Can orphan drug development keep up with rare disease research pace ?

Through continuous research, in particular genetics, more and more we discover that many rare disorders actually consist of various unique subtypes. (e.g. Neuronal ceroid lipofuscinosis, mitochondrial DNA depletion syndrome, Congenital disorder of glycosylation). What it all boils down to is that the number of rare disorders, in particular ultra-rare ones, continues to grow, and is growing at a much higher pace than therapy development.

To illustrate the latter I have compiled a small dataset of 350+ ultra-rare metabolic disorders (prevalence < 1/100,000 or < 5000 patients), and determined for each disorder in the dataset when clinical features were first described. There are different ways to depict the data, I chose to divide the dataset into three prevalence categories (unknown or no data ; 0,1-0,9/1,000,000 ; 1-9/1,000,000), and used time and the cumulative number of rare disorders as independent and dependent variable, respectively.

The data clearly confirm the growth in number of ultra-rare (metabolic) disorders.

Cumulative number of ultra-rare metabolic disorders over time (first clinical features described) for three prevalence categories

The cumulative number of rare disorders with unknown prevalence or 0,1-0,9/1,000,000 easily outnumber the highest prevalence group (1-9/1,000,000; still quite rare !!). However, what strikes me the most is that the number of ultra-rare metabolic disorders have really started to go up (in particular < 1/1,000,000 and unknown), just around the time when the DNA structure was resolved (1953). Of course, the data is far too limited to determine a real cause-effect relation. Over time there have been many pivotal discoveries in genetics that combined have made, and are making the difference (see wikipedia). Just to name two: DNA sequenced first time (1977) and completion human genome project (2003). Also important discoveries in disciplines like biochemistry, cell biology, molecular biology have made considerable contributions.

I would like to emphasize that the availability of two remarkable open-access databases enabled me to do this kind of research: Orphanet and OMIM

You may think so far nothing new under the sun. I agree, but it does raise a number of fundamental questions that in my view need to be addressed:

  • Is our current healthcare system able to handle this development ?
  • Is there sufficient disease understanding that can be translated into healthcare or pharmaceutical innovations ?
  • Is therapy development realistic for patients with these ultra-rare disorders ?

A quick scan of the 350+ ultra-rare metabolic disorders already reveals that for some products are on the market, such as tyrosinemia type I (Nitisinone; Orfadin®) and N -acetylglutamate synthetase (NAGS) deficiency (Carglumic acid; Carbaglu®). For others, products are in development. Apparently, given the right circumstances orphan drug development for ultra-rare metabolic disorders is feasible.

The question that I am particular interested in is can we drive the rare disease research process towards product development or healthcare innovation, and if so what are important drivers ?

For example the quick scan hints to the important role of patients (or parents of) in rare disease research and orphan drug development (See Role of patient for some admirable examples). Other factors that may be relevant are a.o. availability of an animal model, registry for natural history, diagnostics, biochemical elucidation, role of genetics, sharing molecular pathway or target with other (rare) disorders with approved therapy. An example of the latter is the aforementioned Nitisinone that is currently being tested in the clinic for alkaptonuria, an ultra-rare metabolic disorder.

In the interest of patients, but also other stakeholders, better understanding of the dynamics in rare disorder research is warranted as it may provide the right boost to research into currently underserved rare disorders (why each rare disease matters). Ultimately it could lead to the development of the much-wanted therapy or healthcare innovations.

Feel free to share your thoughts and views with me……

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