Roche Commits $3 Billion to Advance Gene Therapy; Industry Grapples with Challenges in Affordability and Durability

On August 24, Shape Therapeutics (ShapeTX) announced a collaboration agreement with Roche to co-develop gene therapies targeting certain targets in Alzheimer’s disease, Parkinson’s disease, and rare diseases. Shape Therapeutics is eligible to receive over $3 billion in upfront and milestone payments.

On the same day, Vertex Pharmaceuticals and Arbor Biotechnologies announced a new collaboration to leverage Arbor’s proprietary CRISPR gene-editing technology to advance the development of innovative cell therapies for the treatment of serious diseases. Co-founded by renowned scientist Dr. Feng Zhang, Arbor will receive an upfront payment under the terms of the agreement and is eligible for potential milestone payments of up to $1.2 billion.

The concept of gene therapy was first proposed as early as 1972. After nearly half a century, gene therapy has transitioned from a theoretical concept to a clinical reality. In recent years, the field has gained significant momentum, characterized by a booming IPO market and strong pursuit by Big Pharma, leading to frequent mergers and acquisitions. According to projections by the renowned consulting firm Frost & Sullivan, the global gene therapy market is expected to reach $30.54 billion by 2025, with the Chinese market reaching $17.89 billion. However, gene therapy still faces numerous challenges that must be addressed, such as safety concerns and high treatment costs.

What Is Gene Therapy?

According to the definition in the *General Chapter on Human Gene Therapy Products* published by the Chinese Pharmacopoeia Commission, gene therapy products typically consist of vectors or delivery systems containing engineered genetic constructs, whose active ingredients may be DNA, RNA, genetically modified viruses, bacteria, or cells. By introducing exogenous genes into target cells or tissues, they replace, supplement, block, or correct specific genes for the purpose of treating diseases.

Gene therapy products consist of two major components: a vector and a therapeutic gene. The choice of vector determines the type and capacity of the genetic payload that can be packaged and delivered. Commonly used vectors include adenoviruses, adeno-associated viruses (AAV), retroviruses, lentiviruses, and oncolytic viruses. The selection of different genes enables distinct therapeutic objectives. Based on their mechanisms of action on target genes in vivo, they are primarily classified into three categories: augmentation, suppression, and correction.

In 1990, the United States approved the first clinical trial for gene therapy. Since then, over 2,000 gene therapy candidates worldwide have entered clinical trials. Over the past nearly half-century, gene therapy has transitioned from a theoretical concept to a clinical reality. To date, more than 20 gene therapy products have been granted marketing approval globally for the treatment of cancers, viral infections, genetic disorders, and other indications.

In 2017, the U.S. FDA approved Luxturna, the first *in vivo* gene therapy, for pediatric and adult patients with vision loss due to homozygous mutations in the RPE65 gene who retain a sufficient number of viable retinal cells, thereby restoring and improving their vision. Developed by Spark Therapeutics (which has since been acquired by Novartis), this product represents the first true gene therapy in the U.S. market and officially marks the advent of the gene therapy era.

In January this year in China, Boya Biomedicine announced that the Center for Drug Evaluation (CDE) of China's National Medical Products Administration (NMPA) had approved the clinical trial application for ET-01, its CRISPR/Cas9 gene-editing therapeutic product targeting transfusion-dependent β-thalassemia. This marks the first gene-editing therapy and hematopoietic stem cell product in China to receive clinical trial approval from the NMPA.

In August, BBM-H901 injection, independently developed by Shanghai Xinzhi Pharmaceutical Technology Co., Ltd., a wholly-owned subsidiary of Belief BioMed (an AAV gene therapy drug indicated for the prevention of bleeding in adult male patients with hemophilia B), received clinical trial approval from the National Medical Products Administration (NMPA). This is the first hemophilia AAV gene therapy drug approved for registration clinical trials in China, and the first systemically administered gene therapy for rare diseases in China.

Gene Therapy Durability Under Scrutiny: What Are the Future Optimization Pathways?

Currently, most gene therapy strategies utilize engineered viruses as delivery vectors, with adeno-associated virus (AAV) vectors being the most common. However, since the AAV vector genome cannot integrate into the human genome, the delivered therapeutic genes may be diluted due to cell division, cell death, or other factors, thereby limiting the long-term durability of the therapeutic effect.

According to the GENEr8-1 data published by BioMarin in January this year, endogenous FVIII expression levels in subjects treated with valoctocogene roxaparvovec for at least 2 years decreased from 42.2 (SD 50.9, median 23.9) IU/dL at the end of year 1 to 24.4 (SD 29.2, median 14.7) IU/dL at the end of year 2, demonstrating sustained hemostatic efficacy, with an ABR of 0.9 (median 0.0) episodes/year.

Although patients' Factor VIII levels are declining, they remain within the therapeutic range. In July, valrox had its Marketing Authorization Application (MAA) accepted by the European Medicines Agency (EMA) for the treatment of adult patients with severe hemophilia A, with a CHMP opinion expected in the first half of 2022.

Dr. Ruhong Jiang, Founder and CEO of ASC Therapeutics (USA), stated that there are approximately three approaches to optimizing gene therapy: 1. increasing the transduction efficiency of viral vectors; 2. engineering optimized genes for higher expression levels; 3. enhancing the secretion of the expressed protein from cells.

Furthermore, in vivo gene editing technology is also a potential approach to addressing durability concerns.

Gene Therapy's "Sky-High" Treatment Costs: How Much Room for Future Price Reductions?

Dr. Jiang Ruhong stated that the pricing of the therapeutic drug must account for all costs from research and development to manufacturing. Initially, establishing the platform entails high costs and requires considerable time, making the first product inevitably expensive. However, as the platform continues to be utilized for subsequent product development, prices will decline. Within approximately the next five years, the cost is expected to drop to around $100,000.

Dr. Sun Xiulian, Chairman and Chief Scientific Officer of ImmuneOnco, stated that in reality, the manufacturing costs of gene therapy products are not high. However, for drug development, the focus is not on production costs; clinical development costs account for the majority of expenses.

As a novel therapeutic product, the high cost of gene therapy is justifiable. However, with continuous technological advancements and platform-based R&D and manufacturing, it is entirely feasible that affordable treatments will be realized in the future.

Conclusion

Gene therapy was initially developed for the treatment of inherited genetic disorders. Following promising outcomes, the field has advanced at an increasingly rapid pace. The market size of the gene therapy industry is expanding swiftly, with major pharmaceutical companies such as Roche and Novartis actively establishing strategic positions in the sector.

In China, a large number of outstanding domestic gene therapy companies and scientific research institutions have emerged in the field, with pipelines already covering numerous indications, including hemophilia A and B, β-thalassemia, immunodeficiency diseases, and various solid tumors. It is believed that, driven by the concerted efforts of numerous gene therapy companies, the industry will usher in a golden era for gene therapy.

Managing Editor: Liuli

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