Recently, Johnson & Johnson's highly anticipated bota-vec therapy failed in the Phase III clinical trial, causing it to fall heavily from the limelight stage of AAV gene therapy.

1. Phase III clinical trial failure

Recently, Johnson & Johnson, which has been making great strides in the field of gene therapy, has suffered a major setback. Its highly anticipated AAV gene therapy bota-vec failed to achieve the primary endpoint of improving patients' visual navigation ability in the Phase III LUMEOS study for the treatment of X-linked retinitis pigmentosa (XLRP). This result not only makes the future of this star therapy, which has been certified by the FDA as both a fast track and orphan drug, uncertain, but also rings the alarm 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 is a rare genetic eye disease that mainly affects male children, characterized by progressive photoreceptor degeneration, which eventually leads to complete blindness. Currently, there are about hundreds of thousands of patients in the world who are in urgent need of effective treatments, and the clinical failure of bota-vec has put this group of patients in a treatment dilemma again.

Looking back at the development 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 $415 million to complete the acquisition of global rights to bota-vec, including a down payment of $65 million. However, after the release of the Phase III clinical data, MeiraGTx's stock price fell 11.03%. This "win-win" transaction is facing a revaluation.

The LUMEOS III study enrolled a total of 95 patients (including a small number of female patients), of whom 58 received low-dose or high-dose bota-vec. In a pooled analysis of all patients treated with bota-vec, the primary endpoint of improvement in the ability of patients to visually pass through a virtual maze did not meet expectations, but positive trends in secondary indicators such as retinal sensitivity suggested that the therapy may have target effectiveness. Johnson & Johnson is currently analyzing all the data and evaluating strategic options and follow-up plans.

2. MNCs withdraw

Gene therapy was once hailed as "the future of medicine", but the reality is far less than ideal. In recent years, the withdrawal of major MNCs from the field of AAV gene therapy has attracted industry attention.

In May 2021, Biogen's gene therapy XIRIUS for XLRP failed in a Phase II/III trial. Although the therapy delivered the RPGR gene through an AAV8 vector to repair the mutation, the patient's vision did not improve significantly, resulting in a setback to its strategic layout after the acquisition of Nightstar Therapeutics.

Coincidentally, Takeda also terminated its AAV gene therapy cooperation with JCR Pharmaceuticals in 2023, and cut 18 early pipelines, shifting resources to core areas such as tumors and neurological diseases. Behind its decision was the halving of net profit (down to 144.1 billion yen in 2024) and the pressure of patent expiration, forcing the company to focus on projects with clear short-term benefits.

In February 2025, Pfizer also stopped the development and commercialization of its hemophilia B gene therapy Beqvez. The therapy was approved in April 2024 and priced at $3.5 million, but no patients received commercial treatment after 10 months on the market. At the end of 2024, Pfizer also terminated the research and development of giroctocogene fitelparvovec, a gene therapy for hemophilia A in cooperation with Sangamo. In just one year, the pharmaceutical giant completely withdrew from the field of gene therapy.

Pfizer is not alone. At almost the same time, Roche carried out a "fundamental reorganization" of Spark Therapeutics, a gene therapy company it acquired for $4.3 billion in 2019, laying off 337 employees and merging the remaining team into the parent company. Vertex Pharmaceuticals publicly announced that it would no longer use AAV (adeno-associated virus) as a delivery vector for gene therapy in the future, citing the risk of immunogenicity and the complexity of the production process.

Even more regrettable is the fate of Bluebird Bio. This once-prosperous 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 product commercialization, high treatment costs (such as Zynteglo's price of $2.8 million) and safety disputes, the company was eventually acquired by private equity giant Carlyle for a "bargain price" of $29 million in February 2025.

3. Where to go from here?

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, the world's first AAV gene therapy Glybera was approved in the European Union, marking a major breakthrough in the transition of this technology from laboratory to clinical application.

As of 2025, nine AAV therapies have been approved for marketing worldwide, covering multiple fields including rare genetic diseases, blood system diseases, and ophthalmic diseases.

Among the drugs already on the market, Novartis' AAV gene drug Zolgensma for SMA achieved sales of approximately US$1.351 billion in 2021, and maintained annual sales of over US$1 billion in the following years, becoming the first blockbuster drug in this category.

In China, the approval of Xinxin Pharmaceutical's Xinjiuning in April 2025 not only filled the gap in domestic in vivo gene therapy, but also pushed China into the first echelon of global gene therapy. However, with the exposure of technical bottlenecks, the rise of emerging delivery systems and dramatic changes in the industry landscape, AAV gene therapy is facing unprecedented challenges and transformation pressures.
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 improved its safety and delivery efficiency. In China, policy support and capital influx have spawned more than 50 AAV gene therapy companies. As of April 2025, 50 drugs have been approved for IND, and some pipelines have entered Phase III clinical trials.

However, behind this prosperity lies a fundamental contradiction in the technological route. AAV faces inherent defects including the problem of pre-existing antibodies caused by immunogenicity, a maximum gene load limit of 4.7kb, and high viral vector production costs, which are gradually exposed as the scale of clinical trials expands.

The limitations of AAV provide an opportunity for the development of new delivery technologies. Non-viral delivery systems represented by lipid nanoparticles (LNPs), polymer carriers and exosomes have rapidly gained industry attention due to their low immunogenicity, large loading capacity and repeatable dosing.

The success of mRNA vaccines in the COVID-19 pandemic has verified the clinical feasibility of LNP technology, and its large-scale production cost is low, forming a strong demonstration effect. Data show that by 2028, the share of AAV in the gene therapy pipeline may drop from the current 41% to 20%, while the share of LNP and polymer carriers will jump from 6% to 28%. This shift in technology routes has been simultaneously reflected in the adjustment of corporate strategies. Vertex has gradually shifted its focus to CRISPR cell therapy and cooperated with Orna to develop a circular RNA-LNP platform; domestic leading companies have also begun to deploy mRNA-LNP combined gene editing technology in an attempt to bypass AAV's patent barriers.

Gene therapy is standing at a historical node from "technological enthusiasm" to "rational development". On the one hand, AAV therapy developers need to break through the existing technical framework, such as reducing immunogenicity through engineering capsids, developing split vectors to solve load limitations, or establishing modular production platforms to reduce costs; on the other hand, companies must re-evaluate their indication selection strategies, shifting from ultra-rare diseases to disease areas with a larger patient base, and verifying long-term efficacy through clinical research data.

4. Conclusion

Johnson & Johnson’s setback reflects the pain of the golden age of AAV gene therapy. The future of gene therapy may no longer belong exclusively to AAV, but this exploration will still write the next chapter of medicine.

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