Strimvelis: Telethon experience

Strimvelis represents a strategic alliance between a non­‐profit organization and a pharma company, that should be taken as an example for the future.

Over the past 15 years, Italy has played a leading role in the field of advanced therapies, such as Holoclar and Strimvelis.
Holoclar, approved and registered in 2015, is the first stem cell-­based therapy to enable corneal regeneration following severe burns, while Strimvelis is the first ex-vivo gene therapy based on hematopoietic stem cells intended to treat patients with a severe genetic immunodeficiency, the adenosine deaminase deficiency (ADA-­SCID) (Cicalese et a. Blood. 2016 Apr 29); Strimvelis received a positive opinion from the EMA in April 2016. Indeed, Strimvelis is the epitome of a product born thanks to a strategic alliance between a non-­profit organization and a pharma company; not only should this model be taken as an example for the future, but it should also be promoted and made sustainable.
The story of this drug can be traced back to the early nineties when Telethon, an Italian charity founded to address the research void claimed by patients associations in the rare genetic disease field, and San Raffaele Hospital in Milan, a major Italian scientific and clinical research institute, created the San Raffaele-Telethon Institute for gene therapy (SR-TIGET). Since the very beginning SR-­TIGET was conceived to bring under the same roof all the necessary skills, plus the human and technological resources, to effectively transfer the results of basic research into clinical practice. Key factors enabling the successful development of Strimvelis therapy, and also quintessential to the “Telethon model”, were:

  • granting of financial support through a strict evaluation method (i.e. based on peer review) and in line with international best practices.
  • renewal of the grant every five years allowing a long term perspective for planning and a significant time frame for the research program to properly develop; this has ensured a competitive advantage to a type of research that, even in countries like the United States, is usually subject to high pressure to produce short term "results or evidences";
  • access to state of the art facilities, clinical expertise and research excellence through the San Raffaele Scientific Institute;
  • the provision of a team of professionals dedicated to support research translation. This is accomplished through a set of actions: defining intellectual property strategies, protecting IP rights, scouting for industrial partnership opportunities, negotiating industrial agreements and managing industrial partnerships, defining the regulatory strategy for progression into clinic, managing regulatory activities (filing ODD and PIP applications, seeking advice from the National Competent Authority and from EMA).

The key elements of the success have been obtained through a combination of basic research, platform technology and disease pathogenesis study, preclinical research and clinical research spanning from natural history trials throughout interventional clinical studies. The first pilot study for gene therapy based on the SR-­TIGET research was initiated in two patients with ADA-­SCID in 2001 and followed up in 2002 by a phase 1-­2 pivotal study involving 12 patients treated in the subsequent years. In 2005, when the therapy obtained the orphan drug designation by EMA, the Telethon Foundation found itself facing a dilemma: how to develop and make available a gene therapy that had proven to be effective for an extremely rare disease but was still in an experimental stage? How to bring it to the market through the resources of a non-­‐profit organization? In light of this scenario, in 2007 Telethon -­ the first charity to do this- requested a Protocol Assistance to the European Medicines Agency (EMA), with a subsequent follow-­‐up one year later.
The technical, scientific and regulatory support by the agency was crucial for the Foundation both to confirm the robustness of the data available, and to encourage subsequent actions such as reaching out to a big profit company and entering a strategic alliance that would pave the way to the achievement of the research goal. The agreement signed by the Telethon Foundation and the San Raffaele Hospital with GlaxoSmithKline in 2010 allowed the deployment of the economic resources, the technical expertise and the infrastructures required to complete research development and achieve pharmaceutical production at the industrial level. In 2015 a marketing authorization application for the therapy was submitted to which less than one year later the Committee for Medicinal Products for Human Use (CHMP) gave a positive opinion. Should the European Commission, whose decision is expected within 67 days from the EMA’s opinion, view it positively, Strimvelis will be the first ex-vivo gene therapy to be registered and authorized in the world to offer effective and long-­ term treatment option to patients with a severe and rare genetic disease Though Strimvelis is certainly a success story showing a viable synergy between non-­profit and pharma, even in a niche sector like that of rare genetic diseases, it highlights a number of areas for improvement. While non-­profit research confirms its translational potential [in fact 17% of the EU registered pharmaceutical products originate from academic research (Lincker H., Ziogas C., Carr M., Porta N., Eichler, H. G. Regulatory watch: Where do new medicines originate from in the EU? Nature Reviews Drug Discovery. 2014; 13(2): 92-­‐93)], the need to make the process more sustainable and feasible is undeniable. For instance, encouraging academic researchers to produce their own data in a format and with such soundness as to be easily acquired by pharma and biotech companies, will be crucial to facilitate and replicate cases such as that of Strimvelis and increase the contribution of academia to new products development.
EMA can play a leading advisory role throughout this process, but it is necessary for the EU Commission to revise the Orphan Medicinal Products incentive, by:

  • recognizing to academia and charities/non-profit organizations the same fee reductions allowed to small and medium-­sized enterprises (SME)
  • providing to academia and charities/non-­profit organizations the possibility to request data certification (as done for SME)
  • finding a way of defraying the costs of qualified clinical testing expenses incurred in connection with the development of drugs for rare diseases and conditions (as defined in US by the Orphan Drug Act)

It is desirable that EMA keeps Regulatory Dossier Structure and Format during development as simple as possible. In particular, the Pediatric Investigational Plan (PIP) should be submitted as early as possible during development; if so, this step would be likely to happen at a time when the project is still managed by Academia/non-­profit organizations. Since the eSubmission Web Client for the submission of PIP applications to the Agency is not manageable by Academia/non-­profit organizations, we would encourage to keep submission processes managed during the development as simple as possible (i.e. Submissions only through Eudralink as done for ODD or Scientific Advice/Protocol Assistance applications).
If the academic research is conducted according to "high" standards from the start, the development process will undoubtedly be faster and sustainable and the contribution of non-­‐profit research to the drug development will grow significantly. EMA can play a leading advisory role through this process by providing free webinars (broader access, without costs for travel and lodging to attend workshops) on different topics needed to comply with a Marketing Authorization Application (i.e., how the data has to be generated, collected and archived during the development, how the analytical method has to be validated in research, etc.).

Strimvelis is the epitome of a product born thanks to a strategic alliance between a non-­‐profit organization and a pharma company; not only should this model be taken as an example for the future, but it should also be promoted and made sustainable.