied widely, with some patients not responding at all to the therapy. This underscores a need for better ways to personalize treatment, they said.

The study, “Real-World Outcomes of Iptacopan in C3 Glomerulopathy and Primary Immune Complex–Mediated Membranoproliferative Glomerulonephritis,” was published in Kidney International Reports. The work was supported by the CompCure Association, a nonprofit focused on C3G and related diseases, and the European Reference Network for Rare Kidney Diseases.

C3G is a rare disorder in which a part of the immune system called the alternative complement pathway becomes overactive, triggering damage in the kidneys’ filtering units. It can be divided into two main types based on the pattern of deposits of the complement protein C3: dense deposit disease (DDD) and C3 glomerulonephritis (C3GN).

Because the kidneys are responsible for filtering out urine, kidney damage often leads to high levels of protein in the urine (proteinuria). Fabhalta is a twice-daily oral therapy that works by blocking the activation of this immune pathway. It is approved in the U.S. to reduce proteinuria in adults with C3G.

Fabhalta in the real world

Regulatory approval was based on clinical trial data showing that the therapy was significantly better than a placebo at reducing proteinuria among adults with C3G. While trials are the gold standard for determining a therapy’s safety and efficacy, their strict eligibility criteria prevent these studies from fully capturing what happens in real-world clinical practice.

An international team of scientists reported outcomes for C3G patients who received Fabhalta outside clinical trials. The study involved 24 people with C3G — 22 with DDD and two with C3GN — and four with another rare kidney disease, primary immune complex-membranoproliferative glomerulonephritis (IC-MPGN).

Nearly half (46%) of all participants were younger than 18, and most had previously received other immunosuppressive medications. In most cases, initial treatments decreased urine protein levels, but proteinuria worsened again, requiring additional therapies to maintain kidney function.

By the time they started Fabhalta, most patients in the study had been living with C3G or IC-MPGN for more than three years. Participants had been taking the therapy for more than a year on average.

Most patients (85.7%) continued to receive certain treatments for kidney disease, while more than half (54.7%) also received immunosuppressive treatments.

Fabhalta was associated with a significant reduction in proteinuria at one, three, six, and 12 months, with the strongest drop, by 56%, seen after six months. Most (75%) of the patients — 21 out of 28 — saw proteinuria levels drop, suggesting a response to the treatment.

The extent of response varied, however: In a few patients, Fabhalta treatment triggered complete proteinuria remission, but in most cases, proteinuria was decreased but not eliminated.

And in seven patients — five with C3G and two with IC-MPGN — Fabhalta didn’t effectively control proteinuria. The researchers noted that two of these nonresponders experienced a dip in urine protein levels immediately after starting the therapy, but levels rose again within a few months.

“Kidney function remained stable throughout the follow-up,” they wrote.

Safety data showed that overall, Fabhalta was tolerated well. No safety issues were documented, apart from one episode of mild inflammation of the air-filled cavities around the nose and one mild elevation in pancreatic enzymes that was reversible and didn’t cause symptoms.

The data indicate that Fabhalta is effective in most, but not all, people with hard-to-treat C3G in real-world settings. The researchers called for further studies to identify factors that can help clinicians predict which patients will be most likely to benefit from Fabhalta.

“Despite the overall reduction in proteinuria in this clinically complex population, in whom conventional immunosuppression had often failed to provide sustained disease control, responses varied widely, from complete remission to nonresponse,” the researchers wrote. “This variability underscores the need for better molecular characterization and biomarker-based patient stratification.”

Fabhalta is sold by Novartis. The company provided some logistical support for the work, but was not involved in the study’s design, conduct, or analysis.