Alternative strategies in orphan drug development

Abstract

Charging high prices for orphan drugs is unsustainable due to limited healthcare budgets. New models of orphan drug development are needed to help find treatments for the majority of rare diseases which have no treatment. This article discusses the challenges of value-based pricing and whether this would be a viable solution to the pricing problem. It explores how the search for cheaper models of orphan drug development could be through non-profit initiatives and drug repurposing. It ends with a case study of DevelopAKUre, an EC-funded consortium developing a repurposed drug for AKU, a rare genetic disease.

Keywords::

• not-for-profit
• orphan drug
• rare disease
• repurposing

1. Introduction

There are 6,000 to 8,000 rare diseases [1], yet there are only 66 authorised orphan medicines in Europe (432 in the US) [2,3]. Although the number of treatments for rare diseases has increased significantly since the introduction of the orphan drug legislation, there is clearly a long way to go. At the present rate, producing treatments for even a significant portion of these rare diseases seems unachievable within a reasonable timeframe.

2. The problem of pricing

The legislative incentives which have helped us come this far may prove less effective in the future, as it is increasingly difficult to obtain a premium price for an orphan drug once it reaches the market. As more of these drugs reach the market and impact health budgets, prices will need to come down.

Several attempts to address the issue of high prices for orphan drugs have focussed on their value rather than their cost. For patients and their families, no price is too high for a treatment which may save lives, or significantly improve quality of life. But since the standard criteria for assessing the value of a medicine rarely apply to orphan drugs, how can the value of an expensive orphan drug be judged?

A number of proposals have been put forward, such as CAVOMP (Clinical Added Value of Orphan Medicinal Products), an initiative started by EURORDIS and developed by Hughes-Wilson et al. [4]. These authors propose that each new orphan drug should be evaluated against several criteria at the time of pricing and reimbursement, including:

• the rarity of the condition;

• the level of research undertaken;

• the level of uncertainty of effectiveness;

• manufacturing complexity;

• follow-up measures required by regulatory authorities;

• disease severity;

• available alternatives/unmet medical need;

• the level of impact on the condition/disease modification;

• use in unique indication or not.

Each country would then need to determine the monetary value it places on the different criteria.

While this approach might be helpful as a stop-gap, it is hard to see how simply ensuring that orphan drugs provide value will overcome the main problem of finite and limited healthcare budgets. With so many rare diseases, affecting 6 – 8% of the world's population, having treatments for most of these diseases and still demanding high prices will not be possible.

An obvious solution is to price drugs more cheaply. But for an industry used to striving for billion-dollar blockbusters, this might prove too difficult to accept. The pharmaceutical industry maintains that it costs, on average, approximately $1.14 billion to bring a new medicine to market [5,6]. The price of medicines is then set in order to recoup the high investment and offset the high risk of drug development. But this figure remains controversial, with others suggesting the cost might be as low as $43 million on average [7]. Indeed the CEO of GSK, Sir Andrew Witty, recently proclaimed that the billion dollar figure was “one of the great myths of the industry” [8]. He said that in the future new approaches to drug development will make it possible to develop drugs more cheaply. Price reduction (as technologies progress) “is completely normal in other industries”, he said.

3. Lower development costs for orphan drugs

Sir Andrew Witty's remarks are particularly relevant for orphan drugs, where the cost of development is likely to be significantly less than for traditional drugs for several reasons [9]:

• development is faster (average of 3.9 vs 5.42 years from Phase II to launch for orphan vs non-orphan drugs) [10];

• clinical trial programmes are usually smaller;

• it is often possible to use surrogate endpoints;

• special regulatory pathways are more likely to apply to orphan drugs;

• the chances of regulatory success are higher [10];

• the development may be less risky;

• in cases where a drug is being repurposed, the development costs can be very low;

• marketing costs are considerably less;

• financial incentives of the orphan legislation and various grants programs can significantly reduce the financial burden for orphan drug development.

Ultimately, the solution to the problem is likely to be multifactorial. New advances in medicine should allow more targeted approaches to drug development, resulting in better patient selection and a lower failure rate. Innovative clinical development programmes using adaptive designs or (newly discovered) biomarkers may reduce the size and duration of clinical trials. Changes in the regulatory framework for the licensing of medicines, such as conditional approval and adaptive licensing may speed up approvals [11].

For rare diseases, other initiatives may also play a major role. Patient groups, public–private partnerships and other alliances and consortia are driving innovation in new ways. The Duchenne muscular dystrophy patient organisations, in Europe and the US, are a strong voice here. In France, the Téléthon has been an annual event since 1987. Organised by the French Muscular Dystrophy Association (AFM), it raises up to 100 million Euros every year from the public. The money is used mainly to fund research into Duchenne muscular dystrophy, although other rare diseases also benefit. Indeed, the AFM finances the gene therapy company Généthon, which was created by AFM in 1991. The company carries out research and development for gene therapies for rare diseases and has an annual budget of 27 million Euros, of which 85% is funded by the AFM.

Dutch company Prosensa is another example of using non-traditional routes to discover and develop potentially ground-breaking treatments for rare diseases. Founded in 2002 as a spin-off from academic research at the University of Leiden, Prosensa was funded for the first few years by a patient organisation. In 2009, Prosensa agreed a major development deal with GSK, securing the financial resources to continue the development of exon-skipping treatments for Duchenne muscular dystrophy and other neuromuscular disorders.

These examples show how alternative approaches to the traditional drug company model are paving the way for novel, ground-breaking developments for rare diseases. Advances in molecular biology, resulting from this type of research, may have major implications for the treatment of other diseases.

4. Findacure: the foundation for fundamental diseases

Findacure, a new charity, has seized upon by this idea. It seeks to establish a new paradigm to help us think differently about medical research and accelerate it. It has been known for centuries that the study of extreme and exceptional diseases is fundamental for understanding common diseases. That is why Findacure has coined the term ‘fundamental disease’ to describe these extreme and exceptional diseases, the study of which will advance our understanding of complex disease mechanisms, helping medicine to progress faster. Hence the study of rare diseases is relevant for all, not just the unfortunate few.

As well as campaigning for funding research into fundamental diseases, Findacure has created Findacure Development, a social enterprise which aims to develop new treatments for fundamental diseases on a non-commercial basis.

Findacure Development is not alone. Other recently formed organisations are taking up the non-profit approach to drug development, in particular for rare diseases:

• The Swiss-based Blackswan Foundation raises funds to support research on orphan diseases and improve public understanding of them. The foundation has already raised funds to support a number of projects.

• The Therapeutic Research Foundation is a non-profit biotechnology company in the US which aims to develop innovative, affordable, and therapeutic medical solutions for unmet medical needs.

• aPODD Foundation is a London-based non-profit organisation which aims to accelerate the development of new therapeutic agents that are effective and safe for the treatment of cancer in children.

• Orphan Biotech Research Foundation is a non-profit Swiss foundation for rare diseases which funds research and development of new drugs for rare diseases and raises public awareness about this.

• The EspeRare foundation was launched at the first conference of the International Rare Diseases Research Consortium (IRDiRC) in April this year. It seeks to drive translational research and development to advance treatments for rare diseases. Merck Serono is donating an initial €2.8 million to EspeRare and will transfer the rights of rimeporide, a compound which Merck previously developed for heart failure. The foundation will test this compound for Duchenne Muscular Dystrophy.

5. Repurposing for orphan drugs

EspeRare highlights an important aspect of orphan drug development; many existing molecules may be ‘repurposed’ for rare diseases. They may be already licensed for (an)other indication(s), or the originator company may never have fully developed them for commercial or strategic reasons, but they have already been through pre-clinical testing. In addition, a number of medications are available as specially compounded products and are used without a marketing authorisation (MA). These may be used to treat specific named patients (with rare diseases) and there is often a wealth of published literature already available, such that a marketing authorisation may be granted on the basis of very little additional work and therefore minimal cost to the MA holder. For example, 3,4-diaminopyridine for the treatment of Lambert-Eaton myasthenic syndrome [12].

Repurposed drugs can often be developed relatively quickly and cheaply. Indeed, several currently licensed orphan medicines are repurposed drugs. The relative simplicity of the development programme may make it viable to develop a treatment for a rare condition which would otherwise be commercially non-viable. It also lends itself nicely to a not-for-profit approach.

A good example is the repurposing of nitisinone for the treatment of alkaptonuria (AKU), sometimes known as black bone disease due to the black pigment which accumulates in the joints leading to early and severe arthritis. Although AKU was described over 100 years ago, no treatment has been developed to treat this condition which affects only 1 in 500,000 people. Nitisinone (a drug licensed for another rare disorder, hereditary tyrosinaemia type I) is highly likely to be an effective treatment for AKU because of its effect on the tyrosine metabolic pathway. Spearheaded by the AKU Society, the clinical development of nitisinone AKU is underway, funded by a European Union FP7 grant. The consortium running the programme includes world-leading academics, patient organisations, SMEs and a pharmaceutical company.

The AKU project also highlights two of the other points made above: the fundamental diseases concept (the study of AKU is helping to understand the much more common osteoarthritis); the use of an evolving regulatory framework (the use of a biochemical surrogate features heavily in the development programme).

6. Conclusion

To conclude, it is clear that the model of high pricing for orphan drugs is unsustainable and that new models of drug development, such as those mentioned above, are needed. A key challenge is access to funding, which is where the internet comes in. Crowdfunding through websites such as WiSEED, Indiegogo or Kickstarter is increasingly used to fund technology start-ups by allowing them to bypass the traditional financing routes. In the rare disease sector, this will help social entrepreneurs interested in accelerating alternative models of drug development, some of which are described in detail in a recent book, ‘Rare Diseases: Challenges and Opportunities for Social Entrepreneurs' [13]. One thing seems certain: the development of medicines is no longer the exclusive territory of the pharmaceutical companies.

Declaration of interest

The lead author is a founder of the Findacure Foundation. The co-author is also a founder of the Findacure and Head of the AKU Society. The authors state no conflict of interest and have received no payment in preparation of this manuscript.