U.S. patent application number 17/465141 was filed with the patent office on 2022-03-31 for treatment of autism with cannabidiol.
This patent application is currently assigned to ZYNERBA PHARMACEUTICALS, INC.. The applicant listed for this patent is ZYNERBA PHARMACEUTICALS, INC.. Invention is credited to Marcel Bonn-Miller, Donna Gutterman, Terri Sebree.
Application Number | 20220096396 17/465141 |
Document ID | / |
Family ID | |
Filed Date | 2022-03-31 |
United States Patent
Application |
20220096396 |
Kind Code |
A1 |
Sebree; Terri ; et
al. |
March 31, 2022 |
TREATMENT OF AUTISM WITH CANNABIDIOL
Abstract
The present technology relates to a method of treating one or
more behavioral symptoms of Autism Spectrum Disorder (ASD) in a
subject by transdermally administering an effective amount of
cannabidiol (CBD) to the subject wherein one or more behavioral
symptoms of ASD are treated in the subject.
Inventors: |
Sebree; Terri; (Gladwyne,
PA) ; Bonn-Miller; Marcel; (Lexington, NC) ;
Gutterman; Donna; (Raleigh, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ZYNERBA PHARMACEUTICALS, INC. |
Devon |
PA |
US |
|
|
Assignee: |
ZYNERBA PHARMACEUTICALS,
INC.
Devon
PA
|
Appl. No.: |
17/465141 |
Filed: |
September 2, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16737326 |
Jan 8, 2020 |
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17465141 |
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16411248 |
May 14, 2019 |
10568848 |
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16737326 |
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16220249 |
Dec 14, 2018 |
10314792 |
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16411248 |
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16144632 |
Sep 27, 2018 |
10213390 |
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16220249 |
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62632532 |
Feb 20, 2018 |
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62564834 |
Sep 28, 2017 |
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International
Class: |
A61K 31/05 20060101
A61K031/05; A61K 36/185 20060101 A61K036/185; A61P 25/00 20060101
A61P025/00; A61K 9/00 20060101 A61K009/00; A61K 9/06 20060101
A61K009/06 |
Claims
1-30. (canceled)
31. A method of treating a human suffering from an autism spectrum
disorder comprising: transdermally administering via a gel or cream
a therapeutically effective amount of purified cannabidiol to the
human suffering from the autism spectrum disorder to effectively
treat the autism spectrum disorder in the human in need thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of and priority to U.S.
provisional application No. 62/564,834 filed Sep. 28, 2017 and U.S.
provisional application No. 62/632,532 filed Feb. 20, 2018. The
contents of each of which are hereby incorporated herein in their
entirety.
FIELD OF THE TECHNOLOGY
[0002] The present disclosure relates to methods 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.
BACKGROUND
[0003] Cannabinoids are a class of chemical compounds found in the
Cannabis plant. The two primary cannabinoids contained in Cannabis
are cannabidiol, or CBD, and .DELTA.9-tetrahydrocannabinol, or THC.
CBD lacks the psychoactive effects of THC. Studies have 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. It is caused by a mutation in the Fragile X Mental
Retardation 1 (FMR1) gene located on the X chromosome and leads to
dysregulation of the endocannabinoid system including reductions in
endogenous cannabinoids (2-AG and anandamide [AEA]). The disorder
negatively affects synaptic function, plasticity and neuronal
connections, and results in a spectrum of intellectual
disabilities, social anxiety, and memory problems. In the US, there
are about 71,000 patients suffering with FXS.
[0005] "Behavior problems are often the most significant concern
reported by parents, and high levels of stress and depression and
low levels of quality of life for parents are commonly associated
with elevated problem behaviors in children." Wheeler A, Raspa M,
Bann C, Bishop E, Hassl D, Sacco H, Bailey D B. 2014. Anxiety
attention problems, hyperactivity, and the Aberrant Behavior
Checklist in fragile X syndrome. Am J Med Genet Part A
164A:141-155, 141. "As a result, reduction in behavior problems is
a primary focus of ongoing clinical trials testing the efficacy of
new medications for FXS." Wheeler at pages 141-142.
[0006] The Anxiety, Depression, and Mood Scale (ADAMS) is an
instrument that is used by clinicians, doctors, and researchers to
assess the level of anxiety, depression and mood in patients with
intellectual disabilities, including FXS. ADAMS consists of
questions grouped into five subscales, including (i) general
anxiety, (ii) social avoidance, (iii) compulsive behavior, (iv)
manic/hyperactive behavior, and (v) depressed mood. Each question
is answered by a clinician/doctor on a four-point scale ranging
from 0 ("not a problem") to 3 ("severe problem"). In addition to
subscale scores, the ADAMS yields a total score.
[0007] The original Aberrant Behavior Checklist (ABC) was "designed
to assess behavioral concerns of adults within institutional
settings." Wheeler at page 142. Since then, the original ABC has
been adapted to address patients who are not institutionalized and
specifically to address FXS. Id. The Aberrant Behavior
Checklist--FXS Specific (ABC-FXS) scale is used by clinicians,
doctors, and researchers to access certain behaviors in patients
with FXS. The ABC-FXS scale has six subscales including (i)
irritability, (ii) hyperactivity, (iii) socially
unresponsive/lethargic, (iv) social avoidance, (v) stereotypy, and
(vi) in appropriate speech. Similar to ADAMS, the ABC-FXS scale is
a four-point Likert-type scale ranging from 0 (not a problem) to 3
(problem is severe).
SUMMARY
[0008] The present disclosure relates to a method of treating one
or more behavioral symptoms of Fragile X Syndrome in a subject. The
method includes 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.
[0009] In some embodiments, the CBD is (-)-CBD. The effective
amount of CBD can be between about 50 mg to about 500 mg daily. In
some embodiments, the effective amount of CBD is initiated at about
50 mg daily and titrated up to about 500 mg daily. The effective
amount of CBD can be initiated at about 50 mg daily and titrated up
to about 250 mg daily. In some embodiments, the effective amount of
CBD is initiated at 250 mg daily. The effective amount of CBD can
be initiated at 500 mg daily. In some embodiments, the 500 mg daily
dose is administered to patients that weigh greater than 35 kg. The
CBD can be administered in a single daily dose or in two daily
doses. In some embodiments, the effective amount of CBD can be 390
mg in divided daily doses.
[0010] The CBD can be formulated as a gel or an oil. In some
embodiments, the CBD is formulated as a permeation-enhanced gel.
The gel can contain between 1% (wt/wt) CBD to 7.5% (wt/wt) CBD. In
some embodiments, the gel contains 4.2% (wt/wt) CBD. In some
embodiments, the gel contains 7.5% (wt/wt) CBD.
[0011] In some embodiments, the transdermal preparation can be a
cream, a salve or an ointment. The CBD can be delivered by a
bandage, pad or patch.
[0012] Alleviating one or more behavioral symptoms of Fragile X
Syndrome can include an improvement in a total score of an Anxiety,
Depression and Mood Scale (ADAMS). In some embodiments, alleviating
one or more behavioral symptoms of FXS can include improvement in
one or more subscales of ADAMS. Alleviating one or more behavioral
symptoms of Fragile X Syndrome can include improvement in one or
more measures of an Aberrant Behavior Checklist for Fragile X
(ABC-FXS).
[0013] In some embodiments, the one or more behavioral symptoms is
selected from the group consisting of general anxiety, social
avoidance, compulsive behavior, manic/hyperactive behavior,
irritability, lethargy, stereotypy, and inappropriate speech. The
behavioral symptom that is alleviated can be any one of general
anxiety, social avoidance, compulsive behavior, manic/hyperactive
behavior, irritability, lethargy, stereotypy, inappropriate speech,
emotional functioning, psychosocial health, written communication,
socialization, play and leisure, coping skills, internalizing
behavior, externalizing behavior, tantrum/mood liability,
hyperactivity/impulsivity, quality of life, or any combination
thereof. In some embodiments, a single symptom is alleviated. In
some embodiment, two, three, four, five, six, seven, eight, or nine
symptoms are alleviated.
[0014] The CBD can be administered transdermally on the subject's
upper arm and shoulder. In some embodiments, the CBD is
administered transdermally on the subject's thigh or back.
[0015] The CBD can be synthetic CBD. The CBD can be purified CBD.
The CBD can be botanically derived.
[0016] Transdermally administering an effective amount of
cannabidiol (CBD) can reduce an intensity of at least one adverse
event or side effect relative to orally administering CBD. The at
least one adverse event or side effect can be a gastrointestinal
(GI) adverse event. The at least one adverse event or side effect
can be liver function. In some embodiments, the at least one
adverse event is somnolence. In some embodiments, the frequency and
intensity of somnolence is reduced as an adverse event.
[0017] In another aspect, a method is provided to treat one or more
behavioral symptoms of an autism spectrum disorder (ASD) in a
subject by transdermally administering an effective amount of CBD
to the subject wherein the one or more behavioral symptoms of ASD
are treated in the subject.
[0018] ASD is a behavioral diagnosis having a range of symptoms
that are generally characterized by an impaired ability to
communicate and interact socially with other people.
[0019] The one or more behavioral symptoms of ASD that can be
treated include, for example, social avoidance, general anxiety,
hyperactivity, depressed mood and compulsive behavior. Alleviating
one or more behavioral symptoms of ASD can include an improvement
in a total score of an Anxiety, Depression and Mood Scale (ADAMS).
In some embodiments, alleviating one or more behavioral symptoms of
ASD can include improvement in one or more subscales of ADAMS.
[0020] In some embodiments, the CBD is (-)-CBD. The effective
amount of CBD can be between about 50 mg to about 500 mg daily. In
some embodiments, the effective amount of CBD is initiated at about
50 mg daily and titrated up to about 500 mg daily. The effective
amount of CBD can be initiated at about 50 mg daily and titrated up
to about 250 mg daily. In some embodiments, the effective amount of
CBD is initiated at 250 mg daily. The effective amount of CBD can
be initiated at 500 mg daily. In some embodiments, the 500 mg daily
dose is administered to patients that weigh greater than 35 kg. The
CBD can be administered in a single daily dose or in two daily
doses. In some embodiments, the effective amount of CBD can be 390
mg in divided daily doses.
[0021] The CBD can be formulated as a gel or an oil. In some
embodiments, the CBD is formulated as a permeation-enhanced gel.
The gel can contain between 1% (wt/wt) CBD to 7.5% (wt/wt) CBD. In
some embodiments, the gel contains 4.2% (wt/wt) CBD. In some
embodiments, the gel contains 7.5% (wt/wt) CBD.
[0022] In some embodiments, the transdermal preparation can be a
cream, a salve or an ointment. The CBD can be delivered by a
bandage, pad or patch.
[0023] Alleviating one or more behavioral symptoms of ASD can
include an improvement in a total score of an Anxiety, Depression
and Mood Scale (ADAMS). In some embodiments, alleviating one or
more behavioral symptoms of ASD can include improvement in one or
more subscales of ADAMS.
[0024] In some embodiments, the one or more behavioral symptoms is
selected from the group consisting of general anxiety, social
avoidance, compulsive behavior, manic/hyperactive behavior. The
behavioral symptom that is alleviated can be any one of general
anxiety, social avoidance, compulsive behavior, manic/hyperactive
behavior, or any combination thereof. In some embodiments, a single
symptom is alleviated. In some embodiment, two, three, or four
behavioral symptoms are alleviated.
[0025] The CBD can be administered transdermally on the subject's
upper arm and shoulder. In some embodiments, the CBD is
administered transdermally on the subject's thigh or back.
[0026] The CBD can be synthetic CBD. The CBD can be purified CBD.
The CBD can be botanically derived.
[0027] Transdermally administering an effective amount of
cannabidiol (CBD) can reduce an intensity of at least one adverse
event or side effect relative to orally administering CBD. The at
least one adverse event or side effect can be a gastrointestinal
(GI) adverse event. The at least one adverse even or side effect
can be a liver function adverse event. In some embodiments, the at
least one adverse event is somnolence. In some embodiments, the
frequency and intensity of somnolence is reduced as an adverse
event.
DETAILED DESCRIPTION
[0028] 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.
[0029] 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.
[0030] 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.
[0031] 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.
[0032] 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.
[0033] 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.
[0034] 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.
[0035] 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.
[0036] The CBD gel can include diluents and carriers as well as
other conventional excipients, such as wetting agents,
preservatives, and suspending and dispersing agents.
[0037] 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
[0038] 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.
[0039] 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.
[0040] 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-US-00001 TABLE 1 Percent Change from Baseline Week 12
Baseline (n = 18) (n = 18) (%; n = 18) p Value* ADAMS: 32.1 18.1
-43.61 p < 0.0001 Total Score (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).
[0041] The subscales of the ADAMS are summarized in Table 2,
detailing efficacy scales mean (standard deviation) values at
baseline and week 12.
TABLE-US-00002 TABLE 2 Percent Change from Baseline Week 12
Baseline (n = 18) (n = 18) (%; n = 18) p Value* ADAMS: Manic/ 8.8
6.1 -30.68 p = 0.0003 Hyperactive (3.99) (3.29) Behavior Subscale
ADAMS: 2.9 2.0 -31.03 p = 0.1417 Depressed Mood (3.94) (2.35)
Subscale ADAMS: Social 9.9 4.8 -51.52 p = 0.0002 Avoidance (5.18)
(2.07) Subscale ADAMS: 9.4 4.6 -51.06 p < 0.0001 General Anxiety
(4.35) (3.35) Subscale ADAMS: 2.7 1.4 -48.15 p = 0.0262 Compulsive
(2.40) (1.42) Behavior Subscale *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).
[0042] 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.
[0043] 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.TM.).
Both the PARS-R and the Vineland scales are clinician-rated, while
the other scales are caregiver-rated.
[0044] 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).
[0045] 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.
[0046] Results from the ABC-FXS are summarized in Table 3,
detailing efficacy scales mean (standard deviation) values at
baseline and week 12.
TABLE-US-00003 TABLE 3 Percent Change from Baseline Week 12
Baseline (n = 18) (n = 18) (%; n = 18) p Value* ABC: Irritability
17.7 10.6 -40.11 p = 0.0096 (12.68) (11.03) ABC: Hyperactivity 13.7
9.8 -28.47 p = 0.0237 (9.09) (7.38) ABC: Socially 9.2 4.1 -55.43 p
= 0.0034 Unresponsive/ (6.40) (4.09) Lethargic ABC: Social 5.1 2.3
-54.90 p = 0.0005 Avoidance (3.46) (2.22) ABC: Stereotypy 8.1 3.2
-60.49 p = 0.0006 (5.91) (3.07) ABC: Inappropriate 5.9 3.5 -40.68 p
= 0.0018 Speech (2.30) (2.66) *P-values are presented for the
comparison of the Week 12 value to the Baseline, among those who
completed the study (n = 18).
[0047] Results from the PARS-R are summarized in Table 4, detailing
efficacy scales mean (standard deviation) values at baseline and
week 12.
TABLE-US-00004 TABLE 4 Percent Change from Baseline Week 12
Baseline (n = 18) (n = 18) (%; n = 18) p Value* PARS-R-5 Item 15.7
10.6 -32.48 p = 0.0006 (3.88) (3.43) PARS-R-7 Item 21.3 14.4 -32.39
p = 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).
[0048] Results from the VAS for Anxiety, Hyperactivity and
Tantrum/Mood Lability are summarized in Table 5.
TABLE-US-00005 TABLE 5 Percent Change from Baseline Week 12
Baseline (n = 18) (n = 18) (%; n = 18) p Value* VAS-Hyperactivity/
5.9 3.6 -38.98 p = 0.0002 Impulsivity (2.43) (2.49)
VAS-Tantrum/Mood 4.7 3.2 -31.91 p = 0.0023 Liability (2.09) (2.18)
VAS-Anxiety 6.0 3.8 -36.67 p = 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).
[0049] Results from the PedsQL are summarized in Table 6, detailing
efficacy scales mean (standard deviation) values at baseline and
week 12.
TABLE-US-00006 TABLE 6 Percent Change from Baseline Week 12
Baseline (n = 18) (n = 18) (%; n = 18) p Value* PedsQL: Total Score
57.8 67.7 17.13 p = 0.0100 (18.78) (18.27) PedsQL: Physical 67.9
78.0 14.87 p = 0.0606 Functioning (27.36) (22.39) PedsQL: Emotional
64.0 78.3 22.34 p = 0.0394 Functioning (20.72) (16.63) PedsQL:
Social 37.3 49.0 31.37 p = 0.0717 Functioning (24.70) (24.35)
PedsQL: School 55.7 59.1 6.10 p = 0.3580 Functioning (19.17)
(22.47) PedsQL: Psychosocial 52.4 62.2 18.70 p = 0.0408 Health
(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).
[0050] Results from the VLD III are summarized in Table 7,
detailing efficacy scales mean (standard deviation) values at
baseline and week 12.
TABLE-US-00007 TABLE 7 Percent Change from Baseline Week 12
Baseline (n = 18) (n = 18) (%; n = 18) p Value* VLD III: Overall
46.1 48.9 6.07 p = 0.0472 Adaptive Behavior (16.29) (16.49)
Composite VLD III: Communication 36.7 39.2 6.81 p = 0.2968 (18.52)
(20.34) VLD III: Communication- 3.9 5.3 35.90 p = 0.0752 Receptive
(3.43) (4.34) VLD III: Communication- 3.3 3.7 12.12 p = 0.5070
Expressive (3.63) (4.07) VLD III: Communication- 4.4 3.8 -13.64 p =
0.0293 Written (3.81) (3.64) VLD III: Daily Living 52.7 54.6 3.61 p
= 0.3911 Skills (21.19) (18.46) VLD III: Daily Living 5.7 6.2 8.77
p = 0.3374 Skills-Personal (4.26) (4.33) VLD III: Daily Living 9.6
9.5 -1.04 p = 0.9395 Skills-Domestic (3.42) (3.09) VLD III: Daily
Living 4.6 4.7 2.17 p = 0.5636 Skills-Community (3.09) (2.93) VLD
III: Socialization 45.9 50.9 10.89 p = 0.0344 (16.22) (17.83) VLD
III: Socialization- 5.3 5.9 11.32 p = 0.2937 Interpersonal (3.51)
(3.64) Relationships VLD III: Socialization- 3.4 4.5 32.35 p =
0.0350 Play and Leisure (2.91) (3.93) VLD III: Socialization- 6.6
7.8 18.18 p = 0.0246 Coping Skills (2.93) (2.84) VLD III:
Maladaptive 19.9 18.7 -6.03 p = 0.0486 Behavior-Internalizing
(1.71) (1.79) VLD III: Maladaptive 18.7 17.2 -8.02 p = 0.0090
Behavior-Externalizing (2.42) (2.66) *P-values are presented for
the comparison of the Week 12 value to the Baseline value, among
those who completed the study (n = 18).
[0051] 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 ABC.sub.FXS ranging from 28% (Hyperactivity subscale;
p0<0.05) to 60% (Stereotypy subscale; p0<0.01) 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).
[0052] 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.
[0053] 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 ABC.sub.FXS). 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.
[0054] The open-label extension continues to be ongoing and data
has been collected through Week 51. The results are summarized in
Table 8 (ABC.sub.FXS) and Table (ADAMS).
TABLE-US-00008 TABLE 8 (ABC.sub.FXS) Week 12 Week 38 Week 51
Screening Mean Mean Mean (baseline Change Change Change score) (%)
(%) (%) Week 51 N = 12 N = 12 N = 9 N = 9 P values Irritability
22.3 51.1 63.7 59.2 0.0007 Hyperactivity 16.6 36.7 48.2 40.4 0.0037
Socially 10.8 65.7 83.3 72.2 0.0035 Unresponsive/ Lethargic Social
Avoidance 5.7 57.9 75.4 77.2 0.0013 Stereotypy 9.7 60.8 73.2 64.9
0.0012 Inappropriate 6.2 56.5 66.1 56.5 <0.0001 Speech
TABLE-US-00009 TABLE 9 (ADAMS) Week 12 Week 38 Week 51 Screening
Mean Mean Mean (baseline Change Change Change score) (%) (%) (%)
Week 51 N = 12 N = 12 N = 12 N = 12 P values Manic/ 8.8 34.1 53.4
45.5 0.0014 Hyperactivity Depressed Mood 3.2 43.8 62.5 59.4 0.0032
Social Avoidance 9.9 52.5 61.6 55.6 0.0004 General Anxiety 9.8 55.1
58.2 58.2 <0.0001 Compulsive 3.2 50.0 59.4 59.4 0.0213 Behavior
Total Score 33.3 48.6 59.2 54.4 <0.0001
[0055] 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.
[0056] 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
[0057] 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.
[0058] 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.
[0059] 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.
[0060] 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.
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