Patent ID: 12226373

DETAILED DESCRIPTION

As used herein, the term “treating” or “treatment” refers to mitigating, improving, relieving, or alleviating at least one symptom (such as a behavioral symptom) of a condition, disease or disorder in a subject, such as a human, or the improvement of an ascertainable measurement associated with a condition, disease or disorder.

As used herein, the term “clinical efficacy” refers to the ability to produce a desired effect in humans as shown through a Food and Drug Administration (FDA), or any foreign counterparts, clinical trial.

As used herein, the term “cannabidiol” or “CBD” refers to cannabidiol; cannabidiol prodrugs; pharmaceutically acceptable derivatives of cannabidiol, including 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 as well as to pharmaceutically acceptable salts, solvates, metabolites (e.g., cutaneous metabolites), and metabolic precursors thereof. The synthesis of CBD is described, for example, in Petilka et al.,Helv. Chim. Acta,52:1102 (1969) and in Mechoulam et al.,J. Am. Chem. Soc.,87:3273 (1965), which are hereby incorporated by reference.

As used herein, the term “transdermally administering” refers to contacting the CBD with the patient's or subject's skin under conditions effective for the CBD to penetrate the skin.

Fragile X Syndrome (FXS) is a genetic condition that causes intellectual disability, behavioral and learning challenges and various physical characteristics. FXS affects 1 in 4,000 males and 1 in 8,000 females. Patients with FXS can exhibit one or more characteristics of ASD.

The present disclosure relates to a method of treating one or more behavioral symptoms of Fragile X Syndrome in a subject by transdermally administering an effective amount of cannabidiol (CBD) to the subject wherein one or more behavioral symptoms of Fragile X Syndrome are treated in the subject.

Clinical and preclinical data support the potential for CBD in treating epilepsy, arthritis, cancer, and Fragile X Syndrome. Therapeutic medicines have been developed that utilize innovative transdermal technologies to allow for sustained and controlled delivery of therapeutic levels of CBD. Transdermal delivery of cannabinoids (e.g., CBD) has benefits over oral dosing because it allows the drug to be absorbed through the skin directly into the bloodstream. This avoids first-pass liver metabolism, potentially enabling lower dosage levels of active pharmaceutical ingredients with a higher bioavailability and improved safety profile. Transdermal delivery also avoids the gastrointestinal tract, lessening the opportunity for GI related adverse events and the potential degradation of CBD by gastric acid into THC, which can be associated with unwanted psychoactive effects. Moreover, transdermal delivery of CBD reduces the intensity and frequency of somnolence adverse events, which are typically present in oral dosing of CBD. Transdermal delivery of CBD can avoid liver function adverse events, which are typically present in oral dosing of CBD. In some embodiments, transdermally administering an effective amount of CBD reduces an intensity of at least one adverse event by about 15% to about 95% relative to orally administering CBD.

The CBD can be in a gel form and can be pharmaceutically-produced as a clear, permeation-enhanced gel that is designed to provide controlled drug delivery transdermally with once- or twice-daily dosing. The CBD gel can between 1% (wt/wt) CBD to 7.5% (wt/wt) CBD. The CBD gel can have, for example, 4.2% (wt/wt) CBD or 7.5% (wt/wt) CBD). The CBD gel can be applied topically by the patient or caregiver to the patient's upper arm and shoulder, back, thigh, or any combination thereof.

The CBD gel can include diluents and carriers as well as other conventional excipients, such as wetting agents, preservatives, and suspending and dispersing agents.

The CBD gel can include a solubilizing agent, a permeation enhancer, a solubilizer, antioxidant, bulking agent, thickening agent, and/or a pH modifier. The composition of the CBD gel can be, for example, a. cannabidiol present in an amount of about 0.1% to about 20% (wt/wt) of the composition; b. a lower alcohol having between 1 and 6 carbon atoms present in an amount of about 15% to about 95% (wt/wt) of the composition; c. a first penetration enhancer present in an amount of about 0.1% to about 20% (wt/wt) of the composition; and d. water in a quantity sufficient for the composition to total 100% (wt/wt). Other formulations of the CBD gel can be found in International Publication No. WO 2010/127033, the entire contents of which are incorporated herein by reference.

EXAMPLES

Example 1: Study Design and Data

A total of 20 patients (mean age=10.8, SD=4.0) were enrolled in a 12-week study. Eighteen patients (14 males, 4 females) aged 6 to 17 years of age (mean=11.2 SD=3.96) with Fragile X as confirmed by molecular documentation of FMR1 full mutation completed the open label FAB-C study through week 12. CBD gel was added on to other medications being administered. The first six weeks of the study were designed to titrate dosing in patients. Dosing was initiated at 50 mg CBD daily and could be increased to 250 mg CBD daily. Weeks 7 through 12 of the study comprised the maintenance period where patients were treated at the dose established by week six at a maximum of 250 mg CBD daily. At the completion of the study, patients could enter an open label extension study for up to 12 months.

The primary endpoint for the trial was the change in the total score of the Anxiety, Depression, and Mood Scale (ADAMS) from baseline to week 12. The ADAMS is a 28-item scale designed to assess general anxiety, social avoidance, compulsive behavior, manic/hyperactive behavior, and depressed mood. It has been validated in patients with FXS.

Results for the primary endpoint are summarized in Table 1, detailing efficacy scales mean (standard deviation) values at baseline and week 12 for the ADAMS Total Score.

TABLE 1Percent ChangeBaselineWeek 12from Baseline(n = 18)(n = 18)(%; n = 18)p Value*ADAMS: Total32.118.1−43.61p < 0.0001Score(14.36)(8.32)*P-values are presented for the comparison of the Week 12 value to the Baseline value for the total score and each subscale, among those who completed the study (n = 18).

The subscales of the ADAMS are summarized in Table 2, detailing efficacy scales mean (standard deviation) values at baseline and week 12.

TABLE 2Percent ChangeBaselineWeek 12from Baseline(n = 18)(n = 18)(%; n = 18)p Value*ADAMS: Manic/8.86.1−30.68p = 0.0003Hyperactive(3.99)(3.29)BehaviorSubscaleADAMS:2.92.0−31.03p = 0.1417Depressed Mood(3.94)(2.35)SubscaleADAMS: Social9.94.8−51.52p = 0.0002Avoidance(5.18)(2.07)SubscaleADAMS:9.44.6−51.06p < 0.0001General Anxiety(4.35)(3.35)SubscaleADAMS:2.71.4−48.15p = 0.0262Compulsive(2.40)(1.42)BehaviorSubscale*P-values are presented for the comparison of the Week 12 value to the Baseline value for the total score and each subscale, among those who completed the study (n = 18).

Compared to the baseline total score, the CBD transdermal gel treated patients has a 44% reduction (p<0.0001) in the ADAMS Total Score. Furthermore, the CBD transdermal gel treated patients has statistically and clinically significant improvement compared to baseline in all but one of the ADAMS subscales (i.e., manic/hyperactive behavior, social avoidance, general anxiety, and compulsive behavior) at week 12. A significant change was not observed for the depressed mood subscale of the ADAMS.

Multiple secondary efficacy endpoints including the Aberrant Behavior Checklist-FXS Specific (ABC-FXS), the Pediatric Anxiety Rating Scale (PARS-R), Visual Analog Scale (VAS) for Anxiety, Hyperactivity and Tantrum/Mood Lability, the Vineland Adaptive Behavior (VLD) III, and the Pediatric Quality of Life (PedsQL™). Both the PARS-R and the Vineland scales are clinician-rated, while the other scales are caregiver-rated.

The primary and secondary endpoints were evaluated prior to and following 12 weeks of drug administration. The results of the secondary endpoints reinforce the results demonstrated in the ADAMS. Consistent with findings from the ADAMS, patients taking the CBD transdermal gel demonstrated statistically and clinically significant 12-week reductions in all subscales of the ABC-FXS (i.e., irritability, hyperactivity, socially unresponsive/lethargic, social avoidance, stereotypy, and inappropriate speech), and both total score calculations of the PARS-R (i.e., 5- and 7-item).

Patients also showed significant improvement between Baseline and Week 12 scores for all remaining scales except for the Physical Function, School Functioning, and Social Functioning subscales of the PedsQL, as well as some subscales of the VLD (e.g., communication, daily living skills). Both the VLD and ADAMS are being administered in the extension Phase 2 of the trial.

Results from the ABC-FXS are summarized in Table 3, detailing efficacy scales mean (standard deviation) values at baseline and week 12.

TABLE 3PercentChange fromBaselineWeek 12Baseline(n = 18)(n = 18)(%; n = 18)p Value*ABC: Irritability17.7(12.68)10.6(11.03)−40.11p = 0.0096ABC: Hyperactivity13.7(9.09)9.8(7.38)−28.47p = 0.0237ABC: Socially9.2(6.40)4.1(4.09)−55.43p = 0.0034Unresponsive/LethargicABC: Social5.1(3.46)2.3(2.22)−54.90p = 0.0005AvoidanceABC: Stereotypy8.1(5.91)3.2(3.07)−60.49p = 0.0006ABC: Inappropriate5.9(2.30)3.5(2.66)−40.68p = 0.0018Speech*P-values are presented for the comparison of the Week 12 value to the Baseline, among those who completed the study (n = 18).

Results from the PARS-R are summarized in Table 4, detailing efficacy scales mean (standard deviation) values at baseline and week 12.

TABLE 4PercentChange fromBaselineWeek 12Baseline(n = 18)(n = 18)(%; n = 18)p Value*PARS-R - 5 Item15.710.6−32.48p = 0.0006(3.88)(3.43)PARS-R - 7 Item21.314.4−32.39p = 0.0004(5.55)(4.54)*P-values are presented for the comparison of the Week 12 value to the Baseline value, among those who completed the study (n = 18).

Results from the VAS for Anxiety, Hyperactivity and Tantrum/Mood Lability are summarized in Table 5.

TABLE 5PercentChange fromBaselineWeek 12Baseline(n = 18)(n = 18)(%; n = 18)p Value*VAS-5.93.6−38.98p = 0.0002Hyperactivity/Impulsivity(2.43)(2.49)VAS-Tantrum/Mood4.73.2−31.91p = 0.0023Liability(2.09)(2.18)VAS-Anxiety6.03.8−36.67p = 0.0005(2.05)(1.93)*P-values are presented for the comparison of the Week 12 value to the Baseline value, among those who completed the study (n = 18).

Results from the PedsQL are summarized in Table 6, detailing efficacy scales mean (standard deviation) values at baseline and week 12.

TABLE 6PercentChange fromBaselineWeek 12Baseline(n = 18)(n = 18)(%; n = 18)p Value*PedsQL: Total Score57.867.717.13p = 0.0100(18.78)(18.27)PedsQL: Physical67.978.014.87p = 0.0606Functioning(27.36)(22.39)PedsQL: Emotional64.078.322.34p = 0.0394Functioning(20.72)(16.63)PedsQL: Social37.349.031.37p = 0.0717Functioning(24.70)(24.35)PedsQL: School55.759.16.10p = 0.3580Functioning(19.17)(22.47)PedsQL: Psychosocial52.462.218.70p = 0.0408Health(17.22)(18.91)*P-values are presented for the comparison of the Week 12 value to the Baseline value, among those who completed the study (n = 18).

Results from the VLD III are summarized in Table 7, detailing efficacy scales mean (standard deviation) values at baseline and week 12.

TABLE 7PercentChange fromBaselineWeek 12Baseline(n = 18)(n = 18)(%; n = 18)p Value*VLD III: Overall46.1(16.29)48.9(16.49)6.07p = 0.0472Adaptive BehaviorCompositeVLD III: Communication36.7(18.52)39.2(20.34)6.81p = 0.2968VLD III:3.9(3.43)5.3(4.34)35.90p = 0.0752Communication-ReceptiveVLD III:3.3(3.63)3.7(4.07)12.12p = 0.5070Communication-ExpressiveVLD III:4.4(3.81)3.8(3.64)−13.64p = 0.0293Communication-WrittenVLD III: Daily Living52.7(21.19)54.6(18.46)3.61p = 0.3911SkillsVLD III: Daily Living5.7(4.26)6.2(4.33)8.77p = 0.3374Skills-PersonalVLD III: Daily Living9.6(3.42)9.5(3.09)−1.04p = 0.9395Skills-DomesticVLD III: Daily Living4.6(3.09)4.7(2.93)2.17p = 0.5636Skills-CommunityVLD III: Socialization45.9(16.22)50.9(17.83)10.89p = 0.0344VLD III: Socialization-5.3(3.51)5.9(3.64)11.32p = 0.2937InterpersonalRelationshipsVLD III: Socialization-3.4(2.91)4.5(3.93)32.35p = 0.0350Play and LeisureVLD III: Socialization-6.6(2.93)7.8(2.84)18.18p = 0.0246Coping SkillsVLD III: Maladaptive19.9(1.71)18.7(1.79)−6.03p = 0.0486Behavior-InternalizingVLD III: Maladaptive18.7(2.42)17.2(2.66)−8.02p = 0.0090Behavior-Externalizing*P-values are presented for the comparison of the Week 12 value to the Baseline value, among those who completed the study (n = 18).

Among the 18 patients who completed 12 weeks of treatment, average improvement in overall anxiety and depression (ADAMS Total Score) reached 44% (p<0.01), with particular benefit observed for the General Anxiety (51%; p<0.01) and Compulsive Behavior subscales (48%; p<0.05). Additionally, improvements as measured by ABCFXSranging from 28% (Hyperactivity subscale; p0<.05) to 60% (Stereotypy subscale; p0<.01) were observed in aberrant behavior, with the Social Avoidance (p<0.01) and Social Unresponsiveness/Lethargy subscales (p<0.01) each improving by 55% during the treatment period. Beyond individual symptoms, quality of life improved by 17% (p=0.01).

The trial successfully met its primary endpoint, achieving a 44% improvement (P<0.0001) in the total ADAMS score at week twelve compared to baseline. The trial also achieved clinically meaningful improvements in all measures of the ABC-FXS, which address the key symptoms of FXS including irritability, hyperactivity, social unresponsiveness, social avoidance, stereotypy, and inappropriate speech.

Following the 12-week open-label study, patients were allowed to roll into a 1-year open-label extension study. 72% (n=13) of the 18 patients who completed the initial 12-week study rolled into the extension. While the open-label extension is ongoing, some data have been collected through Week 38 (12 weeks in initial study and up to 6 months in the extension study). Results from the extension study demonstrate continued gains in the two measures collected (ADAMS and ABCFXS). Indeed, those who have completed a Week 38 visit (n=4) showed significant gains from screening in overall anxiety and depression, with participants experiencing an average improvement in the ADAMS total score of 74%. Similar improvement was observed for aberrant behavior, ranging from 75% (Irritability subscale) to 96% (Social Avoidance subscale) and 97% (Socially Unresponsiveness/Lethargy subscale) at Week 38.

The open-label extension continues to be ongoing and data has been collected through Week 51. The results are summarized in Table 8 (ABCFXS) and Table (ADAMS).

TABLE 8(ABCFXS)Week 12Week 38Week 51ScreeningMeanMeanMean(baselineChangeChangeChangescore)(%)(%)(%)Week 51N = 12N = 12N = 9N = 9P valuesIrritability22.351.163.759.20.0007Hyperactivity16.636.748.240.40.0037Socially10.865.783.372.20.0035Unresponsive/LethargicSocial Avoidance5.757.975.477.20.0013Stereotypy9.760.873.264.90.0012Inappropriate6.256.566.156.5<0.0001Speech

TABLE 9(ADAMS)Week 12Week 38Week 51ScreeningMeanMeanMean(baselineChangeChangeChangescore)(%)(%)(%)Week 51N = 12N = 12N = 12N = 12P valuesManic/8.834.153.445.50.0014HyperactivityDepressed Mood3.243.862.559.40.0032Social Avoidance9.952.561.655.60.0004General Anxiety9.855.158.258.2<0.0001Compulsive3.250.059.459.40.0213BehaviorTotal Score33.348.659.254.4<0.0001

CBD gel was well tolerated, with excellent skin tolerability. One patient discontinued due to worsening of pre-existing eczema. No other adverse events led to discontinuation and no adverse events were considered severe. The most common adverse events were mild-moderate gastroenteritis (n=6) and upper respiratory tract infection (n=5). However, no patient experienced drug-related GI events during the 12-week treatment period and no THC was detected in the plasma.

The clinical results of the trial are significant for the many patients worldwide with FXS who currently have no approved therapeutic options to treat their symptoms. The data, in particular 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.

Example 2: Patient Monograph as Reported by Parent

This is the report regarding a 7 year old child participating in the above study and continuing on an extension study—as reported by the caregiver. The caregiver's son has full mutation Fragile X Syndrome. He is reported, prior to the trial, to be non-verbal, severely intellectually impaired, visually impaired, still in need of diapers and as having very severe GI issues requiring that he is fed by a feeding tube every two hours. Prior to the beginning the trial the child never ever made eye contact, rarely could leave his home without severe emotional distress, did not initiate any form of communication at all, intensely disliked being touched including by his parents, would not allow even family to sit next to him, and would leave the room if anyone walked into it.

Within the first two weeks of the trial, the patient began to make more eye contact, initiated physical contact with his family, e.g., grabbing his mother's hand, initiated emotional contact with his family including seeking to be in the same room with his family, and exhibited improved ability to leave the house, even to the extent the family could take their very first vacation together.

After the end of the initial trial and a few weeks into the extended trial, the caregiver recorded another big change in the patient. He started greeting his family, initiated and engaged in games that are more complex, exhibited/shared preferences for things instead of only rejecting all choices, and he began acknowledging the family pets. He also allowed his doctor to touch him and hold onto him without getting distressed. Patient began to use body signing (sign language) for the very first time. Patient communicated very clearly that he missed his mother for the very first time and was eager to be embraced and held by his mother.

Patient is reported to be happier, more relaxed, able to engage the world in ways he could not before, and able to learn new skills that he could not previously. His teachers, therapists and aids have also remarked in the changes in the patient.