Xingming Youjian Reports Positive Interim Results from Pioneering Optogenetic Gene Therapy IIT for Ocular Diseases

CGT (Cell and Gene Therapy) is becoming one of the most promising fields in the biopharmaceutical industry.

Among all diseases treated with gene therapy, eye diseases are one of the most favored indications. On one hand, the eye, as an immune-privileged space, has multiple barriers that make it relatively independent from the immune system. On the other hand, localized drug delivery is possible, with lower dosage, significantly reducing cost and safety risks.

In 2021, UgeneX was established in Suzhou Industrial Park, focusing on the development of gene therapies for ophthalmic diseases, and is one of the Biotechs incubated by Fosun Health Capital's innovative drug fund.Since its establishment three years ago, UgeneX has confirmed two technical routes: optogenetics and neuroregeneration, with three pipelines under research. The fastest pipeline has been advanced to IIT clinical trials, and some interim results have been announced, showing excellent safety and efficacy.

UgeneX Conducted In-depth Industry Research and Strategic Planning When Choosing Directions and Tracks, Tan Chang Revealed: "Systemic, Whole-body Gene Therapy Still Faces Some Bottlenecks, Including Manufacturing Costs, Quality Control, and Safety Risks." According to the VCBeat database, Since the World’s First Gene Therapy Was Approved for Marketing in 2017, a Total of 29 Gene Therapies Have Been Approved Globally (Excluding Genetic Engineering Antibodies and Gene Vaccines). Most of the Gene Therapy Pipelines at Different Stages Focus on Rare Diseases, Which Also Determines Their Limited Price Reduction Space – Lenmeldy, Approved This Year for the Treatment of Metachromatic Leukodystrophy (MLD), Set a New Drug Pricing Record at $4.25 Million Upon Launch. "However, the Risks of Local Administration in Ophthalmic Gene Therapy Are Much Lower," Said Tan Chang.

Moreover, UgeneX has assembled a core team with international perspectives, covering the entire process from R&D to industrialization. This team includes members who graduated from Fudan University, have worked in multiple biopharmaceutical companies, and possess over 10 years of experience in the research, production, and application of viral vectors.Dr. Tan Chang。

In 2022, Dr. Jian Tan joined UgeneX as the Vice President in charge of quality and production: "Firstly, UgeneX's pipeline focuses on common disease areas, which is different from other gene therapy companies, and I believe this makes gene therapy more accessible to patients; secondly, the fund incubation model also significantly reduces risks for start-up biotech companies, which is beneficial for long-term company development."

Adeno-associated virus (AAV) is capable of infecting a wide range of tissues with low immunogenicity and low integration capacity, and is considered to have good safety. Since the first clinical trial using AAV for gene therapy in 1995, AAV has become one of the most cutting-edge, promising, and commonly used viral vectors in the field of gene therapy through recent years' development. "The current state of AAV is very similar to that of antibody drugs in their early days. With the increase in AAV production, improvements in delivery efficiency, reduced toxicity, and gradually enhanced safety, it has also further addressed cost issues," said Tan Chang.

In the field of gene therapy, the eye is a relatively popular treatment site. Due to its small size, transparent medium, and other characteristics, the eye has clear methods for assessing visual function. A small dose of AAV vector can achieve robust delivery, and due to the presence of the blood-retinal barrier, it possesses immune privilege, making local drug administration relatively safe. In 2007, the world's first clinical trial for hereditary blindness was launched, marking a milestone chapter in ocular gene therapy, attracting countless researchers to dedicate themselves to this field.

Currently, the indications for ophthalmic gene therapy are mainly inherited retinal diseases (IRDs) associated with single-gene mutations, including retinitis pigmentosa, choroideremia, Leber's hereditary optic neuropathy (LHON), Leber congenital amaurosis (LCA), Stargardt disease, achromatopsia (ACHM), and X-linked retinoschisis (XLRS), among others. "Take retinitis pigmentosa as an example: as photoreceptor cells gradually degenerate to complete degeneration, the disease progressively advances to its late stage. In the early stage of the disease, treatment may be possible through gene editing or neuroprotective techniques, but in the late stage, there is currently no available treatment," said Tan Chang.

Retinitis pigmentosa is a blinding genetic disease involving more than 100 types of gene mutations. The degeneration of photoreceptor cells leads to slow and irreversible progressive blindness. According to NIH statistics, the global prevalence of retinitis pigmentosa is 1 in 5000, with 29% being in the advanced stage.

Since the birth of optogenetics more than 20 years ago, researchers have regarded it as a promising technical approach to address blindness, Parkinson's disease, and more. "The key point is that the optogenetic method can bypass the conventional approach of replacing or repairing individual genes, without considering the type of genetic mutation. As long as the symptom involves photoreceptor degeneration, treatment can be administered. Moreover, it can target common diseases like age-related macular degeneration, which are not monogenic hereditary conditions. Therefore, this represents a broad-spectrum therapy, significantly expanding the population of treatable patients and moving gene therapy towards 'large indications,'" said Tan Chang.

In 2021, *Nature Medicine* reported a case study of a patient with retinitis pigmentosa who experienced functional recovery after receiving optogenetic therapy. This was also the first report of functional recovery in a neurodegenerative disease patient following optogenetic therapy. Aside from gene-editing therapies, which are only effective in the early stages of the disease, no treatments have currently been approved for retinitis pigmentosa.

Based on the foundation of optogenetics, UgeneX has developed two FIC/BIC pipelines: UGX-201 & 202, which will be introduced separately below.

UGX-201 is a broad-spectrum gene therapy product targeting retinal photoreceptor degenerative diseases (such as retinitis pigmentosa, dry age-related macular degeneration, etc.). It uses AAV to deliver the gene of recombinant opsin (a genetically engineered GPCR-type photosensitive protein) to retinal ganglion cells, enabling them to perform the light-sensing function originally belonging to photoreceptor cells, thereby rescuing vision. UGX-201 is a global first-in-class product with independent intellectual property rights and global rights owned by UgeneX. It is also the first product of its kind to enter clinical research, initiating investigator-initiated clinical research (IIT) in mid-2022. The interim results released at the 27th ASGCT Annual Meeting demonstrated excellent safety and efficacy.

UGX-202 utilizes a principle similar to UGX-201, employing an ion channel-type photosensitive protein to function. Compared to other similar pipelines worldwide, it will further enhance light sensitivity, broaden the sensitive wavelength range, and accelerate photosensitive kinetics, thereby achieving better vision restoration effects. Currently, UGX-202 has completed initial efficacy studies and is preparing to initiate IIT.

In the capital winter of the biopharmaceutical industry, UgeneX's model is particularly worth learning from. "In addition to sufficient financial support, the fund incubation model is backed by the ecosystem of Fosun Healthcare and Fosun Pharma, which can help early-stage Biotech companies avoid initial ‘pitfalls,’ quickly build a complete team with industry background, balance risks, and get on the right track of new drug development," said Tan Chang.

In UgeneX's pipeline layout, we can see the shadow of industrial thinking. From the principle of optogenetics, UGX-201 and UGX-202 only differ in their targets; the former is a First-in-Class (FIC) pipeline, while the latter is striving towards Best-in-Class (BIC). There are many pipelines under research based on optogenetics and targeting light-sensitive ion channels, with the fastest having progressed to Phase 2b clinical trials. "However, our design for light-sensitive ion channels is different, and preclinical study data indicates its potential to become best-in-class."

In addition to optogenetics, UgeneX is also placing significant focus on optic nerve regeneration. According to data released by the World Health Organization, glaucoma is the second leading cause of blindness globally after cataracts, with over 80 million patients worldwide. The "White Paper on Comprehensive Prevention and Treatment Management of Glaucoma" published in Shanghai in 2023 shows that awareness of glaucoma is low in China, with two-thirds of patients already at the middle or late stage at the time of their initial diagnosis, and there is a trend toward younger patients. Current treatments, whether medication or surgery, can only control or delay the progression of the disease, lacking effective means for reversing blindness.

For glaucoma and other optic nerve degenerative diseases, UgeneX has developed the pipeline UGX-101, which transforms other neurons in the retina into ganglion cells to rebuild the neural connection between the retina and the brain, enabling blind patients to regain their sight. Currently, UGX-101 is being tested in mouse models.

Currently, UgeneX is initiating a new round of financing.