In a commentary published last month in Nature Reviews Drug Discovery, Kym Boycott and Diego Ardigo, Chairs of the IRDiRC Diagnostics and Therapies Scientific Committees, respectively, discussed diagnostic and therapeutic challenges for rare diseases and options on how to tackle them.
The introduction of next generation sequencing (NGS) in 2010 as a diagnosis method for patients was a great accelerator in rare disease gene discovery. However, a substantial proportion of patients defined as “complex” are often left without a molecular diagnosis, either because they are suffering from more than one rare disease or because the molecular mechanism underlying their disease cannot be detected by NGS. The pace of straightforward gene discovery by NGS has recently slowed down, mainly due to the “n-of-1” rule (i.e. the need to document pathogenic variations in the same gene in at least two unrelated individuals in order to confirm a novel gene discovery). A example of international collaboration is the Matchmaker Exchange, which connects federated databases to facilitate such discovery. However, for the “complex” patients, new methods or ‘omics’ approaches will be required to identify all pathogenic genetic lesions to inform therapy development.
The pace of orphan drug designations significantly increased after 2010. If this pace is maintained for the next ten years, it will still leave 90% of rare diseases without a treatment. Rethinking the traditional drug development process for rare diseases will be critical, including trial design for small populations, real-world evidence collection, stronger patient engagement for data collection and definition of clinical end-points. The cost of orphan drug development remains an important challenge and the authors express the need for alternative approaches to “achieve better care for patients, value for money payers and a return on investment for companies”. Opportunities lie ahead in the creation of strong partnerships with patients to collect post-approval, real-world data on treatment outcomes, and in the use of patient-led registries to both cut drug development costs and generate data on disease history/treatment outcomes.
The authors concluded on the observation that “the grand challenges for rare diseases will require international cooperation and stakeholder engagement at an unprecedented level”. It is with these challenges in mind that IRDiRC presented its new and bold vision for the next decade: “Enable all people living with a rare disease to receive an accurate diagnosis, care, and available therapy within one year of coming to medical attention”.
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