Trial Outcomes & Findings for NEURO-TTRansform: A Study to Evaluate the Efficacy and Safety of Eplontersen (Formerly Known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx) in Participants With Hereditary Transthyretin-Mediated Amyloid Polyneuropathy (NCT NCT04136184)

Last Updated: 2024-12-13

Results Overview

mNIS+7 composite score is a measure of neurologic impairment evaluating muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. mNIS+7 consists of 2 composite scores: the NIS composite score (maximum of 244 points) \& the modified +7 composite score (maximum of 102.32 points). mNIS+7 composite total score range= -22.32 to 346.32. Higher score indicated a lower function. Least square (LS) mean \& standard error (SE) were analyzed using Mixed Effects Model with Repeated Measures (MMRM). As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

168 participants

Primary outcome timeframe

Baseline, Week 66

Results posted on

2024-12-13

Participant Flow

Participants took part in the study at 46 investigative sites in 15 countries (Argentina, Australia, Brazil, Canada, Cyprus, France, Germany, Italy, New Zealand, Portugal, Spain, Sweden, Taiwan, Turkey, and the United States) from 11 December 2019 to 12 July 2023.

Participants with a diagnosis of hereditary transthyretin-mediated amyloid Polyneuropathy (hATTR-PN) were randomized in a 6:1 ratio to receive eplontersen (ION-682884) or inotersen respectively. As pre-specified in the protocol, the placebo-cohort group from ISIS 420915-CS2 (NEURO-TTR) study (NCT01737398-3), which was used as an external control for efficacy analysis in this study.

Participant milestones

Participant milestones
Measure	Inotersen Participants received inotersen, 300 milligrams (mg), subcutaneously (SC), once weekly up to Week 34. After Week 35 assessment, participants received eplontersen, 45 mg, SC, once every 4 weeks starting from Week 37 up to Week 81.	Eplontersen Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.
Overall Study STARTED	24	144
Overall Study COMPLETED	1	22
Overall Study NOT COMPLETED	23	122

Reasons for withdrawal

Reasons for withdrawal
Measure	Inotersen Participants received inotersen, 300 milligrams (mg), subcutaneously (SC), once weekly up to Week 34. After Week 35 assessment, participants received eplontersen, 45 mg, SC, once every 4 weeks starting from Week 37 up to Week 81.	Eplontersen Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.
Overall Study Lost to Follow-up	0	3
Overall Study Voluntary Withdrawal (including enrolled OLE)	23	119

Baseline Characteristics

Randomized set included participants who were screened and who received a randomization assignment. Number analyzed is the number of participants with data available for analysis.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Inotersen n=24 Participants Participants received inotersen, 300 milligrams (mg), subcutaneously (SC), once weekly up to Week 34. After Week 35 assessment, participants received eplontersen, 45 mg, SC, once every 4 weeks starting from Week 37 up to Week 81.	Eplontersen n=144 Participants Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.	Total n=168 Participants Total of all reporting groups
Age, Continuous	51.1 years STANDARD_DEVIATION 14.38 • n=24 Participants	53.0 years STANDARD_DEVIATION 15.00 • n=144 Participants	52.8 years STANDARD_DEVIATION 14.88 • n=168 Participants
Sex: Female, Male Female	8 Participants n=24 Participants	44 Participants n=144 Participants	52 Participants n=168 Participants
Sex: Female, Male Male	16 Participants n=24 Participants	100 Participants n=144 Participants	116 Participants n=168 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=24 Participants	22 Participants n=144 Participants	27 Participants n=168 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	18 Participants n=24 Participants	120 Participants n=144 Participants	138 Participants n=168 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=24 Participants	2 Participants n=144 Participants	3 Participants n=168 Participants
Race/Ethnicity, Customized Asian	2 Participants n=24 Participants	22 Participants n=144 Participants	24 Participants n=168 Participants
Race/Ethnicity, Customized Black or African American	0 Participants n=24 Participants	5 Participants n=144 Participants	5 Participants n=168 Participants
Race/Ethnicity, Customized White	19 Participants n=24 Participants	112 Participants n=144 Participants	131 Participants n=168 Participants
Race/Ethnicity, Customized Other	2 Participants n=24 Participants	3 Participants n=144 Participants	5 Participants n=168 Participants
Race/Ethnicity, Customized Multiple	0 Participants n=24 Participants	1 Participants n=144 Participants	1 Participants n=168 Participants
Race/Ethnicity, Customized Unknown or Not Reported	1 Participants n=24 Participants	1 Participants n=144 Participants	2 Participants n=168 Participants
Serum Transthyretin (TTR) Concentration	0.22 grams per litre (g/L) STANDARD_DEVIATION 0.069 • n=24 Participants	0.23 grams per litre (g/L) STANDARD_DEVIATION 0.075 • n=144 Participants	0.23 grams per litre (g/L) STANDARD_DEVIATION 0.074 • n=168 Participants
Modified Neuropathy Impairment Score Plus 7 (mNIS+7) Composite Score	65.06 scores on a scale STANDARD_DEVIATION 33.515 • n=24 Participants	81.28 scores on a scale STANDARD_DEVIATION 43.401 • n=144 Participants	78.97 scores on a scale STANDARD_DEVIATION 42.43 • n=168 Participants
Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Total Score	40.05 scores on a scale STANDARD_DEVIATION 21.488 • n=24 Participants • Randomized set included participants who were screened and who received a randomization assignment. Number analyzed is the number of participants with data available for analysis.	44.09 scores on a scale STANDARD_DEVIATION 26.590 • n=137 Participants • Randomized set included participants who were screened and who received a randomization assignment. Number analyzed is the number of participants with data available for analysis.	43.49 scores on a scale STANDARD_DEVIATION 25.87 • n=161 Participants • Randomized set included participants who were screened and who received a randomization assignment. Number analyzed is the number of participants with data available for analysis.

PRIMARY outcome

Timeframe: Baseline, Week 66

Population: FAS: all randomized participants who received at least 1 injection of ION-682884/inotersen \& had a baseline \& 1 post-baseline efficacy assessment for mNIS+7 score/Norfolk QOL-DN questionnaire total score. NEURO-TTR, FAS: all randomized participants who received at least 1 injection of study drug \& had a baseline \& 1 post-baseline efficacy assessment for the mNIS+7 or Norfolk QOL-DN questionnaire total score. Overall number analyzed = number of participants with data available for analysis.

Outcome measures

Outcome measures
Measure	Eplontersen n=128 Participants Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.	External Placebo n=52 Participants Participants in the external placebo arm received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks of the NEURO-TTR study.
Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 66	0.2964 scores on a scale Standard Error 2.4123	25.0557 scores on a scale Standard Error 2.3874

PRIMARY outcome

Timeframe: Baseline, Week 66

The Norfolk QoL-DN score is a measure of physical function/large fiber neuropathy, symptoms, activities of daily living, small fiber neuropathy, and autonomic neuropathy. The Norfolk QoL-DN total score has a range of -4 to 138, and a higher score indicates poorer quality of life. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.

Outcome measures

Outcome measures
Measure	Eplontersen n=128 Participants Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.	External Placebo n=52 Participants Participants in the external placebo arm received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks of the NEURO-TTR study.
Change From Baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66	-5.4964 scores on a scale Standard Error 2.2976	14.2388 scores on a scale Standard Error 2.3488

PRIMARY outcome

Timeframe: Baseline, Week 65

Population: FAS was defined as all randomized participants who received at least 1 injection of ION-682884/inotersen and had a baseline \& at least 1 post-baseline efficacy assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. For NEURO-TTR trial, FAS included all randomized participants who received at least 1 injection of study drug and had a baseline and at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QOL-DN questionnaire total score.

As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. Overall number analyzed is the number of participants with data available for analysis.

Outcome measures

Outcome measures
Measure	Eplontersen n=135 Participants Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.	External Placebo n=51 Participants Participants in the external placebo arm received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks of the NEURO-TTR study.
Percent Change From Baseline in Serum TTR Concentration at Week 65	-81.65 percentage Standard Error 1.605	-11.24 percentage Standard Error 1.910

PRIMARY outcome

Timeframe: Baseline, Week 35

Outcome measures

Outcome measures
Measure	Eplontersen n=139 Participants Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.	External Placebo n=57 Participants Participants in the external placebo arm received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks of the NEURO-TTR study.
Percent Change From Baseline in Serum TTR Concentration at Week 35	-81.14 percentage Standard Error 1.674	-14.49 percentage Standard Error 1.966

PRIMARY outcome

Timeframe: Baseline, Week 35

mNIS+7 composite score is a measure of neurologic impairment evaluating muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. mNIS+7 consists of 2 composite scores: NIS composite score (maximum of 244 points) \& the modified +7 composite score (maximum of 102.32 points). mNIS+7 composite total score range= -22.32 to 346.32. Higher score indicated a lower function. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.

Outcome measures

Outcome measures
Measure	Eplontersen n=138 Participants Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.	External Placebo n=55 Participants Participants in the external placebo arm received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks of the NEURO-TTR study.
Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 35	0.6795 scores on a scale Standard Error 1.9073	10.0337 scores on a scale Standard Error 1.8544

SECONDARY outcome

Timeframe: Baseline, Week 35

Outcome measures

Outcome measures
Measure	Eplontersen n=130 Participants Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.	External Placebo n=57 Participants Participants in the external placebo arm received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks of the NEURO-TTR study.
Change From Baseline in Norfolk QOL-DN at Week 35	-3.6306 scores on a scale Standard Error 2.0678	8.1896 scores on a scale Standard Error 2.0730

SECONDARY outcome

Timeframe: Baseline, Week 35, Week 66

NSC score is a questionnaire composed of 38 questions divided into 5 domains: muscle weakness, sensory (hypo/loss of sensation), sensory (paresthesia, hyper sensation), autonomic (gastrointestinal \& urinary incontinence), \& autonomic (non-GI/non-urinary incontinence)\]. Answers to questionnaire are yes/no and if yes, then degree of severity is graded as 1 (slight +), 2 (moderate ++) and 3 (severe +++). 0=no symptom. NSC total score is a sum of scores across all 5 domains. Total score= 0-114. Higher scores=more neuropathy symptoms. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.

Outcome measures

Outcome measures
Measure	Eplontersen n=141 Participants Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.	External Placebo n=57 Participants Participants in the external placebo arm received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks of the NEURO-TTR study.
Change From Baseline in Neuropathy Symptom and Change (NSC) Score at Weeks 35 and 66 At Week 35	0.79 scores on a scale Standard Error 0.867	4.73 scores on a scale Standard Error 0.870
Change From Baseline in Neuropathy Symptom and Change (NSC) Score at Weeks 35 and 66 At Week 66	-0.03 scores on a scale Standard Error 0.955	8.18 scores on a scale Standard Error 0.962

SECONDARY outcome

Timeframe: Baseline, Week 65

SF-36 comprises 36 items that yield 8 subscales and 2 summary measures (PCS and Mental component summary \[MCS\]). Multi-item subscales (35 items) includes: physical function=10 items, role physical =4 items, bodily pain=2 items, general health=5 items, vitality=4 items, social functioning=2 items, role emotional =3 items and mental health=5 items. 8 subscales are scored from 0-100. Higher scores indicate better health. 8 subscales are aggregated into a PCS score ranging from 0-100. Higher scores indicate better health. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.

Outcome measures

Outcome measures
Measure	Eplontersen n=136 Participants Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.	External Placebo n=50 Participants Participants in the external placebo arm received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks of the NEURO-TTR study.
Change From Baseline in the Physical Component Summary (PCS) Score of the 36-Item Short Form Survey (SF-36) at Week 65	0.851 scores on a scale Standard Error 0.7913	-4.455 scores on a scale Standard Error 0.8338

SECONDARY outcome

Timeframe: Baseline, Week 65

PND is a 5-stage scoring system. PND score is defined as I=sensory disturbances in limbs without motor impairment; II=difficulty walking without the need of a walking aid; IIIa=one stick or one crutch required for walking; IIIb=two sticks or two crutches needed; IV=wheelchair required or patient confined to bed. For analysis, no impairment is scored as 0, I is scored as 1, II as 2, IIIa as 3, IIIb as 4 and IV as 5. Lower scores indicate greater ambulatory function. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.

Outcome measures

Outcome measures
Measure	Eplontersen n=134 Participants Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.	External Placebo n=51 Participants Participants in the external placebo arm received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks of the NEURO-TTR study.
Change From Baseline in Polyneuropathy Disability (PND) Score at Week 65	0.1 scores on a scale Standard Error 0.07	0.3 scores on a scale Standard Error 0.07

SECONDARY outcome

Timeframe: Baseline, Week 65

mBMI is defined as body mass index in kilograms per square meter (kg/m\^2) multiplied by serum albumin in grams per liter (g/L). As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.

Outcome measures

Outcome measures
Measure	Eplontersen n=130 Participants Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.	External Placebo n=49 Participants Participants in the external placebo arm received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks of the NEURO-TTR study.
Change From Baseline in Modified Body Mass Index (mBMI) at Week 65	-8.0655 kilogram(kg)/metre(m)^2*gram(g)/litre(L) Standard Error 10.3786	-90.7645 kilogram(kg)/metre(m)^2*gram(g)/litre(L) Standard Error 10.9465

Adverse Events

Eplontersen

Serious events: 27 serious events

Other events: 131 other events

Deaths: 4 deaths

Inotersen (Prior to Switch)

Serious events: 3 serious events

Other events: 24 other events

Deaths: 0 deaths

Inotersen to ION-682884 (After Switch)

Serious events: 3 serious events

Other events: 18 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Ionis Pharmaceuticals, Inc.

Phone: 760-603-2346

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place