Gaboxadol in Fragile X Syndrome: A 12-Week Randomized, Double-Blind, Parallel-Group, Phase 2a Study

Dejan B Budimirovic, Kelli C Dominick, Lidia V Gabis, Maxwell Adams, Mathews Adera, Linda Huang, Pamela Ventola, Nicole R Tartaglia, Elizabeth Berry-Kravis, Dejan B Budimirovic, Kelli C Dominick, Lidia V Gabis, Maxwell Adams, Mathews Adera, Linda Huang, Pamela Ventola, Nicole R Tartaglia, Elizabeth Berry-Kravis

Abstract

Background: Fragile X syndrome (FXS), the most common single-gene cause of intellectual disability and autism spectrum disorder (ASD), is caused by a >200-trinucleotide repeat expansion in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. Individuals with FXS can present with a range of neurobehavioral impairments including, but not limited to: cognitive, language, and adaptive deficits; ASD; anxiety; social withdrawal and avoidance; and aggression. Decreased expression of the γ-aminobutyric acid type A (GABAA) receptor δ subunit and deficient GABAergic tonic inhibition could be associated with symptoms of FXS. Gaboxadol (OV101) is a δ-subunit-selective, extrasynaptic GABAA receptor agonist that enhances GABAergic tonic inhibition, providing the rationale for assessment of OV101 as a potential targeted treatment of FXS. No drug is approved in the United States for the treatment of FXS. Methods: This 12-weeks, randomized (1:1:1), double-blind, parallel-group, phase 2a study was designed to assess the safety, tolerability, efficacy, and optimal daily dose of OV101 5 mg [once (QD), twice (BID), or three-times daily (TID)] when administered for 12 weeks to adolescent and adult men with FXS. Safety was the primary study objective, with key assessments including treatment-emergent adverse events (TEAEs), treatment-related adverse events leading to study discontinuation, and serious adverse events (SAEs). The secondary study objective was to evaluate the effect of OV101 on a variety of problem behaviors. Results: A total of 23 participants with FXS (13 adolescents, 10 adults) with moderate-to-severe neurobehavioral phenotypes (Full Scale Intelligence Quotient, 41.5 ± 3.29; ASD, 82.6%) were randomized to OV101 5 mg QD (n = 8), 5 mg BID (n = 8), or 5 mg TID (n = 7) for 12 weeks. OV101 was well tolerated across all 3 treatment regimens. The most common TEAEs were upper respiratory tract infection (n = 4), headache (n = 3), diarrhea (n = 2), and irritability (n = 2). No SAEs were reported. Improvements from baseline to end-of-treatment were observed on several efficacy endpoints, and 60% of participants were identified as treatment responders based on Clinical Global Impressions-Improvement. Conclusions: Overall, OV101 was safe and well tolerated. Efficacy results demonstrate an initial signal for OV101 in individuals with FXS. These results need to be confirmed in a larger, randomized, placebo-controlled study with optimal outcomes and in the most appropriate age group. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03697161.

Keywords: FMR1; GABAA; OV101; efficacy; fragile X syndrome; gaboxadol; randomized study; safety.

Conflict of interest statement

Authors MA (4th author), MA (5th author), and LH were employed by the company Ovid Therapeutics, Inc. DB has received research funding from Akili, Alcobra, Forest, Lundbeck, Medgenics, Neuren, Ovid Therapeutics, Inc., Pfizer, Purdue, Roche, Seaside Therapeutics, Shire, Sunovion, Supernus, SyneuRX, and Zynerba Pharmaceuticals. All funds have been directed to the Kennedy Krieger Institute and Johns Hopkins medical institutions. KD has received research funding from the American Academy of Child and Adolescent Psychiatry, Roche, and Ovid Therapeutics Inc. All funds have been directed to Cincinnati Children’s Hospital Medical Center. NT has received research funding from Alcobra, Neuren, Novartis, Ovid Therapeutics, Inc., Roche, Seaside Therapeutics, and Zynerba. All funds have been directed to University of Colorado or CHCO in support of Fragile X and autism programs. EB-K has received research funding from Acadia, Alcobra, Anavex, Asuragen Inc., Biogen, BioMarin, Cydan, Fulcrum, GeneTx, GW, Ionis, Lumos, Marinus, Neuren, Neurotrope, Novartis, Orphazyme, Ovid, Roche, Seaside Therapeutics, Tetra Discovery Partners, Ultragenyx, Vtesse/Sucampo/Mallinckrodt Pharmaceuticals, Yamo, and Zynerba. All funds have been directed to Rush University Medical Center in support of rare disease programs. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Budimirovic, Dominick, Gabis, Adams, Adera, Huang, Ventola, Tartaglia and Berry-Kravis.

Figures

FIGURE 1
FIGURE 1
Study design. R, randomization; OV101, gaboxadol; QD, once daily; BID, twice daily; TID, 3-times daily; EOT, end of treatment; EOS, end of study.
FIGURE 2
FIGURE 2
Patient disposition. OV101, gaboxadol; QD, once daily; BID, twice daily; TID, 3-times daily.
FIGURE 3
FIGURE 3
CGI-I score at week 12. Among the 3 dosing regimens, the percentage of CGI-I responders was greatest with OV101 5 mg BID. CGI-I, Clinical Global Impressions–Improvement; OV101, gaboxadol; QD, once daily; BID, twice daily; TID, 3-times daily.

References

    1. Adams J. B., Audhya T., McDonough-Means S., Rubin R. A., Quig D., Geis E., et al. (2011). Effect of a Vitamin/mineral Supplement on Children and Adults with Autism. BMC Pediatr. 11, 111. 10.1186/1471-2431-11-111
    1. Aman M. G., Singh N. N., Stewart A. W., Field C. J. (1985). Psychometric Characteristics of the Aberrant Behavior Checklist. Am. J. Ment. Defic. 89, 492–502.
    1. Bagni C., Tassone F., Neri G., Hagerman R. (2012). Fragile X Syndrome: Causes, Diagnosis, Mechanisms, and Therapeutics. J. Clin. Invest. 122, 4314–4322. 10.1172/JCI63141
    1. Berry-Kravis E., Des Portes V., Hagerman R., Jacquemont S., Charles P., Visootsak J., et al. (2016). Mavoglurant in Fragile X Syndrome: Results of Two Randomized, Double-Blind, Placebo-Controlled Trials. Sci. Transl. Med. 8, 321ra5. 10.1126/scitranslmed.aab4109
    1. Berry-Kravis E., Hagerman R., Visootsak J., Budimirovic D., Kaufmann W. E., Cherubini M., et al. (2017). Arbaclofen in Fragile X Syndrome: Results of Phase 3 Trials. J. Neurodev. Disord. 9, 3. 10.1186/s11689-016-9181-6
    1. Berry-Kravis E., Sumis A., Hervey C., Mathur S. (2012). Clinic-based Retrospective Analysis of Psychopharmacology for Behavior in Fragile X Syndrome. Int. J. Pediatr. 2012, 843016. 10.1155/2012/843016
    1. Berry-Kravis E. M., Erickson C., Hagerman R., Tartaglia N., Cohen J., Sebree T., et al. (2020). “ZYN002 Cannabidiol Transdermal Gel in Children and Adolescents with Fragile X Syndrome: Role of Methylation Status as a Correlate to Disease Severity and as a Prognostic Biomarker,” in Poster presented at: The Joint International Child Neurology Congress and Child Neurology Society Meeting, October, 2020. virtual.
    1. Berry-Kravis E. M., Lindemann L., Jønch A. E., Apostol G., Bear M. F., Carpenter R. L., et al. (2018). Drug Development for Neurodevelopmental Disorders: Lessons Learned from Fragile X Syndrome. Nat. Rev. Drug Discov. 17, 280–299. 10.1038/nrd.2017.221
    1. Bird L. M., Ochoa-Lubinoff C., Tan W. H., Heimer G., Melmed R. D., Rakhit A., et al. (2021). The STARS Phase 2 Study: a Randomized Controlled Trial of Gaboxadol in Angelman Syndrome. Neurology 96, e1024–e1035. 10.1212/WNL.0000000000011409
    1. Brašić J. R., Nandi A., Russell D. S., Jennings D., Barret O., Martin S. D., et al. (2021). Cerebral Expression of Metabotropic Glutamate Receptor Subtype 5 in Idiopathic Autism Spectrum Disorder and Fragile X Syndrome: a Pilot Study. Int. J. Mol. Sci. 22, 2863. 10.3390/ijms22062863
    1. Brašić J. R., Nandi A., Russell D. S., Jennings D., Barret O., Mathur A., et al. (2020). Reduced Expression of Cerebral Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome. Brain Sci. 10, 899. 10.3390/brainsci10120899
    1. Brickley S. G., Mody I. (2012). Extrasynaptic GABA(A) Receptors: Their Function in the CNS and Implications for Disease. Neuron 73, 23–34. 10.1016/j.neuron.2011.12.012
    1. Budimirovic D. B., Berry-Kravis E., Erickson C. A., Hall S. S., Hessl D., Reiss A. L., et al. (2017). Updated Report on Tools to Measure Outcomes of Clinical Trials in Fragile X Syndrome. J. Neurodev. Disord. 9, 14. 10.1186/s11689-017-9193-x
    1. Budimirovic D. B., Bukelis I., Cox C., Gray R. M., Tierney E., Kaufmann W. E. (2006). Autism Spectrum Disorder in Fragile X Syndrome: Differential Contribution of Adaptive Socialization and Social Withdrawal. Am. J. Med. Genet. A. 140A, 1814–1826. 10.1002/ajmg.a.31405
    1. Budimirovic D. B., Schlageter A., Filipovic-Sadic S., Protic D. D., Bram E., Mahone E. M., et al. (2020). A Genotype-Phenotype Study of High-Resolution FMR1 Nucleic Acid and Protein Analyses in Fragile X Patients with Neurobehavioral Assessments. Brain Sci. 10, 694. 10.3390/brainsci10100694
    1. Budimirovic D. B., Subramanian M. (2016). “Neurobiology of Autism and Intellectual Disability: Fragile X Syndrome,” in Neurobiology of Disease. 2nd ed. (New York, NY, USA: Oxford University Press; ), 375–384.
    1. Conners C. K., Sitarenios G., Parker J. D., Epstein J. N. (1998). Revision and Restandardization of the Conners Teacher Rating Scale (CTRS-R): Factor Structure, Reliability, and Criterion Validity. J. Abnorm. Child. Psychol. 26, 279–291. 10.1023/a:1022606501530
    1. Cope D. W., Hughes S. W., Crunelli V. (2005). GABAA Receptor-Mediated Tonic Inhibition in Thalamic Neurons. J. Neurosci. 25, 11553–11563. 10.1523/JNEUROSCI.3362-05.2005
    1. Cordeiro L., Ballinger E., Hagerman R., Hessl D. (2011). Clinical Assessment of DSM-IV Anxiety Disorders in Fragile X Syndrome: Prevalence and Characterization. J. Neurodev. Disord. 3, 57–67. 10.1007/s11689-010-9067-y
    1. Crawford D. C., Acuña J. M., Sherman S. L. (2001). FMR1 and the Fragile X Syndrome: Human Genome Epidemiology Review. Genet. Med. 3, 359–371. 10.1097/00125817-200109000-00006
    1. Dueck A., Reis O., Bastian M., van Treeck L., Weirich S., Haessler F., et al. (2020). Feasibility of a Complex Setting for Assessing Sleep and Circadian Rhythmicity in a Fragile X Cohort. Front. Psychiatry 11, 361. 10.3389/fpsyt.2020.00361
    1. Duy P. Q., Budimirovic D. B. (2017). Fragile X Syndrome: Lessons Learned from the Most Translated Neurodevelopmental Disorder in Clinical Trials. Transl. Neurosci. 8, 7–8. 10.1515/tnsci-2017-0002
    1. Eckert E. M., Dominick K. C., Pedapati E. V., Wink L. K., Shaffer R. C., Andrews H., et al. (2019). Pharmacologic Interventions for Irritability, Aggression, Agitation and Self-Injurious Behavior in Fragile X Syndrome: an Initial Cross-Sectional Analysis. J. Autism Dev. Disord. 49, 4595–4602. 10.1007/s10803-019-04173-z
    1. Erickson C. A., Kaufmann W. E., Budimirovic D. B., Lachiewicz A., Haas-Givler B., Miller R. M., et al. (2018). Best Practices in Fragile X Syndrome Treatment Development. Brain Sci. 8, 224. 10.3390/brainsci8120224
    1. Esbensen A. J., Rojahn J., Aman M. G., Ruedrich S. (2003). Reliability and Validity of an Assessment Instrument for Anxiety, Depression, and Mood Among Individuals with Mental Retardation. J. Autism Dev. Disord. 33, 617–629. 10.1023/b:jadd.0000005999.27178.55
    1. Ethridge L. E., De Stefano L. A., Schmitt L. M., Woodruff N. E., Brown K. L., Tran M., et al. (2019). Auditory EEG Biomarkers in Fragile X Syndrome: Clinical Relevance. Front. Integr. Neurosci. 13, 60. 10.3389/fnint.2019.00060
    1. Gabis L. V., Baruch Y. K., Jokel A., Raz R. (2011). Psychiatric and Autistic Comorbidity in Fragile X Syndrome across Ages. J. Child. Neurol. 26, 940–948. 10.1177/0883073810395937
    1. Gantois I., Vandesompele J., Speleman F., Reyniers E., D'Hooge R., Severijnen L. A., et al. (2006). Expression Profiling Suggests Underexpression of the GABA(A) Receptor Subunit delta in the Fragile X Knockout Mouse Model. Neurobiol. Dis. 21, 346–357. 10.1016/j.nbd.2005.07.017
    1. Hagerman R. J., Berry-Kravis E., Kaufmann W. E., Ono M. Y., Tartaglia N., Lachiewicz A., et al. (2009). Advances in the Treatment of Fragile X Syndrome. Pediatrics 123, 378–390. 10.1542/peds.2008-0317
    1. Kaufmann W. E., Capone G. T., Clarke M., Budimirovic D. B. (2008). Autism in Genetic Intellectual Disability: Insights into Idiopathic Autism. Totowa, NJ, USA: Humana Press.
    1. Kaufmann W. E., Kidd S. A., Andrews H. F., Budimirovic D. B., Esler A., Haas-Givler B., et al. (2017). Autism Spectrum Disorder in Fragile X Syndrome: Cooccurring Conditions and Current Treatment. Pediatrics 139, S194. 10.1542/peds.2016-1159F
    1. Kim K., Hessl D., Randol J. L., Espinal G. M., Schneider A., Protic D., et al. (2019). Association between IQ and FMR1 Protein (FMRP) across the Spectrum of CGG Repeat Expansions. PLoS One 14, e0226811. 10.1371/journal.pone.0226811
    1. Lam K. S., Aman M. G. (2007). The Repetitive Behavior Scale-Revised: Independent Validation in Individuals with Autism Spectrum Disorders. J. Autism Dev. Disord. 37, 855–866. 10.1007/s10803-006-0213-z
    1. Lee A. W., Ventola P., Budimirovic D., Berry-Kravis E., Visootsak J. (2018). Clinical Development of Targeted Fragile X Syndrome Treatments: an Industry Perspective. Brain Sci. 8, 214. 10.3390/brainsci8120214
    1. Lee V., Maguire J. (2014). The Impact of Tonic GABAA Receptor-Mediated Inhibition on Neuronal Excitability Varies across Brain Region and Cell Type. Front. Neural Circuits 8, 3. 10.3389/fncir.2014.00003
    1. Luu S., Province H., Berry-Kravis E., Hagerman R., Hessl D., Vaidya D., et al. (2020). Response to Placebo in Fragile X Syndrome Clinical Trials: an Initial Analysis. Brain Sci. 10, 629. 10.3390/brainsci10090629
    1. Martin B. S., Corbin J. G., Huntsman M. M. (2014). Deficient Tonic GABAergic Conductance and Synaptic Balance in the Fragile X Syndrome Amygdala. J. Neurophysiol. 112, 890–902. 10.1152/jn.00597.2013
    1. Niu M., Han Y., Dy A. B. C., Du J., Jin H., Qin J., et al. (2017). Autism Symptoms in Fragile X Syndrome. J. Child. Neurol. 32, 903–909. 10.1177/0883073817712875
    1. Nolin S. L., Glicksman A., Houck G. E., Jr, Brown W. T., Dobkin C. S. (1994). Mosaicism in Fragile X Affected Males. Am. J. Med. Genet. 51, 509–512. 10.1002/ajmg.1320510444
    1. Olmos-Serrano J. L., Corbin J. G., Burns M. P. (2011). The GABA(A) Receptor Agonist THIP Ameliorates Specific Behavioral Deficits in the Mouse Model of Fragile X Syndrome. Dev. Neurosci. 33, 395–403. 10.1159/000332884
    1. Olmos-Serrano J. L., Paluszkiewicz S. M., Martin B. S., Kaufmann W. E., Corbin J. G., Huntsman M. M. (2010). Defective GABAergic Neurotransmission and Pharmacological rescue of Neuronal Hyperexcitability in the Amygdala in a Mouse Model of Fragile X Syndrome. J. Neurosci. 30, 9929–9938. 10.1523/JNEUROSCI.1714-10.2010
    1. Raspa M., Wylie A., Wheeler A. C., Kolacz J., Edwards A., Heilman K., et al. (2018). Sensory Difficulties in Children with an FMR1 Premutation. Front. Genet. 9, 351. 10.3389/fgene.2018.00351
    1. Reisinger D. L., Shaffer R. C., Tartaglia N., Berry-Kravis E., Erickson C. A. (2020). Delineating Repetitive Behavior Profiles across the Lifespan in Fragile X Syndrome. Brain Sci. 10, 239. 10.3390/brainsci10040239
    1. Roth T., Lines C., Vandormael K., Ceesay P., Anderson D., Snavely D. (2010). Effect of Gaboxadol on Patient-Reported Measures of Sleep and Waking Function in Patients with Primary Insomnia: Results from Two Randomized, Controlled, 3-month Studies. J. Clin. Sleep Med. 6, 30–39. 10.5664/jcsm.27707
    1. Rousseau F., Heitz D., Tarleton J., MacPherson J., Malmgren H., Dahl N., et al. (1994). A Multicenter Study on Genotype-Phenotype Correlations in the Fragile X Syndrome, Using Direct Diagnosis with Probe StB12.3: the First 2,253 Cases. Am. J. Hum. Genet. 55, 225–237.
    1. Sansone S. M., Schneider A., Bickel E., Berry-Kravis E., Prescott C., Hessl D. (2014). Improving IQ Measurement in Intellectual Disabilities Using True Deviation from Population Norms. J. Neurodev. Disord. 6, 16. 10.1186/1866-1955-6-16
    1. Sansone S. M., Widaman K. F., Hall S. S., Reiss A. L., Lightbody A., Kaufmann W. E., et al. (2012). Psychometric Study of the Aberrant Behavior Checklist in Fragile X Syndrome and Implications for Targeted Treatment. J. Autism Dev. Disord. 42, 1377–1392. 10.1007/s10803-011-1370-2
    1. Simpson K., Adams D., Alston-Knox C., Heussler H. S., Keen D. (2019). Exploring the Sensory Profiles of Children on the Autism Spectrum Using the Short Sensory Profile-2 (SSP-2). J. Autism Dev. Disord. 49, 2069–2079. 10.1007/s10803-019-03889-2
    1. Tassone F., Iong K. P., Tong T. H., Lo J., Gane L. W., Berry-Kravis E., et al. (2012). FMR1 CGG Allele Size and Prevalence Ascertained through Newborn Screening in the United States. Genome Med. 4, 100. 10.1186/gm401
    1. Weber J. D., Smith E., Berry-Kravis E., Cadavid D., Hessl D., Erickson C. (2019). Voice of People with Fragile X Syndrome and Their Families: Reports from a Survey on Treatment Priorities. Brain Sci. 9, 18. 10.3390/brainsci9020018
    1. Whissell P. D., Lecker I., Wang D. S., Yu J., Orser B. A. (2015). Altered Expression of δGABAA Receptors in Health and Disease. Neuropharmacology 88, 24–35. 10.1016/j.neuropharm.2014.08.003
    1. Wright-Talamante C., Cheema A., Riddle J. E., Luckey D. W., Taylor A. K., Hagerman R. J. (1996). A Controlled Study of Longitudinal IQ Changes in Females and Males with Fragile X Syndrome. Am. J. Med. Genet. 64, 350–355. 10.1002/(SICI)1096-8628(19960809)64:2<350:AID-AJMG23>;2-D
    1. Youssef E. A., Berry-Kravis E., Czech C., Hagerman R. J., Hessl D., Wong C. Y., et al. (2018). 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 43, 503–512. 10.1038/npp.2017.177
    1. Zafarullah M., Tassone F. (2019). Molecular Biomarkers in Fragile X Syndrome. Brain Sci. 9, 96. 10.3390/brainsci9050096

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