Therorna's TI-0032, a Circular RNA-Based In Vivo CAR-T Therapy, Enters Phase 1 Clinical Trial
TI-0032: Expanding the Potential of Circular RNA for In Vivo CAR-T Therapy
Therorna Inc., a China-based biopharmaceutical company, has initiated a Phase 1 clinical trial (NCT07413341) of TI-0032-III, an investigational therapy that utilizes circular RNA to deliver CD19-targeted CAR (chimeric antigen receptor) T cells directly within the patient's body. Unlike conventional ex vivo CAR-T therapies, which involve extracting, genetically modifying, and culturing a patient's T cells, TI-0032-III aims to transiently generate CD19 CAR-T cells in vivo. The use of circular RNA is intended to enhance intracellular stability and prolong protein expression compared to linear mRNA. Furthermore, the non-viral delivery system offers the potential for repeated administration while mitigating the risk of permanent genetic integration.
Phase 1 Trial to Evaluate Safety and Immunomodulatory Effects
The Phase 1 trial of TI-0032-III will evaluate patients with relapsed or refractory autoimmune diseases. The study includes patients with moderate to severe active systemic lupus erythematosus (SLE) and progressive systemic sclerosis. The primary objectives are to assess the safety and tolerability of TI-0032-III, as well as to evaluate the levels of circular RNA in peripheral blood and the dynamics of B-cell depletion and reconstitution. A key hypothesis is that TI-0032-III will selectively eliminate CD19-positive pathogenic B cells, leading to the reconstitution of a normal B-cell repertoire and immune rebalancing. However, the efficacy, durability of response, and potential for cytokine release syndrome (CRS) will need to be evaluated in clinical trials. Current standard-of-care treatments for these conditions include corticosteroids, immunosuppressants, Benlysta (belimumab), a BLyS-targeting therapy from GSK, and Saphnelo (anifrolumab), an anti-Type I interferon receptor antibody from AstraZeneca.
Advancing China's Circular RNA Pipeline
Therorna's TI-0093 is another investigational therapy based on circular RNA technology. It is a therapeutic vaccine targeting HPV16 E6 and E7 antigens and is currently being evaluated in a Phase 1 clinical trial (NCT07081984) in patients with recurrent or metastatic HPV16-positive solid tumors. The National Medical Products Administration (NMPA) of China, through its Center for Drug Evaluation (CDE), accepted the IND application for TI-0093 on June 6, 2025. The planned clinical trial involves a dose-escalation design with five intramuscular injections. This program differs from prophylactic HPV vaccines, such as Gardasil 9, by targeting established HPV16-positive cancers. It may be used as a standalone therapy or in combination with standard treatments, such as surgery, radiation therapy, platinum-based chemotherapy, and Keytruda (pembrolizumab), a PD-1 inhibitor from Merck.
With the addition of a Phase 1 clinical trial for its COVID-19 vaccine, TI-0010, Therorna has expanded the application of its platform technology to include infectious diseases, cancer vaccines, and autoimmune diseases.
Funding and Competitive Landscape Drive Corporate Value
Therorna raised USD 42 million in a Series A equity financing round in 2022, bringing its total funding to over USD 60 million. A key benchmark for circular RNA deals is the 2022 agreement between Merck and Orna Therapeutics, which included an upfront payment of USD 150 million, potential development, regulatory, and commercial milestone payments of up to USD 3.5 billion, a separate equity investment of USD 100 million, and royalties on product sales. However, TI-0032 faces direct competition from Capstan Therapeutics' CPTX2309, a CD19-targeted mRNA-tLNP therapy in Phase 1 development. In China, MagicRNA Biotechnology's HN2301 is also in clinical development for SLE. While the global market for SLE treatments is projected to reach USD 2.61 billion in 2025, the early stage of clinical development means that key variables for technology transfer value include per-patient CAR expression levels, the duration of B-cell depletion, and the safety profile of repeated administration.
The initiation of the Phase 1 clinical trial for TI-0032-III represents a significant milestone for Therorna, demonstrating the clinical validation of its circular RNA platform for in vivo CAR-T therapy. In the USD 2.61 billion SLE treatment market projected for 2025, where Benlysta and Saphnelo are primarily used for long-term treatment, TI-0032 offers a strategy to reduce manufacturing and logistical burdens through in vivo immune rebalancing. Capstan Therapeutics' CPTX2309, also in Phase 1 development, is a direct competitor, and the leading therapy will be determined by safety, depth of B-cell depletion, and duration of response data. The USD 150 million upfront payment and up to USD 3.5 billion in milestone payments in the Merck-Orna deal highlight the strategic value of circular RNA platforms. In the short term, initial safety data from the trial will influence partnership negotiations, and in the long term, if repeated administration and large-scale production are proven, it could disrupt the cost structure of ex vivo CAR-T therapies.