Regulus Therapeutics Announces Positive Clinical and Regulatory Updates from its Autosomal Dominant Polycystic Kidney Disease (ADPKD) Program for Farabursen (RGLS8429)

Topline data from an interim analysis of the fourth cohort of its Phase 1b Multiple-Ascending Dose (MAD) clinical trial showed continued mechanistic dose response

Exploratory results of imaging-based biomarkers continued to show reduction in height-adjusted total kidney volume (htTKV) growth rate

Successful End-of-Phase 1 meeting with the U.S. Food and Drug Administration (FDA) with agreement on key components of a Phase 3 single pivotal trial for potential Accelerated Approval

Company to hold conference call at 8:30 a.m. ET today

SAN DIEGO, Jan. 29, 2025 /PRNewswire/ -- Regulus Therapeutics Inc. (NASDAQ:RGLS), a biopharmaceutical company focused on the discovery and development of innovative medicines targeting microRNAs (the "Company" or "Regulus"), today announced positive clinical and regulatory updates from its ADPKD program.  The update includes positive topline results from an interim analysis of the fourth cohort of its Phase 1b Multiple Ascending Dose (MAD) study of farabursen (RGLS8429) for the treatment of ADPKD and an overview on its recent 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 (PK/PD) of farabursen in adult patients with ADPKD. The study is evaluating farabursen treatment across three different weight-based dose levels and one fixed dose level, including measuring changes in urinary polycystins 1 and 2 (PC1 and PC2), htTKV, and overall kidney function. 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.

In the fourth cohort, 26 subjects received a fixed dose of 300 mg of farabursen every other week for three months. An interim analysis of efficacy data from the first 14 subjects of the cohort demonstrated continued evidence of a mechanistic dose response based on urinary PC1 and PC2 levels as well as a notable reduction in htTKV growth rate. In addition, review of complete safety data from all 26 subjects demonstrated farabursen was well tolerated.

Cohort 4 data highlights:

• Effects on polycystin biomarker levels were similar to cohort 3 at 3 mg/kg which is predicted to achieve optimal kidney exposure and resulting miR-17 inhibition
• Exploratory results continue to suggest a notable impact on htTKV growth rate after 3 months of treatment
• htTKV results are consistent across Mayo Imaging Class and PKD1 truncating vs non-truncating mutations
• Exploratory conditional probability analyses suggest high probability of success to meet or exceed targeted htTKV efficacy threshold
• Safety and tolerability profile is encouraging and consistent with earlier cohorts

In December 2024, the Company met with the FDA for an End-of-Phase 1 meeting. Alignment with the FDA was achieved regarding the acceptability of the program's CMC, non-clinical and clinical pharmacology plans and key components of a Phase 3 trial design as a single pivotal study, including:

• 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

"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 farabursen appears to be well tolerated, reinforcing its potential as a safe option in the treatment of ADPKD."

"The results from Cohort 4 are very promising, further validating the impact of farabursen 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," said Alan Yu, M.D., University of Kansas Medical Center. "As Regulus moves into a pivotal study of farabursen, those patients living with ADPKD are one step closer to a potentially safer and more tolerable treatment option."

"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 farabursen in ADPKD," 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."

More information about the MAD clinical trial is available at clinicaltrials.gov (NCT05521191).

Conference Call Information

The Company will host a conference call and live audio webcast on Wednesday, January 29 at 8:30 am Eastern Time. To access the call, please dial (833) 816-1394 (domestic) or (412) 317-0487 (international).  To access the telephone replay of the call, dial (877) 344-7529 (domestic) or (412) 317-0088 (international), passcode ID 1454429.  The webcast and telephone replay will be archived on the Company's website at www.regulusrx.com following the call.

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 50% of ADPKD patients by age 60. Approximately 160,000 individuals are diagnosed with the disease in the United States alone, with an estimated global prevalence of 4 to 7 million.

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 first 14 patients from the fourth cohort in January 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 San Diego, CA.

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 and preclinical pipeline, the potential that farabursen may be eligible for an Accelerated Approval pathway, predictions based on and future results and outcomes suggested by the Cohort 4 data, our Phase 3 trial design including whether the FDA will ultimately determine its components and the overall design to be acceptable and sufficient to serve as a single pivotal study, the advancing of farabursen into a pivotal study later this year, farabursen potentially being a safe and effective treatment option for ADPKD, 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 "anticipates," "believes," "expects," "goal," "intends," "look forward to," "plans," "potential," "predict," "suggest," "will" 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; the risk that preclinical and clinical studies may not be successful; risks related to regulatory review and approval; risks related to our reliance on third-party collaborators and other third parties; risks related to intellectual property; risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics; the risk that additional data may be negative; and risks related to our ability to successfully secure and deploy capital. 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' quarterly report on Form 10-Q for the quarter ended September 30, 2024, 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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