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Cited by 336Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchAutism Spectrum Disorder Research

Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome

Open access
Berry-Kravis, Elizabeth M., Lindemann, Lothar, Jønch, Aia E., Apostol, George, Bear, Mark F., Carpenter, Randall L., Crawley, Jacqueline N., Curie, Aurore +12 more·2018·Nature Reviews Drug Discovery
DOI 10.1038/nrd.2017.221PMC PMC6904225
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Abstract

Neurodevelopmental disorders such as fragile X syndrome (FXS) result in lifelong cognitive and behavioural deficits and represent a major public health burden. FXS is the most frequent monogenic form of intellectual disability and autism, and the underlying pathophysiology linked to its causal gene, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches. These robust preclinical findings have led to the implementation of the most comprehensive drug development programme undertaken thus far for a genetically defined neurodevelopmental disorder, including phase IIb trials of metabotropic glutamate receptor 5 (mGluR5) antagonists and a phase III trial of a GABA B receptor agonist. However, none of the trials has been able to unambiguously demonstrate efficacy, and they have also highlighted the extent of the knowledge gaps in drug development for FXS and other neurodevelopmental disorders. In this Review, we examine potential issues in the previous studies and future directions for preclinical and clinical trials. FXS is at the forefront of efforts to develop drugs for neurodevelopmental disorders, and lessons learned in the process will also be important for such disorders.

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  • Findingcitation

    Many classic behavioural phenotypes used as preclinical outcome measures are inconsistently observed in Fmr1-knockout mice.

    “many of the other classic behavioural phenotypes used as outcome measures in preclinical studies are inconsistently observed in Fmr1-KO mice (such as open field, rotarod, elevated plus-maze, marble burying, self-grooming and most social paradigms).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [30] Gantois, I. et al. Chronic administration of AFQ056/Mavoglurant restores social behaviour in Fmr1 knockout mice. Behav. Brain Res. 239, 72–79 (2013). source

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    • cites [49] Bhattacharya, A. et al. Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron 76, 325–337 (2012). source

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    • cites [56] Hebert, B. et al. Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule. Orphanet J. Rare Dis. 9, 124 (2014). source

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    • cites [64] de Esch, C. E. et al. Fragile X mice have robust mGluR5-dependent alterations of social behaviour in the automated tube test. Neurobiol. Dis. 75, 31–39 (2015). source

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    • cites [65] Westmark, C. J. et al. Reversal of fragile X phenotypes by manipulation of AβPP/Aβ levels in Fmr1KO mice. PLoS ONE 6, e26549 (2011). source

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  • Findingcitation

    Core FXS mouse deficits, including protein synthesis, dendritic spine density and morphology, long-term depression, and audiogenic seizures, are consistently rescued by more than ten genetic approaches and multiple drug classes.

    “One striking conclusion of the broad array of preclinical studies is that these core deficits can be consistently rescued by more than ten genetic approaches and multiple classes of pharmacological compounds including mGluR antagonists (MPEP, fenobam, mavoglurant and CTEP), GABA agonists, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), mechanistic target of rapamycin (mTOR) inhib”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [26] Dölen, G. et al. Correction of fragile X syndrome in mice. Neuron 56, 955–962 (2007). This study demonstrates in the fragile X mouse model the rescue of a range of phenotypes relevant to the human disorder by reducing mGluR5 expression. source

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    • cites [31] Gross, C. et al. Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome. J. Neurosci. 30, 10624–10638 (2010). source

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    • cites [32] Michalon, A. et al. Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron 74, 49–56 (2012). This study reported efficacy of a long-acting mGluR5 antagonist in adult Fmr1 -KO mice. The comprehensive phenotype correction after development of the phenotype sparked great interest for testing mGluR5 antagonists in adult and adolescent patients with FXS. source

      Not checked in the free run.

    • cites [49] Bhattacharya, A. et al. Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron 76, 325–337 (2012). source

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    • cites [50] Bilousova, T. V. et al. Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J. Med. Genet. 46, 94–102 (2009). source

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    • cites [51] Boda, B., Mendez, P., Boury-Jamot, B., Magara, F. & Muller, D. Reversal of activity-mediated spine dynamics and learning impairment in a mouse model of Fragile X syndrome. Eur. J. Neurosci. 39, 1130–1137 (2014). source

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    • cites [52] Busquets-Garcia, A. et al. Targeting the endocannabinoid system in the treatment of fragile X syndrome. Nat. Med. 19, 603–607 (2013). source

      Not checked in the free run.

    • cites [53] Dolan, B. M. et al. Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486. Proc. Natl Acad. Sci. USA 110, 5671–5676 (2013). source

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    • cites [54] Gross, C. et al. Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome. Cell Rep. 11, 727–736 (2015). source

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    • cites [55] Hayashi, M. L. et al. Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice. Proc. Natl Acad. Sci. USA 104, 11489–11494 (2007). source

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  • Findingcitation

    Standard learning and memory tasks detect cognitive deficits in Fmr1-knockout mice in some reports but normal performance in others, within and across laboratories, independent of genetic background.

    “Standard learning and memory tasks for mice — including the Morris water maze, fear conditioning, passive avoidance, novel object recognition, visual discrimination and delayed non-matching to position — detected deficits in Fmr1-KO mice in some reports, but normal performance in others, both within and across laboratories and unrelated to the genetic background (FVB/NJ, FVB/AntJ or C57BL/6J)61–63”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [61] Gross, C., Hoffmann, A., Bassell, G. J. & Berry-Kravis, E. M. Therapeutic strategies in fragile X syndrome: from bench to bedside and back. Neurotherapeutics 12, 584–608 (2015). source

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    • cites [62] Kazdoba, T. M., Leach, P. T., Silverman, J. L. & Crawley, J. N. Modeling fragile X syndrome in the Fmr1 knockout mouse. Intractable Rare Dis. Res. 3, 118–133 (2014). source

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    • cites [63] Leach, P. T., Hayes, J., Pride, M., Silverman, J. L. & Crawley, J. N. Normal performance of Fmr1 mice on a touchscreen delayed nonmatching to position working memory task. eNeuro http://dx.doi.org/10.1523/eneuro.0143-15.2016 (2016). source

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  • Findingnone given

    Cognition was not formally investigated in the overall mavoglurant trial.

    “Cognition was not formally investigated in the overall trial.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    No human data are available for spinocerebellar ataxia type 1 because no suitable drug for clinical trials exists.

    “No human data are available for SCA1 in the absence of a drug suitable for clinical trials30,32,37.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [30] Gantois, I. et al. Chronic administration of AFQ056/Mavoglurant restores social behaviour in Fmr1 knockout mice. Behav. Brain Res. 239, 72–79 (2013). source

      Not checked in the free run.

    • cites [32] Michalon, A. et al. Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron 74, 49–56 (2012). This study reported efficacy of a long-acting mGluR5 antagonist in adult Fmr1 -KO mice. The comprehensive phenotype correction after development of the phenotype sparked great interest for testing mGluR5 antagonists in adult and adolescent patients with FXS. source

      Not checked in the free run.

    • cites [37] Henderson, C. et al. Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABAB receptors with arbaclofen. Sci. Transl Med. 4, 152ra128 (2012). source

      Not checked in the free run.

  • May combine two claims. 39
  • Classified as probably not a substantial claim. 33

  • May combine two claims.

    Findingown data

    Basimglurant was generally well tolerated in FragXis, with most adverse events classified as psychiatric disorders.

    “Basimglurant was overall well tolerated in the trial, with most adverse events classified as psychiatric disorders.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Post-hoc analysis of a mavoglurant phase IIa trial showed improvement in fully methylated FXS patients, but this was not replicated in the phase IIb trials.

    “Results from post-hoc analyses of a mavoglurant phase IIa trial71 showed improvement in patients with FXS and full methylation but were not replicated in the two phase IIb trials.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Jacquemont, S. et al. Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci. Transl Med. 3, 64ra61 (2011). source

      Not checked in the free run.

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    Findingcitation

    In the arbaclofen phase III study, children receiving the highest dose improved over placebo on the secondary ABC-CFX Irritability subscale and the Parenting Stress Index, both with P = 0.03.

    “In the phase III study, children receiving the highest dose of arbaclofen also showed improvement over placebo on the secondary end points of the ABC-CFX Irritability subscale (P = 0.03) and the Parenting Stress Index (P = 0.03).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Berry-Kravis, E. et al. Arbaclofen in fragile X syndrome: results of phase 3 trials. J. Neurodev. Disord. 9, 3 (2017). source

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    Findingcitation

    Preclinical data and receptor occupancy measures in mice and healthy subjects showed that the study drugs entered the brain, bound their target receptors, and produced pharmacodynamic effects.

    “A wealth of preclinical data and direct receptor occupancy measures for basimglurant in mice66 and healthy subjects70 demonstrated that the study drugs entered the brain, engaged their target receptors and showed pharmacodynamic effects.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [66] Lindemann, L. et al. Pharmacology of basimglurant (RO4917523, RG7090), a unique metabotropic glutamate receptor 5 negative allosteric modulator in clinical development for depression. J. Pharmacol. Exp. Ther. 353, 213–233 (2015). source

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    • cites [70] US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01483469 (2016).

      Not checked in the free run.

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    Findingown data

    In the FragXis secondary endpoint analysis, all treatment groups improved, but neither basimglurant group improved over placebo.

    “Similarly, in the secondary end point analysis, all treatment groups improved, but neither of the basimglurant groups showed improvement over placebo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In a substudy of 56 participants from the mavoglurant trials, exploratory biomarkers and endophenotypes suggested improvement versus placebo in gaze toward the eye region and in a computerized executive function battery.

    “Exploratory biomarkers and endophenotypes tested in a substudy (n = 56) of the mavoglurant trials suggests an improvement relative to placebo in gaze towards the eye region on an eye-tracking task and in performance on a computerized executive function battery69.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Berry-Kravis, E. et al. Mavoglurant in fragile X syndrome: results of two randomized, double-blind, placebo-controlled trials. Sci. Transl Med. 8, 321ra325 (2016). This article presents the results of two of the largest randomized, placebo-controlled studies undertaken in adolescents and adults with FXS. These studies did not show efficacy of mavoglurant, but they have stimulated further study of mavoglurant in younger children with FXS. source

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    Premisecitation

    The FMR1 expansion causes hypermethylation and silencing of FMR1, leading to absent or reduced FMRP.

    “This mutation results in hyper methylation and silencing of FMR1 and absence or reduction of its gene product, fragile X mental retardation protein 1 (FMRP)1,2.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Oberle, I. et al. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 252, 1097–1102 (1991). source

      Not checked in the free run.

    • cites [2] Pieretti, M. et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66, 817–822 (1991). References 1 and 2 are seminal papers of the simultaneous discovery of FMR1 by several research groups. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In under 1% of FXS patients, FMR1 inactivation is caused by mutations other than trinucleotide repeat expansions.

    “In a small fraction (less than 1%) of patients with FXS, the inactivation of FMR1 is caused by other non-trinucleotide repeat mutations3.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Handt, M. et al. Point mutation frequency in the FMR1 gene as revealed by fragile X syndrome screening. Mol. Cell Probes 28, 279–283 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Rescue of these behavioural phenotypes has been difficult to consolidate and to use as a guide for clinical studies.

    “As a result, the rescue of these behavioural phenotypes has been difficult to consolidate and to use as a guide for clinical studies30,49,56,64,65.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [30] Gantois, I. et al. Chronic administration of AFQ056/Mavoglurant restores social behaviour in Fmr1 knockout mice. Behav. Brain Res. 239, 72–79 (2013). source

      Not checked in the free run.

    • cites [49] Bhattacharya, A. et al. Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron 76, 325–337 (2012). source

      Not checked in the free run.

    • cites [56] Hebert, B. et al. Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule. Orphanet J. Rare Dis. 9, 124 (2014). source

      Not checked in the free run.

    • cites [64] de Esch, C. E. et al. Fragile X mice have robust mGluR5-dependent alterations of social behaviour in the automated tube test. Neurobiol. Dis. 75, 31–39 (2015). source

      Not checked in the free run.

    • cites [65] Westmark, C. J. et al. Reversal of fragile X phenotypes by manipulation of AβPP/Aβ levels in Fmr1KO mice. PLoS ONE 6, e26549 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reinstating Ube3a in Ube3a-knockout mice restores synaptic plasticity at any age, but behaviour improves only when reinstatement occurs during early development.

    “reinstatement of ubiquitin protein ligase E3A (Ube3a) in Ube3a-KO mice can restore synaptic plasticity at any age, but behaviour can only improve when reinstatement occurs during early development78.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Silva-Santos, S. et al. Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model. J. Clin. Invest. 125, 2069–2076 (2015). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The arbaclofen effect sizes highlight the need for adequately powered studies and new statistical designs that use clusters of several endpoints as a primary outcome.

    “which highlights the importance of properly powered studies and new statistical designs encompassing clusters of several end points as a primary outcome.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Confidence in a new mechanism's therapeutic potential is considerably strengthened when consistent findings are obtained in at least two distinct disease models, preferably in two species.

    “Generally, the confidence in the therapeutic potential of a new mechanism of action is considerably strengthened when consistent findings are obtained in at least two distinct disease models, preferably in two different species.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Behaviour is often the primary reason for referral and will remain a major treatment objective.

    “Behaviour is often the primary motive for referral and will remain a major objective for treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    The arbaclofen phase III trial was limited by incomplete enrolment due to sponsor financial issues, fixed rather than flexible dosing, and possible symptom inflation by families to meet inclusion criteria.

    “This trial was limited by a lack of full enrolment due to financial issues for the sponsor, the use of fixed rather than flexible dosing and possible inflation of symptoms by families in order to meet inclusion criteria72.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Berry-Kravis, E. et al. Arbaclofen in fragile X syndrome: results of phase 3 trials. J. Neurodev. Disord. 9, 3 (2017). source

      Not checked in the free run.

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    Premisecitation

    In Fmr1-knockout mice, mGluR antagonists, GABAB agonists, and gene reinstatement beginning in young adult or adult mice can fully correct most behavioural, physiological, biochemical, and neuroanatomical alterations.

    “treatment with mGluR antagonists (mavoglurant) and GABAB agonists (arbaclofen), as well as gene reinstatement in Fmr1-KO mice starting in young adult or adult mice, can fully correct most behavioural, physiological, biochemical and neuroanatomical alterations30,32,37.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [30] Gantois, I. et al. Chronic administration of AFQ056/Mavoglurant restores social behaviour in Fmr1 knockout mice. Behav. Brain Res. 239, 72–79 (2013). source

      Not checked in the free run.

    • cites [32] Michalon, A. et al. Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron 74, 49–56 (2012). This study reported efficacy of a long-acting mGluR5 antagonist in adult Fmr1 -KO mice. The comprehensive phenotype correction after development of the phenotype sparked great interest for testing mGluR5 antagonists in adult and adolescent patients with FXS. source

      Not checked in the free run.

    • cites [37] Henderson, C. et al. Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABAB receptors with arbaclofen. Sci. Transl Med. 4, 152ra128 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Lack of reproducibility in preclinical models and lack of translation from SOD1 mouse efficacy to ALS patients explain why drug profiling in the SOD1 mouse poorly translated into clinical efficacy.

    “Lack of reproducibility in preclinical models and lack of translation from preclinical efficacy for drugs tested in the SOD1 mouse model to patients with ALS explain why the profiling of drug candidates in the SOD1 mouse model poorly translated into clinical efficacy85.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Scott, S. et al. Design, power, and interpretation of studies in the standard murine model of ALS. Amyotroph. Lateral Scler. 9, 4–15 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Multiple issues may account for the negative FXS trials, and those negative results do not persuasively invalidate the preclinical models and drug treatments.

    “there are multiple issues that may account for the negative trials in FXS, and the negative trial results thus do not persuasively invalidate the preclinical models and drug treatments.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    In the adult and adolescent FragXis study, patients were randomly assigned to basimglurant or placebo with stratification by gender and age group.

    “Patients were randomly assigned to receive basimglurant (0.5 or 1.5 mg once a day (q.d.)) or placebo, with stratification by gender and age group (14–17 and 18–50 years) to ensure that about one-third of participants were adolescents.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Youssef, E. A. et al. Effect of the mGluR5-NAM basimglurant on behavior in adolescents and adults with fragile X syndrome in a randomized, double-blind, placebo-controlled trial: fragXis phase 2 results. Neuropsychopharmacology http://dx.doi.org/10.1038/npp.2017.177 (2017). This reference reports the large randomized, double-blind, placebo-controlled phase II trial with the mGluR5 antagonist basimglurant in adult and adolescent patients with FXS. source

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  • May combine two claims.

    Interpretationnone given

    Complex aberrant behaviours in patients with fragile X syndrome arise from interactions between the effects of FMRP deficiency on brain functioning and environmental variability, whereas genetic background and environmental factors in animal models are held constant.

    “these behaviours arise in patients as a result of complex interactions between the resultant effects of FMRP deficiency on brain functioning and variability in environmental factors — such as family environment, parenting, the school or learning environment and other variables — whereas the genetic background and environmental factors in animal models are held constant.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Research and development costs increased while the number of drugs approved remained static.

    “In reality, research and development costs increased while the number of drugs approved remained static106,107.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [106] Cook, D. et al. Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework. Nat. Rev. Drug Discov. 13, 419–431 (2014). source

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    • cites [107] Pammolli, F., Magazzini, L. & Riccaboni, M. The productivity crisis in pharmaceutical R&D. Nat. Rev. Drug Discov. 10, 428–438 (2011). source

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  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationnone given

    Measuring changes in core deficits across developmental trajectories would likely require longer studies using learning paradigms focused on younger patients.

    “To measure changes in core deficits (learning, adaptive behaviour, cognition) across developmental trajectories, one would likely need longer studies involving learning paradigms that are focused on younger patients.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: There is consensus on cognitive domains that are crucial to fragile X syndrome outcomes, such as attention, response inhibition and working memory, but there is no consensus on which specific measures should be used to evaluate changes in cognition.

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    Interpretationreasoning

    These problems also apply to fragile X syndrome trials, many of which are statistically underpowered and open label.

    “These issues also apply to FXS trials, many of them being statistically underpowered and open label.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Cellular evidence suggests that dopamine release is dysregulated in neuronal cultures of full-mutation neurons and is improved by adding either FMRP or methylphenidate.

    “evidence at a cellular level suggests that dopamine release is dysregulated in neuronal culture in full-mutation neurons, and this is improved with the addition of either FMRP or methylphenidate to the cell culture98.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Wang, L. W., Berry-Kravis, E. & Hagerman, R. J. Fragile X: leading the way for targeted treatments in autism. Neurotherapeutics 7, 264–274 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Inconclusive studies may inhibit new efforts and investments in the development of novel medicines.

    “Inconclusive studies may inhibit new efforts and investments in the development of novel medicines.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    The median sample size for randomized controlled trials in that review was 25 patients, with a range of 2 to 537, and less than one third had an acceptable Jadad score above 3.

    “The median sample size for RCTs was 25 patients (range: 2–537), and less than a third of RCTs had an acceptable Jadad score exceeding 3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] van der Vaart, T., Overwater, I. E., Oostenbrink, R., Moll, H. A. & Elgersma, Y. Treatment of cognitive deficits in genetic disorders: a systematic review of clinical trials of diet and drug treatments. JAMA Neurol. 72, 1052–1060 (2015). source

      Not checked in the free run.

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    Premisecitation

    Expressive Language Sampling has excellent test-retest validity after weeks and has been validated against the expressive language subtest of the Vineland Adaptive Behavior Scales.

    “ELS has excellent test and retest validity after weeks, and it has been validated against the expressive language subtest of the VABS94.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] McDuffie, A. et al. A spoken-language intervention for school-aged boys with fragile X syndrome. Am. J. Intellect. Dev. Disabil. 121, 236–265 (2016). source

      Not checked in the free run.

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    Premisecitation

    In 44% of those studies, authors reported potential efficacy, but this led to only two approved treatments: dietary restriction for phenylketonuria and miglustat for Niemann-Pick disease type C.

    “In 44% of these studies, authors reported potential efficacy, but this led to only two approved treatments: dietary restriction for phenylketonuria and miglustat for Niemann–Pick disease type C105.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] van der Vaart, T., Overwater, I. E., Oostenbrink, R., Moll, H. A. & Elgersma, Y. Treatment of cognitive deficits in genetic disorders: a systematic review of clinical trials of diet and drug treatments. JAMA Neurol. 72, 1052–1060 (2015). source

      Not checked in the free run.

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    Premisecitation

    Available mouse operant touchscreen paradigms seem to have face validity relative to human cognitive touchscreen tasks, although there is concern that the cognitive profile of Fmr1-KO mice may not emulate the cognitive deficits in the human syndrome.

    “available mouse operant touchscreen paradigms seem to have face validity63,89,101–104 relative to human cognitive touchscreen tasks97, although there is concern that the cognitive profile of Fmr1-KO mice may not emulate the cognitive deficits in the human syndrome63.”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [63] Leach, P. T., Hayes, J., Pride, M., Silverman, J. L. & Crawley, J. N. Normal performance of Fmr1 mice on a touchscreen delayed nonmatching to position working memory task. eNeuro http://dx.doi.org/10.1523/eneuro.0143-15.2016 (2016). source

      Not checked in the free run.

    • cites [89] Dawson, G. et al. Randomized, controlled trial of an intervention for toddlers with autism: the early start denver model. Pediatrics 125, e17–e23 (2010). source

      Not checked in the free run.

    • cites [101] Brigman, J. L., Bussey, T. J., Saksida, L. M. & Rothblat, L. A. Discrimination of multidimensional visual stimuli by mice: intra- and extradimensional shifts. Behav. Neurosci. 119, 839–842 (2005). source

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    • cites [102] Brigman, J. L., Graybeal, C. & Holmes, A. Predictably irrational: assaying cognitive inflexibility in mouse models of schizophrenia. Front. Neurosci. http://dx.doi.org/10.3389/neuro.01.013.2010 (2010). source

      Not checked in the free run.

    • cites [103] Bussey, T. J. et al. New translational assays for preclinical modelling of cognition in schizophrenia: the touchscreen testing method for mice and rats. Neuropharmacology 62, 1191–1203 (2012). source

      Not checked in the free run.

    • cites [104] Bussey, T. J. et al. The touchscreen cognitive testing method for rodents: how to get the best out of your rat. Learn. Mem. 15, 516–523 (2008). source

      Not checked in the free run.

    • cites [97] Hessl, D. et al. The NIH toolbox cognitive battery for intellectual disabilities: three preliminary studies and future directions. J. Neurodev. Disord. 8, 35 (2016). source

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    Premisecitation

    Re-scoring of the Wechsler Intelligence Scale for Children and the Stanford-Binet for populations with intellectual disability has been completed and yields more sensitive estimates of true ability below the traditional test floor.

    “re-scoring of the Wechsler Intelligence Scale for Children (WISC)92 and Stanford–Binet10 for populations with intellectual disability has been completed, yielding much more sensitive estimates of true ability below the traditional test floor.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [92] Hessl, D. et al. A solution to limitations of cognitive testing in children with intellectual disabilities: the case of fragile X syndrome. J. Neurodev. Disord. 1, 33–45 (2009). source

      Not checked in the free run.

    • cites [10] Sansone, S. M. et al. Improving IQ measurement in intellectual disabilities using true deviation from population norms. J. Neurodev. Disord. 6, 16 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    These landmark studies will have profound implications at every step of the drug development process for neurodevelopmental disorders.

    “These landmarks studies will have profound implications at every step of the drug development process for NDDs.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    For the treatment of lifelong neurodevelopmental disorders, short trials may not be sufficient to evaluate the full impact of study drugs on the developmental trajectory.

    “For the treatment of lifelong NDDs, we expect that short trials may not be sufficient to evaluate the full impact of study drugs on the developmental trajectory.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    New trial designs and outcome measures need to be scientifically validated and receive regulatory acceptance to be effectively implemented in future proof-of-concept trials.

    “It is clear that new trial designs and outcome measures need to be scientifically validated and receive regulatory acceptance to be effectively implemented in future proof-of-concept trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Toxicological studies from start to finish take much longer than the actual treatment duration, generally 6 to 9 months for a study with a 4-week treatment, so it takes several years of sequential studies for the completion of the comprehensive toxicology or safety programme for a new drug.

    “Toxicological studies from start to finish take much longer than the actual treatment duration (generally 6–9 months for a study with a 4 week treatment), so it takes several years of sequential studies for the completion of the comprehensive toxicology or safety programme for a new drug.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    This situation can improve only with the development of translational animal models and with the use of preclinical assessments that translate to clinical outcome measures.

    “This situation can improve only with the development of translational animal models and with the use of preclinical assessments translating to clinical outcome measures.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The FDA and EMA currently require phase II and phase III clinical trials to select only one assessment as the primary end point against which the success of the trial is measured.

    “The FDA and EMA currently require phase II and phase III clinical trials to select only one assessment as the primary end point against which the success of the trial is measured.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    It cannot be known whether drugs that fail or show minimal short-term effects in adolescents and adults will be effective in children with a developmental disorder.

    “It cannot be known whether drugs that fail or show minimal short-term effects in adolescents and adults will be effective in children with a developmental disorder.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Safety requirements become even more crucial and complex in the long-term treatment of children, as the mechanism of action itself may have adverse and potentially irreversible effects.

    “Yet safety requirements become even more crucial and complex in the long-term treatment of children, as the mechanism of action (such as inhibition of an enzyme or receptor) itself may have adverse and potentially irreversible effects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Regulatory acceptance of novel outcome measures as primary end points will require a significant body of clinical validation in naturalistic and drug intervention studies.

    “It is expected that regulatory acceptance of novel outcome measures as primary end points will require a significant body of clinical validation in naturalistic and drug intervention studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    This approach provides some flexibility and may facilitate an early progression into clinical paediatric studies.

    “This approach provides some flexibility and may facilitate an early progression into clinical paediatric studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The sequential approach of studies with increasing treatment duration is necessary because the maximal tolerated dose or exposure often decreases and the number or severity of safety-relevant findings often increases with treatment duration.

    “The sequential approach of studies with increasing treatment duration is necessary because the maximal tolerated dose or exposure often decreases and the number and/or severity of safety-relevant findings often increases with treatment duration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In neurodevelopmental disorders, the regulatory environment is less well established, leading to uncertainties in clinical trial design.

    “Thus, in the area of NDDs, the regulatory environment is less well established, leading to uncertainties in clinical trial design.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Regulatory acceptance of novel study designs and primary end points will require a substantial body of clinical validation in naturalistic and drug intervention studies as well as close collaboration with the FDA and the EMA.

    “It is expected that regulatory acceptance of novel study designs and primary end points will require a substantial body of clinical validation in naturalistic and drug intervention studies as well as close collaboration with the FDA and the EMA.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The general toxicity programme for a drug is typically composed of sequential studies of increasing duration in rats and a non-rodent species, ultimately leading to chronic toxicity studies of 6 to 24 months.

    “The general toxicity programme for a drug is typically composed of sequential studies of increasing duration (typical increments are 4, 13, 26 and 52 weeks) in rats and a non-rodent species, ultimately leading to chronic toxicity studies of 6–24 months duration.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [117] US Food and Drug Administration. Pharmacology/toxicology. FDA http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065014.htm (2017).

      Not checked in the free run.

    • cites [118] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Safety guidelines. ICH http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html (2017).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The larger studies of mavoglurant, basimglurant and arbaclofen included over 100 participants and were able to provide conclusions across secondary outcome measures.

    “Conversely, the larger studies of mavoglurant, basimglurant and arbaclofen included over 100 participants and were able to provide conclusions across secondary outcome measures69.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Berry-Kravis, E. et al. Mavoglurant in fragile X syndrome: results of two randomized, double-blind, placebo-controlled trials. Sci. Transl Med. 8, 321ra325 (2016). This article presents the results of two of the largest randomized, placebo-controlled studies undertaken in adolescents and adults with FXS. These studies did not show efficacy of mavoglurant, but they have stimulated further study of mavoglurant in younger children with FXS. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    To achieve the level of quality and power required to draw unequivocal conclusions on the benefits of a given compound, trials will have to be conducted through large international consortia.

    “In order to achieve the level of quality and power required to draw unequivocal conclusions on the benefits of a given compound, trials will have to be conducted through large international consortia.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The design of juvenile toxicological studies is typically developed in collaboration with the regulatory agencies.

    “Unlike the tightly prescribed core of the general toxicity studies, the design of juvenile toxicological studies is typically developed in collaboration with the regulatory agencies.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [118] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Safety guidelines. ICH http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html (2017).

      Not checked in the free run.

    • cites [119] US Food and Drug Administration. Guidance for industry: nonclinical safety evaluation of pediatric drug products. FDA http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm079247.pdf (2006).

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The choice of clinical outcome measures was largely informed by feedback from families on disruptive behaviours, by the applicability of scales and measures to patient symptoms, and by the acceptance of particular scales by regulators based mostly on their use in other neurodevelopmental disorder populations.

    “Instead, the choice of clinical outcome measures was largely informed by feedback from families on disruptive behaviours and by the applicability of scales and measures to patient symptoms, as well as the acceptance of particular scales by regulators based mostly on their use in other NDD populations.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Recently, funders and regulators have recognized that addressing these challenges requires strategic approaches and have set up initiatives to bring together academics, industry, patient organizations and other stakeholders.

    “Recently, funders and regulators have recognized that addressing these challenges requires strategic approaches and have set up initiatives to bring together academics, industry, patient organizations and other stakeholders.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [120] National Academies of Sciences, Engineering and Medicine. Neuroscience Trials of the Future: Proceedings of a Workshop (The National Academies Press, 2016).

      Not checked in the free run.

    • cites [121] Innovative Medicines Initiative. IMI2 10 th call for proprosals. Innovative Medicines Initiative http://www.imi.europa.eu/sites/default/files/uploads/documents/IMI2Call10/IMI2_Call10_TopicsText.pdf (2016).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationnone given

    Confidence in the robustness of treatment effects tested on more than one end point could be increased by backing up clinical measures with validated objective surrogate outcome measures or target engagement biomarkers.

    “In the future, confidence in the robustness of treatment effects tested on more than one end point could be increased by backing up clinical measures with validated objective surrogate outcome measures (such as eye tracking, EEG and fMRI) or target engagement biomarkers, which also increase the understanding of the processes by which a target impacts on behaviour.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Regulatory requirements for safety and toxicological data include information on maximum tolerated dose or exposure for any given treatment duration, the type of adverse drug effects, the target organs affected when the highest tolerated dose or exposure is exceeded, drug metabolism, pharmacokinetic properties, and the potential of the drug to interact with co-medication.

    “Regulatory requirements for safety and toxicological data117,118 include information on maximum tolerated dose or exposure for any given treatment duration, the type of adverse drug effects, the target organs affected when the highest tolerated dose or exposure is exceeded, drug metabolism, pharmacokinetic properties and the potential of the drug to interact with co-medication.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [117] US Food and Drug Administration. Pharmacology/toxicology. FDA http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065014.htm (2017).

      Not checked in the free run.

    • cites [118] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Safety guidelines. ICH http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html (2017).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    A challenge for drug development in neurodevelopmental disorders is the very limited precedence of approved medicines compared with drugs for other indications such as schizophrenia or major depressive disorder.

    “A challenge for drug development in NDDs is the very limited precedence of approved medicines compared with drugs for other indications such as schizophrenia or major depressive disorder.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The robustness of detecting a treatment effect may also be increased by introducing aggregate measures composed of several individual outcome measures, thereby increasing the chance of capturing improvement of symptoms in a heterogeneous patient population with differential response to treatment.

    “In addition, the robustness of detecting a treatment effect may also be increased by introducing aggregate measures composed of several individual outcome measures, thereby increasing the chance of capturing improvement of symptoms in a heterogeneous patient population with differential response to treatment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Trials of new investigational drugs in paediatric populations and longer trial durations require specific preclinical toxicological and safety examination.

    “Trials of new investigational drugs in paediatric populations and longer trial durations require specific preclinical toxicological and safety examination as outlined below.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationreasoning

    This approval will require the dedicated effort of academic and industrial partners working together with regulators, as well as a combination of observational trials and trials applying well-characterized interventions.

    “This approval will require the dedicated effort of academic and industrial partners working together with regulators, as well as a combination of observational trials (that is, without drug intervention) and trials applying well-characterized interventions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The Innovative Medicines Initiative (IMI-2) has set out to develop a strategic framework for the development of pharmacotherapies for autism spectrum disorder.

    “Another example of a public–private partnership joining forces in the area of NDDs is the Innovative Medicines Initiative (IMI-2), which has set out to develop a strategic framework for the development of pharmacotherapies for ASD121.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Innovative Medicines Initiative. IMI2 10 th call for proprosals. Innovative Medicines Initiative http://www.imi.europa.eu/sites/default/files/uploads/documents/IMI2Call10/IMI2_Call10_TopicsText.pdf (2016).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The EMA will evaluate paediatric development on a case-by-case basis, taking into account the totality of available information, including scientific rationale, preclinical and clinical efficacy and safety data, the severity of the indication, and ethical risk-benefit considerations.

    “In essence, the EMA will evaluate paediatric development on a case-by-case basis, taking into account the totality of available information, including scientific rationale, preclinical and clinical efficacy and safety data and the severity of the indication, as well as ethical risk–benefit considerations.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] European Medicines Agency. Extrapolation of efficacy and safety in paediatric medicine development. European Medicines Agency http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001367.jsp&mid=WC0b01ac0580029572 (2016).

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    In recent fragile X syndrome trials, the choice of end point was hampered by the fact that readouts from preclinical studies did not match established clinical outcome measures and by the lack of a truly mechanistic understanding of the link between the molecular and physiological disease mechanism and behavioural symptoms.

    “In recent FXS trials, the choice of end point was hampered by the fact that readouts from preclinical studies did not match established clinical outcome measures and by the lack of a truly mechanistic understanding of the link between the molecular and physiological disease mechanism and behavioural symptoms.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Factors that may have contributed to the negative findings reported above are not unique to fragile X syndrome research, and other medical fields are facing the same challenges.

    “Factors that may have contributed to the negative findings reported above are not unique to research on FXS, and other medical fields are facing the same challenges.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Toxicity studies must identify both a dose or exposure level that produces no toxicological findings of concern and a dose or exposure level that causes relevant toxicological findings.

    “Toxicity studies must identify both a dose or exposure level that produce no toxicological findings of concern and a dose or exposure level that causes relevant toxicological findings.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [117] US Food and Drug Administration. Pharmacology/toxicology. FDA http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065014.htm (2017).

      Not checked in the free run.

    • cites [118] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Safety guidelines. ICH http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html (2017).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    For the mGluR5 antagonist trials, even a focus on subscales would not have changed the outcome of the trials.

    “However, for the mGluR5 antagonist trials, for example, even the focus on subscales would not have changed the outcome of the trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The National Academies of Sciences, Engineering, and Medicine have organized a series of workshops to discuss opportunities for improving the integrity, efficiency and validity of clinical trials of CNS disorders, including the implementation of cutting-edge technologies in future trials.

    “For example, the National Academies of Sciences, Engineering, and Medicine have organized a series of workshops to discuss opportunities for improving the integrity, efficiency and validity of clinical trials of CNS disorders, including the implementation of cutting-edge technologies in future trials120.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] National Academies of Sciences, Engineering and Medicine. Neuroscience Trials of the Future: Proceedings of a Workshop (The National Academies Press, 2016).

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The stepwise approach has been ineffective because most phase II studies were grossly underpowered, with sample sizes ranging from 30 to 60, to adequately explore the utility of secondary measures.

    “This stepwise approach has been ineffective because most phase II studies were grossly underpowered (n ranging from 30 to 60) to adequately explore utility of the secondary measures.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The cited article presents results of two of the largest randomized, placebo-controlled studies in adolescents and adults with FXS.

    “This article presents the results of two of the largest randomized, placebo-controlled studies undertaken in adolescents and adults with FXS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Berry-Kravis, E. et al. Mavoglurant in fragile X syndrome: results of two randomized, double-blind, placebo-controlled trials. Sci. Transl Med. 8, 321ra325 (2016). This article presents the results of two of the largest randomized, placebo-controlled studies undertaken in adolescents and adults with FXS. These studies did not show efficacy of mavoglurant, but they have stimulated further study of mavoglurant in younger children with FXS. source

      Not checked in the free run.

63 of 63

  • The paper relies on this without support.

    There is consensus on cognitive domains that are crucial to fragile X syndrome outcomes, such as attention, response inhibition and working memory, but there is no consensus on which specific measures should be used to evaluate changes in cognition.

    “There is consensus on cognitive domains that are crucial to FXS outcomes (such as attention and response inhibition and working memory) but not on which specific measures should be used to evaluate changes in cognition.”

  • The paper relies on this without support.

    The average IQ for males with fragile X syndrome is estimated to be in the low 40s, about 4 standard deviations below normal, which represents the floor of most standardized tests.

    “the average IQ for males with FXS is estimated to be in the low 40s (4 s.d. below normal), which represents the floor of most standardized tests.”

  • The paper relies on this without support.

    In neurodevelopmental disorders, there is currently no consensus on what constitutes disease modification and no definition recognized by regulatory agencies.

    “In NDDs, there is currently no consensus on what constitutes disease modification, and there is currently no definition recognized by regulatory agencies.”

  • The paper relies on this without support.

    Several biomarkers, such as ERP and eye tracking, have been studied but have not yet been validated as core deficits and linked to quality of life or clinical measures.

    “Several biomarkers (such as ERP and eye tracking) have been studied but have not yet been validated as core deficits and linked to quality of life or clinical measures.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • R-baclofen and several mGluR5 negative allosteric modulators have failed in clinical trials for Fragile X patients.

    “However, R-baclofen and several mGluR5 NAMs have produced negative results in clinical trials with Fragile X patients [98].”

    From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [98]

The citation lists haven’t been fetched yet

References 143 · Cited by 336

Research works printed but not linked: 1

  1. National Academies of Sciences, Engineering and Medicine. Neuroscience Trials of the Future: Proceedings of a Workshop (The National Academies Press, 2016).

Authors
Berry-Kravis, E. M., Lindemann, L., Jønch, A. E., Apostol, G., Bear, M. F., Carpenter, R. L., Crawley, J. N., Curie, A., Des Portes, V., Hossain, F., Gasparini, F., Gomez-Mancilla, B., Hessl, D., Loth, E., Scharf, S. H., Wang, P. P., Von Raison, F., Hagerman, R., Spooren, W., & Jacquemont, S.
Affiliations
  • F. Hoffmann-La Roche AG (CH)
  • University of Southern Denmark (DK)
  • Novartis (Switzerland) (CH)
  • Massachusetts Institute of Technology (US)
  • University of California Davis Medical Center (US)
  • Centre National de la Recherche Scientifique (FR)
  • King's College London (GB)
  • Simons Foundation (US)
  • Centre Hospitalier Universitaire Vaudois (CH)
Corresponding author
Jacquemont, Sébastien
ORCID
Venue
Nature Reviews Drug Discovery
Publisher
Springer Science and Business Media LLC
Published
2017-12-08
Volume
17
Issue
4
Pages
280-299
ISSN
  • 1474-1776 (ISSN-L)
  • 1474-1784
DOI
10.1038/nrd.2017.221
PMC
PMC6904225
OpenAlex
W2772067948
Cited by
336
References
143
Citations by year
2026: 19 · 2025: 30 · 2024: 27 · 2023: 32 · 2022: 57 · 2021: 51 · 2020: 46 · 2019: 45 · 2018: 25 · 2017: 1 · 2014: 1 · 2012: 1
FWCI
4.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Drug Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, other-oa)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
Funders
  • National Science Foundation (FP7/2007-2013)
  • U.S. Department of Defense (DOD PR101054)
  • Autism Speaks (115300)
  • FRAXA Research Foundation
  • European Federation of Pharmaceutical Industries and Associations (FP7/20072013)
  • European Commission (2007–2013, FP7 2007-2013, 115300, FP7/2007)
  • Institut National de la Santé et de la Recherche Médicale
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (69002, FP7/2007-2013)
  • Odense Universitetshospital
  • Hospices Civils de Lyon
  • National Institutes of Health (FP7/2007-2013, R40MC22641)
  • Health Resources and Services Administration (R40MC27701, R40MC22641)
  • Intellectual and Developmental Disabilities Research Center (U54-HD079125)
  • National Institute of Mental Health (R01MH106469)
  • National Institute of Neurological Disorders and Stroke (U01NS096767, R01NS085709)
  • NIH Clinical Center
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD079125, R01HD076189)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
fragile X syndrome, neurodevelopmental disorders, drug development, FMR1 gene, mGluR5 antagonist, GABA-B receptor agonist, clinical trial design, translational failure, intellectual disability, autism spectrum disorder, synaptic dysfunction, animal models
MeSH terms
Drug Development, Animals, Clinical Trials as Topic, Drug Evaluation, Preclinical, Fragile X Syndrome, Humans, Randomized Controlled Trials as Topic, Neurotransmitter Agents, Neurodevelopmental Disorders

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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