Regulus Therapeutics (RGLS) Study Update summary

Study design and objectives

• Phase 1b multiple ascending-dose, double-blind, placebo-controlled trial of RGLS8429 in adults with ADPKD, evaluating three weight-based cohorts (1, 2, 3 mg/kg) and a fourth fixed-dose cohort (300 mg) underway.

• Primary objectives: safety, tolerability, pharmacokinetics, and mechanistic activity via urinary polycystin; exploratory endpoints include kidney volume changes by MRI and novel imaging markers.

• Patients enrolled had moderate to severe disease, with inclusion based on Mayo Imaging Classification, reduced eGFR (30–90 mL/min), and large kidney volumes.

• Each cohort received seven subcutaneous doses over 12 weeks, with biomarker and imaging follow-up; third cohort received 3 mg/kg every two weeks.

• The study is designed to support dose selection and design for pivotal Phase 2/3 trials targeting accelerated approval.

Key results and findings

• RGLS8429 at 3 mg/kg was well tolerated, with no serious safety concerns; most adverse events were mild injection site reactions.

• Statistically significant, dose-dependent increases in urinary polycystin (PC1 and PC2) observed at 3 mg/kg compared to placebo, with the most consistent response at this dose.

• 70% of patients at 3 mg/kg showed reductions in height-adjusted total kidney volume (htTKV) after three months, with reductions ranging from 2.5% to 6%.

• Exploratory analyses suggest a correlation between increased polycystin and reductions in kidney and cyst volume, as well as potential improvements in eGFR.

• No significant changes in eGFR were observed over the short treatment period, as expected.

Mechanism of action and disease context

• RGLS8429 is an antisense oligonucleotide targeting miR-17, a microRNA upregulated in ADPKD that represses polycystin production and disrupts gene networks.

• Blocking miR-17 restores gene expression balance, increases polycystin, and reduces cystogenesis in preclinical models.

• ADPKD is a severe, hereditary kidney disease with high unmet need; current therapy (tolvaptan) slows but does not halt disease progression and has safety limitations.

• RGLS8429 is a next-generation oligonucleotide designed to preferentially target the kidney and has shown favorable safety and PK in prior studies.

• The mechanism is expected to be effective across genotypes due to miR-17's central role in disease biology.