Setbacks for AAV Gene Therapy: Vertex Exits, J&J's Bota-vec Fails Phase III

The AAV Gene Therapy Field Has Been Seeing a Lot of Activity Recently. Vertex Pharmaceuticals recently announced that it would halt its research using AAV as a gene therapy vector. Coincidentally, Johnson & Johnson also recently reported that its ocular AAV gene therapy, bota-vec (botaretigene sparoparvovec), failed to meet the primary endpoint in Phase III clinical trials, as patients did not show the expected improvement in visual navigation ability through a virtual maze. In recent years, several large pharmaceutical companies, including Biogen, Pfizer, Roche, and Takeda, have cut back on their AAV gene therapy research. What is the future of this field?

01

Challenging but not giving up

Although bota-vec did not meet the primary endpoint, Johnson & Johnson claimed that the trial results showed a positive trend in secondary indicators such as retinal sensitivity and demonstrated improvement in several secondary endpoints. Specifically, this Phase III trial recruited a total of 95 patients, with 58 receiving a single low or high dose of bota-vec treatment. Among them, 22 showed improvement in two or more endpoints, while no patients in the control group exhibited improvement.

Bota-vec is a gene replacement therapy based on an AAV vector. Its therapeutic mechanism involves delivering the functional retinitis pigmentosa GTPase regulator (RPGR) gene to the patient's retinal tissue via a viral vector. This therapy specifically targets X-linked retinitis pigmentosa (XLRP), a rare hereditary eye disease. XLRP is a genetic subtype of retinitis pigmentosa (RP), inherited in an X-linked recessive pattern. The disease predominantly affects males and is caused by mutations in the RPGR gene, leading to progressive degeneration of retinal photoreceptor cells. Patients typically exhibit early symptoms such as night blindness during adolescence, and as photoreceptor cells suffer irreversible damage, they may ultimately develop complete blindness by around the age of 40.

This therapy was initially developed by Johnson & Johnson in collaboration with MeiraGTx, a genetic medicine biotechnology company. Before Johnson & Johnson's introduction, it had already been granted Fast Track designation and Orphan Drug designation by the FDA. In 2020, the 6-month data from the Phase I/II trial of bota-vec was released: interim results showed that low and medium doses of bota-vec were well-tolerated, with significant improvement in patients' vision.

In December 2023, Johnson & Johnson acquired all rights to the project for up to $415 million. A commercial supply and technology transfer agreement was reached for bota-vec. However, this setback did not deter Johnson & Johnson, which stated that it still plans to advance related research.

02

Four Reasons Not to Be Overlooked

This setback, along with the first treatment-related death case involving Sarepta's gene therapy Elevidys in March this year, has cast a shadow over AAV treatments.

Although Johnson & Johnson did not disclose the specific reasons, I believe there are several aspects that cannot be ignored:

1. Bota-vec uses a truncated RPGR protein, targeting peripheral vision repair, while gene therapy needs to break through the "partial repair" mindset and shift towards more comprehensive functional reconstruction. For example, the expression of full-length proteins may require combining regulation of the retinal cell microenvironment, rather than solely relying on gene replacement.

2. In the high-dose group of bota-vec, 53% of patients experienced treatment-related adverse events (such as ocular inflammation), revealing potential technical bottlenecks of AAV vectors in dose control, immunogenicity, and long-term expression stability. Novel vectors (e.g., lipid nanoparticles or dual AAV systems) or gene-editing tools (e.g., base editing) could be explored in the future to reduce dose requirements and enhance safety. In China, Jinlan Gene's dual AAV vector trials have already been positioned in this direction.

3. The primary endpoint of this Phase III trial is "virtual maze navigation ability." A virtual maze refers to a three-dimensional maze environment generated by a computer, where participants are required to complete navigation tasks in the virtual space using visual cues (such as wall textures, path markers, and target locations). This method is commonly used to assess the visual perception, spatial cognition, or navigation abilities of participants. However, whether this metric is reliable and comprehensive still needs further confirmation.

4. The refinement of patient stratification may have certain shortcomings. Individualized gene therapy requires the integration of genetic diagnosis and mutation-specific vector design.

03

Hope Remains for Further Progress

AAV Therapy Temporarily Clouded, But Hope Remains. For example, Novartis' AAV gene drug Zolgensma for spinal muscular atrophy achieved approximately $1.351 billion in sales in 2021, with $327 million in sales in the first quarter of 2025, becoming the first blockbuster drug in this category.

In China, this February, Zhongyin Technology reached an agreement with the FDA on the international multi-center Phase III clinical trial protocol for its self-developed AAV therapy ZVS101e injection for crystalline retinal degeneration. According to the protocol, Zhongyin Technology will simultaneously conduct registrational clinical trials in the United States, Japan, the European Union, and the Asia-Pacific region.

In April, the Class 1 new drug Bopipedacog Injection from Belief BioMed was approved for marketing by the NMPA in April this year. It is used to treat adult patients with Hemophilia B (congenital Factor IX deficiency). This is the first AAV gene therapy drug approved for marketing in China, and also the first gene therapy drug targeting rare diseases.

Editor: Zhang Jieying

Layout Editor: Chen Tiemao

Reviewed by: Ma Fei, Zhang Song

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