Regulus Therapeutics Announces Successful Completion of its Phase 1b Multiple-Ascending Dose (MAD) Clinical Trial of Farabursen (RGLS8429) for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Regulus Therapeutics (Nasdaq: RGLS) reported positive topline results from its Phase 1b Multiple-Ascending Dose clinical trial of farabursen (RGLS8429) for treating Autosomal Dominant Polycystic Kidney Disease (ADPKD). The fourth cohort, involving 26 patients receiving 300mg fixed dose, demonstrated:
- Mean halting of height-adjusted total kidney volume (htTKV) growth over 4 months
- Significant increases in urinary PC1 (p=0.026) and PC2 (p=0.014) levels compared to placebo
- Mean htTKV growth rate of 0.05% vs placebo's 2.58%
An exploratory analysis of high-dose cohorts (n=35) showed statistical significance in htTKV change compared to historical placebo-treated patients (n=550), with treated patients experiencing -0.14% mean reduction vs +1.87% increase in placebo group (p=0.0056). The company plans to initiate a Phase 3 single pivotal trial in Q3 2025.
Regulus Therapeutics (Nasdaq: RGLS) ha riportato risultati positivi dai dati preliminari del suo studio clinico di Fase 1b su dosi multiple ascendenti di farabursen (RGLS8429) per il trattamento della Malattia Policistica Renale Autosomica Dominante (ADPKD). La quarta coorte, che ha coinvolto 26 pazienti in trattamento con una dose fissa di 300mg, ha dimostrato:
- Un arresto medio della crescita del volume totale del rene aggiustato per l'altezza (htTKV) nel corso di 4 mesi
- Aumenti significativi nei livelli urinari di PC1 (p=0.026) e PC2 (p=0.014) rispetto al placebo
- Un tasso medio di crescita dell'htTKV dello 0.05% rispetto al 2.58% del gruppo placebo
Un'analisi esplorativa delle coorti ad alta dose (n=35) ha mostrato una significatività statistica nel cambiamento dell'htTKV rispetto ai pazienti storicamente trattati con placebo (n=550), con i pazienti trattati che hanno registrato una riduzione media dello -0.14% rispetto a un aumento del +1.87% nel gruppo placebo (p=0.0056). L'azienda prevede di avviare un trial pivotale di Fase 3 nel terzo trimestre del 2025.
Regulus Therapeutics (Nasdaq: RGLS) informó sobre resultados positivos de los datos preliminares de su ensayo clínico de Fase 1b de dosis múltiples ascendentes de farabursen (RGLS8429) para el tratamiento de la Enfermedad Renal Poliquística Autosómica Dominante (ADPKD). La cuarta cohorte, que involucró a 26 pacientes que recibieron una dosis fija de 300mg, demostró:
- Un cese medio del crecimiento del volumen total del riñón ajustado por altura (htTKV) durante 4 meses
- Aumentos significativos en los niveles urinarios de PC1 (p=0.026) y PC2 (p=0.014) en comparación con el placebo
- Una tasa media de crecimiento del htTKV del 0.05% frente al 2.58% del grupo placebo
Un análisis exploratorio de las cohortes de alta dosis (n=35) mostró significancia estadística en el cambio del htTKV en comparación con pacientes tratados históricamente con placebo (n=550), con los pacientes tratados experimentando una reducción media del -0.14% frente a un aumento del +1.87% en el grupo placebo (p=0.0056). La empresa planea iniciar un ensayo pivotal de Fase 3 en el tercer trimestre de 2025.
Regulus Therapeutics (Nasdaq: RGLS)는 farabursen (RGLS8429)의 자가우성 다낭성 신장병(ADPKD) 치료를 위한 1b상 다중 상승 용량 임상 시험의 긍정적인 최종 결과를 보고했습니다. 300mg 고정 용량을 투여받은 26명의 환자가 포함된 네 번째 집단은 다음과 같은 결과를 보였습니다:
- 4개월 동안의 신장 총 용적(htTKV) 성장의 평균 정지
- 위약과 비교하여 소변에서 PC1(p=0.026) 및 PC2(p=0.014) 수준의 유의미한 증가
- 위약의 2.58%에 비해 0.05%의 평균 htTKV 성장률
고용량 집단(n=35)에 대한 탐색적 분석에서는 위약 치료를 받은 역사적 환자(n=550)와 비교하여 htTKV 변화에서 통계적 유의성이 나타났습니다. 치료를 받은 환자들은 -0.14%의 평균 감소를 경험했으며, 위약 그룹은 +1.87%의 증가를 보였습니다(p=0.0056). 회사는 2025년 3분기에 3상 단일 주요 시험을 시작할 계획입니다.
Regulus Therapeutics (Nasdaq: RGLS) a rapporté des résultats préliminaires positifs de son essai clinique de Phase 1b sur des doses multiples ascendantes de farabursen (RGLS8429) pour le traitement de la Maladie Polykystique Rénale Autosomique Dominante (ADPKD). La quatrième cohorte, comprenant 26 patients recevant une dose fixe de 300 mg, a montré :
- Un arrêt moyen de la croissance du volume total rénal ajusté à la taille (htTKV) sur 4 mois
- Des augmentations significatives des niveaux urinaires de PC1 (p=0.026) et de PC2 (p=0.014) par rapport au placebo
- Un taux moyen de croissance de l'htTKV de 0.05% contre 2.58% dans le groupe placebo
Une analyse exploratoire des cohortes à forte dose (n=35) a montré une signification statistique dans le changement de htTKV par rapport aux patients traités historiquement avec placebo (n=550), avec des patients traités enregistrant une réduction moyenne de -0.14% contre une augmentation de +1.87% dans le groupe placebo (p=0.0056). L'entreprise prévoit de lancer un essai pivot de Phase 3 au troisième trimestre de 2025.
Regulus Therapeutics (Nasdaq: RGLS) berichtete über positive vorläufige Ergebnisse aus seiner Phase 1b-Studie zu mehrfachen aufsteigenden Dosen von farabursen (RGLS8429) zur Behandlung der autosomal dominanten polyzystischen Nierenerkrankung (ADPKD). Die vierte Kohorte, bestehend aus 26 Patienten, die eine feste Dosis von 300 mg erhielten, zeigte:
- Ein durchschnittliches Stoppen des Wachstums des höhenangepassten Gesamtniervolumens (htTKV) über 4 Monate
- Signifikante Erhöhungen der Urin-PC1 (p=0.026) und PC2 (p=0.014) Werte im Vergleich zur Placebo-Gruppe
- Eine durchschnittliche Wachstumsrate des htTKV von 0.05% im Vergleich zu 2.58% in der Placebo-Gruppe
Eine explorative Analyse der Hochdosis-Kohorten (n=35) zeigte eine statistische Signifikanz in der htTKV-Veränderung im Vergleich zu historisch mit Placebo behandelten Patienten (n=550), wobei die behandelten Patienten einen durchschnittlichen Rückgang von -0.14% im Vergleich zu einem Anstieg von +1.87% in der Placebo-Gruppe erlebten (p=0.0056). Das Unternehmen plant, im dritten Quartal 2025 eine Phase-3-Studie einzuleiten.
- Successful halting of kidney volume growth (htTKV 0.05% vs placebo 2.58%)
- Statistically significant improvement in PC1 and PC2 biomarkers
- FDA alignment on Phase 3 trial design with potential Accelerated Approval pathway
- Strong safety and tolerability profile at 300mg dose
- Statistical significance vs historical placebo data (-0.14% vs +1.87%, p=0.0056)
- Phase 3 trial initiation not until Q3 2025
- treatment period of only 3 months in current trial
- Requires frequent dosing (every other week)
Insights
The Phase 1b MAD trial results for farabursen represent a significant clinical milestone for Regulus. The consistent demonstration of polycystin biomarker impact across multiple cohorts provides robust pharmacodynamic validation of farabursen's mechanism of action. What's particularly impressive is the mean halting of htTKV growth (
The statistical significance achieved when comparing high-dose cohorts to historical controls (p=0.0056) substantially derisks the upcoming Phase 3 trial. This comparison showing actual htTKV reduction (
The confirmation of the 300mg fixed dose achieving optimal kidney exposure streamlines the path forward, eliminating dose-finding uncertainty ahead of pivotal studies. FDA alignment on the Phase 3 design with dual endpoints (12-month htTKV for Accelerated Approval; 24-month eGFR for Full Approval) creates a clear regulatory pathway. For a disease with treatment options, these data suggest farabursen could meaningfully impact ADPKD's natural progression by directly targeting the underlying cystic pathology.
These Phase 1b results significantly enhance Regulus' clinical and commercial prospects. The consistent biomarker data across dose cohorts demonstrates robust target engagement, while the htTKV stabilization data provides compelling evidence of disease-modifying potential after just 3 months of treatment - a remarkably rapid response in ADPKD therapeutics.
The statistical significance achieved in the exploratory analysis comparing high-dose cohorts to historical controls (p=0.0056) substantially derisks the primary efficacy endpoint for the upcoming pivotal trial. This directly addresses one of the key investor concerns about program advancement.
The regulatory strategy is equally impressive - securing FDA alignment on a single pivotal Phase 3 trial with dual endpoints enables a capital-efficient development path with two approval opportunities. The 12-month htTKV endpoint for Accelerated Approval could potentially bring farabursen to market years earlier than traditional approval pathways.
For context, ADPKD affects approximately 140,000 Americans with treatment options. The current standard therapy, tolvaptan, has notable tolerability issues and modest efficacy. If farabursen maintains this efficacy and safety profile in Phase 3, it could capture significant market share in this underserved indication. The Q3 2025 Phase 3 initiation timeline provides a clear development roadmap and near-term catalyst pathway for Regulus.
Positive Topline Data from the Fourth Cohort of Patients
Consistent demonstration of polycystin (PC) biomarker impact confirming 300 mg fixed dose selection to achieve optimal kidney exposure
Patients receiving 300 mg farabursen demonstrated a mean halting of height-adjusted total kidney volume (htTKV) growth over 4 months
Exploratory analysis of patients from high-dose cohorts demonstrates statistical significance in htTKV change compared to a large cohort of historical placebo-treated patients, which meaningfully derisks the 12-month htTKV endpoint in the planned Phase 3 trial
Company on track for initiation of Phase 3 single pivotal trial in third quarter 2025
The Phase 1b MAD study is a double-blind, placebo-controlled trial which evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics (PK/PD) of farabursen in adult patients with ADPKD. The study evaluated farabursen treatment for three months followed by one month of follow up across three weight-based dose levels (1, 2 and 3 mg/kg) and one fixed dose level (300 mg). Primary endpoints were changes in urinary PC1 and PC2, with an exploratory examination of change in htTKV growth rate. PC1 and PC2 are the protein products of the PKD1 and PKD2 genes and their levels have been shown to inversely correlate with disease severity; htTKV has been shown to inversely correlate with kidney function.
In the fourth cohort, 26 subjects received a fixed dose of 300 mg of farabursen every other week for three months. Consistent with the previously announced interim analysis of efficacy data from the first 14 subjects of this fixed-dose cohort, the full cohort of 26 patients demonstrated similar mechanistic response based on urinary PC1 and PC2 levels as well as a mean halting of htTKV growth over the four-month study period.
Cohort 4 data highlights:
- Increases in urinary PC1 and PC2 levels were similar to cohort 3 and reached a similar level of statistical significance compared to placebo (PC1 p=0.026; PC2 p=0.014).
- Mean htTKV growth rate over 4 months was
0.05% (SE -0.86% to +0.92% ) while placebo subjects in the trial experienced a mean growth rate of2.58% (SE +1.09% to +4.10% ). - Changes in htTKV were highly correlated with changes in renal cyst volume, suggesting farabursen directly impacts disease progression by limiting abnormal cyst growth.
- In an exploratory analysis, the combination of patients treated with 3 mg/kg or 300 mg fixed dose farabursen (n=35) were compared to a combined historical control group of placebo-treated patients from prior pivotal ADPKD trials (n=550). Farabursen-treated patients experienced mean reduction in htTKV growth rate (-
0.14% ) compared to a mean increase of (+1.87% ) in placebo-treated patients (p=0.0056). - Farabursen at 300 mg demonstrated a favorable safety and tolerability profile in this study, consistent with earlier cohorts.
"We are pleased that the results of cohort 4 demonstrate a level of mechanistic response, as measured by urinary PC1 and PC2, that indicates maximal anti-miR-17 activity. Along with the observed favorable safety and tolerability profile, these results give us confidence that 300 mg provides optimal target exposure and is the appropriate dose to take forward into Phase 3," said Preston Klassen, M.D., President and Head of Research & Development of Regulus Therapeutics. "Even more encouraging is the repeated demonstration across multiple cohorts in the trial that, on average, growth of the kidney in ADPKD patients is halted after only a relatively short treatment period with farabursen. Based on exploratory analysis of Cohorts 3 & 4, which deliver overlapping drug exposures, we are confident that the htTKV effects seen with farabursen in this trial are clinically meaningful and provide important insight into the probability of success for the 12-month htTKV endpoint in the planned Phase 3 trial."
"With full data from cohort 4 now analyzed, we are pleased with the positive results, in line with our expectations based on previous cohorts. These data suggest that farabursen has the potential to be an important addition to the limited therapeutic options for patients with ADPKD," said Jay Hagan, CEO of Regulus Therapeutics. "I would like to thank all the patients, physicians, and support staff who have been vital to the ongoing development of farabursen. We are excited to move forward with initiation of the pivotal Phase 3 trial later this year."
In January, the Company announced that it held a meeting with
More information about the MAD clinical trial is available at clinicaltrials.gov (NCT05521191).
About ADPKD
Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in the PKD1 or PKD2 genes, is among the most common human monogenic disorders and a leading cause of end-stage renal disease. The disease is characterized by the development of multiple fluid filled cysts primarily in the kidneys, and to a lesser extent in the liver and other organs. Excessive kidney cyst cell proliferation, a central pathological feature, ultimately leads to end-stage renal disease in approximately
About Farabursen (RGLS8429)
Farabursen is a novel, next generation oligonucleotide for the treatment of ADPKD designed to inhibit miR-17 and to preferentially target the kidney. Administration of farabursen has shown clear improvements in kidney function, size, and other measures of disease severity in preclinical models. Regulus announced completion of the Phase 1 SAD study in September 2022. The Phase 1 SAD study demonstrated that farabursen has a favorable safety and PK profile. Farabursen was well-tolerated with no serious adverse events reported and plasma exposure was approximately linear across the four doses tested. In the Phase 1b MAD study, Regulus announced topline data from the first cohort of patients in September 2023, from the second cohort of patients in March 2024, from the third cohort of patients in June 2024, and from the fourth cohort in March 2025. Patients in the fourth cohort received an open-label 300 mg fixed dose of farabursen which was administered every other week for three months. Review of complete safety data from all cohorts demonstrated that farabursen was well tolerated.
About Regulus
Regulus Therapeutics Inc. (Nasdaq: RGLS) is a biopharmaceutical company focused on the discovery and development of innovative medicines targeting microRNAs. Regulus has leveraged its oligonucleotide drug discovery and development expertise to develop a pipeline complemented by a rich intellectual property estate in the microRNA field. Regulus maintains its corporate headquarters in
Forward-Looking Statements
Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements associated with the Company's farabursen (RGLS8429) program, the potential that farabursen may be eligible for an Accelerated Approval pathway, predictions based on and future results and clinical outcomes suggested by the Cohort 4 data, our Phase 3 trial design including whether the selected fixed dose will be efficacious or whether the FDA will ultimately determine its components and the overall design to be acceptable and sufficient to serve as a single pivotal study, planned data announcements and, the timing and future occurrence of other preclinical and clinical activities. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as "confident," "expectations," "on track," "plans," "probability," "potential," "suggest," and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Regulus' current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation: the risk that the approach we are taking to discover and develop drugs is novel and may never lead to marketable products; preliminary or topline results are based on a preliminary analysis of key efficacy and safety data, and such data may change following a more comprehensive review of the data related to the clinical trial and may not be indicative of future results; an Accelerated Approval pathway designation may not be received, or even if it is received, lead to a faster development, regulatory review or approval process, and does not increase the likelihood that farabursen will receive marketing approval; our clinical development strategy may change; the risk that future clinical studies may not be successful; risks related to regulatory review and approval; risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics; and the risk that additional data may be negative. These and other risks are described in additional detail in Regulus' filings with the Securities and Exchange Commission, including under the "Risk Factors" heading of Regulus' most recently filed annual report on Form 10-K or subsequently filed quarterly report on Form 10-Q, available on the Company's website or at www.sec.gov. All forward-looking statements contained in this press release speak only as of the date on which they were made. Regulus undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.
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