Lilly aims for in vivo autoimmune therapeutics via USD 2.4b acquisition of Orna Therapeutics

Eli Lilly and Co. has unveiled plans to acquire Orna Therapeutics, a Cambridge-based biotech specializing in in vivo engineered cell therapies. The deal, valued at up to USD 2.4 billion in cash and milestone payments, marks a major escalation in Lilly’s push into next-generation genetic medicines.

Under the deal terms, Lilly will provide an upfront cash payment to Orna shareholders, with additional contingent payments tied to clinical and regulatory success. This acquisition follows a series of strategic deals by Lilly aimed at diversifying its pipeline beyond traditional biologics and into “living” medicines that can be manufactured at scale.

circRNA and targeted LNPs

Orna’s proprietary platform leverages circular RNA (circRNA) encapsulated in novel Lipid Nanoparticles (LNPs) to reprogram immune cells directly within the patient’s body. Lead candidate ORN-252 is a clinical-ready, CD19-targeting in vivo CAR-T therapy designed to deplete pathogenic B-cells in patients with severe autoimmune diseases like Lupus.

Unlike linear mRNA, circRNA’s closed-loop structure is inherently resistant to exonucleases (enzymes that break down RNA). This enables more durable protein expression and prolonged therapeutic activity without the need for genomic integration.

Extrahepatic delivery: A primary hurdle in RNA therapy has been “liver sequestration,” where LNPs are filtered out by the liver. Orna’s platform claims a breakthrough in extrahepatic delivery, successfully targeting immune cells in the lymphatic system and bloodstream.

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Industry context

The “Ex Vivo” era of CAR-T—which requires expensive, complex laboratory manufacturing of a patient’s own cells—is facing a challenge from these in vivo “off-the-shelf” alternatives. Key competitors and platforms include:

Eli Lilly (via Orna Therapeutics): Utilizes circRNA + LNP technology. Their lead program targets CD19 for autoimmune reset and is currently clinical-trial ready.

Bristol Myers Squibb (via Orbital Therapeutics): Following a USD 1.5 billion acquisition in October 2025, BMS is advancing OTX-201. Like Orna, this platform uses circRNA delivered via LNPs to target CD19.

AbbVie (via Capstan Therapeutics): Acquired for USD 2.1 billion in mid-2025. AbbVie uses linear mRNA paired with targeted LNPs (tLNPs) to engineer CD8+ T-cells in vivo. Their lead asset, CPTX2309, is currently in Phase 1 trials.

Gilead/Kite (via Interius BioTherapeutics): Acquired for USD 350 million in August 2025. Unlike the LNP-based approaches, Interius uses a lentiviral vector to deliver genetic instructions directly to immune cells.