Citations

Abstract Aims HELIOS-A was a Phase 3, open-label study of vutrisiran, an RNA interference therapeutic, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy. This analysis evaluated vutrisiran's impact on exploratory cardiac endpoints in HELIOS-A patients. Methods and results Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months or intravenous patisiran 0.3 mg/kg every 3 weeks (reference group) for 18 months. Exploratory cardiac endpoints included change from baseline in N-terminal prohormone of brain-type natriuretic peptide (NT-proBNP) and echocardiographic parameters versus external placebo (APOLLO study). The modified intent-to-treat (mITT) population comprised randomized patients receiving any study drug (n = 122). A cardiac subpopulation with evidence of cardiac amyloid involvement (n = 40) was prespecified. 99mTc scintigraphy exploratory assessments in a planned vutrisiran-treated cohort at select sites were compared with baseline. At Month 18, vutrisiran demonstrated beneficial effects on NT-proBNP versus external placebo in the mITT and cardiac subpopulations (adjusted geometric mean fold change ratio [95% confidence interval] 0.480 [0.383–0.600], p = 9.606 × 10−10 and 0.491 [0.337–0.716], p = 0.0004, respectively). Benefits or trends towards benefit in echocardiographic parameters versus external placebo were observed for both populations. In 99mTc scintigraphy assessments, 32/47 (68.1%) and 31/48 (64.6%) patients exhibited reduced normalized left ventricular total uptake and heart-to-contralateral lung ratio, respectively. Perugini grade was reduced or unchanged versus baseline in 55/57 (96.5%) evaluable patients. No increase in cardiac adverse events was observed with vutrisiran versus external placebo. Conclusions Vutrisiran demonstrated evidence of potential benefit on cardiac manifestations in patients with ATTRv amyloidosis with polyneuropathy, with an acceptable safety profile.

Abstract Background Transthyretin-mediated (ATTR) amyloidosis is a rapidly progressive, debilitating, and fatal disease caused by misfolded TTR accumulating in multiple organs and tissues. Patients with hereditary (hATTR) amyloidosis (also known as ATTRv amyloidosis) or wild-type (wtATTR) amyloidosis with cardiomyopathy exhibit decreased survival. Patisiran, an IV RNAi therapeutic that inhibits synthesis of wt and variant TTR, was approved for the treatment of hATTR amyloidosis with polyneuropathy. Exploratory analyses of a predefined cardiac subpopulation in the APOLLO study demonstrated the potential for patisiran to improve the manifestations of cardiomyopathy in patients with hATTR amyloidosis with polyneuropathy. Objective To investigate the safety and efficacy of patisiran in patients with ATTR amyloidosis with cardiomyopathy in the ongoing APOLLO-B study (NCT03997383). Material & Methods Patients were 18–85 years of age with evidence of cardiac amyloidosis by echocardiography (end-diastolic interventricular wall thickness >12 mm), and either ATTR amyloid deposition on tissue biopsy or fulfilling nonbiopsy diagnostic criteria for ATTR amyloidosis with cardiomyopathy. Patients had a medical history of heart failure (HF) due to ATTR amyloidosis with at least 1 prior hospitalization for HF, or current clinical evidence of HF. Patients were randomized (1:1) to receive patisiran IV 0.3 mg/kg or placebo Q3W for 12 months. After the double-blind, placebo-controlled period, all patients may receive patisiran in an open-label extension period for up to 36 months. The primary endpoint was change from baseline in 6-MWT at Month 12 with patisiran treatment, compared with placebo. Secondary endpoints evaluated the effect of patisiran vs placebo at Month 12 on QOL (KCCQ-OS score) as well as two sets of composite endpoints: 1) All-cause mortality, frequency of CV events (CV hospitalizations and urgent HF visits) and change from baseline in 6-MWT; and 2) All-cause mortality and frequency of all-cause hospitalizations and urgent HF visits. The pharmacodynamic effect of patisiran on serum TTR level (change from baseline through Month 12) was also assessed. Results & Discussion Enrollment completed (359 patients) in May 2021. About 80% of patients have wtATTR amyloidosis. Primary and secondary endpoint data will be presented, including change in 6-MWT and KCCQ-OS score at Month 12, in addition to safety data. Summary & Conclusion The primary results of the APOLLO-B study will inform the potential of patisiran as a treatment for the cardiomyopathy of ATTR amyloidosis. APOLLO-B will continue to investigate the efficacy and safety of patisiran on ATTR amyloidosis in an open-label extension period.

Abstract Background Hereditary transthyretin-mediated (hATTR) amyloidosis, also known as ATTRv amyloidosis, is a fatal, multisystem disease that presents with progressive polyneuropathy and/or cardiomyopathy. HELIOS-A (NCT03759379) assessed the efficacy of vutrisiran, an investigational RNA interference therapeutic, in patients with hATTR amyloidosis with polyneuropathy. Purpose To evaluate the effect of 18 months of vutrisiran treatment on exploratory cardiac endpoints in the HELIOS-A Phase 3 study. Methods Patients were randomised (3:1) to vutrisiran (25 mg SC, q3m) or patisiran (0.3 mg/kg IV, q3w), a reference comparator. The APOLLO placebo group (n=77) was an external control. Primary endpoint was change from baseline in the modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months, vs. external placebo. Exploratory cardiac endpoints included change from baseline in NT-proBNP levels, echocardiography parameters, and technetium (Tc) scintigraphy parameters at 18 months. A prespecified cardiac subpopulation was included (baseline left ventricular wall thickness ≥1.3 cm and no medical history of aortic valve disease or hypertension). Results HELIOS-A enrolled 164 patients and the primary endpoint was met. In the cardiac subpopulation (n=40/122 vutrisiran; n=36/77 placebo), 18 months of vutrisiran treatment significantly improved NT-ProBNP levels vs. external placebo (adjusted geometric fold change ratio: 0.49; p=0.0004) and demonstrated a trend towards improvement in echocardiographic parameters vs. external placebo (including a significant difference in cardiac output [least squares mean difference: 0.41; p=0.043]). Of the 122 vutrisiran-treated patients, 99mTc scintigraphy assessment was captured for 64 vutrisiran-treated patients at baseline, 35 (54.7%) of whom had Perugini grade ≥2 (moderate/intense) cardiac uptake of 99mTc. Among patients with evaluable scintigraphy parameters repeated at 18 months (evaluable patients), heart-to-contralateral lung ratio and normalised LV total uptake on scintigraphy improved (decrease from baseline) in 64.6% (31/48) and 68.1% (32/47), respectively, at 18 months. Of the evaluable patients, 28.1% (16/57) had an improvement (reduction from baseline) in Perugini grade of cardiac uptake, 68.4% (39/57) had no change in grade, and 3.5% (2/57) worsened in grade. Of evaluable patients with baseline Perugini grade ≥2, the proportion with improvement in heart-to-contralateral lung ratio and normalised LV total uptake was 76.9% (20/26) and 100% (25/25) respectively. No cardiac safety concerns were identified with vutrisiran treatment. Conclusions In this exploratory analysis, vutrisiran treatment was associated with a positive impact on NT-ProBNP levels and echocardiographic parameters vs. external placebo in the cardiac subpopulation. Vutrisiran treatment also reduced cardiac uptake of 99mTc potentially suggesting reduction in cardiac amyloid, although the clinical significance of this is not yet clear.

Background: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease that presents with cardiomyopathy or polyneuropathy. The APOLLO study assessed the efficacy and tolerability of patisiran in patients with hATTR amyloidosis. The effects of patisiran on cardiac structure and function in a prespecified subpopulation of patients with evidence of cardiac amyloid involvement at baseline were assessed. Methods: APOLLO was an international, randomized, double-blind, placebo-controlled phase 3 trial in patients with hATTR amyloidosis. Patients were randomized 2:1 to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. The prespecified cardiac subpopulation comprised patients with a baseline left ventricular wall thickness ≥13 mm and no history of hypertension or aortic valve disease. Prespecified exploratory cardiac end points included mean left ventricular wall thickness, global longitudinal strain, and N -terminal prohormone of brain natriuretic peptide. Cardiac parameters in the overall APOLLO patient population were also evaluated. A composite end point of cardiac hospitalizations and all-cause mortality was assessed in a post hoc analysis. Results: In the cardiac subpopulation (n=126; 56% of total population), patisiran reduced mean left ventricular wall thickness (least-squares mean difference ± SEM: –0.9±0.4 mm, P =0.017), interventricular septal wall thickness, posterior wall thickness, and relative wall thickness at month 18 compared with placebo. Patisiran also led to increased end-diastolic volume (8.3±3.9 mL, P =0.036), decreased global longitudinal strain (–1.4±0.6%, P =0.015), and increased cardiac output (0.38±0.19 L/min, P =0.044) compared with placebo at month 18. Patisiran lowered N -terminal prohormone of brain natriuretic peptide at 9 and 18 months (at 18 months, ratio of fold-change patisiran/placebo 0.45, P <0.001). A consistent effect on N -terminal prohormone of brain natriuretic peptide at 18 months was observed in the overall APOLLO patient population (n=225). Median follow-up duration was 18.7 months. The exposure-adjusted rates of cardiac hospitalizations and all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups, respectively (Andersen–Gill hazard ratio, 0.54; 95% CI, 0.28–1.01). Conclusions: Patisiran decreased mean left ventricular wall thickness, global longitudinal strain, N -terminal prohormone of brain natriuretic peptide, and adverse cardiac outcomes compared with placebo at month 18, suggesting that patisiran may halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01960348.