SynBio Pharma-Style Biotech: How SyntheX Sustains Its Strategic Collaboration with Orna Therapeutics

In January 2023, Simnova announced a collaboration with Orna, a rising star in circular RNA, to jointly develop cell therapies based on mRNA technology. The next frontier in cell therapy has found some answers in Simnova.

After the most representative cell therapy, CAR-T, entered commercialization, cell therapy companies are eager to find more innovative and differentiated footholds. Focusing on the two core challenges of universal applicability and solid tumors, new targets and technologies have been emerging one after another. Facing the limitations of CAR-T application scenarios, the industry has expanded indications from cancer to autoimmune diseases. While the entire industry is betting on the next breakthrough in cell therapy, Simnova has firmly chosen to integrate with the current cutting-edge mRNA technology. This collaboration is quite leading in the field of cell therapy.

Why did Simnova choose to bet on the mRNA+ cell therapy technology, which is still an emerging field in the industry? What are the next steps and strategies?VCBeat had a conversation with Dr. Cao Zhuoxiao, CEO of Simnova, during which we formed an impression of Simnova as pragmatic and highly efficient.

On January 5, 2023, Simnova announced a collaboration with Orna, a rising star in the circular RNA field. The in vivo cell therapy products developed by Orna using its breakthrough circular mRNA technology will be handled by Shanghai-based Simnova for product development and commercialization in Greater China, including Orna's leading pipeline candidate, the anti-CD19 in situ CAR (isCAR) program, named "ORN-101." Additionally, certain programs may accelerate clinical validation of innovative technologies through investigator-initiated trials (IITs) in China, benefiting patients earlier.

For the research on mRNA+ cell therapy, it is currently in the early exploration stage. The most advanced progress disclosed so far is the combination therapy of BioNTech's product BNT211 enhancing CAR-T cells. Its Phase 1/2 clinical data shows that cancer metastasis in patients with advanced solid tumors has been completely alleviated. This further validates the feasibility of mRNA+ cell therapy.

The application of mRNA technology is indeed another innovative approach to solving the challenges of cell therapy. This method avoids the need for ex vivo preparation of CAR immune cells by directly infusing mRNA drugs encoding the CAR sequence into the patient's body, enabling immune cells to express CAR and generate CAR-T cells in vivo, which then identify and kill tumor cells.

Simnova has recognized the tremendous potential of mRNA technology in the field of cell therapy, thus conducting more than a year of early-stage research and development along with POC validation. During this period, the company verified the anti-tumor effects through linear RNA and also discovered additional advantages of circular RNA.

This prompted Simnova to start looking for a suitable circular RNA company as a partner, and the U.S.-based Orna came into their view. The isCAR project mentioned in this collaboration with Simnova is Orna's flagship program, which can utilize Orna's innovative circular RNA and lipid nanoparticle delivery platform to directly generate CAR cell therapy in vivo.

The collaboration with Orna is a well-considered decision made by Simnova.Cao Zhuoxiao mentioned: "We are not blindly pursuing innovation. Instead, we decided to cooperate with Orna after conducting technical verification internally. We don't want this to be just a storytelling technology; we hope it is truly feasible.""Therefore, Simnova simultaneously focused on its own technical accumulation and validation while negotiating cooperation with Orna. During this process, we fully recognized the advanced nature and immense development potential of Orna's technology."

Simnova is firmly committed to exploring the potential of mRNA technology. Once this technology is realized, it will serve as two powerful tools alongside the company's universal CAR-NK therapy, enabling combined or synergistic treatments in cell therapy.

The help from Simnova was indispensable in facilitating this collaboration with Orna.

With the support of Simcere Pharmaceutical, Simnova was established in Boston, USA, in 2019, starting early-stage drug research and strategic planning in cell therapy. To provide Simnova with broader growth opportunities, in 2021, Simcere Pharmaceutical spun it off to operate independently, allowing Simnova to embark on a new journey.

"The reason for making such a decision, Cao Zhuoxiao revealed, is that 'Independent operation was proposed from the perspective of the company's development because Sinopharm Simcere is a large entity with several thousand employees, and we are a relatively small unit within it. When making many decisions, we are somewhat restricted by the larger entity. In fact, the smaller the company, the easier it is to make decisions. Once the entire process system is simplified, development will also accelerate. For the better development of Simnova and to better reflect our value, we have become independent from the listed entity.'"

In the cell therapy industry, Simnova is not among the earliest entrants, a situation that gives rise to two challenges: not being overtaken by latecomers and catching up with predecessors while standing out. "Speed" is what they need to focus on, and it has been a principle they have practiced since their establishment.

In the past three years, Simnova has developed and grown very rapidly.: Focusing on universal CAR-NK and CAR-T technologies, Simnova has established seven product pipelines, possessing mature process development technology. In 2020, a GMP facility was completed in Shanghai. In 2022, the clinical results of its universal allogeneic CAR-NK product were remarkable. Preclinical research findings of the next-generation dual-target universal CAR-NK were presented at the ASH Annual Meeting. In 2023, Simnova announced a collaboration with Orna, a star company in circular RNA, to jointly develop in vivo CAR-T therapy.

This speed is attributed to the先天优势 that Simnova has drawn from Sinopharm: "Simnova appears to be a Biotech company on the surface, but it operates with the status of a Pharma.".\" This is Cao Zhuoxiao's best summary of Simnova.

Biotechs that are incubated and spun off by established pharmaceutical companies to operate independently differ from other startups. Simnova was positioned at its inception to pursue an international development path, not only inheriting the innovative gene of Sinopharm but also gaining an early advantage in team building and resource aggregation.

Simnova's founder has a deep background in both academia and industry, and the core management team possesses extensive international experience.

Before Simnova operated independently, Cao Zhuoxiao had already worked at Sinopharm for many years. On one hand, she was responsible for building the platform and pipeline for biologic macromolecules, and on the other hand, she managed the advancement of early research in cell therapy at Simnova. With 15 years of experience in the industry, from Novo Nordisk to Hengrui, and then to Sinopharm and Simnova, Cao Zhuoxiao has consistently focused on the development of first-in-class and best-in-class innovative drugs. Particularly during her time at Hengrui, she participated in the establishment of the UCAR-T cell therapy platform. This experience, gained in 2015 when cell therapy in China was just emerging, provided her with valuable insights for leading Simnova.

Another co-founder is Professor Pin Wang, a tenured professor at the University of Southern California. He is a highly renowned expert in the field of cell therapy both internationally and in China, with extensive experience in molecular engineering, cell engineering, CMC for cell therapy, and even clinical research. Professor Wang is not only a senior scientist recognized within the industry but also highly successful in entrepreneurship. He has co-founded several companies, including Immune Design, which he established with Nobel laureate in life sciences, Professor David Baltimore. Immune Design went public successfully and was acquired by MSD in 2018.

In addition, Simnova's new drug research and development team has rich industry experience ranging from ten to thirty years. The entire team not only focuses on technological innovation and pipeline development but also is more closely aligned with industrialization. This has enabled Simnova to establish a more mature strategic approach in the cell therapy sector, distinct from other start-up companies:

First, the Simnova team covers various stages of new drug development, including early R&D, CMC, clinical advancement, and commercialization. This has enabled Simnova to establish a complete process from drug development to market launch. Its leading and mature technology system can accelerate the progress of the pipeline more rapidly and ensure that the product reaches its sales peak in a short time after commercialization.

Secondly, Simnova can quickly and comprehensively achieve resource integration, especially in terms of pipeline synergy. Cao Zhuoxiao introduced that many of Simnova's cell therapy products can be synergistically clinically developed with Sinopharm's pipeline in terms of indications, to achieve better efficacy. This strategy of drug combination has been proven to be highly feasible and ensures that Simnova’s products maximize their value in clinical and commercial aspects.

Currently, the most advanced cell therapy, CAR-T therapy, has left two pressing issues for the industry: one is its high cost, and the other is the persistent inability to achieve breakthroughs in treating solid tumors. All of Simnova's pipeline developments are centered around these two bottlenecks, hoping to solve them by researching and developing universal CAR-NK and CAR-T therapies.

Between 2019 and 2021, Simnova had already conducted extensive and in-depth research in cell therapy, developing its own understanding and accumulation of various technical pathways, which has enabled the company to achieve a state of steady growth with potential for rapid advancement.Simnova has the longest research time in the universal CAR-NK field, which is also the company's core research area."At present, there are many CAR-NK companies. Although they are similar companies, their technical routes may vary, and the sources of NK cells and technical formats will also differ. Over the past few years, we have conducted internal validation and comparison of the most common technical routes for CAR-NK, gaining deep insights. Therefore, the route we have currently chosen is the one we believe has the best chance of succeeding soon," said Cao Zhuoxiao.

Such pipeline layout underlying logic is equally applicable to Simnova's CAR-T therapy. It is also based on this underlying logic,Simnova has built three unique technology platforms:

• NK Cell Product Technology Platform: Developing universal CAR-NK technology to address the high cost of cell therapy.Simnova started with the differentiated design of CAR, holding global independent research and development patents. This innovative CAR design ensures the persistence of drugs in the body and the functionality of CAR-NK cells. Meanwhile, Simcere Pharmaceutical has brought Simnova an innate advantage in antibody sequences, and the optimized antibody sequences selected in the CAR design make the antibodies loaded on Simnova’s CAR highly competitive and differentiated. Simnova also possesses a high level of drug development technology, not only achieving efficient gene transduction and editing of NK cells but also developing a mature NK cell expansion system.

• CAR-T Product Technology Platform: Breaking Through the Dilemma of Solid Tumor TreatmentSimnova's CAR-T product technology platform shares commonalities with NK cell platforms. Simnova has implemented a differentiated design for its CAR and holds global patents. The company utilizes a CAR+BiTE approach, achieving the combined effect of CAR-T therapy and tri-specific antibody macromolecular drugs through a single-cell format. Meanwhile, the indications chosen by Simnova allow for intratumoral administration, ensuring that a sufficient number of T cells can migrate into the tumor to take effect. This guarantees both efficacy and safety while suppressing cancer recurrence. Currently, Simnova has observed positive signals in preclinical studies.

• mRNA Cell Therapy Technology Platform: Combining mRNA and CAR-T technologies to tackle the challenge of universalization. Simnova has partnered with ORNA, a rising star in circular RNA, to jointly build a platform and develop pipelines.

With the support of the three major technology platforms, Simnova's products show very distinct differentiation at the design stage.For differentiation, Cao Zhuoxiao gave a stricter standard:"Our products must demonstrate a clear advantage in antitumor efficacy compared to international competitors to achieve true differentiation."This enables Simnova to have stricter control over new drug development.

Simnova Product Pipeline, Source: Simnova

Currently, Simnova has yielded more positive outcomes in its product pipeline. Among them, the CAR-NK product is progressing the fastest. The CD19-targeted CAR-NK cell therapy has achieved remarkable research results in the IIT phase and has registered for a Phase I clinical trial. Meanwhile, the dual-targeting CAR-NK cell product targeting BCMA and GPRC5D was showcased at the 2022 ASH Annual Meeting. Preclinical experimental data showed that the BCMA/GPRC5D dual-targeting CAR-NK cells improved animal survival rates, and compared with single-targeting CAR-NK cells, this product significantly reduced tumor recurrence.

Regarding Simnova's future plans, Cao Zhuoxiao focused on rapidly advancing the clinical progress of the company’s pipeline. Simnova continues to move forward efficiently and pragmatically in the cell therapy sector.