Addressing the challenges of novel therapies in rare diseases with mechanistic perspectives: Missed opportunities or the way forward?

Abstract

There is no universally agreed definition of what is a rare disease.Depending upon the jurisdiction, the incidence of rare is defined as occurring in less than one in 1500 (in the United States) to one in 2000 (European Union). Rare Diseases Day falls on the 29 February but often celebrated on 28 February during a non-leap year. While individually such conditions are clearly uncommon, with approximately 8000 rare diseases identified, they cumulatively encompass a significant portion of the population. It is estimated that, worldwide, there are 400 million people living with a rare disease. Rare diseases have, in the past, been largely neglected by the pharmaceutical industry who calculated that the development of a therapy for an uncommon indication was unlikely to be profitable. This lacuna was recognised by governments internationally with the enactment of the Orphan Drug Act in the United States in 1983, and the EU orphan drug designation 2000. This led to huge impetus towards the discovery of new therapies for rare diseases. 1 This special issue of the British Journal of Clinical Pharmacology Reviews, in fact, attempts to address the knowledge gained in the last few decades on novel perspectives and mechanism in the search for new potential treatments for rare diseases. The issue includes six papers encompassing a variety of rare diseases where the authors have used varying perspectives in the identification of innovative tools in this quest.Various stakeholders have become motivated (for various and not always altruistic reasons) to search for new therapies for these conditions as described in Kesselheim and Solomon 2 in their discussion of the use of colchicine for some rare diseases. Yet the path is far from smooth. The initial monetary outlay needed, with huge attrition rates of what seem to be promising lead compounds, have led to big pharma seeking to think out of the box and turn to novel mechanistic perspectives to identify new opportunities for those rare conditions which previously were considered to be without hope. 3 As Forbes et al. 4 describe in their review for this special issue, the scarcity of disease-modifying therapies for rare diseases is a challenge, not only due to a lack of understanding of the underlying molecular disease mechanisms, but also the difficulties in recruiting the number of patients which will ensure that clinical trials of these drugs are sufficiently powered to pass regulatory hurdles.

Preparing for patient-customized N-of-1 Antisense Oligonucleotide Therapy to Treat Rare Diseases

“…Despite our growing ability to diagnose rare diseases, developing treatments for these conditions is hampered by a plethora of difficulties [4,5]. Due to their low individual prevalences, minimal data is available in databases, making it more difficult to elucidate their varied mechanisms and design appropriate therapies.…”

Preparing for Patient-Customized N-of-1 Antisense Oligonucleotide Therapy to Treat Rare Diseases

“…Despite our growing ability to diagnose rare diseases, developing treatments for these conditions is hampered by a plethora of difficulties [4,5]. Due to their low individual prevalence, minimal data are available in databases, making it more difficult to elucidate their varied mechanisms and design appropriate therapies.…”