RGLS4326 / Bio-Techne, Novartis - LARVOL DELTA

From Laboratory to Clinic: Translational Challenges, Lessons, and Future Strategies for microRNA Delivery Systems. (PubMed, Curr Drug Deliv) - "This review critically evaluates representative clinical and advanced translational programs, including Miravirsen, MRX34, Cobomarsen, Remlarsen, RGLS4326, and farabursen (RGLS8429), to compare molecular designs, delivery approaches, development outcomes, and translational bottlenecks. Drawing on these lessons, we propose a Four-Pillar Framework integrating Delivery Systems, Immune Safety, CMC and Manufacturing Readiness, and biomarker-guided Clinical Design. Together, these principles support coordinated optimization across biological, pharmaceutical, and clinical dimensions rather than isolated improvement of individual delivery parameters."

Journal

Pharmacokinetics, Safety, and Tolerability of Anti-miR-17 Oligonucleotide RGLS4326 in Healthy Adult Subjects. (PubMed, J Clin Pharmacol) - "The mean dose excreted in the urine for the 0.1 and 0.3 mg/kg doses was 35.2% to 39.3% compared to 46.5% to 48.1% for the 1.0 mg/kg dose. RGLS4326 was generally well tolerated, and no dose limiting treatment emergent adverse events were observed."

Clinical • Journal • PK/PD data • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • MIR17

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

CARACTERIZACIÓN CLÍNICA Y EPIDEMIOLÓGICA DE LA ENFERMEDAD RENAL POLIQUÍSTICA EN PACIENTES ATENDIDOS EN UN CENTRO DE REFERENCIA DE CUARTO NIVEL DEL CARIBE COLOMBIANO DURANTE EL PERIODO 2008-2022 (ISN-WCN 2024) - "Los pacientes que presentan una progresión rápida de esta patología se benefician del antagonista del receptor V2 de la vasopresina Tolvaptan, único aprobado hasta el momento por la FDA (34)(35). Se encuentran en investigación moléculas como lixivaptan, venglustat, bardoxolona, tesevatinib, RGLS4326 (oligonucleótido inhibidor de microARN miR-17), GLPG2737 (corrector regulador de conductancia transmembrana de fibrosis quística), los cuales han venido demostrando efectos benéficos potenciales (36)(37)(38)(39). Otros medicamentos como everolimus ha evitado la progresión del volumen renal, pero no evitó la progresión de la enfermedad (40)... La ERP es una patología sistémica de relevancia importante debido al gran impacto que puede producir al deteriorar la salud de la persona comprometida, puede cursar desde estados asintomáticos a casos donde la función renal esta severamente deteriorada y por..."

Fibrosis • Gastroenterology • Gastrointestinal Disorder • Immunology • Oncology • MIR17 • PKD1 • PRKD1

Pharmacokinetics and Absorption, Distribution, Metabolism and Excretion of RGLS4326 in Mouse and Monkey, an anti-miR-17 Oligonucleotide for the Treatment of Polycystic Kidney Disease. (PubMed, Drug Metab Dispos) - "Subcutaneous administration results in preferential exposure of RGLS4326 to the intended target organ (kidney) to drive maximum target engagement. These studies support the interpretation of toxicology and efficacy studies and help characterize the disposition of RGLS4326 in humans."

Journal • PK/PD data • Preclinical • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • MIR17

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

Discovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease. (PubMed, Nat Commun) - "Importantly, RGLS4326 demonstrates a favorable preclinical safety profile and attenuates cyst growth in human in vitro ADPKD models and multiple PKD mouse models after subcutaneous administration. The preclinical characteristics of RGLS4326 support its clinical development as a disease-modifying treatment for ADPKD."

Journal • Preclinical

A Study of RGLS4326 in Patients With Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P1b; N=19; Completed; Sponsor: Regulus Therapeutics Inc.; Active, not recruiting ➔ Completed

Clinical • Trial completion • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • KIM1 • LCN2 • MRI

A Study of RGLS4326 in Patients With Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P1b; N=27; Active, not recruiting; Sponsor: Regulus Therapeutics Inc.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • KIM1 • LCN2 • MRI

[VIRTUAL] RGLS4326 Increases Urinary PC1 and PC2 Levels in Individuals with Autosomal Dominant Polycystic Kidney Disease (ADPKD) (KIDNEY WEEK 2021) - "Conclusion These data provide clinical proof that RGLS4326 delivers to cystic kidneys of individuals with ADPKD, where it inhibits miR-17 and thereby derepresses PC1 and PC2. The results also imply ongoing miR-17-mediated repression of Pkd1 and Pkd2 in humans, further validating miR-17 as a therapeutic target for ADPKD treatment."

Clinical • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • KIM1 • LCN2 • MIR17 • PRKD1

Regulus Therapeutics Announces Completion of Enrollment in First Cohort of Phase 1b Clinical Trial of RGLS4326 for the Treatment of Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) (PRNewswire) - "Regulus Therapeutics...today announced it has completed enrollment of the first cohort of patients into its Phase 1b clinical study of RGLS4326....Concurrent with completion of enrollment in the first cohort and based on the review of the available interim safety data, the first patient of the second cohort has received the first dose of RGLS4326....Results from the first cohort are expected to be available early in the second quarter of this year."

Enrollment status • P1 data • Autosomal Dominant Polycystic Kidney Disease

Regulus Therapeutics Announces Closing of $19.4 Million Private Placement of Equity (PRNewswire) - "Regulus Therapeutics Inc....today announced the closing of its previously announced private placement of equity. The Company received gross proceeds of approximately $19.4 million...The Company expects to use the net proceeds from the transaction primarily to advance RGLS4326 for the treatment of Autosomal Dominant Polycystic Kidney Disease and for general corporate purposes."

Financing • Autosomal Dominant Polycystic Kidney Disease

Regulus Therapeutics Collaborates With Bio-Techne For Biomarker Development (PRNewswire) - "Bio-Techne Corporation...and Regulus Therapeutics...announced a collaboration to support Regulus with biomarker analysis for the clinical development of RGLS4326, an Autosomal Dominant Polycystic Kidney Disease (ADPKD) treatment....The Phase 1b trial is an adaptive design, open-label, multiple dose study in up to three cohorts of patients with ADPKD....This study is designed to assess whether different dose levels of RGLS4326 can increase levels of PC1 and PC2 in ADPKD patients. Regulus has elected to collaborate with Bio-Techne for the development of high-performance biomarker assays to support the assessment of PC1 and PC2 levels using the fully automated Simple Western instrument as a read-out."

Licensing / partnership • Autosomal Dominant Polycystic Kidney Disease

Regulus Therapeutics Announces First Patient Dosed in Phase 1b Clinical Trial of RGLS4326 for the Treatment of Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) (PRNewswire) - "Regulus Therapeutics Inc....today announced initiation of dosing in its Phase 1b clinical study of RGLS4326 in patients with ADPKD....The first cohort is expected to enroll up to nine patients who will receive RGLS4326 every two weeks over a six week period. The Company anticipates availability of results from the first cohort by the end of Q1 2021."

Enrollment status • P1 data • Trial status • Autosomal Dominant Polycystic Kidney Disease

A Study of RGLS4326 in Patients With Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P1b; N=27; Recruiting; Sponsor: Regulus Therapeutics Inc.; Not yet recruiting ➔ Recruiting

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

A Study of RGLS4326 in Patients With Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P1b; N=27; Not yet recruiting; Sponsor: Regulus Therapeutics Inc.

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

Regulus Therapeutics Announces FDA Orphan Drug Designation of RGLS4326 for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) (PRNewswire) - "Regulus Therapeutics Inc....today announced that the U.S. Food and Drug Administration ('FDA') has granted Orphan Drug Designation to RGLS4326 for the treatment of patients with ADPKD."

Orphan drug • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Polycystic Kidney Disease

Regulus Therapeutics Completes Dosing in Phase 1 Multiple Ascending Dose Study of RGLS4326 in Healthy Volunteers for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) (PRNewswire) - "Regulus Therapeutics Inc....today announced the completion of dosing for the Phase 1 multiple ascending dose ('MAD') clinical study for RGLS4326 in healthy volunteers....'RGLS4326 was well-tolerated with no serious adverse events reported. We plan to initiate a Phase 1b short-term dosing study in patients with ADPKD to further evaluate RGLS4326 for safety, pharmacokinetics, and the ability to improve biomarkers of the disease.'"

New P1 trial • Trial status • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Polycystic Kidney Disease

Regulus Therapeutics reports first quarter 2020 financial results and recent updates (PRNewswire) - "Initiated Dosing of the Third and Final Cohort in RGLS4326 Phase 1 for ADPKD: In April 2020, the Company initiated dosing of the third and final cohort of the MAD clinical study of RGLS4326, a novel oligonucleotide designed to inhibit miR-17 for the treatment of ADPKD."

Trial status • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Polycystic Kidney Disease

Regulus Therapeutics reinitiates multiple ascending dose study of RGLS4326 for the treatment of ADPKD (PRNewswire) - "Regulus Therapeutics Inc....today announced that it initiated dosing of the second cohort of its Phase 1 multiple ascending dose clinical trial (the 'MAD study') of RGLS4326 for the treatment of autosomal dominant polycystic kidney disease (ADPKD). The Company expects to complete this study in mid-2020 with topline results available thereafter. The Company is also planning to initiate a Phase 1b short-term dosing study in patients with ADPKD in the second half of 2020..."

New P1 trial • P1 data • Trial completion • Trial status

Regulus Therapeutics announces FDA removal of partial clinical hold for multiple ascending dose study of RGLS4326 (Regulus Therapeutics Press Release) - "Regulus Therapeutics...today announced the U.S. Food and Drug Administration ('FDA') has lifted the Partial Clinical Hold on the Company's Phase 1 multiple ascending dose clinical study of RGLS4326 for the treatment of autosomal dominant polycystic kidney disease...The Company plans to recommence the MAD study in the first quarter of 2020. With the Partial Clinical Hold on the MAD study lifted, the Company is also planning to enroll patients with ADPKD in an additional short-term dosing study in the second half of 2020 to evaluate RGLS4326 for safety, pharmacokinetics, and biomarkers of pharmacodynamic activity as part of its comprehensive Phase 1b program."

FDA event • New P1 trial • Trial status

Regulus Therapeutics to present at the Stifel Healthcare Conference (PRNewswire) - "Regulus Therapeutics...today announced that Jay Hagan, President and Chief Executive Officer of Regulus, will present a company overview at the Stifel Healthcare Conference in New York City on Wednesday, November 20, 2019. The company overview will include an update on RGLS4326 for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) and the Company's recent submission to FDA in response to the Partial Clinical Hold."

Clinical

Regulus Therapeutics reports third quarter 2019 financial results and recent updates (PRNewswire) - "R&D expenses were $2.4 million and $10.3 million for the three and nine months ended September 30, 2019...The decreases were driven by decreases in external development expenses, primarily attributable to the voluntary pause of the RGLS4326 Phase 1 MAD clinical study in the third quarter of 2018..."

Commercial

Regulus Therapeutics presents preclinical data identifying RGLS4326 as a potential disease-modifying treatment for autosomal dominant polycystic kidney disease at OTS Annual Meeting (PRNewswire) - "Regulus Therapeutics Inc...announced that it presented preclinical data that identifies RGLS4326, a first-in-class anti-miR-17 oligonucleotide, as a potential disease-modifying treatment for autosomal dominant polycystic kidney disease (ADPKD) at the Oligonucleotide Therapeutics Society (OTS) Annual Meeting held October 13-16, 2019 in Munich, Germany."

Preclinical

Regulus Therapeutics announces publication in Nature Communications identifying RGLS4326 as a potential promising treatment for ADPKD (PRNewswire) - "Regulus Therapeutics...today announced that Nature Communications has published an article entitled, 'Discovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease.' The article highlights preclinical research that identifies RGLS4326...for autosomal dominant polycystic kidney disease (ADPKD)..."

Preclinical