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Ultra-Rare Diseases and the Need to Invent a New Business Model

Updated: Oct 22, 2022

AFM-Telethon claims to be fighting to invent a new business model adapted to the specificities of developing and marketing drugs for ultra-rare diseases, at fair and controlled prices (words used on the AFM- Telethon website, June 9, 2022, or in its Annual and financial report 2019).

What new business model is AFM-Téléthon referring to?

Without attempting to cover all aspects of an issue that is of great relevance to social pharmaceutical innovation (SPIN), let’s examine the main points of the argument developed by the AFM-Téléthon.

But first a quick word about AFM-Telethon. For 30 years, this French patient organisation has been proactive in the fight against muscular dystrophies, and more broadly against rare diseases. Its actions include, in addition to activism at national and European levels (e.g. AFM-Téléthon is a founding member of both the French Rare Diseases Alliance and Eurordis, the European alliance of rare diseases patient organisations), the financing of research, the creation and/or financing and co-financing of infrastructures dedicated to the research, development and production of new drugs, in particular gene therapy (e.g. Genethon, which specializes in the identification of genetic targets, the design and manufacture of gene therapy products, and their pre-clinical and clinical development, or its own pharmaceutical company, Yposkesi, in which Korean group SK is today the majority shareholder).

Rare and Ultra-Rare

What does the term ultra-rare stand for?

Various ways of defining it can be found, e.g., whereas a Canadian comparative study on HTA submissions proposes to distinguish between rare and ultra-rare diseases according to their prevalence (i.e., > 1 and ≤ 50 patients per 100 000 versus ≤ 1 patient per 100 000 people) (Richter et al., 2018), for the U.S. Foundation n-Lorem it means “patients having a mutation unique to them (an N of 1) or having a mutation that has been identified as causing disease in fewer than 30 patients worldwide and is therefore out of the reach of traditional commercial drug programs” (Crooke, 2021).

The term "ultra-rare", as used by the AFM-Telethon, provides a more dynamic perspective, and seems in fact an observation of failure. It stems from the view that existing mechanisms and incentives meant to foster drug development and access for the treatment of rare diseases have reached their limits. The AFM-Telethon website states that rare diseases “represent a major challenge in terms of development model, clinical trial design and business model. The usual marketing mechanisms are unsuitable and the actors who, in recent years, have been pioneers with these diseases, are gradually refocusing on the most common rare diseases or on common pathologies” (AFM-Téléthon website, June 9, 2022; Tiennot-Herment 2018). This refocusing movement has left rare diseases on the sidelines, and these are the ones coined as ultra-rare diseases. According to the AFM-Téléthon, ultra-rare diseases represent 85% of rare diseases (AFM-Téléthon, June 9, 2022).

A necessity to account for the entanglement of scientific innovation, industrial development, and the sustainability of the health care system

Inventing a new business model is an alternative that the organisation has been advocating for years. The AFM-Telethon’s claim that it is urgently needed is based on past experience, and a critical assessment of the current situation in France and in Europe. If there is no business model for the development of innovative therapies for ultra-rare diseases, it is because in France, as in Europe, both public and profit-oriented private financing are non-existent, and development depends on resources raised from the public (notably financing proofs of concept) (Tiennot-Herment, 2018; AFM-Telethon, February 21, 20222). The AFM-Telethon denounces the inaction of European and national leaders, the absence of a proactive policy for the development of therapeutic innovation, and the apathy of European private investors. It describes a counterproductive cycle that is not only detrimental to patients (loss of opportunity) (AFM-Telethon, February 21, 2022), but also to research, R&D, the pharmaceutical industry and beyond to the healthcare system:

Despite the “excellence of French, and more broadly European, research,” the insufficient “culture of valorisation” (in France in particular) leads to innovations created in academic laboratories, or funded from resources raised from the public, being valorised abroad (Tiennot-Herment, 2018).

“It is the world gone topsy turvey. There is continual talk about the reindustrialization of France, but it is possible that ten years from now, most gene therapy drugs will be developed and produced outside of France, even though they were designed here. There is a significant risk that these innovations will be marketed at exorbitant price by American companies, something that might be difficult for our health systems to afford", says the President of AFM-Telethon, Laurence Tiennot-Herment (Barret, February 19, 2022, JDD).

Or worse, there is a risk of not having access to drugs, as exemplified by Skysona. This gene therapy for X-linked adrenoleucodystrophy, “derived like many others, from research conducted by French teams (Dr. Cartier-Lacave/Pr. Aubourg, Inserm) with the support of the Telethon”, is marketed by the U.S. company Bluebird Bio. After Skysona receiving a marketing authorization from the European Medicines Agency (EMA) in July 2021, the company decided the following October to restrict its distribution to the USA, making it unavailable in Europe (AFM-Telethon, February 21, 2022).

The lack of French or European investors for innovative projects initiated in France, both industrial (as AFM-Telethon encountered in the search for a partnership needed to develop Yposkesi) and clinical (as was the case for Skynosa), is a major challenge. "Are we thus doomed to the eternal dilemma: abandon the innovations made in France in the closets of our research labs or see them become drugs in the USA or Asia?", AFM-Telethon provocatively asks (February 21, 2022).

Perhaps one of the most striking aspects of this critique is also the plea it includes, to not deal with each problem separately, but rather take into account the entanglement of scientific innovation, industrial development, and the sustainability of the health care system (in particular preserving coverage for high-cost medical care). AFM-Telethon is calling on national and European leaders to develop public policies to "create, in our territory, all the conditions for research, development and valorisation to be organized and deployed" (Tiennot-Herment, 2018).

Genethon CEO Frederic Revah gives an example of the inventiveness and multi-partners initiative needed to bring a nationwide solution to the problem of the high price of certain gene therapies, whose production amounts today to several hundred million euros for a single dose. There is nothing to expect, according to him, from economies of scale. "Only fundamental innovation in virology and cell biology will bring prices down. In short, we need to move from the candle to the LED. It is about a multidisciplinary applied research and has nothing to do with the passage from artisanal production to an industrial scale. New jobs are to be invented, a bioengineering applied to production. We encourage the development of this new sector in France. (...) We are expecting the creation of an institute dedicated to innovation in bio-production for gene therapy. However, we must move quickly. Initiatives are being taken in other countries.” (Noussenbaum, 09/07/2020).

Value and Valuation

The challenge to invent a business model designed for the European territory includes rethinking the questions of value and valuation of drugs. The view that the issue of the economic value of ultra-rare diseases drugs also needs to be addressed by broadening the focus has long been advocated by the AFM-Telethon. As states the CEO of Généthon Frédéric Revah (Table ronde 4, 2014) “The economic value of gene therapy products - and of rare disease research in general - goes far beyond the value of the product itself. As an analogy, I would say that going to the moon has no economic interest. However, the benefits of this human adventure are considerable in the air transport, the space field, etc. The same is true for rare diseases. Rare diseases are in fact a springboard for frequent diseases, the former requiring us to carry out cutting-edge innovations, which will have a knock-on effect on the latter. It would be a major mistake to restrict the economic analysis of rare diseases to the individual product market. Clearly, the overall economic value of rare disease research must be understood beyond the specific market for a given product.”

AFM-Telethon calls for an overall revision of drug pricing mechanisms, arguing that value alone should not be the only criterion considered. “In the current system, for an equivalent ASMR [i.e. improvement on the medical service offered by the drug, which is part of the HTA, and serve as a basis for price negotiations], a repositioning product and a breakthrough therapeutic innovation should obtain the same price, which is not conceivable. Similarly, a breakthrough innovation that allows for a one-time treatment, such as gene therapy, cannot be priced the same as a recurrent treatment. It is therefore necessary to innovate in this area as well, using other criteria.” Among the points to consider in this revision process is the transparency that needs to be developed between all stakeholders; or the "jurisprudence" phenomenon, whereby as a drug of a new class develops – e.g. gene therapy - and the first ones obtain a significant price, all drugs of the same class follow and demand the same level (Tiennot-Herment, 2018).

Building an innovative model of public-private cooperation

AFM-Telethon's fight may be seen in the perspective of a dynamic in which the project carried out for 30 years to contribute to the production of treatments for rare diseases has been partially successful, since treatments exist and are being developed. And if ultra-rare diseases are to come off the sidelines and back into the game to tackle the drug market they need a business model. One of the main characteristics of the business model advocated by AFM-Telethon is best described on Genethon’s website as “an innovative model of public-private cooperation between pharmaceutical companies, non-profit laboratories and public institutions, to finance the development of therapeutic innovations and make these treatments available to patients” (Genethon, February 28, 2022).



AFM-Telethon. Les Maladies rares exclues de l’innovation thérapeutique : Il est urgent d’agir face à l’inacceptable ! [Rare Diseases excluded from therapeutic innovation: Urgent action is needed against the unacceptable!]. Published on their website on February 21, 2022. Accessed on October 12, 2022.

AFM-Telethon. Agir pour les maladies rares [Taking action for rare diseases]. Published on their website on June 9, 2022. Accessed on October 12, 2022.

AFM-Telethon. Des ressources diversifiées. Rapport annuel et financier 2019 [Diversified resources. Annual and financial report 2019]. Accessed on October 12, 2022.

Barret Anne-Laure. La présidente de l’AFM-Téléthon au JDD : « On prive des enfants de traitement pour des raisons commerciales ». [The President of the AFM-Telethon to the JDD: “Children are deprived of treatment for commercial reasons”]. Le Journal du Dimanche, February 19, 2022. Accessed on October 12, 2022.

Crooke Stanley T. A call to arms against ultra-rare diseases. Nature Biotechnology, 2021; 39, 671–677.

Genethon. Thérapie génique et maladies rares : des défis complexes, un enjeu mondial [Gene therapy and rare diseases: complex challenges, a global issue]. Published on their website on Februray 28, 2022. Accessed on October 12, 2022.

Noussenbaum Gilles. Frédéric Revah (Généthon) : « Qui avait prévu une telle inflation des prix ? » [Frédéric Revah (Genethon): "Who foresaw such price inflation?]. Décision & Stratégie, 09/07/2020.

Richter Trevor, Janoudi Ghayath, Amegatse William & Nester-Parr Sandra. Characteristics of drugs for ultra-rare diseases versus drugs for other rare diseases in HTA submissions made to the CADTH CDR. Orphanet Journal of Rare Diseases, 2018; 13, Article number: 15.

Table ronde 4: Faut-il de nouveaux modèles économiques ou outils de financement pour accélérer le développement de nouveaux traitements des maladies rares ? [Roundtable 4: Are new business models or financing tools needed to accelerate the development of new treatments for rare diseases?]. RARE 2013 – Les Rencontres Eurobiomed des Maladies Rares : L’innovation et les partenariats au service des malades [The Eurobiomed Meeting on Rare Diseases: Innovation and partnerships for the benefit of patients], 3rd edition, Montpellier, France, November 28 & 29, 2013. Médecine/sciences, 2014; 30 (hors série n° 1) : 47-53.

Tiennot-Herment Laurence.Les besoins en recherche et développement pour les maladies rares : le point de vue des malades [Needs for more R&D in the field of rare diseases: The patients' point of view]. Médecine/sciences, 2018 ; 34 (hors série n° 1) : 48-49.

Photo credit : Nikki Pirch (2008). Full moon. (CC BY-NC 2.0)


Written by: Florence Paterson

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