Therapeutics


Table 2: The treatment of MPS diseases. See drugs@FDA.com and www.ema.europa.eu/ema/


be severe and progress rapidly in the pediatric pop- ulation. For example, assessment of a variety of clinical endpoints and functional tasks in patients of different ages with Pompe disease8 provides a strong argument for the value of neonatal screen- ing for this rapidly progressing disease. In the US there is currently a panel of 29 diseases that are routinely screened for at birth9, with certain States having expanded newborn screening beyond this panel. With the expansion of knowledge related to the genetic basis for disease and improvements in technologies to measure specific biomarkers10,11, there will be an increasing opportunity to expand newborn screening such that clinical outcomes may be predicted earlier for individual patients, with therapeutic intervention improving outcomes for these patients.


such studies, and only a small proportion of these patients may be treatment-naïve. In these cases, comparison of physicochemical characteristics and data in preclinical models may be appropriate, fol- lowed by careful monitoring in the clinical setting to ensure safety and efficacy.


The challenge of finding patients may continue in the post-approval setting, where identifying patients is usually critical for commercial success of rare disease therapies. The requirement to find patients highlights the need for rare disease com- panies to establish effective educational pro- grammes and develop and validate diagnostic tools. Diagnostics can also play an important role in identifying patients as early as possible in the course of their disease as history studies and clini- cal experience have established that for a number of rare diseases the earlier that diagnosis can occur and therapy initiated, the greater the clinical bene- fit that may be achieved for patients. Indeed, it has been projected that for the top 350 rare diseases, approximately 27% of patients will not reach their first birthday. Furthermore, it is clear that expan- sion of newborn screening, possibly in parallel with a potential treatment for a rare disease, has the potential to provide tremendous benefit to patients suffering from such a disease, which may


12


In addition to the logistical challenges associated with running clinical studies with very few patients, small patient numbers result in challenges to generate the type of data achievable with dis- eases of higher prevalence. Specifically, it can be unrealistic to expect to be able to power studies to achieve the degree of statistical significance with certain clinical endpoints as can be achieved in more common indications, to explore multiple doses in the clinic, or to assess appropriate dose intervals. In studies where less than 20 patients may be enrolled, every patient makes an important contribution and trade-offs need to be made with regard to what may be explored in the clinic; for example, enrolling patients in placebo arms can compromise valuable data on drug effects if there are high quality alternate sources of historical con- trol data. Moreover, in life-threatening pediatric diseases where there is no available therapy, if effi- cacy can be demonstrated in Phase II clinical stud- ies it can provide an ethical dilemma to include a no treatment arm in subsequent pivotal studies, particularly in rapidly progressing diseases. This highlights the importance of industry and regula- tors carefully considering appropriately controlled natural history studies as no-treatment compara- tors for pivotal studies in certain rare diseases. Even for the rare diseases which have been more widely studied such as MPS diseases, it is clear that there are frequently complex clinical phenotypes, with clear differences between patients and effects on multiple organ systems12. For MPS diseases where there is an approved therapy, Table 2 shows the primary endpoints which were used as the basis for regulatory approval, and the major post-mar- keting commitments which were requirements in the US and/or EU. It is noteworthy that for these diseases there are biological markers which are


Drug Discovery World Spring 2013


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