It occurs when the protein immunoglobulin A builds up, becomes trapped within the glomeruli and damages the kidney.
It becomes progressively worse with time and approximately 30% of patients will ultimately lose kidney function, subsequently requiring dialysis or a kidney transplant.
A potential treatment, felzartamab, is being developed by Biogen, having initially been launched by MorphoSys for multiple myeloma and licensed to Human Immunology Biosciences (subsequently acquired by Biogen).
It is a fully human monoclonal antibody targeting CD38, a protein expressed on mature plasma cells, that has potential in a range of immune-mediated diseases — including IgAN.
It has been shown to selectively deplete CD38+ plasma cells. In a Phase II study, 54 patients with IgAN and a high risk of progressive kidney dysfunction were given nine doses of the antibody for 5 months.1
It gave substantial reductions in proteinuria levels as assessed by the urinary protein:creatinine ratio (UPCR) and stabilisation function as measured by the estimated glomerular filtration rate (with measurements taken for 2 years from the start of the trial).
Patients maintained a mean reduction of approximately 50% in the UPCR up to the end of the 2-year period, more than 18 months after they had received their last dose.
This, they suggested, means that it could preserve kidney function and be given in treatment cycles rather than requiring a continuous dosing regimen.
Additional analysis showed that the antibody gave selective and durable reductions in the levels of IgA, whereas the levels of two other immunoglobulins, IgG and IgM, recovered to baseline 3 months after treatment ended.
This could facilitate the maintenance of significant immune functions required for protection against infections. It was generally well tolerated.
Phase III studies are now being planned in this indication. Studies have also been done in other kidney conditions, including primary membranous nephropathy (PMN), another autoimmune disease that damages the glomeruli.
It most often results from the formation of autoantibodies to the phospholipase A2 receptor.
In a Phase Ib/IIa trial, 31 patients with PMN who were refractory to immunosuppressive therapy were given nine 16 mg/kg infusions of the antibody in a 24-week treatment period, followed by a 28-week follow-up period.2
Treatment-emergent adverse events were experienced by 27 patients, which included infusion-related reactions, hypogammaglobulinaemia, peripheral oedema and nausea. An immunologic response was achieved by 20 of the 26 efficacy evaluable patients, with anti-PLA2R titre reductions being rapid.
Nine patients had achieved partial proteinuria remission by the end of the study. A double-blind, randomised, placebo-controlled Phase II trial has also been done in antibody mediated rejection after kidney transplantation.3
In all, 22 patients with antibody mediated rejection that occurred at least 180 days after transplantation were given the nine-dose regimen.
At week 24, morphologic antibody mediated rejection resolved in nine treated patients and two given a placebo.
References
- J. Barratt, et al., J. Am. Soc. Nephrol. 35, Abstr. FR-OR69 (2024).
- B.H. Rovin, et al., Kidney Int. Rep. 9, 2635 (2024).
- K.A. Mayer, et al., N. Engl. J. Med. 11, 122 (2024).