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Interview with B Eymard

Prof. Bruno Eymard
An effective drug used for the treatment of Lambert Eaton syndrome (LEMS), 3,4-DAP has just obtained European marketing authorisation. Bruno Eymard, head of the Neuromuscular Diseases Unit at the Institute of Myology, convinced of the benefit of this drug for patients, is strongly committed to facilitating its availability, thanks to support from the AFM and the AP-HP (public hospital system).
How long did it take to obtain this marketing authorisation?
It is now ten years since I undertook the task of facilitating the availability of 3,4-DAP. In France, treatment of LEMS has been based on guanidine for a long time, with severe toxicity notably at the haematological and renal level. 3,4-DAP is a much less toxic product with proven efficacy and has already been used in many countries. Therefore, as a clinician, I saw that there was an absolute need to change treatment for my patients and I acted as a spur to the regulatory authorities to raise awareness and assist them in their efforts to obtain marketing authorisation.
Presently, marketing authorisation has only been obtained form EU authorities (EMA). To be marketed in France, 3,4-DAP must now be approved by the French authorities (AFSSAPS) for patients with Lambert Eaton syndrome as well as those who suffer from certain congenital myasthenic syndromes. However, the authorization is about to be granted for a period of five years.
What were the respective roles of the AFM and the AP-HP?
Both organisations collaborated closely. For nearly twenty years, the hospital pharmacies in large cities produced 3,4-DAP on demand, with obtainment conditions that were sometimes difficult for patients. It has become necessary to standardize the manufacture, amongst others, for pharmacovigilance reasons. A team from the General Agency for Equipment and Health Products (AGEPS), of the AP-HP, has thus developed a 3,4-DAP tablet. The Office of Technology Transfer and Industrial Partnerships of the AP-HP (OTT & PI) subsequently obtained a patent for the use of the active substance in the treatment of various diseases, including Lambert-Eaton syndrome. To develop and market the resulting product, AP-HP then entered into two partnerships: one financial, with the AFM to carry out additional toxicity studies in animals, the other industrial OPi-EUSA/Huxley-Biomarin, as part of a worldwide license agreement *.
Can you describe the mechanism of action of 3,4-DAP?
Lambert Eaton syndrome is a rare disease of the neuromuscular junction due to insufficient presynaptic release of acetylcholine (ACh), resulting in muscular weakness. 3,4-DAP blocks voltage-gated potassium channels in the axon. This blockage causes depolarisation of the presynaptic membrane and slows or even inhibits repolarisation of the presynaptic membrane. The prolonged depolarisation induces the opening of slow voltage-gated calcium channels and the influx of calcium. The increase in concentration of intracellular calcium causes exocytosis of vesicles containing ACh and consequently improves neuromuscular transmission**.
And for patients?
This treatment is very positive: it is the most effective first line drug for this disease of the neuromuscular junction and its secondary effects are minor. If it was extremely difficult to obtain before, it will become simpler and faster, thus facilitating the treatment of patients with certain myasthenic syndromes.
May 2010
Interview by Anne Berthomier, translation by Racquel N. Cooper