News
Article
RAG-01 elicits complete responses in NMIBC
Author(s):
Key Takeaways
- RAG-01 demonstrated preliminary anti-tumor activity in BCG-unresponsive NMIBC, with complete responses in some patients and a 66.7% disease-free survival rate in papillary tumors.
- The therapy upregulates the p21 tumor suppressor gene, showing minimal systemic exposure and dose-dependent urine concentration.
"The striking CR rates observed in these early cohorts are highly encouraging, particularly for BCG-unresponsive NMIBC patients who currently have limited treatment options," says Paul D. Anderson, MBBS, FRACS.
RAG-01, a small activating RNA therapeutic, demonstrated preliminary anti-tumor activity and a favorable safety profile in patients with BCG-unresponsive non–muscle invasive bladder cancer (NMIBC), according to data from a phase 1 study (NCT06351904) presented at the European Association of Urology Annual Congress in Madrid, Spain.1
RAG-01 was previously awarded a fast track designation by the FDA in May 2024. The therapy is designed to upregulate the p21 tumor suppressor gene.
The phase 1 study of the therapeutic was conducted using a 3+3 design, with eligible patients receiving RAG-01 at the escalating dose levels of 30 mg, 100 mg, 300 mg, and 600 mg. In total, 9 patients had been enrolled across the first 3 cohorts at the time of data cutoff (December 15, 2024).
Overall, RAG-01 demonstrated preliminary anti-tumor activity in patients enrolled in the 2 lowest dose cohorts (30 mg and 100 mg). Among those with carcinoma in situ (CIS), 2 of 3 evaluable patients achieved a complete response. Further, the disease-free survival among patients with papillary tumors was 66.7% (2/3) at 3 months.
The safety profile was also favorable. There were no dose-limiting toxicities, treatment discontinuations, serious adverse events (AEs), or deaths reported. In total, 88.9% of patients experienced an AE, and 33.3% of patients experienced an AE related to treatment. The majority of treatment-related AEs were grade 1, with the most common being micturition urgency, pollakiuria, urinary tract infection, dyspnea, lethargy, nausea, and decrease appetite (all, 11.1%).
Paul D. Anderson, MBBS, FRACS
Regarding data on pharmacokinetics, presenting author Paul D. Anderson, MBBS, FRACS, explained, “The pharmacokinetics show that there was minimal plasma concentration, so there was negligible systemic exposure. We also showed a dose-dependent urine concentration.”
Specifically, the dose-dependent increases in urine concentration ranged from 83.3 to 1820 µg/mL at 2 hours post-instillation.
Anderson added, “With regard to pharmacodynamics, we were able to demonstrate expression of the p21 protein in a dose-dependent manner. We [also] show that the target had been engaged, and this was shown on immunohistochemistry.”
The dose escalation phase of the trial remains ongoing, with plans to enroll 15 patients across all dose cohorts.2 To be eligible for enrollment, patients need to have pathologically confirmed high-grade (grade 2 or 3) NMIBC, a life expectancy of at least 6 months, an ECOG performance score of 2 or higher, and adequate organ function. Patients enrolled in the trial will receive an induction course of 6 weekly instillations of RAG-01 followed by an efficacy assessment at 12 weeks and 3 weekly maintenance instillations every 12 weeks thereafter.
Following dose escalation, the study will proceed to the dose expansion phase, where patients with be randomly assigned 1:1 to 2 dose levels of RAG-01 based on data from part 1 of the study.
"The striking CR rates observed in these early cohorts are highly encouraging, particularly for BCG-unresponsive NMIBC patients who currently have limited treatment options,” concluded Anderson, an investigator at The Royal Melbourne Hospital in Australia, in a news release on the findings.3 “These results pave the way for further exploration of RAG-01's capabilities in this challenging disease."
REFERENCES
1. Krieger L, Anderson P, Sewak S, et al. First-in-human study of RAG-01, a novel small activating RNA therapeutic in BCG failure Non-Muscle Invasive Bladder Cancer (NMIBC) patients. Presented at: 40th Annual European Association of Urology Congress. Madrid, Spain. March 21-24, 2025. Abstract LB11
2. A study of RAG-01 in patients with non-muscle-invasive bladder cancer (NMIBC) who have failed Bacillus Calmette Guérin (BCG) therapy. ClinicalTrials.gov. Last updated December 2, 2024. Accessed March 26, 2025. https://clinicaltrials.gov/study/NCT06351904
3. Ractigen's RAG-01 shows promising early complete responses in phase I NMIBC trial, data presented at EAU 2025. News release. Ractigen Therapeutics. March 24, 2025. Accessed March 26, 2025. https://www.ractigen.com/ractigens-rag-01-shows-promising-early-complete-responses-in-phase-i-nmibc-trial-data-presented-at-eau-2025/
