Revelation Biosciences' Gemini Shows Promise in Phase 1b Trial for Chronic Kidney Disease
Key Insights
Revelation Biosciences' Gemini demonstrated significant reduction in inflammatory activity and restoration of normal cellular response in stage 3 and 4 chronic kidney disease (search) patients during a Phase 1b PRIME clinical study.
The drug successfully corrected immunoparalysis (search) typical of chronic disease, with effects lasting up to one week after a single dose administration.
Gemini was well-tolerated at the target dose with only mild adverse events, while meeting the primary safety endpoint in 40 enrolled patients.
Revelation Biosciences has announced positive top-line results from its Phase 1b PRIME clinical study evaluating Gemini in patients with stage 3 and 4 chronic kidney disease (search) (CKD (search)). The study met its primary safety endpoint while demonstrating significant anti-inflammatory activity that persisted for up to one week following a single dose.
Study Design and Patient Population
The PRIME study enrolled 40 patients aged 32 to 78 years across three US clinics in San Diego and San Antonio specializing in CKD (search) care. The trial utilized a placebo-controlled design with five cohorts of eight patients each (six treated, two placebo) across four dose levels: subtherapeutic, low, target, and high doses. An extension protocol collected additional peripheral blood mononuclear cell (PBMC) and biomarker samples from eight Gemini-naive or secondary-naive patients.
Inflammatory Response Normalization
Gemini significantly reduced inflammatory activity and restored normal cellular response to stimuli as measured in PBMCs isolated from patients at predose, 2, 24, and 168 hours post-dose. The study divided patients into two subgroups based on baseline inflammation levels: those with minimal background inflammation activity (≤40 pg/mL IL-1β (search)) and normal response to stimuli, and those with significant background inflammation activity (>40 pg/mL IL-1β) and no response to stimuli. Approximately 50% of patients fell into each category.
In patients with high background PBMC activity, Gemini significantly reduced inflammation relative to placebo across multiple cytokines: IL-1β (search) (p<0.01), TNF-α (search) (p=0.05), IL-6 (p<0.01), IL-10 (p<0.01), and IL-1RA (p<0.001). These reductions remained significantly below baseline values through seven days and reached levels comparable to PBMCs isolated from healthy subjects.
Correction of Immunoparalysis
Beyond reducing inflammation, Gemini demonstrated the ability to correct immunoparalysis (search) typical of chronic disease. The drug significantly increased responsiveness to lipopolysaccharide (LPS) stimulation in high background patient PBMCs relative to placebo at all timepoints across multiple cytokines: IL-1β (search) (p<0.0001), TNF-α (search) (p<0.002), IL-6 (p<0.0002), IL-10 (p=0.09), and IL-1RA (p<0.01).
Similarly, Gemini significantly increased responsiveness to high mobility group box-1 protein (HMGB1) stimulation in high background patients compared to placebo: IL-1β (search) (p<0.05), TNF-α (search) (p<0.01), IL-6 (p<0.01), IL-10 (p<0.05), and IL-1RA (p<0.002). The increased responsiveness was comparable to PBMCs isolated from healthy subjects, demonstrating Gemini's ability to restore normal cell function even one week after a single dose.
Safety Profile
Gemini administration was well-tolerated at the target dose, with all events reported as mild (Grade I). Adverse events at the target dose included transient headache, chills, loose stool, and body aches. At the highest dose (above the target dose), three adverse events were reported as severe (Grade III): chills, nausea, and vomiting, all resolving within three hours or less.
No serious adverse events were reported. Gemini administration did not result in clinically significant trends in clinical safety blood or urinalysis parameters, aside from expected immune cell mobilization. There were no clinically significant changes in vital sign parameters or ECG assessments following administration.
Expert Commentary
"The activity observed with a single dose of Gemini in patients is shocking," said Principal Investigator Adam Horeish, MD, from Balboa Research (search). "This effect suggests a meaningful step forward in addressing the underlying immune dysregulation observed in patients with chronic kidney disease (search), and I am intrigued by the potential of Gemini to treat multiple types of acute and chronic inflammation."
Principal Investigator Pablo Pergola, MD, PhD, Research Director at Clinical Advancement Center (search), PLLC, described the results as "a possible breakthrough in the treatment of inflammation. By addressing the inflammatory component of CKD (search), we may be able to improve patient outcomes and bring meaningful benefit to those living with this challenging condition."
Julia K. Bohannon, Ph.D., Associate Professor at Vanderbilt University Medical Center, noted that "the clear results from the PRIME study demonstrate the power of Gemini to elicit trained immunity. It is highly validating to see results consistent with the findings from our animal studies, as I would have expected. The strength of the effect of a single dose reinforces my confidence in the potential of Gemini as a promising treatment for burn patients."
Mechanism and Development
Gemini is Revelation Biosciences' proprietary formulation of phosphorylated hexaacyl disaccharide (PHAD®), a toll-like receptor 4 (search) (TLR4 (search)) agonist. TLR4 stimulation with Gemini rebalances the innate immune response and is being developed as a treatment and prevention for acute and chronic diseases associated with dysregulated inflammation.
"The results of the PRIME study demonstrate the potential of Gemini to be a game-changer in the treatment of acute and chronic inflammation," said James Rolke, Chief Executive Officer of Revelation. "We look forward to our scheduled End of Phase 1 meeting with the FDA later this year to discuss the advancement of this exciting program."
The company plans to seek publication of these results and those from ongoing additional data analysis. Revelation Biosciences has multiple ongoing programs evaluating Gemini, including as prevention for post-surgical infection and acute kidney injury, in addition to chronic kidney disease (search) treatment.