Trial Outcomes & Findings for Extension Study Assessing Long Term Safety and Efficacy of IONIS-TTR Rx in Familial Amyloid Polyneuropathy (FAP) (NCT NCT02175004)

Last Updated: 2023-11-18

Results Overview

An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. An SAE is any untoward medical occurrence that at any dose that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect, or is an important medical event. TEAEs considered related to the study drug as assessed by the Investigator are reported.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

135 participants

Primary outcome timeframe

From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

Results posted on

2023-11-18

Participant Flow

A total of 135 participants, out of which 50 participants had received placebo, and 85 participants had received inotersen in the previous study ISIS 420915-CS2 (NCT01737398 - CS2 Study). Participants were enrolled into this study to receive inotersen. This study consisted of a 260-week Treatment Period, and a 3-month Post-treatment Evaluation Period. The data is reported as per the previous treatment received in CS2 study.

Participant milestones

Participant milestones
Measure	Previous Placebo-Inotersen 300 mg Participants received subcutaneous (SC) doses of 300 milligrams (mg) inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 (NCT01737398) were included in this group.	Previous Inotersen-Inotersen 300 mg Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Overall Study STARTED	50	85
Overall Study COMPLETED	9	9
Overall Study NOT COMPLETED	41	76

Reasons for withdrawal

Reasons for withdrawal
Measure	Previous Placebo-Inotersen 300 mg Participants received subcutaneous (SC) doses of 300 milligrams (mg) inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 (NCT01737398) were included in this group.	Previous Inotersen-Inotersen 300 mg Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Overall Study Adverse Event or Serious Adverse Event (SAE)	5	14
Overall Study Investigator Judgment	1	4
Overall Study Voluntary Withdrawal	6	19
Overall Study Liver Transplant	1	0
Overall Study Disease Progression	1	0
Overall Study Participants Started Treatment With Commercially Available/Post-study Inotersen	27	39

Baseline Characteristics

Number analyzed is the number of participants with data available for analysis.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=85 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.	Total n=135 Participants Total of all reporting groups
Age, Continuous	60.5 years STANDARD_DEVIATION 14.62 • n=50 Participants	60.3 years STANDARD_DEVIATION 11.86 • n=85 Participants	60.4 years STANDARD_DEVIATION 12.90 • n=135 Participants
Sex: Female, Male Female	15 Participants n=50 Participants	26 Participants n=85 Participants	41 Participants n=135 Participants
Sex: Female, Male Male	35 Participants n=50 Participants	59 Participants n=85 Participants	94 Participants n=135 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants n=50 Participants	12 Participants n=85 Participants	18 Participants n=135 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	44 Participants n=50 Participants	73 Participants n=85 Participants	117 Participants n=135 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=50 Participants	0 Participants n=85 Participants	0 Participants n=135 Participants
Race/Ethnicity, Customized Race · Asian	3 Participants n=50 Participants	0 Participants n=85 Participants	3 Participants n=135 Participants
Race/Ethnicity, Customized Race · Black	0 Participants n=50 Participants	1 Participants n=85 Participants	1 Participants n=135 Participants
Race/Ethnicity, Customized Race · White	44 Participants n=50 Participants	81 Participants n=85 Participants	125 Participants n=135 Participants
Race/Ethnicity, Customized Race · White & Grayish-Brown	1 Participants n=50 Participants	0 Participants n=85 Participants	1 Participants n=135 Participants
Race/Ethnicity, Customized Race · Other	2 Participants n=50 Participants	3 Participants n=85 Participants	5 Participants n=135 Participants
Percentage of Participants Abnormal Electroretinogram Results at Baseline	51.3 percentage of participants n=39 Participants • Number analyzed is the number of participants with data available for analysis.	18.4 percentage of participants n=76 Participants • Number analyzed is the number of participants with data available for analysis.	29.6 percentage of participants n=115 Participants • Number analyzed is the number of participants with data available for analysis.

PRIMARY outcome

Timeframe: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

Population: SS included all enrolled participants who received at least 1 injection of inotersen in CS3.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=85 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug TEAEs	100 percentage of participants	96.5 percentage of participants
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug Serious TEAEs	36.0 percentage of participants	54.1 percentage of participants
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug TEAEs Related to Study Drug	82.0 percentage of participants	69.4 percentage of participants

PRIMARY outcome

Timeframe: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

Population: SS included all enrolled participants who received at least 1 injection of inotersen in CS3.

Vital signs included blood pressure, heart rate, respiratory rate, and temperature. Only categories with at least one participant with event are reported.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=85 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Percentage of Participants With Change From Baseline in Vital Signs Systolic Blood Pressure: <90 millimeters of mercury (mmHg)	12.0 percentage of participants	18.8 percentage of participants
Percentage of Participants With Change From Baseline in Vital Signs Systolic Blood Pressure: >140 mmHg	32.0 percentage of participants	41.2 percentage of participants
Percentage of Participants With Change From Baseline in Vital Signs Systolic Blood Pressure: >160 mmHg	8.0 percentage of participants	20.0 percentage of participants
Percentage of Participants With Change From Baseline in Vital Signs Diastolic Blood Pressure: <50 mmHg	6.0 percentage of participants	9.4 percentage of participants
Percentage of Participants With Change From Baseline in Vital Signs Diastolic Blood Pressure: >90 mmHg	30.0 percentage of participants	28.2 percentage of participants
Percentage of Participants With Change From Baseline in Vital Signs Diastolic Blood Pressure: >100 mmHg	10.0 percentage of participants	7.1 percentage of participants
Percentage of Participants With Change From Baseline in Vital Signs Heart Rate: <60 beats per minute (bpm)	30.0 percentage of participants	38.8 percentage of participants
Percentage of Participants With Change From Baseline in Vital Signs Heart Rate: >100 bpm	16.0 percentage of participants	9.4 percentage of participants
Percentage of Participants With Change From Baseline in Vital Signs Temperature (°C): <36.0°C	46.0 percentage of participants	55.3 percentage of participants
Percentage of Participants With Change From Baseline in Vital Signs Respiratory Rate (breaths/minute): >20 breaths/minute	24.0 percentage of participants	21.2 percentage of participants

PRIMARY outcome

Timeframe: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

Population: SS included all enrolled participants who received at least 1 injection of inotersen in CS3. Overall number analyzed are the number of participants available for analyses.

As prespecified in the protocol, percentage of participants with change from baseline in weight is reported in 2 categories, decrease of ≥7% from Baseline and increase of ≥7% from Baseline.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=85 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Percentage of Participants With Change From Baseline in Weight Weight (kg): Decrease of ≥7% From Baseline	30.0 percentage of participants	47.1 percentage of participants
Percentage of Participants With Change From Baseline in Weight Weight (kg): Increase of ≥7% From Baseline	24.0 percentage of participants	11.8 percentage of participants

PRIMARY outcome

Timeframe: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

Population: SS included all enrolled participants who received at least 1 injection of inotersen in CS3. Number analyzed is the number of participants with data available for analysis for the given category.

Clinical laboratory tests included the analysis of chemistry, haematology, and urinalysis. Any value outside the normal range will be flagged for the attention of the investigator who will assess whether or not a flagged value is of clinical significance. Only those categories with at least one participant with event are reported. Normal range of creatinine clearance is 110 to 150 mL/min in males and 100 to 130 mL/min in females. Normal urine protein to creatinine (P/C) ratio= \<0.2. Normal range for Alanine Aminotransferase (ALT) is 4 to 36 units per liter (U/L). Platelets normal range=140×10\^9/L to 400×10\^9/L.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=85 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values Confirmed Creatinine Clearance by CKD-EPI <30 ml/min/1.73m^2	4.0 percentage of participants	4.7 percentage of participants
Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values Confirmed Urine P/C Ratio >5 × Upper Limit of Normal (ULN)	8.0 percentage of participants	10.6 percentage of participants
Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values Confirmed Alanine Aminotransferase (ALT) ≥3 x ULN	4.0 percentage of participants	4.7 percentage of participants
Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values Confirmed Value of Platelets <75 × 10^9/L	12.0 percentage of participants	12.9 percentage of participants

PRIMARY outcome

Timeframe: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

Population: SS included all enrolled participants who received at least 1 injection of inotersen in CS3.

Normal QTcF at Baseline is defined as ≤450 milliseconds (ms) for males or ≤470 ms for females. Percentage of participants with QT interval outside of normal range are reported.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=85 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG) QTcF >450 ms	44.0 percentage of participants	43.5 percentage of participants
Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG) QTcF >480 ms	20.0 percentage of participants	23.5 percentage of participants
Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG) QTcF >500 ms	12.0 percentage of participants	16.5 percentage of participants

PRIMARY outcome

Timeframe: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

Population: SS included all enrolled participants who received at least 1 injection of inotersen in CS3.

A concomitant therapy was any non-protocol-specified drug or substance (including over-the counter medications, herbal medications, and vitamin supplements) administered between signing of informed consent and the final post-treatment visit for treating nervous and cardiovascular system disorders.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=85 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Percentage of Participants Using Concomitant Medication for Nervous and Cardiovascular System Disorders Nervous System Disorders	88.0 percentage of participants	81.2 percentage of participants
Percentage of Participants Using Concomitant Medication for Nervous and Cardiovascular System Disorders Cardiovascular System Disorders	68.0 percentage of participants	75.3 percentage of participants

PRIMARY outcome

Timeframe: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

Population: SS included all enrolled participants who received at least 1 injection of inotersen in CS3.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=85 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Percentage of Participants With Change From Baseline in Ophthalmic Examination as Assessed by Visual Acuity Changes	0.0 percentage of participants	2.4 percentage of participants

PRIMARY outcome

Timeframe: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

Population: SS included all enrolled participants who received at least 1 injection of inotersen in CS3. Overall number analyzed are the number of participants available for analyses. Number analyzed is the number of participants with data available for analysis at the given time point.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=39 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=76 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography Participants With Change From Baseline at Week 78	25.0 percentage of participants	12.7 percentage of participants
Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography Participants With Change From Baseline at Week 156	31.3 percentage of participants	9.1 percentage of participants

SECONDARY outcome

Timeframe: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

Population: Full Analysis Set (FAS) included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk quality of life-diabetic neuropathy (QoL-DN) questionnaire total score collected after CS3 Study Day 1. Number analyzed is the number of participants with data available for analysis at the given time point.

The mNIS+7 composite score is a measure of neurologic impairment that evaluates muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. The mNIS+7 Composite Score has a range of -22.32 to 346.32 and a higher mNIS+7 composite score indicates worsening disease. A positive change from Baseline indicates worsening of polyneuropathy impairments. Mixed Effects Model with Repeated Measures (MMRM) was used for the analysis.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=81 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at Weeks 78 and 156 Change From Baseline at Week 78	33.11 score on a scale Standard Deviation 28.915	10.11 score on a scale Standard Deviation 18.204
Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at Weeks 78 and 156 Change From Baseline at Week 156	37.34 score on a scale Standard Deviation 29.030	17.21 score on a scale Standard Deviation 27.307

SECONDARY outcome

Timeframe: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Number analyzed is the number of participants with data available for analysis at the given time point.

Heart rate to deep breathing is a quantitative autonomic test using the CASE IV instrument that measures a participant's change in heart rate after deep breathing. The score of this component ranges from 0 to 3.72 points. Higher scores indicate impairment. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=81 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Weeks 78 and 156 Change From Baseline at Week 78	0.23 score on a scale Standard Deviation 0.977	0.11 score on a scale Standard Deviation 0.761
Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Weeks 78 and 156 Change From Baseline at Week 156	0.44 score on a scale Standard Deviation 1.099	0.30 score on a scale Standard Deviation 0.504

SECONDARY outcome

Timeframe: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

The nerve conduction tests are quantitative tests that measure the conduction attributes of preselected nerves. The score range of this component is 0 to 18.6 points. Higher scores indicate impairment. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=81 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Weeks 78 and 156 Change From Baseline at Week 78	1.86 score on a scale Standard Deviation 2.313	0.57 score on a scale Standard Deviation 1.361
Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Weeks 78 and 156 Change From Baseline at Week 156	2.05 score on a scale Standard Deviation 2.351	0.77 score on a scale Standard Deviation 1.724

SECONDARY outcome

Timeframe: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

The Heat-Pain Sensory test uses the CASE IV instrument to perform standardized psychophysical measurement to determine pain sensory thresholds in response to heat. The maximum score of this component is 0 to 40 points. Higher scores indicate impairment. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=81 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Weeks 78 and 156 Change From Baseline at Week 78	2.60 score on a scale Standard Deviation 8.440	2.45 score on a scale Standard Deviation 7.557
Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Weeks 78 and 156 Change From Baseline at Week 156	2.90 score on a scale Standard Deviation 9.224	3.40 score on a scale Standard Deviation 8.774

SECONDARY outcome

Timeframe: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

The Touch-Pressure Sensory test uses the CASE IV instrument to perform standardized psychophysical measurement to determine pressure sensory thresholds in response to touch. The score range of this component is 0 to 40 points. Higher scores indicate impairment. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=81 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Weeks 78 and 156 Change From Baseline at Week 78	1.00 score on a scale Standard Deviation 6.886	-3.05 score on a scale Standard Deviation 8.878
Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Weeks 78 and 156 Change From Baseline at Week 156	1.95 score on a scale Standard Deviation 6.866	-2.34 score on a scale Standard Deviation 8.306

SECONDARY outcome

Timeframe: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5

Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Overall number analyzed are the number of participants available for analyses.Number analyzed is the number of participants with data available for analysis at the given time point.

The NIS score is a measure of neurologic impairment. The NIS Score has a range of 0 to 244 and a higher NIS score indicates lower function. A positive change from Baseline indicates worsening. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=9 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=14 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Change From Baseline in the Neuropathy Impairment (NIS) Composite Score at Week 52 of Years 4 and 5 Change From Baseline at Week 52 of Year 4	35.78 score on a scale Standard Deviation 21.071	18.32 score on a scale Standard Deviation 20.970
Change From Baseline in the Neuropathy Impairment (NIS) Composite Score at Week 52 of Years 4 and 5 Change From Baseline at Week 52 of Year 5	—	17.75 score on a scale Standard Deviation NA Standard deviation (SD) was not estimable for 1 participant.

SECONDARY outcome

Timeframe: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5

Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Overall number analyzed are the number of participants available for analyses. Number analyzed is the number of participants with data available for analysis at the given time point.

Cranial Nerve assessment involves testing 3rd and 6th nerves and facial, palate, and tongue weakness. The score range for this component is 0 to 40 points. Higher scores indicate worsening. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=9 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=14 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Change From Baseline in the NIS Component: Cranial Nerves Score at Week 52 of Years 4 and 5 Change From Baseline at Week 52 of Year 4	0.0 score on a scale Standard Deviation 0.0	0.0 score on a scale Standard Deviation 0.0
Change From Baseline in the NIS Component: Cranial Nerves Score at Week 52 of Years 4 and 5 Change From Baseline at Week 52 of Year 5	—	0.0 score on a scale Standard Deviation NA SD was not estimable for 1 participant.

SECONDARY outcome

Timeframe: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5

Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Overall number analyzed are the number of participants available for analyses. Number analyzed is the number of participants with data available for analysis at the given time point.

Muscle weakness involves testing 19 movements of muscles. The score range of this component is 0 to 152 points. Higher scores indicate worsening. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=9 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=14 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Change From Baseline in the NIS Component: Muscle Weakness Score at Week 52 of Years 4 and 5 Change From Baseline at Week 52 of Year 4	23.67 score on a scale Standard Deviation 16.712	14.71 score on a scale Standard Deviation 19.479
Change From Baseline in the NIS Component: Muscle Weakness Score at Week 52 of Years 4 and 5 Change From Baseline at Week 52 of Year 5	—	13.75 score on a scale Standard Deviation NA SD was not estimable for 1 participant.

SECONDARY outcome

Timeframe: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5

Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Overall number analyzed are the number of participants available for analyses. Number analyzed is the number of participants with data available for analysis at the given time point.

The Reflexes Score involves testing 5 reflexes to stimuli. The score range of this component is 0 to 20 points. Higher scores indicate worsening. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=9 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=14 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Change From Baseline in the NIS Component: Reflexes Score at Week 52 of Years 4 and 5 Change From Baseline at Week 52 of Year 4	4.17 score on a scale Standard Deviation 3.553	2.32 score on a scale Standard Deviation 1.957
Change From Baseline in the NIS Component: Reflexes Score at Week 52 of Years 4 and 5 Change From Baseline at Week 52 of Year 5	—	4.00 score on a scale Standard Deviation NA SD was not estimable for 1 participant.

SECONDARY outcome

Timeframe: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5

Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Overall number analyzed are the number of participants available for analyses. Number analyzed is the number of participants with data available for analysis at the given time point.

The Sensory Score is based on testing an index finger and a big toe each to 4 stimuli. The score of this component ranges from 0 to 32 points. Higher scores indicate impairment. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=9 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=14 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Change From Baseline in the NIS Component: Sensory Score at Week 52 of Years 4 and 5 Change From Baseline at Week 52 of Year 4	7.94 score on a scale Standard Deviation 5.288	1.29 score on a scale Standard Deviation 3.662
Change From Baseline in the NIS Component: Sensory Score at Week 52 of Years 4 and 5 Change From Baseline at Week 52 of Year 5	—	0.00 score on a scale Standard Deviation NA SD was not estimable for 1 participant.

SECONDARY outcome

Timeframe: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of Years 4 and 5)

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 136, and a higher Norfolk QoL-DN score indicates poorer QoL. A positive change from Baseline indicates worsening in the QoL. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=81 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156 Change From Baseline at Week 78	15.22 score on a scale Standard Deviation 24.024	3.76 score on a scale Standard Deviation 20.832
Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156 Change From Baseline at Week 156	14.94 score on a scale Standard Deviation 28.944	5.98 score on a scale Standard Deviation 22.891
Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156 Change From Baseline at Week 52 of Year 4	6.22 score on a scale Standard Deviation 18.600	2.36 score on a scale Standard Deviation 25.120
Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156 Change From Baseline at Week 52 of Year 5	—	-1.00 score on a scale Standard Deviation NA SD was not estimable for 1 participant.

SECONDARY outcome

Timeframe: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the Week 52 of Year 4

Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Overall number analyzed are the number of participants available for analyses. Number analyzed is the number of participants with data available for analysis at the given time point.

The Norfolk QoL-DN physical functioning/large fiber neuropathy domain score is a sub-score of the total Norfolk QoL-DN Questionnaire. The Norfolk QoL-DN physical function/large fiber neuropathy domain score has a range of -4 to 56, and a higher Norfolk QoL-DN domain score indicates poorer quality of life (QoL). A positive change from Baseline indicates worsening in the QoL. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=18 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=26 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score Change From Baseline at Week 78	11.21 score on a scale Standard Deviation 11.026	3.61 score on a scale Standard Deviation 11.500
Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score Change From Baseline at Week 156	12.60 score on a scale Standard Deviation 10.784	-0.55 score on a scale Standard Deviation 8.042
Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score Change From Baseline at Week 52 of Year 4	9.50 score on a scale Standard Deviation 9.192	3.50 score on a scale Standard Deviation 7.047

SECONDARY outcome

Timeframe: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

BMI=weight (kg)/\[height (m)\^2\]. The mBMI is the BMI multiplied by the serum albumin (g/L).

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=81 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Change From Baseline in the Modified Body Mass Index (mBMI) at Weeks 78 and 156 Change From Baseline at Week 78	-166.27 kg/m^2*g/L Standard Deviation 159.644	-161.52 kg/m^2*g/L Standard Deviation 134.779
Change From Baseline in the Modified Body Mass Index (mBMI) at Weeks 78 and 156 Change From Baseline at Week 156	-191.68 kg/m^2*g/L Standard Deviation 130.370	-172.52 kg/m^2*g/L Standard Deviation 131.602

SECONDARY outcome

Timeframe: Baseline, Weeks 78 and 156

BMI=weight (kg)/\[height (m)\^2\].

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=81 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Change From Baseline in the Body Mass Index (BMI) at Weeks 78 and 156 Change From Baseline at Week 78	-0.16 kg/m^2 Standard Deviation 2.617	-0.44 kg/m^2 Standard Deviation 1.427
Change From Baseline in the Body Mass Index (BMI) at Weeks 78 and 156 Change From Baseline at Week 156	-0.34 kg/m^2 Standard Deviation 1.908	-0.66 kg/m^2 Standard Deviation 2.220

SECONDARY outcome

Timeframe: Baseline, Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of each year)

PND score is defined as I = sensory disturbances in limbs without motor impairment; II = difficulty walking without the need of a walking aid; III = one stick or one crutch required for walking; IV = two sticks or two crutches needed. V = wheelchair required or patient confined to bed. The change from Baseline values have been categorized as: improved, not changed, worsened, and unknown. Percentage of participants with changes from Baseline are presented category-wise in this outcome measure. Only categories with at least one participant with event are reported.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=81 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score Change From Baseline at Week 78: Improved	5.6 percentage of participants	11.3 percentage of participants
Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score Change From Baseline at Week 78: Not Changed	69.4 percentage of participants	62.0 percentage of participants
Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score Change From Baseline at Week 78: Worsened	25.0 percentage of participants	26.8 percentage of participants
Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score Change From Baseline at Week 156: Improved	4.8 percentage of participants	7.3 percentage of participants
Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score Change From Baseline at Week 156: Not Changed	52.4 percentage of participants	56.1 percentage of participants
Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score Change From Baseline at Week 156: Worsened	42.9 percentage of participants	36.6 percentage of participants
Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score Change From Baseline at Week 52 of Year 4: Improved	11.1 percentage of participants	14.3 percentage of participants
Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score Change From Baseline at Week 52 of Year 4: Not Changed	33.3 percentage of participants	42.9 percentage of participants
Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score Change From Baseline at Week 52 of Year 4: Worsened	55.6 percentage of participants	42.9 percentage of participants
Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score Change From Baseline at Week 52 of Year 5: Not Changed	—	100 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Weeks 78 and 156

Population: The Cardiomyopathy-echocardiogram (CM-ECHO) Set included the subset of the 420915-CS2 Randomized Set that had a diagnosis of transthyretin (TTR) cardiomyopathy at study entry of the parent study, but were not in the ECHO Subgroup in the parent study, plus participants who qualified to participate in the ECHO Subgroup (whether consented or not). Number analyzed is the number of participants with data available for analysis at the given time point.

GLS by ECHO is a measure of cardiac systolic function.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=27 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=52 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Percent Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) in the Cardiomyopathy-ECHO (CM-ECHO) Set Change From Baseline at Week 78	0.38 percent change Standard Deviation 3.178	-0.74 percent change Standard Deviation 3.120
Percent Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) in the Cardiomyopathy-ECHO (CM-ECHO) Set Change From Baseline at Week 156	1.46 percent change Standard Deviation 5.313	0.07 percent change Standard Deviation 4.318

SECONDARY outcome

Timeframe: Weeks 78 and 156

GLS by ECHO is a measure of cardiac systolic function.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=17 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=30 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Percent Change From Baseline in GLS by ECHO in the CS3 ECHO Subgroup Percent Change From Baseline at Week 78	-6.93 percent change Standard Deviation 20.232	8.99 percent change Standard Deviation 26.201
Percent Change From Baseline in GLS by ECHO in the CS3 ECHO Subgroup Percent Change From Baseline at Week 156	-2.79 percent change Standard Deviation 24.580	11.46 percent change Standard Deviation 29.383

SECONDARY outcome

Timeframe: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

Transthyretin protein concentration in serum was measured.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=81 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Change From Baseline in Transthyretin (TTR) Level Change From Baseline at Week 78	-0.1581 g/L Standard Deviation 0.05887	-0.1555 g/L Standard Deviation 0.06751
Change From Baseline in Transthyretin (TTR) Level Change From Baseline at Week 156	-0.1498 g/L Standard Deviation 0.06366	-0.1692 g/L Standard Deviation 0.06025

SECONDARY outcome

Timeframe: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156, and at the end of each subsequent treatment year (Week 52 of Years 4 and 5)

RBP4 protein concentration in serum was measured.

Outcome measures

Outcome measures
Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=81 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Change From Baseline in Retinol Binding Protein 4 (RBP4) Level Change From Baseline at Week 78	-21073.1 micrograms per liter (µg/L) Standard Deviation 11038.53	-19365.9 micrograms per liter (µg/L) Standard Deviation 10511.83
Change From Baseline in Retinol Binding Protein 4 (RBP4) Level Change From Baseline at Week 156	-21489.4 micrograms per liter (µg/L) Standard Deviation 10670.52	-22372.3 micrograms per liter (µg/L) Standard Deviation 10372.05
Change From Baseline in Retinol Binding Protein 4 (RBP4) Level Change From Baseline at Week 52 of Year 4	-28307.1 micrograms per liter (µg/L) Standard Deviation 9539.75	-24893.7 micrograms per liter (µg/L) Standard Deviation 5559.01
Change From Baseline in Retinol Binding Protein 4 (RBP4) Level Change From Baseline at Week 52 of Year 5	—	-24444.0 micrograms per liter (µg/L) Standard Deviation NA SD was not estimable for 1 participant.

SECONDARY outcome

Timeframe: Pre-dose on Days 1, 43, 85, 120, 176, 267, 358, 449, 540, 631, 722, 813, 904, 995, 1086, 1268; Days 1359 and 1450 of Year 4; Days 1632, 1723 and 1814 of Year 5

Population: CS3 Pharmacokinetic (PK) Set included all enrolled participants who received at least 1 dose of inotersen in CS3 and who had at least 1 evaluable PK sample collected and analyzed with reportable result in CS3. Number analyzed is the number of participants with data available for analyses at the given time point.

Outcome measures

Adverse Events

Previous Placebo-Inotersen 300 mg

Serious events: 18 serious events

Other events: 50 other events

Deaths: 2 deaths

Previous Inotersen-Inotersen 300 mg

Serious events: 46 serious events

Other events: 80 other events

Deaths: 15 deaths

Serious adverse events

Other adverse events

Additional Information

Ionis Pharmaceuticals, Inc.

Phone: 800-679-4747

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Previous Placebo-Inotersen 300 mg n=50 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group.	Previous Inotersen-Inotersen 300 mg n=85 Participants Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 1	NA nanograms per milliliter (ng/ml) Geometric Coefficient of Variation NA The data was below the lower limit of quantification (LLOQ), hence the geometric mean and geometric coefficient of variation were not estimable.	34.1 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 247
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 43	22.9 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 97.6	74.0 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 123
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 85	28.6 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 43.6	83.0 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 138
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 120	31.5 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 43.7	81.9 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 142
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 176	38.0 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 52.9	80.0 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 104
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 267	47.3 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 83.4	98.2 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 183
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 358	56.2 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 102	110 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 130
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 449	71.1 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 158	130 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 218
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 540	78.7 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 163	111 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 219
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 631	83.8 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 211	141 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 187
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 722	97.6 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 245	101 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 127
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 813	98.0 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 354	150 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 273
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 904	91.4 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 230	116 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 148
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 995	147 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 809	134 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 246
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 1086	131 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 340	101 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 159
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 1268 of Year 4	167 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 258	102 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 202
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 1359 of Year 4	432 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 307	157 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 233
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 1450 of Year 4	55.0 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 61.1	83.0 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 111
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 1632 of Year 5	37.4 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation NA The data was below the LLOQ, hence the geometric coefficient of variation was not estimable.	75.3 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation 26.9
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 1723 of Year 5	113 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation NA The data was below the LLOQ, hence the geometric coefficient of variation was not estimable.	—
Ctrough: Trough Plasma Concentration of ISIS 420915 Day 1814 of Year 5	—	62.1 nanograms per milliliter (ng/ml) Geometric Coefficient of Variation NA The data was below the LLOQ, hence the geometric coefficient of variation was not estimable.