At the 48^th Health Policy Shanghai Round Table with the topic of “How to Make Innovative Therapies Accessible?”, Dr. Richard Liqun Wang, Founder, Chairman, and CEO of Neukio Biotherapeutics, presented the current state, trends, bottlenecks, and prospects of Cell and Gene Therapy (CGT) research and development in China.

Dr. Wang believes that the current inaccessibility of CGTs is caused by the customization nature of the autologous cells. Path forward direction is to focus on developing allogenic therapies via technological innovation and to expand indications from hematologic malignancies to solid tumors, and even non-oncological conditions such as autoimmune diseases. This approach is not only to drive down the cost but also a transformation from a follower to innovator for Chinese cell therapy industry.

Currently, the cellular therapies approved at home and abroad are fundamentally the same type—autologous cells. This indicates that China is keeping pace with global standards. Why is it expensive? It primarily caused by the customized autologous cells manufacturing, we need to maintain the therapeutic efficacy while solving the high cost issue. In fact, there has been ongoing exploration to change the current state.

Why are cell therapy products cannibalising? Not only in China, but also the global approved CAR-T products are all concentrated on two available targets. For China, with a shorter development history, the CGT industry is still in the imitative innovation phase. The possible path to reduce the cannibalization really depends on the ability to innovate.

Moreover, the innovation environment in China may not be as conducive as it may be perceived, enterprises are facing considerable pressures. Under excessive competition within the industry, innovation lacks funding, talent, sufficient time, and trust of investors. Companies have to choose conservative management strategies to survive. A supportive industrial ecosystem is essential to accelerate the development of next generation cell therapies in global market, giving hope to cancer patients worldwide!

Why the results of commercialization of autologous CAR-T do not meet expectations?A substantial influx of capital into the CGT field during 2017-2020, has cultivated many CAR-T companies. Despite recognizing the difficulty and complexity of this research, the failure to meet commercial expectations was unexpected. Dr. Wang believes that there are many other reasons, besides the limited patient population and non-differentiated competition:

1. The absence of government sponsored medical insurance coverage impact patient’s accessibility. The sales of similar products in U.S are 20 times higher than China's. In 2017, the first CAR-T product in the U.S. was priced over $400,000 but with good insurance, while the price in China reduced to around 40% but counted affordability issue because of all expanses are out-of-pocket.

2. Clinical trials (free) greatly attract the patients diluting the commercialization pool.

Judging from the current trajectory, the expansion from hematologic to solid tumors, and even into non-oncological areas, as well as the shift from autologous to allogeneic therapies, represents opportunities to Chinese and global companies. Dr. Wang believes that it is entirely possible for China to evolve from an imitator to an originator of completely independent innovation. Several directions are emerging:

1. Expand Indications for Autologous CAR-T: Due to the limited number of patients eligible for last-line treatments, it is potentially to transit from approved last-line indications to earlier lines of treatment, including the second line and even the first line. This approach can also extend into related hematologic malignancies and chronic non-tumor diseases, such as the treatment of autoimmune diseases. B-cell depletion therapy, which targets and eradicates autoreactive B cells responsible for producing self-destructive antibodies, has already demonstrated significant efficacy. As the increase of treatments, it will contribute to cost reduction.

2. Development of CAR-T for Solid Tumors: Solid tumors account for over 90% of all types of tumors, that is why a lot of companies have been concentrating on CAR-T research for solid tumors in recent years. However, the curing of solid tumors is much more complex than treating hematologic malignancies, and even second-generation CAR-T therapies are not directly applicable. The pronounced heterogeneity and the intricating microenvironment of solid tumors present substantial technical challenges, making the achievement of complete remission (CR) elusive. There have also been tried developments in TCR-T and TIL therapies still autologous, yet they will suffer from issues related to high costs, accessibility, and efficacy. If treatments cost millions but only extend a patient's life by a few months, the willingness to pay will be diminished. It is curable to treat hematologic malignancies through CAR-T therapies, very different from extending a few months patient's life, therefore the patient will be more willing to pay.

3. Technological Innovation and Development of Universal Products: To develop the next generation cell therapy products, it is necessary to upgrade autologous CAR-T into universal, scalable manufacturing products, return it to the traditional essence of biomedicine, ensuring safety and efficacy while lowering costs and retail prices, making therapies accessible to a broader patient population by revolutionizing technologies. It will also enable competition with antibodies, ADCs, another therapeutic modalities, providing better solutions for clinical practice and finally achieving commercial success. Many companies are progressing on this promise, but none have reached the NDA approval yet, while the fastest progressing universal product is on a phase II clinical trial. The development of innovative drugs, such as small-molecule compounds and antibody drugs, typically takes 7-10 years from conception to market launch, emphasizing that innovation is not an overnight process and requires patience from society and practitioners.

4. Exploration in Autoimmunity: Over 30 companies have announced that they are pursuing the development of an engineered cell therapy for the treatment of autoimmune diseases. NK cells are inherently universal cell products, but their therapeutic effects need to be enhanced through multiple gene editing. The largest challenge in creating universal NK cells lies in preventing the rejection of allogeneic cells by the patient's immune system.

Dr. Wang believes that, theoretically, iPSC-CAR-NK is better for treating auto-Immune desease. Firstly, it is an off-shelf product same as primary NK cells, allowing multiple dose and outpatient treatment with no life-threatening side effects like CRS and ICAN that have been clinically validated. Secondly, Single iPSC clone can be scaled up and differentiated into NK cells, avoiding repeated sourcing. Once a GMP-compliant 3-tiere cell bank is established, it can continuously scaled manufacturing for homogeneous final products. Thirdly, iPSCs is amendable for multiple gene editing and clonal isolation to generate homogenic product with enhanced in vivo homing, persistence, allo-rejection and resistance to TME suppression. Site specifical insertion of CAR via gene editing, with no risk of random inactivation of endogenous genes by viral transduction, enhance targeted killing. The CAR molecule can be precisely inserted into the genome via gene editing, augmenting the intrinsic natural killing and ADCC effects while enhancing the specific killing potential against solid tumors.

China has Advantages in Cell Therapy Innovation:

1. Healthcare and innovation are the focus of national strategy.

2. There exists a large unmet clinical needs in China.

3. China has amassed a wealth of talent and rich clinical experiences in the field of cell therapy.

4. The IIT (investigator-initiated trial) mechanism in China accelerates the cell therapy products launch for universal solid tumor curing with essential safety guarantees and ethical reviews, which potentially position China a global leader in this field.

5. Some information has indicated that the National Health Commission is considering to raise the access standards or even closing the pathway of IIT, while we advocate for strengthened supervision to ensure clinical research orderly and in a high quality, apparently not supporting simply close it that one size fits all.

Neiko Biotherapeutics focuses on development of allogeneic cell therapies for technology platform and pipelines targeting both solid tumor indications and autoimmune diseases that are readily manufactured in large scale, via iPSC-CAR-NK approach. Since the manufacturing process is a crucial aspect of cell product performance, Neukio has set clear goals for process development to create differentiated technological solutions. Notably, our self-developed iNK production process shows significant advantages, with feeder cell free, fully closed operation, 3D suspension culture with perfusion, and the early products will quickly enter clinical validation.

In conclusion, Dr. Wang hopes that the perception of cell therapies will connect with both high efficacy and affordability in the near future.