CirCode Biomed is emerging at the forefront of a small but fast-evolving field seeking to turn circular RNA into a new class of medicines. From its roots in pioneering academic research, the Chinese biotech has moved circRNA into the clinic while building a diversified pipeline across ischaemic disease, in vivo CAR therapies and vaccines. CEO Chenxiang Tang explains how the challenge now is to convert the modality’s scientific promise into clinical proof and convince global pharmaceutical partners that circRNA can succeed where existing approaches have fallen short.
What is the science behind CirCode Biomed, and how has the company evolved from its academic origins?
CirCode grew directly out of academic research into the protein-coding potential of circular RNA. Although circRNA had been known since the 1970s, it was largely regarded as non-coding for many years. In 2015, our scientific co-founder Zefeng Wang and colleagues showed that engineered circular RNAs generated through backsplicing could efficiently produce functional proteins in mammalian cells. In 2017, Yun Yang, Zefeng Wang and colleagues demonstrated the translation of endogenous circRNAs and identified an N6-methyladenosine-dependent mechanism that can initiate translation. These studies helped establish the scientific foundation for developing circular RNA as a protein-producing therapeutic modality. Our founders recognised that potential early and established CirCode in 2018, making us one of the earliest companies worldwide focused specifically on circRNA therapeutics.
RNA has long been considered a promising therapeutic modality, but mRNA is naturally short-lived because cells need to adjust protein levels rapidly. That creates a natural barrier to its therapeutic use, especially when sustained protein expression is required. At CirCode, we have also optimised translation efficiency while using only the four natural RNA nucleotides. Through our sequence design, manufacturing and purification processes, our circRNA has shown low immunogenicity in our studies. The combination of prolonged expression and higher translation efficiency means greater cumulative protein production at a lower dose, which we believe can improve efficacy and tolerability and create a wider therapeutic window. That is the underlying rationale for why we see circular RNA as the next generation of mRNA therapeutics.
However, historically raising capital in China for such a new modality has been extremely difficult, especially without an established US counterpart. But the environment changed in 2021, when the success of mRNA vaccines during the COVID-19 pandemic brought much greater attention to RNA therapeutics and companies such as Orna Therapeutics and Laronde attracted significant financing. We were able to raise two rounds that year and start operating as a full-time biotechnology company. I joined as CEO at the end of 2021, when we had around ten people and one laboratory. Today, we have more than 60 employees and capabilities spanning early discovery, platform optimisation and preclinical development through CMC and clinical development.
Our initial focus was on transferring the technology from academia into CirCode and bringing it to an industrial standard, where we could produce circRNA consistently and at scale. We also placed a strong emphasis on intellectual property from the beginning because, for the first time, we saw an opportunity for a Chinese biotech to help lead a new modality and build the patent barriers around its own innovation rather than work around those established elsewhere. We therefore built our patent estate around core technologies including circRNA translation and circularisation, while exploring different therapeutic areas to understand where the modality could provide the greatest advantage. We generated data across those applications and used it to determine where to focus our pipeline, laying the foundation for the programmes we are advancing today.
What guides your pipeline strategy as you determine where circular RNA can have the greatest therapeutic impact?
Because circular RNA is still a new modality, we did not have an established path or another company to follow. Throughout 2022 and 2023, we explored different applications, starting with the theoretical advantages of circRNA and then generating data internally to understand where those advantages could translate into meaningful patient benefit. That process led us to three criteria for selecting programmes: there must be a significant unmet medical need, circRNA must offer a genuine advantage over existing modalities, and the underlying biology should be well established. We are not trying to compete simply on speed or cost. As true innovators, we want to pursue areas where circular RNA can do something other modalities cannot and where that difference can translate into a meaningful benefit for patients.
That thinking led us to ischaemic heart disease and HM2002, our lead programme. Current medicines can lower lipids, prevent clotting or improve vascular function, while percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) can restore blood flow through larger coronary vessels. However, there remains a significant challenge in restoring the microvasculature within ischaemic tissue. Vascular endothelial growth factor (VEGF) is one of the best-characterised and most potent drivers of angiogenesis, so the biology is well understood. The difficulty has always been delivering VEGF effectively to poorly perfused tissue and maintaining its expression at the right level for long enough to generate functional new blood vessels.
Several groups have explored this biology before us. AstraZeneca and Moderna developed AZD8601, a linear mRNA encoding VEGF-A that was administered directly into the myocardium during CABG, while XyloCor Therapeutics has investigated adenoviral delivery of VEGF in patients with refractory angina. These programmes have provided useful clinical evidence around the concept of therapeutic angiogenesis, but we believe circRNA can address an important limitation by sustaining local VEGF expression for longer. In our preclinical studies, HM2002 has produced VEGF for at least 14 days, with expression declining substantially by day 30. That is important because angiogenesis requires sustained signalling, but we also do not want VEGF expression to continue indefinitely.
Our aim has therefore been to connect every step of the mechanism, from circRNA and protein expression through angiogenesis and perfusion to cardiac function and, eventually, patient benefit. We have been able to establish that sequence in animal studies, while clinical evaluation necessarily relies on less invasive measures because cardiac tissue cannot simply be sampled from patients. Taken together, the high unmet need, well-established biology and potential for circRNA to provide sustained but transient VEGF expression made ischaemic heart disease a logical starting point for our pipeline.
How is HM2002 progressing clinically, and how could its delivery strategy broaden its therapeutic potential?
We initiated HM2002 in 2023 and moved into an investigator-initiated trial (IIT) roughly a year later, with the first patient dosed during CABG in September 2024. To our knowledge, this was the first therapeutic circRNA administered to a patient. We subsequently pursued regulatory development in China and the United States in parallel, receiving clinical trial authorization from China’s NMPA in January 2025 and IND clearance from FDA in May 2025. We are now advancing Phase I development in China, and based on our clinical experience to date, we have not observed adverse events that we consider related to HM2002. Meanwhile, although it is still too early to claim efficacy, positive efficacy signals have further boost our confidence in HM2002 and in circRNA as a new modality in general.
Delivery is central to the programme because systemic administration is inherently difficult in ischaemic tissue, where blood flow is already compromised. We therefore administer HM2002 locally into the myocardium as naked circRNA, without LNP encapsulation, which simplifies the formulation and also reduces the LNP-related inflammatory and immune responses. Our first Phase I approach involves injection during CABG, when the heart is already accessible, so the administration itself adds little additional burden for the patient. It provides a practical route to establish the therapy clinically, although it naturally limits treatment to patients who are already undergoing open-heart surgery.
For that reason, we are also developing catheter-based endocardial delivery, which has received regulatory clearance in China. The catheter approach is considerably less invasive and could allow us to reach a much broader patient population, potentially moving HM2002 earlier in the treatment pathway. Our longer-term vision is that patients whose symptoms are no longer adequately controlled with medical therapy could receive HM2002 before they progress to PCI or CABG. Local administration will remain a procedure, but we believe it can eventually become a relatively minor intervention that may not require hospitalisation.
Our CABG-based Phase I study is designed to enroll 9-12 patients, while we are also advancing the catheter-based programme. If the data continue to support HM2002, we hope to progress into Phase II, with the size and design of those studies informed by the Phase I results. Much of this early development is likely to remain in China, where we can work closely with experienced investigators to refine the clinical protocols, before potentially expanding into a multiregional clinical trial at a later stage. From both a practical and capital perspective, that is the most efficient path for us today, while we continue to engage with the FDA on how Chinese clinical data can support broader development.
What response are you seeing from potential partners, and where does CirCode stand within the evolving circular RNA landscape?
There is significant interest from large pharmaceutical companies, especially those with cardiovascular expertise, but they understandably want to see more clinical data. We are introducing both a new modality and a therapeutic concept that does not exist today, as there is currently no approved VEGF-based therapy that regenerates blood vessels in ischaemic heart disease. Most companies have much greater experience with established cardiovascular approaches such as lipid lowering, so assessing an entirely different mechanism requires both education and time to build internal expertise. That has been an important part of our discussions with potential partners, but we believe the conversation could change considerably as our Phase I data mature, given the scale of the unmet need and the potential to restore microvascular circulation rather than simply slow disease progression.
The broader circular RNA field has taken a somewhat different direction, with much of the industry now focused on in vivo CAR-T. Orna Therapeutics made this a major part of its strategy and was acquired by Eli Lilly in 2026 in a transaction worth up to USD 2.4 billion. Sail Biomedicines (merger by Laronde and Senda Biosciences), which is also developing in vivo CAR-T programmes, formed a large collaboration with Johnson Johnson with acquisition potential, worth up to USD 3.5 billion. We are investing significantly in this area as well with the best-in-class non-human-primate experiment data, but we do not want to rely on a single application or asset. Our strategy is more diversified, with therapeutic proteins for ischaemic diseases as our most advanced area, alongside in vivo CAR therapies and vaccines.
Within ischaemic disease, we are already extending the approach beyond the heart through HM2003, which expresses hepatocyte growth factor (HGF) to promote therapeutic angiogenesis in chronic limb-threatening ischaemia. We are particularly interested in patients whose disease cannot be adequately treated through surgical or endovascular revascularisation and who remain at risk of persistent pain, non-healing ulcers and amputation. HM2002 and HM2003 have both received FDA IND clearance and Fast Track designation, giving us two clinical programmes built around the same principle of sustained local expression of angiogenic proteins.
Beyond ischaemic disease, where are you seeing the most promising opportunities for the platform?
In vivo CAR is the second major part of our pipeline, although our strategy differs somewhat from much of the field. Most companies are pursuing CD19-targeting in vivo CAR-T for autoimmune diseases, with the aim of achieving deep B-cell depletion and potentially resetting the immune system. We are working on this as well. Leveraging our proprietary tLNP delivery system, we have achieved deep B-cell depletion at ultra-low dose in non-human primate model, and we are pushing this programme toward the clinical trial. Concurrently, we are also developing an in vivo CAR-M approach using macrophages. Solid tumours remain challenging for CAR-T because of limited tissue penetration and the immunosuppressive tumour microenvironment, whereas macrophages have intrinsic tissue-trafficking and tumour-infiltrating properties, which gives us a strong biological rationale for exploring whether they can provide a complementary approach.
Rather than starting with a broad solid tumour indication, our initial CAR-M programme focuses on malignant ascites in patients with late-stage gastrointestinal cancers. This provides a more localised setting in which to test the approach, as we can administer the therapy intraperitoneally, directly into the environment where the ascites, tumour cells and macrophages are located. It also gives us a pragmatic initial measure of clinical benefit because reducing ascites and the need for repeated drainage could already make a meaningful difference for patients. The programme is approaching an investigator-initiated trial, and while we hope to see antitumour activity, an important objective is simply to understand how in vivo CAR-M performs in humans. If the initial signal is encouraging, we could then explore combinations with PD-1 checkpoint inhibitors or other immunotherapies.
We are also considering how CAR-M could complement CAR-T in autoimmune disease. One of the challenges with non-viral in vivo CAR-T is achieving B-cell depletion that is both deep and durable enough to produce a lasting immune reset. T cells can generate a powerful initial response, but persistence and penetration across different tissues remain important considerations, whereas macrophages are naturally adapted to tissue penetration and longer-term activity. Our thinking is that the two approaches may eventually prove complementary, much as combination therapies have been required in other complex diseases. It is still early, so rather than assume that one cell type will provide the complete solution, we want the clinical data to guide us.
The third part of our pipeline is vaccines, where we have developed circRNA programmes for influenza and varicella-zoster virus (VZV), both of which have generated encouraging preclinical immune responses. We have paused internal development for the time being because the commercial environment for new vaccines has been challenging and we are fundamentally a therapeutics company rather than a vaccine company. However, this work has allowed us to establish a strong vaccine platform, and we are beginning to see renewed interest from pharmaceutical companies and research institutions. As that interest returns, our preferred strategy would be to advance these programmes through partnerships, allowing us to develop the platform collaboratively while keeping our internal resources focused on our core therapeutic pipeline.
As CirCode moves further into clinical development, what are your priorities for de-risking the pipeline?
De-risking has been part of our strategy from the beginning because we are developing a new modality and recognise that we cannot do everything ourselves. We started engaging with major pharmaceutical companies very early, establishing a research collaboration with Pfizer in 2022 and another with Bristol Myers Squibb in 2024, while Johnson & Johnson Innovation, JJDC, co-led our Series A financing in 2023. We have now worked with several of the world’s largest pharmaceutical companies through relationships ranging from material transfer agreements to broader research collaborations exploring where circular RNA could be a good fit. These have primarily been platform collaborations rather than pipeline partnerships, but they have allowed us to build relationships with potential partners while giving them an opportunity to generate data and understand the technology firsthand.
The other part of de-risking is being very disciplined about where we commit resources. We deliberately made ischaemic disease our lead area because the biology is well established and we believe circular RNA offers a clear therapeutic advantage, whereas we saw in vivo CAR-T as a more complex and biologically risky direction. Rather than rushing into the clinic, we first worked with Peking University to establish proof of concept, leading to a 2025 paper in Cell Reports Medicine demonstrating the use of CAR-encoding circRNA to generate CAR-T cells directly in vivo in preclinical models. Only after generating that evidence did we begin advancing the approach as part of our pipeline. We faced considerable pressure to move faster, but in vivo CAR-T requires us to get every component right, from the RNA itself to the LNP and targeting binder, with additional challenges around specificity, formulation, manufacturing consistency and safety. We have to respect the complexity of the technology and, above all, be responsible to patients, particularly in autoimmune disease where the tolerance for serious treatment-related risk is very low.
That discipline, combined with diversification, is fundamental to how we manage risk. We do not want to move into an area simply because the rest of the industry is moving quickly, nor do we want CirCode to depend on a single programme such as in vivo CAR-T. Our approach is to establish a strong scientific foundation, generate convincing data and then commit the resources required to move a programme forward. It may not always be the fastest path, but for a new modality, we believe it is the right one.
Looking ahead to 2026 and 2027, what will be critical to sustaining CirCode’s development and growth?
Our research collaborations generate some revenue, but at this stage they do not materially extend our runway, so financing remains an important part of the strategy. We were fortunate to complete two financing rounds in 2021, around the peak of the biotech market, before the environment deteriorated significantly in 2022 and became extremely difficult in 2023. Despite that, we brought Johnson & Johnson Innovation, JJDC, into our Series A as a co-lead investor in 2023, and we are now close to completing another financing round. For us, getting the pace right is critical. We are a Chinese biotech with finite resources, so we cannot spend as freely as some Western companies and have to be rational about where we deploy capital. The advantage is that we can accomplish a great deal efficiently in China, particularly during a downturn when suppliers and other partners are also operating in a more cost-conscious environment.
We are also encouraged by the level of strategic interest now developing around circular RNA and in vivo cell therapy. Eli Lilly’s agreement to acquire Orna Therapeutics for up to USD 2.4 billion and Bristol Myers Squibb’s USD 1.5 billion acquisition of Orbital Therapeutics show that large pharmaceutical companies are taking the space seriously. In vivo CAR-T is already a highly active field, so we no longer need to spend as much time educating potential partners about the opportunity. What matters now is doing solid work, generating strong data and demonstrating that our approach can differentiate itself. We believe we have some distinctive designs within in vivo CAR-T, while our CAR-M programme gives us another angle that relatively few companies are pursuing.
Looking into 2026 and 2027, our objective is to maintain that balance. A larger partnership around in vivo CAR could accelerate that part of the pipeline, while renewed interest in RNA vaccines may create additional opportunities for collaboration. Even without those partnerships, our ischaemic disease programmes give us a clinical path that we can continue advancing ourselves. We believe that combination of internal programmes, a diversified platform, disciplined financing and selective partnerships leaves us relatively well positioned to manage risk while continuing to move CirCode forward.
