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European Pharmaceutical Contractor

Paediatric Pioneers

Karen Aiach of Alliance SANFILIPPO reviews the development of an advanced therapy medicinal product to treat Sanfilippo Syndrome, a paediatric orphan disease

At first glance, diseases individually affecting a small number of children worldwide are usually perceived as less attractive by drug developers. There are objective reasons for that. The scientific, medical and ethical challenges to be faced in order to develop safe treatments for small and fragmented populations of children are considerable when compared with the perceived lack of commercial attractiveness they are associated with. However, paradoxically, the ‘ultra outsider’ status of biotechnology-based paediatric orphan drugs is also what makes them unique pioneers. When new therapies emerge, each success in overcoming an extraordinary and specific demand to develop an orphan advanced therapy medicinal product (ATMP) can become a unique and precious asset. Announcements of a mega-transaction in the field between a pharmaceutical giant and a leading biotech specialist in orphan diseases, and of a strategic collaboration on gene therapy for rare diseases between another pharmaceutical giant and an academic player, confirm that a renewed energy has been put into this highly promising pharmaceutical segment (1,2).


Rare diseases (RDs) are defined as conditions affecting less than five in 10,000 people in Europe, or fewer than 200,000 patients for a given condition in the US (3,4). Although any rare condition, by definition and taken individually, occurs infrequently in the general population, there are almost 8,000 rare diseases identified to date that affect millions of people in the world. Experts estimate that more than 60 million people are affected by an RD in Europe and the US alone. RDs are most often severely debilitating diseases associated with complex mixes of life-long symptoms that lead to drastically reduced life expectancies. Eighty per cent of orphan patients are children (5). In the illustrative case of Sanfilippo Syndrome, an incurable lysosomal storage disease (LSD) with a strong central nervous system involvement, patients do not usually live longer than their second decade (6).

Developing drugs for RDs is an arduous task due to many underlying factors, including:

  • For most diseases, pathophysiological mechanisms are only partly known, and epidemiological data are often missing
  • Populations are small and often geographically scattered
  • Disease-specific scientific and medical resources are scarce and scattered
  • Patients are extremely vulnerable and often young, which raises concerns of protocol adherence and informed consent
  • RDs are often severely debilitating and characterised by a complex mix of symptoms, making it difficult to determine biological and clinical endpoints in order to assess the efficacy of treatments
  • Commercial attractiveness is perceived as lacking and successful initiatives are still unknown to many people
  • Funding is inadequate

Until the early 1980s, orphan diseases, paediatric or not, were completely ignored by health authorities, policy makers and even by pharmaceutical companies. When governments were urged to design and enhance initiatives for rare diseases, mainly under the pressure of patient organisations, such as Eurordis in Europe, things started to change (7). Years later, the implementation of the incentive-based orphan drug regulations in Europe and in the US has had an undeniably positive impact in terms of stimulating research on rare diseases, scientific and medical innovation, as well as orphan drug discovery and development. This has had a global effect that is unanimously considered to be positive. In Europe alone, since the inception of the orphan drug regulation, approximately 60 new treatments for orphan diseases have received the centralised market approval, giving access to all member states across the EU, and more than 600 experimental drugs have been designated as ‘orphan’. This blossoming of activities in orphan drug development has greatly contributed to the emergence of specialised biotech companies in both Europe and the US, stimulating employment and investment in innovation (8).

Additional regulations have been passed during the same period, such as paediatric regulations – applying to virtually 80 per cent of orphan drugs – aiming at enhancing high quality and ethical paediatric biomedical research through an appropriate and stringent regulatory framework and policies on advanced therapies. These regulations have not been dictated by the need to develop orphan paediatric ATMPs; however, if you want to observe their effects, the latter are the best candidates because they fall under each of these policies concomitantly.

From experience, the most blatant effect of those regulations on the drug development process we have seen until now is the pressing need to design and enforce a completely new body of best practices that can undoubtedly serve the whole pharmaceutical community.


Our programme was launched in 2007 and we will be preparing our product’s entry into the clinical stage at the end of 2010. The speed of the programme’s progression is heavily linked to increasing demand from the orphan and paediatric regulations, which compel sponsors to enforce the best practices available, and to work hand-in-hand with regulators in order to keep track of these constantly evolving regulations. Examples of challenges that we have to face include:

  • Providing evidence that animal models are predictive
  • Designing studies in juvenile animals of different species to assess toxicology and biodistribution parameters that are able to mimic and reflect the drug’s effects with respect to the anatomical and physiological specificities of each class of age (brain myelinisation, heart maturation and so on)
  • Validating human biomarkers
  • Building epidemiological body of data
  • Identifying robust endpoints in multisymptomatic diseases
  • Building a paediatric investigation plan (PIP) while having no data in adults to extrapolate from
  • Having a perfect understanding of and respect for the ethical challenges to be faced with extremely vulnerable patients and legal representatives, involving patient organisations and so on

To manage such a programme, we are urged to mobilise a complex mix of highly specialised and scarce talent (such as researchers, RD-specific specialist paediatricians and clinicians, pharmacologists, experts in paediatric PK/PD study) and non-human resources (databases, biological samples, epidemiological data and so on). We must attempt to optimise all of them through multi-disciplinary, coordinated and streamlined approaches and processes.

Fortunately, these regulations are mainly incentive-based. Thanks to the orphan designation, sponsors have access to strong incentives such as protocol assistance, fee reductions and other valuable incentives during preclinical and clinical development, as well as a 10-year market exclusivity when the product reaches the EU market through the centralised procedure. The paediatric regulation in turn is accompanied by a powerful incentive through two-year market exclusivity. This totals to 12 years’ market exclusivity for paediatric orphans; a well-deserved reward.


The known level of risk in severe lifethreatening diseases, such as most RDs, even while remaining within the strict boundaries of ethics and safety, can be outweighed by the potential benefit of emerging therapies. For this reason, they are the perfect candidates to develop cutting-edge knowledge and methodologies.

Many key players have long since realised the potential of orphan diseases. They understand that research in RDs significantly increases knowledge about specific biological mechanisms and physiological pathways. A good example is the fact, for instance, that research on specific RDs has given much insight into the pathophysiology of migraine (9). In the case of Sanfilippo Syndrome, we have a model of dysfunction of single biological pathways involving the degradation of complex chains of sugar called mucopolysaccharidoses within the endosomal/lysosomal system, particularly in the brain. This adds to the body of knowledge for many other common and rare neurodegenerative diseases.

On the drug development side, successful programmes aiming at developing paediatric orphan drugs contribute greatly to the emergence of unique conjunctions of cutting-edge expertise and skills. The experience is all the more rewarding as these disciplines are evolving and so continually improving. All the stakeholders, including the regulators themselves, realise that they are on a learning curve. Sponsors should grab the opportunity to integrate the constraints on a streamlined and timely basis. We are acquiring invaluable knowledge of highly complex processes that prefigure the next generation of drugs.

The potential is even greater when a medicinal product is derived from advances in biotechnology. Enzyme replacement therapies for LSDs and recent gene therapy programmes for severe combined immunodeficiencies (SCID and ADA-SCID), adrenoleucodystrophy, duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA) and Wiskott Aldrich syndrome are perfect examples of this paradigm. The knowledge gained within these programmes is considerable as all conceivable complexities are to be tackled for the sake of safety, efficiency and ethics. These approaches again lead to improvements in scientific understanding of complex domains such as immunological self tolerance.

Today, medical needs remain unmet and less than 150 rare diseases out of more than 8,000 have a marketed drug. Most patients remain victims of delayed diagnoses, lack of treatments and exclusion from the benefits of research. This leaves space for pioneers to join the search for safe and efficient treatments in extremely challenging situations where excellence is to be the sole rule. This also leaves room for traditional key players to invest in programmes that carry more than the germs of an entirely new generation of drugs.


  1. Sanofi Aventis – Genzyme Corp
  2. GlaxoSmithKline partnership with Fondazione Telethon and Fondazione San Raffaele in Italy,
  3. 1999 EU Regulation 141/2000/EC on Orphan Medicinal Products
  4. 1983 US Orphan Drug Act
  5. Orphanet DataBase
  6. Mucopolysaccharidosis type III, OMIM #252900
  7. European Organisations for Rare Diseases,
  8. Reaves ND, A model of effective health policy: the 1983 Orphan Drug Act, Journal of Health & Social Policy 17(4): pp61-71, February 2004
  9. De Vries B et al, Molecular genetics of migraine, Hum Genet 126(1): pp115-132, 2009

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Karen Aiach is a former alternate member at the Paediatric Committee of the European Medicines Agency on behalf of Eurordis, and a former member of a French Ethics Committee. After graduating with an MBA in finance and business, Karen worked in a major consulting firm for seven years. She then created her own consultancy in strategy, organisation and finance. Currently her time is almost fully dedicated to the preparation of the gene therapy clinical trial sponsored by Alliance SANFILIPPO, a group which she founded when her elder daughter was diagnosed with Sanfilippo disease in 2005.
Karen Aiach
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