A Platform for mRNA Platforms

The Alliance for mRNA Medicines (AMM) will convene a meeting of global regulatory leaders in Washington, D.C from April 4–5, 2024. The core topic will be to assess the merits of a potential single shared regulatory streamlined platform pathway through FDA, the National Medical Products Administration (NMPA), the Ministry of Health, Labor, and Welfare (MHLW), the European Medicines Agency (EMA), the Pharmaceuticals and Medical Devices Agency (PMDA), the International Council for Harmonization (ICH), stakeholders, and others. Each jurisdiction will likely diverge—ultimately, but hopefully after having initially worked through a common “shared tree trunk” schematic for messenger RNA (mRNA) current good manufacturing practice (CGMP) compliance.

The meeting is intended to discuss what that tree trunk might look like and what it might further grow into. Realistically, a single tree trunk isn’t a good metaphor, and instead we should perhaps be thinking in terms of multiple trunks—as in a copse, thicket, spinney, or grove. Functionally, there isn’t just one type of structural modality. So be it self-amplifying RNA (saRNA) or circular RNA (circRNA), handling and manufacturing aspects vary significantly. As they also do in terms of quantities, potency profiles, or absorption, distribution, metabolism, and excretion (ADME) considerations, or when discussing a generalized vaccine versus personalized oncology vaccines, gene editing, chimeric antigen receptors (CAR-T), antibodies, or protein replacement therapies.

Still, Peter Marks, director of the Center for Biologics Evaluation and Research at FDA, has long been supportive of the concept of a shared regulatory mRNA platform pathway, telling Pharmaceutical Technology, “With over a billion doses administered, the COVID-19 mRNA vaccines have demonstrated the value proposition of this safe and effective platform in viral respiratory diseases. We anticipate that additional studies may expand the reach of mRNA vaccine technology.”

Meanwhile, activities such as mRNA vaccine production currently fall into catch-all categories like “genetic immunogens, derived from principles defined for plasmid DNA vaccines and gene therapy vectors. For vaccine development, the World Health Organization’s (WHO) guidelines around the quality, safety, and efficacy of plasmid DNA vaccines [are] regarded as a basic overarching guideline applicable for the development of RNA-based vaccines” (1). The coming meeting is timely. EMA has called for input into an mRNA regulations guideline for influenza vaccines and beyond (2).

There is now a strong trend toward taking what has worked so well in infectious disease treatment—there is a wealth of data generated during the COVID-19 pandemic response, to refer to Marks’ comment—and marrying this in a hybrid, or often combination therapy, approaches. “Having agreed upon templates to work from as a new basic starting point,” says the AMM executive director, Clay Alspach, “will serve to accelerate exciting and potentially game changing treatments.”

Alspach also noted the recent approval of ARCT-154 (from Arcturus and CSL), a sa-mRNA COVID-19 vaccine for initial vaccination and booster for adults 18 years and older, through Japan's MHLW. Alspach states, “second generation approaches, such as self-amplifying and various novel emerging methods, need to be better coordinated and their manufacturing processes optimized. Regulatory compliance is a huge part of that picture.”

Andy Geall, inaugural AMM board chair and CEO of Replicate Biosciences (working on self-replicating RNA) calls for more frequent international dialogue on both the science and also the regulations involved, due to the extreme speed with which technologies were advancing and converging. He emphasized, “there needs to be a coordinated effort to educate the public about what’s coming, because this is arriving at a speed that no one is used to. This isn’t traditional pharmaceutical development. This is coming at light speed, and with such an array of different approaches and technologies. We need to get out in front in terms of education for the public, our governments, the regulators to help de-mystify all of this for them.” Over and above combating vaccine disinformation, Geall returned to the scope and scale of impending innovation, saying, “We have people working in rare diseases. We’ve got gene editing happening,gene therapy, not forgetting vaccines in infectious diseases, oncology, and even early work in neurology. It’s not scary; it’s just an unknown to the nonscientists.And we need to communicate clearly why all of this is so positive and positively transformative” (3).

References

1. Greene, C. The Regulatory Environment for the Development of mRNA Vaccines during COVID-19. biopharma-excellence.com (accessed Dec. 20, 2023).
2. EMA. Concept Paper on the Revision of the Non-clinical and Clinical Module of the Influenza Vaccines Guideline. EMA.europa.eu. Oct. 12, 2023.
3. Geall, A.; Alspach, C.; Kuhn A. Introduction to the Alliance of mRNA Medicine, 11th International mRNA Health Conference, Berlin, Nov. 1, 2023.