Long-term safety and tolerability of transdermal cannabidiol gel in children and adolescents with Fragile X syndrome (ZYN2-CL-017): an interim analysis of an ongoing open-label extension study / Elizabeth BERRY-KRAVIS in Journal of Neurodevelopmental Disorders, 17 (2025)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 17 (2025) Titre : Long-term safety and tolerability of transdermal cannabidiol gel in children and adolescents with Fragile X syndrome (ZYN2-CL-017): an interim analysis of an ongoing open-label extension study Type de document : texte imprimé Auteurs : Elizabeth BERRY-KRAVIS, Auteur ; Randi HAGERMAN, Auteur ; Jonathan COHEN, Auteur ; Dejan BUDIMIROVIC, Auteur ; Caroline B. BUCHANAN, Auteur ; Natalie SILOVE, Auteur ; Nancy TICH, Auteur ; Anthony THIBODEAU, Auteur ; Thomas DOBBINS, Auteur ; Terri SEBREE, Auteur ; Stephen O'QUINN, Auteur ; David S. ALBERS, Auteur ; Kristen G. BZDEK, Auteur ; George NOMIKOS, Auteur ; Kumar BUDUR, Auteur Langues : Anglais (eng) Mots-clés : Humans  Fragile X Syndrome/drug therapy  Adolescent  Child  Male  Administration, Cutaneous  Cannabidiol/administration & dosage/adverse effects  Female  Gels  Child, Preschool  Endocannabinoid system  Fragile x syndrome  Irritability  Social avoidance  Transdermal cannabidiol  conducted in accordance with the ethical principles outlined in the Declaration  of Helsinki and was approved by Advarra, Inc. Institutional Review Board (IRB  Approval Number: Pro00060799. Consent for publication: Not applicable. Competing  interests: EB-K, RH, JC, DB, CBB, and NS have received funding from Harmony  Biosciences for the conduct of this trial as investigators. TD, TS, and SOQ are  paid consultants of Harmony Biosciences. CBB is a paid consultant of Acadia  Pharmaceuticals. NT, AT, DSA, KGB, GN, and KB are employees of Harmony  Biosciences. Index. décimale : PER Périodiques Résumé : BACKGROUND: Dysregulated endocannabinoid signaling is involved in Fragile X syndrome (FXS), suggesting a potential role for the endocannabinoid signaling modulator, cannabidiol, in treatment. ZYN002 is a synthetic cannabidiol that has been uniquely formulated as a gel for transdermal delivery and is currently under investigation for the treatment of behavioral symptoms associated with FXS. DESIGN: ZYN2-CL-017 is an ongoing, long-term, open-label extension (OLE) safety trial of ZYN002 in patients with FXS. We are enrolling patients from past and current ZYN002 clinical trials to evaluate the safety and tolerability of ZYN002 in patients with FXS. METHODS: Primary safety assessments were conducted in patients who enrolled into the OLE from 2 completed ZYN002 trials. Secondary analyses, conducted in a subgroup enrolled from a completed placebo-controlled trial of ZYN002, included the FXS-specific Aberrant Behavior Checklist-Community Social Avoidance and Irritability subscales (ABC-C(FXS) SA and ABC-C(FXS) Irr, examined change from baseline of the randomized study) and the Caregiver Global Impression of Change (CaGI-C, examined change from baseline of the OLE), in which caregivers were asked to rate the change in their child's overall behavior. RESULTS: At the time of this interim analysis data cut (January 31, 2024), 240 patients had been enrolled from 2 completed ZYN002 trials. Mean age at entry to the OLE was 9.7 years (range 3-17 years), and the majority were male (76.3%) and White (80.4%). Mean exposure to ZYN002 during the initial trials and OLE was 28 months. Treatment-related adverse events (AEs) were reported in 12.9% of patients; the most common (6.7% of patients) was short-term application site pain. The highest degree of skin irritation reported by investigators was moderate erythema in 7 patients (2.9%). In the secondary analysis cohort (n=196 evaluable patients), patients demonstrated clinically meaningful changes in ABC-C(FXS) SA, ABC-C(FXS) Irr, and CaGI-C scores. CONCLUSIONS: Interim analysis results of the ongoing OLE in children, adolescents, and young adults with FXS demonstrated that ZYN002 has a favorable long-term safety profile and is generally well tolerated. Clinically meaningful changes in behaviors from baseline continued to be observed during the OLE. These findings support further study of ZYN002 in patients with FXS. TRIAL REGISTRATION: ZYN2-CL-017 is registered on Clinicaltrials.gov (NCT03802799) on December 26, 2018. En ligne : https://dx.doi.org/10.1186/s11689-025-09657-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] Long-term safety and tolerability of transdermal cannabidiol gel in children and adolescents with Fragile X syndrome (ZYN2-CL-017): an interim analysis of an ongoing open-label extension study [texte imprimé] / Elizabeth BERRY-KRAVIS, Auteur ; Randi HAGERMAN, Auteur ; Jonathan COHEN, Auteur ; Dejan BUDIMIROVIC, Auteur ; Caroline B. BUCHANAN, Auteur ; Natalie SILOVE, Auteur ; Nancy TICH, Auteur ; Anthony THIBODEAU, Auteur ; Thomas DOBBINS, Auteur ; Terri SEBREE, Auteur ; Stephen O'QUINN, Auteur ; David S. ALBERS, Auteur ; Kristen G. BZDEK, Auteur ; George NOMIKOS, Auteur ; Kumar BUDUR, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 17 (2025) Mots-clés : Humans  Fragile X Syndrome/drug therapy  Adolescent  Child  Male  Administration, Cutaneous  Cannabidiol/administration & dosage/adverse effects  Female  Gels  Child, Preschool  Endocannabinoid system  Fragile x syndrome  Irritability  Social avoidance  Transdermal cannabidiol  conducted in accordance with the ethical principles outlined in the Declaration  of Helsinki and was approved by Advarra, Inc. Institutional Review Board (IRB  Approval Number: Pro00060799. Consent for publication: Not applicable. Competing  interests: EB-K, RH, JC, DB, CBB, and NS have received funding from Harmony  Biosciences for the conduct of this trial as investigators. TD, TS, and SOQ are  paid consultants of Harmony Biosciences. CBB is a paid consultant of Acadia  Pharmaceuticals. NT, AT, DSA, KGB, GN, and KB are employees of Harmony  Biosciences. Index. décimale : PER Périodiques Résumé : BACKGROUND: Dysregulated endocannabinoid signaling is involved in Fragile X syndrome (FXS), suggesting a potential role for the endocannabinoid signaling modulator, cannabidiol, in treatment. ZYN002 is a synthetic cannabidiol that has been uniquely formulated as a gel for transdermal delivery and is currently under investigation for the treatment of behavioral symptoms associated with FXS. DESIGN: ZYN2-CL-017 is an ongoing, long-term, open-label extension (OLE) safety trial of ZYN002 in patients with FXS. We are enrolling patients from past and current ZYN002 clinical trials to evaluate the safety and tolerability of ZYN002 in patients with FXS. METHODS: Primary safety assessments were conducted in patients who enrolled into the OLE from 2 completed ZYN002 trials. Secondary analyses, conducted in a subgroup enrolled from a completed placebo-controlled trial of ZYN002, included the FXS-specific Aberrant Behavior Checklist-Community Social Avoidance and Irritability subscales (ABC-C(FXS) SA and ABC-C(FXS) Irr, examined change from baseline of the randomized study) and the Caregiver Global Impression of Change (CaGI-C, examined change from baseline of the OLE), in which caregivers were asked to rate the change in their child's overall behavior. RESULTS: At the time of this interim analysis data cut (January 31, 2024), 240 patients had been enrolled from 2 completed ZYN002 trials. Mean age at entry to the OLE was 9.7 years (range 3-17 years), and the majority were male (76.3%) and White (80.4%). Mean exposure to ZYN002 during the initial trials and OLE was 28 months. Treatment-related adverse events (AEs) were reported in 12.9% of patients; the most common (6.7% of patients) was short-term application site pain. The highest degree of skin irritation reported by investigators was moderate erythema in 7 patients (2.9%). In the secondary analysis cohort (n=196 evaluable patients), patients demonstrated clinically meaningful changes in ABC-C(FXS) SA, ABC-C(FXS) Irr, and CaGI-C scores. CONCLUSIONS: Interim analysis results of the ongoing OLE in children, adolescents, and young adults with FXS demonstrated that ZYN002 has a favorable long-term safety profile and is generally well tolerated. Clinically meaningful changes in behaviors from baseline continued to be observed during the OLE. These findings support further study of ZYN002 in patients with FXS. TRIAL REGISTRATION: ZYN2-CL-017 is registered on Clinicaltrials.gov (NCT03802799) on December 26, 2018. En ligne : https://dx.doi.org/10.1186/s11689-025-09657-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX) / Elizabeth BERRY-KRAVIS in Journal of Neurodevelopmental Disorders, 14 (2022)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 14 (2022) Titre : A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX) Type de document : texte imprimé Auteurs : Elizabeth BERRY-KRAVIS, Auteur ; Randi HAGERMAN, Auteur ; Dejan BUDIMIROVIC, Auteur ; Craig ERICKSON, Auteur ; Helen HEUSSLER, Auteur ; Nicole TARTAGLIA, Auteur ; Jonathan COHEN, Auteur ; Flora TASSONE, Auteur ; Thomas DOBBINS, Auteur ; Elizabeth MERIKLE, Auteur ; Terri SEBREE, Auteur ; Nancy TICH, Auteur ; Joseph M. PALUMBO, Auteur ; Stephen O'QUINN, Auteur Langues : Anglais (eng) Mots-clés : Child  Male  Humans  Adolescent  Female  Fragile X Syndrome/drug therapy/genetics  Cannabidiol/pharmacology/therapeutic use  DNA Methylation  Behavioral Symptoms  Gels/therapeutic use  Fragile X Mental Retardation Protein/genetics  Cannabidiol  Clinical trial  Endocannabinoid system  Fragile X syndrome  for the conduct of the study as investigators and are on scientific advisory  board for fragile X syndrome for Zynerba Pharmaceuticals. DB, HH, JC, and FT have  received funding from Zynerba Pharmaceuticals for the conduct of the study as  investigators. TD and EM are paid consultants for Zynerba Pharmaceuticals. TS,  NTich, and SO’Q are employees of Zynerba Pharmaceuticals. JMP was an employee of  Zynerba Pharmaceuticals at the time of the study. Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS) is associated with dysregulated endocannabinoid signaling and may therefore respond to cannabidiol therapy. DESIGN: CONNECT-FX was a double-blind, randomized phase 3 trial assessing efficacy and safety of ZYN002, transdermal cannabidiol gel, for the treatment of behavioral symptoms in children and adolescents with FXS. METHODS: Patients were randomized to 12 weeks of ZYN002 (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist-Community Edition FXS (ABC-C(FXS)) SA subscale in a full cohort of patients with a FXS full mutation, regardless of the FMR1 methylation status. Ad hoc analyses assessed efficacy in patients with ≥ 90% and 100% methylation of the promoter region of the FMR1 gene, in whom FMR1 gene silencing is most likely. RESULTS: A total of 212 patients, mean age 9.7 years, 75% males, were enrolled. A total of 169 (79.7%) patients presented with ≥ 90% methylation of the FMR1 promoter and full mutation of FMR1. Although statistical significance for the primary endpoint was not achieved in the full cohort, significant improvement was demonstrated in patients with ≥ 90% methylation of FMR1 (nominal P = 0.020). This group also achieved statistically significant improvements in Caregiver Global Impression-Change in SA and isolation, irritable and disruptive behaviors, and social interactions (nominal P-values: P = 0.038, P = 0.028, and P = 0.002). Similar results were seen in patients with 100% methylation of FMR1. ZYN002 was safe and well tolerated. All treatment-emergent adverse events (TEAEs) were mild or moderate. The most common treatment-related TEAE was application site pain (ZYN002: 6.4%; placebo: 1.0%). CONCLUSIONS: In CONNECT-FX, ZYN002 was well tolerated in patients with FXS and demonstrated evidence of efficacy with a favorable benefit risk relationship in patients with ≥ 90% methylation of the FMR1 gene, in whom gene silencing is most likely, and the impact of FXS is typically most severe. TRIAL REGISTRATION: The CONNECT-FX trial is registered on Clinicaltrials.gov (NCT03614663). En ligne : https://dx.doi.org/10.1186/s11689-022-09466-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX) [texte imprimé] / Elizabeth BERRY-KRAVIS, Auteur ; Randi HAGERMAN, Auteur ; Dejan BUDIMIROVIC, Auteur ; Craig ERICKSON, Auteur ; Helen HEUSSLER, Auteur ; Nicole TARTAGLIA, Auteur ; Jonathan COHEN, Auteur ; Flora TASSONE, Auteur ; Thomas DOBBINS, Auteur ; Elizabeth MERIKLE, Auteur ; Terri SEBREE, Auteur ; Nancy TICH, Auteur ; Joseph M. PALUMBO, Auteur ; Stephen O'QUINN, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 14 (2022) Mots-clés : Child  Male  Humans  Adolescent  Female  Fragile X Syndrome/drug therapy/genetics  Cannabidiol/pharmacology/therapeutic use  DNA Methylation  Behavioral Symptoms  Gels/therapeutic use  Fragile X Mental Retardation Protein/genetics  Cannabidiol  Clinical trial  Endocannabinoid system  Fragile X syndrome  for the conduct of the study as investigators and are on scientific advisory  board for fragile X syndrome for Zynerba Pharmaceuticals. DB, HH, JC, and FT have  received funding from Zynerba Pharmaceuticals for the conduct of the study as  investigators. TD and EM are paid consultants for Zynerba Pharmaceuticals. TS,  NTich, and SO’Q are employees of Zynerba Pharmaceuticals. JMP was an employee of  Zynerba Pharmaceuticals at the time of the study. Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS) is associated with dysregulated endocannabinoid signaling and may therefore respond to cannabidiol therapy. DESIGN: CONNECT-FX was a double-blind, randomized phase 3 trial assessing efficacy and safety of ZYN002, transdermal cannabidiol gel, for the treatment of behavioral symptoms in children and adolescents with FXS. METHODS: Patients were randomized to 12 weeks of ZYN002 (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist-Community Edition FXS (ABC-C(FXS)) SA subscale in a full cohort of patients with a FXS full mutation, regardless of the FMR1 methylation status. Ad hoc analyses assessed efficacy in patients with ≥ 90% and 100% methylation of the promoter region of the FMR1 gene, in whom FMR1 gene silencing is most likely. RESULTS: A total of 212 patients, mean age 9.7 years, 75% males, were enrolled. A total of 169 (79.7%) patients presented with ≥ 90% methylation of the FMR1 promoter and full mutation of FMR1. Although statistical significance for the primary endpoint was not achieved in the full cohort, significant improvement was demonstrated in patients with ≥ 90% methylation of FMR1 (nominal P = 0.020). This group also achieved statistically significant improvements in Caregiver Global Impression-Change in SA and isolation, irritable and disruptive behaviors, and social interactions (nominal P-values: P = 0.038, P = 0.028, and P = 0.002). Similar results were seen in patients with 100% methylation of FMR1. ZYN002 was safe and well tolerated. All treatment-emergent adverse events (TEAEs) were mild or moderate. The most common treatment-related TEAE was application site pain (ZYN002: 6.4%; placebo: 1.0%). CONCLUSIONS: In CONNECT-FX, ZYN002 was well tolerated in patients with FXS and demonstrated evidence of efficacy with a favorable benefit risk relationship in patients with ≥ 90% methylation of the FMR1 gene, in whom gene silencing is most likely, and the impact of FXS is typically most severe. TRIAL REGISTRATION: The CONNECT-FX trial is registered on Clinicaltrials.gov (NCT03614663). En ligne : https://dx.doi.org/10.1186/s11689-022-09466-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

Role of the endocannabinoid system in fragile X syndrome: potential mechanisms for benefit from cannabidiol treatment / Joseph M. PALUMBO in Journal of Neurodevelopmental Disorders, 15 (2023)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 15 (2023) Titre : Role of the endocannabinoid system in fragile X syndrome: potential mechanisms for benefit from cannabidiol treatment Type de document : texte imprimé Auteurs : Joseph M. PALUMBO, Auteur ; Brian F. THOMAS, Auteur ; Dejan BUDIMIROVIC, Auteur ; Steven SIEGEL, Auteur ; Flora TASSONE, Auteur ; Randi HAGERMAN, Auteur ; Christopher FAULK, Auteur ; Stephen O'QUINN, Auteur ; Terri SEBREE, Auteur Langues : Anglais (eng) Mots-clés : Humans  Fragile X Syndrome/drug therapy/genetics  Cannabidiol/pharmacology/therapeutic use  Endocannabinoids/metabolism  Fragile X Mental Retardation Protein/genetics  Cannabidiol  Cannabinoid receptors  Endocannabinoid system  Fragile X syndrome  development. BFT was a consultant to Zynerba Pharmaceuticals at the time of the  manuscript development. DB was an investigator for the CONNECT-FX study for  Zynerba Pharmaceuticals. SS is on the Scientific Advisory Board for fragile X  syndrome for Zynerba Pharmaceuticals. FT and CF have no competing interests. RH  has received funding from Zynerba Pharmaceuticals for the conduct of the study as  an investigator and is on scientific advisory board for fragile X syndrome for  Zynerba Pharmaceuticals. SO’Q and TS are employees of Zynerba Pharmaceuticals. Index. décimale : PER Périodiques Résumé : Multiple lines of evidence suggest a central role for the endocannabinoid system (ECS) in the neuronal development and cognitive function and in the pathogenesis of fragile X syndrome (FXS). This review describes the ECS, its role in the central nervous system, how it is dysregulated in FXS, and the potential role of cannabidiol as a treatment for FXS. FXS is caused by deficiency or absence of the fragile X messenger ribonucleoprotein 1 (FMR1) protein, FMRP, typically due to the presence of >200 cytosine, guanine, guanine sequence repeats leading to methylation of the FMR1 gene promoter. The absence of FMRP, following FMR1 gene-silencing, disrupts ECS signaling, which has been implicated in FXS pathogenesis. The ECS facilitates synaptic homeostasis and plasticity through the cannabinoid receptor 1, CB(1), on presynaptic terminals, resulting in feedback inhibition of neuronal signaling. ECS-mediated feedback inhibition and synaptic plasticity are thought to be disrupted in FXS, leading to overstimulation, desensitization, and internalization of presynaptic CB(1) receptors. Cannabidiol may help restore synaptic homeostasis by acting as a negative allosteric modulator of CB(1), thereby attenuating the receptor overstimulation, desensitization, and internalization. Moreover, cannabidiol affects DNA methylation, serotonin 5HT(1A) signal transduction, gamma-aminobutyric acid receptor signaling, and dopamine D(2) and D(3) receptor signaling, which may contribute to beneficial effects in patients with FXS. Consistent with these proposed mechanisms of action of cannabidiol in FXS, in the CONNECT-FX trial the transdermal cannabidiol gel, ZYN002, was associated with improvements in measures of social avoidance, irritability, and social interaction, particularly in patients who are most affected, showing ≥90% methylation of the FMR1 gene. En ligne : https://dx.doi.org/10.1186/s11689-023-09475-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Role of the endocannabinoid system in fragile X syndrome: potential mechanisms for benefit from cannabidiol treatment [texte imprimé] / Joseph M. PALUMBO, Auteur ; Brian F. THOMAS, Auteur ; Dejan BUDIMIROVIC, Auteur ; Steven SIEGEL, Auteur ; Flora TASSONE, Auteur ; Randi HAGERMAN, Auteur ; Christopher FAULK, Auteur ; Stephen O'QUINN, Auteur ; Terri SEBREE, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 15 (2023) Mots-clés : Humans  Fragile X Syndrome/drug therapy/genetics  Cannabidiol/pharmacology/therapeutic use  Endocannabinoids/metabolism  Fragile X Mental Retardation Protein/genetics  Cannabidiol  Cannabinoid receptors  Endocannabinoid system  Fragile X syndrome  development. BFT was a consultant to Zynerba Pharmaceuticals at the time of the  manuscript development. DB was an investigator for the CONNECT-FX study for  Zynerba Pharmaceuticals. SS is on the Scientific Advisory Board for fragile X  syndrome for Zynerba Pharmaceuticals. FT and CF have no competing interests. RH  has received funding from Zynerba Pharmaceuticals for the conduct of the study as  an investigator and is on scientific advisory board for fragile X syndrome for  Zynerba Pharmaceuticals. SO’Q and TS are employees of Zynerba Pharmaceuticals. Index. décimale : PER Périodiques Résumé : Multiple lines of evidence suggest a central role for the endocannabinoid system (ECS) in the neuronal development and cognitive function and in the pathogenesis of fragile X syndrome (FXS). This review describes the ECS, its role in the central nervous system, how it is dysregulated in FXS, and the potential role of cannabidiol as a treatment for FXS. FXS is caused by deficiency or absence of the fragile X messenger ribonucleoprotein 1 (FMR1) protein, FMRP, typically due to the presence of >200 cytosine, guanine, guanine sequence repeats leading to methylation of the FMR1 gene promoter. The absence of FMRP, following FMR1 gene-silencing, disrupts ECS signaling, which has been implicated in FXS pathogenesis. The ECS facilitates synaptic homeostasis and plasticity through the cannabinoid receptor 1, CB(1), on presynaptic terminals, resulting in feedback inhibition of neuronal signaling. ECS-mediated feedback inhibition and synaptic plasticity are thought to be disrupted in FXS, leading to overstimulation, desensitization, and internalization of presynaptic CB(1) receptors. Cannabidiol may help restore synaptic homeostasis by acting as a negative allosteric modulator of CB(1), thereby attenuating the receptor overstimulation, desensitization, and internalization. Moreover, cannabidiol affects DNA methylation, serotonin 5HT(1A) signal transduction, gamma-aminobutyric acid receptor signaling, and dopamine D(2) and D(3) receptor signaling, which may contribute to beneficial effects in patients with FXS. Consistent with these proposed mechanisms of action of cannabidiol in FXS, in the CONNECT-FX trial the transdermal cannabidiol gel, ZYN002, was associated with improvements in measures of social avoidance, irritability, and social interaction, particularly in patients who are most affected, showing ≥90% methylation of the FMR1 gene. En ligne : https://dx.doi.org/10.1186/s11689-023-09475-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

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