Clinical trials in Fragile X Syndrome, Lessons learned, perspectives.

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1 Clinical trials in Fragile X Syndrome, Lessons learned, perspectives sebastien.jacquemont@umontreal.ca

2 Disclosures Consultancy fees, grants and honoraria from : Novartis Pharma AG GW Pharmaceutical

3 Fragile X syndrome (FXS)

4 FXS- Molecular basis How (CGG) n repeat interferes in FMR1 function? Normal (CGG) 5<54 mrna FMRP Gene FMR1 Premutation (CGG) 55<200 mrna FMRP Gene FMR1 Full mutation (CGG) >200 Gene FMR1 X FXS : I.D. = FMRP X or FMRP

5 Landscape of core pathways in FXS Bagni et al. 2012

6 Alterations of the protein synthesis-dependent synaptic homeostasis 15q CYFIP1 Deletions 1/500 16p11.2 Deletions & Duplications 2 x 1/2000? Idiopathic ASD Modified from Auerbach et al

7 FMRP, a master regulator of translation at the synapse Iossifov et al. Nature.

8 Net increase in protein synthesis is a major outcome measure in preclinical studies. Nature Reviews, 2017

9 History of clinical trials studies in Fragile X Nature Reviews Drug Discovery, 2017

10 12 to 17 y. 18 to 45 y. Science Translational Medicine, 2016

11 Primary outcome Measure Adults, CM and PM Children, CM and PM Aberrant Behavior Checklist, ABC-CFX least square (LS) mean change from baseline (after placebo run-in). Science Translational Medicine, 2016

12 High expectations and Placebo effects An Experimental Drug s Bitter End With fragile X, you re like living in a box and someone is holding the lid down. The medication opened the lid and let Parker out.

13 Conclusions from mglur5 antagonist and GABA B agonist trials The trials were sufficiently long to measure behavioural changes related to symptomatic effects. The broad age range (12 40 years) should have enabled the detection of agerelated therapeutic benefits. For arbaclofen, a signal was seen in the 5 11 years group. Lack of power has been an issue for many trials The utility of these small studies is questionable and incompatible with heavy post-hoc exploratory analyses. Nature Reviews Drug Discovery, 2017

14 The utility of smaller trials Carter et al, Biol Psych 2016 ; Locher et al, JAMA Psych 2017; Fung et al, Pediatrics 2016

15 The utility of smaller trials Carter et al, Biol Psych 2016 ; Locher et al, JAMA Psych 2017; Fung et al, Pediatrics 2016

16 Conclusions from mglur5 antagonist and GABA B agonist trials Windows of plasticity: very young patients were not included. This may be the only group in which effects cognition and development can be seen using additional learning interventions. Primary outcome measures were mostly behaviour questionnaires performed by caregivers. Objective measures of core phenotypes (ie. cognition and language) need to be implemented in future trials. Biomarkers Nature Reviews Drug Discovery, 2017

17 Acknowledgments Positions available for talented students! Laboratoire de Cytogénétique Sainte Justine France Léveillé, PhD; Géraldine Mathonnet, PhD; Frédérique Tihy PhD; Sonia Nizard, MD Catalina Maftei, MD Emmanuelle Lemyre, MD Fondation J.-Louis Lévesque and Suzanne Lévesque

18 Acknowledgments Hôpitaux de Lyon Aurore Curie, MD PhD Gérald Bussy Vincent Des Portes, MD PhD Novartis Georges Apostol, MD F.lorian von Raison, MD Baltazar Gomez-Mancilla, MD Fabrizio Gasparini, Phd Families!! Centre Hospitalier Universitaire Vaudois Nathalie Isidor, study nurse Fei Chen, PhD Loyse Hippolyte, PhD Mandy Barker, MD Sandra Martin, Aurélie Pain Marzia Passeggeri, MD Sébastien Jacquemont, MD The principal investigators: Dr Natalie Silove, Dr Martin Delatycki, Dr Marie Nassogne, Dr Hilde Van Esch, Dr Jacques Michaud, Dr Elena Lopez, Dr François Bolduc, Dr Karen Brondum-Nielsen, Dr Vincent des Portes, Dr Perrine Charles, Dr Gottfried Barth, Dr Veit Rößner, Dr Michael Huss, Dr Adam Alfred, Dr Klaus-Ulrich Oehler, Dr Karl Reitzle, Dr Sultana MH Faradz, Dr Lidia Gabis, Dr Maria Torrioli, Dr Eugenio Mercuri, Dr Edvige Veneselli, Dr Alessandra Murgia, Dr Hulya Kayserili Karabey, Dr Shimriet Zeidler, Dr Ana Roche, Dr Josep Artigas, Dr Ernest Balaguer, Dr Lucia Perez Costillas, Dr Maibritt Giacobini, Dr Anita Rauch, Dr Sebastien Jacquemont, Dr Andrew Stanfield, Dr Elizabeth Berry Kravis, Dr Joan Daughton, Dr Mark Fleisher, Dr Randi Hagerman, Dr Jeannie Visootsak, Dr Jeremy Veenstra- VanderWeele, Dr Lisa Albers Prock, Dr Ramzi Nasir, Dr William Brown and Dr Diana Treadwell. Centre de référence X Fragile Déficience Mentales liées à X Centre Hospitalier Universitaire Vaudois