Early Regulatory Engagement – The Key to Fast-Tracking Nucleic Acid Drug Development

Thanks to the evolution of drug action mechanisms, the development of manufacturing and delivery technologies, and the rising demand for precision treatments, the advanced medical products industry is growing by leaps and bounds. In particular, emerging therapies involving short-chain nucleic acids such as antisense oligonucleotides (ASOs), DNA aptamers, and siRNAs have taken center stage in the industry. With the aim of exploring the major regulatory issues and challenges related to nucleic acid drugs, under the guidance of the Department of Industrial Technology of the Ministry of Economic Affairs (MOEA), the Science and Technology Law Institute (STLI) organized the second session of the “Webinar Series on International Regulatory Affairs” on August 7 in cooperation with GeneOnline.

Unveiling the Great Potential of Nucleic Acid Drugs

Following the success of the first session, there were nearly 400 participants online at its peak. Under the theme of “Voice of the Genes – Understanding Regulatory Affairs of Nucleic Acid Drugs”, speakers of the webinar included Dr. Jailal Ablack, Head of Preclinical Research at Entos Pharmaceuticals, a Canadian genetic medicines company, and Sophia Lugo, CEO of Radar Therapeutics, a California-based mRNA biotech company.

In his welcome speech, Dr. Lu Cheng-Yen, Legal Researcher of STLI, highlighted that nucleic acid drugs hold the promise of becoming powerful tools for personalized precision medicine in the future. In fact, the global nucleic acid drug industry is growing rapidly, and Taiwan is also catching up as more and more biotech companies establish technology platforms and related facilities in areas such as drug discovery, nucleic acid synthesis, vector development, and CDMO services. Therefore, it is imperative to keep abreast of technological advances and regulatory issues in the international arena to optimize the domestic regulatory framework and help Taiwan’s biotech companies explore global business opportunities.

Overcoming Bottlenecks in Drug Delivery by Innovative Proteolipid Vehicle

Dr. Jailal Ablack kicked off the webinar by elaborating on challenges and recent technological breakthroughs in nucleic acid drugs. He noted that there are still bottlenecks to be overcome in terms of how researchers can seize the right timing to deliver therapeutic nucleic acids to the right cell types, which in turn leads to considerations of drug safety and redosability. Currently, adeno-associated virus (AAV) and lipid nanoparticles (LNPs) are commonly used vectors for delivering nucleic acids, but both of them have some clinical limitations. Although AAVs are compatible with multiple organs or tissues, they can only be used with DNA payloads and are difficult to re-dose owing to the risk of triggering immune responses or even cytotoxicity; while LNPs are re-doseable, they can only be used with RNA payloads. The tendency of LNPs to accumulate in the liver also limits their scope of application. Besides, he pointed out that both vectors were found to pose a risk of toxicity at high doses. Therefore, innovations in vector development to address these shortcomings are essential for transforming the field of nucleic acid drugs.

With this in mind, Entos Pharmaceuticals has developed a proteolipid vehicle (PLV) called Fusogenix. As its name suggests, this novel vector employs a “fusion-associated small transmembrane protein (FAST protein)” derived from fusogenic orthoreovirus and incorporates a lipid formulation that differs from that of traditional LNPs, allowing the vector to readily fuse with the membranes of the target cells to enhance drug delivery efficiency.

Citing available experimental results in mice and primates, Dr. Ablack noted that Fusogenix brings together the strengths of AAV and LNP, being suitable for both DNA and RNA payloads as well as diverse delivery modes to a multitude of organs and tissues, including the central nervous system (CNS) and the digestive system. Moreover, it has been found that drug delivery using the new vector allows nucleic acid payloads to be expressed in the target cells for a longer period of time, without triggering an immune response even upon repeated dosing. Entos’ success is an example that shows the potential for precision therapy, improved safety and a broader range of indications by addressing the shortcomings of existing vectors through modifications and innovations.

mRNA as the Fourth Pillar for Biopharmaceutical Innovation

Sophia Lugo analyzed the regulatory framework and approval process of nucleic acid drugs in the US FDA and European Medicines Agency (EMA) and shared valuable insights into current trends and challenges. “We are entering the age of RNA and mRNA can be called the fourth pillar for biopharmaceutical innovation, alongside small molecules, biologics, and cell and gene therapy,” said Lugo. Actually, the number of therapeutic mRNAs in the R&D stage has skyrocketed from about 100 to over 1,300 (as of June 2024) in just a few years compared to the pre-COVID-19 days. This, coupled with the success of mRNA COVID-19 vaccines and the progress of Moderna’s cancer vaccine into Phase 3 clinical trials, highlights the tremendous possibilities of the mRNA market.

Speaking about the regulatory issues of nucleic acid drugs, Lugo mentioned that one of the major difficulties is that even the FDA has not yet established specific regulatory guidelines to comprehensively cover mRNA drugs. Thus, biotech companies usually refer to regulations for biologics and adjust their R&D workflows accordingly. In the U.S., most nucleic acid drugs are currently under the oversight of the FDA’s Center for Biologics Evaluation and Research (CBER). In other words, the approval process for nucleic acid drugs is similar to that for biologics. Fast Track designation, Breakthrough Therapy designation, and Priority Review are also applicable if certain conditions are met. She took the COVID vaccine as an example, noting that mRNA vaccines exactly enjoyed the benefits of these channels, allowing them to be quickly put to use in the battle against the pandemic. This precedent may also serve as a reference for developing regulatory strategies for mRNA-based therapies.

Early Engagement is the Key to Regulatory Success

In the context of biotech company management, Lugo believes that early engagement with authorities is critical to effectively addressing regulatory complexities and ensuring compliance with efficacy and safety milestones for new drugs. Nowadays, both FDA and EMA have early communication mechanisms, such as pre-IND meetings and fast-track approval programs, and can offer scientific advice and technical support. She therefore suggested that biotech companies should make good use of these measures to accelerate their R&D efforts. She also mentioned the FDA’s “Platform Technology Designation” program proposed in May 2024, which aims to streamline the review process and expedite the review of technologies known to be applicable to multiple drugs and reusable (known as “platform technologies”), thereby minimizing waste of time and resources. Although the inclusion of technologies used in the R&D of nucleic acid drugs (e.g., payload modification, LNP vectors, etc.) remains debatable, the FDA’s willingness to listen to the industry’s views in the process of formulating this program is still an encouraging step forward.

Another breakthrough is the January 2024 update of the FDA’s industry guidance on human gene therapy products. The latest version of this guidance, which is also applicable to mRNA therapeutics, allows biotech companies to replace in vivo animal studies with in vitro and/or in silico (computer simulation) studies at the non-clinical stage, and to use the resulting data to seek regulatory clearance. Given that the new guidance can significantly reduce R&D costs and shorten clinical development time, this can be considered a major victory for the field of nucleic acid drugs.

Panel Discussion on Regulatory Issues and Emerging Indications

Dr. Ablack began the panel discussion by describing the field of nucleic acid drugs as “uncharted waters. As such, he recognized the importance of early communication between biotech companies and regulatory bodies. Citing Entos’ experience with Health Canada as an example, he pointed out that a data-driven approach to discussing experimental models and data with regulators early in the R&D process can help address their concerns regarding manufacturing and safety.

Sophia Lugo reminded the audience that as there are no established regulatory references for nucleic acid drugs, investors tend to be risk averse in the face of various unknowns. Therefore, biotech companies should approach regulators as early as possible to win their trust and demonstrate a clear pathway from bench to bedside to reassure investors.

Regarding the development trend, both speakers agreed that liver diseases are currently popular among market players, while CNS indications are also gaining prominence. The former is because of the relative ease of delivering nucleic acids to the liver, and thus the lower R&D barriers; while the latter faces a formidable blood-brain barrier, many biotech companies are eager to challenge this area in light of evolving targeted drug delivery technologies and the large unmet medical need for neurological diseases such as Alzheimer’s Disease. Lugo added that in addition to infectious diseases, liver diseases and neurological disorders, autoimmune disorders also represent a promising area of development.

Navigating the Uncharted Waters and Striving for Regulatory Success

Dr. Ablack believes that there are two major bottlenecks when navigating the uncharted waters of nucleic acid drug development. The first one involves public misconceptions, particularly worries about the possible adverse consequences arising from the fusion of nucleic acids with cellular genomes. He emphasized that a large amount of clinical data accumulated over the past decades has shown that the risk of DNA integration is even lower than the mutation rate of human genes. Nevertheless, accurate scientific communication and data-driven strategies are necessary to dispel these deep-rooted myths. Another challenge is that nucleic acid drugs are often targeted at patients with serious illnesses and extreme frailty such as those with rare diseases or late-stage cancers. Therefore, he advised researchers to dose carefully based on the minimum effective dose to reduce safety risks.

Lugo agreed that drug developers should pay extra attention to safety when working with frail and critically ill subjects. Biopharma companies also need to communicate clearly with patients and physicians to dispel any misunderstandings and win their trust. She also pointed out that the regulatory framework for nucleic acid drugs has not yet been fully agreed upon by the major regulatory authorities, especially the definition of “active ingredients”, and that this uncertainty may be confusing for biotech companies. 

Lastly, the two speakers also shared their insights for medical policymakers in Taiwan and the Asia-Pacific region. Dr. Ablack urged regulators to be flexible and open-minded, allowing biotech companies to share information early enough to identify potential problems. Besides, by creating large, anonymized datasets, researchers will be able to understand the in vivo expression of nucleic acids in different populations, enabling them to answer key questions about pharmacokinetics, efficacy and safety.

Lugo concluded by saying that understanding the regulatory processes and patient populations of individual regions is critical to the success of nucleic acid developers in exploring new markets. For the Taiwan market, she noted that regulatory agencies in Taiwan offer supportive measures such as pre-IND meetings, consultation services and module-based rolling review systems, not only assisting biotech companies in interpreting NDA requirements, but also providing a useful reference for other emerging markets. She recommended that companies should identify influential clinicians and experts and contact them at an early stage, thus gaining a better understanding of how to respond to regulatory inquiries and reviews, and making the process of clinical trials and applications for approval much easier.

Author

Richard Chau