Vutrisiran Treatment Leads to Quality of Life Enhancements in hATTR-Polyneuropathy

A new analysis of the phase 3 HELIOS-A trial (NCT03759379) showed that treatment with vutrisiran (Amvuttra; Alnylam), an FDA-approved medication, improved quality of life in patients with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN), most notably through preserved functional activity and social participation.¹

The analysis, presented at the 2024 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held October 15-18, in Savannah, Georgia, included vutrisiran-treated patients from HELIOS-A, as well as placebo-adminsitered patients from APOLLO (NCT01960348), patisiran’s (Onpratto; Alnylam) pivotal phase 3 trial of patients with hATTR-PN. At baseline, the analysis included 122 patients on vutrisiran and 76 patients on placebo who had raw scores on the Rasch-built Overall Disability Scale (R-ODS), a patient-reported outcome measure.

Led by Varun Kumar, director of Value & Evidence Strategy at Alnylam, the study assessed vutrisiran’s impact over an 18-month period. At 18 months, median R-ODS raw scores were recorded in 113 patients on vutrisiran and 54 patients on placebo. Overall, results at that time point showed stable raw R-ODS and Logits among vutrisiran-treated patients (R-ODS: baseline = 35; M18 = 36; Logit: baseline: 2.04; M18 = 2.28), indicating preservation of activity. This was reflected by patients’ ability to walk outdoors for less than 1 km, whereas investigators observed deterioration in the placebo arm (R-ODS: baseline = 30.5; M18 = 19.5; Logit: baseline = 1.05; M18 = 1.06).

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Vutrisiran was originally approved as a therapy for ATTR amyloidosis by the FDA in 2022, with 9-month data from HELIOS-A serving as the basis for its approval. In the study, the treatment met its primary end point, demonstrating a statistically significant change vs placebo in the modified Neuropathy Impairment Score (mNIS+7) at 9 months (P <.001). Additionally, vutrisiran achieved statistically significant results (P <.001) on secondary measures such as the Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (Norfolk QoL-DN) and timed 10-meter walk test (10-MWT) as compared with historical placebo results.^2,3

The therapy was also considered safe and well tolerated, with diarrhea, pain in an extremity, fall, and urinary tract infections, each of which occurred at a similar or lower rate than historical placebo, as the most common treatment-emergent adverse events (AEs). Overall, there were 2 discontinuations from AEs by month 9, both due to deaths, but neither considered related to the study drug. Disability, measured by R-ODS scores, was decreased by 1.5 points in the vutrisiran group from baseline, compared with a 9.9-mean decrease in the external placebo group, resulting in an 8.4-point mean increase relative to placebo.

Vutrisiran, a subcutaneously administered RNA interference therapeutic agent, is also being tested as a potential therapy for ATTR-cardiomyopathy (CM). Earlier this year, the company released topline data from the phase 3 HELIOS-B study (NCT04153149), a trial assessing vutrisiran in ATTR-CM, with results showing that the therapy met its primary and secondary end points. As a result, the company stated it was planning on filing a supplemental new drug application to extend vutrisiran’s treatment profile to include ATTR-CM.⁴

HELIOS-B was a randomized, double-blind, placebo-controlled trial that randomized 655 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy to either vutrisiran 25 mg or placebo every 3 months for a 36-month treatment period. The therapy met its primary end point, demonstrating a statistically significant reduction in the composite of all-cause mortality and recurrent cardiovascular events in both the overall population (HR, 0.718; P = .0118; n = 654) and those who received a monotherapy of vutrisiran without tafamidis at baseline (HR, 0.672; P = .0162; n = 395).

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REFERENCES
1. Kumar V, Doenges M, Duque DR, Bender S, Capocelli K. Impact of vutrisiran on activities of daily living and functional status in patients with hATTR amyloidosis. Presented at: American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting; October 15-18, 2024; Savannah, GA. ABSTRACT 209
2. Alnylam announces FDA approval of Amvuttra (Vutrisiran), an RNAi therapeutic for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. News release. Alnylam. June 13, 2022. Accessed October 11, 2024. https://investors.alnylam.com/press-release?id=26776
3. Alnylam reports positive topline results from HELIOS-A phase 3 study of vutrisiran in patients with hATTR amyloidosis with polyneuropathy. News release. Alnylam Pharmaceuticals. January 7, 2021. Accessed October 11, 2024. https://www.businesswire.com/news/home/20210107005224/en/Alnylam-Reports-Positive-Topline-Results-from-HELIOS-A-Phase-3-Study-of-Vutrisiran-in-Patients-with-hATTR-Amyloidosis-with-Polyneuropathy
4. Alnylam reports positive topline results from HELIOS-B phase 3 study of vutrisiran, achieving statistical significance on primary and secondary end points in both overall and monotherapy populations. Alnylam Pharmaceuticals. June 24, 2024. Accessed October 11, 2024. https://www.businesswire.com/news/home/20240624263080/en/Alnylam-Reports-Positive-Topline-Results-from-HELIOS-B-Phase-3-Study-of-Vutrisiran-Achieving-Statistical-Significance-on-Primary-and-All-Secondary-Endpoints-in-Both-Overall-and-Monotherapy-Populations