Treatment with Vutrisiran Reduces Neurologic Impairment and Improves Quality of Life in Patients with Hereditary ATTR Amyloidosis with Polyneuropathy

Treatments based on RNA interference (RNAi) provide a powerful technique for quickly recognizing specific and potent inhibitors of disease targets from all molecular classes. An RNAi drug is currently being developed for the treatment of transthyretin amyloidosis (ATTR). In January 2021, results of the HELIOS-A phase 3 study were published, showing that at 9 months, treatment with vutrisiran met primary and all secondary end points. Relative to placebo, there was a statistically significant improvement in progression of neuropathy, quality of life (QOL), and gait speed. Relative to baseline, there was a reversal of disease manifestations with improvements in neuropathy impairment and QOL in the majority of patients. In addition, as measured by the 9-month exploratory cardiac end point of N-terminal-pro hormone B-type natriuretic peptide (NT-proBNP), vutrisiran showed improvement relative to placebo. The safety and tolerability profile were encouraging.

In the phase 3 global, randomized, open-label study, researchers evaluated the efficacy and safety of vutrisiran. In total, 164 patients with ATTR with polyneuropathy were enrolled in the study from 22 countries that included 57 sites. Patients were randomized (3:1) to receive either subcutaneous injection of vutrisiran 25 mg (N = 122) once every 3 months, or (as a reference comparator) intravenous infusion of patisiran 0.3 mg/kg (N = 42) once every 3 weeks for 18 months. Change from baseline in modified Neuropathy Impairment Score +7 neurophysiologic tests (mNIS+7) at 9 months was the primary end point. The secondary end points were Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) score and timed 10-Meter Walk Test (10-MWT) at 9 months, and the change from baseline was compared with historical placebo. As an exploratory end point at 9 months, changes from baseline in NT-proBNP were evaluated.

The investigators compared historical placebo control data from the landmark APOLLO phase 3 study to the efficacy results of vutrisiran in HELIOS-A. The patient populations were similar in the HELIOS-A and APOLLO studies, which evaluated the safety and efficacy of patisiran. In the HELIOS-A study, secondary end points at 18 months will be evaluated, including serum transthyretin levels, change from baseline in mNIS+7, modified body mass index, Norfolk QoL-DN, 10-MWT, and Rasch-built Overall Disability Scale. At the 18-month time point, additional exploratory cardiac end point data will be evaluated, including echocardiographic measures, NT-proBNP, and cardiac amyloid assessments with technetium scintigraphy imaging. All patients will be eligible to receive vutrisiran for an additional 18 months as part of an open-label extension study, following the 18-month study period. In early 2021, full 9-month results will be presented at a medical conference and topline 18-month results are expected to be announced in late 2021, which will include further exploratory cardiac end point data.

An encouraging safety profile has been demonstrated by vutrisiran. Discontinuations due to death occurred at a rate of 1.6% and were attributed to adverse events in the vutrisiran arm by month 9; however, they were not considered related to the study drug. The study investigator deemed serious adverse events (dyslipidemia and urinary tract infection) were related to vutrisiran. Treatment-emergent adverse events occurred in ≥10% of patients, including diarrhea, fall, pain in extremity, and urinary tract infections, with each of these events occurring at a similar or lower rate when compared with historical placebo. Mild and transient injection-site reactions were reported in 5 (4.1%) patients. No clinically significant changes in liver function tests were reported.

To date, in the United States and the European Union, vutrisiran has been granted orphan drug designation for the treatment of ATTR. Fast Track designation in the United States for the treatment of the polyneuropathy of hereditary ATTR in adults has also been granted. In patients with ATTR with cardiomyopathy, the ongoing HELIOS-B phase 3 clinical trial began in late 2019 and is currently enrolling at sites around the world.

Source: Business Wire. Alnylam reports positive topline results from HELIOS-A phase 3 study of vutrisiran in patients with hATTR amyloidosis with polyneuropathy. Press release. Accessed March 23, 2021.

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