The development of fumagillin at HCL
Drug shortages reached their peak during the covid-19 pandemic. The international dimension of these shortages is due to "unforeseen market fluctuations (23%), problems related to production itself (20%), problems with the supply of active ingredients (15%), regulatory constraints (10%), and economic constraints (7%)" . Faced with these shortages, actions have been taken in Europe and abroad, including a reflection on regulatory flexibility and the use of the magistral exception as a credible, complementary and non-competitive alternative to shortages of medicinal products of major therapeutic interest (MITM). Furthermore, a MITM stock out becomes particularly worrying when it affects the anti-infectious treatment of an orphan disease for which the marketing of the only commercial product has stopped due to a lack of production of pharmaceutical raw materials (MPUP).
During the first phase of the pandemic (2020-2021), the supply difficulties of raw materials for pharmaceutical use for the production of MITMs were limited by the joint actions of ANSM and AGEPS, allowing a network of in hospital pharmacies to be structured in order to propose an integrated system for the production and control of MITMs. From this experience, our hospital-university platform FRIPHARM® (Hospices Civils de Lyon) reports the availability of a magistral preparation following an end of commercialization of an oral form of fumagillin, antimicrobial agent used in the treatment of Enterocytozoon bieneusi intestinal microsporidiosis causing severe diarrhoea, sometimes fatal in immunocompromised patients (1.3 to 2.4 persons out of 10,000).
Thanks to the gracious donation of the former marketing authorization holder, the last world stock of pharmaceutical grade fumagillin (240 g) was shipped to FRIPHARM® in May 2021. The extreme instability of fumagillin to heat, light, and oxidants required transport and storage of the MPUP at - 80°C. In the absence of a monograph in the European and American pharmacopoeia, quality controls of the MPUP were carried out by our control laboratory taking into account the supplier’s analysis bulletins and the scientific bibliography ( 500 Pubmed and Sciencedirect articles). In parallel, a feasibility and risk analysis based on a formulation patent allowed the production of an oral oily suspension of fumagillin (20 mg/mL) and the treatment of a first patient in August 2021. At the end of this treatment, under strict hematological monitoring, a clear clinical improvement was noted and confirmed by
a negativation of the presence of Enterocytozoon bieneusi in the stools. To date, nearly 33 patients, i.e. approximately three patients per month, have benefited from this treatment in France.
Finally, a recent media campaign has brought potential fumagillin producers into contact with our organization, making it possible to consider renewing the only stock of fumagillin available, to our knowledge. This example shows that, in the face of a breakdown in the supply of care and with a view to equal access to care, recourse to magistral, hospital and special hospital preparations is a robust and reliable integrated device in a therapeutic arsenal marked by pandemic fluctuations.
1. Pénurie de médicaments : le plan d’actions du Leem. Atelier presse 19 février 2019.