In the past few years, Next Generation RNA therapeutics have emerged as one of the key therapeutic modalities in the modern healthcare industry. These RNA based therapeutics play a crucial role in protein production and regulation of gene functions. In addition, they offer enhanced therapeutic and safety profiles as compared to traditional treatment approaches. However, these therapeutic modalities are accompanied by a set of challenges that pose as a restriction to their application for therapeutic purposes. Some of the challenges include:
Some of the challenges have been briefly discussed below:
Stability: RNA therapies are inherently unstable owing to the presence of loose 3’ and 5’ ends, which are easily recognised and rapidly degraded by RNA exonucleases.
Delivery: Negatively charged RNA requires packaged delivery across hydrophobic cytoplasmic membrane in order to circumvent immune system detection and degradation by exonucleases
Immunogenicity: RNA therapies generate expansive immune response, which leads to enhanced cell toxicity and decreased, impaired and impure translation into therapeutic proteins
The next generation RNA therapeutics and RNA vaccines are modified treatment molecules aimed at specifically targeting and treating diseases that were earlier considered undruggable. Further, these molecules are believed to be highly stable and have an extended impact at relatively low doses. Among these, innovative modalities include:
Circular RNA (circRNA): Circular RNA refers to a closed loop-structure of single stranded RNA that is covalently bonded at the 3’ and 5’ ends, forming a highly stable molecule. The circular structure of the molecules resists degradation by RNA exonucleases due to unavailability of loose ends.
The next generation RNA therapeutics and RNA vaccines pipeline currently features the presence of more than 20 circular RNA therapeutics and vaccines, being developed across initial stages of drug development (discovery and preclinical). The primary target indications for circular RNA therapeutics include oncological, neurological and infectious diseases. Key players engaged in the development of circular RNA based therapeutics include (in alphabetical order) Chimerna Therapeutics, Esperovax, Orna Therapeutics, Ring Code Biotech, SYTE.bio, Targovax and Therorna. Notably, since 2019, more than USD 380 million has been raised / invested by companies engaged in the development of circular RNA, reflecting significant funding activity for circular RNA-based therapies in this domain.
It is worth highlighting that industry players are actively collaborating with circular RNA therapy developers in order to support the discovery, development and delivery of circular RNA therapeutics. For instance, Renagade Therapeutics has entered into a collaboration with Orna Therapeutics in order to support the delivery of circular RNA therapies being discovered by Orna Therapeutics. Considering the potential of these therapies, several industry stakeholders are actively engaging in the development of such therapeutics. The support from venture capitalists and big pharmaceutical companies will continue to drive the development of circular RNA therapeutics and RNA therapeutics market growth over the forecast period.
Self-amplifying RNA (saRNA): Self amplifying RNA is an engineered form of RNA, combining the amplifying genome (native to certain viruses) to the therapeutic gene of interest. This allows generation of multiple copies of the gene of interest at the target owing to the amplification property of the template.
The next generation RNA therapeutics and RNA vaccines pipeline currently features the presence of more than 50 self amplifying RNA therapeutics and vaccines, being developed across all the stages of drug development (ranging from discovery to late stage clinical). It is worth highlighting that one such vaccine, Gemcovac, has been approved for emergency use against Omicron COVID variant in India. The primary target indications for saRNA therapies include infectious diseases and oncological disorders. Key players engaged in the development of self amplifying RNA based therapeutics include (established before 2010, in alphabetical order) Alphavax, GlaxoSmithKline, BioNTech and Pfizer.
Transfer RNA (tRNA): Transfer RNA is an indispensable adaptor molecule central to the translation of mRNA to proteins. The stable structure and sequence diversity offered by these molecules accentuate their potential as a plausible therapeutic moiety for the treatment of multiple disorders.
The next generation RNA therapeutics and RNA vaccines pipeline currently features the presence of more than five transfer RNA therapeutics and vaccines, being developed across initial stages of drug development (discovery and preclinical). It is worth highlighting that one such therapeutic, ATRY1923 is currently in phase III of clinical development and has received fast track and orphan drug designations from the US Food and Drug Administration. The primary target indications for tRNA therapeutics include genetic and oncological disorders. Key players engaged in the development of transfer RNA based therapeutics include (in alphabetical order) Alltrna, aTyr Pharma, hC Bioscience, ReCode Therapeutics and Tevard Biosciences.
Endless RNA (eRNA): Endless RNA is a closed-loop, programmable RNA molecule that is capable of expressing therapeutic proteins inside the body. The unique properties of endless RNA include high stability, enhanced durability, wide applicability and target specificity.
Key player engaged in the development of endless RNA based therapeutics is Laronde. It is worth highlighting that this is currently a niche treatment modality, having significant potential in the coming decade, owing to its structural characteristics and stability.
In addition to the above mentioned types of modalities, the RNA therapeutics and vaccines domain features the presence of a number of next generation / novel therapeutic modalities, which include: Self-replicating RNA (srRNA), Small Activating RNA (sacRNA), Controllable Self-replicating RNA (c-srRNA), Antibody-RNA Conjugates and Long-acting mRNA (lamRNA).
Many stakeholders are undertaking initiatives to forge alliances with other industry / non-industry players. Of the strategic partnerships focused on next generation RNA therapeutics and RNA vaccines that have been inked since 2019, close to 22% of partnerships are research and development agreements, indicating that the stakeholders are actively engaged in research and development of these next generation RNA therapeutics and RNA vaccines. Interestingly, it was observed that many big pharma players, such as Merck, Gilead Sciences, AstraZeneca and others have partnered with several next generation RNA therapeutics and RNA vaccines players, in order to expand their respective portfolios. It is worth highlighting that a sum of $2.9 billion has been raised / invested by players engaged in the therapy development, indicating the interest of stakeholders in the RNA vaccines and RNA therapeutics market .
Some of the recent developments in the next generation RNA therapeutics and vaccines domain include:
In February 2023, Tevard Biosciences entered into a research and development agreement with Vertex Pharmaceuticals for the development of novel tRNA therapeutics, intended for the treatment of Duchenne Muscular Dystrophy.
In January 2023, Esperovax entered into a product development agreement with Gingko Bioworks for the development of circular RNA therapeutics, specifically targeting colorectal cancer.
Further, in January 2023, HDT Bio entered into a technology utilization agreement with the Pan African Cancer Research Institute (PACRI), in order to develop self amplifying RNA vaccines and therapeutics.
Recently, the increasing number of orphan and fast track designations granted by the regulatory authorities, such as the USFDA and the EMA, has intrigued interest and increased the confidence of the pharmaceutical industry in these novel targeted therapies. Given the inclination towards development of novel next generation RNA therapeutics and RNA vaccines, along with the engagement of big pharma players and high investments, we believe that the next generation RNA vaccines and RNA therapeutics market is likely to evolve at a rapid pace over the forecast period.