Treatment of Fragile X Syndrome with Cannabidiol

Abstract

The present technology relates to methods of treating one or more symptoms of complete methylation (Fmet) Fragile X syndrome in a subject, comprising administering to the subject an effective amount of cannabidiol such that one or more symptoms of Fragile X syndrome are treated.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit and priority of U.S. Provisional Application No. 63 / 045,664, filed Jun. 29, 2020, entitled “Treatment of Fragile X syndrome with Cannabidiol”. The content thereof is hereby incorporated by reference in its entirety into this specification.

[0002] This disclosure relates to a method of treating one or more behavioral symptoms of Fragile X syndrome in a subject having complete methylation (Fmet) of the FMR1 gene by administering an effective amount of cannabidiol (CBD) to the subject.

Background Art

[0003] Cannabinoids are a class of chemical compounds found in the Cannabis plant. The two main cannabinoids contained in Cannabis are cannabidiol, i.e., CBD, and Δ9 - tetrahydrocannabinol, i.e., THC. CBD lacks the psychoactive effects of THC. Research has shown that CBD can be used to treat disorders such as epilepsy, arthritis and cancer.

[0004] FXS is the most common inherited intellectual disability in males and a significant cause of intellectual disability in females. FXS is caused by mutations in the Fragile X Mental Retardation 1 (FMR1) gene located on the X chromosome, resulting in dysregulation of the endogenous cannabinoid system, including a decrease in endogenous cannabinoids (2 - AG and anandamide [AEA]). This disorder affects synaptic function, plasticity and neuronal connections, resulting in a wide range of intellectual disabilities, social anxiety and memory impairments. There are approximately 71,000 patients in the United States suffering from FXS.

[0005] "Behavioral problems are often the most significant concern reported by parents, and increased behavioral problems in children are generally associated with high levels of stress and depression and low quality of life for parents." Wheeler A, Raspa M, Bann C, Bishop E, Hassl D, Sacco H, Bailey DB. 2014. Anxiety attention problems, hyperactivity, and the Aberrant Behavior Checklist in fragile X syndrome. Am J Med Genet Part A 164A:141-155, 141. "Consequently, reducing behavioral problems is a primary concern in ongoing clinical trials testing the efficacy of new drugs for FXS." Wheeler, pp. 141-142.

[0006] The Anxiety, Depression, and Mood Scale (ADAMS) is a tool used by clinicians, physicians, and researchers to assess levels of anxiety, depression, and mood in patients with intellectual disabilities, including FXS. The ADAMS consists of questions divided into five subscales: (i) generalized anxiety, (ii) social avoidance, (iii) obsessive-compulsive behavior, (iv) manic / hyperactive behavior, and (v) depressed mood. Each question is answered by a clinician / physician on a 4-point scale ranging from 0 ("no problem") to 3 ("severe problem"). In addition to the subscale scores, the ADAMS provides a total score.

[0007] The original Aberrant Behavior Checklist (ABC) was "designed to assess behavioral problems in adults in institutional settings." Wheeler, p. 142. Since then, the original ABC has been modified to address patients not institutionalized, and specifically to address FXS. Ibid. The Aberrant Behavior Checklist-FXS Specific (ABC-FXS) scale is used by clinicians, physicians, and researchers to assess certain behaviors in patients with FXS. The ABC-FXS scale has six subscales, including (i) irritability, (ii) hyperactivity, (iii) social unresponsiveness / lethargy, (iv) social avoidance, (v) stereotypic behavior, and (vi) inappropriate speech. Similar to ADAMS, the ABC-FXS scale is a 4-point Likert scale ranging from 0 ("no problem") to 3 ("severe problem"). [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Wheeler A, Raspa M, Bann C, Bishop E, Hassl D, Sacco H, Bailey DB. Anxiety attention problems, hyperactivity, and the Aberrant Behavior Checklist in fragile X syndrome. Am J Med Genet Part A 2014.164A:141-155,141. [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] This disclosure relates to a method for treating one or more behavioral symptoms of Fragile X syndrome in subjects having complete methylation of the FMR1 gene. The method comprises administering an effective dose of cannabidiol (CBD) transdermally to the subject.

[0010] In some embodiments, one or more symptoms are behavioral symptoms of Fragile X syndrome. In some embodiments, the behavioral symptom is social avoidance. In some embodiments, treatment includes Clinical Global Impression Improvement (CGI-I).

[0011] In some embodiments, the CBD is (-)-CBD. The effective dose of CBD may be between approximately 50 mg and approximately 500 mg per day. In some embodiments, the effective dose of CBD is started at approximately 50 mg per day and can be dosed up to a maximum of approximately 500 mg per day. The effective dose of CBD can be started at approximately 50 mg per day and can be dosed up to a maximum of approximately 250 mg per day. In some embodiments, the effective dose of CBD is started at 250 mg per day. The effective dose of CBD may be started at 500 mg per day. In some embodiments, a daily dose of 500 mg is administered to patients weighing more than 35 kg. CBD can be administered in a single daily dose or in two daily doses. In some embodiments, the effective dose of CBD may be 390 mg in a divided daily dose.

[0012] In some embodiments, the total daily dose of CBD is 250 mg. In some embodiments, the total daily dose of CBD is 500 mg. In some embodiments, the total daily dose of CBD is 250 mg or 500 mg. Dosage is based on body weight in some embodiments. In some embodiments, CBD is administered in a single daily dose. In some embodiments, CBD is administered in two daily doses.

[0013] CBD can be formulated as a gel or oil. In some embodiments, CBD is formulated as a gel, for example, an impregnation-enhanced gel. The gel can contain between 1% (weight / weight) and 7.5% (weight / weight) of CBD. In some embodiments, the gel contains 4.2% (weight / weight) of CBD. In some embodiments, the gel contains 7.5% (weight / weight) of CBD.

[0014] In some embodiments, the transdermal preparation may be a cream, ointment, or patch. CBD may be delivered by bandage, pad, or patch.

[0015] CBD can be administered transdermally to the upper arm and shoulder of the subject. In some embodiments, CBD is administered transdermally to the thigh or back of the subject. In some embodiments, CBD is administered transdermally by application to the arm of the subject.

[0016] CBD may be synthetic CBD. CBD may be purified CBD. CBD may be plant-derived. In some embodiments, CBD is not plant-derived.

[0017] Transdermal administration of an effective dose of cannabidiol (CBD) can reduce the severity of at least one adverse event or side effect compared to oral administration of CBD. At least one adverse event or side effect may be a gastrointestinal (GI) adverse event. At least one adverse event or side effect may be liver function. In some embodiments, at least one adverse event is somnolence. In some embodiments, the frequency and intensity of somnolence are reduced as an adverse event. In some embodiments, psychostimulant effects are reduced or eliminated. [Modes for carrying out the invention]

[0018] Detailed explanation As used herein, the terms "treating" or "treatment" refer to reducing, ameliorating, alleviating, or relieving at least one symptom (such as a behavioral symptom) of a condition, disease, or disorder in a subject such as a human, or improving a measurable parameter associated with the condition, disease, or disorder.

[0019] As used herein, the term "clinical efficacy" refers to the ability to produce a desired effect in a human, as demonstrated through clinical trials by the Food and Drug Administration (FDA) or any corresponding foreign agency.

[0020] As used herein, the terms "cannabidiol" or "CBD" refer to pharmaceutically acceptable derivatives of cannabidiol, including cannabidiol; cannabidiol prodrugs; and pharmaceutically acceptable salts of cannabidiol, cannabidiol prodrugs, and cannabidiol derivatives. CBD includes 2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol and its pharmaceutically acceptable salts, solvates, metabolites (e.g., skin metabolites), and metabolic precursors. The synthesis of CBD is described, for example, in Petilka et al, Helv. Chim. Acta, 52:1102 (1969) and Mechoulam et al., J. Am. Chem. Soc., 87:3273 (1965), which are incorporated herein by reference.

[0021] As used herein, the term "administered transdermally" refers to contacting CBD with the skin of a patient or subject under conditions effective for CBD to penetrate the skin.

[0022] <Fragile X syndrome> Fragile X syndrome (FXS) is a rare genetic developmental disorder that is a major known cause of both hereditary intellectual disability and autism spectrum disorder, affecting approximately 1 in 3,600 - 4,000 males and 1 in 4,000 - 6,000 females. FXS is the most common hereditary intellectual disability in males and a significant cause of intellectual disability in females, and is the leading genetic cause of autism spectrum disorder (ASD). This disorder affects synaptic function, plasticity, and neuronal connectivity, leading to a wide range of intellectual disabilities and behavioral symptoms such as social avoidance and irritability. In the United States, there are approximately 71,000 people with FXS, and approximately 60% of them have full methylation of the FMR1 gene.

[0023] FXS is caused by mutations in the FMR1 gene, which is a gene that regulates several systems, including having important effects on the endogenous cannabinoid system, and most importantly, encodes a protein called FMRP. This protein helps regulate the production of other proteins and plays a role in the development of synapses and the regulation of synaptic plasticity, which are extremely important for relaying nerve impulses. FMR1 mutations appear as multiple repeats of a DNA segment known as the CGG triplet repeat. In most typically developing people, the FMR1 gene correctly encodes the FMRP protein. In typically developing individuals, CGG repeats are present, but these repeats occur only 5 - 40 times. As a result, FMRP is produced at levels that allow for control over behaviors such as social avoidance and anxiety. In people with FXS, the CGG segment is repeated more than 200 times, and in most cases, this renders the FMR1 gene non-functional. However, methylation of the FMR1 gene also plays a role in determining gene functionality. At methylation levels above 90%, considered "full methylation," the FMR1 gene is silenced, and thus FMRP is not produced, and the systems and processes expected to be affected by FMRP become dysregulated.

[0024] Patients with FXS can be classified as mosaic or non-mosaicin. Mosaicism is described as the coexistence of complete mutations and pre-mutant CGG repeats in adjacent cells within the body. Because the FMR1 gene is not completely deexpressed in all cells of the body, patients with mosaic FXS may still produce some level of FMRP. The amount of FMRP produced is generally regulated by methylation of the FMR1 gene. With methylation exceeding 90% (considered complete methylation), the FMR1 gene is thought to be completely deexpressed.

[0025] Individuals with genetically confirmed complete mutations in the Vulnerable X gene and complete methylation of the FMR1 gene are generally the most severely affected by this disorder.

[0026] This disclosure relates to a method for treating one or more behavioral symptoms of fully methylated (Fmet) fragile X syndrome in a subject by transdermal administration of an effective dose of cannabidiol (CBD), wherein one or more behavioral symptoms of fragile X syndrome are treated in the subject.

[0027] Clinical and preclinical data support the potential of CBD in treating epilepsy, arthritis, cancer, and fragile X syndrome. Therapeutic medicines have been developed using innovative transdermal technologies to enable sustained and regulated delivery of therapeutic levels of CBD. Transdermal delivery of cannabinoids (e.g., CBD) has advantages over oral administration because it allows the drug to be absorbed directly into the bloodstream through the skin. This bypasses first-pass hepatic metabolism, allowing for lower dose levels of the active pharmacological component, potentially resulting in higher bioavailability and improved safety properties. Transdermal delivery also bypasses the gastrointestinal tract, reducing the chance of gastrointestinal adverse events, which can involve unwanted psychoactive effects, and the possibility of CBD being broken down to THC by stomach acid. Furthermore, transdermal delivery of CBD reduces the intensity and frequency of somnolence, an adverse event typically present with oral CBD administration. Transdermal delivery of CBD can also avoid hepatic adverse events typically present with oral CBD administration. In some embodiments, transdermal administration of an effective dose of CBD reduces the severity of at least one adverse event by approximately 15% to approximately 95% compared to oral administration of CBD.

[0028] CBD may be in gel form and can be pharmaceutically manufactured as a clear, permeability-enhanced gel designed to deliver a controlled drug delivery transdermally in one or two daily doses. CBD gels may contain between 1% (weight / weight) and 7.5% (weight / weight) of CBD. For example, a CBD gel may have 4.2% (weight / weight) or 7.5% (weight / weight) of CBD. CBD gels can be applied topically by the patient or caregiver to the patient's upper arms and shoulders, back, thighs, or any combination thereof.

[0029] The CBD gel may contain diluents and carriers, as well as other conventional excipients such as wetting agents, preservatives, and suspension and dispersing agents.

[0030] CBD gels may contain solubilizers, penetration enhancers, solubilizing substances, antioxidants, bulking agents, thickeners, and / or pH modifiers. The composition of a CBD gel may be, for example, a. cannabidiol present in an amount of about 0.1% to about 20% (weight / weight) of the composition; b. a lower alcohol having between 1 and 6 carbon atoms present in an amount of about 15% to about 95% (weight / weight) of the composition; c. a first penetration enhancer present in an amount of about 0.1% to about 20% (weight / weight) of the composition; and d. water in an amount sufficient to bring the composition to a total of 100% (weight / weight). Other formulations of CBD gels can be found in International Publication No. 2010 / 127033, the entire contents of which are incorporated herein by reference. [Examples]

[0031] [Example 1]: Treatment of FXS with CBD A total of 20 patients (mean age = 10.8, standard deviation = 4.0) participated in the 12-week study. Eighteen patients (14 males, 4 females) aged 6–17 years (mean = 11.2, standard deviation = 3.96) with fragile X confirmed by molecular recording of complete FMR1 mutations completed the open-label FAB-C study over 12 weeks. CBD gel was added to other medications being administered. The first 6 weeks of the study were designed to establish the dosage in patients. Dosage was started at 50 mg of CBD per day and could be increased up to 250 mg of CBD per day. Weeks 7–12 of the study consisted of a maintenance period in which patients were treated with the established dose up to 250 mg of CBD per day by week 6. At completion of the study, patients could enter an open-label extension study for up to 12 months.

[0032] The primary endpoint of this study was the change in total score on the Anxiety, Depression and Mood Scale (ADAMS) from baseline to 12 weeks. The ADAMS is a 28-item scale designed to assess generalized anxiety, social avoidance, obsessive-compulsive behavior, manic / hyperactive behavior, and depressed mood. The ADAMS has been validated in patients with FXS.

[0033] The results for the primary endpoint are summarized in Table 1, which details the mean (standard deviation) values ​​of the efficacy scale at baseline and at 12 weeks for the ADAMS total score.

[0034] [Table 1]

[0035] The subscales of ADAMS are summarized in Table 2, which details the mean (standard deviation) values ​​of the effectiveness scale at baseline and 12 weeks.

[0036] [Table 2]

[0037] Compared to baseline total scores, patients treated with CBD transdermal gel showed a 44% reduction in ADAMS total scores (p<0.0001). Furthermore, at 12 weeks, patients treated with CBD transdermal gel showed statistically and clinically significant improvements compared to baseline in all but one ADAMS subscale (i.e., manic / hyperactive behavior, social avoidance, generalized anxiety, and obsessive-compulsive behavior). No significant changes were observed for the depressive mood subscale of ADAMS.

[0038] Abnormal Behavior Checklist - FXS-Specific (ABC-FXS), Pediatric Anxiety Rating Scale (PARS-R), Visual Analog Scale (VAS) for Anxiety, Hyperactivity, and Anger / Mood Swing, Vineland Adaptive Behavior (VLD) III, and Quality of Life for Children (PedsQL) TM Multiple secondary efficacy endpoints, including ). The PARS-R and Vineland scales are both assessed by clinicians, while the other scales are assessed by caregivers.

[0039] Primary and secondary endpoints were assessed before drug administration and 12 weeks after drug administration. The results for the secondary endpoints reinforce the findings demonstrated in ADAMS. Consistent with the findings from ADAMS, patients taking CBD transdermal gel showed statistically and clinically significant 12-week reductions in all subscales of the ABC-FXS (i.e., irritability, hyperactivity, social unresponsiveness / lethargy, social avoidance, stereotypic behavior, and inappropriate speech) and both total scores of the PARS-R (i.e., items 5 and 7).

[0040] With the exception of the physical functioning, school adaptation, and social adaptation subscales of the PedsQL and some subscales of the VLD (e.g., communication, daily living skills), patients showed significant improvement between baseline and 12-week scores on all remaining scales. Both the VLD and ADAMS were also administered in the extended Phase 2 trial.

[0041] The results obtained from ABC-FXS are summarized in Table 3, which details the mean (standard deviation) values ​​of the effectiveness scale at baseline and at 12 weeks.

[0042] [Table 3]

[0043] The results obtained from PARS-R are summarized in Table 4, which details the mean (standard deviation) values ​​of the effectiveness scale at baseline and at 12 weeks.

[0044] [Table 4]

[0045] Table 5 summarizes the results obtained from the VAS for anxiety, hyperactivity, and anger / mood swings.

[0046] [Table 5]

[0047] The results obtained from PedsQL are summarized in Table 6, which details the mean (standard deviation) values ​​of the efficacy scale at baseline and at 12 weeks.

[0048] [Table 6]

[0049] The results obtained from VLDIII are summarized in Table 7, which details the mean (standard deviation) values ​​of the effectiveness scale at baseline and at 12 weeks.

[0050] [Table 7]

[0051] Of the 18 patients who completed 12 weeks of treatment, the mean improvement in overall anxiety and depression (ADAMS total score) reached 44% (p<0.01), with particular benefits observed for generalized anxiety (51%; p<0.01) and obsessive-compulsive behavior subscales (48%; p<0.05). Furthermore, ABCs were observed in a range of 28% (hyperactivity subscale; p0<.05) to 60% (stereotypic subscale; p0<.01). FXS Improvements measured by the assessment were observed in abnormal behaviors, with social avoidance (p<0.01) and social unresponsiveness / lethargy subscales improving by 55% each during the treatment period (p<0.01). Beyond individual symptoms, quality of life improved by 17% (p=0.01).

[0052] This study successfully met its primary endpoint, achieving a 44% improvement in the total ADAMS score at 12 weeks compared to baseline (P<0.0001). The study also achieved clinically significant improvements in all ABC-FXS indices describing the major symptoms of FXS, including irritability, hyperactivity, social unresponsiveness, social avoidance, stereotypic behavior, and inappropriate speech.

[0053] After a 12-week open-label study, patients were permitted to participate in a one-year open-label extension study. 72% (n=13) of the 18 patients who completed the initial 12-week study participated in the extension study. The open-label extension study is ongoing, and several data have been collected over 38 weeks (12 weeks in the initial study and up to 6 months in the extension study). Results from the extension study are being evaluated using two collected metrics (ADAMS and ABC). FXS ) demonstrates continued progress. In fact, those who completed the 38-week visit (n=4) showed significant progress from screening for overall anxiety and depression, with 74% of participants experiencing an average improvement in their ADAMS total score. Similar improvements were observed for abnormal behaviors at 38 weeks, ranging from 75% (irritability subscale) to 96% (social avoidance subscale) and 97% (social unresponsive / lethargy subscale).

[0054] The open-label extension study is continuing, and data have been collected throughout 51 weeks. The results are shown in Table 8 (ABC). FXS This is summarized in the table (ADAMS).

[0055] [Table 8]

[0056] [Table 9]

[0057] The CBD gel was well-tolerated and exhibited excellent skin tolerance. One patient discontinued treatment due to exacerbation of a pre-existing eczema. No other adverse events led to discontinuation, and those that did occur were not considered severe. The most common adverse events were mild to moderate gastroenteritis (n=6) and upper respiratory tract infection (n=5). However, during the 12-week treatment period, no patients experienced drug-related GI events, and THC was not detected in the plasma.

[0058] The clinical results of this study are important for many FXS patients worldwide who currently have no approved therapeutic options to treat their symptoms. The data, particularly the improvements in anxiety, social avoidance, and irritability as measured by ADAMS, ABC-FXS, and PARS-R, are significant. The CBD gel was very well tolerated in children and adolescents with FXS.

[0059] [Example 2]: Patient study report by parent This is a report by a caregiver regarding a 7-year-old child who participated in the above study and is continuing the extended study. The caregiver's son has fully variant fragile X syndrome. Prior to this study, he was reported to be non-verbal, have severe intellectual and visual impairments, still require diapers, and have extremely severe gastrointestinal problems requiring tube feeding every two hours. Before starting this study, the child had never made eye contact, rarely left the house without significant emotional distress, never initiated any form of communication, had an extreme aversion to being touched, including by his parents, would not allow family members to sit next to him, and would leave the room if someone walked in.

[0060] Within the first two weeks of the trial, the patient began making more eye contact, initiated physical contact with his family, such as holding his mother's hand, and began emotional contact with his family, such as asking to be in the same room as them, and showed improvement in his ability to go out to the extent that his family was able to take their first vacation together.

[0061] A few weeks after the completion of the initial trial and into the extended trial, the caregiver noted another significant change in the patient. He began greeting family members, initiating and engaging in more complex games, showing / sharing preferences for things instead of simply rejecting all choices, and beginning to accept family pets. He also allowed doctors to touch and hold him without becoming upset. For the very first time, the patient began using physical cues (sign language). For the very first time, the patient expressed his longing for his mother very clearly and strongly desired to be hugged and held by her.

[0062] Patients have reported being happier, more relaxed, able to interact with the world in ways they were previously unable to, and able to learn new skills they were previously unable to acquire. Patient teachers, therapists, and assistants have also noted the changes in the patients.

[0063] [Example 3]: Treatment of subjects with complete methylation (Fmet) FXS by CBD A 14-week central clinical study of cannabidiol (CBD) in children and adolescents / young adults with fragile X. C clinical study O f Ca NN abidiol (CBD) in Child E n and Adoles C en T s with F ragile X The CONNECT-FX trial was conducted. The randomized, double-blind, placebo-controlled CONNECT-FX trial evaluated the efficacy and safety of Zygel CBD gel as a treatment for behavioral symptoms of FXS.

[0064] Twenty-five patients with fragile X syndrome, identified by a complete mutation in the FMR1 gene, were enrolled at 21 clinical sites in the United States, Australia, and New Zealand. For the first two weeks, all patients received a placebo (often referred to as "placebo induction" in neuropsychiatric clinical trials), resulting in 33 patients not being randomized. The remaining 212 patients were included in the intention-to-treatment (ITT) population (Zygel: n=110; placebo: n=102) and randomized to receive either the study drug or placebo for an additional 12 weeks. One patient did not receive the study drug, so 211 patients were included in the safety analysis (Zygel: n=109; placebo: n=102). One patient did not have a post-baseline efficacy measure, so the maximum analysis population was 210 patients (Zygel: n=109; placebo: n=101).

[0065] The largest efficacy analysis population enrolled 210 patients (Zygel: n=109; placebo: n=101). Patients were given either 250 mg or 500 mg of Zygel daily, based on their body weight. The primary endpoint was ABD-C FXS This was a subscale of social avoidance. Secondary assessment items included ABC-C FXS Irritability subscale, ABC-C FXS This included the Social Unresponsiveness / Lethargy Subscale and the Clinical Global Impression Improvement-I (CGI-I).

[0066] The Clinical Global Impression Improvement (CGI-I) is commonly used in clinical trials because it allows clinicians to utilize medical history obtained from caregivers and incorporate scores into clinical assessment scales for symptom severity (Leigh et al., 2013). The CGI-I is a seven-point scale that requires clinicians to assess how much a patient's condition has improved or worsened compared to their baseline state at the start of the intervention, and is rated as follows: 1-Greatly improved; 2-Greatly improved; 3-Minimally improved; 4-No change; 5-Minimal worsening; 6-Greatly worsened; or 7-Greatly worsened. Information from both the clinician's and the parent / caregiver's medical history is incorporated into the clinical assessment scale.

[0067] Patients with FXS have a complete mutation in the FMR1 gene and can be described as follows: (i) non-mosaic (the patient has all cells with a complete mutation in the FMR1 gene, and all genes are completely methylated; note - methylation inactivates the FMR1 gene); (ii) size mosaicism (the patient has some cells with a complete mutation in the FMR1 gene and some cells with a pre-mutation in the FMR1 gene, and not all genes are methylated); and (iii) methylated mosaicism (all cells have a complete mutation in the FMR1 gene, but not all genes are methylated).

[0068] Patients with over 90% methylation are thought to have a fully methylated FMR1 gene, which does not produce mRNA and therefore does not produce FMR protein. To investigate the differences between the two patient groups—those with and without complete methylation—we planned an analysis.

[0069] <Result> Table 10 summarizes the CONNECT-FX results for the primary endpoint and important secondary endpoints in the largest analysis population.

[0070] [Table 10]

[0071] In the primary outcome measure, improvement in the Social Avoidance subscale of the Abnormal Behavior Checklist-Community FXS (ABC-CFXS), Zygel did not achieve statistical significance compared to placebo. Zygel also failed to demonstrate statistical significance compared to placebo in three key secondary outcome measures: irritability subscale scores on the ABC-CFXS, social unresponsiveness / lethargy subscale scores on the ABC-CFXS, and changes from baseline to the end of the treatment period in Clinical Global Impression Improvement (CGI-I).

[0072] Analysis of the most severely affected patients in the trial, defined as those with at least 90% methylation of the affected FMR1 gene ("complete methylation"), showed that patients given Zygel compared to placebo showed a ABC-C score. FXSStatistical significance was achieved in the primary outcome measure of improvement in the social avoidance subscale after 12 weeks of treatment (p=0.020). This group comprised 80% of the patients enrolled in the CONNECT-FX study, and it is estimated that complete methylation occurs in approximately 60% of the entire FXS patient population. The term “Fragile X syndrome in subjects with complete methylation of the affected FMR1 gene” refers to subjects with “Fmet fragile X syndrome” or “FmetFXS”. Patients with genetically confirmed complete mutation fragile X and complete methylation of the affected FMR1 gene are generally the most severely affected by this disorder. Within the CONNECT-FX trial, this was supported by patients with higher anxiety, lower IQ, lower adaptive functioning, and more severe autism compared to patients without the completely methylated FMR1 gene in baseline analyses.

[0073] 169 patients met the criteria for complete methylation of the affected FMR1 gene. One patient was untreated and one did not have efficacy measures after baseline, resulting in 167 patients (Zygel: n=91; placebo: n=76). Table 11 summarizes patient data for complete methylation (≥90% methylation, Fmet) versus incomplete methylation (≤90% methylation, non-Fmet).

[0074] [Table 11]

[0075] Table 12 summarizes the CONNECT-FX results in the analysis population of patients with complete methylation of the affected FMR1 gene across primary and key secondary endpoints.

[0076] [Table 12]

[0077] The median improvement in the ABC-CFXS social avoidance subscale after 12 weeks of treatment was 40% in Zygel patients and 21.1% in placebo patients.

[0078] The interaction test for heterogeneity across the social avoidance subscales was statistically significant (p=0.002), meaning that the difference in treatment effects between subgroups was statistically significant.

[0079] <Safety Data> Zygel was very well tolerated in CONNECT-FX, and its safety profile was consistent with previously published data from other Zygel clinical trials. No safety signals were identified. Approximately half (54%) of the 211 patients in the safety analysis population experienced a treatment-induced adverse event (any event, whether related to or unrelated to the study drug), all of which were mild or moderate. The frequency of treatment-induced adverse events was similar across treatment groups (58% in Zygel patients and 50% in placebo patients). No serious or critical adverse events were reported during the study. There were seven total psychiatric disorders (TEAEs), five of which occurred in the placebo group.

[0080] Only 15 patients (7%) experienced procedure-related adverse events (20 events in total); 11 patients in the Zygel group experienced 14 procedure-related TEAEs, compared to 4 patients in the placebo group who experienced 6 TEAEs. The most common procedure-related TEAE was application site pain (Zygel: 6.4%; placebo: 1.0%).

[0081] Chemistry and hematological laboratory values ​​were similar between the placebo and Zygel groups, and no clinically relevant abnormalities were observed in either group. Specifically, there were no elevated liver function tests (LFT) in the Zygel group, while there were two moderately elevated LFTs in the placebo group.

[0082] This study identified a key group of patients who appear likely to significantly benefit from Zygel's treatment of behavioral symptoms of FXS. Combined with the excellent tolerability observed in this trial, Zygel may be an important therapeutic option for the most severely affected patients with fragile X syndrome.

Claims

1. Use of cannabidiol (CBD) in the manufacture of a pharmaceutical product for the percutaneous treatment of one or more symptoms of fragile X syndrome in subjects having fragile X syndrome with complete methylation of the FMR1 gene.

2. The use according to claim 1, wherein one or more symptoms are behavioral symptoms of Fragile X syndrome.

3. The use according to claim 2, wherein the behavioral symptom is social avoidance.

4. The use according to any one of claims 1 to 3, wherein the treatment includes the clinically comprehensive impression improvement (CGI-I).

5. The use according to any one of claims 1 to 4, wherein the total daily dose of CBD is between approximately 50 mg and approximately 500 mg per day.

6. The use according to any one of claims 1 to 5, wherein the total daily dose of CBD is 250 mg.

7. The use according to any one of claims 1 to 5, wherein the total daily dose of CBD is 500 mg.

8. The use according to any one of claims 1 to 7, wherein the CBD is formulated as a gel.

9. The use according to any one of claims 1 to 8, wherein CBD is administered in a single daily dose.

10. The use according to any one of claims 1 to 8, wherein CBD is administered in two daily doses.

11. The use according to any one of claims 1 to 10, wherein CBD is administered transdermally to the arm of the subject.

12. The use according to any one of claims 1 to 11, wherein the CBD is synthetic CBD.

13. The use according to any one of claims 1 to 11, wherein the CBD is derived from a plant.

14. The use according to any one of claims 1 to 13, wherein transdermal administration of CBD reduces the severity of at least one adverse event compared to oral administration of CBD.

15. The use according to claim 14, wherein at least one adverse event is selected from the group consisting of somnolence, psychostimulant effects, liver function, and gastrointestinal adverse events.

16. The use according to claim 1, wherein the subject has a complete mutation in the FMR1 gene.

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