The Oligonucleotide Safety Working Group (OSWG)

The past decade saw a shift from the development of oligonucleotides as a mainly academic interest to an active industry. Today many small and medium sized companies are developing oligonucleotides for therapeutic use, and even large companies are keeping a close watch on progress.

Recognizing that this new class of pharmaceutical compound faces regulatory challenges that perhaps might not be best served by the current rules for small molecules (under which they are currently regulated) or biological products (Table 1), the Food and Drug Administration (FDA) and Drug Information Association (DIA) convened the Oligonucleotide-Based Therapeutics Conference in 2007. This conference was attended by academics, regulators, and industrial scientists all seeking clarification of the path forward for early, preclinical, and clinical development for a multitude of oligonucleotide-based compounds for a range of diseases, which in many cases have hitherto not been the targets of conventional drug treatment using small molecules.

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Table 1.

The General Properties of Small Molecules, Oligonucleotides, and Biologics

	Small molecules	Oligonucleotides	Biologics
Molecular weight	Low (<1,000 Daltons)	6,000–7,000 Daltons	High (>30,000 Daltons)
Manufacture	Chemical synthesis	Chemical synthesis	Biological synthesis or biologically derived
Structure	Single entity, high purity	Single entity with some product-related impurities	Complex, heterogeneous
Target distribution	Intra- and extracellular	Intra- and extracellular	Largely extracellular
SAR	Database may be available	No database but (chemistry-specific) class effects	No database
PK/ADME	Species-specific metabolites Distribution to many tissues	Catabolized to nucleotides and other metabolites depending on modifications; selected tissue distribution	Catabolized to amino acids; distribution limited
Immunogenicity	Never	Rare	Often
Species specificity	Sometimes	Sometimes	Generally (often NHP only relevant species)
Off-target toxicity	Often	Sometimes	Rare

Adapted from Cavagnaro, J.A. (2002). Preclinical safety evaluation of biotechnology-derived pharmaceuticals. Nat. Rev. Drug Discov. 1, 469–475.

SAR, structure-activity relationship; PR/ADME, pharmacokinetics/absorption, distribution, metabolism, excretion; NHP, non-human primate.

At this inaugural meeting, it was agreed to establish an Oligonucleotide Safety Working Group (OSWG) for ongoing discussion such that emerging scientific data from academia and industry could be shared amongst participants and with regulatory authority members. This forum was felt to be the best way to collectively tackle the formidable hurdles involved with developing a completely new class of therapeutic.

Since then, the DIA and FDA have organized and run several successful follow-up Oligonucleotide meetings that complement the activities of other societies and organizations. The members of OSWG have been very involved with the planning and execution of these meetings. In addition, because safety is a very broad term, the OSWG has established a number of subcommittees run by, and composed of, members representing the following aspects of safety assessment, specifically as related to oligonucleotides:

• Genotoxicity

• Off-target effects

• Reproductive toxicology and carcinogenicity

• Exaggerated pharmacology

• Safety pharmacology

• Immunomodulatory effects

• Specific issues relating to inhaled delivery

These subcommittees, and the overall OSWG, have been holding regular (monthly) conference calls to discuss the evolving science, and each has had input from participants from various regulatory authorities. This useful exchange of data, ideas, and suggestions has allowed the various subcommittees to draft consensus documents, sometimes with the additional help of invited experts and panel discussions, with a view to publishing these as White Papers. While not intended to provide any form of regulatory guidance to those developing oligonucleotides, these papers do present very detailed discussion on the issues currently facing both the developers and regulatory reviewers of oligonucleotide therapeutics. The papers are intended to help industry, academia, and regulatory scientists understand the issues and to provide the consensus view of scientific recommendations for ways to tackle these issues. As such, perhaps they should provide a stimulus for formal guidelines in due course. The first of these White Papers from Alton et al. from the Inhaled Oligo Subcommittee appears in this issue of Nucleic Acid Therapeutics.

This decade will be an exciting one for oligonucleotide developers, as a New Drug Application (NDA) for a systemically delivered oligonucleotide (KYNAMRO^™, Isis-Genzyme) was submitted in spring 2012, and many other oligonucleotides are now being studied in phase 2 and phase 3 clinical programs. By the end of this decade, it is hoped that many will have made it to NDA and approval, and the efforts to advance oligonucleotide therapeutics will have been realized. By publishing these White Papers, the OSWG hopes to foster quality and worthy research involving thoughtful development and leading to the successful approval of a number of oligonucleotides, several of which provide hope for patients with rare and lethal diseases who have hitherto had no therapy available to them.

The OSWG and the various subcommittees will continue to work for the dissemination of information and education of the wider scientific and regulatory audiences as these programs expand and multiply.

If you would like to join the OSWG please, please send an email to oswg.members@gmail.com.