A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AKCEA-TTR-LRx in Healthy Volunteers and Patients With Hereditary Transthyretin-Mediated Amyloidosis

• ClinicalTrials.gov Identifier: NCT03728634
• Recruitment Status: Completed
• First Posted: November 2, 2018
• Last Update Posted: March 13, 2020
• Sponsor: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Ionis Pharmaceuticals, Inc.

Study Description

Brief Summary:

To evaluate the safety and tolerability, as well as the pharmacokinetic and pharmacodynamic profiles of single and multiple doses of AKCEA-TTR-LRx administered subcutaneously to healthy volunteers and patients with Hereditary Transthyretin-Mediated Amyloidosis (hATTR ).

Condition or disease	Intervention/treatment	Phase
Healthy Volunteers; hATTR Amyloidosis	Drug: AKCEA-TTR-LRx; Drug: Placebo	Phase 1; Phase 2

Detailed Description:

This will be a Phase 1/2, double-blind, randomized, placebo-controlled, dose-escalation study conducted at a single center for the healthy volunteer cohorts in up to 56 participants. It will consist of 1 single-dose cohort and 3 multiple-dose cohorts (n = 12 per cohort, 10 active:2 placebo). The open-label, hATTR patient cohort portion of the study will be conducted at multiple centers.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 47 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ION-682884, an Antisense Inhibitor of Transthyretin Production, in Healthy Volunteers and Patients With Hereditary Transthyretin-Mediated Amyloidosis
• Actual Study Start Date: December 21, 2018
• Actual Primary Completion Date: February 20, 2020
• Actual Study Completion Date: February 20, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: AKCEA-TTR-LRx; Single and multiple doses of AKCEA-TTR-LRx administered subcutaneously	Drug: AKCEA-TTR-LRx; Single and multiple doses of AKCEA-TTR-LRx administered subcutaneously; Other Name: ION-682884
Placebo Comparator: Placebo; Placebo comparator calculated volume to match active comparator administered subcutaneously	Drug: Placebo; Placebo comparator calculated volume to match active comparator administered subcutaneously

Outcome Measures

Primary Outcome Measures :

1. Safety and Tolerability as Measured by the Number of Participants with at least one Treatment-Emergent Adverse Event [ Time Frame: Up to 176 Days ]
2. Safety and Tolerability as Measured by the Number of Participants with clinically significant lab values [ Time Frame: Up to 176 Days ]
3. Safety and Tolerability as Measured by the Number of Participants with clinically significant physical examination findings [ Time Frame: Up to 176 Days ]
4. Safety and Tolerability as Measured by the Number of Participants with clinically significant ECG values [ Time Frame: Up to 176 Days ]

Secondary Outcome Measures :

1. Cmax: maximum observed drug concentration in plasma of ION-TTR-LRx [ Time Frame: Up to Day 176 ]
2. Tmax: time taken to reach maximal concentration in plasma of ION-TTR-LRx [ Time Frame: Up to Day 176 ]
3. AUCt: area under the plasma concentration-time curve from time zero to time t for ION-TTR-LRx [ Time Frame: Up to Day 176 ]
4. CL/F: apparent total clearance of ION-TTR-LRx [ Time Frame: Up to Day 176 ]
5. t1/2λz: termination half-life of ION-TTR-LRx [ Time Frame: Up to Day 176 ]
6. The amount of administered dose of ION-TTR-LRx excreted in urine over a 24-hour period [ Time Frame: Up to Day 86 ]
7. Change from Baseline in plasma TTR levels following single and multiple-dose administration of ION-TTR-LRx [ Time Frame: Day 29 (Cohort C); Day 99 (Cohorts A, B, C, and E) ]
8. Change from Baseline in plasma RBP4 levels following single and multiple-dose administration of ION-TTR-LRx [ Time Frame: Day 29 (Cohort C); Day 99 (Cohorts A, B, C, and E) ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria for Healthy Volunteers (Cohorts A, B, C, and E)

1. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal
2. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the subject or the subject's non-pregnant female partner must be using a highly effective contraceptive method
3. Weight ≥ 50 kg and BMI < 32 kg/m2

Exclusion Criteria for Healthy Volunteers (Cohorts A, B, C, and E)

1. Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a subject unsuitable for inclusion including abnormal safety labs
2. Drug or alcohol dependency or abuse
3. Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer
4. Blood donation within 28 days
5. Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the Study

Inclusion Criteria for hATTR Patients (Cohort D)

1. Aged 18 to 82 years at the time of informed consent
2. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal
3. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the subject or the subject's non-pregnant female partner must be using a highly effective contraceptive method
4. Diagnosis of hereditary transthyretin-mediated polyneuropathy
5. BMI > 16 kg/m2

Exclusion Criteria for hATTR Patients (Cohort D)

1. Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a subject unsuitable for inclusion, including but not limited to abnormal safety labs
2. Karnofsky performance status ≤ 50
3. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease), including uncontrolled diabetes
4. Prior liver transplant or anticipated liver transplant within 1-yr of Screening
5. New York Heart Association (NYHA) functional classification of ≥ 3
6. Acute coronary syndrome or major surgery within 3 months of Screening
7. Other types of amyloidosis
8. Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the Study

Contacts and Locations

Locations

Canada, Ontario

Bio Pharma Services, Inc.

Toronto, Ontario, Canada, M9L 3A2

Sponsors and Collaborators

Ionis Pharmaceuticals, Inc.

More Information

• Responsible Party: Ionis Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03728634
• Other Study ID Numbers: ION-682884-CS1
• First Posted: November 2, 2018
• Last Update Posted: March 13, 2020
• Last Verified: March 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Amyloidosis; Proteostasis Deficiencies; Metabolic Diseases