Rise Therapeutics Enrolls Phase 1 Trial of R-5780 in Combination with PD-1 Inhibitor
Phase 1 Trial Enrollment and Design
U.S. private biotech company Rise Therapeutics LLC is enrolling a Phase 1 trial NCT06398418 in the U.S. combining R-5780 with a PD-1 pathway immune checkpoint inhibitor. This open-label, single-arm trial, which began in August 2025, will enroll 33 patients with advanced melanoma, basal cell carcinoma, and squamous cell carcinoma to evaluate single and repeated dosing as well as dose-escalation cohorts. The primary endpoint is safety and tolerability within four weeks post-dosing, while drug exposure, tumor response, blood inflammatory markers, and fecal microbial levels will also be measured to assess clinical activity signals and biological mechanism.
R-5780 Targeting and Differentiation
R-5780 is an oral live biotherapeutic based on Lactococcus lactis engineered to express Secreted Antigen A (SagA), and it is an investigational code name without a commercial brand. The muramyl dipeptide (MDP) generated by SagA activates the innate immune receptor NOD2, inducing dendritic cell maturation and anti-tumor T-cell responses. In a mouse colorectal cancer model, the combination with anti-PD-1 significantly suppressed tumor growth and reduced PD-1, LAG-3, and TIM-3 expression on tumor-infiltrating CD8+ T cells. However, this trial is the first small-scale human safety evaluation, so clinical tumor response data will be needed to assess efficacy.
Regulatory History and Combination Market
The U.S. FDA accepted the Investigational New Drug (IND) application for R-5780 on January 13, 2025, allowing entry into Phase 1, but it is not an approved drug or subject to FDA advisory committee voting. The PD-1 standard-of-care combination includes Merck & Co. (MRK)'s Keytruda (pembrolizumab) and Bristol Myers Squibb (BMY)'s Opdivo (nivolumab), both of which block PD-1 and received FDA approval on September 4, 2014, and December 22, 2014, respectively. The global PD-1/PD-L1 antibody market was approximately USD 53.7 billion in 2024, and if R-5780 can demonstrate expansion of responder patients or overcome acquired resistance, its commercial reach could broaden.
Competitive Landscape and Investment Interpretation
Direct competitors include NuBiyota's 30-strain consortium MET-4, Seres Therapeutics' SER-401, 4D pharma's Enterococcus gallinarum-based MRx0518, and Evelo Biosciences' Bifidobacterium-based EDP1503. SER-401 was discontinued after Phase 1, and MRx0518's solid tumor Phase 1/2 trial was also terminated, indicating challenges in the microbiome combination space in terms of reproducible clinical efficacy and manufacturing consistency beyond early safety. R-5780 differentiates itself through a single, precisely engineered strain and the NOD2-targeting mechanism, offering advantages in manufacturing and mechanistic clarity over multi-strain products. However, the single-arm trial with 33 patients lacks a control group, making interpretation of objective response rates and duration limited.
From an investment perspective, R-5780 is a Phase 1 asset that could enter the USD 53.7 billion PD-1/PD-L1 market in 2024 as an oral adjunct therapy, but its current value is concentrated in the human biological validation of the 33-patient safety and dose-escalation trial. Short-term catalysts include the planned interim data release in April 2027, covering safety, fecal strain detection, inflammatory markers, and tumor response. For researchers, this trial represents the first validation of whether the SagA-MDP-NOD2 axis can link to dendritic cell activation and reduced T-cell exhaustion in humans. For the industry, it serves as a case study following the discontinuation of SER-401 and MRx0518, exploring whether single-engineered strain approaches can overcome the efficacy and manufacturing challenges of complex microbiome products. Long-term enterprise value will depend on reproducible objective responses in Keytruda/pembrolizumab or Opdivo/nivolumab-resistant patients and the ability to advance into subsequent controlled trials.
Source: ClinicalTrials.gov (api_ct)