In a new post-hoc analysis of the phase 3 HELIOS-A study (NCT03759379) assessing vutrisiran (Amvuttra; Alnylam), an FDA-approved RNA interference therapeutic, the therapy demonstrated benefit in key measures, compared with external placebo, across all baseline polyneuropathy severities among patients with hereditary transthyretin-mediated (hATTR) amyloidosis. These results suggest patients who initiate vutrisiran earlier in their disease course would retain a higher level of neurologic function after 18 months, also highlighting the importance of early diagnosis and treatment.1
In the study, investigators randomized patients 3:1 to vutrisiran 25 mg subcutaneous q3m or patisiran 0.3 mg/kg intravenous q3w, a reference group. The post-hoc analysis divided patients into quartiles with approximately equal number of patients with increasing baseline Neuropathy Impairment Score (NIS): Q1 ≥5.0─≤20.5; Q2 >20.5─≤44.1; Q3 >44.1─≤73.1; Q4 >73.1─≤127. Mean change from baseline to Month 18 was summarized by quartile for efficacy endpoints.
Across baseline NIS quartiles, vutrisiran showed benefit in mNIS+7 score compared with the external placebo at 18 months. The mean change from baseline in mNIS+7 at month 9/18 was -3.3/-3.0 in Q1 with vutrisiran in comparison with +13.8/+18.4 in the external placebo. In Q2, investigators recorded mean changes of -0.6/-3.1 with vutrisiran compared with +12.1/+24.5 placebo and changes of -2.1/+6.2 with vutrisiran and with +16.5/+33.1 placebo in Q3. In the final quarter, vutrisiran-treated patients showed changes of +1.6/+3.2 compared with +16.5/+30.7 on placebo. These findings were presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held November 1-4, in Phoenix, Arizona, by lead author Marco Luigetti, MD, PhD, a neurologist at Gemelli University Hospital in Rome, Italy, and colleagues.
- Vutrisiran demonstrated significant benefit in preserving neurologic function in patients with hATTR amyloidosis, suggesting the importance of early treatment.
- The recent analysis shows that early intervention with vutrisiran can lead to improved outcomes in patients with hATTR amyloidosis.
- Vutrisiran also positively affects quality of life, disability, gait speed, and nutritional status, particularly in patients with lower neuropathy impairment scores, while the placebo group's condition worsens over time.
HELIOS-A was a global, open-label, multicenter study that evaluated 164 patients with hATTR amyloidosis who were randomized 3:1 to either 25 mg of vutrisiran (n = 122) or 0.3 mg/kg of patrisiran (Onpratto; Alnylam) (n = 42) via intravenous infusion once every 3 weeks for 18 months. The efficacy of vutrisiran was assessed by comparing the results of the drug relative to placebo in HELIOS from the landmark APOLLO phase 3 study of patisiran, a randomized controlled study in a comparable patient population.
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In the new analysis, vutrisiran also showed benefit in comparison with the external placebo across NIS quartiles for quality of life (QOL) (Norfolk QOL-DN), disability (Rasch-built Overall Disability Scale), gait speed (10-meter walk test), and nutritional status (modified body mass index). At month 18, patients in lower NIS quartiles at baseline maintained better scores and at the same time, the external placebo group progressively worsened in all measures.
In June 2022, the FDA approved vutrisiran for the treatment of ATTR amyloidosis once every 3 months based on positive 9-month results from the HELIOS-A.1 Results from the study showed that the treatment met the primary end point of change from baseline 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 QoL-DN and timed 10-meter walk test (10-MWT) as compared with historical placebo results.3
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).2
In HELIOS-A, vutrisiran demonstrated an encouraging safety profile, with 2 study discontinuations (1.6%) from adverse events by month 9, both due to deaths, but neither considered related to the study drug. There were 2 serious AEs (SAEs), consisting of dyslipidemia and urinary tract infection, that were deemed related to vutrisiran by the study investigator. Diarrhea, pain in an extremity, fall, and urinary tract infections, each of which occurred at a similar or lower rate than historical placebo, were among the treatment-emergent AEs occurring in 10% or more of patients.
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 a 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 Rasch-built Overall Disability Scale 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.4
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1. Luigetti M, Quan D, Berk J, et al. Impact of Baseline Polyneuropathy Severity on Vutrisiran Treatment Response in the Phase 3 HELIOS-A Study. Presented at: American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting; November 1-4, 2023; Phoenix, AZ. Abstract 183.
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 November 1, 2023. 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 November 1, 2023. 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 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 November 1, 2023. https://www.businesswire.com/news/home/20220121005075/en/Alnylam-Presents-Positive-18-Month-Results-from-HELIOS-A-Phase-3-Study-of-Investigational-Vutrisiran-in-Patients-with-hATTR-Amyloidosis-with-Polyneuropathy