Growing interest in RNA-based medicines may necessitate a new class of pharmaceuticals

Last month, the EMA held a public stakeholder meeting to discuss regulatory and scientific considerations for RNA-based medicines. The sessions covered introductory views, quality, nonclinical and clinical aspects for these novel therapeutics. This first analysis discusses the potential need for identification of a new pharmaceutical class for these molecular entities, which don’t fit neatly into the existing chemical or biologic categories.

Background on RNA-based medicines

• RNA-based medicines can be divided into two large categories: messenger ribonucleic acid (mRNA) and non-coding RNA-based medicines. The mRNA category would include mRNA used in therapeutics, mRNA-based vaccines and mRNA-based cell therapies. Just as a quick recap: mRNA serves as the carrier of genetic information from deoxyribonucleic acid (DNA) in the cell nucleus to the cell’s cytoplasm, where the information is used to construct proteins. mRNA-based vaccines can be developed to prevent infectious disease such as Covid-19, or to prevent or treat non-infectious diseases such as cancer. Vaccines against infectious disease were specifically excluded from last month’s EMA’s stakeholder meeting on RNA-based medicines.
• On the other hand, non-coding RNAs interfere with or moderate gene expression, rather than providing instructions for protein construction. This category includes a wide range of RNA types, including anti-sense oligonucleotides (ASOs). These are small pieces of modified DNA or RNA that are chemically synthesized from nucleotides; they target mRNA to either decrease the construction of a toxic protein, or restore the construction of a missing protein. Pharmaceutical production of these oligonucleotides was the primary focus of EMA’s stakeholder meeting. Other types of non-coding RNAs include interfering RNAs (e.g., small interfering RNAs or siRNAs and micro-RNAs or miRNAs), small activating RNAs (saRNAs), RNA aptamers and RNA guides.
• The EMA’s February 2023 stakeholder meeting discussed regulatory considerations for the pharmaceutical development of these therapies. The all-day event covered general aspects of RNA-based technologies, as well as quality, nonclinical and clinical considerations for medicinal product development. This first analysis focuses on some of the general concepts of RNA-based medicines. AgencyIQ will not provide a play-by-play coverage of each session but distil the important concepts, regulatory challenges, opportunities, and questions to be addressed in a series of articles.
• The history of other product categories projects a steep increase in development for RNA-based therapeutics. Sol Ruiz, head of biologics and ATMPs (advanced therapy medicinal products) at the Spanish regulator AEMPS, highlighted that there were only 10 monoclonal antibodies authorized between 1980 and 2000. As of January 25, 2023, that number stands at 136. Similarly, clinical trials for gene therapy products averaged about 100 per year from 1999 to 2016, while in 2017 and 2018, there were well over 200 gene therapy clinical trials initiated each year. At the time of the stakeholder meeting, 25 advanced therapies, including gene therapies, had been authorized in the E. U., with one (Hemgenix, etranocogene dezparvovec) pending and since authorized.
• Thirteen marketing authorization applications for RNA-based medicines have been submitted to the EMA. Ten of those have been accepted as valid applications. Ruiz noted that there were 95 requests for scientific advice with 10 follow-up procedures. Additionally, 50 requests for protocol assistance (i.e., scientific advice for orphan drug designated products) were received, with 20 follow up requests. In all, EMA has received 110 orphan drug designation requests for RNA/ASO-based therapeutics, with 10 being for maintenance of the designation. Additionally, there are 24 agreed-upon pediatric investigational plans.

RNA-based medicines may fall into a new pharmaceutical class

• From a regulatory perspective, the first challenge is the classification of RNA-based therapeutics. Depending on the source material or how the product is obtained, they might be classified as chemical, biologic, or advanced therapy. Ruiz noted that although RNA-based medicines are well covered by the current regulatory framework, certain definitions may need to be adapted.
• RNA-based medicines include a diverse array of therapeutics that have been categorized into various existing pharmaceutical classes. The diversity of categorization is exemplified by a recent publication collating RNA-based medicines currently authorized or under development in the E.U. mRNA-based medicines generally fall into advanced therapies, while non-coding RNA-based medicines generally are classed as chemical entities. However, even mRNA-based cancer vaccines may be classified as either cell or gene therapy products. Additionally, for RNA guides/direct genome editing products, the drug’s status is determined by the associated nuclease, according to the authors.
• “Are ‘RNA medicines’ a third pharmaceutical class distinct enough from NCEs [new chemical entities] and biologics?” asked Tal Zaks, partner at OrbiMed Advisors. Current scientific knowledge and regulatory expectations suggest that a better definition is required, Zaks observed, adding that “emerging technologies do not fit neatly into categories.” NCEs are medicines derived by chemical synthesis. On the other hand, biologics are derived from a biological source and may include immunological products (e.g., vaccines, allergens), biotechnological products (e.g., hormones, monoclonal antibodies), or advanced therapies (e.g., cell and gene therapies).
• What factors should drive the definition of RNA-based medicines? Zaks suggested that the definition could be based on the entity’s nucleic acid makeup, including the source, or could alternatively be based on the mechanism of action. Generally, the RNA’s sugar-phosphate backbone determines where in the human body and cell the medicine goes and how it functions. Factors involving his backbone, the delivery vehicle (e.g., nanoparticle, plasmid) and the mechanism of action can all influence the benefit-risk assessment; these factors can be very different for different types of RNA-based medicines.
• What factors would warrant a technology being considered a discrete platform? The composition – the delivery vehicle and backbone – would provide the platform for different medicines containing different sequences. It will become important to determine which safety and benefit factors are associated with the platform, rather than the sequence. An example is liquid nanoparticle encapsulation, where Zaks pointed out that the liquid nanoparticle may complex differently with different types of RNA (e.g., mRNA vs siRNA), with some similarities, but also some substantial differences in the encapsulation process. Relatedly, an unanswered question is how the benefit-risk relationship translates from one platform product to another. Ruiz noted, that the question of what can be considered a platform has still not been resolved for monoclonal antibodies.
• Regulators need to provide industry with a consistent and science-based set of expectations to add predictability to product development programs, to support the translation of science into medicinal products. These expectations for nonclinical and clinical data should be harmonized across regulatory regions to ensure efficiency in global development programs – principles that apply across all product categories. Additionally, good communication is required to enable stakeholder understanding of what the product developer is doing, noted Zaks. Ruiz pointed to the OPEN initiative, which allows global regulators to observe the EMA’s review procedures to build trust and enable communication and a common understanding of how EMA’s regulatory experiences will continue outside of Covid-19.

There are special regulatory considerations for medicines intended for ultrarare indications and for individual patients

• Typically, medicinal products are developed for populations of patients. However, technological progress has initiated a shift to the development of more personalized or even individualized therapeutics that treat very few patients, or even just one. The potential for RNA-based technologies to deliver such “n-of-one” medicines was touched on, but not discussed in detail, during the stakeholder meeting, Two speakers highlighted specific technologies that raise questions regarding regulatory requirements for the development program.
• A therapeutic personalized cancer vaccine would present opportunities but also pose regulatory challenges. For these therapies, an automated algorithm determines the mRNA composition of a cancer vaccine for each individual patient, based on their DNA profile. The medicine itself is already a platform, since every patient’s vaccine differs in mRNA composition, noted Zaks, with the mRNA profile for each patient developed by publicly available software based on the algorithm. This software is updated periodically, incorporating data as they become available – boosting the predictive accuracy of the algorithm. The software will likely be in its sixth version once a vaccine reaches Phase 3 clinical trials.
• “It is inconceivable that every time the software bit improves we have to run a new Phase 3 trial,” argued Zaks. But a regulatory question still remains about how to incorporate changes in the software’s performance characteristics, once the mRNA vaccine product has demonstrated a benefit in a randomized Phase 3 trial. Zaks proposed that real-world evidence, rather than a new round of Phase 3 trials, will play the critical role in ensuring ongoing patient benefit.
• Cryptic splicing mutations are another example that could be addressed by RNA-based medicines. According to Annemieke Aartsma-Rus, professor of translational genetics at the Leiden University Medical Center in the Netherlands, a cryptic splicing mutation “is a mutation within an intron that suddenly makes part of an intron look like an exon.” Splicing is the process of removing introns (i.e., non-coding sequences) from the mRNA transcript to link up the coding exon regions. This means that the cryptic splicing mutation includes information in the mRNA that does not code for a function protein. Splicing modulation ASOs provide the opportunity to skip these splicing mutations, which then would restore the function of the normal protein. Batten disease and other lysosomal storage disorders are examples of neurodegenerative conditions caused by such splicing mutations.
• These mutations are very rare, affecting very few patients. Generally, development of treatments is conducted in the academic setting since the low number of individuals holds less appeal for the pharmaceutical industry. Milasen is an example of such a splice-modulating ASO to treat Batten disease. The team that developed this ASO was able to identify the mutation and run an “N-of-1” study within one year after first seeing the patient. Subsequent collaborations support further development of these therapeutics. The N=1 Collaborative was launched “as the first international hub for individualized medicines for rare diseases,” supporting transparent data-sharing in the field. Similarly, 1 mutation 1 medicine is a European collaboration to develop individualized medicines; the Dutch Center for RNA therapeutics supports development of RNA-based medicines.
• There are currently no guidelines in the E.U. for medicines intended to treat very few or even individual patients, but the U.S. FDA issued new draft guidance aiming at facilitating these “n-of-one” ASO therapeutics in 2021. The regulator subsequently issued a trilogy of guidance documents addressing chemistry, manufacturing, and controls (CMC), nonclinical, and clinical considerations for individualized ASO-based therapies. Guidelines will certainly be needed in the E.U. to enable efficient development of RNA-based therapies in general, with additional guidance needed for N-of-1 treatments. [Read AgencyIQ’s analysis of the policy, CMC, nonclinical, and clinical guidance.]

What’s next

• Novel classes of therapeutics may allow delivery to novel tissues. RNA-based therapeutics may allow for delivery to tissues such as the brain that are harder to reach. Although gene therapies were excluded from the stakeholder meeting scope, Zaks noted that such a division may not be possible in future, since he has already observed the use of mRNA-based delivery of genetic components. Aartsma-Rus observed that solving the delivery issue will be key, since it determines what diseases can be addressed.
• Ensuring appropriate classification of RNA-based therapeutics will be paramount. Ruiz confirmed that regulators have taken note that classification is an important point to address, and that’s especially important that a potential new classification does not create additional requirements. She confirmed that regulators are already working on developing a definition, which may eventually need to be included in legislation.
• Results in this burgeoning field – including failures – should be published earlier. Aartsma-Rus argued that it would be more beneficial to publish results as they are analyzed, so regulators and industry can see what works and what doesn’t early, rather than waiting years to try to elucidate any observations. This need for publication also extends to regulatory assessments, Aartsma-Rus pointed out; information on how regulators assess medicines and what factors are important during review are invaluable for academic researchers.
• More guidance on RNA-based therapeutics is certainly needed, especially for quality and nonclinical development, said Ruiz. Industry would benefit from more regulatory alignment in general, and especially for platform approaches. For their part, regulators noted limitations in translating information from nonclinical studies to clinical studies, as has already been seen with some advanced therapy products. Still, the regulatory system overall has become more transparent over time, allowing learnings from failed product development programs, as well as the successes.

To contact the author of this analysis, please email Kirsten Messmer.
To contact the editor of this analysis, please email Kari Oakes.

Key Documents and Dates

• EMA website – Regulatory and scientific virtual conference on RNA-based medicines – held on February 2, 2023
• Report – Regulatory and scientific virtual conference on RNA-based medicines – published February 24, 2023