The Asia-Pacific gene therapy market was valued at $349.1 million in 2020 and is expected to grow at a compound annual growth rate (CAGR) of 36.8% to reach nearly $7 billion in 2030. This predicted exponential growth is attributed to factors that include the surging burden of chronic diseases, the growing number of positive clinical trials, and the increase in gene therapy-based biotech companies. We discuss here the journeys of three gene therapy startups in South Korea, Japan and China, and how their products will or are already making a difference for patients.
Rznomics was founded in 2017 by Seong-Wook Lee, PhD, of the department of bioconvergence engineering at Dankook University, Yongin, South Korea. The core technology of the company is “trans-splicing ribozyme-based RNA editing,” in which the trans-splicing ribozyme specifically targets and cleaves disease-causing or related RNA, and trans-ligates with the therapeutic RNA to induce therapeutic effect. This brings about a down-regulation of the target RNA, and the therapeutic RNA is expressed selectively in cells that express the target.
“There are numerous advantages of our platform,” says Lee, CEO of Rznomics. “No cellular machinery in the cell is needed and no external protein needs to be provided as the ribozyme performs trans-splicing and ligation by itself. The target RNA can be any RNA species including mRNA and non-coding RNA, which expands the range of therapeutic targets. Additionally, all mutated RNAs can be edited with one molecule through targeting the upstream region of known mutation sites.”
Currently, Rznomics has five pipeline drugs based on its trans-splicing ribozyme technology to address different human diseases such as cancer, neurodegeneration, and genetic eye disorders. One of its products, RZ-001, is already in phase I/IIa trials for treatment of hepatocellular carcinoma and glioblastoma.
“RZ-001 is replication-incompetent adenoviral vector encoding a human telomerase reverse transcriptase (hTERT) targeting trans-splicing ribozyme,” says Lee. “The trans-splicing ribozyme recognizes and cleaves the hTERT mRNA, and it replaces the hTERT mRNA with Herpes Simplex Virus thymidine kinase, which is used as a suicide gene. With the co-administration of prodrug ganciclovir (GCV), the phosphorylated GCV blocks DNA replication in targeted cancer cells, thereby leading to apoptosis and anti-cancer effect.”
The company has received Orphan Drug Designation for RZ-001 targeting hepatocellular carcinoma and Fast Track Designation for RZ-001 treating glioblastoma from the US FDA. The phase 1 clinical trial for RZ-001 treating glioblastoma already began in Korea and patient screening process is underway. The company also plans to commence clinical trial for RZ-001 in combination with atezolizumab and bevacizumab in subjects with hepatocellular carcinoma later this year.
For this clinical trial, Rznomics has signed a Clinical Trial Collaboration and Supply Agreement with Roche and Celltrion, who will provide atezolizumab and bevacizumab, respectively. “We are expanding indications beyond cancer to incurable and rare diseases with highly unmet medical needs that are difficult to be addressed with the existing therapies,” says Lee. “As part of this effort, CTN was recently secured from the Australian TGA for a clinical trial treating autosomal dominant retinitis pigmentosa.”
Gene therapy cures deaf children in China
Congenital deafness affects approximately twenty-six million individuals worldwide and has no current pharmacological treatments. Traditional interventions for hearing loss, such as cochlear implants and hearing aids, have been the mainstay of clinical management. While these devices can provide substantial benefit, they do not restore natural hearing. Cochlear implants, though effective for severe hearing loss, also have shortcomings, such as sound discrimination in noisy environments and music appreciation due to transmitting sound through electrical signals.
Preliminary results from their recent study, which was published in The Lancet, demonstrated remarkable outcomes for patients who received unilateral gene therapy and exhibited an improvement of hearing and enhancement of capability of speech perception. Those receiving gene therapy bilaterally not only regained hearing in both ears but also showed improvements in distinguishing sounds in noisy environments, the ability to locate sound sources, and the capability to appreciate music.
“Gene therapy is a promising advancement in the treatment of deafness and offers hope to other patients who suffer from congenital deafness around the world,” says Shu. “Our team at Fudan University is collaborating with Refreshgene Therapeutics, a company in Shanghai, China that specializes in the development of gene therapy drugs for rare diseases, genetic disorders, and other chronic conditions, to develop a gene therapy drug targeting the OTOF gene.”
Shu adds that given that the multitude of over two-hundred identified genes that contribute to deafness, his team is dedicated to advancing treatments for various forms of hearing loss. “Beyond OTOF, we are exploring new strategies such as gene editing and gene replacement for other genes like GJB2, KCNQ4, and TMC1. Additionally, we’re delving into treatments for acquired hearing loss to benefit a wider patient population suffering from hearing loss.”
In addition to treating deafness, a gene therapy product developed in partnership with Refreshgene Therapeutics named RRG001, is designed for patients with neovascular age-related macular degeneration. This drug is currently undergoing Phase I/IIa clinical trials in China, marking a significant step forward in the treatment of the eye disease in the country.
Japan’s first gene therapy
Collategen® is the first gene therapy product approved in Japan as well as the first such therapy in Asia as well as the world targeted at critical limb ischemia. Collategen is a naked plasmid DNA that is delivered intramuscularly before being transcribed and translated in cells into hepatocyte growth factor. The product has been shown to promote blood vessel formation (angiogenesis) and is indicated for patients with arteriosclerosis obliterans and Buerger’s disease accompanying critical limb ischemia that is not amenable to surgical revascularization, leaving no other effective treatments available. There are about 500,000 such patients in the U.S., 20–40% of whom find conventional treatments ineffective.
Collategen was initially developed in the lab of Ryuichi Morishita, MD, PhD, professor of clinical gene therapy at Osaka University and further developed at AnGes, a company founded by Morishita and where he now serves as a medical advisor. “It took us many years before getting Collategen approved,” he says. “As we were the first company to do so, we had to educate regulators what gene therapy is, and to show that it is efficacious and safe. This indication is also challenging as regulators are more familiar with life-threatening diseases like cancer, and critical limb ischemia is not considered life threatening.”
Morishita sees a bright future for gene therapy in Asia and the world and expects to see more products in the next 10 years. However there are still a few challenges to address to make gene therapy more widely available.
Another challenge, Morishita adds, is translation from preclinical models to human subjects. “There is obviously a translational gap,” he says. “In order for us to accurately determine gene therapy dose, we need more data, but clinical trials for gene therapy are rare and expensive. Essentially, it is a chicken and egg problem here. We need ways to make clinical trials more affordable and faster so we can move the products quicker into the clinics to benefit patients.”
The future of gene therapy in Asia
Morishita shared his experience launching Collategen and how payment models in countries affect the progress of gene therapy. “In Japan, the government sets the price of new products such as for gene therapy, but in the United States the private companies set the price. When governments set the price, they calculate it based on quality-adjusted life years which can be hard to determine and often restrictive. This can disincentivize homegrown companies in Japan and Asia from launching products in their home countries in favor of the United States market. Researchers therefore need to work closely with regulators on product pricing so that residents in their home countries can also benefit from biomedical innovations.”
Shu shares Morishita’s sentiments and adds that investment in healthcare infrastructure is needed to ensure that hospitals and clinics have the facilities and expertise to administer gene therapy safely and effectively. There is also a need to increase public understanding of genetic diseases and the potential of gene therapy, which can help build trust and support for these treatments. Educational activities should target both the general public and healthcare professionals. Gene therapies can be prohibitively expensive, so innovative pricing models, insurance coverage, and government subsidies may be required to make these treatments affordable to a broader population.
“By addressing these challenges, the Asia-Pacific region can pave the way for patients having greater accessibility and affordability to gene therapy,” says Shu. “It will not only benefit patients by providing them with potentially life-changing treatments but also contribute to the global advancement of medical science. Collaboration among governments, industry, academic institutions, hospitals, and patient advocacy groups will be crucial in realizing this vision.”
Andy Tay, PhD, is a science writer living in Singapore.
