Paradigm Shift in Ex Vivo Therapies Following Casgevy Approval

In December 2023, the approval of Casgevy (exagamglogene autotemcel) by Vertex Pharmaceuticals and CRISPR Therapeutics, the first CRISPR/Cas9 gene editing therapy, ushered in a new era in the treatment of Sickle Cell Disease (SCD). However, Casgevy and its competitor, Lyfgenia (lovotibeglogene autotemcel) from bluebird bio, are ex vivo therapies that involve collecting and correcting a patient's stem cells outside the body, which has been criticized for its high cost of $2.2 million and complex infrastructure requirements. Consequently, in 2026, the biopharmaceutical industry is focusing on developing next-generation therapies that not only improve efficacy but also maximize treatment convenience and scalability.

Evolution of Base Editing and In Vivo Delivery Technologies

Beam Therapeutics is conducting a Phase 1/2 trial of risto-cel (BEAM-101), which utilizes base editing technology to precisely correct single bases without double-strand breaks, and aims to submit an application for approval by the end of 2026. This approach has achieved a fetal hemoglobin (HbF) production efficiency of over 60%, while reducing the risk of genome damage associated with conventional CRISPR technology. Meanwhile, companies such as Ensoma and Orna Therapeutics are pursuing the development of in vivo gene therapies that bypass the complex ex vivo correction process and directly deliver gene therapy materials into the body, aiming to significantly improve market accessibility. Notably, Orna entered into a co-development partnership with Vertex in January 2025, with a total value of $700 million, to jointly develop next-generation in vivo therapies based on lipid nanoparticle (LNP) technology.

Next-Generation Approaches Through Oral Drugs and Metabolic Regulation

In addition to gene editing, there is intense competition in the development of oral therapies that can be taken daily by patients, maximizing treatment convenience. Agios Pharmaceuticals, based on Phase 3 trial results of mitapivat (Pyrukynd), an activator of pyruvate kinase (PK) that enhances red blood cell metabolism, submitted a supplemental new drug application (sNDA) to the FDA in May 2026. Furthermore, Fulcrum Therapeutics has demonstrated significant improvements in hemoglobin levels in a Phase 1b trial of pociredir, an oral small molecule therapy that inhibits EED, a key component of the PRC2 complex, to induce fetal hemoglobin expression. These oral drugs, compared to expensive cell therapies, offer the potential for immediate prescription and large-scale production, which is expected to help alleviate global healthcare disparities and expand the paradigm of overall red blood cell biology.

New Scalability in Cultured Red Blood Cells and Cell Engineering

Furthermore, innovation continues in the field of artificial red blood cells, which involves mass-producing standardized cells in the laboratory, rather than relying solely on a patient's own stem cells. Safi Biotherapeutics completed the transfer of technology for a 10-liter scale manufactured red blood cell (mRBC) production system in January 2026, establishing a standardized blood supply chain for patients who require chronic transfusions. Additionally, Scarlet Therapeutics is developing a platform that delivers therapeutic proteins through engineered red blood cells, enabling long-term circulation of the therapy in the body without immune rejection, and secured a £3.2 million seed investment in May 2026. These advances in cell engineering technology can reduce the risk of alloimmunization in transfusion-dependent patients and provide a long-term treatment option in areas with poor medical infrastructure.