Vutrisiran-mediated knockdown of transthyretin in patients with transthyretin amyloidosis
M Fontana, V Algalarrondo, P Garcia-Pavia, M S Maurer, J D Gillmore, F Cappelli, K Kolachana, X Gao, S B Jadhav, G Robbie, P BadriAbstract
Background
Transthyretin amyloidosis (ATTR) is a progressive, debilitating disease caused by misfolded transthyretin (TTR) protein accumulating as amyloid fibrils in multiple organs and tissues. ATTR can result from inherited TTR gene variants (hereditary or variant ATTR [ATTRv]) or occurs with ageing in those with wild-type TTR (wild-type ATTR). Vutrisiran, an N-acetylgalactosamine (GalNAc)-conjugated RNA interference (RNAi) therapeutic, inhibits hepatic synthesis of both wild-type and variant TTR, resulting in rapid knockdown of amyloidogenic TTR protein. It is approved for the treatment of ATTRv with polyneuropathy (ATTRv-PN) and for ATTR with cardiomyopathy (ATTR-CM).
Purpose
To assess the consistency of serum TTR knockdown with the RNAi therapeutic vutrisiran across patients with ATTRv-PN in HELIOS-A (NCT03759379) and ATTR-CM in HELIOS-B (NCT04153149).
Methods
Patients received vutrisiran 25 mg subcutaneously every 3 months (Q3M). During randomised treatment, serum TTR was measured through Month 18 in HELIOS-A (post-dose/peak and pre-dose/trough sampling) and Month 30 in HELIOS-B (trough only, except Week 6). The effects of intrinsic (e.g., age, variants) and extrinsic factors (e.g., prior TTR stabiliser use) on serum TTR knockdown from baseline were assessed. Pharmacokinetic/pharmacodynamic modelling was used to generate predicted median peak and trough TTR knockdown values across both studies to assess consistency.
Results
Median (95% confidence interval [CI]) serum TTR knockdown with vutrisiran was 64.2% (61.6, 67.8) at Week 3 (n = 114), with steady-state trough knockdown 86.2% (84.1, 92.6; n = 118) in HELIOS-A, and 69.0% (66.0, 72.0) at Week 6 (n = 294), with steady-state trough knockdown of 82.5% (80.5, 84.9; n = 307) in HELIOS-B (Figure). Knockdown of serum TTR was generally consistent across patient subgroups, regardless of baseline characteristics such as age, sex, ethnicity/race, weight, TTR genotype, N-terminal pro-B-type natriuretic peptide and serum TTR concentration in both the studies, as well as ATTR type, disease stage/severity, troponin I, tafamidis use (HELIOS-B) or presence of anti-drug antibodies. Model-predicted peak serum TTR knockdown in HELIOS-B was sustained and aligned with observed knockdown in HELIOS-A, with a predicted median (95% CI) reduction at Month 30 of 87.1% (84.8, 89.4).
Conclusion
Vutrisiran treatment produced rapid, sustained and consistent TTR knockdown in HELIOS-A and HELIOS-B, supporting fixed dose of 25 mg Q3M across patients with ATTRv-PN and ATTR-CM.For image description, please refer to the figure legend and surrounding text.