Anneliene H. Jonker, Elena-Alexandra Tataru, Holm Graessner, David Dimmock , Adam Jaffe, Gareth Baynam, James Davies, Shruti Mitkus, Oxana Iliach, Rich Horgan, Erika F. Augustine, Alison Bateman-House, Anna Maria Gerdina Pasmooij, Tim Yu, Matthis Synofzik, Julie Douville, Larissa Lapteva, Philip John Brooks, Daniel O’Connor, Annemieke Aartsma-Rus Force on behalf of The N-of-1 Task Force of the International Rare Diseases Research Consortium (IRDiRC)* (Nature Reviews Drug Discovery)
November 4, 2024
Abstract
In recent years, a small number of people with rare diseases caused by unique genetic variants have been treated with therapies developed specifically for them. This pioneering field of genetic N-of-1 therapies is evolving rapidly, giving hope for the individualized treatment of people living with very rare diseases. In this Review, we outline the concept
of N-of-1 individualized therapies, focusing on genetic therapies, and illustrate advances and challenges in the field using cases for which therapies have been successfully developed. We discuss why the traditional drug development and reimbursement pathway is not fit for purpose in this field, and outline the pragmatic, regulatory and ethical challenges this poses for future access to N-of-1 therapies. Finally, we provide a roadmap for N-of-1 individualized therapy development.
Introduction
Rare diseases can be defined as conditions with a prevalence of fewer than 1 in 2,000 people in any World Health Organization (WHO)-defined region of the world1. However, with approximately 10,000 recognized rare diseases, there are an estimated 250–450 million people living with rare or ultra-rare diseases worldwide2–4. Given this large number of people, it is striking that fewer than 5% of rare diseases have spe- cific pharmacological therapies, and many treatments only address some aspects of the symptoms5. This is due to the challenges related to small population research such as the relative rarity of each disease, heterogeneous presentation, lack of disease knowledge, including lack of natural history data, low commercial interest and regulatory challenges6,7. Furthermore, most rare diseases are much less prevalent than the threshold for rarity, with 85% of rare diseases having a preva- lence of <1 in 1,000,000 and diseases sometimes only being known to affect a single person8.
Over the last few decades, research on therapeutics for rare dis- eases has seen remarkable progress, with the development of specific funding opportunities, dedicated regulatory incentives, improve- ments in data sharing and increased collaboration between aca- demic and industry researchers, clinicians, people living with rare diseases and regulatory agencies9–14. Simultaneously, advances in understanding of disease biology and progress with diagnostics have led to increases in the number of potentially druggable targets and growing recognition of people with potentially treatable disorders15.
The current drug development model for rare diseases often starts with gathering information on a disease and identifying a potential therapeutic target for it. Therapeutic candidates progress to preclini- cal studies and then to clinical trials, with those that are successful in these studies being submitted to regulatory agencies and assessed by health technology assessment agencies and payers before they reach clinical application16. This model has resulted in the approval of mul- tiple drugs from well-established therapeutic modalities such as small molecules and recombinant proteins, as well as a growing number of oligonucleotide therapies, gene therapies and cell therapies17.
Although this model for developing a therapy for people with a specific rare disease exists for good reasons, it is often not viable for developing therapeutics for very small populations (sometimes just individuals), even if some of these individuals could benefit from the same type of therapies. This is especially true given the emergence of genetically targeted therapeutic modalities such as oligonucleotide therapies and genome editing therapies that can be very precise in their action, such that the target population may be as small as one or a few individuals. In such cases, a new development model is needed (Fig. 1). Notably, developing a treatment for a single individual — an ‘N-of-1 therapy’ — has already been shown to be feasible. One of the best-known examples is the development of an oligonucleotide therapy known as milasen for a child with CLN7-related Batten disease18.
In this Review, after defining N-of-1 therapy, we discuss the state-of- the-art of N-of-1 therapy development, highlighting examples of N-of-1 therapies based on different therapeutic modalities. We then con- sider the multiple aspects involved in developing N-of-1 therapies and propose a roadmap for such efforts. We also discuss some of the key challenges for N-of-1 approaches and how they might be addressed.
Jonker, A.H., Tataru, EA., Graessner, H. et al. The state-of-the-art of N-of-1 therapies and the IRDiRC N-of-1 development roadmap. Nat Rev Drug Discov (2024). https://doi.org/10.1038/s41573-024-01059-3