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

Phase 1

Completed

• Conditions: Polycystic Kidney Disease, Autosomal Dominant
• Interventions: Drug: RGLS4326

• Registration Number: NCT04536688
• Lead Sponsor: Regulus Therapeutics Inc.

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.

Study Timeline

• Study First Submitted: 2020-08-24
• Study First Submitted QC: 2020-08-28
• Study First Posted: 2020-09-03
• Study Start: 2020-10-13
• Primary Completion: 2021-11-12
• Study Completion: 2021-11-12
• Status Verified: 2021-12
• Last Update Submitted: 2021-12-14
• Last Update Posted: 2021-12-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 19

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
RGLS4326 1 mg/kg Q2W	RGLS4326	Eligible participants will receive subcutaneous injection of 1 mg/kg of RGLS4326 every other week for 4 doses
RGLS4326 0.3 mg/kg Q2W	RGLS4326	Eligible participants will receive subcutaneous injection of 0.3 mg/kg of RGLS4326 every other week for 4 doses
RGLS4326 0.1 or 0.5 mg/kg Q2W	RGLS4326	Eligible participants will receive subcutaneous injection of 0.1 or 0.5 mg/kg of RGLS4326 every other week for 4 doses

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (12)

Swedish Polycystic Kidney Disease Center; 🇺🇸 Seattle, Washington, United States

St. Clair Nephrology Research; 🇺🇸 Roseville, Michigan, United States

Academic Medical Research Institute; 🇺🇸 Los Angeles, California, United States

Tufts Medical Center; 🇺🇸 Boston, Massachusetts, United States

ICON Early Phase Services; 🇺🇸 San Antonio, Texas, United States

Accel Research Sites- Mid-Florida Kidney and Hypertension Care; 🇺🇸 Altamonte Springs, Florida, United States

Beth Israel Deaconess Medical Center; 🇺🇸 Boston, Massachusetts, United States

UT Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States

Balboa Nephrology Medical Group; 🇺🇸 La Mesa, California, United States

Yale Nephrology Clinical Research; 🇺🇸 New Haven, Connecticut, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

University of Kansas Medical Center; 🇺🇸 Kansas City, Kansas, United States