Results provide clinical demonstration of best-in-class immunogenicity achieved with an RNA-based platform and good tolerability
RBI-4000's potential to offer a meaningful improvement over existing vaccines for rabies, an ongoing global public health concern, supports further development
SAN DIEGO, Feb. 7, 2025 -- Replicate Bioscience, a clinical-stage company pioneering novel self-replicating RNA (srRNA) technology for applications across infectious disease, immunology, and other therapeutic areas, today announced that data from the Phase I study of its srRNA-based rabies vaccine candidate, RBI-4000, have been published in Nature Communications.
The article, "Safety and immunogenicity of an optimized self-replicating RNA platform for low dose or single dose vaccine applications: a randomized, open label Phase I study in healthy volunteers," includes full data from the company's rabies vaccine candidate, RBI-4000. The data reinforce interim Phase I results presented last year at the 2024 American Society of Gene & Cell Therapy (ASGCT) Annual Meeting, which demonstrated class-leading safety and immunogenicity for Replicate's optimized srRNA platform.
The Phase I study showed that a single dose of RBI-4000 elicited immune responses that attained a World Health Organization (WHO)-established immune threshold of protection against rabies across all dose levels tested, with good tolerability. No serious adverse events, dose-limiting toxicities, or maximum tolerated dose level were observed in the study.
"These clinical results position RBI-4000 as a promising alternative capable of inducing rabies protective immunity at unprecedentedly low doses and with a single dose," said Parinaz Aliahmad, Ph.D., Head of Research and Development at Replicate. "Furthermore, the data showcase RBI-4000's favorable safety profile, which we attribute to our optimized and scalable manufacturing processes. We are encouraged by the strength of the robust clinical data package supporting continued development of RBI-4000 and look forward to advancing it into further clinical studies."
"The RBI-4000 Phase I data demonstrate compelling immunogenicity and a broad therapeutic index for Replicate's srRNA platform," said Phil Dormitzer, M.D., Ph.D., Founder and President, Dormitzer Biologics LLC and former Chief Scientific Officer for Viral and RNA Vaccines at Pfizer. "The vaccine candidate's high potency and the boostable immunity elicited by well tolerated dose levels suggest the potential utility of Replicate's srRNAs to prevent complex infectious diseases, for which targeting of multiple antigens may be needed."
About the Phase I trial of RBI-4000
The Phase I randomized, open label clinical trial study (NCT06048770) enrolled 89 healthy volunteers, age 18-45 years. Safety and immunogenicity of RBI-4000 was evaluated across three dose levels including 0.1, 1, and 10 micrograms (mcg) in a prime-boost regimen, along with a prime only (10 mcg) cohort to assess single dose feasibility. RabAvert, an approved inactivated virus vaccine, was included as an active comparator arm.
All dose levels of RBI-4000 tested, including those as low as 0.1 mcg, elicited de novo protective immune responses, with the majority of participants across all dose cohorts achieving the WHO-established threshold of a protective rabies neutralizing antibody response when administered in a prime-boost schedule. Results from the study also suggest single dose efficacy – 89 to 94% of participants who received a single 10 mcg dose of RBI-4000 achieved or surpassed the WHO serological metric for protection.
Additional key takeaways from the study
- The therapeutic index of RBI-4000 exceeded 100-fold as demonstrated by clinical bioactivity at the lowest dose level tested (0.1 mcg) coupled with a lack of dose-limiting toxicities at the highest dose level tested (10 mcg). In contrast, linear mRNA and first-generation srRNA have demonstrated therapeutic indices that range from 1-10-fold.
- RBI-4000 elicited immune responses that were equivalent to those elicited by a gold standard licensed vaccine, RabAvert, administered by the standard dosing schedule.
- Further preclinical analyses demonstrated superior bioactivity of Replicate's optimized srRNA, exemplified by higher protein production and robust elicited immune responses at dose levels as much as 1,000,000-fold lower than that reported for linear, nucleoside-modified mRNA.
About Rabies
Endemic in over 150 countries, rabies is a deadly disease with a 99% mortality rate if left untreated, causing 59,000 deaths annually. Deaths due to rabies are fully preventable if exposed individuals receive an effective vaccine before the virus spreads to the central nervous system and clinical symptoms appear. Rabies is most frequently addressed through post-exposure prophylaxis including a course of human rabies vaccine. Although effective, current rabies vaccines require 3 to 5 doses and are subject to supply shortages due to complicated manufacturing processes, limiting accessibility and increasing complexity of administration in resource-limited settings. Rabies is included in WHO's 2021-2030 Roadmap for the global control of neglected tropical disease. And as part of the 21st Century Cures Act, the U.S. Food and Drug Administration (FDA) included rabies in its Tropical Disease Priority Review Voucher Program List.
About Replicate Bioscience
Replicate Bioscience is a clinical-stage company amplifying the power of RNA therapeutics by pioneering its novel self-replicating RNA (srRNA) technology to overcome the shortcomings of existing mRNA approaches, with potential improvements in bioactivity, induction of more potent immune responses, and improved therapeutic index. RBI-4000, the company's clinical-stage srRNA rabies vaccine, has demonstrated protective levels of immunity at doses lower than any other reported mRNA or srRNA vaccine in Phase I trials. Funded by Apple Tree Partners, Replicate is advancing a robust pipeline of srRNA vaccines and therapeutics, fueled by its proprietary library of customizable viral vectors. With deep expertise in srRNA and end-to-end development capabilities, Replicate is uniquely positioned to expand the reach of RNA treatments toward widespread use in infectious disease, immunology, immuno-oncology and more. Visit us at www.replicatebioscience.com.
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