Safety, Tolerability, and Pharmacodynamics of IONIS-DGAT2Rx in Adult Patients With Type 2 Diabetes

A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study to Evaluate the Safety, Tolerability and Pharmacodynamics of ISIS 484137 (IONIS-DGAT2Rx, an Antisense Inhibitor of Diacylglycerol Acyltransferase 2) Administered Once-Weekly for 13 Weeks in Adult Patients With Type 2 Diabetes

The purpose is to assess the Safety, Tolerability, and Pharmacodynamics effect of IONIS DGAT2Rx in up to 45 Adult Patients with Type 2 Diabetes.

Study Overview

• Status: Completed
• Conditions: Hepatic Steatosis
• Intervention / Treatment: Drug: IONIS DGAT2Rx; Drug: Placebo

Detailed Description

This short-term study will assess changes in hepatic steatosis over a 13-week treatment period in a patient population with higher risk for development of Nonalcoholic fatty liver disease (NAFLD) and Nonalcoholic steatohepatitis (NASH), obese type 2 diabetes mellitus (T2DM) with elevated HbA1c.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Ionis Investigational Site
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Ionis Investigational Site
• Hungary
  • Budapest, Hungary, 1036
    • Ionis Investigational Site
  • Budapest, Hungary, 1083
    • Ionis Investigational Site
  • Budapest, Hungary, 1088
    • Ionis Investigational Site
  • Hatvan, Hungary, 3000
    • Ionis Investigational Site
  • Miskolc, Hungary, 3529
    • Ionis Investigational Site
  • Szekesfehervar, Hungary, 8000
    • Ionis Investigational Site
• Poland
  • Bydgoszcz, Poland, 85-863
    • Ionis Investigational Site
  • Bytom, Poland, 41-902
    • Ionis Investigational Site
  • Chełm, Poland, 22-100
    • Ionis Investigational Site
  • Katowice, Poland, 40-752
    • Ionis Investigational Site
  • Kraków, Poland, 31-501
    • Ionis Investigational Site
  • Kraków, Poland, 31-530
    • Ionis Investigational Site
  • Mysłowice, Poland, 41-400
    • Ionis Investigational Site
  • Wierzchosławice, Poland, 33-122
    • Ionis Investigational Site
  • Wrocław, Poland, 50-127
    • Ionis Investigational Site
  • Wrocław, Poland, 50-220
    • Ionis Investigational Site
  • Wrocław, Poland, 50-349
    • Ionis Investigational Site
  • Łódź, Poland, 93-509
    • Ionis Investigational Site
• United Kingdom
  • Dundee, United Kingdom, DD1 9SY
    • Ionis Investigational Site
  • Nottingham, United Kingdom, NG7 2UH
    • Ionis Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Must have given written informed consent and be able to comply with all study requirements.
• Males or females aged 18-75, inclusive, at the time of Informed Consent.
• Females must be non-pregnant and non-lactating, and either surgically sterile or post- menopausal.
• Males must be surgically sterile, abstinent or using an acceptable contraceptive method.
• Body mass index (BMI) ≥ 27.0 - ≤ 39.0 kilograms per square meter (kg/m^2).
• Diagnosis of Type 2 Diabetes Mellitus with an Hemoglobin A1C (HbA1c) ≥7.3% and ≤9.5% at screening.
• Must have been on a stable dose of Oral Antidiabetic Therapy for a minimum of 3 months prior to Screening.
• ≥ 10% liver fat prior to randomization assessed by MRI-PDFF.
• Stable body weight for at least 3 months before screening.

Exclusion Criteria:

• Clinically-significant abnormalities in medical history or physical examination.
• Clinically-significant abnormalities in screening laboratory values that would render a participant unsuitable for inclusion, per Sponsor.
• Evidence of uncorrected hypothyroidism or hyperthyroidism results at Screening.
• History of solid organ transplantation or renal dialysis.
• Clinically-significant complications of diabetes.
• Treatment with another Study Drug, biological agent, or device within one-month of screening.
• Known history or evidence of liver disease with a positive test for human immunodeficiency virus (HIV), Hepatitis C virus (HCV), or chronic Hepatitis B virus (HBV), or chronic liver disease other than NASH.
• Recent history of, or current drug or alcohol abuse.
• Current use of concomitant medications known to significantly impact body weight or that may cause liver toxicity, per Investigator
• Use of anticoagulant/Antiplatelet agents unless the dose has been stable for 4 weeks prior to the first dose of study drug]
• Use of non-steroidal anti-inflammatory drug nimesulide or any other drug influencing coagulation (except lose-dose aspirin).
• Use of obeticholic acid or ursodeoxycholic acid
• Considered unsuitable for inclusion by the Principal Investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IONIS DGAT2Rx; Single Dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks	Drug: IONIS DGAT2Rx; Single Dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks
Placebo Comparator: Placebo (sterile saline 0.9); Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks	Drug: Placebo; Saline 0.9%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change in Liver Fat Percentage (Randomized Population)	Absolute change in liver fat percentage as quantified by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) from baseline to post-treatment MRI.	Baseline to Week 15
Absolute Change in Liver Fat Percentage (Per Protocol Population)	Absolute change in liver fat percentage as quantified by MRI-PDFF from baseline to post-treatment MRI.	Baseline to Week 15
Percentage of Participants With Adverse Events That Were Related to Treatment With IONIS DGAT2Rx	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.	Up to 176 days
Percentage of Participants With Adverse Events, Graded by Severity, That Were Related to Treatment With IONIS DGAT2Rx	AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, June 2010. Grades: mild - the event is easily tolerated by the participant and does not affect the participant's usual daily activities; moderate - the event causes the participant more discomfort and interrupts the participant's usual daily activities; severe - the event is incapacitating and causes considerable interference with the participant's usual daily activities.	Up to 176 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in Liver Fat Percentage	Relative percent change in liver fat percentage from baseline to post-treatment MRI.	Baseline to Week 15
Percentage of Participants With ≥ 30% Relative Reduction in Liver Fat Percentage	Percentage of participants with ≥ 30% relative reduction in liver fat percentage from baseline to post-treatment.	Week 15
Percent Change in Liver Volume	Assessed from Baseline MRI to Post-Treatment MRI.	Baseline to Week 15
Percent Change in Plasma Lipoprotein Profile	Percent change in plasma lipoprotein profile (total cholesterol, apolipoprotein B [ApoB], high density lipoprotein (HDL), low density lipoprotein cholesterol [LDL-C], non-HDL, triglycerides, and very low density lipoproteins [VLDL]) from baseline to the average of the post-treatment values assessed 1 and 2 weeks after the last dose (Post-Treatment 1 and Post-Treatment 2 visits).	Week 15
Percent Change in Parameters of Insulin Resistance (IR)	Percent change in parameters of IR (fasting plasma glucose [FPG], homeostatic model assessment - insulin resistance [HOMA-IR], and insulin) from baseline to post-treatment.	Week 14
Absolute Change in Hemoglobin A1C (HbA1C)	Absolute change in HbA1C from baseline to post-treatment.	Week 14

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.
• Investigators: Study Director: Sanjay Bhanot, Ionis Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Loomba R, Morgan E, Watts L, Xia S, Hannan LA, Geary RS, Baker BF, Bhanot S. Novel antisense inhibition of diacylglycerol O-acyltransferase 2 for treatment of non-alcoholic fatty liver disease: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol Hepatol. 2020 Sep;5(9):829-838. doi: 10.1016/S2468-1253(20)30186-2. Epub 2020 Jun 15.

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2017
• Primary Completion (Actual): November 28, 2018
• Study Completion (Actual): November 28, 2018

Study Registration Dates

• First Submitted: October 23, 2017
• First Submitted That Met QC Criteria: November 2, 2017
• First Posted (Actual): November 7, 2017

Study Record Updates

• Last Update Posted (Actual): January 27, 2020
• Last Update Submitted That Met QC Criteria: January 15, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Type 2 Diabetes; Hepatic Steatosis; IONIS-DGAT2Rx
• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Liver Diseases; Diabetes Mellitus, Type 2; Fatty Liver
• Other Study ID Numbers: ISIS 484137-CS2; 2017-003197-13 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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