Olivia Kim-McManus, Joseph G. Gleeson, Laurence Mignon, Amena Smith Fine, Winston Yan, Nicole Nolen, Scott Demarest, Elizabeth Berry-Kravis, Richard Finkel, Stefanie Leonard, Samuel Finlayson, Erika Augustine, Gholson J. Lyon, Rebecca Schule, & Timothy Yu (Nature Communications)
November 12, 2024
Abstract
Individualized genetic therapies—medicines that precisely target a genetic variant that may only be found in a small number of individuals, as few as only one—offer promise for addressing unmet needs in genetic disease, but present unique challenges for trial design. By nature these new individualized medi- cines require testing in individualized N-of-1 trials. Here, we provide a frame- work for maintaining scientific rigor in N-of-1 trials. Building upon best practices from traditional clinical trial design, recent guidance from the United States Food and Drug Administration, and our own clinical research experi- ence, we suggest key considerations including comprehensive baseline natural history, selection of appropriate clinical outcome assessments (COAs) indivi- dualized to the patient genotype-phenotype for safety and efficacy assessment over time, and specific statistical considerations. Standardization of N-of-1 trial designs in this fashion will maximize efficient learning from this next genera- tion of targeted individualized therapeutics.
Introduction
Maturing platforms for targeted cell and gene-based therapies— including but not limited to antisense oligonucleotides (ASOs), siRNA, mRNA, DNA/RNA editing—are offering great hope for treatment of the over 8000 rare genetic diseases (defined as those affecting less than 1:200,000 individuals). The promise of these therapeutic approaches stems from their ability to directly target the underlying root causes of genetic disease at the level of the RNA or DNA—correcting the impact of genetic mutations, or even the mutations themselves. These technologies have been used under existing regulatory and drug development frameworks to support successful commercial drug development for several of the most prevalent rare genetic diseases1. However, commercial incentives have largely failed to support development of treatments for the “long tail” of the rarest genetic conditions, 85% of which have an estimated prevalence of less than 1:1,000,000.
Recent examples demonstrate that it is possible to use genetically-targeted technologies to develop therapies tailored to an individual’s unique genetic pathology2–7. Because of their precise targeting, the resulting drugs are often applicable to vanishingly small “markets” of only a handful of patients (or even just one), turning many facets of traditional drug development on their head2. A series of FDA guidances have been recently drafted to govern the development and investigational clinical deployment of such individualized therapies (“Individualized Antisense Oligonucleotide Drug Products for Severely Debilitating or Life-Threatening Diseases”)8, but specialized approa- ches to trial design and clinical outcome measures will be required to evaluate them rigorously. Here, we discuss design challenges associated with N-of-1 trials, and propose a clinical framework with which to begin to address them.
N-of-1 trials of individualized, genetically targeted therapies
We refer here to a specific type of N-of-1 trial design involving inves- tigational therapies for which the therapeutic itself is individualized: targeting genetic variants that may be found in only one or a few individuals. We note that these fall in the specific subcategory of single case experimental design (SCED) studies, in which drug and trial design are designed for a single patient. We further note that this is distinct from the traditional concept of N-of-1 trials, a term which has been used to refer to studies involving single patients who are treated with (non-individualized) therapeutics in a repeat cycle of treatment challenge and withdrawal (A-B-A-B)—where non-individualized refers to interventions not specifically designed based on a patient’s unique genetic makeup9. Furthermore, the genetically targeted modalities discussed in this perspective do not naturally lend themselves to crossover clinical trial designs (for instance, due to their long half-life of ASOs, or the single dose nature of AAV or CRISPR therapies).
Kim-McManus, O., Gleeson, J.G., Mignon, L. et al. A framework for N-of-1 trials of individualized gene-targeted therapies for genetic diseases. Nat Commun 15, 9802 (2024). https://doi.org/10.1038/s41467-024-54077-5
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