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Comparing Injectable DaxibotulinumtoxinA and OnabotulinumtoxinA in Moderate and Severe Glabellar Lines

Additional Analyses From a Phase 2, Randomized, Dose-Ranging, Double-Blind, Multicenter Study

Bertucci, Vince MD*; Humphrey, Shannon MD; Carruthers, Jean MD; Solish, Nowell MD*; Muhn, Channy MD§,‖; Swift, Arthur MD; Rubio, Roman G. MD#; Shears, Gill PhD**; Rosen, Nathan MD§,‖

doi: 10.1097/DSS.0000000000001364
Original Article
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BACKGROUND Injectable daxibotulinumtoxinA (RT002) is an investigational botulinum toxin Type A. Published Phase 2 data show that, compared with 20U onabotulinumtoxinA, 40U daxibotulinumtoxinA is associated with a significantly greater response rate and significantly longer duration of response (median 24 weeks), and appears generally safe and well tolerated (www.clinicaltrials.gov NCT02303002).

OBJECTIVE To evaluate whether these efficacy and safety findings are influenced by baseline glabellar line severity.

MATERIALS AND METHODS In the Phase 2, randomized, dose-ranging, parallel-group, double-blind, multicenter study, subjects with moderate or severe glabellar lines at maximum frown were randomly assigned to 20U, 40U, or 60U daxibotulinumtoxinA, 20U onabotulinumtoxinA, or placebo. Efficacy was evaluated by investigators for ≥24 weeks.

RESULTS Data from the per protocol population (n = 191) stratified by baseline glabellar line severity (125 moderate, 66 severe) suggest that the clinical advantage of 40U daxibotulinumtoxinA over 20U onabotulinumtoxinA is maintained for a range of efficacy outcomes regardless of whether glabellar lines are moderate or severe at baseline. Statistical evaluations were not completed due to the limited size of each subgroup.

CONCLUSION 40U daxibotulinumtoxinA appears to offer a clinical efficacy advantage over 20U onabotulinumtoxinA in both moderate and severe glabellar lines—with a greater advantage observed in severe glabellar lines.

*Division of Dermatology, University of Toronto, Toronto, Ontario, Canada;

Departments of Dermatology and Skin Science, and

Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada;

§Faculty of Medicine, McMaster University, Hamilton, Ontario, Canada;

Dermetics, Burlington, Ontario, Canada;

The Westmount Institute of Plastic Surgery, Montreal, Québec, Canada;

#Clinical Development Department, Revance Therapeutics, Inc., Newark, California;

**Write on Target Ltd., Leighton Buzzard, United Kingdom

Address correspondence and reprint requests to: Vince Bertucci, MD, Division of Dermatology, University of Toronto, 100-8333 Weston Road, Woodbridge, Ontario L4L 8E2 Canada, or e-mail: vince.bertucci@utoronto.ca

This study and the post hoc analyses were funded by Revance Therapeutics, Inc. DaxibotulinumtoxinA is an investigational agent. V. Bertucci is an investigator, consultant and/or speaker for Allergan, Evolus, Galderma, Merz and Revance. S. Humphrey is an investigator, consultant and/or speaker for Allergan, Galderma, Revance, Merz, Evolus, and Zeltiq. J. Carruthers is a consultant and researcher for Revance, Allergan, Merz, Alphaeon, and Zeltiq. She has received grant money, consulting fees/honoraria, support for travel to meetings, and writing assistance, medicines, equipment, or administrative support. N. Solish is in receipt of a grant from Revance for participating in this study, and is a consultant to Revance, Allergan, and Galderma. A. Swift is in receipt of an investigator fee from Revance Therapeutics, Inc. R.G. Rubio is an employee of, and holder of stock/stock options in, Revance Therapeutics, Inc. G. Shears is an employee of Write on Target Ltd., which has received fees from Revance Therapeutics, Inc. for medical writing services. N. Rosen is an investigator, consultant and/or speaker for Allergan, Galderma, Merz, and Revance. The remaining author has indicated no significant interest with commercial supporters.

Injectable daxibotulinumtoxinA is in clinical development for the treatment of glabellar lines. Phase 2 data have documented the superior efficacy and tolerability of 40U daxibotulinumtoxinA compared with 20U onabotulinumtoxinA.1 Of particular clinical interest is the significantly longer duration of response reported with daxibotulinumtoxinA—a median of 24 weeks with 40U daxibotulinumtoxinA versus 19 weeks with 20U onabotulinumtoxinA (p = .030).1 This is an important clinical benefit as it could reduce the frequency of injections and enhance patient satisfaction. Indeed, 79% of the per protocol population in the Phase 2 trial reported that the duration of response was important or very important to them, and 87% reported that it was at least somewhat important.

Injectable daxibotulinumtoxinA (RT002) is a purified 150 kDa botulinum toxin Type A (RTT150) that is devoid of accessory proteins. It is formulated in a lyophilized powder containing a proprietary peptide (RTP004)1—a straight chain molecule consisting of a backbone and 2 protein transduction domains. The backbone is a sequence of consecutive lysines that carry a positive charge and form an electrostatic bond with RTT150, resulting in the peptide binding avidly to RTT150. As a result, daxibotulinumtoxinA is produced without any animal or human blood products (e.g., serum albumin) and is stable at room temperature.

Injectable daxibotulinumtoxinA has been observed to prolong the duration of response in both the preclinical and clinical settings. Results from preclinical studies indicate daxibotulinumtoxinA exhibits less diffusion than onabotulinumtoxinA and may suggest that daxibotulinumtoxinA offers a relatively greater degree and duration of response at the intended target.2 As is common with clinical trials of botulinum toxins in glabellar lines, the Phase 2 trial with daxibotulinumtoxinA used a 1-point improvement in a facial wrinkle scale as a primary efficacy outcome measure and included subjects with moderate or severe glabellar lines at maximum frown.3 Findings published to date detail the results from the entire cohort regardless of baseline glabellar line severity.1 The proportion of subjects achieving at least a 1-point improvement in glabellar line severity was significantly greater with all neuromodulator treatments—20U, 40U, or 60U daxibotulinumtoxinA, and 20U onabotulinumtoxinA—compared with placebo (p ≤ .05 at all timepoints, i.e., Week 2–24, for both investigator and subject ratings).1 Importantly, even though the study had not been powered to detect statistically significant differences between the neuromodulator treatment groups, a significantly greater proportion of subjects achieved at least a 1-point improvement in investigator ratings of glabellar line severity with 40U daxibotulinumtoxinA than with 20U onabotulinumtoxinA (p < .05 at Weeks 8, 16, and 20).1 Similarly, an evaluation of only those subjects who achieved at least a 2-point improvement in investigator ratings of glabellar line severity showed a significantly greater proportion of subjects achieved this level of improvement with 40U daxibotulinumtoxinA than with 20U onabotulinumtoxinA (p < .05 at Weeks 8, 12, 16, and 20).1

All 3 doses of daxibotulinumtoxinA evaluated in the Phase 2 trial were efficacious. The 40U dose had the most favorable risk:benefit profile and was selected for Phase 3 evaluation. The 60U dose generally did not enhance or prolong efficacy further, and it was postulated that this could be attributable to a “ceiling effect” or the fact that the 60U cohort contained a higher proportion of subjects with severe glabellar lines, and a higher proportion of males, relative to the other groups.1 It is generally assumed that botulinum toxin Type A treatment of severe glabellar lines is likely to be less effective than the same treatment of moderate glabellar lines, and that severe lines may therefore require a higher dose.4 However, although there is some evidence in support of a lower response rate in severe glabellar lines (suggesting that greater muscle mass may have a higher threshold for response),5 the notion appears to be more of a general assumption than a finding that has been tested rigorously. As a result, the data from the Phase 2 trial were stratified by baseline glabellar line severity, and post hoc analyses were performed to evaluate the efficacy and safety of the treatments in moderate glabellar lines separately from those in severe glabellar lines.

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Methods

Study Design

As previously detailed,1 the study was a randomized, dose-ranging, parallel-group, double-blind, multicenter evaluation of injectable daxibotulinumtoxinA (20U, 40U, or 60U) compared with onabotulinumtoxinA 20U and placebo. The protocol was approved by the relevant institutional review boards and conformed to the ethical guidelines of the Declaration of Helsinki.

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Subjects

Subjects eligible to enroll in the study were required to be 30 to 65 years of age and 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 scale (Table 1). Details of inclusion and exclusion criteria are published elsewhere.1

TABLE 1

TABLE 1

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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 1 in the procerus muscle.

The assigned product was reconstituted by an unblinded preparer, and the masked product was provided to the investigator in a syringe. The subjects, investigators, and other site staff remained blinded to the treatment assignments.

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Outcome Measures

The severity of glabellar lines at maximum frown was assessed at least every 4 weeks by investigators using the IGA-FWS scale. Evaluations continued until Week 24 and, if the score had not yet returned to baseline at this time, evaluations continued until this had occurred (up to Week 36). Efficacy evaluations included the proportion of subjects with an improvement from baseline in IGA-FWS score, and the proportion with a global improvement in aesthetics as evaluated by investigators using the Global Aesthetic Improvement Scale (GAIS) (Table 1).

The duration of response was defined as the time since injection for at least a 1- or 2-point improvement in IGA-FWS score to revert to the baseline level (the duration of response being considered zero if no response was attained by Week 4). At the last study visit (Week 24, 28, 32, or 36 unless discontinuation had occurred earlier), subjects rated their satisfaction with the duration of their response to treatment using a 7-point scale (Table 1).

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Statistical Analyses

The median duration of response and 95% confidence intervals were calculated using the Kaplan-Meier method and Statistical Analysis System software, version 9.3 or higher. The study was not powered to detect statistically significant differences between active treatment groups and no other statistical evaluations were performed on the stratified data.

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Results

Subjects

A total of 268 subjects were enrolled (from 9 university-affiliated clinical trial centers across Canada) and included in the safety analyses. Three subjects discontinued from the placebo group and 2 from the 20U daxibotulinumtoxinA group (due to subject withdrawals or loss to follow-up). Efficacy analyses used the per protocol population comprising 191 subjects1 (Table 2).

TABLE 2

TABLE 2

The analyses in this publication focus on the most clinically relevant doses of each neuromodulator—that is 40U daxibotulinumtoxinA (the dose evaluated in Phase 3 glabellar line trials) and 20U onabotulinumtoxinA (the dose approved for the treatment of glabellar lines6).

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Efficacy

Compared with 20U onabotulinumtoxinA, there was a trend for 40U daxibotulinumtoxinA to be associated with a higher likelihood of subjects achieving at least a 1- or 2-point improvement in IGA-FWS score at maximum frown regardless of whether glabellar lines had been moderate or severe at baseline (Figure 1). In moderate lines, the proportion of subjects achieving at least 1- and 2-point improvements was numerically higher with daxibotulinumtoxinA than onabotulinumtoxinA from Week 2 onward (Figure 1A). In severe lines, the proportion of subjects achieving such improvements was numerically higher from Week 8 for at least 2-point improvements, and from Week 12 for at least 1- point improvements (Figure 1B).

Figure 1

Figure 1

For moderate lines, the proportion of subjects showing at least a 1-point improvement in IGA-FWS score after treatment with 40U daxibotulinumtoxinA and 20U onabotulinumtoxinA was 70% and 44% at Week 16, 52% and 30% at Week 20, and 37% and 14% at Week 24, respectively (Figure 1A). The equivalent proportions showing a 2-point improvement were 19% and 4% at Week 16, 11% and 0% at Week 20, and 4% and 0% at Week 24 (Figure 1A). Thus, the proportion of subjects with moderate lines showing improved IGA-FWS scores was more than twice as great with daxibotulinumtoxinA than onabotulinumtoxinA for 1-point improvements at Week 24, and more than 4 times as great for 2-point improvements at Week 16.

For severe lines, the proportion of subjects showing at least a 1-point improvement in IGA-FWS score after treatment with 40U daxibotulinumtoxinA and 20U onabotulinumtoxinA was 100% and 71% at Week 16, 75% and 36% at Week 20, and 33% and 29% at Week 24, respectively (Figure 1B). The equivalent proportions showing at least a 2-point improvement were 58% and 7% at Week 16, 33% and 7% at Week 20, and 17% and 7% at Week 24 (Figure 1B). Thus, the proportion of subjects with severe lines showing at least a 2-point improvement in IGA-FWS score was more than 8 times as great with daxibotulinumtoxinA than onabotulinumtoxinA at Week 16, and more than twice as great at Week 24—and, compared with the onabotulinumtoxinA curve at Week 16, the daxibotulinumtoxinA curve was shifted to the right by at least 8 weeks (as also occurred with the curves showing 2-point improvement in IFA-FWS score in moderate lines). The proportion of subjects with severe glabellar lines achieving a 3-point improvement was also greater with 40U daxibotulinumtoxinA (peaking at 82%–83% at Weeks 2–4) compared with 20U onabotulinumtoxinA (peaking at 50% at Weeks 2–4) (Figure 2).

Figure 2

Figure 2

The decline to a 0% response rate occurred earlier with onabotulinumtoxinA than daxibotulinumtoxinA. In moderate glabellar lines, the proportion of subjects with a 2-point improvement had declined to 0% with onabotulinumtoxinA by Week 20 (whereas this had not occurred with daxibotulinumtoxinA by Week 24) (Figure 1A). And, in severe glabellar lines, the proportion of subjects with at least a 2-point improvement had declined to the minimum level of 7% with onabotulinumtoxinA by Week 16 (whereas this had not occurred with daxibotulinumtoxinA by Week 24) (Figure 1B). Finally, the proportion of subjects with a 3-point improvement declined to 0% with onabotulinumtoxinA at Week 12 (whereas this occurred with daxibotulinumtoxinA at Week 16) (Figure 2).

Similar to the IGA-FWS data, 40U daxibotulinumtoxinA also showed a trend associated with a higher likelihood of subjects achieving at least a 1- or 2-point improvement in investigator ratings of GAIS score at maximum frown regardless of whether glabellar lines had been moderate or severe at baseline (Figure 3). For moderate lines, the proportion of subjects showing at least a 1-point improvement in GAIS score after treatment with 40U daxibotulinumtoxinA and 20U onabotulinumtoxinA was 96% and 81% at Week 16, and 44% and 14% at Week 24, respectively (Figure 3A). For severe lines, the proportion of subjects showing at least a 1-point improvement after treatment with 40U daxibotulinumtoxinA and 20U onabotulinumtoxinA was 100% and 79% at Week 16, and 42% and 29% at Week 24, respectively (Figure 3B).

Figure 3

Figure 3

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Duration of Response

Kaplan-Meier curves showed a clear and consistent trend toward more durable responses with 40U daxibotulinumtoxinA relative to 20U onabotulinumtoxinA in both moderate and severe glabellar lines—the duration (and 95% CI) of at least a 1-point improvement in IGA-FWS score was a median of 20.1 (18.6–27.6) versus 16.2 (15.4–20.0) weeks in moderate lines (Figure 4A), and 23.8 (19.4–28.6) versus 20.0 (15.4–28.1) weeks in severe lines; Figure 4B). The duration of at least a 2-point improvement in IGA-FWS score was a median of 11.7 (8.0–12.0) versus 8.1 (4.1–11.3) weeks in moderate lines (Figure 5A), and 18.0 (11.4–23.3) versus 12.8 (8.9–15.4) weeks in severe lines (Figure 5B).

Figure 4

Figure 4

Figure 5

Figure 5

These curves also allow comparisons between 20U doses of both neuromodulators. With regard to the duration of at least a 1-point improvement in IGA-FWS score, 20U daxibotulinumtoxinA showed a trend toward a more durable improvement than 20U onabotulinumtoxinA in moderate lines (Figure 4A; median [and 95% CI] duration of 19.7 [16.6–24.0] vs 16.2 [15.4–20.0] weeks, respectively), and was comparable to 20U onabotulinumtoxinA in severe lines (Figure 4B; median duration of 20.1 [12.6–28.3] vs 20.0 [15.4–28.1] weeks, respectively). With regard to the duration of at least a 2-point improvement in IGA-FWS score, this appeared to be comparable between both treatments in moderate lines (Figure 5A; median duration of 8.1 [4.0–11.9] vs 8.1 [4.1–11.3] weeks, respectively) and 20U daxibotulinumtoxinA showed a trend toward a more durable improvement than 20U onabotulinumtoxinA in severe lines (Figure 5B; median duration of 14.5 [7.4–20.0] vs 12.8 [8.9–15.4] weeks, respectively).

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Satisfaction With Duration of Response

In both moderate and severe glabellar lines, there was a greater likelihood of subjects reporting at the last study visit that they were satisfied or very satisfied with the duration of treatment response when they were treated with 40U daxibotulinumtoxinA compared with 20U onabotulinumtoxinA (74% vs 64% in moderate lines, and 83% vs 50% in severe lines, respectively; Figure 6). Conversely, in both moderate and severe glabellar lines, there was a lower likelihood of subjects reporting that they were dissatisfied or very dissatisfied with 40U daxibotulinumtoxinA compared with 20U onabotulinumtoxinA (4% vs 7% in moderate lines and 8% vs 21% in severe lines, respectively; Figure 6).

Figure 6

Figure 6

The proportion of subjects reporting at the last study visit they were satisfied or very satisfied with 40U daxibotulinumtoxinA was higher when glabellar lines were severe rather than moderate at baseline (83% vs 74%). In contrast, the proportion of subjects reporting they were satisfied or very satisfied with 20U onabotulinumtoxinA was considerably lower when glabellar lines were severe rather than moderate at baseline (50% vs 64%).

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Safety and Tolerability

As previously detailed,1 all doses of daxibotulinumtoxinA evaluated in the Phase 2 trial appear generally safe and well tolerated. Adverse events were predominantly localized, transient, and mild, and there were no serious adverse events.

When adverse events occurring in more than 1 subject in a treatment group and considered at least possibly related to treatment were stratified by baseline glabellar line severity, there were no clear differences between the 2 treatment groups in the type or incidence of adverse events reported (Table 3).

TABLE 3

TABLE 3

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Discussion

As mentioned in the original publication from this study, the data for all subjects (before stratification into moderate and severe subgroups) showed a significantly greater proportion of subjects achieved 1- and 2-point improvements in IGA-FWS score at maximum frown with 40U daxibotulinumtoxinA than with onabotulinumtoxinA.1 The data presented here demonstrate that the clinical advantage of 40U daxibotulinumtoxinA over 20U onabotulinumtoxinA in the treatment of glabellar lines is maintained regardless of whether glabellar lines are moderate or severe at baseline. In general, the proportion of subjects with at least a 1- or 2-point improvement in glabellar line severity at maximum frown trended higher with 40U daxibotulinumtoxinA than with 20U onabotulinumtoxinA for both moderate and severe lines. The GAIS evaluations also showed a trend toward clinical advantage of 40U daxibotulinumtoxinA over 20U onabotulinumtoxinA in both moderate and severe lines. Overall, the greatest advantage of daxibotulinumtoxinA over onabotulinumtoxinA (represented by the shift of the daxibotulinumtoxinA IGA-FWS and GAIS curves to the right of the onabotulinumtoxinA curves) occurred from Week 12 onward in severe glabellar lines—for example, compared with the onabotulinumtoxinA curve for at least 2-point improvements in IGA-FWS score in severe lines at Week 16, the daxibotulinumtoxinA curve was shifted to the right by at least 8 weeks. As the maximal advantage of daxibotulinumtoxinA over onabotulinumtoxinA was in severe glabellar lines (for IGA-FWS, GAIS, and satisfaction evaluations)—and as subjects with severe glabellar lines were underrepresented in the Phase 2 trial (comprising only 35% of the per protocol population1)—it might be anticipated that the previously published Phase 2 data1 would have shown an even greater advantage for daxibotulinumtoxinA over onabotulinumtoxinA if a greater proportion of subjects with severe rather than moderate glabellar lines had been recruited.

Duration of response curves showed a clear trend toward more durable responses with 40U daxibotulinumtoxinA relative to 20U onabotulinumtoxinA in both moderate and severe glabellar lines (20.1 vs 16.2 weeks in moderate lines, and 23.8 vs 20.0 weeks in severe lines for at least a 1-point improvement, and 11.7 vs 8.1 weeks in moderate lines and 18.0 vs 12.8 weeks in severe lines for at least a 2-point improvement, respectively). This was presumably reflected in the numerically greater satisfaction ratings for 40U daxibotulinumtoxinA relative to 20U onabotulinumtoxinA, where a greater proportion of daxibotulinumtoxinA-treated subjects considered they were satisfied or very satisfied with the duration of their response compared with onabotulinumtoxinA-treated subjects for both moderate and severe glabellar lines (74% vs 64% in moderate lines, and 83% vs 50% in severe lines, respectively). It is also notable that subjects with severe glabellar lines were at least as satisfied as those with moderate lines after the 40U daxibotulinumtoxinA treatment, whereas satisfaction trended lower in severe lines than moderate lines with the 20U onabotulinumtoxinA treatment.

This manuscript is focused on comparing the most clinically relevant doses of each neuromodulator—that is the dose of onabotulinumtoxinA approved for the treatment of glabellar lines (20U) and the dose of daxibotulinumtoxinA evaluated in Phase 3 glabellar line trials (40U). The potency units of botulinum toxins are not interchangeable,7 and the relative potencies of daxibotulinumtoxinA and onabotulinumtoxinA have not been established. As a result, units of daxibotulinumtoxinA cannot be equated with units of onabotulinumtoxinA. Nevertheless, to illustrate that the duration of response advantage of 40U daxibotulinumtoxinA relative to 20U onabotulinumtoxinA is not simply attributable to the difference in the number of units used, the Kaplan-Meier curves in this manuscript also include data from 20U daxibotulinumtoxinA treatment so that the results from 20U doses of both neuromodulators can be compared. As previously shown in the first manuscript from this study1 (i.e., in the whole study population rather than in subgroups stratified by baseline glabellar severity), the Kaplan-Meier curves show that the duration of response with 20U daxibotulinumtoxinA is at least as prolonged as with 20U onabotulinumtoxinA. The earlier manuscript from this study1 also depicts trends toward greater efficacy with 20U daxibotulinumtoxinA relative to 20U onabotulinumtoxinA (in terms of the incidence of at least a 1-point improvement in IGA-FWS score, the incidence of none or mild glabellar lines, and the incidence of improvement in GAIS score). Two dose-ranging studies have been conducted with onabotulinumtoxinA, and any dose–response effect appears to depend on the gender of the subjects.8,9 One of the studies was in males only and the authors showed a dose–response effect between 20U and 40U.8 However, the other study was in females only and the authors concluded there was no significant dose–response effect between 20U and 40U doses.9 Thus, in the patient population most likely to receive onabotulinumtoxinA (i.e., females) there may not be a dose–response effect between 20U and 40U doses of onabotulinumtoxinA. Although males do show a dose–response effect between these 20U and 40U doses of onabotulinumtoxinA, the duration of response after a 20U onabotulinumtoxinA dose is lower than that in females receiving the same dose and, even though this increases after a 40U dose, it still does not reach the duration achieved in females after a 20U dose. Thus, because the only subjects who may achieve a longer duration of response if given a higher dose of onabotulinumtoxinA (i.e., males) also start from a position of an inferior duration of response relative to females and comprise only a small proportion of treated subjects, we would not expect any meaningful influence on the findings in our study if we had also included a group receiving 40U onabotulinumtoxinA.

In the earlier manuscript,1 it was hypothesized that the lack of additional efficacy with 60U daxibotulinumtoxinA compared with 40U daxibotulinumtoxinA may be at least partly attributable to a relatively higher proportion of subjects with severe glabellar lines in the 60U group (as it was assumed that efficacy may be lower in severe glabellar lines than moderate glabellar lines). Although it has been claimed that patients with severe wrinkles require a higher dose of botulinum toxin Type A, this assumption is challenged by the findings presented in this paper which show both neuromodulators achieve greater and more prolonged efficacy in severe glabellar lines than moderate glabellar lines. For example, at Week 16, the proportion of subjects treated with 40U daxibotulinumtoxinA who achieved at least a 1- or 2-point improvement in IGA-FWS score was 100% and 58%, respectively, in severe lines compared with 70% and 19%, respectively, in moderate lines. When defining response as at least a 1-point improvement in IGA-FWS score, the same subjects attained a median duration of response of 23.8 weeks in severe lines and 20.1 weeks in moderate lines. And, when defining response as at least a 2-point improvement in IGA-FWS score, the subjects attained a median duration of response of 18.0 weeks in severe lines and 11.7 weeks in moderate lines. Although the reason for the greater and more prolonged efficacy in severe lines is unclear, this rather surprising finding suggests that we should be careful not to assume that neuromodulator treatment is less effective or less durable in severe glabellar lines than moderate glabellar lines. As subject numbers were relatively small in this analysis, especially in the severe subgroups, it would be valuable to further evaluate this topic in other studies. Like the evaluation reported here, this could include post hoc analyses of data from trials that have already been completed. Although such explorations of data have various limitations (e.g., analyses for statistical significance may be precluded because of low subject numbers in subgroups), the data presented here demonstrate that they can reveal previously hidden trends and unexpected insights that could be of clinical significance. As such, they can play an important role in complementing other clinical trial evaluations where all outcome measures are defined a priori.

With regard to the original hypothesis mentioned earlier, it appears that the higher proportion of subjects with severe glabellar lines in the 60U daxibotulinumtoxinA group does not explain why the efficacy in this group was generally no greater than in the 40U daxibotulinumtoxinA group (as the data presented here show that efficacy is generally greater in severe glabellar lines than moderate glabellar lines). Nevertheless, it is still possible that the higher proportion of males in the 60U daxibotulinumtoxinA group could have played a role especially as there was a larger between-group difference in the proportion of males than in the proportion of subjects with severe glabellar lines.

Although clear trends show a clinical advantage of 40U daxibotulinumtoxinA over 20U onabotulinumtoxinA for a variety of efficacy outcomes, the ability to detect between-group differences in adverse events is more constrained given the generally low incidence of adverse events with both neuromodulators. The stratified data do not appear to offer any further insights into the risk of adverse events in the different botulinum toxin treatment groups beyond those already mentioned in the previous publication.1 However, the data do allow us to suggest that baseline glabellar line severity does not generally appear to influence the pattern or incidence of adverse events.

The daxibotulinumtoxinA data presented here refer to the Revance injectable formulation of botulinum toxin Type A (RT002) and cannot be generalized to any other formulations or serotypes of botulinum toxin Type A.

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Conclusions

This post hoc subgroup analysis of daxibotulinumtoxinA Phase 2 trial data confirms that the clinical advantage of 40U daxibotulinumtoxinA over 20U onabotulinumtoxinA is valid not only in moderate glabellar lines but also in severe glabellar lines. Regardless of baseline glabellar line severity, 40U daxibotulinumtoxinA demonstrated an advantage over 20U onabotulinumtoxinA in terms of the: proportion of subjects with reduced severity of glabellar lines; proportion of subjects with global aesthetic improvement; durability of response; and subject satisfaction with the duration of response.

Furthermore, after 40U daxibotulinumtoxinA treatment, subjects with severe glabellar lines at baseline were at least as satisfied as those with moderate glabellar lines (which was not the case after 20U onabotulinumtoxinA treatment).

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References

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2. Stone HF, Zhu Z, Thach TQ, Ruegg CL. Characterization of diffusion and duration of action of a new botulinum toxin type A formulation. Toxicon 2011;58:159–67.
3. Kane MAC, Gold MH, Coleman WP, Jones DH, et al. Equivalence of incobotulinumtoxinA and onabotulinumtoxinA for glabellar frown lines. Dermatol Surg 2015;41:1310–9.
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8. Carruthers A, Carruthers J. Prospective, double-blind, randomized, parallel-group, dose-ranging study of botulinum toxin type A in men with glabellar rhytids. Dermatol Surg 2005;31:1297–303.
9. Carruthers A, Carruthers J, Said S. Dose-ranging study of botulinum toxin type A in the treatment of glabellar rhytids in females. Dermatol Surg 2005;31:414–22.
© 2017 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.