As an emerging medical technology, gene therapy has shown great potential and development momentum, especially in the treatment of refractory diseases. In the first half of 2024, three gene therapies around the world were approved by the U.S. Food and Drug Administration (FDA). my country has also made breakthrough progress in the research and development of gene therapies, and many have been approved to enter the clinical trial stage. This article reviews the approval progress of new drug clinical trial applications (INDs) for seven types of gene therapies in my country in the third quarter of 2024 (Note, the gene therapies described in this article do not include immune cell therapies such as CAR-T, small nucleic acid drugs, stem cells and regenerative therapy).

▲Progress on the approval of Q3 gene therapy drugs in 2024

As shown in the above table, in the third quarter of this year, a total of 7 gene therapy pipelines (based on pipeline names) were approved for INDs in my country, and the number approved this time is roughly the same as the total number of IND approved in the second half of 2023. According to incomplete statistics, more than a dozen gene therapies were approved for INDs in the first half of 2024. This shows that the development momentum of gene therapy in my country is strong. Among them, Ruizheng Gene's ART001 injection has obtained two clinical implied licenses from the Center for Drug Evaluation (CED) and the US FDA.

From the perspective of subdivision in this field, my country's gene therapy has also shown a trend of multiple breakthroughs and steady progress. CRISPR editing technology has greatly improved the accuracy and efficiency of gene editing and opened up a new path for gene therapy. In addition to the traditional viral vector types of herpes simplex virus (HSV) and adenovirus-associated virus (AAV), a new generation of lipid nanoparticles (LNP) with more efficient, safer, more stable and precise tissue targeting characteristics has been developed. In addition, it also uses the homing characteristics of mesenchymal stem cells to achieve the combination of gene therapy and stem cells, playing the dual role of gene intervention and tissue repair. In terms of indications, the development direction of gene therapy not only focuses on the treatment of rare diseases and solid tumors, but also expands to fields such as type 2 diabetes (T2DM).

Oncolytic virus achieves dual treatment of "fighting poison with poison" and immune regulation.

1、MVR-T3011

On July 5, Yinuo Micromedicine's Class 1 innovative biological product MVR-T3011 Herpesvirus injection received tacit approval from the CDE clinical trial for intraperitoneal administration for the treatment of advanced solid tumors.

MVR-T3011 is an innovative three-in-one herpes oncolytic virus product with independent intellectual property rights. It is based on a new design of the wild HSV-I herpesvirus skeleton to ensure that the virus has strong replication in tumor cells. At the same time, its replication ability in normal cells is suppressed, achieving optimal attenuation effect. In addition, MVR-T3011 carries two new and fully verified exogenous immunoregulatory genes, PD-1 antibodies and IL-12, to promote immune responses in the tumor microenvironment. It allows it to lyse tumor cells, thereby exerting dual treatment of tumor oncolytic and immunity.

The latest Phase 1 clinical data of MVR-T3011 showed that after administering a RP2D dose of MVR-T3011 to patients with non-muscular invasive bladder cancer (NMIBC) who had failed high-risk BCG (BCG), the three-month CR rate reached 81.8%(9/11). Of the 9 patients who reached the 6-month assessment, 8 maintained CR, and all 4 patients who reached the 9-month assessment were in CR status. and demonstrate good safety.

2、R130   

On July 26, the third-generation recombinant oncolytic virus "Recombinant Herpes Simplex Virus Type I R130 Injection (Vero Cells)" independently developed by Yunying Biotech was approved and issued the "Drug Clinical Trial Approval Notice" by the State Food and Drug Administration. The indication is advanced solid tumors.

This therapy can play the dual role of "oncolytic virus killing"+"immune system activation", activating the immune system through the "three roads" carried by R130, reversing exhausted T cells, and revitalizing them.

During the investigator-initiated clinical investigation project (IIT) phase, R130 demonstrated excellent clinical efficacy and safety, and no serious adverse events were observed.

China's first in vivo gene editing therapy based on non-viral vectors cleared by FDA for clinical trials

On July 22, Ruizheng announced that its "ART001 injection" had received tacit approval from the CDE clinical trial on July 19 for the treatment of transthyroxin amyloidosis (ATTR). On September 2, Ruizheng Gene announced that ART001 had recently obtained U.S. FDA clinical trial approval, becoming my country's first non-viral vector-based in vivo gene editing candidate to obtain U.S. FDA clinical trial approval.

ATTR is a rare and fatal disease caused by the deposition of amyloid fibers formed by unstable transthyroxine (TTR) tetramers in multiple organs of the body.

ART001 is an in vivo gene editing therapy under development. It uses lipid nanoparticles (LNP) as a delivery vehicle to deliver gene editing components targeting the TTR gene to the liver, safely and specifically edit the TTR gene, block the expression of TTR protein, and avoid abnormal deposition of amyloid material from the root cause. In addition, the therapy's in vivo gene technology platform uses LNP as a delivery carrier and does not require the use of viruses and cells, which is expected to significantly reduce the cost of new drug development and production.

ART001 is currently conducting clinical Phase 1 trials in China. The IIT study showed that all subjects had completed at least 24 weeks of follow-up, and TTR protein dropped by more than 90% from baseline 4 weeks after dosing, and remained stable after 24 weeks.

China's first treatment for type 2 diabetes using genetically modified mesenchymal stem cells

On August 28, the IND submitted by Jiyuan Biotech for the "Human GLP-1 and FGF21 Dual Factor Highly Expressed Adipose Stem Cell Injection" received CDE clinical tacit approval, and the indication is Type 2 diabetes mellitus (T2DM). This is the first clinical trial application in China to use genetically modified mesenchymal stem cells to treat T2DM, and is expected to bring new hope to diabetic patients.

Human GLP-1 and FGF21 dual factor high-expression adipose stem cell injection is a cryopreserved stem cell preparation independently developed by Jiyuan Biotech. It is derived from patient abdominal fat. It uses the company's stem cell technology platform and genetic modification technology platform to incorporate GLP-1 and FGF21, two metabolic disease treatment drugs, are packed into stem cell drugs and are clinically used to treat refractory T2DM. This therapy gives ordinary mesenchymal stem cells new targets and functions. It not only realizes the regulatory effects of GLP-1 and FGF21 on glycolipid metabolism, but also uses its homing characteristics to achieve targeted local treatment, which plays a role in protecting pancreatic beta cells and inhibiting complications. Breakthroughs have been made in correcting metabolic disorders in T2DM and repairing tissues and organs.

Gene therapy based on AAV vectors shines in many fields

1、XMVA09

On August 19, the second new IND application for the Class I innovative gene therapy drug "XMVA09 Injection" independently developed by Star Eye Biotech was approved by CDE. The newly approved indication this time is diabetic macular edema (DME). In March this year, XMVA09 injection received CDE clinical implied approval for the IND application for the indication of wet age-related macular degeneration (wAMD).

XMVA09 injection is the first gene therapy candidate to achieve dual specific targets and intravitreal injection of capsid. It uses a new AAV capsid, which can infect retinal pigment epithelium (RPE) cells close to choroidal lesions through intravitreal injection, providing a more convenient way for subsequent clinical application. In addition, XMVa09 injection adopts a dual antibody design and targets both vascular endothelial growth factor (VEGF) and angiopoietin-2 (ANG-2) targets, improving the therapeutic effect of the drug and increasing the coverage of patients insensitive to VEGF.

2、BN-1001   

On August 28, the IND application for the Class I innovative gene therapy drug "BN-1001 Ophthalmic Injection" independently developed by Besio Biotech officially received CDE implicit approval for the treatment of neovascular wAMD.

BN-1001 ophthalmic injection adopts AAV gene therapy strategy. It is the product with the lowest dose among similar products disclosed at home and abroad and can continuously and stably express anti-VEGF molecules. The injection can minimize the incidence of symptoms in patients, and is expected to achieve the goal of "one treatment, lifelong cure" and meet the current increasing clinical needs.

3、RM-101   

On September 17, the U.S. FDA officially approved Ruifeng Biotech's IND application for RM-101, an innovative drug for Usher Syndrome. This approval marks a milestone breakthrough and progress in the development of the world's first AAV-based gene editing candidate drug for Usher syndrome.

RM-101 is an innovative gene therapy developed by Ruifeng Biotech for USH2A gene-related retinitis pigmentosa in Usher syndrome. It is an AAV-based gene editing candidate drug that can specifically target USH2A RNA and regulate alternative splicing biological processes., induce the expression of normal functional proteins. Recovery. RM-101 is administered by subretinal injection and is expected to achieve one-time administration and long-term effectiveness.

Previous experimental results showed that injection of RM-101 in a mouse model could induce up to 90% USH2A exon 13 skipping, with a lasting and stable effect and no effect on the retina. At the same time, injection of RM-101 into the subretinal space of non-human primates mediated a higher level of target exon skipping, with a stable effect and no abnormalities in the eye during the observation period.

Summary

To sum up, my country has made major breakthroughs in gene therapy technology and is expected to provide accessibility and curative drugs for patients with serious diseases. It has a high-level technical accumulation in the development of gene editing technology and new vectors, and has continued to accumulate groundbreaking results in the fields of solid tumors and ophthalmology, and has two major innovative drug directions in vivo and in vitro. With the continuous deepening of policy support and international cooperation, the gene therapy independently developed by China has entered the "fast lane of transformation" and will benefit patients around the world.