Perspectives of development of High Doses Ascorbic Acid as a treatment for Charc

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(Oral Presentation from Antwerp Consortium July 2009)

Perspectives of development of High Doses Ascorbic Acid as a treatment for

Charcot-Marie-Tooth disease type lA and preliminary results of French clinical

trial.

K. Pinachyanl, J. Micallef, S. Attarian3 , O. Dubourg4, P.M. Gonnaud5

, J.Y. Hogrel6 , E.Jouve7 , D. Tanesse8 , M. Fontes9 , J. Pouget3 and O. Blin2

IMurigenetics SAS, Marseille, France; 'ClC-UPCEl, CHU La Timone, AP-HM, UMR

CNRS-Universite de la Meditenanee 6193, Marseille, France; 'Service de

Neurologie et Maladies Neuromusculaires, CHU la limone, Marseille, France;

'Service d'Explmation Fonctionnelle, Neurologie, H6pital de la Salpetliere,

AP-HP, Paris, France; 'Service d'Explorations et Consultations Neurologi~ues,

Hospices Civils de lyon, France; 'lnstitut de Myologie, H6pital de la

Salpetliere, AP-HP, Paris, France; ClC-UPCEI, CHU La limone, AP-HM, Marseille,

France; 8Charcot-Marie-Iooth France Association, Lempdes, France; 'EA4263,

Faculte de Medecine de la I imone, Marseille, France

Charcot-Marie-Tooth disease type lA (CMTlA) is one of the most common inherited

neuropathies. After the description of the role of Ascorbic Acid (AA) in

correction of a CMT IA mouse model's phenotype, several clinical trials were

launched worldwide.

In 2008, the European Commission designated AA as an " orphan medicinal product "

under the European Regulation 14112000 after a positive evaluation by the

European Medicines Agency. These regulatory decisions open the access to

incentive measures and aids from public institution.

The French CMT clinical trial was conducted between 2005 and 2008 on 180 adult

patients, to study the efficacy and safety of two doses of AA (lg/d and 3 g/d)

on CMT IA patients in one-year, randomized, double-blind placebo contrulled

trial. The primary endpoint was CMT

Neuropathy Score (CMTNS).

No significant difference was shown on the primary endpoint However, a tendency

seems to be identified: CMTNS values of placebo and Ig AA groups were increasing

from the 3rd month of the treatment (i.e. a disease progression was observed),

while values of 3g AA group appear to be stable after 1 year. A similar pattern

was observed with the CMT

Examination score (CMTES), a sub-scale of CMTNS, that significantly differed

between groups. AA was safe and well tolerated.

Some reasons could explain non significant results for the group comparison for

the primary endpoints, and significant difference found on CMTES score analysis

The analyses of these reasons (e g the slow evolution of CMTNS and insufficient

sample size, short treatment period) will help us to define a better phase III

trial protocol.

This analysis should be realised within the framework of study design and

protocol assistance procedure of EMEA and FDA to increase chances of a positive

answer in case of the Marketing Authorisation Application.