Introduction
Hereditary transthyretin (ATTRv, v for variant) amyloidosis, also known as hATTR amyloidosis, is a rare, progressive, debilitating, and fatal disease caused by variants in the transthyretin (
TTR) gene [
1‐
4]. Pathogenic
TTR variants lead to misfolding of TTR proteins, which accumulate as amyloid deposits in multiple organs and tissues [
5,
6], including nerves, heart, gastrointestinal tract, and musculoskeletal tissues [
1,
2,
4,
7]. As such, ATTRv amyloidosis is a multisystem disease with a heterogeneous clinical presentation typically involving sensory, motor, and autonomic neuropathy, and cardiomyopathy [
2,
8‐
10], with the majority of patients presenting with a mixed phenotype of polyneuropathy and cardiomyopathy [
11,
12]. ATTRv amyloidosis has an aggressive course, and disease progression is associated with increased symptom severity, decreased quality of life (QOL), loss of physical function, and death [
3,
13,
14]. In untreated patients, prognosis is poor, with a median survival of 4.7 years following diagnosis [
15], and a reduced survival of 3.4 years in patients with cardiomyopathy [
16].
The natural course of ATTRv amyloidosis highlights the need for early and effective treatment that can minimize the burden of disease and the progressive worsening of QOL and physical function. The rapid progression of the disease when not treated is evident in natural history studies [
3,
17,
18] and the placebo arms of pivotal clinical studies in patients with ATTRv amyloidosis [
13,
19‐
22], in which outcomes measures related to neuropathy severity (e.g., modified Neuropathy Impairment Score + 7 [mNIS + 7]), QOL (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN] questionnaire), disability (Rasch-built Overall Disability Scale [R-ODS]), and nutritional status (modified body mass index [mBMI]) steadily deteriorate over time.
Current disease-modifying treatment strategies for ATTRv amyloidosis include those that reduce levels of pathogenic TTR protein by silencing the
TTR gene (RNA interference [RNAi] therapeutics; antisense oligonucleotides [ASO]), or those that stabilize the TTR tetramer (TTR stabilizers). These strategies have shown different levels of clinical benefit versus placebo in various manifestations in patients with ATTRv amyloidosis [
19‐
21,
23].
The RNAi therapeutic patisiran, approved for treatment of patients with ATTRv amyloidosis with polyneuropathy [
24], demonstrated the potential to halt polyneuropathy progression and improve multiple QOL and disability measures compared with placebo at 18 months in the pivotal phase 3 APOLLO study [
13,
19]. A post hoc analysis also demonstrated that these improvements or stabilizations in neurologic function and QOL with patisiran versus placebo were evident across a wide range of baseline neuropathy severities [
25]. Vutrisiran, another RNAi therapeutic that, like patisiran, acts by reducing the synthesis of both variant and wild-type TTR in the liver, and resulting in rapid knockdown of circulating TTR, has also been approved for the treatment of the polyneuropathy of ATTRv amyloidosis [
26]. In the phase 3 HELIOS-A study in patients with ATTRv amyloidosis with polyneuropathy, vutrisiran met the primary endpoint of change from baseline in neuropathy impairment (mNIS + 7) compared with an external placebo group from the APOLLO study, as well as all secondary efficacy endpoints, and demonstrated an acceptable safety profile [
27].
To better understand the disease trajectory of ATTRv amyloidosis, following a similar analysis to the aforementioned post hoc analysis of the APOLLO study, we report the efficacy of vutrisiran observed in the HELIOS-A study in patients with various baseline severities of neuropathy (as categorized by Neuropathy Impairment Score [NIS] quartiles).
Discussion
This post hoc analysis assessed the impact of baseline neuropathy severity on the outcomes of neurologic function, QOL, disability, and nutritional status in vutrisiran-treated patients with ATTRv amyloidosis with polyneuropathy from the HELIOS-A study compared with an external placebo group from the APOLLO study. Overall, vutrisiran demonstrated a beneficial treatment effect compared with external placebo for all endpoints at Month 18 across all subgroups of baseline neuropathy severity.
In the vutrisiran group, there was a trend for improvement or stabilization at Month 18 versus baseline across the different disease outcomes in patients from most baseline NIS quartiles. Although a modest amount of worsening was observed for some of the outcomes in patients who had more severe neuropathy at baseline (Q3 and/or Q4), vutrisiran continued to demonstrate a beneficial effect compared with external placebo even in those quartiles. In general, patients who had more severe neuropathy at baseline (Q3 and Q4) were not able to recover to the same level of function as those who initiated vutrisiran treatment earlier in their disease course (Q1 and Q2). These results demonstrate that earlier intervention allows greater opportunity to improve or stabilize disease-related endpoints, highlighting the benefits of early diagnosis and treating patients early in their disease course.
These observations also mirror those demonstrated in a similar post hoc analysis from the APOLLO study, where treatment benefit with another RNAi therapeutic, patisiran, versus placebo was demonstrated in patients with ATTRv amyloidosis across the full range of baseline NIS quartiles [
25]. Previous studies evaluating the effect of TTR stabilizers on the NIS-Lower Limb or NIS assessments similarly found that patients with lower baseline disease severity were likely to have the greatest response to treatment, and thus the slowest disease progression [
31‐
33]. Further, during the Italian compassionate use program for inotersen, patients with familial amyloid polyneuropathy (FAP) stage 1 at baseline demonstrated disease stability over 24 months, whereas those with FAP stage 2 at baseline showed worsening disease stage following treatment with inotersen [
34]. Taken together, these data re-iterate the need for early and accurate diagnosis, and rapid treatment initiation in order to delay disease progression.
The availability of disease-modifying treatments, such as
TTR gene silencers, has changed the treatment landscape of ATTRv amyloidosis [
35]. In addition to these advanced treatment options, disease awareness has improved, leading to earlier diagnosis of patients [
36‐
38], which—along with treating early to delay clinical progression and preserve QOL—is one of the key goals of disease management [
35]. Our results are in line with these treatment goals and reinforce the benefits of vutrisiran, a disease-modifying treatment, across a wide range of baseline neuropathy severities.
Certain limitations when interpreting the data should be noted, including the post hoc nature of the analysis and its lack of power to report significant differences between the groups within each baseline NIS quartile due to the small sample sizes. Another limitation was the use of an external placebo control rather than a within-trial placebo group, although the APOLLO and HELIOS-A studies had similar eligibility criteria. Finally, the rate of study discontinuation in the HELIOS-A vutrisiran arm was low (4.1%) and similar to other studies conducted in the same patient population, and it was not considered to have an impact on the interpretation of the results of the current analysis.
Acknowledgements
The authors would like to thank the patients and their families for their participation in the HELIOS-A study. The authors would like to thank the HELIOS-A study staff and members of the HELIOS-A Collaborators Group for their work on the study. A full list of the members of the HELIOS-A Collaborators Group is provided in the Supplementary Material.
Declarations
Conflict of Interest
Marco Luigetti reports consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Alnylam Pharmaceuticals, Pfizer, and Sobi. Dianna Quan reports research funding from Alnylam Pharmaceuticals, Avidity Biosciences, Cytokinetics, Ionis Pharmaceuticals, Janssen Pharmaceuticals (formerly Momenta Pharmaceuticals), Pfizer, and Viela Bio, and consulting fees from Alnylam Pharmaceuticals and Ionis Pharmaceuticals. John L. Berk reports research funding from Alnylam Pharmaceuticals, AstraZeneca, Eidos Therapeutics, and Ionis Pharmaceuticals, consulting fees from Alnylam Pharmaceuticals, AstraZeneca, Eidos Therapeutics, Intellia Therapeutics, and Ionis Pharmaceuticals, and data safety monitoring and/or advisory board membership for Alnylam Pharmaceuticals, AstraZeneca, Corino Therapeutics, Intellia Therapeutics, and Ionis Pharmaceuticals. Isabel Conceição reports consulting fees from Alnylam Pharmaceuticals, AstraZeneca, Pfizer, and Sobi, payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Akcea Therapeutics, Alnylam Pharmaceuticals, AstraZeneca, and Pfizer, and data safety monitoring and/or advisory board membership for Akcea Therapeutics, Alnylam Pharmaceuticals, and Intellia Therapeutics. Yohei Misumi reports research funding and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Alnylam Pharmaceuticals and Pfizer. Chi-Chao Chao has nothing to disclose. Shaun Bender, Emre Aldinc, and John Vest are all employees of Alnylam Pharmaceuticals. Emre Aldinc and John Vest report ownership of equity in Alnylam Pharmaceuticals. David Adams reports consulting fees from Alnylam Pharmaceuticals and AstraZeneca.