Dosing the first person with srRNA: Advancing a novel technology platform with a strategic development approach

Replicate recently announced initiation of a Phase 1 trial of RBI-4000, a self-replicating RNA (srRNA) vaccine developed to protect humans against the rabies virus. Learn more below about how this milestone supports further advancement of Replicate’s next-generation RNA technology in infectious disease and beyond.

A Meaningful Milestone

Initiation of a clinical trial is a significant milestone for any biotech company. Replicate’s dosing of the first participant in a Phase 1 trial of RBI-4000 for the prevention of rabies brought with it an even more meaningful inflection point: the first time a human has ever been dosed with its next-generation srRNA technology. Replicate is now the first company to advance a next-generation RNA technology into clinical evaluation. Performance in this setting offers data points that provide critical insights that can elevate the next-generation RNA landscape.    

srRNA offers the potential to amplify the impact of in vivo protein expression and unlock new opportunities to treat patients across a broad range of diseases. srRNA vectors encode copy machinery that is produced by the cell to generate many natural mRNA copies of the designated gene. These mRNA copies are subsequently translated into the intended protein, resulting in an enhanced benefit with minimal amounts of synthetic material.

An Approach with Expansive Potential

Existing mRNA approaches are limited by transient protein expression, requiring higher doses to obtain biological activity in humans and resulting in undesirable side effects. srRNA holds the promise of bioactivity at lower doses due to amplification of protein expression within the body. Replicate’s next-generation srRNA toolbox and end-to-end manufacturing infrastructure are poised to advance the capabilities of RNA technology, resulting in enhanced biological activity. This translates into a reduction in dose levels, dosing frequency, and unwanted side effects, expanding RNA treatments into new realms.

For some, this begs the question: with a technology platform that offers transformative potential spanning several disease indications with high unmet medical need, why was rabies identified as an ideal indication for Replicate’s first clinical trial?

Rationale for Rabies

Rabies provides an ideal opportunity to rapidly evaluate critical aspects of srRNA in a clinical setting with both a large exposure-naïve population and established correlates for protection as measured by the World Health Organization.

Further, rabies remains a public health threat in several geographical regions and is designated an NIAID Priority Pathogen. A next-generation rabies vaccine with improved immunogenicity and simplified manufacturing represents an opportunity to establish wider accessibility to rabies prevention worldwide.

In preclinical studies, intramuscular administration of RBI-4000 provided durable protection against the rabies virus, inducing antibody production and robust virus-specific T cells. The ongoing Phase 1 trial will evaluate the safety, tolerability, and immunogenicity of RBI-4000 in healthy participants in the U.S.

Evaluation of RBI-4000 also derisks Replicate’s delivery and manufacturing infrastructure, which are critical components for pipeline advancement. The results of the study will serve as a benchmark of the utility of srRNA in rabies and other infectious diseases.

Future Advancement

Replicate’s development approach builds upon a strong foundation of discovery and preclinical work supporting its srRNA platform, enabling even more thorough vetting of critical aspects of the platform, including protein inserts, vector optimization, delivery technology, and manufacturing processes. Clinical studies provide opportunities to assess the translation of srRNA attributes observed in preclinical models into humans, grounding vast potential with supportive data packages and providing insights that will inform future clinical trials, most notably in complex infectious disease, oncology, and autoimmune diseases.

By design, Replicate’s srRNA platform enables rapid development of vaccine candidates to treat or prevent illness and offers potential to simultaneously target multiple antigens of interest for a complex infectious disease, or multiple strains for highly effective multivalent vaccines. Advancement of RBI-5000, another of Replicate’s srRNA vaccine programs, will provide insights to demonstrate srRNA’s mechanism of action in complex infectious diseases.      

Beyond infectious disease, we are applying the promise of srRNA to  cancer treatment as a targeted immunotherapy.  Resistance mutations remain an ongoing challenge associated with many targeted standard of care (SOC) cancer treatments. Harnessing srRNA provides the opportunity for us to induce synthetic immune lethality in which cancer can either remain the same and be eliminated by the SOC targeted therapy or mutate and be destroyed by srRNA-trained immune cells. Known as Precision Immuno-Oncology (PIO), we are actively advancing this approach to address breast cancer and other solid tumors where existing immunotherapy with checkpoint inhibitors has not provided benefit to patients. Replicate’s most advanced oncology program, RBI-1000, has entered IND-enabling studies. Clinical assessment of this program will evaluate the mechanism of action for srRNA in cancer and provide the first clinical evidence supporting our PIO approach.

As another priority application, srRNA can deliver instructions for in vivo production of therapeutic proteins, providing opportunities to replace protein-based drugs, which can be challenging and costly to synthesize and manufacture. srRNA vectors enable durable expression of therapeutic proteins, naturally extending biological half-life and thereby reducing frequency of dosing. Replicate’s programs in this area of focus will provide additional insight into the durability and therapeutic impact of target proteins encoded by our srRNA vectors.      

Propelled by strong data and rigorous science, we envision a future in which billions of lives around the globe are improved with next-generation RNA therapeutics.