Injectable DaxibotulinumtoxinA for the Treatment of

Glabellar Lines: A Phase 2, Randomized, Dose-Ranging,

Double-Blind, Multicenter Comparison With
OnabotulinumtoxinA and Placebo
Jean Carruthers, MD,* Nowell Solish, MD,† Shannon Humphrey, MD,‡
Nathan Rosen, MD,xk Channy Muhn, MD,xk Vince Bertucci, MD,¶ Arthur Swift, MD,#
Andrei Metelitsa, MD,** Roman G. Rubio, MD,†† Jacob Waugh, MD,†† John Quiring, PhD,‡‡
Gill Shears, PhD,xx and Alastair Carruthers, MDkk

BACKGROUND Injectable daxibotulinumtoxinA (RT002) is an investigational botulinum toxin Type A in

clinical development. It is formulated with a proprietary peptide and offers the potential of a longer acting
neurotoxin therapy.

OBJECTIVE To compare the safety, efficacy, and duration of response of daxibotulinumtoxinA with
onabotulinumtoxinA and placebo [www.clinicaltrials.gov NCT02303002].

METHODS In this Phase 2, randomized, dose-ranging, parallel-group, double-blind, multicenter study, sub-
jects with moderate or severe glabellar lines at maximum frown were randomly assigned to 20U, 40U, or 60U
daxibotulinumtoxinA, 20U onabotulinumtoxinA, or placebo. Glabellar line severity was evaluated by inves-
tigators and subjects at least every 4 weeks, for at least 24 weeks.

RESULTS Overall, 268 subjects enrolled. Statistical and clinical superiority were observed for 40U and 60U
daxibotulinumtoxinA over 20U onabotulinumtoxinA for a range of efficacy outcomes despite the study not
being powered to detect statistically significant differences between these active treatment groups.

CONCLUSION The 40U dose of daxibotulinumtoxinA was well tolerated (e.g., absence of ptosis) and had the
most favorable risk: benefit profile. Compared with 20U onabotulinumtoxinA, it exhibited a significantly greater
response rate and a significantly longer duration of response (median of 24 weeks vs 19 weeks; p = .030).

Supported by Revance Therapeutics, Inc. J.D. Carruthers is a consultant and researcher for Revance, Allergan,
Merz, and Alphaeon. N. Solish received a grant from Revance for participating in this study and is a consultant
to Revance, Allergan, and Galderma. S. Humphrey has received research grants from Revance Therapeutics.
V. Bertucci is a consultant to, and receives payment for lectures, including service on speaker bureaux, from
Allergan, Galderma, and Merz. He is also an investigator for Allergan, Galderma, Alphaeon, Merz, and
Revance. A. Swift received an investigator fee from Revance Therapeutics, Inc. A. Metelitsa has been a con-
sultant for Galderma and Merz. R.G. Rubio is an employee of, and holder of stock/stock options in, Revance
Therapeutics, Inc. J. Waugh was an employee of, and held stock/stock options in, Revance Therapeutics, Inc.
J. Quiring is an employee of QST Consultations, Ltd., which has received fees from Revance Therapeutics, Inc.
for performing statistical analyses. G. Shears is an employee of Write on Target Ltd., which has received fees
from Revance Therapeutics, Inc. for medical writing services. A. Carruthers is a consultant and researcher for
Revance, Allergan, Merz, and Alphaeon. The remaining authors have indicated no significant interest with
commercial supporters. DaxibotulinumtoxinA is an investigational agent.

*Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia,
Canada; †Division of Dermatology, University of Toronto, Toronto, Ontario, Canada; ‡Department of Dermatology and
Skin Science, University of British Columbia, Vancouver, British Columbia, Canada; xFaculty of Medicine, McMaster
University, Hamilton, Ontario, Canada; kDermetics, Burlington, Ontario, Canada; ¶Division of Dermatology, University
of Toronto, Toronto, Ontario, Canada; #The Westmount Institute of Plastic Surgery, Montreal, Québec,
Canada; **Division of Dermatology, University of Calgary, Calgary, Alberta, Canada; ††Revance Therapeutics, Inc.,
Newark, California; ‡‡QST Consultations, Ltd., Allendale, Michigan; xxWrite on Target Ltd., Leighton Buzzard, United
Kingdom; kkFaculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

© 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.
· ·
ISSN: 1076-0512 Dermatol Surg 2017;0:1–11 DOI: 10.1097/DSS.0000000000001206

© 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 INJECTABLE DAXIBOTULINUMTOXINA
B otulinum toxin Type A has been widely used to
improve the appearance of glabellar lines since its
first approval in Canada in 2001 and the United States
in 2002. Three injectable formulations are now
approved in the United States and Canada for this
indication—onabotulinumtoxinA,
abobotulinumtoxinA, and incobotulinumtoxinA.
Injectable daxibotulinumtoxinA is in clinical
development.
Injectable daxibotulinumtoxinA is composed of
a purified 150 kDa botulinum toxin Type A (RTT150)
formulated without additives in a lyophilized powder
containing a proprietary peptide (RTP004).1 The
peptide is a single straight-chain peptide consisting of
a backbone and 2 protein transduction domains. The
backbone is a sequence of consecutive lysines, which
carry a positive charge and form an electrostatic bond
with daxibotulinumtoxinA. This results in the peptide
binding to the neurotoxin with high avidity. The
botulinum toxin is produced without using any animal
or human blood derivatives and contains no inactive
proteins.
Injectable daxibotulinumtoxinA has been observed to
prolong the duration of response in both the preclinical
and clinical settings. Results from animal studies have
confirmed that injectable daxibotulinumtoxinA exhibits
less diffusion than onabotulinumtoxinA2 and suggest
that it may offer a relatively greater degree and duration
of response at target sites.2 In a dose-escalation study,
98% of subjects treated with injectable
daxibotulinumtoxinA attained a reduction in glabellar
line severity at maximum frown at Week 4.3 The median
duration of response was evaluated in the group who had
received the highest dose (64U using the current potency
method or 100U with the method in use at the time) and
found to be 29.4 weeks.3 Injectable daxibotulinumtoxinA
was generally well tolerated and there was no evidence of
spread beyond the treatment area.
A Phase 2 study has now been performed to further
evaluate the efficacy, duration of response, and safety
and tolerability of injectable daxibotulinumtoxinA
in comparison with placebo and with
onabotulinumtoxinA.
2 DERMATOLOGIC SURGERY
© 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Methods
Study Design
The study was a randomized, dose-ranging, parallel-
group, double-blind, multicenter evaluation of inject-
able daxibotulinumtoxinA (20U, 40U, or 60U)
compared with onabotulinumtoxinA 20U and pla-
cebo. The protocol was approved by the relevant
institutional review boards and conformed to the
ethical guidelines of the Declaration of Helsinki. All
subjects provided written informed consent.
Subjects
Subjects eligible to enroll in the study were required to
have moderate or severe glabellar lines during maximum
frown according to both the Investigator Global
Assessment—Facial Wrinkle Severity (IGA-FWS) scale
and the Patient Facial Wrinkle Severity (PFWS) scale.
The subjects were also required to be 30 to 65 years of
age and to be willing to refrain from treatment with facial
fillers, lasers, and products that could affect skin
remodeling or cause an active dermal response in the
treatment area. They were not allowed to have a history
of a topical steroid on the treatment area, or any
immunosuppressants, in the previous 30 days; a pre-
scription retinoid in the treatment area during the pre-
vious 3 months; botulinum toxin Type A in the face in the
previous 6 months; or chemical peels of at least medium
depth during the previous 9 months. They were also not
allowed to have undergone any procedure that may
affect the glabellar region during the previous 12 months.
Treatment
Subjects were randomly assigned in an equal ratio to 5
groups: 20U, 40U, or 60U injectable
daxibotulinumtoxinA (RT002; Revance Therapeutics,
Inc., Newark, CA), 20U onabotulinumtoxinA (BOTOX
Cosmetic, Allergan, Inc., Irvine, CA), or placebo. All
treatments consisted of five 0.1 mL injections, 2 in each
corrugator muscle and one in the procerus muscle.
An independent statistician provided a randomiza-
tion scheme of treatment assignments for each study
site and subjects eligible for randomization were
given the next available subject number. The

assigned product was reconstituted by an unblinded
preparer and the masked product was provided to
the investigator in a syringe. The subjects, inves-
tigators, and other site staff remained blinded to the
treatment assignments.
The onabotulinumtoxinA 20U dose was prepared
from a 100U vial and reconstituted with 2.5 mL of
preservative free saline as per label, so that 0.5 mL of
product was present in the prepared syringe for
injection enabling a dose of 4U per 0.1 mL to be
administered per injection site. A serial dilution
technique using preservative free saline was used to
prepare the RT002 study treatments from a 160U
stock vial of lyophilized RT002, to arrive at 20U,
40U, or 60U per 0.5 mL in the prepared syringe for
injection.
Outcome Measures
In an effort to standardize the rating of wrinkle
severity across investigators, a set of training photo-
graphs exhibiting the grades of wrinkle severity was
used to train investigators how to assess the force of
muscular contraction using the IGA-FWS scale that
classifies wrinkle severity to be none (0), mild (1),
moderate (2), or severe (3). A photograph guide was
provided showing examples of none (no wrinkles),
mild (very shallow wrinkles), moderate (moderate
wrinkles), and severe (deep and furrowed wrinkles).
Subjects were evaluated for IGA-FWS score at least
every 4 weeks and if the score at maximum frown had
not yet returned to baseline at Week 24, evaluations
were continued every 4 weeks until this had occurred
(up to Week 36). One of the primary outcome meas-
ures was the proportion of responders at Week 24 (a
responder being a subject with at least a 1-point
improvement from baseline in glabellar severity at
maximum frown according to the IGA-FWS scale).
The median duration of response (time since injection
for at least a 1-point improvement in IGA-FWS score
to revert to baseline levels) was another primary out-
come measure.
Glabellar line severity was also evaluated by the sub-
jects at maximum frown using the PFWS. The PFWS is
similar to the IGA-FWS scale, with the following
© 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CARRUTHERS ET AL
descriptions for clarification: none = no wrinkles; mild
= very shallow wrinkles; moderate = moderate wrin-
kles; and severe = deep wrinkles.
Investigators and subjects evaluated the global
improvement in aesthetics at each postbaseline visit
using the Global Aesthetic Improvement Scale (GAIS)
(Table 1).
Statistical Analyses
A sample size of 50 in each group was planned to be
sufficient to detect statistical trending for the
difference between each active treatment group
and placebo in duration of response through 36
weeks of follow-up. The study was not
powered to detect statistically significant
differences between active treatment groups.
All statistical analyses were performed using
Statistical Analysis System (SAS) software, version
9.3 or higher, with all comparisons assessed at an
alpha level of 0.05 without adjusting for
multiplicity.
Between-group differences in the proportion of sub-
jects showing improvements from baseline or attain-
ing glabellar line severity of none or mild were
evaluated using the Cochran–Mantel–Haenszel test.
The median duration of response and 95% confidence
intervals were calculated using the Kaplan–Meier
method. The mean duration of response was estimated
using the area under the Kaplan–Meier curve. If no
response was attained by Week 4, the duration of
response was considered zero. Between-group differ-
ences in the duration of response were evaluated using
the log-rank test.
TABLE 1. Global Aesthetic Improvement Scale
(GAIS)
Rating Score Wrinkle Improvement
23 Very much worse
22 Much worse
21 Worse
0 No change
1 Improved
2 Much improved
3 Very much improved
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 INJECTABLE DAXIBOTULINUMTOXINA

Results IGA-FWS score at maximum frown was 100%,

Subjects
A total of 268 subjects were enrolled in 9 private
practice settings (experienced university-affiliated
clinical trial centers) in Canada and included in the
safety analyses. The first treatment was on
December 23, 2014 and the last visit was on
December 1, 2015.
Overall, 98% of subjects completed the study (3
discontinued from the placebo group and 2 from the
20U daxibotulinumtoxinA group due to subject
withdrawals or loss to follow-up). Per protocol
analyses required the exclusion of 77 subjects,
most of these (57/77) being attributable to the
Week 24 visit being more than 5 days off schedule
(Table 2).
Across the treatment groups, most subjects were
Caucasian (89%–95%) and women (76%–92%), and
their mean age ranged from 47 to 50 years. Baseline
characteristics were generally similar in each group,
although it should be noted that the 60U dax-
ibotulinumtoxinA group had a relatively greater pro-
portion of men and glabellar lines that investigators
rated as severe (Table 3).
100%, and 100% with daxibotulinumtoxinA
(20U, 40U, and 60U, respectively), 95% with
onabotulinumtoxinA, and 3% with placebo (p < .001
for all botulinum toxin groups vs placebo) (Figure
1 and Table 4). At Week 24, the corresponding
percentages were 18%, 36%, and 29% with
daxibotulinumtoxinA (20U, 40U, and 60U, respec-
tively), 19% with onabotulinumtoxinA, and 3% with
placebo (p < .05 for all botulinum toxin groups vs
placebo).
For both investigator and subject ratings of wrinkle
severity, greater efficacy was achieved with 60U,
and especially 40U, daxibotulinumtoxinA than
with 20U onabotulinumtoxinA—with statistical
superiority achieved at several time points (Figures
1 and 2; p < .05). Thus, for investigator ratings,
40U daxibotulinumtoxinA showed
statistically significantly greater efficacy than 20U
onabotulinumtoxinA at Weeks 8, 16, and 20
(Figure 1). And for subject ratings, 40U
daxibotulinumtoxinA showed statistically signifi-
cantly greater efficacy than 20U onabotuli-
numtoxinA at Weeks 12 and 16 (Figure 2). The 20U
daxibotulinumtoxinA group showed a smaller
trend toward greater efficacy relative to 20U
onabotulinumtoxinA.

Efficacy
All botulinum toxin groups were highly
effective—at Week 4, the proportion of
subjects with at least a 1-point improvement in the
Similar results were obtained with the other efficacy
measures (Figures 3–5). The proportion of subjects
with at least a 2-point improvement in IGA-FWS
score was higher with all doses of

TABLE 2. Subjects Excluded From Analyses

Placebo DaxibotulinumtoxinA OnabotulinumtoxinA

(N = 54) 20U (N = 54) 40U (N = 53) 60U (N = 53) 20U (N = 54)

Intent-to-treat population 0 0 0 0 0
and safety population
Per protocol population* 19 20 14 12 12
Week 24 off schedule 12 14 10 10 11
by $5 days
Use of prohibited medication 4 6 3 1 0
Missed Week 24 visit 3 1 0 1 0
Incorrect dose or treatment 0 0 1 0 1

*Subjects may have more than one reason for exclusion.

4 DERMATOLOGIC SURGERY

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 CARRUTHERS ET AL

TABLE 3. Subject Characteristics at Baseline (per Protocol Population)

Placebo DaxibotulinumtoxinA OnabotulinumtoxinA

(N = 35) 20U (N = 34) 40U (N = 39) 60U (N = 41) 20U (N = 42)

Mean age, yrs (range) 50 (32–64) 49 (30–62) 50 (30–63) 47 (34–64) 50 (36–63)
Males, n (%) 4 (11) 3 (9) 3 (8) 10 (24) 4 (10)
Caucasian, n (%) 31 (89) 31 (91) 37 (95) 38 (93) 38 (90)
IGA-FWS rating at
maximum frown, n (%)
Moderate 24 (69) 22 (65) 27 (69) 24 (59) 28 (67)
Severe 11 (31) 12 (35) 12 (31) 17 (41) 14 (33)
PFWS rating at maximum
frown, n (%)
Moderate 21 (60) 24 (71) 26 (67) 27 (66) 24 (57)
Severe 14 (40) 10 (29) 13 (33) 14 (34) 18 (43)

IGA-FWS, Investigator Global Assessment—Facial Wrinkle Severity scale; PFWS, Patient Facial Wrinkle Severity scale.

daxibotulinumtoxinA than with onabotuli- daxibotulinumtoxinA group at Week 24, where it

numtoxinA at all visits from Weeks 2 to 24 except
for the 20U dose group at Weeks 4 and 8 (Figure 3
and Table 4). The 40U dose of
daxibotulinumtoxinA achieved the most sustained
efficacy and the proportion of subjects in this group
achieving at least a 2-point improvement in IGA-
FWS score was significantly higher than with 20U
onabotulinumtoxinA at Weeks 8, 12, 16, and 20
(p < .05). The proportion of subjects with glabellar
lines of none or mild severity on the IGA-FWS scale
was greater with all doses of daxibotulinumtoxinA
than with 20U onabotulinumtoxinA at almost all
visits from Weeks 2 to 24 (excepting only the 20U
was equivalent)—and for the 40U
daxibotulinumtoxinA group, the proportion was
significantly higher at Weeks 8, 16, 20, and 24
(p < .05) (Figure 4 and Table 4).
Duration of Response
The median duration of response (i.e., duration of at
least a 1-point improvement from baseline in IGA-
FWS score at maximum frown) was longer with
daxibotulinumtoxinA (20.0, 23.6, and 20.9 weeks
for 20U, 40U, and 60U doses, respectively) than
with 20U onabotulinumtoxinA (18.8 weeks) or

Figure 1. Subjects with at least a 1-point improvement in Investigator Global Assessment—Facial Wrinkle Severity (IGA-
FWS) score at maximum frown (per protocol population). *p < .05, **p < .01, ***p < .001 versus placebo, †p < .05, ††p < .01
versus onabotulinumtoxinA.

0:0:MONTH 2017 5

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 INJECTABLE DAXIBOTULINUMTOXINA

TABLE 4. Efficacy Overview (per Protocol Population)

Placebo DaxibotulinumtoxinA OnabotulinumtoxinA

Parameter (N = 35) 20U (N = 34) 40U (N = 39) 60U (N = 41) 20U (N = 42)
IGA-FWS rating at maximum
frown
1-point improvement, %
Week 4 2.9 100*** 100*** 100*** 95.2***
Week 16 2.9 67.6*** 79.5***†† 82.9***†† 53.7***
Week 24 2.9 17.6* 35.9*** 29.3** 19.0*
2-point improvement, %
Week 4 0.0 73.5*** 84.6*** 95.1***† 76.2***
Week 16 0.0 14.7* 30.8***†† 22.0**† 4.9
Week 24 0.0 2.9 7.7 4.9 2.4
None or mild, %
Week 4 0.0 97.1*** 97.4*** 97.6*** 92.9***
Week 16 0.0 52.9***† 66.7***†† 65.9***††† 31.7***
Week 24 0.0 11.8* 30.8***† 17.1** 11.9*
PFWS rating at maximum
frown
1-point improvement, %
Week 4 2.9 100*** 100*** 97.6*** 92.9***
Week 16 2.9 58.8*** 76.9***† 70.7*** 58.5***
Week 24 5.7 32.4** 35.9** 39.0*** 35.7**
2-point improvement, %
Week 4 0.0 70.6*** 56.4*** 73.2*** 64.3***
Week 16 0.0 14.7* 25.6*** 24.4** 12.2*
Week 24 0.0 0.0 5.1 7.3 4.8
None or mild, %
Week 4 0.0 97.1*** 94.9*** 95.1*** 85.7***
Week 16 0.0 41.2*** 61.5***† 56.1*** 36.6***
Week 24 0.0 20.6** 20.5** 22.0** 19.0**
Investigator GAIS score at
maximum frown
Improvement, %
Week 4 0.0 100*** 100*** 100*** 97.6***
Week 16 0.0 88.2*** 97.4***† 85.4*** 80.5***
Week 24 0.0 29.4*** 43.6***† 43.9***† 19.0**
Subject GAIS score at
maximum frown
Improvement, %
Week 4 2.9 100*** 100*** 100*** 95.2***
Week 16 2.9 82.4*** 89.7***† 87.8*** 70.7***
Week 24 2.9 29.4** 46.2*** 46.3*** 31.0**

*p < .05, **p < .01, ***p < .001 versus placebo.
†p < .05, ††p < .01, †††p < .001 versus onabotulinumtoxinA.
GAIS, Global Aesthetic Improvement Scale; IGA-FWS, Investigator Global Assessment—Facial Wrinkle Severity scale; PFWS, Patient
Facial Wrinkle Severity scale.

placebo (0.0 weeks) (p < .001 for all botulinum toxin (Table 5 and Figure 6). Photographic documenta-
groups vs placebo and p = .030 for dax- tion of examples of durable responses is shown in
ibotulinumtoxinA 40U vs onabotulinumtoxinA) Figures 7 and 8.

6 DERMATOLOGIC SURGERY

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 CARRUTHERS ET AL

Figure 2. Subjects with at least a 1-point improvement in Patient Facial Wrinkle Severity (PFWS) score at maximum frown
(per protocol population). **p < .01, ***p < .001 versus placebo, †p < .05 versus onabotulinumtoxinA.

Safety and Tolerability onabotulinumtoxinA and the highest dose of dax-

ibotulinumtoxinA (60U). These cases of eyelid ptosis
DaxibotulinumtoxinA was generally well tolerated at
were mild in severity with onabotulinumtoxinA (1) and
all 3 doses evaluated. Adverse events were pre-
mild (1) or moderate (3) with daxibotulinumtoxinA,
dominantly localized, transient, and mild, and there
and lasted 51 days with onabotulinumtoxinA and an
were no serious adverse events. The only severe
average of 47 days with daxibotulinumtoxinA. Facial
adverse event that was at least possibly related to
asymmetry occurred in 4 subjects who were treated
treatment was a migraine in 1 subject in the 20U
with daxibotulinumtoxinA. This was also transient,
daxibotulinumtoxinA dose group.
with all cases resolved within 2 to 11 days. Three of the
cases were considered to be mild and the fourth did not
Adverse events considered at least possibly related to
have severity reported.
treatment and occurring in more than 1 subject in any
group are shown in Table 6. The incidence of headache
Discussion
and injection site erythema was lower in all dax-
ibotulinumtoxinA dose groups than in the onabotuli- A sizeable number of subjects were excluded from the
numtoxinA group. Eyelid ptosis occurred in 5 subjects per protocol analyses because of their Week 24 visits
(notably, none of these were men) and only with being at least 5 days off schedule. Even though this

Figure 3. Subjects with at least a 2-point improvement in Investigator Global Assessment—Facial Wrinkle Severity (IGA-
FWS) score at maximum frown (per protocol population). *p < .05, **p < .01, ***p < .001 versus placebo, †p < .05, ††p < .01
versus onabotulinumtoxinA.

0:0:MONTH 2017 7

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 INJECTABLE DAXIBOTULINUMTOXINA

Figure 4. Subjects with a glabellar line severity score of none or mild on the Investigator Global Assessment—Facial
Wrinkle Severity (IGA-FWS) scale at maximum frown (per protocol population). *p < .05, **p < .01, ***p < .001 versus
placebo, †p < .05, ††p < .01, †††p < .001 versus onabotulinumtoxinA.

occurred with a similar frequency in all cohorts, the
per protocol population was used for all efficacy
analyses because accurately comparing the duration of
response between groups was an important goal of the
study.
All botulinum toxin groups showed considerably
greater efficacy than placebo, and 40U dax-
ibotulinumtoxinA offered greater efficacy than 20U
daxibotulinumtoxinA. The 60U dose did not generally
enhance efficacy further, which could be attributable
to a “ceiling effect” or the relatively greater proportion
of severe glabellar lines and men in this group at
baseline (it is known that men require a higher dose of
botulinum toxin Type A than women to achieve
a similar effect4,5).
Statistical and clinical superiority were observed for
40U daxibotulinumtoxinA over 20U
onabotulinumtoxinA for a range of efficacy out-
comes (improvements in IGA-FWS, PFWS, and
GAIS scores; proportion of subjects achieving gla-
bellar lines of none or mild severity; and duration of
response) even though the study was not powered to
detect statistically significant differences between
active treatment groups. For example, the pro-
portion of subjects with glabellar line severity rated
by investigators as none or mild with 40U dax-
ibotulinumtoxinA was more than double—and
significantly greater than—that with 20U
onabotulinumtoxinA at Weeks 16, 20, and 24
(67% vs 32% at Week 16 [p = .002] and 31% vs
12% at Week 24 [p = .041]). The last time point at

Figure 5. Subjects with an investigator-rated improvement on the Global Aesthetic Improvement Scale (GAIS) at maximum
frown (per protocol population). **p < .01, ***p < .001 versus placebo, †p < .05 versus onabotulinumtoxinA.

8 DERMATOLOGIC SURGERY

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 CARRUTHERS ET AL

TABLE 5. Duration of Response Based on at Least a 1-Point Improvement From Baseline in IGA-FWS
Score in the per Protocol Population

Placebo DaxibotulinumtoxinA OnabotulinumtoxinA

(N = 35) 20U (N = 34) 40U (N = 39) 60U (N = 41) 20U (N = 42)

Median (95% CI) duration 0.0 (N/A) 20.0 (17.0–24.0) 23.6 (19.6–24.7) 20.9 (20.0–24.1) 18.8 (15.9–20.0)
of response, wk*
Mean (6SE) duration of 0.4 (0.3) 20.8 (0.9) 23.2 (1.0) 22.5 (0.9) 18.8 (1.1)
response, wk*
p-value vs placebo† — <.001 <.001 <.001 <.001
p-value vs — .373 .030 .058 —
onabotulinumtoxinA†

*Median (95% CI) was based on Kaplan–Meier method and mean (SE) was estimated using the area under the Kaplan–Meier curve.
†p-value was based on a pairwise log-rank test.
CI, confidence interval; IGA-FWS, Investigator Global Assessment—Facial Wrinkle Severity scale; SE, standard error.

which onabotulinumtoxinA was able to match the
31% responder rate achieved with dax-
ibotulinumtoxinA at Week 24 was Week 16—that
is 8 weeks earlier than with daxibotulinumtoxinA.
Data evaluating the duration of $1-point improve-
ments in IGA-FWS score also show a significantly
longer duration of response with 40U
daxibotulinumtoxinA than with 20U onabotuli-
numtoxinA (median of 23.6 vs 18.8 weeks, p = .030).
Perhaps somewhat surprisingly, the duration of
response was also greater with 40U dax-
ibotulinumtoxinA than 60U daxibotulinumtoxinA.
A previous small open-label study3 reported an even
longer median duration with a higher dose of
daxibotulinumtoxinA (29 weeks with a correspond-
ing dose of 64U calculated using a saline potency
method).
In addition to its prolonged duration of efficacy, the
data showing at least a 2-point improvement in IGA-
FWS scores suggest that daxibotulinumtoxinA can
also achieve greater initial efficacy—because, at Week
4, the proportion of subjects achieving such improve-
ment was 76% with 20U onabotulinumtoxinA, 85%
with 40U daxibotulinumtoxinA, and 95% with 60U
daxibotulinumtoxinA.
Although the key findings summarized above focus on
the 40U dose of daxibotulinumtoxinA (because this is

Figure 6. Kaplan–Meier curve depicting duration of response ($1-point improvement in Investigator Global Assessment—
Facial Wrinkle Severity [IGA-FWS] score at maximum frown) in per protocol population.

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 INJECTABLE DAXIBOTULINUMTOXINA

Figure 7. Photographic documentation of a sustained 2-point improvement in investigator and subject ratings of glabellar
line severity (IGA-FWS and PFWS) at maximum frown with daxibotulinumtoxinA 40U. The improvement evident at Week 4
is still maintained at Week 24.

the dose generally associated with the greatest clinical
benefit), the 20U dose of daxibotulinumtoxinA also
showed apparent clinical superiority over 20U
onabotulinumtoxinA. This was most notable when
comparing the proportion of subjects achieving at
least a 1-point improvement in the investigator rating
of glabellar line severity (Figure 1) and when com-
paring the proportion of subjects whose glabellar lines
were rated as none or mild severity (Figure 4). The
difference was even statistically significant at Week 16
for the proportion of subjects whose glabellar lines
were rated as none or mild severity (despite the study
not being powered to detect such differences). These
results show that the overall superiority of the 40U
dose of daxibotulinumtoxinA is not just an effect of
the higher dose as there are also differences when the
same number of units of each botulinum toxin are
compared.
There was no apparent dose relationship in the inci-
dence of adverse events with daxibotulinumtoxinA,
with the probable exception of eyelid ptosis. The
absence of eyelid ptosis with the 20U and 40U doses of
daxibotulinumtoxinA is encouraging, and it is also
reassuring that the cases with 60U of
daxibotulinumtoxinA had a similar duration on
average to the case with onabotulinumtoxinA, par-
ticularly in the context of a longer lasting treatment for
glabellar lines. Overall, the efficacy and tolerability
data suggest that 40U is the optimal dose to pursue in
Phase 3 studies. Nevertheless, as no eyelid ptosis was
observed in men, it is tempting to speculate that the
60U dose might also be appropriate for men.
The results of this study refer to the Revance
injectable formulation of botulinum toxin Type A
and cannot be generalized to any other

Figure 8. Photographic documentation of a 3-point improvement in investigator and subject ratings of glabellar line
severity (IGA-FWS and PFWS) at maximum frown with daxibotulinumtoxinA 40U. A 1-point improvement is still evident at
Week 24.

10 DERMATOLOGIC SURGERY

© 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 CARRUTHERS ET AL

TABLE 6. Incidence of Adverse Events Considered by the Investigator to be Possibly, Probably, or

Definitely Related to Treatment and Occurring in More than 1 Subject in a Treatment Group

Placebo DaxibotulinumtoxinA OnabotulinumtoxinA

(N = 54) 20U (N = 54) 40U (N = 53) 60U (N = 53) 20U (N = 54)

Headache, % 3.7 9.3 7.5 3.8 13.0
Injection site erythema, % 7.4 5.6 7.5 5.7 9.3
Eyelid ptosis, % 0.0 0.0 0.0 7.5 1.9
Injection site bruising, % 0.0 3.7 1.9 3.8 0.0
Injection site pain, % 0.0 1.9 1.9 3.8 1.9
Facial asymmetry, % 0.0 1.9 3.8 1.9 0.0
Injection site pruritus, % 0.0 0.0 3.8 1.9 0.0
Periorbital edema, % 0.0 1.9 0.0 3.8 0.0
Injection site edema, % 0.0 0.0 0.0 0.0 3.7

formulations or serotypes of botulinum toxin Type onabotulinumtoxinA—the gold standard neuro-

A. The potency units of botulinum toxins are not
interchangeable. As a result, units of
daxibotulinumtoxinA should not be equated with
the same number of units of onabotulinumtoxinA as
the relative potencies of daxibotulinumtoxinA and
onabotulinumtoxinA have not been established.
Conclusion
The 40U dose of daxibotulinumtoxinA has the most
favorable risk:benefit profile and will be evaluated in
Phase 3 studies. Compared with 20U
onabotulinumtoxinA, it offers significantly greater
efficacy and a significantly longer duration of response
(median of 24 weeks vs 19 weeks; p = .030), and was well
modulator—has been fully justified in developing an
enviable reputation globally, daxibotulinumtoxinA
deserves very careful study, as it is currently the only
new neuromodulator to challenge both the quality and
duration of response of onabotulinumtoxinA.
References
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using a macromolecule transport system (MTS) peptide for delivery of
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botulinum toxin therapy and reducing the frequency of
injections would be a significant advantage that would
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Injectable daxibotulinumtoxinA could represent the
first of a new generation of botulinum toxin treat-
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Address correspondence and reprint requests to: Jean
Carruthers, MD, Department of Ophthalmology,
University of British Columbia, Vancouver, BC 0223,
Canada, or e-mail: drjean@carruthers.net

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