MNC Exodus from AAV Gene Therapy: Clinical Failures and Strategic Retreats Reshape the Landscape

Recently, Johnson & Johnson's highly anticipated bota-vec therapy stumbled in its Phase III clinical trial, causing a significant setback on the high-profile stage of AAV gene therapy.

1.Phase III Clinical Trial Failure

Recently, Johnson & Johnson, which has been making significant progress in the gene therapy field, encountered a major setback. Its highly anticipated AAV gene therapy, bota-vec, failed to meet the primary endpoint of improving patients' visual navigation abilities in the Phase III LUMEOS study for the treatment of X-linked retinitis pigmentosa (XLRP).This outcome not only casts uncertainty over the future of this once highly anticipated therapy, which had received both FDA Fast Track and Orphan Drug designations, but also sounds a warning bell for the field of gene therapy.

As a potential first-in-class gene therapy for XLRP, bota-vec uses an adeno-associated virus vector to deliver the retinitis pigmentosa GTPase regulator (RPGR) gene, aiming to repair the genetic defect that causes the disease. XLRP, a rare hereditary eye disease that primarily affects male children, is characterized by progressive photoreceptor degeneration, ultimately leading to complete blindness. Currently, there are hundreds of thousands of patients worldwide in urgent need of effective treatment, and the clinical setback of bota-vec has left this group once again in a therapeutic predicament.

Looking back at the development process of this therapy, the strategic cooperation between Johnson & Johnson and MeiraGTx was once regarded as an industry model. In late December 2023, Johnson & Johnson spent a whopping $415 million to acquire the global rights to bota-vec, including a $65 million upfront payment. However, after the Phase III clinical data was released, MeiraGTx's stock price plummeted by 11.03%, leading to a reevaluation of the value of this "win-win" deal.

The LUMEOS III study enrolled a total of 95 patients (including a small number of female patients), of which 58 received either a low or high dose of bota-vec. In the pooled analysis of all patients treated with bota-vec, the primary endpoint of improved ability to navigate a virtual maze visually was not met as expected. However, positive trends were observed in secondary endpoints such as retinal sensitivity, suggesting potential target efficacy of the therapy.Johnson & Johnson is currently analyzing all the data while evaluating strategic options and subsequent plans.

2. MNCs Are Exiting One After Another

Gene therapy was once hailed as "the future of medicine," but reality has proven far more challenging than the ideal. In recent years, the wave of exits by major multinational corporations (MNCs) from the AAV gene therapy field has drawn significant industry attention.

May 2021,BiogenGene Therapy XIRIUS for XLRP Fails in Phase II/III Trial; Despite RPGR Gene Delivery via AAV8 Vector to Repair Mutation, No Significant Improvement in Patient Vision Observed, Impacting Strategic Layout Post-Acquisition of Nightstar Therapeutics.

Coincidentally,TakedaAlso terminated the AAV gene therapy collaboration with JCR Pharmaceuticals in 2023, cut 18 early-stage pipelines, and shifted resources to core areas such as oncology and neurological diseases. Behind this decision was a halving of net profit (dropping to 144.1 billion yen in 2024) and the pressure of expiring patents, forcing the company to focus on projects with clear short-term returns.

February 2025,PfizerPfizer Halts Development and Commercialization of Hemophilia B Gene Therapy Beqvez. This therapy was approved in April 2024, priced at $3.5 million, but after 10 months on the market, no patients had received commercial treatment. By the end of 2024, Pfizer also terminated the development of giroctocogene fitelparvovec, a hemophilia A gene therapy collaboration with Sangamo. Within a year, the pharmaceutical giant had completely exited the gene therapy field.

Pfizer is not alone. Almost at the same time,RocheJohnson & Johnson is undergoing a "fundamental restructuring" of Spark Therapeutics, the gene therapy company it acquired for $4.3 billion in 2019, laying off 337 employees and integrating the remaining team into the parent company. Vertex Pharmaceuticals, on the other hand, has publicly announced that it will no longer use AAV (adeno-associated virus) as a delivery vector for gene therapy in the future, citing risks of immunogenicity and complexities in the production process.

More sadly,Bluebird Bio's fate. This once highly promising gene therapy pioneer saw its stock price soar to $230 per share in 2018, with a market value approaching $30 billion. However, due to slow progress in product commercialization, high treatment costs (such as Zynteglo priced at $2.8 million), and safety controversies, the company was ultimately acquired by private equity giant Carlyle for a mere $29 million in February 2025.

3. What to Do and Where to Go?

3

Since its discovery in the 1960s, adeno-associated virus (AAV) has gradually become a core vector tool in the field of gene therapy due to its advantages such as low pathogenicity, long-term expression potential, and tissue targeting. In 2012, Glybera, the world's first AAV gene therapy, was approved by the EU, marking a major breakthrough for this technology moving from laboratory to clinical application.

As of 2025, nine AAV therapies have been approved globally, covering multiple fields including rare genetic disorders, hematological diseases, and ophthalmic conditions.

Among the drugs already on the market,Novartis' AAV gene therapy Zolgensma for SMA achieved approximately $1.351 billion in sales in 2021 and has maintained annual sales exceeding $1 billion in subsequent years, becoming the first blockbuster drug in its category.

In China, the approval of Belief BioMed's XJ-9 in April 2025 not only fills the gap in domestic in vivo gene therapy but also propels China into the global first-tier group for gene treatment. However, with the exposure of technical bottlenecks, the rise of emerging delivery systems, and dramatic changes in the industrial landscape, AAV gene therapy is facing unprecedented challenges and transformation pressures.

Table 1 Globally Approved AAV Gene Therapies

Data Source: Pharma Data, Public Data Compilation

Over the past decade, AAV gene therapy has undergone rapid technological iteration and industrialization. Globally, directed evolution of AAV capsid proteins, optimization of tissue-specific promoters, and improvements in large-scale production processes have significantly enhanced its safety and delivery efficiency. In China, policy support and capital inflows have given rise to over 50 AAV gene therapy companies. As of April 2025, 50 drugs have been approved for IND, with some pipelines entering Phase III clinical trials.

However, behind this prosperity lies a fundamental contradiction in the technical route. AAV faces inherent defects, including pre-existing antibody issues caused by immunogenicity, a maximum 4.7kb gene payload limitation, and the high cost of viral vector production, which gradually become exposed as clinical trial scales expand.

The limitations of AAV provide development opportunities for novel delivery technologies. Non-viral delivery systems, represented by lipid nanoparticles (LNP), polymeric carriers, and exosomes, have quickly gained industry attention due to their low immunogenicity, large payload capacity, and the advantage of repeatable administration.

The success of mRNA vaccines during the COVID-19 pandemic has validated the clinical feasibility of LNP technology, which features low-cost scalability and creates a strong demonstration effect. Data shows that by 2028, the share of AAV in gene therapy pipelines may drop from the current 41% to 20%, while the share of LNPs and polymer carriers will jump from 6% to 28%. This shift in technological approach is also reflected in corporate strategy adjustments: Vertex is gradually shifting its focus to CRISPR cell therapies and has partnered with Orna to develop a circular RNA-LNP platform; leading companies in China have also started to invest in mRNA-LNP combined with gene-editing technologies, attempting to bypass the patent barriers of AAV.

Gene therapy is standing at the historical juncture of transitioning from "technological enthusiasm" to "rational development." On one hand, AAV therapy developers need to break through the existing technical framework, for instance, by engineering capsids to reduce immunogenicity, developing split vectors to address payload limitations, or establishing modular production platforms to lower costs. On the other hand, companies must reassess their indication selection strategies, shifting from ultra-rare diseases to disease areas with larger patient populations, and validate long-term efficacy through clinical study data.

4. Conclusion

Johnson & Johnson's setback reflects the growing pains of the golden age of AAV gene therapy. The future of gene therapy may no longer belong solely to AAV, but this exploration will continue to write the next chapter in medicine.

References

1. PharmaData

2.https://www.fiercebiotech.com/biotech/jj-gene-therapy-fails-improve-visual-navigation-late-stage-rare-eye-disease-trial

3. Official websites of major companies, various public materials, etc.

Content Cooperation:A Jie 13051235100