Vutrisiran Meets Primary and Secondary End Points in Phase 3 Study of ATTR Amyloidosis With Cardiomyopathy

Pushkal Garg, MD

According to a recent announcement, vutrisiran (Amvuttra), an FDA-approved RNAi therapeutic, met its primary and secondary end points in the phase 3 HELIOS-B study (NCT04153149) demonstrating statistical significance against placebo in a cohort of patients with transthyretin-mediated amyloidosis with cardiomyopathy (ATTR-CM). Alnylam, the drug manufacturers, are planning on filing a supplemental new drug application for vutrisiran as a potential therapy for ATTR-CM using a priority review voucher.¹

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).

Vutrisiran, which gained FDA approved for ATTR amyloidosis in July 2022, demonstrated statistically significant improvements across all secondary end points in both the overall and monotherapy populations. Such enhancements were seen across the 6-minute walk test, Kansas City Cardiomyopathy Questionnaire, and New York Heart Association Class for up to month 30 (P <.025 for all). In addition, treatment with the medication resulted in attenuated all-cause mortality in the overall population (HR, 0.645; P <.025) and in the monotherapy population (HR, 0.655; P <.05) up to 42 months, which comprised 6 months of the open-label extension.

"I’m thrilled by these overwhelmingly positive data from the HELIOS-B study, which suggest that vutrisiran has the potential to address the needs of patients with ATTR amyloidosis with cardiomyopathy, a steadily progressive, debilitating, and ultimately fatal disease," Pushkal Garg, MD, chief medical officer at Alnylam, said in a statement.¹ "The results showed that vutrisiran improved cardiovascular outcomes, including survival, function and quality of life in all patient groups with ATTR cardiomyopathy. We are moving with urgency to file these compelling data with regulators to bring this medicine to patients around the world."

Throughout the study, vutrisiran maintained its treatment effect across several subgroups of patients, including baseline tafamidis use, ATTR disease type, and measures of disease severity. In addition, it continued to show a safe and tolerable profile, with adverse event (AE) rates and serious AEs that were similar between placebo- and active-treated groups. In addition, investigators found no AEs that had more than 3% increased rate in the vutrisiran arm compared with placebo.

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HELIOS-B included those with documented diagnosis of ATTR-CM, classified as either hereditary ATTR or wild-type ATTR amyloidosis. Entering the study, patients had a medical history of heart failure with at least 1 prior hospitalization for heart failure. The study excluded those with a known primary amyloidosis or leptomeningeal amyloidosis, patients with New York Heart Association (NYHA) Class IV heart failure, or NHYA Class II heart failure and is at high risk based on pre-specified criteria. Notably, the study also did not allow those who received prior TTR-lowering treatment or those with non-TTR cardiomyopathy, hypertensive cardiomyopathy, cardiomyopathy due to valvular heart disease, or cardiomyopathy due to ischemic heart disease.

Vutrisiran, administered once every 3 months, was approved as a therapy for ATTR amyloidosis in June 2022 based on 9-month data from the phase 3 HELIOS-A study (NCT03759379). In that study, vutrisiran met its primary end point of change in the modified Neuropathy Impairment Score (mNIS+7) after 9 months (P <.001), while also demonstrating statistical significance on other secondary measures such as the Norfolk Quality of Life Questionnaire–Diabetic Neuropathy and timed 10-meter walk test, as compared with historical placebo results.^2,3

At the 2023 American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) Annual Meeting, post-hoc data from the phase 3 APOLLO (NCT01960348) and HELIOS-A studies showed that patients with hereditary ATTR treated with vutrisiran or patisiran (Onpattro; Alnylam) had decreases in neurofilament light (NfL), a biomarker of neuroaxonal damage. In APOLLO, placebo-treated patients demonstrated increased NfL plasma levels after 4 months (+19.0 pg/mL; P <.001) and 18 months (+36.3 pg/mL; P <.001) from baseline whereas those who were treated with patisiran showed decreased NfL levels at the same time points (4 months: –20 pg/mL; P <.001; 18 months: –23.2 pg/mL; P <.001). Similarly, in HELIOS-A, NfL in patisiran and vutrisiran groups decreased from baseline at 4 months (–9.7 and –11.0 pg/mL, respectively; P <.05) and these decreases were maintained at 18 months (–16.4 and –19.9 pg/mL, respectively; P <.001).⁴

REFERENCES
1. 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 June 27, 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
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. June 27, 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 June 27, 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. Aldinc E, Ticau S, Polydefkis M, et al. Neurofilament light chain levels significantly decrease in response to treatment with patisiran or vutrisian in hereditary transthyretin-mediated amyloidosis with polyneuropathy. Presented at: AANEM 2023; November 1-4; Phoenix, AZ. POSTER 184