Wainua.ca | Trial Design

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NEURO-TTRansform: A Phase III, randomized, multicentre, open-label, externally-controlled trial of WAINUA in adult patients with polyneuropathy associated with hATTR^1,2

Adapted from the WAINUA Product Monograph and Coelho T, et al.^1,2

* Reference group to allow for cross-trial comparison of disease progression and treatment responses.²

† A randomized, double-blind, multicentre clinical trial in adult patients with hATTR-PN (the inotersen pivotal study). This group received SC injections of placebo QW. Both studies employed identical eligibility criteria. The characteristics of the WAINUA and external placebo groups were generally similar, and the potential imbalances in key baseline characteristics were
accounted for in the prespecified statistical analysis.¹

‡ The final analysis endpoints were distributed over 2 visits (Week 65 and Week 66), as prespecified in the protocol.²

Assessments were based on a comparison of the WAINUA arm vs. external placebo¹

Week 85 data are not available for the external placebo group, as the treatment period in the NEURO-TTR study was limited to 66 weeks.¹

Interim (Week 35) and final (Week 65/66^§) analysis endpoints

Co-primary efficacy endpoints included the changes from baseline in:¹

The mNIS+7 composite score at Week 35^¶** and Week 66^††
The Norfolk QoL-DN total score at Week 66^††

Co-primary pharmacodynamic endpoint was the change from baseline in:¹

Serum TTR concentration^‡‡ at Week 35 and Week 65

Secondary efficacy endpoints included the changes from baseline in:¹

The Norfolk QoL-DN total score at Week 35^¶**
Neuropathy symptoms and change (NSC) at Week 66
The physical component score (PCS) of short-form 36-item health survey (version 2) (SF-36) at Week 65
Polyneuropathy disability (PND) score at Week 65
Modified body mass index (mBMI) at Week 65

mNIS+7 results

The mNIS+7 is an objective assessment of neuropathy with a range of -22.3 to 346.3 points, where higher scores represent a greater severity of disease.¹

The NIS measures deficits in:¹

Cranial nerve function
Muscle strength
Reflexes
Sensations

And the Modified +7 composite score measures:¹

Heart rate response to deep breathing
Quantitative sensory testing (touch-pressure and heat-pain)
Peripheral nerve electrophysiology

Norfolk QoL-DN results

The Norfolk QoL-DN questionnaire is a patient-reported assessment. The version used in the trial had a range from -4 to 136 points, where higher scores represent greater impairment. It evaluates the subjective experience of neuropathy in the following domains:¹

Physical functioning/large fibre neuropathy
Activities of daily living
Symptoms

Small fibre neuropathy
Autonomic neuropathy

Analysis was based on data collected up to 52 days after last dose of study drug. The statistical significance of the Week 66 results was not formally tested due to statistically significant results at Week 35.¹

All endpoints were also evaluated at the end-of-treatment analysis (Week 85) for patients treated with WAINUA.^1§§

See Efficacy Data

See TTR Suppression Data

Key study demographics & baseline characteristics in the WAINUA treatment group

AGE RANGE:¹

24-82 years (mean age: 53.0)

SEX:¹

69% male, 31% female

22 DIFFERENT TTR VARIANTS WERE REPRESENTED:¹

Most frequent were V30M (59%), A97S (15%), T60A (3%), L58H (3%), F64L (3%), and V122I (3%)

• 54 (38%) patients had the V30M genotype and early onset of symptoms (<50 years old)

DISEASE SEVERITY:¹

80% with stage 1 disease^¶¶

20% with stage 2 disease***

PRIOR TREATMENT:¹

69% had previously taken tafamidis or diflunisal

MIXED PN AND CM PRESENTATION:¹

Of the 39 (27.1%) patients who had a diagnosis of TTR cardiomyopathy at study entry, 41% were classified as NYHA functional class I and 59% were NYHA class II

The characteristics of the WAINUA and external placebo groups were generally similar, and the potential imbalances in key baseline characteristics (Val30Met mutation status, disease stage, and previous treatment) were accounted for in the prespecified statistical analysis.¹

TTR: transthyretin; hATTR: hereditary transthyretin-mediated amyloidosis; SC: subcutaneous; Q4W: every 4 weeks; QW: once weekly; hATTR-PN: hereditary transthyretin-mediated amyloidosis with polyneuropathy; mNIS+7: modified Neuropathy Impairment Score+7; Norfolk QoL-DN: Norfolk Quality of Life – Diabetic Neuropathy; PN: polyneuropathy; NYHA: New York Heart Association.

§ The final analysis endpoints were distributed over 2 visits (Week 65 and Week 66), as prespecified in the protocol.³

¶ Participants with a missing mNIS+7 or Norfolk QoL-DN at Week 35 had value multiply imputed using an imputation model. Each of 500 imputed data sets was analyzed using simple ANCOVA model and the 500 ANCOVA model results were combined using Rubin’s rules.¹

** Based on an ANCOVA model adjusted by propensity score with the effects of treatment, disease stage, Val30M mutation, previous treatment, and the baseline value.¹

†† Based on a MMRM adjusted by propensity score weights with fixed categorical effects for treatment, time, treatment-by-time interaction, disease stage, Val30M mutation, previous treatment, fixed covariates for the baseline value and the baseline-by-time interaction. One participant did not have a mNIS+7 or Norfolk QoL-DN assessment at Week 35 but did have an assessment for at least one of these at Week 66.¹

‡‡ Clinical significance unknown.

§§ Week 85 data are not available for the external placebo group, as the treatment period in the NEURO-TTR study was limited to 66 weeks.¹

¶¶ Unimpaired ambulation; mild sensory, motor, and autonomic neuropathy in the lower limbs.¹

*** Assistance with ambulation required; moderate impairment of the lower limbs, upper limbs, and trunk.¹

References: 1. WAINUA® Product Monograph. AstraZeneca Canada Inc. August 26, 2025. 2. Coelho T, Marques Jr W, Dasgupta NR, et al. Eplontersen for hereditary transthyretin amyloidosis with polyneuropathy. JAMA. 2023;330(15):1448-1458.

WAINUA® Important Safety Information

WAINUA®

Trial Design

NEURO-TTRansform: A Phase III, randomized, multicentre, open-label, externally-controlled trial of WAINUA in adult patients with polyneuropathy associated with hATTR1,2

Interim (Week 35) and final (Week 65/66§) analysis endpoints

mNIS+7 overview

Norfolk QoL-DN overview

Key study demographics & baseline characteristics in the WAINUA treatment group

AGE RANGE:1

SEX:1

22 DIFFERENT TTR VARIANTS WERE REPRESENTED:1

DISEASE SEVERITY:1

PRIOR TREATMENT:1

MIXED PN AND CM PRESENTATION:1

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WAINUA^® Important Safety Information