Regulus Therapeutics' Farabursen Shows Promise in ADPKD Phase 1b Trial and Gains FDA Agreement on Phase 3 Design
Key Insights
Regulus Therapeutics announced positive topline results from an interim analysis of the Phase 1b MAD study of farabursen for ADPKD.
The study demonstrated a continued mechanistic dose response and a notable reduction in htTKV growth rate in ADPKD patients.
Regulus reached an agreement with the FDA on key components of a Phase 3 single pivotal trial for potential accelerated approval of farabursen.
Regulus TherapeuticsView company profile Inc. (Nasdaq: RGLS) has announced positive clinical and regulatory updates regarding its farabursenSearch drug (RGLS8429Search drug) program for the treatment of autosomal dominant polycystic kidney diseaseSearch disease (ADPKDSearch disease). The updates include topline results from an interim analysis of the fourth cohort of its Phase 1b Multiple Ascending Dose (MAD) study and an overview of a successful End-of-Phase 1 meeting with the FDA.
The Phase 1b MAD study is a double-blind, placebo-controlled trial evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of farabursenSearch drug in adult patients with ADPKDSearch disease. The study assesses the impact of farabursen across three weight-based dose levels and one fixed dose level, measuring changes in urinary polycystins 1 and 2 (PC1 and PC2), height-adjusted total kidney volume (htTKV), and overall kidney function. PC1 and PC2 are protein products of the PKD1 and PKD2 genes, with their levels inversely correlated with disease severity.
Interim Analysis of Phase 1b Trial
In the fourth cohort, 26 subjects received a fixed dose of 300 mg of farabursenSearch drug every other week for three months. An interim analysis of efficacy data from the first 14 subjects demonstrated continued evidence of a mechanistic dose response based on urinary PC1 and PC2 levels, along with a notable reduction in htTKV growth rate. Safety data from all 26 subjects indicated that farabursen was well-tolerated.
Data highlights from Cohort 4 include:
- Effects on polycystin biomarker levels similar to Cohort 3 at 3 mg/kg, predicted to achieve optimal kidney exposure and miR-17 inhibition.
- Exploratory results suggesting a notable impact on htTKV growth rate after three months of treatment.
- htTKV results consistent across Mayo Imaging Class and PKD1 truncating vs. non-truncating mutations.
- Exploratory conditional probability analyses suggesting a high probability of success in meeting or exceeding the targeted htTKV efficacy threshold.
- An encouraging safety and tolerability profile consistent with earlier cohorts.
Regulatory Alignment with FDA
In December 2024, Regulus TherapeuticsView company profile had a productive End-of-Phase 1 meeting with the FDA, achieving alignment on key components of a Phase 3 trial design as a single pivotal study. The agreed-upon components include:
- A single active dose and placebo administered every other week in a 2:1 randomization scheme.
- Key inclusion/exclusion criteria for the trial population.
- A 12-month htTKV endpoint for potential Accelerated Approval and a 24-month eGFR endpoint for potential Full Approval.
- An acceptable safety database size.
Management Perspectives
"These trial results extend our understanding of the potential benefits and advantages to Regulus' approach in this area of high unmet medical need," said Preston Klassen, M.D., President and Head of Research & Development of Regulus. "Additionally, the data highlight that farabursenSearch drug appears to be well tolerated, reinforcing its potential as a safe option in the treatment of ADPKDSearch disease."
Alan Yu, M.D., University of Kansas Medical Center, added, "The results from Cohort 4 are very promising, further validating the impact of farabursenSearch drug on urinary exosomal polycystin levels and suggesting an opportunity to beneficially impact kidney volume growth rate, as we have now observed notable improvements across multiple treatment cohorts."
"Following a productive End-of-Phase 1 meeting with the FDA in December along with the interim results announced today, we are encouraged by the feedback from the agency and are excited about the path forward for farabursenSearch drug in ADPKDSearch disease," said Jay Hagan, CEO of Regulus. "The positive results announced today underscore our conviction in the potential of farabursen in ADPKD and we look forward to advancing this program into a pivotal study later this year."
About ADPKD
Autosomal dominant polycystic kidney diseaseSearch disease (ADPKDSearch disease) is a common monogenic disorder and a leading cause of end-stage renal disease, affecting approximately 160,000 individuals in the United States and an estimated 4 to 7 million people globally. The disease is characterized by the development of multiple fluid-filled cysts primarily in the kidneys, leading to excessive kidney cyst cell proliferation and, ultimately, end-stage renal disease in about 50% of patients by age 60.
About Farabursen
FarabursenSearch drug (RGLS8429Search drug) is a novel, next-generation oligonucleotide designed to inhibit miR-17Search term and preferentially target the kidney for the treatment of ADPKDSearch disease. Preclinical models have demonstrated clear improvements in kidney function, size, and other measures of disease severity with farabursen administration. The Phase 1 SAD study showed a favorable safety and PK profile, with farabursen being well-tolerated and exhibiting approximately linear plasma exposure across the tested doses.