New 18-Month Data Highlight Vutrisiran’s Benefit for hATTR Amyloidosis


Patients on the study drug demonstrated improvements in several different exploratory cardiac end points, including NT-proBNP and echocardiographic parameters relative to placebo.

David Adams, MD, PhD

David Adams, MD, PhD

Vutrisiran (Alnylam Pharmaceuticals), an investigational RNA interface (RNAi) therapeutic for patients with hereditary transthyretin-mediated (hATTR) amyloidosis, met its secondary end points measured at 18 months in the phase 3 HELIOS-A study (NCT03759379), the company announced.1

All told, compared with placebo, those treated with the agent demonstrated statistically significant improvements in neuropathy impairment, quality of life (QoL), gait speed, nutritional status, and overall disability, as well as noninferiority of serum TTR reduction relative to those on patisiran (Onpratto; Alnylam), the reference comparator drug. The newly published data expand on previously reported topline findings from 18 months, announced in October 2021,2 and the primary end point data announced in January 2021, which indicated that the drug met its primary and secondary end points.3

Alnylam had its new drug application (NDA) for vutrisiran accepted by the FDA in June 2021, with the agency setting an action date of April 14, 2022, under the Prescription Drug User Fee Act (PDUFA). There is not currently a plan for an advisory committee meeting as part of the NDA review.4

"The 18-month results of the HELIOS-A phase 3 study build on the results observed at 9 months and continue to underscore the potential of vutrisiran as an attractive new treatment option that can be administered subcutaneously 4 times a year,” David Adams, MD, PhD, Department of Neurology, Greater Paris University Hospitals, and principal investigator of HELIOS-A, said in a statement.1 "The data presented today are exciting, demonstrating additional progress from ongoing research focused on meeting the needs of this diverse group of patients living with a progressive, life-threatening, multisystem disease, with a potential new option that may help simplify their treatment."

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This global, open-label study included 164 patients with hATTR amyloidosis with polyneuropathy who were randomized 3:1 to either 25-mg vutrisiran (n = 122) via subcutaneous injection once every 3 months or 0.3-mg/kg patisiran (n = 42) via intravenous infusion once every 3 weeks. The additional secondary end points evaluated at 18 months included changes from baseline in modified Neuropathy Impairment Score (mNIS+7)—otherwise the original primary end point—Norfolk QoL-DN score, 10-MWT, modified body mass index (mBMI), Rasch-built Overall Disability Scale (R-ODS), and serum TTR levels.

At 18 months, treatment with vutrisiran resulted in a 0.46-point mean decrease (denoting improvement) in mNIS+7 from baseline, compared with 28.09-point mean increase for the external placebo group (n = 77). Furthermore, 48% of patients had improvement on mNIS+7 compared with just 4% of those on placebo. These patients also demonstrated a 1.2-point mean decrease (denoting improvement) in Norfolk QoL-DN score at that time point, whereas those on placebo had a 19.8-point mean increase (denoting worsening).

Gait speed, measured by the 10-MWT, decreased by a mean of 0.024 m/s from baseline to 18 months in the vutrisiran group, resulting in mean increase of 0.239 m/s relative to placebo. These patients also had a 25.0-point mean increase (denoting improvement) in mBMI from baseline, whereas those in the external placebo group demonstrated a 115.7-point mean decrease. Disability, measured by R-ODS, 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.

Investigators were expecting the study drug to demonstrate non-inferiority to patisiran in terms of serum TTR reduction, and it did. Overall, relative to the within-study patisiran reference comparator, vutrisiran achieved a rapid and sustained reduction of serum TTR at 18 months, with a mean reduction from baseline of 88%.

Investigators were still encouraged with the safety profile of vutrisrian following the 18-month analysis. Three patients (2.5%) discontinued from the study because of adverse events (AE) from vutrisiran, including one non-fatal event of heart failure and 2 due to deaths, neither considered related to the study drug. Dyslipidemia and urinary tract infection were the 2 serious AEs recorded that were deemed related to treatment with vutrisiran.

Rena N. Denoncourt, vice president, TTR Franchise Lead, Alnylam, said in a statement, "Vutrisiran is currently under review by multiple regulatory authorities around the world, bringing us a step closer to potentially making this low-dose, once-quarterly, subcutaneously administered treatment option available for patients living with the polyneuropathy of hATTR amyloidosis, and furthering our efforts to build an industry-leading franchise of medicines for the treatment of ATTR amyloidosis."

NT-proBNP, a biomarker of cardiac stress, showed an adjusted geometric fold change improvement of 0.94 in patients treated with vutrisiran compared with a change of 1.96 in the placebo group. Those treated with study drug also demonstrated a trend towards improvement in echocardiographic parameters, relative to placebo, including cardiac output (P = 1.144 x 10-5), left ventricular (LV) end diastolic volume (P = 4.021 x 10-5), Global longitudinal strain (P = .3182) and mean LV wall thickness (P = .5228).

NeurologyLive® recently hosted a panel discussion that featured expert conversation around the most recent advances in the treatment of hATTR, which included an episode on the HELIOS-A trial. Watch the commentary from John L. Beck, MD, and others, as they detailed the topline results from the trial published in early 2021.

1. Alnylam presents positive 18-month results from HELIOS-A phase 3 study of investigational vutrisiran in patients with hATTR amyloidosis with polyneuropathy. News release. Alnylam Pharmaceuticals. January 21, 2022. Accessed January 24, 2022.
2. 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 January 24, 2022.
3. Alnylam reports positive topline 18-month results from HELIOS-A phase 3 study of vutrisiran in patients with hATTR amyloidosis with polyneuropathy. News release. Alnylam Pharmaceuticals. October 27, 2021. Accessed January 24, 2022.
4. Alnylam announces US Food and Drug Administration acceptance of new drug application for investigational vutrisiran for the treatment of the polyneuropathy of hereditary ATTR amyloidosis. News release. Alnylam Pharmaceuticals. June 24, 2021. Accessed January 24, 2022.
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