Application Note

New approaches to accelerate drug discovery for rare diseases


here are more than 7,000 known rare diseases and disorders in exis- tence today. While a single orphan

disease may affect just a handful of individ- uals, the global impact is significant – in the US alone between 25 and 35 million people are estimated to be afflicted with a rare disease, and 50-66% of known rare diseases affect children1. These patients simply cannot wait for the timelines associ- ated with traditional drug discovery pro- cesses, which can take a decade or more to get a drug to market. New approaches to facilitate swift and

successful drug development are needed. In response to this need, there is an increasing shift towards true partnership and active collaboration across academia, industry and contract research organisations (CROs). Effective partnerships are the key to finding solutions to what are arguably some of the most difficult to diagnose con- ditions. Academic labs perform ground- breaking research to identify new disease drivers and understand disease biology, and this research is used by biotech and pharma companies to develop targeted therapies for specific rare diseases. Biotech and phar- ma companies are increasingly partnering

with CROs that offer customisable assays and models to rapidly perform pharmacol- ogy and safety studies. Working collabora- tively expedites time to market for thera- pies targeting rare disease, so patients stand to gain the most. Similar partnerships between academic

labs and pharma/biotech companies to dis- cover new approaches for developing more translatable animal models is another key to rapid and efficacious therapies. In vivo models are an essential component to under- standing the biology of specific rare diseases, as a model contains a complete interactive physiology enabling therapeutic evaluation in a more meaningful context. While many models typically do not recapitulate disease pathophysiology, they express many ele- ments of the human disease phenotype. It is critical to understand the benefits and limi- tations of animal models, as it allows researchers to create relevant clinical con- text to apply preclinical research data. This allows researchers to understand which

aspects of a disease phenotype can be mod- elled successfully in different species. This has been done successfully, although not perfectly, for some rare diseases. Some rare diseases are associated with

single-gene mutations, resulting in a disease phenotype at the cellular, tissue and organ level. In theory, introducing the mutation in a research model should induce a disease phenotype and structure-function alter- ations similar to human patients. A good example bearing out this theory is the devel- opment of therapies targeting spinal muscu- lar atrophy (SMA) that were extensively tested in smn2 transgenic mice, and the strong preclinical efficacy data that helped drive clinical testing, ultimately leading to approval of the first drug for SMA. However, there are also cases where the model does not demonstrate the same symp- toms and pathology as human patients, and there is disconnect between underlying dis- ease biology and disease phenotype. A well- studied example is the Mdx mouse model of Duchenne’s muscular dystrophy. Although disease progression does not mimic human disease, the Mdx mice have been used to identify new biomarkers to assess in vivo therapeutic responses using validated trans- lational methods such as preclinical imaging and fine motor skill assessment. Given the thousands of rare diseases

lacking therapies, it is heartening to see the development of a robust collaborative ecosystem to facilitate efficient preclinical drug development. The need for robust preclinical data is underscored by the chal- lenges associated with small patient popu- lations available for clinical trials. Given this limitation, robust preclinical data packages, including translational endpoints such as imaging or cognitive testing, are essential to increasing the chance that clin- ical endpoints will be met in trials.

Reference 1 Orphan Drugs in the United States Research Report Quintiles IMS Institute published October 2017.

40 Drug Discovery World Summer 2018

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