Inotersen

Law S, et al. American Journal of Kidney Diseases, 2023, 81(5), 606-610.

Inotersen is approved for the treatment of polyneuropathy associated with hereditary transthyretin amyloidosis (ATTRv). By targeting transthyretin (TTR) mRNA, inotersen reduces the synthesis of misfolded TTR protein, mitigating disease progression. Despite its efficacy, inotersen has been associated with nephrotoxicity, including focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome.
A documented case involved a woman in her early 30s with ATTRv caused by the V50M TTR variant, presenting with nephrotic syndrome seven months after starting inotersen therapy. Renal biopsy revealed FSGS and minimal amyloid deposition in the glomeruli. Discontinuation of inotersen alone resulted in complete clinical and biochemical recovery without the need for immunosuppression. This outcome underscores the potential for reversibility of inotersen-associated nephrotoxicity through drug withdrawal.
The phase 3 NEURO-TTR trial corroborated these findings, reporting that 3% of patients treated with inotersen developed crescentic glomerulonephritis. Affected individuals predominantly carried the V50M TTR variant, which is linked to renal amyloid accumulation. These observations highlight the importance of close renal function monitoring in patients undergoing inotersen therapy, particularly those with pre-existing renal amyloidosis.