Treatment with transthyretin-lowering RNA interference therapeutics is not associated with ocular or other clinical events due to vitamin A reduction: pooled analysis of vutrisiran and patisiran data
W Blaner, C Whelan, J Gonzalez-Costello, J Wixner, M S Maurer, J S Pulido, Y Sekijima, J L Berk, L Obici, W Zhao, A Chan-Daniels, L A Bilello, K H V Lau, T H BrannaganAbstract
Introduction
Transthyretin (TTR) amyloidosis (ATTR) is a progressive, fatal disease caused by misfolded TTR depositing as amyloid fibrils in various organs, resulting in manifestations including cardiomyopathy and polyneuropathy. Treatment options for wild-type and hereditary ATTR (hATTR) include RNAi therapeutics, which suppress hepatic production of TTR. TTR functions to transport vitamin A to target tissues through interaction with retinol-binding protein. Thus, TTR-lowering therapies reduce serum vitamin A, and vitamin A supplementation is recommended while on treatment. Clinical studies of RNAi therapeutics patisiran and vutrisiran have demonstrated acceptable safety profiles, with no clinical adverse events (AEs) directly attributed to vitamin A reduction reported. However, the risk of vitamin A deficiency has not been formally assessed in cumulative clinical and real-world data.
Purpose
To evaluate clinical study and post-marketing data to assess whether TTR-lowering therapies patisiran and vutrisiran are associated with AEs attributable to vitamin A deficiency in patients with ATTR with cardiomyopathy (ATTR-CM) or hATTR with polyneuropathy (hATTR-PN).
Methods
This safety analysis includes data from patients with ATTR who received ≥1 dose of patisiran, vutrisiran or placebo in the following clinical studies: APOLLO (hATTR-PN), patisiran open-label extension (hATTR-PN), APOLLO-B (ATTR-CM), HELIOS-A (hATTR-PN) and HELIOS-B (ATTR-CM). Preferred and high-level term data for frequency and rate (per 100 patient years [PYs]) of ocular events related to visual impairment and blindness and potentially attributable to vitamin A deficiency were reported. A cumulative post-marketing review of a patisiran/vutrisiran global safety database for signals of ophthalmic AEs or symptoms of vitamin A deficiency was conducted separately.
Results
Overall, 613, 709 and 583 patients treated in clinical studies with patisiran, vutrisiran and placebo, respectively, were included in the analysis with total exposures of 1832, 1915 and 1099 PYs (Table). Low rates (majority <1.0 event [E]/100 PYs) of visual impairment and blindness potentially attributable to vitamin A deficiency were observed and were comparable across groups. Dry eye (0.9–1.3 E/100 PYs) and visual impairment (0.5–0.8 E/100 PYs) were most frequent. No cases of symptomatic vitamin A deficiency were observed in collective data from clinical development programmes or in post-marketing experience. Over 10,000 patients with ATTR have received investigational or commercial patisiran or vutrisiran, some of whom have been followed for up to 7 years, totalling more than 25,000 PYs of treatment exposure.
Conclusion
In this pooled analysis of ATTR clinical studies and in post-marketing data, no safety findings attributable to vitamin A deficiency were reported upon TTR lowering with patisiran or vutrisiran. Alternative pathways independent of TTR facilitate vitamin A transport.For image description, please refer to the figure legend and surrounding text.