U.S. patent application number 13/399960 was filed with the patent office on 2012-09-20 for treatment of submental fat.
This patent application is currently assigned to Kythera Biopharmaceuticals, Inc.. Invention is credited to Patricia Walker.
Application Number | 20120237492 13/399960 |
Document ID | / |
Family ID | 46672971 |
Filed Date | 2012-09-20 |
United States Patent
Application |
20120237492 |
Kind Code |
A1 |
Walker; Patricia |
September 20, 2012 |
TREATMENT OF SUBMENTAL FAT
Abstract
This disclosure relates to compositions, kits and methods for
non-surgical reduction of localized subcutaneous fat such as that
associated with a cosmetic fat accumulation. The methods employ
compositions having specific concentrations of a salt of
deoxycholic acid which provides a superior fat cell necrosis with
modest adverse effects. Examples of localized subcutaneous fat are
found in the submental area, in particular under the chin.
Inventors: |
Walker; Patricia;
(Calabasas, CA) |
Assignee: |
Kythera Biopharmaceuticals,
Inc.
|
Family ID: |
46672971 |
Appl. No.: |
13/399960 |
Filed: |
February 17, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61444613 |
Feb 18, 2011 |
|
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Current U.S.
Class: |
424/94.6 ;
514/171; 514/182 |
Current CPC
Class: |
A61P 29/00 20180101;
A61K 47/10 20130101; A61K 31/575 20130101; A61K 45/06 20130101;
A61K 47/24 20130101; A61K 38/465 20130101; A61P 43/00 20180101;
A61P 41/00 20180101; A61P 1/12 20180101; A61P 31/00 20180101; A61K
9/0019 20130101; A61K 31/167 20130101; A61K 31/56 20130101; A61P
7/02 20180101 |
Class at
Publication: |
424/94.6 ;
514/171; 514/182 |
International
Class: |
A61K 31/575 20060101
A61K031/575; A61P 43/00 20060101 A61P043/00; A61P 31/00 20060101
A61P031/00; A61P 29/00 20060101 A61P029/00; A61P 1/12 20060101
A61P001/12; A61K 38/46 20060101 A61K038/46; A61P 7/02 20060101
A61P007/02 |
Claims
1. A non-surgical method for the reduction of submental fat in a
subject, said method comprising a plurality of subcutaneous
injections of a solution of deoxycholic acid or a salt thereof into
said submental fat, each injection of said plurality administering
about 0.1 mg to about 0.2 mg of said deoxycholic acid or salt
thereof per square centimeter of the skin area over said submental
fat.
2. The method of claim 1, wherein the sites for injection are at
least about 1 cm apart from each other.
3. The method of claim 1, wherein the reduction of submental fat
enhances the facial appearance of said subject.
4. The method of claim 3, wherein said enhanced facial appearance
is due to the reduced appearance or the lack of the double-chin
display.
5. The method of claim 1, wherein said reduction is determined by
at least a physical measurement and/or reading from a scale.
6. The method of claim 5, wherein said physical measurement
comprises MRI and/or caliper.
7. The method of claim 5, wherein said submental fat is reduced in
thickness and/or volume as determined by MRI.
8. The method of claim 7, wherein said thickness and/or volume is
reduced by at least 10%.
9. The method of claim 5, wherein said scale is selected from the
group consisting of: CR-SMFRS, RS-SMFRS, PRSMFIS, any combinations
thereof.
10. The method of claim 3, wherein said facial appearance is
enhanced by at least 1 grade.
11. The method of claim 10, wherein said facial appearance is
enhanced by at least 1 grade, as determined by CR-SMFRS.
12. The method of claim 11, wherein said enhancement is achieved
within eight weeks from said injection.
13. The method of claim 11, wherein said enhancement is achieved
within twelve weeks from said injection.
14. The method of claim 3, wherein said facial appearance is
enhanced by at least 2 grades, as determined by CR-SMFRS.
15. The method of claim 11, wherein said CR-SMFRS is determined
with a score card as shown in FIG. 3.
16. The method of claim 1, wherein the volume for each injection is
about 0.1 ml to about 0.2 ml.
17. The method of claim 16, wherein said deoxycholic acid or salt
thereof is in an aqueous solution buffered at a pH of between about
8.0 and about 8.5.
18. The method of claim 1, wherein the total of said deoxycholic
acid or salt thereof administered is between about 50 mg to about
100 mg.
19. The method of claim 1, which is performed in a plurality of
visit by said subject, said plurality of visit is according to the
schedule shown in FIG. 2.
20. The method of claim 1, wherein said deoxycholic acid is
biologically derived or de novo synthesized.
21. The method of claim 20, wherein said deoxycholic acid is animal
derived.
22. The method of claim 20, wherein said deoxycholic acid is de
novo synthesized and wherein the solution comprising thereof is
free of primary bile acids and/or other secondary bile acids.
23. The method of claim 22, wherein said primary bile acid is
cholic acid.
24. The method of claim 1, wherein the solution further comprises
benzyl alcohol at a concentration of about 0.8% to about 1%.
25. The method of claim 1, comprising co-administering an agent
selected from the group consisting of: anesthetic, anti-microbial
agents, vasoconstrictors, anti-thrombotic agents, anti-coagulation
agents, suds-depressants, anti-inflammatory agents, analgesics,
dispersion agents, anti-dispersion agents, penetration enhancers,
steroids, tranquilizers, muscle relaxants, and anti-diarrhea
agents, or any combinations thereof.
26. The method of claim 25, wherein said co-administering is prior
to, at the same time, or following the said plurality of
injection.
27. The method of claim 1, wherein said injection further comprises
a lipase.
28. The method of claim 1, wherein said injection further comprises
a phospholipid.
29. The method of claim 28, wherein said phospholipid comprises
phosphatidylcholine.
30. The method of claim 29, wherein the ratio of said deoxycholic
acid or salt thereof and said phosphatidylcholine is about 1:0.005,
about 1:0.05, or about 1:0.5.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e) of U.S. Provisional Application Ser. No. 61/444,613,
filed Feb. 18, 2011, the content of which is incorporated by
reference in its entirety.
FIELD OF THE DISCLOSURE
[0002] This disclosure relates to methods for non-surgical
reduction of localized subcutaneous fat such as that associated
with a cosmetic fat accumulation. The methods employ compositions
having specific concentrations of a salt of deoxycholic acid which
provides a superior fat cell necrosis with modest adverse effects.
In one embodiment, the localized subcutaneous fat is found in the
submental area, in particular under the chin.
BACKGROUND
[0003] Fat accumulation under the chin is a unique phenomenon,
which can often occur in individuals who are not otherwise
overweight. This area around the neck can be resistant to weight
reduction measures, with liposuction being the primary
intervention. Deoxycholic acid or a salt thereof represents a
promising nonsurgical treatment for unwanted submental fat
deposition.
[0004] Any assessment of the risks and benefits of a proposed
therapy should necessarily consider the risks and benefits of
alternative treatments. In the case of deoxycholic acid for the
reduction of subcutaneous (SC) fat in the submental area, there are
no approved or rigorously evaluated nonsurgical alternatives.
Surgical alternatives include, on a scale of increasing
invasiveness, various forms of liposuction up to neck
reconstruction. All surgeries are associated with the known risks
of anesthesia, infection, bleeding, bruising, and scarring, as well
as the possibility of poor outcome and the expected discomfort and
"down-time" for the patient.
[0005] Presently, mixtures of phosphatidylcholine (PC) and
deoxycholate (DC), which are not approved by the United States (US)
Food and Drug Administration (FDA), have been used in increasing
frequency to reduce the size of localized deposits of fat. Perhaps
most relevant, Lipostabil.RTM. (5% PC and 4.75% DC) and
extemporaneous, pharmacy-compounded mixtures of PC and DC (PC/DC)
have found increasing use in the treatment of unwanted fat deposits
for cosmetic purposes. Many US physicians and aesthetic clinics
currently use various unapproved formulations of PC/DC prepared by
compounding pharmacies for administration in uncontrolled
environments.
[0006] In spite of these risks, the growing appeal of cosmetic
medical treatment of these procedures is a testament to the
psychological importance of body image and the beneficial outcomes
of these procedures, as perceived by the patients who seek
them.
SUMMARY
[0007] This disclosure provides compositions, kids, and treatment
schedules and methods of effectively removing localized
subcutaneous fat. Such fat is sometimes referred to herein as
"cosmetic fat" in that the so treated fat is not pathogenic in
nature. An example of such cosmetic fat is the fat deposited in the
submental area of a human patient, referred to as "submental fat
(SMF)."
[0008] Thus, one embodiment of the present disclosure provides a
non-surgical method for the reduction of submental fat in a
subject, said method comprising a plurality of subcutaneous
injections of a solution of deoxycholic acid or a salt thereof into
said submental fat, each injection of said plurality administering
about 0.1 mg to about 0.2 mg of said deoxycholic acid or salt
thereof per square centimeter of the skin area over said submental
fat. In one aspect, the sites for injection are at least about 1 cm
apart from each other.
[0009] Another embodiment of the present disclosure provides a
method for decreasing a submental fat deposit under a skin area in
a human subject, which method comprises local injection to the
submental fat deposit, through a plurality of spots on the skin
area, a composition comprising an effective amount of a salt of
deoxycholate, wherein the effective amount is from about 0.1 mg to
about 0.2 mg per square centimeter of the skin area.
[0010] Also provided is a method for decreasing a submental fat
deposit in a human subject which method comprises measuring the
thickness of the submental fat deposit to be decreased; marking, on
skin proximate to the submental fat deposit, a grid comprising a
plurality of spots, each of which is from about 0.8 cm to about 1.2
cm distant from an adjacent spot of the grid; and injecting, with a
suitable needle, through each of the plurality of spots, into about
half way into the submental fat deposit, an effective amount of a
composition comprising from about 0.5% to about 1% (w/w) of a salt
of deoxycholate, wherein each injection constitutes delivery of
from about 0.1 mL to about 0.3 mL of the composition.
[0011] Yet another embodiment provides a method for decreasing a
submental fat deposit in a human subject which method comprises
measuring the thickness of the submental fat deposit to be
decreased; marking, on skin proximate to the submental fat deposit,
a grid comprising about 40-60 spots, each of which is from about 1
cm distant from another spot of the grid; and injecting, with a
suitable needle, through each of the spots, into about half way
into the submental fat deposit, an effective amount of a
composition comprising about 1% (w/w) of a salt of deoxycholate,
wherein each injection constitutes delivery of about 0.2 mL of the
composition.
[0012] These and other aspects of the disclosure will be further
described in details below.
BRIEF DESCRIPTION OF THE DRAWING
[0013] FIG. 1 provides quantitation of fat pad surface area
necrosis in Zucker rats treated with varying concentrations of
deoxycholic acid.
[0014] FIG. 2 depicts the study design and treatment schema used in
Example 3.
[0015] FIG. 3 presents an exemplary score card to be used for
evaluating the grade of submental fat in a patient.
[0016] FIG. 4 shows CR-SMFRS changes from baseline for patients
receiving the treatment of placebo, 0.5% ATX-101 (0.5% sodium
deoxycholate) or 1.0% ATX-101 (1.0% sodium deoxycholate).
[0017] FIG. 5 is a chart showing percentages of subjects with
1-point improvement, as measured by CR-SMFRS, for patients
receiving the treatment of placebo, 0.5% ATX-101 or 1.0%
ATX-101.
[0018] FIG. 6 shows PR-SMFRS changes from baselines for patients
receiving the treatment of placebo, 0.5% ATX-101 or 1.0%
ATX-101.
[0019] FIG. 7 shows percentages of subjects with 1- and 2-point
improvement, as measured by PR-SMFRS, for patients receiving the
treatment of placebo, 0.5% ATX-101 or 1.0% ATX-101.
[0020] FIG. 8 shows SMF changes, as measured by MRI, from baseline
for patients receiving the treatment of placebo, 0.5% ATX-101 or
1.0% ATX-101.
[0021] FIG. 9 shows SMF thickness changes for all subjects at week
16 and 32.
[0022] FIG. 10 shows SMF volume changes from baseline, as measured
by MRI.
[0023] FIG. 11 shows SMF volume changes from baseline, as measured
by MRI, as curves.
[0024] FIG. 12 is chart revealing the results based on subject self
rating scales.
[0025] FIG. 13 presents data from subject self-rating of
attractiveness.
[0026] FIG. 14 shows the volume of study materials used in each
treatment group, at different time points.
[0027] FIG. 15 presents MRI images of a representative patient
before and after the treatment with 0.5% ATX-101.
[0028] FIG. 16 presents MRI images of a representative patient
before and after the treatment with 1.0% ATX-101.
[0029] FIG. 17 shows the body mass index (BMI) of subjects
undergoing the treatments.
[0030] FIG. 18 shows the CR-SMFRS score/BMI ratios for the subjects
in each treatment group.
[0031] FIG. 19 shows the body weight of subjects undergoing the
treatments.
[0032] FIG. 20 shows the CR-SMFRS score/body weight ratios for the
subjects in each treatment group.
[0033] FIG. 21 shows the percent of CR-SMFRS responders by weight
change, at week 32.
[0034] FIG. 22 shows the correlation between caliper measurement
and MRI thickness measurement.
[0035] FIG. 23 compares the effectiveness among ATX-101 0.5%, 1.0%
and 2.0% with the mean SMF score changes at different time
points.
[0036] FIG. 24 shows the summary comparison results using different
types of visual assessment methods and shows the results of adverse
event (AE) observations.
[0037] FIG. 25 illustrates a tattoo useful for applying a
5.times.10 grid on the chin of a subject.
DETAILED DESCRIPTION OF THE DISCLOSURE
Definitions
[0038] Throughout this disclosure, various publications, patents
and published patent specifications are referenced by an
identifying citation. The disclosures of these publications,
patents and published patent specifications are hereby incorporated
by reference into the present disclosure to more fully describe the
state of the art to which this disclosure pertains.
[0039] As used herein, certain terms may have the following defined
meanings. As used in the specification and claims, the singular
form "a," "an" and "the" include singular and plural references
unless the context clearly dictates otherwise.
[0040] As used herein, the term "comprising" is intended to mean
that the compounds and methods include the recited elements, but
not excluding others. "Consisting essentially of" when used to
define compositions and methods, shall mean excluding other
elements of any essential significance to the compounds or method.
"Consisting of" shall mean excluding more than trace elements of
other ingredients for claimed compounds and substantial method
steps. Embodiments defined by each of these transition terms are
within the scope of this disclosure. Accordingly, it is intended
that the methods and compounds can include additional steps and
components (comprising) or alternatively include additional steps
and compounds of no significance (consisting essentially of) or
alternatively, intending only the stated methods steps or compounds
(consisting of).
[0041] The term "pharmaceutically acceptable salt" or simply "salt"
refers to pharmaceutically acceptable salts of deoxycholic acid,
which salts are derived from a variety of organic and inorganic
counter ions well known in the art and include, by way of example
only, lithium (Li.sup.+), sodium (Na.sup.+) potassium (K.sup.+),
calcium (Ca.sup.2+), magnesium (Mg.sup.2+), ammonium
(NH.sub.4.sup.+), and tetraalkylammonium (NR.sub.4.sup.+), wherein
each R is independently an alkyl group having from 1 to 4 carbon
atoms). In one embodiment, the salt employed is sodium
(Na.sup.+).
[0042] The term "pharmaceutically acceptable excipient" refers to a
compound that is useful in preparing a pharmaceutical composition
that is generally safe, non-toxic and neither biologically nor
otherwise undesirable, and includes excipients that are acceptable
for human pharmaceutical use or veterinary use. A pharmaceutically
acceptable excipient as used in the specification and claims
includes both one and more than one such excipient. Some examples
of suitable excipients include lactose, dextrose, sucrose,
sorbitol, mannitol, starches, gum acacia, calcium phosphate,
alginates, tragacanth, gelatin, calcium silicate, microcrystalline
cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup,
methyl cellulose, lubricating agents such as talc, magnesium
stearate, and mineral oil; wetting agents; emulsifying and
suspending agents; and preserving agents such as methyl- and
propylhydroxy-benzoates and benzyl alcohol. The compositions of the
present disclosure can be formulated so as to provide quick,
sustained or delayed release of the active ingredient after
administration to the patient by employing procedures known in the
art.
[0043] The term "pharmaceutically acceptable buffer" when used
herein refers to conventional buffers heretofore used in aqueous
pharmaceutical compositions which are able to resist a change in pH
when H.sup.+ or OH.sup.- is added. A buffering agent can be a
single compound or a combination of compounds. Examples
pharmaceutically acceptable buffers include, without limitation,
solutions of sodium phosphate, potassium phosphate, disodium
hydrogenphosphate, dipotassium hydrogen phosphate, sodium
dihydrogen phosphate, potassium dihydrogen phosphate, phosphoric
acid, for example, phosphate buffered saline. A preferred buffer is
sodium phosphate.
[0044] The term "about" when used before a numerical value
indicates that the value may vary within reasonable range, such as
.+-.10%, .+-.5%, and .+-.1%.
[0045] The term "remove", "removal", "reduce" or "reduction" of a
localized subcutaneous fat deposit means to decrease the size,
volume, or thickness of the fat deposit.
[0046] The term "cosmetic" as it relates to fat deposit refers to
fat deposits which are neither pathological in nature nor which
form a solid mass capable of growth such as lipomas which can grow
to as large as 10 centimeters in diameter. Such cosmetic conditions
are viewed by the patient as merely unsightly and not disease
related. Included in the cosmetic conditions are fat deposits in
the submental area resulting in a "double chin". That is to say a
subcutaneous fat deposit around the neck that sags down and creates
a wrinkle, making the owner appear to have a second chin. Other
subcutaneous fat deposits which are cosmetic in nature include fat
accumulations in the lower eyelid, under the arm, on the waist,
hips and other cosmetic areas.
[0047] The term "subject" refers to a human who is desired to
reduce his or her localized fat from a specific area, for example
under the chin.
Methods
[0048] Various embodiments of the present disclosure provide
methods for decreasing submental fat deposit under a skin area in a
human subject, for enhancing the cosmetic appearance of a human
patient, or for providing a facial cosmetic benefit to a human
subject. In one embodiment, such methods are non-surgical and do
not include liposuction.
[0049] The submental fat deposit treated by the methods of this
disclosure, in one aspect, is cosmetically unappealing but is
non-pathological and the reduction of it is to improve the
appearance of the subject, for example, by reducing the appearance
of a double chin.
[0050] One embodiment of the present disclosure provides a
non-surgical method for the reduction of submental fat in a
subject, said method comprising a plurality of subcutaneous
injections of a solution of deoxycholic acid or a salt thereof into
said submental fat, each injection of said plurality administering
about 0.1 mg to about 0.2 mg of said deoxycholic acid or salt
thereof per square centimeter of the skin area over said submental
fat.
[0051] In alternative embodiments, each rejection comprises at
least about 0.11, or 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18 or
0.19 mg of the deoxycholic acid or salt thereof per square
centimeter of the skin area. In another embodiment, each rejection
comprises no more than about 0.19, 0.18, 0.17, 0.16, 0.15, 0.14,
0.13, 0.12 or 0.11 mg of the deoxycholic acid or salt thereof per
square centimeter of the skin area.
[0052] In some aspects, the sites for injection are at least about
1 cm apart from each other. In alternative embodiments, such
distance is from about 0.9 cm to about 1.1 cm, or from about 0.8 cm
to about 1.2 cm, from about 0.7 cm to about 1.3 cm, from about 0.6
cm to about 1.4 cm, or from about 0.5 cm to about 1.5 cm.
[0053] In one embodiment, provided is a method for decreasing a
submental fat deposit under a skin area in a human subject, which
method comprises local injection to the submental fat deposit,
through a plurality of spots on the skin area, a composition
comprising an effective amount of deoxycholate or a salt thereof,
wherein the effective amount is from about 0.01 mg to about 1 mg
per square centimeter of the skin area.
[0054] In some aspects, the composition that comprises deoxycholate
of a salt thereof is also referred to as a "deoxycholate
composition," more details of which are provided in this disclosure
below.
[0055] In one aspect, the effective amount is at least about 0.02,
0.05, 0.1, 0.15, 0.2, 0.3, 0.4, 0.5 or 1 mg per square centimeter
of the skin area. In another aspect, the effective amount if no
more than about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1 mg
per square centimeter of the skin area.
[0056] In one aspect, the plurality of spots are substantially
evenly distributed on the skin area. The term "substantially
evenly" as used here, refers to spots in an area where there are
substantially the same number of spots per unit of area. In one
aspect, a number is substantially the same as another number is
they are with about 5% or 10%, or 15% or 20%, or 25%
difference.
[0057] In another aspect, each spot is from about 0.8 cm to about
1.2 cm distant from an adjacent spot. In yet another aspect, each
spot is from about 0.9 cm to about 1.1 cm distant from an adjacent
spot. In still another aspect, each spot is about 1 cm distant from
an adjacent spot.
[0058] In some aspects, the plurality of spots comprises at least
20 spots, or alternatively at least 25, 30, 35, 40, 45, 50, 55, 60,
70, 80, 90, or 100 spots. In some aspects, the plurality of spots
consists of no more than about 100, 90, 80, 70, 60, 50, 45, 40, 35,
30, or 25 spots. In a particular aspect, the plurality of spots
consists of from about 40 to about 60 spots, or about 50 spots.
[0059] In one aspect, each spot receives from about 0.005 mL to
about 0.1 mL of the composition. In an alternative aspect, each
spot receives from about 0.01 mL to about 0.05 mL, or alternatively
from about 0.01 to about 0.03, or from about 0.015 to about 0.025
mL of the composition. In a particular aspect, each spot receives
from about 0.02 mL of the composition.
[0060] In another embodiment, the present disclosure provides a
method for decreasing a submental fat deposit in a human subject
which method comprises, measuring the thickness of the submental
fat deposit to be decreased; marking, on skin proximate to the
submental fat deposit, a grid comprising a plurality of spots, each
of which is from about 0.8 cm to about 1.2 cm distant from an
adjacent spot of the grid; and injecting, with a suitable needle,
through each of the plurality of spots, into about half way into
the submental fat deposit, an effective amount of a composition
comprising from about 0.5% to about 1% (w/w) of a salt of
deoxycholate, wherein each injection constitutes delivery of from
about 0.1 mL to about 0.3 mL of the composition.
[0061] In one aspect, the thickness of the submental fat deposit is
measured with magnetic resonance imaging (MRI) or by a caliper.
[0062] In one aspect, the needle is positioned about half-way
through the fat deposit before the injection is initiated. In
another aspect, the needle has a length that is about half of the
thickness.
[0063] In some aspects, the grid comprises at least 20 spots, or
alternatively at least 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90,
or 100 spots. In some aspects, the grid comprises no more than
about 100, 90, 80, 70, 60, 50, 45, 40, 35, 30, or 25 spots. In a
particular aspect, the grid comprises from about 40 to about 60
spots, or about 50 spots.
[0064] In some aspects, the grid is marked by applying a tattoo,
printed with the grid, as illustrated in FIG. 25, to the skin.
[0065] In one aspect, the steps of marking and injecting are
repeated for at least 3 times. In another aspect, steps of marking
and injecting are repeated for 4 times. In another aspect, steps of
marking and injecting are repeated for 6 times. In another aspect,
steps of marking and injecting are repeated for 7, or 8 or 9 times.
In some of the above aspects, each repeat is from about 3 days to
about 7 days, or about 6 days, or about 5 days, or about 4 days
apart.
[0066] In some aspects, the methods further comprise pretreating
the area around the injection sites with a local anesthetic.
[0067] In any of the above embodiments, the methods can further
include steps of ascertaining the effectiveness of the method. In
one aspect, the steps include, before and after the treatment,
identifying a first score and a second score, respectively, for the
localized submental deposit, using a score card comprising a
plurality of images each depicting a localized submental deposit of
a different size and determining that the therapy is effective in
reducing the localized submental deposit if the second score
differs from the first score in a direction reflecting a reduction
in size of the localized submental deposit.
[0068] Also provided, in one embodiment, is a method for
ascertaining the effectiveness of a therapy for reducing a
localized submental deposit in a patient, which method comprises
identifying a first score for a localized submental deposit in a
patient, using a score card comprising a plurality of images each
depicting a localized submental deposit of a different size;
administering to the patient a therapy; identifying a second score
for the submental deposit in the patient using the score card; and
determining that the therapy is effective in reducing the localized
submental deposit if the second score differs from the first score
in a direction reflecting a reduction in size of the localized
submental deposit.
[0069] Still also provided, in one embodiment, is a method for
reducing a localized submental deposit in a patient, which method
comprises: identifying a score for a localized submental deposit in
a patient, using a score card comprising a plurality of images each
depicting a localized submental deposit of a different size; and
administering to the patient an effective amount of a therapy for
reducing a localized submental deposit, wherein the amount of the
therapy is determined on the score.
[0070] In one aspect, the localized fat is reduced by at least 10%
of the volume, or by at least 10% of its thickness, as determined
by MRI or by caliper measurement. The % of the volume reduction is
determined by substracting the volume after treatment (volume after
treatment: Vf) and that of the baseline (initial volume or volume
before treatment: Vi), divided by Vi and multiplied by 100.
Similarly the % of the thickness reduction is determined by
subtracting the thickness after treatment (thickness after
treatment: Tf) and that of the baseline (initial volume or volume
before treatment: Ti), divided by Ti and multiplied by 100. As an
example to determine percentage reduction in volume, if Vi is
6346.8 cc, Vf is 5376.6 cc, then the volume is reduced by 18%.
Similarly to determine percentage reduction in thickness, if Ti is
17.2 mm, Tf is 14.1 mm, then the thickness is reduced by 15%. In
another aspect, the lessening of the double chin appearance can be
determined by CR-SMFRS, RS-SMFRS, or PRSMFIS, or combinations
thereof, using the CR-SMF scale, which is copyrighted by Kythera
Pharmaceuticals, Inc., incorporated herein by reference. The
lessening of the double chin appearance may be determined by the
improvement in the degree of the submental convexity of the area
under the chin as described in the CR-SMF scale. The double chin
appearance is improved when the CR-SMFRS is determined to be
changed by at least 1 grade (for example, from grade 3, which is
prior to treatment, to grade 2 after treatment).
[0071] In some embodiments, the reduction of submental fat enhances
the facial appearance of said subject. In one aspect, the enhanced
facial appearance is due to the reduced appearance or the lack of
the double-chin display.
[0072] In one aspect of any of the above embodiment, the reduction
is determined by at least a physical measurement and/or reading
from a scale. In one aspect, the physical measurement comprises MRI
and/or caliper.
[0073] In one aspect, the submental fat is reduced in thickness
and/or volume as determined by MRI.
[0074] In some aspects, the thickness and/or volume is reduced by
at least about 10%, or by at least about 15%, 20%, 25%, 30%, 35%,
40%, 45%, or 50%.
[0075] In one aspect, the scale is selected from the group
consisting of: CR-SMFRS, RS-SMFRS, PRSMFIS, and any combinations
thereof.
[0076] In one aspect, the facial appearance is enhanced by at least
1 grade, or at least 2 grades. In some aspects, the facial
appearance is enhanced by at least 1 grade or 2 grades, as
determined by CR-SMFRS.
[0077] In one aspect, the enhancement is achieved within 8 weeks
from the injection. In some aspects, the enhancement is achieved
within about 12, 11, 10, 9, 7, 6 or 5 weeks from the injection.
[0078] In one aspect, the facial appearance is enhanced by at least
2 grades, as determined by CR-SMFRS. The CR-SMFRS can be
determined, for instance, with a score card as shown in FIG. 3 and
further described below.
[0079] In any of the above embodiments, the volume for each
injection is about 0.1 ml to about 0.2 ml.
[0080] In one aspect, the deoxycholic acid or salt thereof is in an
aqueous solution buffered at a pH of between about 8.0 and about
8.5.
[0081] In some aspects, the total of said deoxycholic acid or salt
thereof administered is between about 50 mg to about 100 mg, or
from about 60 mg, 70 mg to about 90 mg, 80 mg, without
limitation.
[0082] In one aspect, the treatment is performed in a plurality of
visits by the subject, the plurality of visits are according to the
schedule shown in FIG. 2.
[0083] The deoxycholic acid, in some aspects, is biologically
derived or de novo synthesized. In one aspect, the deoxycholic acid
is animal derived. In another aspect, the deoxycholic acid is de
novo synthesized and wherein the solution comprising thereof is
free of primary bile acids and/or other secondary bile acids. In
another aspect, the primary bile acid is cholic acid. In some
aspects, the solution further comprises benzyl alcohol at a
concentration of about 0.8% to about 1%.
[0084] In some aspects, the method comprises co-administering an
agent selected from the group consisting of: anesthetic,
anti-microbial agents, vasoconstrictors, anti-thrombotic agents,
anti-coagulation agents, suds-depressants, anti-inflammatory
agents, analgesics, dispersion agents, anti-dispersion agents,
penetration enhancers, steroids, tranquilizers, muscle relaxants,
and anti-diarrhea agents, or any combinations thereof. In one
aspect, the co-administering is prior to, at the same time, or
following the said plurality of injection.
[0085] In one aspect, the injection further comprises a lipase. In
another aspect, the injection further comprises a phospholipid. In
yet another aspect, the phospholipid comprises
phosphatidylcholine.
[0086] The ratio of the deoxycholic acid or salt thereof and the
phosphatidylcholine, in one aspect, is about 1:0.005, about 1:0.05,
or about 1:0.5.
Score Cards
[0087] Score cards, as illustrated in FIG. 3, are provided in the
present disclosure. Such score cards are useful for evaluating the
treatment effects and/or provide basis for determining treatment
schedule.
[0088] In one embodiment, the present disclosure provides a score
card for measuring the effectiveness of a therapy for reducing a
localized submental deposit in a patient, which score card
comprises a plurality of images, each image depicting a subject
showing a localized submental deposit of a different size, wherein
each image is annotated with a score indicating the size of the
localized submental deposit.
[0089] In some aspects, the score card in an electronic form or a
printed form. Exemplary images on the score card include, without
limitation, photographs, magnetic resonance images or sketches.
[0090] In one aspect, the score card comprises, for each score, two
of more images showing the localized submental deposit of the
corresponding size, each from a different angle and/or from a
different subject.
[0091] In another aspect, the score card comprises 4, 5, 6, or 7
different scores, each being an integer. In some aspects, the score
card also includes a descriptive text for each score.
[0092] A particular embodiment of the present disclosure provides a
score card for measuring the effectiveness of a therapy for
reducing a localized submental deposit in a patient, which score
card comprises from 4 to 6 groups of images, wherein each group is
annotated with a score indicating the size of a localized submental
deposit, each images depicts a subject showing a localized
submental deposit, and the localized submental deposits shown in
each group correspond to the score of the group, wherein each image
in each group shows the localized submental deposit from a
different angle and/or from a different subject.
Kits
[0093] Kits are also provided, which can facilitate treatment
methods of the present disclosure in a clinical setting, without
limitation. In one aspect, the kit includes a tattoo configured to
mark a grid on a skin, the grid comprising a plurality of spots,
each of which is from about 0.8 cm to about 1.2 cm from a closest
spot of the grid; an effective amount of a composition comprising
from about 0.5% to about 1% (w/v) of a salt of deoxycholate; and a
plurality of syringes and needles.
[0094] In some aspects, the kits further include a score card of
the present disclosure.
Deoxycholate Compositions
[0095] In one embodiment, a deoxycholate composition comprises from
about 0.5 weight percent to less than 2 weight percent of a
pharmaceutically acceptable salt of deoxycholic acid and a
pharmaceutically acceptable excipient. In another aspect of the
embodiment, the composition comprises about 0.5 weight percent or
about 1 weight percent of sodium deoxycholate.
[0096] In another embodiment, the composition comprises from about
0.5 weight percent to less than 2 weight percent of a
pharmaceutically acceptable salt of deoxycholic acid, a
phospholipid at a concentration which is greater than, equal to, or
less than the concentration of the sodium deoxycholate and a
pharmaceutically acceptable excipient. For example, the mass ratio
of sodium deoxycholate and phospholipids may be 1:0.5, 1:0.05,
1.005, etc. In some embodiments, the concentration of the
phospholipids (e.g., phosphatidylcholine) in % w/v is less than the
concentration of % w/v of the detergent(s). For example, a
composition may have about 1% w/v sodium deoxycholate and less than
about 1% w/v phosphatidylcholine. Less than about 1% of
phosphatidylcholine includes about 0.9%, about 0.8%, about 0.7%,
about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about
0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about
0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, etc.,
including the range spanning between any aforementioned two
successive numbers.
[0097] In another aspect, the composition comprises either about
0.5 or 1 weight percent of a pharmaceutically acceptable salt of
deoxycholic acid and a buffer to maintain the pH at about 8 to
about 8.5.
[0098] In some embodiments, the composition comprises about 0.6%,
about 0.7%, about 0.8%, about 0.9% or about 1.0% w/w
(weight/weight), or w/v (weight/volume) of the salt of deoxycholic
acid. In one embodiment, the pharmaceutically acceptable salt of
deoxycholic acid is the sodium salt.
[0099] In some embodiments, the composition used in the methods of
this disclosure is essentially free of phosphatidylcholine. The
term "essentially free of phosphatidylcholine" refers to less than
1% w/w of phosphatidylcholine in the composition, or less than 0.5%
w/w. In some embodiments, the composition is free of
phosphatidylcholine.
[0100] In some embodiments, the deoxycholic acid or the
pharmaceutically acceptable salt thereof is synthetic. Each of U.S.
Patent Application Publication Nos. 2008/0318870 and 2009/0270642,
U.S. Provisional Patent Application No. 61/303,816, as well as
International Patent Application No. PCT/US10/61150 describes
procedures of preparing synthetic deoxycholic acid or a
pharmaceutically acceptable salt thereof, are incorporated by
reference in their entirety.
[0101] In some embodiments, the synthetic deoxycholic acid or the
pharmaceutically acceptable salt thereof has a purity of at least
99%. U.S. Provisional Patent Application No. 61/288,132 as well as
International Patent Application No. PCT/US10/61150, which
discloses methods of preparing synthetic deoxycholic acid or a
pharmaceutically acceptable salt having a purity of at least 99%,
is incorporated by reference in its entirety.
[0102] In some embodiments, the composition used in the methods of
this disclosure further comprises benzyl alcohol. In some
embodiments, the benzyl alcohol is about 0.8 to about 1% w/w. In
some embodiments, the concentration of benzyl alcohol is about 0.9%
w/w.
[0103] In some embodiments, the composition used in the methods of
this disclosure further comprises an effective amount of a
pharmaceutically acceptable buffer to maintain the pH of the
composition at about 8 to 8.5, for example, 8.3. In some
embodiments, the buffer is phosphate buffered saline.
[0104] In some embodiments, the composition used in the methods of
this disclosure a composition comprises either about 0.5 or about 1
weight percent of sodium deoxycholate, about 0.8 to 1 weight
percent benzyl alcohol and an effective amount of a
pharmaceutically acceptable buffer to maintain the pH of the
composition at about 8 to 8.5, wherein said composition is
essentially free of phosphatidyl choline.
[0105] In some embodiments, the compositions can further comprise a
second therapeutic agent selected from the group consisting of:
anti-microbial agents, vasoconstrictors, anti-thrombotic agents,
anti-coagulation agents, suds-depressants, anti-inflammatory
agents, analgesics, dispersion agents, anti-dispersion agents,
penetration enhancers, steroids, tranquilizers, muscle relaxants,
and anti-diarrhea agents.
[0106] The composition is an injectable solution and comprises a
pharmaceutically acceptable excipient which is an aqueous carrier,
examples of which include water, saline, aqueous dextrose.
[0107] In some embodiments, the composition is in a container that
contains up to 500 mL of solution. Such container can be a syringe
or syringe-loadable container.
Unit Doses
[0108] In another aspect, this invention provides a unit dose of a
composition for non-surgical, in particular, cosmetic, reduction of
a localized subcutaneous fat deposit in a patient having such a
deposit and desiring to reduce such a deposit, which unit dose
comprises about 25 mL of a sterile aqueous solution containing
either about 0.5% or about 1% w/w of a salt of deoxycholic acid. In
some embodiments, the aqueous solution is a composition as
described above. The total dosage for a treatment according to the
instant invention is between 200 mg to about 1000 mg of sodium
deoxycholate, in particular, about 200 mg, about 250 mg, about 300
mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about
550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg,
about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000
mg.
[0109] It is understood that the unit dose represents the maximum
amount of the composition to be injected in a single treatment
regimen using multiple injections. That is to say that if a single
treatment regimen constitutes 50 injections with each injection
being limited to 0.2 mL of the aqueous composition then the unit
dose is 10 mL of the composition. In a preferred embodiment, the
unit dose is the amount of the composition maintained in a single
container such as a vial or a syringe.
[0110] In some embodiments, the unit dose is an aqueous composition
of sodium deoxycholate.
[0111] In some embodiments, the unit dose is repeatedly
administered in treatment sessions to the patient until the desired
reduction in subcutaneous fat is reached. In some embodiments, 4, 5
or 6 treatment sessions can be conducted during a 4 week period
which may be varied with plus or minus 5 days.
[0112] In some embodiments, the unit dose is contained in a syringe
for a single subcutaneous injection.
EXPERIMENTAL EXAMPLES
Example 1
[0113] This example presents in vitro and in vivo studies showing
that sodium deoxycholate solutions, at a concentration at or above
0.5% and below 2%, are both effective and safe in inducing fat cell
necrosis resulting in reduced fat accumulation.
[0114] In vitro studies indicated that 0.25% w/v sodium
deoxycholate is the minimal concentration at which micelle
formation was observed. When secreted into the small intestine,
bile acids form micelles with dietary fats to aid in lipolysis and
lipid absorption.
[0115] Data from an in vivo Zucker rats and clinical studies that
employed doses of 0.5% and 1.0% w/v DCA determined that these
concentrations were effective, while doses at and below 0.25% are
no different than vehicle (FIG. 1). In the rats study, 8 rats
received a single injection into the caudal lateral fat pads of 2.5
mL deoxycholic acid at 1%, 0.5%, 0.25%, or 0.1% concentrations, or
2.5 mL vehicle (0.9% benzyl alcohol in water). Examination of the
fat pads showed that when necrosis occurred, it was through the
entire fat pad and was visible on the back (non-skin) side. The
data from this study show that 1.0% deoxycholic acid caused
approximately 2.5 times more necrosis than 0.5%, and that the
deoxycholic acid concentrations that were below the critical level
to form micelles (.ltoreq.0.25%) did not result in fat
necrosis.
[0116] Concentrations of 2.0% and 4.0% were shown by clinical trial
to be associated with marked necrosis, resulting in lipid lake
formation and vessel damage, which might reduce or delay macrophage
and fibroblast migration into the necrotic tissue. The observed
histological changes may explain the decreased efficacy with the
higher concentrations of deoxycholic acid (2.0% and 4.0%) at the
earlier time points. These findings are consistent with the
increased intensity of adverse effects at the higher concentrations
and larger volumes administered (0.4 mL/injection) in clinical
trials. In contrast, a better clinical efficacy and safety profile
was observed at the lower concentrations (0.5% and 1.0%), which may
be attributed to the more rapid resolution of the histological
changes. Concentrations at or below 0.25% were not tested, as they
are at or below the concentration necessary to form micelles. The
formation of micelles is essential for lipolytic activity.
Example 2
[0117] This example present the procedure and results of a clinical
study, showing that sodium deoxycholate solutions, at a
concentration at or above 0.5% and below 2%, demonstrated superior
results, in removing submental fat deposits in human patients, as
compared to concentrations beyond this range.
[0118] A clinical study was conducted to evaluate the effectiveness
of various doses of sodium deoxycholate in removing undesired
submental fat (SMF) deposits. A multicenter, randomized,
double-blind, placebo-controlled, parallel-group comparison of 3
concentrations of sodium deoxycholate (0.5, 1.0, and 2.0 percent
w/v) in sterile water with 0.9% benzyl alcohol and placebo was
conducted to determine the efficacy of reduction in SMF deposits.
Placebo injection consisted of sterile water with 0.9% benzyl
alcohol.
[0119] All subjects were to have up to 4 treatment sessions at
intervals of no less than 4 weeks (.+-.3 days) between
treatments.
[0120] Eligible subjects were concurrently randomized into one of
the following groups: [0121] Placebo injected every 4 weeks for up
to 4 treatments [0122] 0.5% w/v sodium deoxycholate injected every
4 weeks for up to 4 treatments [0123] 1.0% w/v sodium deoxycholate
injected every 4 weeks for up to 4 treatments [0124] 2.0% w/v
sodium deoxycholate injected every 4 weeks for up to 4
treatments
[0125] 85 subjects were randomized: 21 subjects to the 0.5% w/v
sodium deoxycholate group, 20 subjects to the 1.0% w/v sodium
deoxycholate group; 22 subjects to the 2.0% w/v sodium deoxycholate
(DCA) group; and 22 subjects to the placebo group. 73 subjects
completed the study.
[0126] Subject selection included males or non-pregnant,
non-lactating females aged 25 to 65 years, inclusive, on the date
of randomization, with SMF that was considered undesirable by the
subject and graded by the investigator as 2 or 3 using the SMF
rating scale, and a history of maintenance of a stable body weight,
in the judgment of the investigator, for at least 6 months before
randomization.
[0127] The baseline SMF rating scale score was similar across all
treatment groups. At week 16, changes from the baseline were
observed for all treatment groups, including placebo. The ANCOVA
(parametric analysis of covariance) analysis showed that the change
from baseline at week 16 compared to placebo in SMF rating scale
score was statistically significant for the 0.5% w/v DCA (P=0.043;
95% CI for least squares mean [LSM] difference: -0.9, 0.0) and for
1% w/v DCA (P=0.050; 95% CI for LSM difference: -0.8, 0.0) treated
groups but not for the 2% w/v DCA treated group.
[0128] Through repeated numerous analysis, the changes from
baseline in SMF rating scale score compared to placebo were found
to statistically significant at weeks 8, 12, 16 and 24 for the 0.5%
w/v DCA. Statistically significant improvements were seen at weeks
12, 16 and 24 for the 1.0% w/v DCA. Whereas, statistically
significant improvements were seen only at week 24 for the 2% w/v
DCA all compared against placebo (FIGS. 23 and 24). Therefore,
these data show that ATX-101 at 2.0% was less effective than
ATX-101 1.0% or 0.5%, as measured by various visual assessment
methods.
[0129] The data demonstrate that at concentrations at or greater
than about 0.5% w/v and less than 2% w/v, unexpectedly superior
results are obtained for both efficacy and toxicity (the latter
being appropriate only for concentrations at or above 2% w/v) as
compared to the results obtained at concentrations above and below
this range.
Example 3
[0130] This example presents a phase II clinical study
demonstrating that, in addition to the appropriate concentrations
of sodium deoxycholate, a particular set of clinical treatment
protocol showed particular benefit to the patients.
[0131] A clinical study was conducted to evaluate the effectiveness
of various doses of sodium deoxycholate in removing undesired
submental fat (SMF) deposits. This clinical study was multicenter,
randomized, double-blind, placebo-controlled study of sodium
deoxycholate injection ("SDI" or alternatively "ATX-101") versus
placebo for the reduction of localized subcutaneous fat in the
submental area (SMF) using magnetic resonance imaging (MRI) and a
battery of clinician- and subject-reported measurements.
[0132] A total of 274 subjects participated in 6 Phase 1/2 clinical
studies that were conducted with SDI. Of these, 3 studies (n=179)
evaluated SDI for the treatment of submental fat (SMF). Two studies
evaluated SDI for the treatment of superficial lipoma. One study
(SDI-08-10) evaluated the histological effects of SDI in
subcutaneous abdominal tissue in subjects scheduled to undergo
abdominoplasty.
[0133] SDI was safe and well tolerated at all concentrations in
clinical studies. Adverse events from SDI have not been systemic
and have generally involved local, transient injection site
reactions of mild to moderate intensity. The most commonly observed
adverse events associated with the treatment area include pain,
erythema, induration, swelling, bruising, and numbness. Less
frequently, pruritus and paresthesia have been reported. Across
studies, the 0.5% and 1.0% concentrations demonstrated a better
safety profile than the higher concentrations (2.0% and 4.0%). The
pharmacokinetics of SDI is linear, illustrating the predictable
overall exposure. Plasma concentrations were transient with peak
concentrations observed at approximately 15 to 30 minutes,
returning to endogenous deoxycholate levels within 24 hours after
dosing.
[0134] The SMF scale used to assess efficacy in clinical studies
with SDI has been validated and shown to be reliable. Changes in
scores from the Clinician Reported-SMF Rating Scale (CR-SMFRS) and
Patient Reported-Subject Satisfaction Rating Scale (PR-SSRS)
demonstrate that patients respond to therapy. The expected
improvement from treatment with SDI is consistent with what
patients who desire aesthetic changes would find satisfactory. In
clinical studies that evaluated SDI for the treatment of submental
fat, changes in SMFRS score at Week 16 and SSRS scores for the
doses selected for evaluation in this study (0.5% [0.2 mL/1.0 cm]
and 1.0% [0.2 mL/1.0 cm]) were significantly better than placebo.
Both treatment regimens also showed a significant change in SMFRS
score compared to placebo prior to Week 16.
[0135] Study Design:
[0136] FIG. 2 depicts the study Design and Treatment Schema
associated with this procedure. This was a multicenter, randomized,
double-blind, placebo-controlled study in which approximately 120
subjects received either up to 50 mg SDI, up to 100 mg SDI, or
placebo in a 1:1:1 ratio (5 mg/mL:10 mg/mL:placebo) as indicated
below, to evaluate the safety and efficacy of fixed concentrations
of SDI given in up to 50 0.2-mL injections in up to 6 treatment
sessions. No subject received more than 10 mL in any treatment
session, nor did any subject undergo more than 6 treatment
sessions. The initial 30 subjects were enrolled in a 2:2:1 ratio
(i.e., 12, 12 and 6 subjects per group, for the two SDI groups and
placebo, respectively) and the remaining subjects were randomized
to balance the enrollment (approximately 28, 28, and 34 per group
for the two SDI groups and placebo, respectively). This resulted in
a distribution of approximately 40 subjects per treatment
group.
[0137] All qualified subjects had a baseline MRI completed during
the screening period to evaluate pre-treatment SMF volume and
thickness. To measure changes in SMF volume and thickness, MRI
acquisitions were repeated prior to each treatment session and
post-treatment (4 and 12 weeks after the last treatment cycle).
Before subjects completed each MRI visit, the MRI images were
evaluated for acceptability.
[0138] The groups were dosed as in Table 1.
TABLE-US-00001 TABLE 1 Dosage # of Distance Between Amount per # of
Treatment Injections Injections Injection Subjects Placebo Up to 50
Approximately 1.0 cm 0.2 mL 40 apart SDI Up to 50 Approximately 1.0
cm 0.2 mL 40 (5 mg/mL) apart SDI Up to 50 Approximately 1.0 cm 0.2
mL 40 (10 mg/mL) apart
[0139] Subjects who successfully completed screening and baseline
evaluations received up to 50 injections (0.2 mL each for a maximum
volume of 10 mL) per treatment session, depending upon size and
configuration of the SMF. Treatment was given at 4-week (.+-.5
days) intervals. Study material injection sites were positioned
using a 1.0 cm grid, which is designed to achieve an appropriate
distribution of injections across the submental area.
[0140] Study Material, Dose, and Route of Administration:
[0141] SDI (sodium deoxycholate injection) was provided in a
concentration of 5 mg/mL (0.5%) and 10 mg/mL (1.0%) in 10 mM sodium
phosphate, 0.9% (weight per volume [w/v]) sodium chloride, and 0.9%
(w/v) benzyl alcohol in water for injection (WFI). Each vial (for
single use only) contained at least 2.0 mL of accessible material,
accessed by means of sterile syringe and needle through a rubber
stopper closure.
[0142] Matching placebo consists of the vehicle formulation (10 mM
sodium phosphate, 0.9% [w/v] sodium chloride, and 0.9% [w/v] benzyl
alcohol in WFI).
[0143] Packaging:
[0144] Study material (SDI 0.5%, SDI 1.0%, and placebo) was
provided in subject treatment kits. Each subject treatment kit
contained a sufficient number of vials of study material (SDI or
placebo) to administer all required doses for the study (i.e., each
kit had enough vials for 6 treatment sessions).
[0145] Evaluation of Safety:
[0146] The safety of 5 mg/mL SDI and 10 mg/mL SDI transcutaneous
injections in the submental area was evaluated relative to placebo
by assessing the spontaneous adverse event reports, clinical
evaluation of the submental area, and laboratory test results. The
criteria for the safety evaluation included: spontaneously reported
adverse events, laboratory test results, treatment area evaluations
including scoring of edema, bruising, dysphasia, dysphonia,
erythema, hyperpigmentation, hypopigmentation, induration,
numbness, pain, paresthesias, and pruritus.
[0147] Evaluation of Efficacy:
[0148] The effects of 5 mg/mL SDI and 10 mg/mL SDI transcutaneous
injections in the submental area were evaluated relative to placebo
by measuring the following: (1) the reduction of fat using
Clinician-Reported Submental Fat Rating Scale (CR-SMFRS),
Patient-Reported Submental Fat Rating Scale (PR-SMFRS), and
Patient-Reported Submental Fat Impact Scale (PR-SMFIS); (2) the
volume of SMF using MRI; and (3) the thickness of SMF using MRI.
The efficacy evaluation criteria included: Clinician-Reported
Submental Fat Rating Scale (CR-SMFRS), Patient-Reported Submental
Fat Rating Scale (PR-SMFRS), Patient-Reported Submental Fat Impact
Scale (PR-SMFIS) scores, and Magnetic resonance imaging (MRI).
[0149] Other Evaluations:
[0150] The effects of 5 mg/mL SDI and 10 mg/mL SDI transcutaneous
injections in the submental area, relative to placebo, for changes
in skin laxity (SLRS), Subject Self Rating Scale (SSRS), and
subject-reported outcome measures (Self-Ratings of Attractiveness,
Derriford Appearance Scale [DAS], Body Image Quality of Life
Inventory [BIQLI]), other Subject-Reported Questions, and
Post-treatment Questions) were evaluated. Measurements of the
thickness of fat in the submental area were made using calipers.
Photographs were taken to document treatment effects. Other
criteria for evaluation included: Skin Laxity Rating Scale (SLRS)
scores, Subject Self Rating Scale (SSRS) score, Subject-reported
outcome measures (Self-Ratings of Attractiveness, Derriford
Appearance Scale [DAS], Body Image Quality of Life Inventory
[BIQLI]), other Subject-Reported Questions, Subject Global
Questions and Post-treatment Questions.
[0151] Treatment Procedures:
[0152] During the screening period, subjects completed all
eligibility requirements and otherwise qualify for enrollment,
before the baseline MRI is acquired. The baseline MRI was completed
before the first treatment was administered at the baseline visit
(Week 0). Subjects who successfully completed screening and
baseline evaluations received up to 50 injections (0.2 mL each for
a maximum volume of 10 mL) per treatment session, depending on size
and configuration of the SMF. Treatment was given during up to 6
treatment sessions at 4-week (.+-.5 days) intervals. Injection
sites were positioned on a 1.0-cm grid.
[0153] Administration of Study Material: Eligible subjects were
randomized to 1 of 3 treatment groups in the order in which they
completed baseline evaluations: [0154] Placebo (vehicle): 0.2
mL/injection, up to 50 injections per treatment session [0155] SDI
5 mg/mL: 0.2 mL/injection, up to 50 injections per treatment
session [0156] SDI 10 mg/mL: 0.2 mL/injection, up to 50 injections
per treatment session
[0157] Dose preparation by authorized site personnel and
administration by the investigator is performed according to
instructions.
[0158] A 30-gauge, 0.5-inch needle attached to a 1-mL syringe was
used to administer study material. Injections were given
transcutaneously directly into the fat tissue.
[0159] Injection sites were positioned to achieve an appropriate
distribution of study material injections across the target
location. The following procedures or instruction of use were
provided for use with the administration of study material: [0160]
Topical anesthesia (i.e., topical lidocaine preparations, ice) may
be applied in the area of the planned injection sites and recorded
in the case report form (CRF). [0161] Up to 50 injections spaced
approximately 1.0 cm apart is given. A grid is applied to the
treatment area to guide the placement of injections. For each
treatment session, injections are given on a 1.0-cm grid pattern
across the submental area to be treated. The grid can be applied to
the chin of the patient using a tattoo as illustrated in FIG. 25.
[0162] For each study material injection, the investigator palpates
the treatment area to determine the approximate thickness of the
targeted SMF and inject study material into fat tissue at a depth
of approximately mid-way into the SMF. [0163] If at any time
resistance is met as the needle is inserted, indicating the
possibility of contact with fascial or nonfat tissue, the needle
will be withdrawn to an appropriate depth before the injection is
given. [0164] Upon needle withdrawal, pressure is applied to each
injection site for several seconds to minimize bleeding; an
adhesive dressing may be applied. Upon completion of the
injections, the area may be gently massaged to facilitate
distribution of study material. [0165] At each treatment session,
the investigator will determine the number and locations of
injections. He or she will evaluate each planned injection location
to avoid sites for which an injection may not be appropriate (e.g.,
nodule formation, significant residual inflammation, or lack of
SMF). If a sufficient number of locations are not suitable for
injection, the treatment session may be delayed for up to 28 days.
[0166] Subjects may be discharged from the research facility
approximately 60 minutes after study material is administered,
provided it is medically appropriate to do so. [0167] Concomitant
therapy: Throughout the study, investigators may prescribe any
concomitant medications or treatments deemed necessary, with the
exception of investigational drugs.
[0168] Submental Fat Assessments:
[0169] Submental fat ratings using the SMFRS were conducted at
screening, baseline, and Visits 3, 4, 5, 6, 7, 8, and 9.
[0170] The SMFRS score is based on the investigator's clinical
evaluation of the subject, including palpation of the chin and neck
area; anterior, oblique, and profile views of the chin and neck;
and observation of pronation, supination, and lateral movement of
the head. The score was determined using the rating scale
definitions and the representative photographs associated with each
score. The final score was determined while the subject's head is
in the Frankfort plane posture as described in the SMFRS. The score
was recorded as a whole number. At screening and baseline, the
score was determined in conjunction with protocol entry criteria
(e.g., absence of loose skin, diffuse SMF, and prominent platysmal
bands at rest that interfere with evaluation of localized fat).
[0171] Standardized photographs were taken before treatment
(baseline and Visits 3, 4, 5, 6, and 7), and post-treatment (Visits
8 and 9) to document treatment effects.
[0172] At Visit 9 measurements of the thickness of fat in the
submental area were made using calipers.
[0173] Clinician reported scores (Table 2) utilized a score card
(illustrated in FIG. 3) that shows representative photographs with
annotated scores. In this context, the acronym "CR-SMFRS"
(clinician-reported submental fat rating scale) is used
interchangeably with "SMFRS" (submental fat rating scale).
TABLE-US-00002 TABLE 2 Clinician-Reported Submental Fat Rating
Scale (CR-SMFRS) Score SMF Description 0 Absent Submental
Convexity: No localized submental fat evident. 1 Mild Submental
Convexity: Minimal, localized submental fat. 2 Moderate Submental
Convexity: Prominent, localized submental fat. 3 Severe Submental
Convexity: Marked, localized submental fat. 4 Extreme Submental
Convexity.
[0174] A separate score, Skin Laxity Rating Scale (SLRS), was based
on skin laxity assessment using on clinical evaluation and
palpation of the submental area (Table 3).
TABLE-US-00003 TABLE 3 Skin Laxity Rating Scale (SLRS) Score Skin
Laxity Rating 1 No Laxity 2 Minimal Laxity 3 Moderate Laxity 4 Very
Lax
[0175] Statistical Considerations:
[0176] The sample size of approximately 40 subjects per SDI
treatment group (5 mg/mL, 10 mg/mL) and approximately 40 subjects
(placebo) was determined based on clinical rather than statistical
considerations.
Results
[0177] As shown in FIG. 4, both ATX-101 1.0% and 0.5% achieved
marked reduction of submental fat as compared with placebo, in
which the reduction by ATX-101 1.0% was statistically significant
at most time points. Further, at week 16, 24 and 32, the numbers of
patients having at least 1-point improvement were greater in the
ATX-101 1.0% and 0.5% groups than in the placebo group (FIG.
5).
[0178] Similar results were reported by the self-assessment of the
patients (FIGS. 6 and 7) and by measurement of MRI (FIG. 8-11).
Likewise, assessments based on Patient Reported-Subject
Satisfaction Rating Scale (SSRS) (FIG. 12) and subject self-rating
of attractiveness (FIG. 13) confirmed the success of the treatments
using ATX-101 1.0% and 0.5%.
[0179] One of the self assessments was Patient Reported Submental
Fat Impact Scale (PRSMFIS). An illustrative questionnaire is shown
as follows (all questions follow a 0-10 point scale):
[0180] 1. How happy are you with the appearance of your chin
fat?
[0181] 2. How bothered are you by the appearance of your chin
fat?
[0182] 3. How self-conscious are you about the appearance of your
chin fat?
[0183] 4. How embarrassed are you about the appearance of your chin
fat?
[0184] 5. How much older do you look because of your chin fat?
[0185] 6. How much overweight do you look because of your chin
fat?
[0186] A statistically significant different (p<0.01) was
achieved for the ATX-101 1.0% on all measures at week 32.
[0187] Still another assessment, based on the following
questionnaire, showed a statistically significant different
(p<0.01) for both ATX-101 1.0% and 0.5% on all measures at week
32: [0188] 1. Since the start of the study, how would you rate the
fat under your chin right now? [0189] 2. Since the start of the
study, how would you rate the definition between your chin and neck
right now? [0190] 3. How satisfied are you with the treatment you
received in this study?
[0191] Each question followed a 7-point scale: a great deal worse,
moderately worse, a little worse, about the same, moderately
better, and a great deal better.
[0192] FIGS. 15 and 16 include representative MRI images, before
and after the treatment, for ATX-101 0.5% and 1.0%, respectively.
FIG. 14 shows the volume of study materials used in each treatment
group, at different time points.
[0193] FIG. 17 shows that patients receiving the treatments did not
have marked changes of their body mass index (BMI). Nevertheless,
using the BMI as a standard, ATX-101 treatments resulted in
significant submental fat reduction, as measured by CR-SMFRS (FIG.
18).
[0194] Likewise, the body weight of the patients did not undergo
obvious changes during the course of the treatments (FIG. 19), but
the CR-SMFRS/body weight ratio decreased significantly (FIGS. 20
and 21).
[0195] In terms of quality of treatment outcome assessment, FIG. 22
shows a good correlation between caliper measurement and MRI
evaluation.
[0196] In summary, as measured by CR-SMRFS, both ATX-101 1.0% and
0.5% showed good dose response, yet the 1.0% dose was more
effective than 0.5%. Statistically significance was obtained for
1-grade reduction for the 1.0% dose at week 16 and week 32.
[0197] Using PR-SMFRS, both ATX-101 1.0% and 0.5% also showed good
dose response, and the 1.0% dose was more effective than 0.5%.
Statistically significance was obtained for 1-grade reduction for
the 1.0% dose at week 16 and week 32, and 2-grade reduction for the
1.0% dose at week 32.
[0198] Determined by MRI, statistically significant reduction of
both MRI and thickness and volume was observed with both 0.5% and
1.0% doses, whereas 1.0% showed better dose response and greater
reduction.
[0199] Still in other measurements, statistically significant
changes, along with dose response, were observed for both doses, in
SSRS, in patient impact scores, in patient impact questionnaire,
and in improvement in appearance of the chin and satisfaction.
[0200] This example, therefore, shows the clinical efficacy of
ATX-101, at both 0.5% and 1.0% doses, as well as the benefit of the
clinical procedure. Moreover, this example further validates the
utility of various assessment methods employed here, including the
score card used by clinicians.
[0201] The embodiments and example described above are not intended
to limit the disclosure. It should be understood that numerous
modifications and variations are possible in accordance with the
principles of the present disclosure.
[0202] All publications, patent applications, patents, and other
references mentioned herein are expressly incorporated by reference
in their entirety, to the same extent as if each were incorporated
by reference individually. In case of conflict, the present
specification, including definitions, will control.
* * * * *