farabursen (RGLS8429) / Novartis - LARVOL DELTA

Emerging Therapies in Autosomal Dominant Polycystic Kidney Disease. (PubMed, Kidney360) - "Tolvaptan, a vasopressin V2 receptor antagonist, established cAMP modulation as a disease-modifying strategy but is limited by aquaretic effects and hepatotoxicity risk...Gene-directed therapies aim to restore polycystin dosage, including anti-miR-17 oligonucleotides (e.g., farabursen) and pharmacochaperones that rescue misfolded PC1 and restore trafficking in select PKD1 missense variants (e.g., VX-407)...Metabolic reprogramming is targeted by agents such as metformin, bempedoic acid, GLP-1 receptor agonists, and structured dietary interventions...Collectively, these advances signal a transition toward a layered, mechanism-guided framework in which vasopressin blockade is integrated with metabolic, other signaling, and genotype-specific therapies. As biomarkers and risk stratification tools mature, ADPKD management is poised to become increasingly precise, tolerable, and effective."

Journal • Autosomal Dominant Polycystic Kidney Disease • Gene Therapies • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • IGF1 • MIR17 • PKD1 • PRKD1

The nucleobase guanine at the 3'-terminus of oligonucleotide RGLS4326 drives off-target AMPAR inhibition and CNS toxicity. (PubMed, Nat Commun) - "Designing safe and effective oligonucleotide (ON) therapeutics requires thorough understanding of structural-activity relationship (SAR) with the intended on-target(s) as well as the unintended off-target(s). By replacing the 3'-terminal guanine with adenine, we discover the next-generation anti-miR-17 RGLS8429 that is devoid of off-target AMPAR interaction and CNS toxicity while preserving the potency against the on-target miR-17. Here, we show a way to avoid off-target CNS effects and, more importantly, data that support the clinical development of RGLS8429."

Journal • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • MIR17

Novartis will present new data from 33 abstracts across its Cardiovascular, Renal, and Metabolic (CRM) disease portfolio at the upcoming American Society of Nephrology (ASN) Kidney Week 2025 in Houston, Texas and American Heart Association’s (AHA) Scientific Sessions 2025 in New Orleans, Louisiana, advancing scientific insight into these critical disease areas (Novartis Press Release)

Clinical data • Autosomal Dominant Polycystic Kidney Disease • Cardiovascular • Chronic Kidney Disease • IgA Nephropathy

Farabursen Increases Urinary Polycystin-1 and Polycystin-2 and Reduces Height-Adjusted Total Kidney Volume Growth in Patients with ADPKD (KIDNEY WEEK 2025) - "Out results demonstrate the potential of farabursen as a therapeutic agent for ADPKD. A Phase 3 registrational trial is planned."

Clinical • Late-breaking abstract • Autosomal Dominant Polycystic Kidney Disease • Polycystic Kidney Disease • Renal Disease • MIR17 • PKD1 • PKD2 • PRKD1

A Study of RGLS8429 in Patients With Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P1 | N=68 | Completed | Sponsor: Regulus Therapeutics Inc. | Recruiting ➔ Completed

Trial completion • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

RGLS8429 Increases Urinary PC1 and PC2 and May Reduce Height-Adjusted Total Kidney Volume (htTKV) in Patients with ADPKD (KIDNEY WEEK 2024) - "Results provide clinical proof of dose-responsive RGLS8429 mechanistic activity on PC1 and PC2. Exploratory analysis suggests a reduction of htTKV at 2 and 3 mg/kg doses over a relatively short treatment period. Findings validate miR-17 as a potential therapeutic target for ADPKD."

Clinical • Late-breaking abstract • Autosomal Dominant Polycystic Kidney Disease • Polycystic Kidney Disease • MIR17 • PKD1 • PRKD1

RGLS8429-Mediated miR-17 Inhibition Leads to Acute PKD1/2 De-repression and Ameliorates Preclinical ADPKD (KIDNEY WEEK 2024) - "Thus, our goals were to characterize the next-gen anti-miR-17 drug RGLS8429 and its impact on PKD1/2 and ADPKD. We treated murine and human ADPKD kidney cell lines and mouse models with PBS, control oligo, or RGLS8429 to assess for miR-17 inhibition, PKD1/2 de-repression, and therapeutic efficacy before or after PKD onset and in synergy with tolvaptan. RGLS8429-mediated acute pharmaceutical PKD1/2 de-repression holds the potential for a significant disease-modifying effect in ADPKD. This promising drug is currently being evaluated in Phase 1b ADPKD clinical trials."

Preclinical • Autosomal Dominant Polycystic Kidney Disease • Polycystic Kidney Disease • MIR17 • PKD1 • PRKD1

A Study of RGLS8429 in Patients With Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P1 | N=70 | Recruiting | Sponsor: Regulus Therapeutics Inc. | N=36 ➔ 70 | Trial completion date: Dec 2023 ➔ Jun 2025 | Trial primary completion date: Dec 2023 ➔ Apr 2025

Enrollment change • Trial completion date • Trial primary completion date • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • KIM1

A Study of RGLS8429 in Patients With Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: Regulus Therapeutics Inc.

Trial completion date • Trial primary completion date • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • KIM1

A Study of RGLS8429 in Patients With Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: Regulus Therapeutics Inc. | Phase classification: P1b ➔ P1

Phase classification • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • KIM1

Discovery of Next-Generation Anti-miR-17 Oligonucleotide RGLS8429 for Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) (KIDNEY WEEK 2022) - "Importantly, treatment with the first-generation anti-miR-17 oligonucleotide RGLS4326 (1mg/kg) resulted in a statistically significant increase in urinary exosome PC1 and PC2 levels in patients with ADPKD. As RGLS8429 did not cause off-target binding and inhibition of the AMPA-R, no CNS-related toxicity was observed in single- or repeat-dose toxicity studies in mice and monkeys. Conclusion A Phase 1b clinical trial evaluating RGLS8429 in ADPKD patients is planned for the second-half of 2022."

Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • MIR17 • PKD1 • PRKD1

A Study of RGLS8429 in Healthy Volunteers (clinicaltrials.gov) - P1 | N=36 | Completed | Sponsor: Regulus Therapeutics Inc. | Active, not recruiting ➔ Completed

Trial completion

A Study of RGLS8429 in Healthy Volunteers (clinicaltrials.gov) - P1 | N=36 | Active, not recruiting | Sponsor: Regulus Therapeutics Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed

A Study of RGLS8429 in Patients With Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P1b | N=36 | Recruiting | Sponsor: Regulus Therapeutics Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • KIM1

A Study of RGLS8429 in Patients With Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P1b | N=36 | Not yet recruiting | Sponsor: Regulus Therapeutics Inc.

New P1 trial • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • KIM1

A Study of RGLS8429 in Healthy Volunteers (clinicaltrials.gov) - P1 | N=32 | Recruiting | Sponsor: Regulus Therapeutics Inc.

New P1 trial