Phase II and III drugs for the treatment of fragile X syndrome

Figures & data

Figure 1. Illustration of potential targets for drug therapy at a glutamatergic synapse in FXS. When stimulated by presynaptic glutamate release, postsynaptic mGluR1/5 receptors activate intracellular signaling cascades that mobilize translational machinery to translate mRNA into synaptic proteins, examples of which include MMP-9, MAP1B and APP. FMRP inhibits translation of more than 500 target mRNAs in the normal state; in FXS, this negative feedback mechanism is absent or severely reduced, leading to excessive protein synthesis and altered synaptic plasticity. Consequences of increased synaptic protein synthesis include loss of AMPARs and NMDARs from the postsynaptic membrane via endocytosis. Drugs that modulate excitatory glutamatergic and inhibitory GABAergic neurotransmission have the potential to alleviate some phenotypic effects in FXS. Key for labeled mechanisms of action and corresponding drugs: 1) LY2140023 (mGluR2/3 agonist); 2) acamprosate (GABA_AR agonist); 3) arbaclofen (GABA_BR agonist); 4) riluzole (blocks presynaptic glutamate release); 5) riluzole (blocks voltage-dependent sodium channels); 6) riluzole (enhances glutamate reuptake); 7) MPEP, fenobam, AFQ056, RO4917523, STX107, CTEP, acamprosate (mGluR5 antagonists); 8) CX516 (ampakine); 9) memantine (weak NMDA antagonist); d-serine, d-cycloserine, GLYX-13 (glycine site NMDAR partial agonists); 10) lithium, CX516 (increase BDNF); 11) lithium (GSK3 inhibition); 12) minocycline (MMP-9 inhibition).

Table 1. Comparison of Phase II and III clinical trials in FXS.

Compound	Mechanism of action	Clinical findings
Fenobam	mGluR5 antagonist	Open-label, single-dose trial in 12 adults: 6/12 (50%) with > 20% improvement in PPI; 9/12 (75%) with observed ‘calmed' behavior; no effect on attention and response inhibition [85]
AFQ056	mGluR5 antagonist	Randomized, double-blind crossover study in 30 male adults: No improvement on ABC-C subscales in subjects with partial FMR1 methylation; signification improvement in ABC-C sum score and Stereotypy, Hyperactivity and Inappropriate Speech subscales in those with full methylation; fatigue and headache common [87] Phase II trials in adults and adolescents and Phase I trials in children underway [86-89]
Acamprosate	Probable mGluR5 antagonist, GABAAR agonist and weak NMDA antagonist	Open-label study in 3 adult males: subjective improvement in expressive language skills; no improvement in non-verbal communication [94] Phase III trial in children underway [95]
RO4917523	mGluR5 antagonist	Phase II trials in adult males underway [96]
STX107	mGluR5 antagonist	Phase II trials in adult males in development [97]
Riluzole	Exact mechanism unknown; believed to block presynaptic glutamate release, enhance glutamate reuptake, block voltage-dependent sodium channels	Open-label study in 6 adult males: 1/6 (16%) with reduction in repetitive behavior and irritability; decreased ERK activation in all patients; 5/6 (83%) with asymptomatic increase in LFTs [100]
Memantine	NMDA antagonist	Chart review of 6 young adults treated with memantine: 4/6 (67%) with improvement on CGI-I; no specific improvement in specific rating scales; 2/6 (33.3%) with treatment-emergent irritability [101]
Minocycline	MMP-9 inhibitor	Open-label study in 20 young adults: significant improvement in ABC-C Irritability subscale scores, CGI-I and VAS; 2/20 (10%) seroconverted to positive ANA; GI side effects common [106] Phase II trials in children recently completed; results not yet available [109]
Lithium	GSK3 inhibitor; increases BDNF production	Open-label study in 15 children and adults: no improvement in ABC-C irritability subscale scores; mild to moderate improvement in ABC-Hyperactivity and Inappropriate Speech subscale scores, CGI-I, VAS and VABS measures; 11/15 (73%) with polyuria/polydipsia; 4/15 (27%) with elevated TSH [111]
Arbaclofen	GABABR agonist	Phase II randomized, placebo-controlled trial in 63 children and adults: trend toward significance in ABC-C Irritability subscale scores and CGI-I scores; 15 severely affected children with significant improvement in CGI-I and ABC-Social Withdrawal subscale scores [122] Phase III trials in children and adults underway [124]
CX516	Positive modulation of AMPA receptors	Randomized, placebo-controlled trials in 49 adults: no improvement on cognitive and behavioral measures [133]
OT	Neuropeptide involved in pro-social behavior	Randomized, placebo-controlled trial in 10 young adult males: Increased eye contact during social challenge task at lowest dose; decreased cortisol levels at highest dose [138]
Donepezil	Acetylcholinesterase antagonist	Open-label trial in 9 adults: improvement in measures of working memory, cognitive flexibility, hyperactivity, irritability, inattention [139] Randomized controlled trial in young adults underway [140]

ABC-C: Aberrant Behavior Checklist-Community Edition; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF: Brain-derived neurotrophic factor; CGI-I: Clinical Global Impressions-Improvement; FXS: Fragile X syndrome; GSK3: Glycogen synthase kinase-3; LFT: Liver function test; mGluR: Metabotropic glutamate receptor; MMP-9: Matrix metalloproteinase-9; NMDA: N-methyl-d-aspartate; OT: Oxytocin; PPI: Prepulse inhibition; TSH: Thyroid-stimulating hormone; VABS: Vineland Adaptive Behavior Scales; VAS: Visual analog scale.

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