Cell and gene therapy (CGT) is an emerging treatment strategy that stands out for its potential "one-time treatment, permanent cure" capability, offering many patients the possibility of long-term relief from their medical conditions. Data shows that in the first half of 2024, a total of 8 CGT therapies were approved globally:
1. Sarepta Therapeutics' Elevidy Receives Full FDA Approval:
On June 20th, Sarepta announced the label expansion of its gene therapy Elevidys for Duchenne muscular dystrophy (DMD), now approved for patients aged 4 and above. For ambulatory patients, the FDA granted regular approval, while for non-ambulatory patients, it received accelerated approval. Sarepta has committed to conducting and submitting the results of a randomized controlled trial to verify and confirm the clinical benefit of Elevidys in non-ambulatory DMD patients, which is the ongoing ENVISION (SRP-9001-303) study. Elevidys was previously granted accelerated approval in June 2023 for pediatric DMD patients aged 4-5 years, and the expansion to ≥4 years old patients, regardless of their ambulatory status, marks a significant milestone in the treatment of DMD.
2. Geron's Rytelo Becomes the First FDA-Approved Oligonucleotide Telomerase Inhibitor:
On June 6th, Geron announced that Rytelo was approved for the treatment of transfusion-dependent anemia in lower-risk myelodysplastic syndromes (LR-MDS) patients. The approval of Rytelo was based on the positive results of the Phase 3 IMerge trial published in The Lancet, which met its primary and key secondary endpoints, showing Rytelo's significant advantage over placebo in reducing the need for red blood cell transfusions, with durable and sustained responses in responders. This approval marks the fulfillment of a nearly 40-year-long pursuit of a telomerase-targeted therapy, and is viewed as one of the important therapies of the year.
With the approval of Rytelo, Geron's stock price surged by 22%. Evaluate predicts that Rytelo's sales could reach $737 million by 2028, reflecting the market's recognition of the therapy's potential. Geron has set a clear pricing strategy for Rytelo, with a wholesale acquisition cost of $2,471 for a 47 mg single dose and $9,884 for a 188 mg single dose. The dosage will be adjusted based on the patient's weight.
3. Moderna's mRESVIA Vaccine:
Moderna, Inc. (NASDAQ: MRNA) announced on May 31st that its mRNA respiratory syncytial virus (RSV) vaccine, mRESVIA (mRNA-1345), has been approved by the U.S. Food and Drug Administration (FDA) to protect adults aged 60 and above from RSV-associated lower respiratory tract disease. This vaccine, being the only RSV vaccine administered via a pre-filled syringe, marks the first approval of an mRNA vaccine for a non-COVID-19 disease.
The approval was based on the positive results of the global Phase 3 ConquerRSV trial conducted in approximately 37,000 adults aged 60 or older across 22 countries. The primary analysis with a median follow-up of 3.7 months showed the vaccine had an efficacy of 83.7% (95.88% CI 66.0%, 92.2%) against RSV lower respiratory tract disease (LRTD). These results have been published in the New England Journal of Medicine. A longer-term analysis also showed the vaccine's protective effect against RSV LRTD persisted over a median follow-up of 8.6 months. No serious safety concerns were observed in the Phase 3 trial, with the most common adverse reactions including injection site pain, fatigue, headache, muscle pain, and joint pain.
4. Pfizer and its BEQVEZ gene therapy：
On April 26, 2024, Pfizer announced that its adeno-associated virus (AAV) vector-based gene therapy BEQVEZ (fidanacogene elaparvovec-DZKT) has been approved by the US FDA for the treatment of adults (18 years and older) with moderate to severe hemophilia B who test negative for neutralizing antibodies to AAV serotype Rh74. The therapy is priced at $3.5 million, comparable to the price of UniQure's hemophilia B gene therapy Hemgenix.
This approval was primarily based on the positive data from the Phase III BENEGENE-2 study (n=45), which showed that patients receiving a single dose of BEQVEZ had a significantly reduced annualized bleeding rate (ABR) compared to the standard preventive treatment group (1.3 vs. 4.43, P<0.0001) within 12 months, meeting non-inferiority and superiority endpoints. Currently, BEQVEZ is under review by the European Medicines Agency (EMA) and has been approved by the Canadian regulatory authorities. In addition to BEQVEZ, Pfizer is also investigating two phase III gene therapy programs for hemophilia A and Duchenne muscular dystrophy, as well as a novel anti-tissue factor pathway inhibitor marstacimab for the treatment of hemophilia A or B patients with factor VIII (FVIII) or factor IX (FIX) inhibitors. The FDA and EMA are currently reviewing the Biologics License Application and Marketing Authorization Application for marstacimab, respectively.
5. Orchard Therapeutics：
On March 18, the FDA approved Orchard Therapeutics' gene therapy Lenmeldy for the treatment of metachromatic leukodystrophy (MLD) in pediatric patients. The therapy is priced at $42.5 million, making it the most expensive drug in history. Lenmeldy is the only FDA-approved therapy for the treatment of early-onset MLD in children and has also been approved in the EU and UK.
Lenmeldy (atidarsagene autotemcel, formerly OTL-200) utilizes Orchard's core technology, which involves ex vivo modification of autologous stem cells with a lentiviral vector encoding the arylsulfatase-A (ARSA) gene, with the aim of restoring ARSA expression in a single treatment to halt or slow disease progression. The FDA approval was based on data from 37 children, with a median follow-up of 6.76 years, which showed significantly improved overall survival and reduced incidence of motor dysfunction or death in patients receiving Lenmeldy. In terms of safety, Lenmeldy demonstrated good tolerability, with no treatment-related serious adverse events or deaths.
6. BMS's Breyanzi：
On March 14, Bristol Myers Squibb (BMS) announced that the US Food and Drug Administration (FDA) has granted accelerated approval for its CD19-targeted CAR-T cell therapy Breyanzi (lisocabtagene maraleucel; liso-cel). This therapy is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL) or small lymphocytic lymphoma (SLL) who have received at least two prior therapies, including a Bruton's tyrosine kinase (BTK) inhibitor and a BCL-2 inhibitor. According to the company's press release, Breyanzi is the first CAR-T cell therapy approved for adult patients with R/R CLL or SLL.
As an autologous CAR-T cell therapy targeting CD19, Breyanzi has a defined composition and incorporates a 4-1BB co-stimulatory domain. The FDA had previously approved Breyanzi in February 2021 for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (LBCL) who have received two or more lines of systemic therapy. The unique feature of Breyanzi is its controlled ratio of CD8-positive and CD4-positive T cells, which helps to better manage the potential toxicities of cell therapy. Additionally, the 4-1BB signaling domain significantly enhances the expansion and persistence of the CAR-T cells.
The accelerated approval for this indication was based on response rates and duration of response, and further approval will depend on the verification of clinical efficacy in a confirmatory trial. The TRANSCEND CLL 004 trial, which served as the basis for this approval, is an open-label, single-arm, multicenter Phase 1/2 study. The data analysis showed that 20% of patients with relapsed or refractory CLL or SLL achieved complete remission (CR) after receiving Breyanzi, and the safety profile has been established.
7. Carsgen Therapeutics' Selinexor Injection：
On March 1st, Carsgen Therapeutics announced that the new drug application (NDA) for its BCMA CAR-T product Carsgencel® (Selinexor Injection) has been approved by the National Medical Products Administration (NMPA) of China. The product is mainly used to treat adult patients with relapsed or refractory multiple myeloma, who have received at least 3 prior lines of therapy (having received at least one proteasome inhibitor and one immunomodulatory agent). Selinexor Injection is the fifth CAR-T therapy approved in China.
On March 5th, Carsgen Therapeutics announced the launch price of its CAR-T cell therapy Selinexor Injection (brand name: Carsgencel) at 1.15 million RMB. In collaboration with Huadong Medicine (000963.SZ), the company estimates the peak annual sales of this product to be over 1 billion RMB.
Carsgencel® is an autologous BCMA-targeted CAR-T cell product produced through lentiviral transduction. The lentiviral vector encodes a fully human BCMA-specific single-chain variable fragment (scFv), a human CD8α hinge structure, a CD8α transmembrane domain, a 4-1BB co-stimulatory domain, and a CD3ζ activation domain. Carsgen Therapeutics' in-house developed new fully human scFv has demonstrated high binding affinity and stability. Currently, Carsgen Therapeutics is conducting a Phase 1b/2 clinical trial (LUMMICAR STUDY 2) in North America to evaluate the safety and efficacy of Carsgencel® in the treatment of relapsed or refractory multiple myeloma.
In January 2023, Carsgen Therapeutics and Huadong Medicine reached a commercialization collaboration agreement for Carsgencel® in mainland China. According to this agreement, Carsgen Therapeutics has granted the exclusive commercial rights of Carsgencel® in mainland China to Huadong Medicine. In this collaboration, Huadong Medicine (Hangzhou) will pay a 200 million RMB upfront payment to Carsgen Therapeutics' wholly-owned subsidiary Kaixing Life, and Huadong Medicine will be responsible for up to 1.025 billion RMB in future registration and sales milestone payments.
8. Iovance Biotherapeutics, which announced on February 16th that its tumor-infiltrating lymphocyte (TIL) therapy Amtagvi (lifileucel) has received FDA accelerated approval for the treatment of advanced melanoma, with a price tag of $515,000. It is noteworthy that lifileucel is the world's first approved TIL cell therapy.
Amtagvi is a personalized autologous T-cell immunotherapy derived from the patient's tumor tissue. In the initial treatment, the patient's tumor tissue is removed, and T cells are isolated and further expanded in vitro, before being re-infused back into the patient in a single dose. Each Amtagvi dose contains 7.5 to 72 billion active cells, and the entire process from receiving the tumor tissue to completing the product preparation takes approximately 34 days.
Phase 2 clinical trial data showed that after a median follow-up of 27.6 months, the objective response rate (ORR) was 31.4%, including 8 complete responses (CR) and 40 partial responses (PR). In Iovance's 4-year follow-up data, the longest duration of response reached 55.8 months.
Looking ahead, it is expected that 5 other cell and gene therapies (CGTs) may be approved in 2024, including Carsgen's CAR-T therapy Selinexor Injection, Adaptimmune Therapeutics' TCR T-cell therapy, BioCardia's CardiAMP, Pfizer's novel gene therapy Fidanacogene elaparvovec, and Autolus Therapeutics' CAR-T therapy Obecabtagene autoleucel. However, Rocket Pharmaceuticals' gene therapy Kresladi and Abeona Therapeutics' autologous cell therapy Prademagene zamikeracel (pz-cel) were recently rejected by the FDA in June and April, respectively, due to chemistry, manufacturing, and control (CMC) related issues, and they currently need to provide additional CMC information to complete the review.
