Orbital Therapeutics Unveils Preclinical Data for In Vivo Circular RNA CAR-T in Autoimmune Disease

Cambridge, MA July 22, 2025 /Endpoints News/ —  Orbital Therapeutics, a leading circular RNA (circRNA) biotechnology company, has shared its initial preclinical data for a novel in vivo CAR-T cell therapy targeting autoimmune diseases. This marks the first public disclosure of specific pipeline programs from the well-funded startup, which raised $270 million in April 2023 to develop next-generation mRNA technology.

In an interview with Endpoints News ahead of a conference presentation in Boston, CEO Ron Philip revealed that Orbital’s lead program aims to revolutionize CAR-T therapy for autoimmune conditions. Unlike conventional CAR-T approaches that require complex ex vivo cell engineering and chemotherapy preconditioning, Orbital’s method involves a simple infusion of lipid nanoparticles (LNPs) carrying circRNA molecules. These circRNAs are designed to reprogram T cells in vivo to eliminate disease-causing B cells, offering a potential “reset” for autoimmune diseases.

Key Preclinical Findings (Unaudited Data): Orbital’s data, which has not yet been independently vetted, demonstrates significant promise:

• B Cell Depletion in Monkeys: Two infusions of their circRNA therapy, administered a week apart, successfully eliminated B cells in the blood, spleen, and lymph nodes of monkeys across all tested dose levels (0.25, 0.50, and 0.75 mg/kg).
• No Chemotherapy Preconditioning: Crucially, this B cell depletion was achieved without the need for chemotherapy preconditioning, a requirement for currently approved commercial CAR-T cell therapies. This could significantly simplify treatment and reduce patient burden.
• Enhanced T Cell Reprogramming in Mice: The company’s circular RNA molecules demonstrated superior T cell reprogramming efficiency, converting up to 43.3% of T cells in mice, compared to less than 1% with traditional linear mRNA.
• Targeted Depletion: Chief Scientific Officer Gilles Besin emphasized the importance of B cell depletion in the lymph nodes to prevent disease recurrence. The highest dose (0.75 mg/kg) achieved this crucial depletion in the spleen and lymph nodes.

Transformative Potential and Future Plans: Ron Philip highlighted the potential for a “transformative impact” if the therapy can achieve durable effects with just one to three short infusions. Orbital plans to submit its preclinical data to regulators in early 2026 and aims to initiate a clinical trial in the first half of next year for an undisclosed autoimmune condition.

Growing In Vivo CAR-T Landscape: Orbital’s announcement comes amidst a surge of interest in in vivo CAR-T therapies. As of late 2024, over 70 in vivo CAR-T programs, mostly preclinical, were in development, with at least six companies already in clinical trials (predominantly for cancer). Investors like Vineeta Agarwala of Andreessen Horowitz, an Orbital investor, view this as a “holy grail” due to the potential for more accessible, durable therapies.

Competitive Landscape in Circular RNA: Orbital, along with Orna Therapeutics and Sail Biomedicines, represents the leading US startups developing circular RNA therapies. While all three initially had broad ambitions, they have converged on in vivo cell therapies as their immediate focus due to the enhanced stability and potency offered by circular RNA over linear mRNA.

• Orna Therapeutics: Recently presented animal data in May, showing nearly complete B cell depletion in the bone marrow, lymph nodes, and spleen of monkeys at 0.5 and 1.0 mg/kg doses. Orna also plans to begin clinical trials in both cancer and autoimmune disease in 2026.
• Capstan Therapeutics: Notably, Capstan, a competitor utilizing traditional linear mRNA for in vivo CAR-T, was recently acquired by AbbVie for $2.1 billion after initiating its Phase 1 clinical trial.
• Sail Biomedicines: Demonstrated similar B cell depletion in mouse studies, though their clinical trial timeline remains unannounced.

Orbital’s preclinical data positions it as a significant player in the race to develop next-generation in vivo CAR-T therapies, particularly for autoimmune diseases, with the added potential benefits of circular RNA technology.