Designing the Next Fibrillary GN Trial: B-Cell Agents and T-Cell Engagers

Asked by Gerald Appel, MD, how he would design the next trial in fibrillary glomerulonephritis (FGN), drawing on his experience helping secure FDA approval of two drugs for C3 glomerulopathy, Andrew Bomback, MD, MPH, begins by emphasizing why the completion of the FACT trial matters. The trial signals to drug developers that FGN is a disease in need of therapies with patients who can be enrolled, and that even in an ultra-rare disease, a study can be completed and could potentially support a drug approval.

The biggest obstacle, Bomback explains, is that even with DNAJB9 as a reliable diagnostic marker, it remains unclear which cell type produces the fibrils, so he has no definitive answer on which agent to test. Given the signal seen with rituximab, he suggests that newer B-cell agents targeting APRIL or BAFF/APRIL could be reasonable candidates. While FGN is likely autoimmune, whether it is driven by B cells or T cells is uncertain. For that reason, he is drawn to the T-cell engagers used in lupus nephritis, if more safety experience accrues, because they act on both T-cell and B-cell pathways. He stresses that there is clearly a population of patients willing to participate in trials.

Appel agrees that patients are engaged, noting that they often read about their disease. He adds that while there were no glomerular centers when Columbia founded the first around 2000, many now see patients with FGN. A multicenter collaborative study, similar to efforts in C3 glomerulonephritis and dense deposit disease, could enroll a few patients from each center for a controlled trial against placebo or nonspecific therapy, with biopsies before and after treatment to assess changes in the fibrils.

Appel supports testing anti-B-cell agents and newer drugs acting on T cells and B cells, including those used in IgA nephropathy, pointing to the smudgy IgG seen on FGN biopsies as a possible clue to pathogenesis.

In closing, Bomback notes that the FACT trial, while not a perfect answer, shows that some patients benefit from treatment and underscores that lowering proteinuria as quickly and efficiently as possible gives patients the best chance of avoiding end-stage kidney disease. Appel adds that their insights reflect long experience at a glomerular center rather than data validated in hundreds or thousands of patients.