From roadmap to a sustainable end-to-end individualized therapy pathway

Anneliene H. Jonker, Elena-Alexandra Tataru, David P. Dimmock, Alison Bateman-House, Holm Graessner, Gareth Baynam, Erika F. Augustine, Adam Jaffe, Anna M. G. Pasmooij, Oxana Iliach, Richard Horgan, James Davies, Shruti Mitkus, Larissa Lapteva, Matthis Synofzik, Timothy W. Yu, Daniel O’Connor, and Annemieke Aartsma-Rus A.M.Aartsma-Rus@lumc.nl on behalf of the IRDiRC N-of-1 Task Force

May 27, 2025

Abstract

The field of individualized, or N-of-1, therapy development is growing and increasingly gaining attention as a novel option for people with serious diseases, caused by unique genetic variants for whom approved therapies are not available. The N-of-1 taskforce of the International Rare Disease Research Consortium previously outlined a roadmap of aspects involved in N-of-1 therapy development and implementation. Here, this follow-up paper looks forward and reflects on how to address existing gaps to advance the current state of individualized interventions toward an integrated and sustainable treatment development model. It discusses what needs to be established for N-of-1 therapies to be developed and utilized at a larger scale, which involves features like sustainability; safety; efficacy; regulatory aspects; dedicated registries and data sharing; tools; long-term treatment monitoring; partnering with patient advocates; and reimbursement models. It closes with recommendations to shape the future of individualized therapies, focusing on ethical implications, education, creation of tools, incentives for data sharing, and innovative payment models.

Plain language summary

Creating a sustainable, individualized therapy plan

This paper discusses how to improve and expand the development of individualized treatments, known as N-of-1 therapies, for people with rare diseases caused by unique genetic variations. These are patients who often have no approved treatments available. The authors build on earlier guidelines for creating these therapies and explore ways to make them more sustainable and scalable. Key topics include ensuring the safety and effectiveness of treatments, creating systems for data sharing and patient registries, partnering with patient advocates, and developing new payment models. The paper concludes with suggestions for addressing ethical concerns, supporting education, encouraging data sharing, and creating incentives for the future of individualized therapies.

Limitations: While the roadmap is suitable for different kinds of N-of-1 therapies, some variations might not be clarified further in the paper.

Introduction

Developing therapies for people living with untreatable rare diseases is an unmet public health need, impacting children and adults,1–3 with a share of these individuals having genetic aberrations that are very rare or (almost) unique. Worldwide, over 350 million people are affected with a rare disease, being defined as occurring in less than 1 in 2000 individuals, and as such statistics indicate that a number as high as 1 in 20 people could be affected by a rare disease.4,5 N-of-1, or individualized, therapies are increasingly gaining attention as a possible solution for individuals with extremely rare pathogenic variants, for whom traditional commercial treatment development paths are considered unlikely.6 For this perspective paper, we define an N-of-1 approach as an individualized therapy developed for and used by one or very few people living with a rare disease. N-of-1 therapies are different from N-of-1 trials, where one or more drugs targeting a disease symptom and a placebo are compared in a single individual in a crossover design.6 The N-of-1 therapy development or individualized treatment development is aimed toward continuous treatment (although currently still in an experimental setting), focused on the well-being of the single patient.

In this new approach, interventions for individuals with a genetic disease target, specific, causative genetic variants, addressing core disease pathobiology. Over the last 5 years, a growing number of individualized treatments of different therapeutic modalities, including but not limited to antisense oligonucleotides (ASO), gene therapy, small molecules, and personalized cancer vaccines, have been developed and used in N-of-1 cases for individuals with severely debilitating and/or life-threatening genetic disease.7–13 Individualized treatments based on other therapeutic modalities, such as genome editing, are in development. The development of an N-of-1 treatment differs radically from traditional drug development, which can take up to a decade from proof of concept to first in human use. N-of-1 treatments necessitate a faster pathway, as compared to traditional orphan drug development for treatment of a condition, where clinical trials are set up to investigate the drug for larger prospectively defined cohorts of patients. For N-of-1, they need to be delivered before the patient succumbs to the disease or its progression reaches a stage where no benefit can be expected—similar to clinical trials, where enrolling patients unlikely to benefit is also avoided. Attempts to expedite non-clinical proof-of-concept and safety studies and manufacturing are underway; however, a clear end-to-end pathway of what is involved in N-of-1 treatment development has been lacking and the various efforts underway currently are not always globally aligned. Most importantly, from research ethics and public health perspectives, while each N-of-1 candidate treatment and its development is unique, learnings can be distilled from each case—regardless of whether they are considered objective successes or failures. If documented, shared, and analyzed this will facilitate not only the development of additional N-of-1 interventions for patients with the same disease but also such therapies in general. In this respect, N-of-1 treatments might be considered individualized interventions, as much as medicines themselves.14 The opportunity for iterative learning, however, critically depends on processes to facilitate data sharing. Capturing data on preclinical efficacy and safety, and clinical efficacy and safety evaluations is crucial in sustaining and scaling N-of-1 treatment development in addition to justifying payer reimbursements, widening access to eligible patients, and overcoming current concerns about inequitable access.

The International Rare Diseases Research Consortium (IRDiRC) N-of-1 Task Force developed a “roadmap”—that is, a detailed plan to guide progress toward a goal—for the development of N-of-1 candidate therapies.15,16 This roadmap identifies actions and the information necessary to be obtained prior to the next step in the sequence of drug development and its delivery to individual patients (Figure 1). This perspective is grounded in the present but is forward-looking, to identify and address existing gaps needed to advance the field of individualized treatments toward an integrated and sustainable treatment development model.

Figure 1. The roadmap of individualized therapy development.

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