A Study to Assess the Long-Term Safety and Efficacy of Eplontersen (Formerly Known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx) in Patients With Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

Phase 3Active Not RecruitingNCT05071300

Ionis Pharmaceuticals, Inc.151 enrolled

Overview

The purpose of this study is to evaluate the safety and tolerability of extended dosing with eplontersen in participants with hereditary transthyretin-mediated amyloid polyneuropathy (hATTR-PN).

This is a multicenter, open-label, Phase 3 study in up to approximately 165 participants. Participants will also receive daily supplemental doses of the recommended daily allowance (RDA) of vitamin A. This study will consist of the following periods: less than or equal to (≤) 8-week screening period, a 157-week treatment period, and a 24-week post-treatment evaluation period. Participants may continue to receive treatment in this study for up to 2 years or until ION-682884 becomes commercially available in the patient's country, whichever occurs earlier.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

151

Conditions

Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

Interventions

EplontersenDRUG

Eplontersen will be administered by SC injection.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Satisfactory completion of ION-682884-CS3 (NCT04136184) (Index Study) as judged by the Investigator and Sponsor, or diagnosis of hATTR-PN and satisfactory completion of either study ISIS 420915-CS101 or study 2018-P001436 (NCT03702829) (both are Investigator-Sponsored studies with inotersen - the unconjugated version of eplontersen) as judged by the Investigator and Sponsor. 2. Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements. 3. Satisfy the following: 1. Females: must be non-pregnant and non-lactating and either: * Surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy); * Post-menopausal (defined as 12 months of spontaneous amenorrhea in females \> 55 years of age or, in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative medical cause and follicle-stimulating hormone (FSH) levels in the postmenopausal range for the laboratory involved; * Abstinent\*; * If engaged in sexual relations of child-bearing potential, agree to use highly effective contraceptive methods from the time of signing the informed consent form until at least 24 weeks after the last dose of eplontersen and agree to receive pregnancy tests per protocol. 2. Males: Surgically sterile (i.e., bilateral orchidectomy) or abstinent\*, if engaged in sexual relations with a woman of child-bearing potential (WOCBP), the participant or the participant's non-pregnant female partner must use a highly effective contraceptive method from the time of signing the informed consent form until at least 24 weeks after the last dose of eplontersen. \*Abstinence (i.e., refraining from heterosexual intercourse throughout the duration of study participation) is only acceptable as true abstinence, i.e., when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not acceptable methods of contraception. 4. Willingness to adhere to vitamin A supplementation per protocol. Exclusion Criteria: 1\. Have any new condition or worsening of existing condition that in the opinion of the Investigator or Sponsor would make the participant unsuitable for enrollment or could interfere with the participant taking part in or completing the study.

Locations (33)

Outcomes

Primary Outcomes

Change From Baseline in Platelet Count

Time frame: Baseline to Week 181

Number of Participants With Clinically Significant Changes From Baseline in Renal Function

Time frame: Baseline to Week 181

Number of Participants with Clinically Significant Changes from Baseline in Transaminases

Time frame: Baseline to Week 181

Change From Baseline in Adverse Events

Time frame: Baseline to Week 181

Change From Baseline in Number of Concomitant Medications Used

Time frame: Baseline to Week 181

Number of Participants With Clinically Significant Changes From Baseline in Vital Signs

Time frame: Baseline to Week 181

Change From Baseline in Body Weight

Time frame: Baseline to Week 181

Number of Participants With Clinically Significant Changes From Baseline in Physical Examination Findings

Time frame: Baseline to Week 181

Number of Participants With Clinically Significant Changes From Baseline in Clinical Laboratory Tests

Time frame: Baseline to Week 181

Number of Participants With Clinically Significant Changes From Baseline in Electrocardiogram (ECG) Parameters

Time frame: Baseline to Week 181

Number of Participants With Clinically Significant Changes From Baseline in Thyroid Panel Tests

Data from ClinicalTrials.gov

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Scottsdale, Arizona, United States

Indiana University Health University Hospital

Indianapolis, Indiana, United States

Johns Hopkins University Neurology Research Office

Baltimore, Maryland, United States

Boston University School of Medicine

Boston, Massachusetts, United States

The Neurological Institute of New York

New York, New York, United States

University of North Carolina Hospitals - Neurology Clinic

Chapel Hill, North Carolina, United States

Oregon Health and Science University

Portland, Oregon, United States

University of Washington Medical Center

Seattle, Washington, United States

Hospital Italiano de Buenos Aires

Buenos Aires, Argentina

Instituto Fleni

Buenos Aires, Argentina

...and 23 more locations

Secondary Outcomes

Change From Baseline in Neuropathy Impairment Score (NIS)

NIS is a composite, quantitative measure of both large-and small-fiber dysfunction used to evaluate the participant's muscle strength, sensation, and reflexes. Total NIS is graded on a scale of 0-244, with a higher score indicating greater impairment.

Time frame: Baseline to Week 181

Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) Questionnaire

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 score indicates poorer quality of life.

Time frame: Baseline to Week 181

Change From Baseline in Neuropathy Symptom and Change Score (NSC)

NSC score is a questionnaire composed of 38 questions that assess the presence and severity of neuropathy symptoms (including weakness, loss of temperature and pain sensation, and manifestations associated with autonomic nervous system dysfunction).

Time frame: Baseline to Week 181

Change From Baseline in Serum Transthyretin (TTR) Concentration

Time frame: Baseline to Week 181

Change From Baseline in Physical Component Summary Score (PCS) of 36-Item Short Form Survey (SF-36)

The SF-36 is composed of 8 multi-item scales (35 items) assessing physical function (10 items), role limitations due to physical health problems (4 items), bodily pain (2 items), general health (5 items), vitality (4 items), social functioning (2 items), role limitations due to emotional problems (3 items) and emotional well-being (5 items). Each of the 8 scales is scored from 0 to 100 with higher scores indicating better health. The 8 scales can be aggregated into a PCS score, which is also scaled from 0 to 100 with higher scores indicating better health.

Time frame: Baseline to Week 181

Change From Baseline in Polyneuropathy Disability Score (PND)

PND score assesses disease severity using a 5-stage scoring system. It includes Stage 0: no impairment; Stage 1: sensory disturbances but preserved walking capabilities; Stage 2: impaired walking capacity, but ability to walk without a stick or crutches; Stage 3A/B: walking with help of 1 or 2 sticks or crutches; Stage 4: confined to wheel chair or bedridden.

Time frame: Baseline to Week 181

Change From Baseline in Modified Body Mass Index (mBMI)

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).

Time frame: Baseline to Week 181

Change From Baseline in Composite Autonomic Symptom Score-31 (COMPASS-31)

COMPASS-31 is a 31-question participant-reported assessment that measures autonomic symptoms across 6 weighted domains on a 100-point scale: orthostatic intolerance (40 points), vasomotor (5 points), secretomotor (15 points), gastrointestinal (25 points), bladder (10 points), and pupillomotor (15 points). A higher score indicates worse autonomic dysfunction.

Time frame: Baseline to Week 181

Change From Baseline in 5 Level EQ-5D (EQ-5D-5L)

The EQ-5D-5L is a standard measure of health-related quality of life. EQ-5D-5L consists of two components: a health state profile and a visual analog scale (VAS). EQ-5D health state profile comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. The 5D-5L systems are converted into a single index utility score between 0 to 1, where a higher score indicates a better health state. The VAS records the participant's health on a 0-100 mm VAS scale, with 0 indicating "the worst health you can imagine" and 100 indicating "the best health you can imagine". Higher scores of EQ VAS indicate better health.

Time frame: Baseline to Week 181