How many FDA approved circular RNA are there?

Introduction to Circular RNA

Definition and Characteristics
Circular RNAs (circRNAs) are a unique class of RNA molecules distinguished from their linear counterparts by their covalently closed loop structure—this means that both the 5′ and 3′ ends are joined together, eliminating free ends that are typically required for exonuclease degradation. This structure confers remarkable stability in cellular environments, a feature that allows them to persist longer compared to traditional linear messenger RNAs (mRNAs). The discovery of circRNAs dates back to the 1970s when they were first observed in plant viroids and later in the hepatitis delta virus, but it was only in the past decade that circRNAs started to be appreciated for their functional roles rather than being dismissed as splicing artifacts. Their unique molecular configuration also facilitates a number of biological functions; for instance, circRNAs can act as microRNA (miRNA) sponges, interact with RNA-binding proteins, and in some cases even serve as templates for protein translation when equipped with an internal ribosome entry site (IRES). These characteristics, combined with their tissue-specific expression and evolutionary conservation, have spurred significant interest in exploiting circRNAs for both diagnostic and therapeutic applications.

Role in Therapeutics
The inherent stability of circRNAs and their capacity to modulate gene expression render them highly attractive for therapeutic development. Therapeutic approaches using RNA molecules have evolved over the years—from antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) to the breakthrough mRNA vaccines against COVID-19. In contrast to conventional mRNA therapies, circRNAs offer the potential for sustained expression and enhanced stability in vivo, which could translate into lower dosing frequency and prolonged therapeutic effects. Researchers are actively investigating how the circularization of RNA can be utilized to generate more resilient RNA vaccines and gene therapy constructs, overcoming many of the limitations that linear RNAs exhibit under physiological conditions. Despite the rapid progress in elucidating the roles, formation, and potential applications of circRNAs, the technology is still emerging and is currently in the developmental phase regarding clinical translation.

FDA Approval Process

Overview of FDA Approval Stages
Before any therapeutic reaches the market, it must clear several stringent stages dictated by the U.S. Food and Drug Administration (FDA). These stages begin with preclinical studies where the candidate therapeutic is evaluated in vitro and in animal models to gauge its safety, efficacy, pharmacokinetics, and pharmacodynamics. Following successful preclinical evaluation, the therapy enters a series of clinical trial phases:
- Phase I assesses safety, tolerability, and dosage in a small group of healthy volunteers or patients.
- Phase II expands the study to a larger group, aiming to gather preliminary data on efficacy while further evaluating safety.
- Phase III involves even larger populations to confirm efficacy, monitor side effects, and compare the therapy with standard or placebo treatments.
- Phase IV refers to post-marketing studies after the FDA approval, designed to provide additional information on the drug’s risks, benefits, and optimal use.

Specific Requirements for RNA-based Therapies
RNA-based therapies in particular—such as mRNA vaccines or siRNA medications—face unique challenges, including rapid degradation by ubiquitous RNases, potential immunogenicity, and hurdles in delivery across cell membranes. For an RNA therapeutic to be approved by the FDA, it must meet strict criteria regarding stability, specificity, efficacy in downregulating or expressing target proteins, and a delivery mechanism that ensures the RNA reaches the intended cells or tissues without eliciting damaging immune responses. Notably, while several RNA-based drugs have been approved (including ASOs, siRNAs, and linear mRNA vaccines), these therapies are predominantly based on linear RNA molecules rather than circular ones. The approval process for RNA therapeutics also involves comprehensive clinical pharmacology studies to understand absorption, distribution, metabolism, and excretion (ADME) properties.

Circular RNA Therapies

Current FDA Approved Circular RNA
When considering the current state of RNA therapeutics approved by the FDA, it is important to distinguish between RNA atomic classes. As of now, while the FDA has approved a number of RNA-based drugs—such as small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), and notably the linear mRNA vaccines developed for COVID-19—the approval portfolio does not include any therapeutics that are based on circular RNA. This absence remains despite the high potential of circRNAs in the therapeutic space. Reviews and industry analyses confirm that although circRNA therapeutics have exhibited promising preclinical results, they have yet to progress through the FDA clinical trial pipeline to reach approval. In short, there are zero FDA approved circular RNA therapies to date.

Pipeline and Developmental Therapies
While there are no FDA approved circular RNA therapeutics currently available, the research and development landscape for circRNAs is rich with innovative candidates and preclinical studies. For example, some circular RNA constructs, including those designed to encode therapeutic proteins or serve as stable vaccines, have been described in patents and exploratory publications. A news report cited that as of September 2023, there were around 10 circular RNA drug candidates being developed worldwide, many of which are still in the preclinical phase. These candidates cover a range of indications—from cancer gene therapy to vaccine development. Companies are actively investigating synthetic circRNAs that could engage the translation machinery despite their circular configuration, and early-phase preclinical studies have indicated the potential for these molecules to produce sustained expression of therapeutic proteins. However, crossing the translational gap from promising laboratory results to FDA-approved treatments remains challenging due to the need for robust clinical data indicating safety, efficacy, and consistent manufacturing processes.

Challenges and Future Directions

Regulatory Challenges
The leap from preclinical promise to an FDA-approved therapeutic is marked by numerous hurdles. For circular RNA therapeutics, one of the key regulatory challenges arises from their relatively novel nature in the therapeutic field. Regulators require extensive evidence on:
- Safety and Immunogenicity: Although circRNAs are inherently more stable than linear RNAs and may provoke fewer off-target effects, their unique structure necessitates thorough testing to ensure they do not inadvertently trigger innate immune responses via pathways like RIG-I, or lead to the formation of toxic by-products such as linear concatemers.
- Manufacturing and Consistency: The production of circRNAs involves complex methodologies—such as enzymatic ligation, ribozyme-based strategies, or the use of tRNA splicing systems—that must be tightly controlled to guarantee consistent circularity and purity. Any deviation may affect the therapeutic's efficacy or safety profile.
- Delivery Mechanisms: Effective delivery remains a significant barrier. Efficiently transporting circRNAs to target cells or tissues requires advanced nanoparticle systems or alternative carriers that must be optimized to prevent degradation, ensure cellular uptake, and release the payload in a bioactive form.

Regulatory agencies like the FDA scrutinize all these factors, necessitating extensive preclinical and clinical data to confirm that circRNA therapeutics can meet the same rigorous standards required of more traditional RNA-based drugs. Hence, even though there is excitement around their potential, the path to FDA approval for circRNA is complex and still unfolding.

Future Prospects for Circular RNA
Looking forward, the potential of circRNAs in medicine remains high. Their inherent stability, capacity for prolonged protein expression, and versatility as both molecular sponges and templates for protein production could eventually translate into breakthrough therapies, particularly in areas where conventional drugs have limited efficacy (such as targeting undruggable genes in cancer or very rare genetic disorders). Future directions might include:
- Advanced Formulations: Continued improvement in the methods for circularizing RNA, such as chemical modification approaches and optimized ligation methods, will be essential to improve yield, purity, and functional performance.
- Enhanced Delivery Systems: Investing in robust nanoparticle delivery systems and next-generation transfection methods will be crucial for circRNAs to navigate the physiological barriers and reach their intended intracellular targets effectively.
- Expanding Clinical Applications: Beyond their use as therapeutic protein producers, circRNAs might serve as novel vaccine platforms or adjuvants that harness their ability to modulate immune responses. These applications are particularly intriguing given the recent success of linear mRNA vaccines and the ongoing research into circRNA-based vaccine candidates.
- Rigorous Clinical Evaluation: As more circRNA candidates enter first-in-human trials, there will be a need for detailed biomarker studies and clinical endpoints that validate their efficacy and safety profiles relative to existing therapies.

Overall, while the current pipeline shows promise with numerous preclinical candidates actively being developed—some already in early-stage clinical trials—the translation of circRNA therapeutics into FDA-approved drugs remains a goal for the future. Many researchers and biotechnology companies forecast that in the coming years, with a growing understanding of circRNA biology and improved manufacturing and delivery technologies, this gap will start to close.

Conclusion
In summary, despite a considerable body of research and promising preclinical data underscoring the potential of circular RNAs for therapeutic applications, there are currently zero FDA approved circular RNA therapies available in the market. The success of linear RNA-based therapeutics, such as the COVID-19 mRNA vaccines, has set a powerful precedent. However, the regulatory approval process for RNA therapeutics demands rigorous clinical data on safety, efficacy, and quality—which has not yet been amassed for circRNAs.

Researchers are actively exploring various strategies to harness the stability and unique translational capabilities of circRNAs in the realms of gene therapy, cancer treatment, and vaccine development. Patents and preclinical studies suggest that circRNA platforms could offer significant advantages over linear RNAs, including prolonged protein expression and improved serum stability. Nevertheless, challenges such as efficient circularization, purification, and delivery need to be overcome before these therapies can complete the FDA approval process.

Given the rapid pace of technological advancement and the currently expanding pipeline of circRNA therapeutics in preclinical stages—as evidenced by reports of around 10 circRNA drug candidates globally—the future holds real promise for this innovative class. However, until these candidates successfully navigate the multi-phase clinical trial process and demonstrate the necessary safety and efficacy, the number of FDA approved circular RNAs remains at zero.

Thus, while the road ahead for circRNA-based therapies is filled with exciting potential, further research, refinement of production methods, and well-designed clinical studies are imperative to unlock their full therapeutic value and ultimately achieve FDA approval.