The RNA Therapeutics Race: How can pharma stay ahead of the wave?

From the initial studies on RNA in the early 1900s to the approval of RNA-based vaccines for COVID-19 in 2020, the emergence of advanced RNA technology is reshaping the pharmaceutical and medical sectors, revolutionizing disease treatment approaches, bolstering vaccine preventative capabilities, and introducing a new chapter in personalized therapeutic solutions. With RNA-based therapeutics rapidly expanding and gaining prominence, an unprecedented opportunity is open for pharmaceutical companies to venture into the RNA market and broaden their therapeutic horizons.

The global RNA market is on an unprecedented growth trajectory, with projections indicating significant expansion in the coming years. In fact, as of October 2023, more than 970 RNA therapies are currently in the development pipeline, with infectious diseases and rare diseases as the top targeted therapeutic areas. As we navigate through this transformative period in medical innovation, it becomes crucial for pharmaceutical companies to strategically position themselves within the RNA sector — either through leveraging its superior efficacy to invest in vaccines or harnessing its flexibility to tailor RNA therapeutics at relatively low cost compared to other biologics. The market, driven by substantial investments, scientific ingenuity, and major innovations, presents an exciting prospect for expanding both internal development pipelines and external collaborations across a wide range of therapeutic areas.

Making personalized medicine a reality with RNA technologies

RNA therapeutics pave the way for the realization of personalized medicine that can be safer, cheaper to manufacture, accessible, and more scalable compared to current alternative therapies such as cell and gene therapies or small molecule drugs. This is due to several key attributes of RNA therapies:

• Reaching undruggable targets: Advances in medical research continue to identify targets across therapeutic areas that are currently not treatable with existing products or technologies, including antibodies and small molecules. It has previously been shown that small molecules can target less than one-third of target proteins in humans. RNA therapeutics mainly target noncoding RNAs, which are in higher abundance than proteins in the human genome, thus making targeting more precise and efficacious.
• Fast production: Personalized medicine requires not just the specificity and efficacy of a treatment but also therapies well-developed to address patients’ needs worldwide. RNA-based therapeutics can be designed, synthesized, and produced rapidly for clinical testing compared to other therapies, such as antibody-based drugs that require years for production. The value of this became apparent globally during the global COVID-19 pandemic, when mRNA-based vaccines were able to be produced and tested within an incredibly short period of time.
• Long-term effect: The development of novel delivery systems for RNA encapsulation and delivery to the patients in need has allowed for enhanced longevity of their therapeutic effects. One example is inclisiran, whose effect lasts more than six months after a single administration via injection. In comparison, the effectiveness of small molecule-based drugs often halves within several days.
• No risk of genotoxicity: An additional advantage of RNA-based therapeutics (in comparison to gene therapies, for example) is the lack of genotoxic effects, which can cause significant adverse events and pose a big risk with gene therapies.
• Promise for rare disease: Investment in novel drugs for difficult-to-treat indications, such as rare diseases, has often been modest due to ROI risks. RNA-based therapeutics can offer a safer alternative as the cost of developing novel drug variants is greatly reduced once the structure and delivery system are optimized. An example of this is the development of a custom-designed antisense oligonucleotide to treat Batten disease, a previously uncurable rare disease, thus providing an ultimate personalized treatment for a patient.

Despite the big promise of RNA to transform healthcare, there are still numerous challenges that must soon be addressed to ensure the success and optimal performance of those therapies. First, these therapies still require a cold chain due to the fragility of RNA molecules, which are prone to degradation. This poses a limitation on the accessibility of such therapies, particularly in low-income and resource-constrained regions and environments. In addition, several therapeutic platforms used for RNA-based therapeutics such as delivery vesicles, lack long-term safety and efficacy evidence, while targeted delivery in specific tissues or cell types remains a challenge.

The ever-evolving state of RNA technologies

The accelerated public interest and acceptance of RNA technology have been significantly propelled by the successful deployment of mRNA COVID-19 vaccines. This surge reflects the optimism around RNA technology, fuelled by the belief that its potential stretches beyond the presently available prophylactic COVID-19 vaccines.

The transformative potential of RNA therapies can be applied to a spectrum of diseases, including genetic disorders, cancers, and infectious diseases. Personalized RNA-based cancer vaccines are a key area of interest, leveraging the unique genetic makeup of a patient's tumor with the ease of RNA vaccine manufacture to instigate an immune response to destroy cancer cells. Early-stage clinical trials have shown positive results, suggesting a future for effective personalized cancer treatments. In addition, RNA technologies are also being explored for gene modulation, splicing, or translation. This involves the alteration of gene expression or the modification of RNA post-transcription. It presents a novel way to control cell behavior and could have profound implications for the treatment of a range of conditions.

In addition to the constantly growing number of target therapeutic areas and indications, RNA technologies also have advanced significantly in terms of delivery systems, with new technologies emerging that enable improved RNA therapy effectiveness.

• One such example are exosomes, which are natural lipid membrane-enclosed vesicles that offer minimal immune clearance and adverse effects, especially suitable for diverse RNA species delivery.
• Spherical nucleic acids (SNAs) are also being explored as an alternative delivery mechanism for RNA; SNAs enable rapid cellular uptake with negligible immune response and can overcome various biological barriers.
• Finally, DNA nanostructures are being investigated as they offer precise control over size, shape, and plasticity, albeit with several challenges, including high costs and self-assembly errors.

Further to the novel delivery mechanisms being explored, new RNA technologies are being developed to address previously unmet challenges such as increased stability and reduction of adverse effects. One such technology example is endless RNA (eRNA), a circular RNA molecule that can be programmed to express diverse proteins inside the body, similar to circRNA technologies but with the ability to translate into proteins. Unlike linear mRNA, eRNA has no free ends, making it more resistant to degradation by exonucleases and less likely to trigger an immune response. This technology allows for longer-lasting protein expression (weeks vs. days) and repeat dosing, as the translation step is done continuously. The technology is still in early days in terms of development but has attracted significant funding ($490 million raised so far by Laronde) toward developing a new class of programmable medicines capable of expressing therapeutic proteins inside the body.

How can pharma stay ahead in the RNA therapeutics race?

Overall, RNA technologies hold the potential to lead in a new era of precision medicine. With their diverse therapeutic applications and their ability to address a wide array of diseases, they offer promising avenues for treatment. As such, the strategic investment in this rapidly evolving field could prove highly beneficial for pharmaceutical companies seeking to stay ahead in the race for medical innovation. To compete effectively in the RNA therapeutics space, pharma companies need to consider the following strategic actions:

1. Review current portfolio: Determine whether it is time to start investing in RNA therapeutics or “sit and wait,” depending on the impact that the wave of RNA-therapeutics could have on your portfolio of drugs on the market and in the pipeline.
2. Evaluate maturity relative to TAs of interest: Depending on the therapeutic areas of interest, an assessment of therapy maturity will be required to inform potential investment decisions. For example, RNA therapeutics such as mRNA vaccines for infectious diseases are at a more mature stage than mRNA vaccines for oncology. Similarly, RNAi therapeutics for neurological and cardiology indications are less mature than RNAi therapies for rare disease. The level of maturity will help inform either large investments or less risky approaches such as partnerships or no action at all where maturity is still emerging.
3. Decide on the right investment path: This can include investment into fundamental R&D for next-generation treatments, improved manufacturing, or therapy delivery strategies that can provide a competitive advantage in this fast-evolving market. Furthermore, pharma companies could consider partnerships that can help them gain a leading position in the market through a diversified and complementary offering, such as digital diagnostics that can speed up the diagnosis and, hence, administration of therapies for specific indications.

The advancements in RNA biology and nanotechnology, coupled with the ability of RNA-based therapeutics to act on previously “undruggable” targets and cost-effective and rapid development, make the future of these therapies limitless. This poses multiple opportunities for pharma to benefit from this rapidly growing area to actualize personalized medicine and therapeutic outcomes.

This article was originally published in Advancing RNA