Regulatory aspects of oligonucleotides rna drugs

INTRODUCTION Nucleic acid-based medicinal products (NAMPs) are composed of RNA or DNA strands that can interact with the human genome or proteins through various pathways. Depending on the structure, length, and molecular target of the nucleic acid, four main classes of NAMPs can currently be identified: antisense oligonucleotides (ASOs), small-interfering RNAs (siRNAs), aptamers, and messenger RNAs (mRNAs). Unlike mRNAs, other oligonucleotide drugs (ONs) cannot directly translate their “message” into proteins, but they can modulate existing translation/transcription pathways. For example, ASOs are single-stranded ONs (≈12-25 nucleotides) that bind to pre-mRNAs or mRNAs [1]. siRNAs are double-stranded ONs (≈ 20-24 nucleotides) that can inhibit the translation of cytoplasmic RNAs into pathogenic proteins. Aptamers are single-stranded ONs characterized by a peculiar 3D structure that inhibit proteins. This presentation aims to review the features and discuss the challenges of NAMPs authorized in the EU and US, with a focus on oligonucleotide ones (ONMs). REGULATORY LANDSCAPE The regulatory pathways for placing NAMPs on the market present significant differences between the US and the EU. In the US, ONMs are assessed by FDA’s CDER under section 505 of the FD&C Act (21 USC 355), while gene therapy products and vaccines (including mRNA) are categories of biological products managed by FDA’s CBER. In the EU, all NAMPs have been authorized by the EMA following a centralized procedure, under the provisions of Regulation (EC) 726/2004. However, the Regulation (EC) 1394/2007 on Advanced Therapy Medicinal Products (ATMP) may be applicable to NAMPs if they fall within the definition of gene therapy products. Moreover, regulatory guidelines are missing, in most of the cases, to support applicants in the NAMPs’ life cycle. In this regard, the EMA released two concept papers: i) on challenges in manufacturing and quality control of ASOs, siRNAs, and aptamers; ii) on quality aspects of mRNA vaccines against infectious diseases. In parallel, the EDQM published drafts of Pharmaeuropa monographs on addressing specific quality features of mRNA. Meanwhile, the FDA published class-related guidance on ASOs for severely debilitating or life-threatening diseases and about 10 product-specific guidance for already authorized ASO and siRNA to support follow-on products. MARKETED MEDICINAL PRODUCTS Until October 2023, 22 NAMPs (20 ONMs) have been authorized by EMA and/or FDA. The majority of ONMs (67%) are classified as orphan drugs in both regulatory areas. From 1998, 12 ASOs have been examined by both Agencies, but only 4 of them are currently authorized in Europe and 8 in the US. Two products were withdrawn for commercial reasons in the US and/or in the EU. Now, 1 aptamer is authorized only in the US; whereas, following Onpattro® approved by the FDA in 2018, 5 additional siRNAs have been authorized in the last years. In parallel, mRNAs are only available as COVID-19 vaccines in both US and EU. Based on their regulatory history, all ONMs have been qualified as chemical entities since they are chemically synthesized using solid phase methods. On the contrary, the mRNAs are classified as biological medicinal products since they are produced by in vitro transcription (IVT) starting from linear DNA. Most of authorized formulations are as solutions for injection. Only Onpattro® and mRNA vaccines are formulated with lipid nanoparticles. Seven products are developed as prefilled syringes. CONCLUSION The current marketed NAMPs are heterogeneous in terms of both API production methods and formulative features. This opens novel challenges of both EMA and FDA in providing harmonized regulatory requirements and standards for such novel therapeutic classes [2]. A potential conceptual misalignment between the US and EU may emerge from the recent Reform of the EU pharmaceutical legislation, which seems to be aimed at classifying all ONMs as ATMPs [3]. However, grounding the regulatory classification on the nature of the API source may be counterproductive. Otherwise, the benefit/risk balance should be assessed both on their peculiar quality aspects related to the manufacturing process and on their efficacy and safety profiles related to the mechanism of action.