In 2023, FDA approved seven types of cell and gene therapy (CGT), an all-time high. 

So far this year, FDA has given the green light for three innovative CGT, and it is expected that at least seven CGT products will be approved by the end of this year. The first CGT therapy approved by FDA this year is Casgevy, a CRISPR/Cas9 gene editing therapy jointly developed by Vertex/CRISPR, which was approved by FDA in January this year for the treatment of transfusion dependent β-thalassemia. In February, Iovance Biotherapeutics's Amtagvi was approved by FDA for the treatment of advanced melanoma after PD-1/PD-L1 treatment, the world's first approved TIL cell therapy and the first disposable cell therapy for solid tumors; last month, FDA approved Orchard's gene therapy, Lenmeldy, for the treatment of heterochromatic leukodystrophy (MLD) in children, the most expensive drug in the world, priced at $4.25 million.

In the coming months, according to the PDUFA date announced by the companies, FDA will also give approval decisions for five other CGT treatments (one of which received delayed approval on April 22nd). 

Next, this article will make a brief introduction to these five CGT treatments.

Drug name: Beqvez (fidanacogene elaparvovec). 

Company: Pfizer. 

Indication: hemophilia type B. 

PDUFA date: April 27th

Beqvez is a gene therapy for clotting factor IX (FIX) developed by Spark Therapeutics (acquired by Roche). It contains a highly active variant of the capsid (protein shell) of bioengineered adeno-associated virus (AAV) and human FIX gene. In December 2014, Pfizer reached a partnership with Spark to acquire a global interest in the product with a total transaction value of $280 million. The BLA of the drug is mainly based on positive data from the III phase BENEGENE-2 study (nasty 45). 

The results showed that within 12 months after receiving single-dose Beqvez (5e11 vg/kg) treatment, the annual bleeding rate (ABR) was significantly lower than that in the standard preventive treatment group (receiving FIX drugs as prophylactic alternative therapy) (1.3 vs. 4.43 (P < 0.0001), reaching the standard of non-inferior effect and the standard of superior effect.

Earlier this year, Beqvez achieved the world's first batch in Canada for the treatment of adult hemophilia B. 

When Beqvez is approved by FDA, Pfizer will face direct competition with CSL Behring, whose gene therapy Hemgenix, also through a single intravenous infusion, became the first gene therapy approved by FDA to treat hemophilia B in November 2022. Details of the pricing of the Beqvez are unclear, but the Hemgenix costs $3.5 million per dose.

Drug name: prademagene zamikeracel (pz-cel). 

Company: Abeona Therapeutics. 

Indication: recessive dystrophic epidermolysis bullosa (RDEB). 

PDUFA date: TBD

Pz-cel is an autologous COL7A1 gene-corrected epidermis developed by Abeona and is currently being developed for the treatment of RDEB, a rare connective tissue disease caused by COL7A1 gene defects that prevent patients from producing type VII collagen. Pz-cel aims to integrate functional collagen-producing COL7A1 genes into patients' own skin cells and to achieve long-term gene expression by using retroviral vectors to stably integrate into the genomes of mitotic target cells. The original PDUFA date for the treatment was May 25 this year, but unfortunately, Abeona received a full reply (CRL) from FDA on April 22. FDA noted that some additional information requirements for chemical manufacturing and control (CMC) must be satisfactorily addressed before approving the application. In response, Abeona submitted a plan to FDA and said it expected to complete and submit CMC information in the third quarter of 2024.

Once approved, pz-cel will become another gene therapy for DEB after Krystal Biotech's Vyjuvek.

Drug name: Kresladi (marnetegragene autotemcel). 

Company: Rocket Pharmaceuticals. 

Indication: leukocyte adhesion deficiency-type I (LAD-I). 

PDUFA date: June 30th

LAD-I is a rare hereditary immune disease caused by a mutation in the ITGB2 gene that encodes a β 2 integrin component CD18. 

CD18 is a key protein that promotes leukocyte adhesion and extravasation from blood vessels to fight infection. Patients with LAD-I are prone to recurrent and fatal infections and will die in childhood without allogeneic hematopoietic stem cell transplantation. Kresladi contains autologous hematopoietic stem cells, which have been genetically modified with lentiviral vectors to enable normal expression of ITGB2 genes. Previously, the global phase I/II study of Kresladi in patients with LAD-I reached all major and secondary endpoints. The data showed that after 12 months of Kresladi treatment (and the entire follow-up period), the overall survival rate of patients (12-24 years old, 9 cases) was 100%. Compared with those before treatment, the incidence of severe infection decreased significantly, the symptoms of LAD-I-related skin injury subsided, and the wound repair ability also recovered. In addition, RP-L201 is well tolerated.

Although Rocket Pharmaceuticals initially expected FDA to make an approval decision in March, it was also because of CMC issues that FDA asked for more review time and extended the PDUFA date by three months. 

For patients, Kresladi will be a significant improvement in treatment, which provides a potential alternative to bone marrow transplantation, which not only carries a high risk of infection, but also makes it difficult to obtain a matching graft.

Drug name: afami-cel. 

Company: Adaptimmune. 

Indication: advanced synovial sarcoma. 

PDUFA date: August 4

There are more than 50 different types of soft tissue sarcomas, which can be classified according to tumors present in fat, muscle, nerves, fibrous tissue, blood vessels, or deep skin tissue. Synovial sarcomas account for about 5 to 10 per cent of all soft tissue sarcomas (there are about 13400 new soft tissue cases each year in the United States). Patients with synovial sarcoma with 1x3 were diagnosed under the age of 30, and the 5-year survival rate of patients with metastatic disease was only 20%. Afami-cel is a TCR-T cell therapy targeting MAGE-A4. If approved, it will be the world's first approved TCR-T cell therapy and the first approved solid tumor T cell therapy. Clinical data from the key clinical trial codenamed SPEARHEAD-1 support Afami-cel 's BLA, which has reached the main end point, with 39% of patients receiving Afami-cel having a clinical response with a median duration of 12 months. The median overall survival time (mOS) of patients with synovial sarcoma was about 17 months, while that of patients with synovial sarcoma who had received second-line or more-line therapy was less than 12 months. In addition, 70% of patients with advanced synovial sarcomas that responded to Afami-cel survived within 2 years of treatment.

Drug name: obe-cel. 

Company: Autolus Therapeutics. 

Indication: recurrent / refractory adult acute lymphoblastic leukemia (ALL). 

PDUFA date: November 16

In January, FDA accepted BLA from Autolus Therapeutics's next-generation CAR-T therapy, obe-cel, for relapsed / refractory adult acute lymphoblastic leukemia (ALL), and set a target date for PDUFA on November 16. Compared with current CD19 CAR-T cell therapy, obe-cel aims to overcome its limitations in clinical activity and safety. Obe-cel is designed to have a rapid target dissociation rate (target binding off-rate) to minimize the overactivation of engineered T cells, thereby reducing toxicity, reducing T cell depletion, enhancing persistence, and improving the continuous killing ability of engineered T cells against a series of target cancer cells.

In December 2022, Autolus announced the success of the phase II trial codenamed FELIX. Mid-term analysis showed that the total remission rate of leukemia patients was 70%. The concentration of CAR-T cells peaked at 166.5 days after infusion and maintained 75% of the peripheral blood. The trial also showed positive safety results. On February 8, 2024, BioNTech acquired an interest in obe-cel for $250 million. 

Autolus expects obe-cel sales to peak at more than $300m. Autolus may face competition from Kite, a subsidiary of Gilead Science, which received FDA approval for CAR-T therapy Tecartus in 2021. Tecartus is the first CAR-T therapy for ALL, achieving a complete remission rate of 65%.

Looking to the future, more potential cell and gene therapy is constantly developing and diversifying, whether in terms of treatment concepts, global advances, and the degree of attention at the national level, cell and gene therapy is undoubtedly an area with long-term technological breakthroughs, so further research and practice are needed to address the challenges and problems and to ensure the safety and effectiveness of cell and gene therapy.