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A Study of RGLS4326 in Patients With Autosomal Dominant Polycystic Kidney Disease

Primary Purpose

Polycystic Kidney Disease, Autosomal Dominant

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
RGLS4326
Sponsored by
Regulus Therapeutics Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Polycystic Kidney Disease, Autosomal Dominant

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male or female ADPKD patients 18 to 70 years old
  • Class 1C, 1D, or 1E Mayo Imaging Classification of ADPKD (based upon prior MRI or CT Scan or MRI obtained during screening)
  • Estimated GFR at Screening between 30 to 90 mL/min/1.73 m^2 calculated by the investigator using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI)
  • Body mass index (BMI) between 18 and 35 kg/m^2
  • If the patient has hypertension, the antihypertensive regimen must be stable for at least 28 days prior to randomization and the blood pressure adequately controlled prior to randomization
  • Female patients of childbearing potential must not be lactating and must have no plans to become pregnant during the course of the study through 28 days after the last dose of study drug. Female patients of childbearing potential who are heterosexual must agree to use one of the following methods of contraception considered to be highly effective (i.e., results in <1% failure rate when used consistently and correctly) from screening through 28 days after the last dose of study drug:

    • Intrauterine device (IUD) or intrauterine system (IUS) in place for at least 3 months prior to first dose
    • Partner has had a vasectomy. Vasectomy in the partner is only considered to be highly effective provided the partner is the sole sexual partner of the female patient of childbearing potential and the vasectomized partner has had a medical assessment of the surgical success.
    • Stable hormonal contraception associated with inhibition of ovulation (with approved oral, transdermal, or depot regimen) for at least 3 months prior to first dose
    • Bilateral tubal occlusion
  • Female patient of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to the first dose of study drug:

    • Hysterectomy
    • Bilateral oophorectomy
    • Bilateral tubal occlusion
    • Bilateral salpingectomy or be postmenopausal with no periods for at least 1 year prior to the first dose of study drug.
  • Male patients must agree to use a condom during heterosexual intercourse and to not have unprotected sexual intercourse with a female who is pregnant or breastfeeding from screening through 28 days after the last dose of study drug; and must agree to refrain from sperm donation for at least 90 days after the last dose of study drug
  • Screening hematology and clinical chemistries must meet the following criteria:

    • Platelets >150 x 10^9/L
    • Total white blood cell (WBC) count >3.0 x 10^9/L and absolute neutrophil count >1.5 x 10^9/L
    • Hemoglobin >12 g/dL for females and >13.5 g/dL for males
    • Total and direct bilirubin <1.5x upper limit of normal (ULN), unless elevated bilirubin is associated with a known benign condition (e.g., Gilbert's syndrome)
    • Alanine aminotransferase (ALT) <1.5x ULN
    • Aspartate aminotransferase (AST) <1.5x ULN
    • Alkaline phosphatase (ALP) <1.5x ULN
    • Gamma-glutamyl transferase (GGT) <2x ULN Note: At the discretion of the Investigator, screening laboratory testing may be repeated once to confirm out of range (exclusionary) results.
  • Able to understand all study procedures in the informed consent form (ICF) and willing to comply with all aspects of the protocol

Exclusion Criteria:

  • Administration of tolvaptan in the 28 days before randomization
  • Participation in another investigational interventional study within 28 days or 5 half-lives, whichever is longer, before randomization (e.g., bardoxolone, lixivaptan, tesevatinib, venglustat)
  • A history of drug and/or alcohol abuse within the past year
  • Active infection of the urinary tract (e.g., kidney, bladder, etc.)
  • Known hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)
  • Only one kidney or kidney transplant recipient.
  • Patient has concurrent medical condition (e.g., significant infection, other kidney disease, neurologic condition such as seizures, etc.) or social situation that may either present a safety risk or noncompliance with the study procedures
  • History of active malignancy within 5 years of randomization, except adequately treated basal cell or squamous cell carcinoma of the skin
  • History of a clinically significant reaction to an oligonucleotide compound
  • Significant blood loss or blood donation within the 28 days prior to randomization or plasma donation within 7 days prior to randomization
  • A tattoo or scarring on the abdomen or any other condition large enough to interfere with the ability to assess injection site reactions

Sites / Locations

  • Balboa Nephrology Medical Group
  • Academic Medical Research Institute
  • Yale Nephrology Clinical Research
  • Accel Research Sites- Mid-Florida Kidney and Hypertension Care
  • University of Kansas Medical Center
  • Tufts Medical Center
  • Beth Israel Deaconess Medical Center
  • St. Clair Nephrology Research
  • Mayo Clinic
  • UT Southwestern Medical Center
  • ICON Early Phase Services
  • Swedish Polycystic Kidney Disease Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

RGLS4326 1 mg/kg Q2W

RGLS4326 0.3 mg/kg Q2W

RGLS4326 0.1 or 0.5 mg/kg Q2W

Arm Description

Eligible participants will receive subcutaneous injection of 1 mg/kg of RGLS4326 every other week for 4 doses

Eligible participants will receive subcutaneous injection of 0.3 mg/kg of RGLS4326 every other week for 4 doses

Eligible participants will receive subcutaneous injection of 0.1 or 0.5 mg/kg of RGLS4326 every other week for 4 doses

Outcomes

Primary Outcome Measures

Changes in primary biomarker levels from baseline
Changes in polycystin-1 (PC-1) and polycystin-2 (PC-2) protein levels in urinary exosomes from baseline to Day 44

Secondary Outcome Measures

Changes in secondary biomarker levels from baseline
Changes in neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) in urine from baseline to Day 44
Pharmacokinetics (Cmax)
Maximum concentration (Cmax) of RGLS4326 in plasma following RGLS4326 treatment
Pharmacokinetics (Tmax)
Time to maximum concentration (Tmax) of RGLS4326 in plasma following RGLS4326 treatment
Pharmacokinetics (AUC)
Area under the curve (AUC) of RGLS4326 in plasma following RGLS4326 treatment
Number of participants with anti-drug antibodies (ADAs)
Incidence of ADAs following RGLS4326 treatment from baseline to Day 71
Titre of anti-drug antibodies (ADAs) in patients with ADAs
Titre of ADAs following RGLS4326 treatment from baseline to Day 71
Safety profile
Incidence of AEs, lab abnormalities, and ECG abnormalities following RGLS4326 treatment

Full Information

First Posted
August 24, 2020
Last Updated
December 14, 2021
Sponsor
Regulus Therapeutics Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT04536688
Brief Title
A Study of RGLS4326 in Patients With Autosomal Dominant Polycystic Kidney Disease
Official Title
A Phase 1b, Multicenter, Open-Label, Adaptive Design Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RGLS4326 Administered Via SC Injection to Patients With Autosomal Dominant Polycystic Kidney Disease
Study Type
Interventional

2. Study Status

Record Verification Date
December 2021
Overall Recruitment Status
Completed
Study Start Date
October 13, 2020 (Actual)
Primary Completion Date
November 12, 2021 (Actual)
Study Completion Date
November 12, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Regulus Therapeutics Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Primary Objective • To assess the dose response relationship between RGLS4326 and ADPKD biomarkers Secondary Objectives To characterize the pharmacokinetic (PK) properties of RGLS4326 in plasma and urine To assess the safety and tolerability of RGLS4326
Detailed Description
This is a Phase 1b, open-label, adaptive design dose-ranging study to evaluate ADPKD biomarkers, PK, safety, tolerability, and pharmacodynamics (PD) of RGLS4326 administered via SC injection to patients with ADPKD. The goal is to assess the dose response relationship between RGLS4326 and ADPKD biomarkers. The study will consist of three sequential cohorts with approximately 18 to 27 subjects total.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Polycystic Kidney Disease, Autosomal Dominant

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Model Description
Cohorts will be enrolled and treated sequentially. Dosing decisions will be made based on prior cohort's safety and biomarker data. Six to 9 subjects will be enrolled in each cohort based on the magnitude and/or variability of the increase in PC1 and PC2 or to allow for replacement of subjects that do not complete the study. The highest dose (1 mg/kg) will be administered in cohort 1. If the Sponsor determines that the increase in PC1 and PC2 from baseline for cohort 1 is inadequate, the study may be stopped for futility. If the Sponsor determines that the increase from baseline for cohort 1 is adequate, then 0.3 mg/kg will be administered in cohort 2. Based on the increase of PC1 and PC2 from baseline in cohort 2, Sponsor may determine a higher dose needs to be evaluated, then 0.5 mg/kg will be administered in cohort 3. If the Sponsor determines that lower dose needs to be evaluated, then 0.1 mg/kg will be administered in cohort 3.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
19 (Actual)

8. Arms, Groups, and Interventions

Arm Title
RGLS4326 1 mg/kg Q2W
Arm Type
Experimental
Arm Description
Eligible participants will receive subcutaneous injection of 1 mg/kg of RGLS4326 every other week for 4 doses
Arm Title
RGLS4326 0.3 mg/kg Q2W
Arm Type
Experimental
Arm Description
Eligible participants will receive subcutaneous injection of 0.3 mg/kg of RGLS4326 every other week for 4 doses
Arm Title
RGLS4326 0.1 or 0.5 mg/kg Q2W
Arm Type
Experimental
Arm Description
Eligible participants will receive subcutaneous injection of 0.1 or 0.5 mg/kg of RGLS4326 every other week for 4 doses
Intervention Type
Drug
Intervention Name(s)
RGLS4326
Intervention Description
Solution for subcutaneous injection
Primary Outcome Measure Information:
Title
Changes in primary biomarker levels from baseline
Description
Changes in polycystin-1 (PC-1) and polycystin-2 (PC-2) protein levels in urinary exosomes from baseline to Day 44
Time Frame
Baseline to Day 44
Secondary Outcome Measure Information:
Title
Changes in secondary biomarker levels from baseline
Description
Changes in neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) in urine from baseline to Day 44
Time Frame
Baseline to Day 44
Title
Pharmacokinetics (Cmax)
Description
Maximum concentration (Cmax) of RGLS4326 in plasma following RGLS4326 treatment
Time Frame
Baseline to Day 44
Title
Pharmacokinetics (Tmax)
Description
Time to maximum concentration (Tmax) of RGLS4326 in plasma following RGLS4326 treatment
Time Frame
Baseline to Day 71
Title
Pharmacokinetics (AUC)
Description
Area under the curve (AUC) of RGLS4326 in plasma following RGLS4326 treatment
Time Frame
Baseline to Day 71
Title
Number of participants with anti-drug antibodies (ADAs)
Description
Incidence of ADAs following RGLS4326 treatment from baseline to Day 71
Time Frame
Baseline to Day 71
Title
Titre of anti-drug antibodies (ADAs) in patients with ADAs
Description
Titre of ADAs following RGLS4326 treatment from baseline to Day 71
Time Frame
Baseline to Day 71
Title
Safety profile
Description
Incidence of AEs, lab abnormalities, and ECG abnormalities following RGLS4326 treatment
Time Frame
Baseline to Day 71

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female ADPKD patients 18 to 70 years old Class 1C, 1D, or 1E Mayo Imaging Classification of ADPKD (based upon prior MRI or CT Scan or MRI obtained during screening) Estimated GFR at Screening between 30 to 90 mL/min/1.73 m^2 calculated by the investigator using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) Body mass index (BMI) between 18 and 35 kg/m^2 If the patient has hypertension, the antihypertensive regimen must be stable for at least 28 days prior to randomization and the blood pressure adequately controlled prior to randomization Female patients of childbearing potential must not be lactating and must have no plans to become pregnant during the course of the study through 28 days after the last dose of study drug. Female patients of childbearing potential who are heterosexual must agree to use one of the following methods of contraception considered to be highly effective (i.e., results in <1% failure rate when used consistently and correctly) from screening through 28 days after the last dose of study drug: Intrauterine device (IUD) or intrauterine system (IUS) in place for at least 3 months prior to first dose Partner has had a vasectomy. Vasectomy in the partner is only considered to be highly effective provided the partner is the sole sexual partner of the female patient of childbearing potential and the vasectomized partner has had a medical assessment of the surgical success. Stable hormonal contraception associated with inhibition of ovulation (with approved oral, transdermal, or depot regimen) for at least 3 months prior to first dose Bilateral tubal occlusion Female patient of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to the first dose of study drug: Hysterectomy Bilateral oophorectomy Bilateral tubal occlusion Bilateral salpingectomy or be postmenopausal with no periods for at least 1 year prior to the first dose of study drug. Male patients must agree to use a condom during heterosexual intercourse and to not have unprotected sexual intercourse with a female who is pregnant or breastfeeding from screening through 28 days after the last dose of study drug; and must agree to refrain from sperm donation for at least 90 days after the last dose of study drug Screening hematology and clinical chemistries must meet the following criteria: Platelets >150 x 10^9/L Total white blood cell (WBC) count >3.0 x 10^9/L and absolute neutrophil count >1.5 x 10^9/L Hemoglobin >12 g/dL for females and >13.5 g/dL for males Total and direct bilirubin <1.5x upper limit of normal (ULN), unless elevated bilirubin is associated with a known benign condition (e.g., Gilbert's syndrome) Alanine aminotransferase (ALT) <1.5x ULN Aspartate aminotransferase (AST) <1.5x ULN Alkaline phosphatase (ALP) <1.5x ULN Gamma-glutamyl transferase (GGT) <2x ULN Note: At the discretion of the Investigator, screening laboratory testing may be repeated once to confirm out of range (exclusionary) results. Able to understand all study procedures in the informed consent form (ICF) and willing to comply with all aspects of the protocol Exclusion Criteria: Administration of tolvaptan in the 28 days before randomization Participation in another investigational interventional study within 28 days or 5 half-lives, whichever is longer, before randomization (e.g., bardoxolone, lixivaptan, tesevatinib, venglustat) A history of drug and/or alcohol abuse within the past year Active infection of the urinary tract (e.g., kidney, bladder, etc.) Known hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) Only one kidney or kidney transplant recipient. Patient has concurrent medical condition (e.g., significant infection, other kidney disease, neurologic condition such as seizures, etc.) or social situation that may either present a safety risk or noncompliance with the study procedures History of active malignancy within 5 years of randomization, except adequately treated basal cell or squamous cell carcinoma of the skin History of a clinically significant reaction to an oligonucleotide compound Significant blood loss or blood donation within the 28 days prior to randomization or plasma donation within 7 days prior to randomization A tattoo or scarring on the abdomen or any other condition large enough to interfere with the ability to assess injection site reactions
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Karl Cremer, PharmD
Organizational Affiliation
Regulus Therapeutics
Official's Role
Study Director
Facility Information:
Facility Name
Balboa Nephrology Medical Group
City
La Mesa
State/Province
California
ZIP/Postal Code
91942
Country
United States
Facility Name
Academic Medical Research Institute
City
Los Angeles
State/Province
California
ZIP/Postal Code
90022
Country
United States
Facility Name
Yale Nephrology Clinical Research
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States
Facility Name
Accel Research Sites- Mid-Florida Kidney and Hypertension Care
City
Altamonte Springs
State/Province
Florida
ZIP/Postal Code
32701
Country
United States
Facility Name
University of Kansas Medical Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
Tufts Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02111
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
St. Clair Nephrology Research
City
Roseville
State/Province
Michigan
ZIP/Postal Code
48066
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55904
Country
United States
Facility Name
UT Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
ICON Early Phase Services
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78209
Country
United States
Facility Name
Swedish Polycystic Kidney Disease Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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A Study of RGLS4326 in Patients With Autosomal Dominant Polycystic Kidney Disease

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