Therapeutics


References 1 Commission of the European Communities. Communication from the Commission to the European Parliament, The Council, The European Economic and Social Committee and the


Committee of the Regions on Rare Diseases: Europe’s Challenges. Com, 2008. 679 final: p. 1-11. Available from: http://ec.europa.eu/health/ph_t hreats/non_com/docs/rare_ com_en.pdf. 2 Pariser, AR et al. Characteristics of rare disease marketing applications associated with FDA product approvals 2006-2010. Drug Discov. Today, 2012.17(15–16), 898-904. 3 Braun, MM et al. Emergence of orphan drugs in the United States: a quantitative assessment of the first 25 years. Nat. Rev. Drug Disc. 2010. 9, 519-522. 4 Thorat, C et al. What the Orphan Drug Act has done lately for children with rare disease: A 10-year analysis. Pediatrics 2012. 129, 516-521. 5Westermark, K et al. European regulation on orphan medicinal products: 10 years of experience and future perspectives. Nat Rev Drug Discov, 2011. 10, 341-349. 6 Dorsey, ER et al.


Characterization of a large group of individuals with Huntington disease and their relatives enrolled in the COHORT study. PLoS ONE, 2012. 7(2), 1-10. 7 Kishnani, PS et al. A retrospective, multinational, multicenter study on the natural history of infantile- onset Pompe Disease. J. Pediatr. 2006. 148, 671-676. 8 Rigter, T et al. Severely impaired health status at diagnosis of Pompe disease: A cross-sectional analysis to explore the potential utility of neonatal screening. Mol. Genet. Metab. 2012. 107, 448-455.


there may be differences in clinical phenotype which may be due to secondary genetic variation or environmental factors. As technological advances will result in individualised genome sequencing and predictive computational model- ling of disease pathways being more commonplace in the future, there is the potential for an exciting era of powerful insights into the pathophysiology of rare diseases.


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Largely in response to the need for the rapid development of therapies for the treatment of AIDS, in 1992 the Accelerated Approval Rule authorised the FDA to expedite marketing approval for certain new drugs intended to treat serious or life-threatening illnesses upon determi- nation that the product has an effect on a clinical endpoint or on a surrogate endpoint that is ‘rea- sonably likely to predict clinical benefit’. Recognising the difficulty and ethical issues associ- ated with previously defined clinical endpoints in the context of rare diseases, new landmark legisla- tion was signed into law on July 9, 2012 which has the opportunity to significantly benefit rare disease patients. The Food and Drug Administration Safety and Innovation Act (FDASIA) expanded the list of potential scientific data which could be used as surrogate endpoints. This included, for example, epidemiological, pathophysiological and pharma- cological endpoints, as well as biomarkers. In fact, surrogate biomarkers have been used for a number of common indications in the past, including serum cholesterol and LDL for cardiovascular drugs, and CD4+ levels for antiretrovirals. When approval is granted under accelerated review there is a require- ment that there be post-marketing studies conduct- ed to verify the relation of the surrogate endpoint to clinical benefit. In the EU a similar approval pathway known as Conditional Marketing Authorisation exists. While the challenges associat- ed with drug development in rare diseases suggests that these programmes may be appropriate for accelerated approval status, very few examples exist where an orphan drug product has achieved accelerated approval on the basis of a biomarker. Examples include Fabrazyme®, approved in 2003 for the treatment of Fabry Disease, and sapropterin (Kuvan®) approved in 2007 for the treatment of Phenylketonuria. It is likely that increased utilisa- tion of accelerated approval for rare disease thera- pies, in conjunction with appropriate post-market- ing commitments, would have the same positive impact as that realised in oncology and HIV thera- py15. Indeed, in situations where there is clinical variation such as that observed in rare disease, bio- markers related to the measurement of the primary


defect associated with disease (eg correction of enzyme activity in enzyme-deficient patients) may be considered ‘reasonably likely to predict clinical benefit’ and more generally relevant than the cor- rection of clinical endpoints which may only be rel- evant to a subset of patients. While it may be con- sidered that making an approval decision based on biomarkers in the absence of clinical outcomes adds risk, it is noteworthy that no drug with an orphan designation has been withdrawn for reason of safety or lack of efficacy.


Irrespective of the potential utility of surrogate biomarkers for approval, companies developing rare disease therapies frequently need to commit to multi-year post-marketing commitments. Such commitments can include the need for clinical studies for assessing long-term safety, defining effi- cacy with regard to clinical endpoints that can only be assessed following long-term treatment, or measuring clinical effects on subsets of patients that were not sufficiently represented in clinical studies. Patient registries also provide the opportu- nity to assess therapeutic effect in the ‘real world’ outside of the clinical trial setting. In addition to addressing specific questions arising from the regu- latory process, long term post approval studies can provide important insights into the pathophysiolo- gy of disease. For example, as some rare diseases are X-linked recessive genetic diseases, dogma has been that the diseases are limited to males. Fabry disease is an X-linked disease cause by deficiency of the enzyme alpha-galactosidase A. However, careful analysis of a Fabry Outcome Survey associ- ated with an enzyme replacement therapy16 has characterised the clinical manifestation of the dis- ease in females and the benefit of enzyme replace- ment therapy in these patients has been observed. In rare diseases where there are multiple therapies with patient registries, there would be value in con- sidering opportunities for cross-industry partner- ships to combine data which may provide a deeper understanding of disease progression. The numerous factors which add complexity to defining appropriate clinical endpoints in rare dis- ease highlight the need for early engagement and a high degree of transparency between industry and regulatory authorities to define an appropriate reg- ulatory path. While rigorous regulatory standards must be applied irrespective of the size of a patient population, there needs to be recognition that in clinical studies of rare disease the same evidentiary hurdles cannot be reasonably met as compared with those in more prevalent disease, and there must be flexibility and scientific judgment applied to each drug application. An analysis of approved


Drug Discovery World Spring 2013


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