Abstract Details

Title Impact of Baseline Polyneuropathy Severity on Vutrisiran Treatment Response in the Phase 3 HELIOS-A Study

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P2 - Poster Session 2 (11:45 AM-12:45 PM)

Poster/Presentation
Number 11-015

Objective This analysis evaluates the impact of baseline polyneuropathy severity on response to vutrisiran treatment in patients with hereditary transthyretin-mediated (ATTRv; v for variant) amyloidosis with polyneuropathy during the Phase 3 HELIOS-A study (NCT03759379).

Background ATTRv amyloidosis, also known as hATTR amyloidosis, is a rapidly progressive, multisystem disease. Vutrisiran, an RNAi therapeutic, improved neuropathy and quality of life (QOL) versus external placebo in HELIOS-A.

Design/Methods Patients were randomized (3:1) to vutrisiran (25 mg subcutaneous injection Q3M) or patisiran (0.3 mg/kg intravenous infusion Q3W; reference group). The primary endpoint was change from baseline in modified Neuropathy Impairment Score+7 (mNIS+7) at 9 months versus external placebo group from the APOLLO study (n=77). This post-hoc analysis divided patients into approximately equal quartiles of 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.

Results Across NIS quartiles, vutrisiran demonstrated benefit in mNIS+7 versus external placebo (mean change from baseline in mNIS+7 at Month 9/18: Q1 -3.3/-3.0 [vutrisiran] vs +13.8/+18.4 [external placebo]; Q2 -0.6/-3.1 vs +12.1/+24.5; Q3 -2.1/+6.2 vs +16.5/+33.1; Q4 +1.6/+3.2 vs +16.5/+30.7). Vutrisiran also demonstrated benefit versus external placebo across NIS quartiles for endpoints of QOL (Norfolk QOL-DN), disability (Rasch-built Overall Disability Scale), gait speed (10-meter walk test), and nutritional status (modified BMI). Overall, patients in lower NIS quartiles (less severe disease) at baseline maintained better scores at Month 18 than those in higher NIS quartiles. The external placebo group progressively worsened in all measures at Month 18.

Conclusions Vutrisiran demonstrated benefit in neurologic function and other key measures, versus external placebo, across all baseline polyneuropathy severities. Patients who initiated vutrisiran earlier in their disease course retained the highest level of neurologic function after 18 months, highlighting the importance of early diagnosis and treatment.

Authors/Disclosures
Dianna Quan, MD, FAAN (University of Colorado School of Medicine) PRESENTER	The institution of Dr. Quan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alnylam. The institution of Dr. Quan has received research support from Alnylam. The institution of Dr. Quan has received research support from Pfizer. The institution of Dr. Quan has received research support from Cytokinetics. The institution of Dr. Quan has received research support from Argenx. The institution of Dr. Quan has received research support from Momenta. The institution of Dr. Quan has received research support from Ionis. The institution of Dr. Quan has received research support from Alexion. The institution of Dr. Quan has received research support from VielaBio. The institution of Dr. Quan has received research support from Apellis. The institution of Dr. Quan has received research support from Avidity. Dr. Quan has received publishing royalties from a publication relating to health care. Dr. Quan has received publishing royalties from a publication relating to health care. Dr. Quan has a non-compensated relationship as a Board Member/President with AANEM that is relevant to AAN interests or activities.
Marco Luigetti	Marco Luigetti has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alnylam. Marco Luigetti has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AstraZeneca. Marco Luigetti has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alnylam. Marco Luigetti has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AstraZeneca. Marco Luigetti has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for Alnylam. Marco Luigetti has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for AstraZeneca.
John L. Berk	John L. Berk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alnylam Pharmaceuticals. John L. Berk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis Pharmaceuticals. John L. Berk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Astra Zeneca/IONIS. John L. Berk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eidos/BridgBio. John L. Berk has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Intellia Therapeutics. John L. Berk has received research support from Alnylam . John L. Berk has received research support from Ionis. John L. Berk has received research support from Eidos/Bridgbio.
Isabel Conceicao (CHULN- Hospital Santa Maria)	No disclosure on file
Yohei Misumi (Kumamoto University)	No disclosure on file
Chi-Chao Chao	No disclosure on file
Shaun Bender	No disclosure on file
Emre Aldinc	Emre Aldinc has received personal compensation for serving as an employee of Alnylam Pharmaceuticals. Emre Aldinc has stock in Alnylam Pharmaceuticals.
John Vest	John Vest has received personal compensation for serving as an employee of Alnylam Pharmaceuticals. John Vest has received stock or an ownership interest from Alnylam Pharmaceuticals. John Vest has received intellectual property interests from a discovery or technology relating to health care.
David D. Adams (APHP)	David D. Adams has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for ALNYLAM. David D. Adams has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pfizer.

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