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Efficacy and Safety Evaluation of a Novel Botulinum Toxin Topical Gel for the Treatment of Moderate to Severe Lateral Canthal Lines

FREDRIC BRANDT, MD,Ã CHRISTOPHER O'CONNELL, MD,Ã ALEX CAZZANIGA, BS, MBA,Ã JACOB M. WAUGH, MDy

AND

BACKGROUND Botulinum toxin type A (BoNTA) is commonly injected to treat facial wrinkles. Complications include pain, erythema, bruising, and potential infection. RT001 Botulinum Toxin Type A Topical Gel (RT001) is under development for the treatment of lateral canthal lines (LCLs). OBJECTIVE To assess the efficacy and safety of RT001 for the treatment of LCLs using a randomized, double-blind, repeat-dose, placebo-controlled study design. METHODS & MATERIALS Healthy adult subjects were randomized to receive RT001 (N = 19) or placebo (N = 17) applied to their lateral canthal areas (LCAs). To evaluate safety of repeat exposure, treatment was administered at baseline and week 4. The primary efficacy measure was improvement in baseline LCL severity using the Investigator's Global Assessment of Lateral Canthal Line at Rest (IGA-LCL) Severity Scale. RESULTS At 8 weeks, 19 (50%) LCAs treated with RT001 showed a 2-point or greater improvement in baseline IGA-LCL severity, versus none (0%) of the placebo-treated subjects (po.001); 36 (94.7%) LCAs treated with RT001 showed a 1-point or more improvement in baseline IGA-LCL severity, versus five (14.7%) placebo-treated LCAs (po.001). There were no treatment-related adverse events. CONCLUSION RT001 was well tolerated and demonstrated an improvement in LCLs.

This study was sponsored by Revance Therapeutics, Inc., Newark, CA.

he first demonstrated use of botulinum toxin type A (BoNTA) for cosmetic purposes was the treatment of glabellar lines.1 BoNTA was eventually approved for aesthetic use,2,3 and the treatment of glabellar rhytides remains the primary cosmetic indication of BoNTA products. Injections of BoNTA have become the most popular aesthetic procedure in the United States4 and are now widely used off-label for treating a wide variety of wrinkles in the upper and lower face, including lateral canthal lines (LCLs), commonly referred to as crow's feet.5­14 Although cosmetic BoNTA has demonstrated an acceptable safety profile, adverse events occur,15 and misplaced injections may cause unwanted effects in nontarget areas. For example, eyelid and brow

T

ptosis16 and partial lip ptosis17 have been reported after injection of BoNTA into the upper face and periocular areas, respectively, and injection into the pretarsal portion of the orbicularis oculi muscle has resulted in dry eyes.18,19 There have also been complications involving pupillary reactions and light sensitivity.20,21 Limitations of injections include pain, erythema, swelling, bruising, tenderness, and potential infection from needle use.22 The patient's medical regimen is potentially affected by being advised to avoid aspirin, nonsteroidal antiinflammatory drugs, and vitamin E before injection to reduce the risk of bleeding and bruising. Bruising is of particular concern in the lateral canthus and orbicularis oculi region, where the blood vessels are superficial and the skin is thin. The most common

ÃDermatology Research Institute, LLC, Coral Gables, Florida; yRevance Therapeutics, Inc., Newark, California

& 2010 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2010;36:2111­2118 DOI: 10.1111/j.1524-4725.2010.01711.x

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adverse event from BoNTA treatment in the lateral canthal area (LCA) is injection site bruising and pain, which occurs in 6% to 25% of treated subjects.9,13 Attempts to minimize the discomfort of BoNTA injections in the lateral orbital areas have included cryotherapy23,24 and topical anesthetics.25 RT001 Botulinum Toxin Type A Topical Gel Revance Therapeutics, Inc., Newark, CA contains an albumin-free 150-kDa BoNTA and a novel peptide that enables transcutaneous flux of the BoNTA. RT001 is currently under development for the treatment of moderate to severe LCLs, commonly referred to as crow's feet. This novel approach to BoNTA administration may eliminate the local pain and ecchymosis associated with BoNTA injections in the lateral canthus and orbicularis oculi regions. The primary objective of this study was to determine the efficacy and safety of RT001 after two sequential applications (baseline and week 4) using a randomized, double-blind, placebocontrolled study design.

the study. Women of childbearing potential were required to have a negative urine pregnancy test and agree to use an effective method of birth control during the course of the study. Reasons for excluding subjects from the study included a neurological condition that might place them at risk from BoNTA exposure, such as amyotrophic lateral sclerosis or myasthenia gravis; inability to substantially lessen their LCLs by physically spreading them apart; recent use of topical prescription-strength retinoids (r3 months); chemical peels of medium or greater depth ( r9 months); periorbital surgery; brow lift or related procedures; laser skin resurfacing; soft tissue augmentation or any procedures affecting the lateral canthal region (r12 months); eyelid ptosis; muscle weakness or paralysis; active skin disease or irritation; excessive dermatochalasis or deep dermal scarring at the treatment areas; prior facial treatment with BoNTA or recent treatment with more than 200 U of BoNTA anywhere else in the body (r 6 months); prior immunization with any botulinum toxin serotype or a history of allergy or sensitivity to any components of the study medication; concurrent use of other therapeutic agents that might interfere with neuromuscular transmission, such as aminoglycoside antibiotics; and any medical condition or illness that, in the investigator's opinion, put the subject at significant risk or might confound the study results.

Methods Ethics This study was conducted according to U.S. regulations and the International Conference on Harmonisation guidelines. An Institutional Review Board (Quorum Review Inc., Seattle, WA) approved the protocol used in this study. Before undergoing any study procedures, each subject signed an informed consent document. Subjects The study enrolled healthy men and women aged 30 to 60. Subjects were required to have bilateral LCLs rated as moderate (3) or severe (4) at rest using the Investigator's Global Assessment of Lateral Canthal Lines at Rest (IGA-LCL) Severity Scale. Subjects expressed their willingness to refrain from the use of facial fillers, laser treatments, or any product affecting skin remodeling or that might cause an active dermal response during the course of

Investigational Drug RT001 consists of lyophilized BoNTA reconstituted with a poloxamer-based diluent containing a proprietary peptide that enables the transcutaneous delivery of BoNTA. RT001 (22 ng/mL) was prepared before each use and was applied within 2 hours of reconstitution. Consistent with other topical products, RT001 is dosed based on mass. The safety of the RT001 dose used in this study was established in previous Phase 1 and Phase 2 studies (data on file). The poloxamer-based diluent was used as the study control.

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TABLE 1. Investigator's Global Assessment of Lateral Canthal Line Severity Scale

Wrinkle Severity at Rest Absent Minimal

Score 0 1

Description No visible wrinkles Minimal wrinkles, within a 1.5cm radius of the lateral canthus and may be minimally etched Shallow wrinkles, extending to a 1.5- to 2.5-cm radius of the lateral canthus and minimally etched Moderately deep wrinkles extending to a 1.5- to 2.5-cm radius of the lateral canthus and moderately etched Very long wrinkles, exceeding to a 2.5-cm radius of the lateral canthus and may be deeply etched

High-resolution reference photographs were taken of the LCA of each subject at the screening visit and 2, 4, 6, and 8 weeks after treatment (VISIA-CR Multimodal Facial Imaging System, Canfield Scientific, Inc., Fairfield, NJ).

Safety Measures Safety assessments included systemic measures such as 12-lead electrocardiogram (ECG), clinical chemistry, hematology, urinalysis parameters, and serum antibody testing (at screening and week 8). Assessment of cranial nerve II to VII function was done at baseline and each follow-up visit.26 The Regional House-Brackmann Facial Nerve Grading System27 was used to assess facial nerve VIII as part of this evaluation. This approach allowed for direct and specific evaluation of muscle strength for each muscle adjacent to the orbicularis oculi to assess any potential spread. Ocular irritation was assessed using a 4-point scale ranging from 0 (none) to 3 (severe). Skin irritation was assessed using a 6-point erythema scale ranging from 0 (no reaction) to 5 (severe reaction) and by combining the numerical scores with descriptors for other clinical signs and symptoms.28,29 Subject reports of adverse events were coded using the Medical Dictionary for Regulatory Activities (Version 11.1). Assessments were conducted at baseline and weeks 2, 4, 6, and 8.

2

Mild

3

Moderate

4

Severe

Efficacy Measures To evaluate LCL severity at rest, Revance Therapeutics Inc., (Newark, CA) has developed the IGALCL Severity Scale for evaluating treatment effect with the subject's expression at rest. Previous clinical studies (data on file) have shown that assessing LCL severity at rest is the most reliable end point for determining efficacy for treatment of LCLs related to orbicularis oculi activity. This scale is shown in Table 1. As an additional measure of efficacy, subjects were asked to assess their improvement using the Subject Global Assessment (SGA) Questionnaire 4 and 8 weeks after treatment. The question and possible responses are shown in Table 2.

TABLE 2. Subject Global Assessment

How would you rate the appearance of your crow's feet lines today compared with immediately before your topical treatment? Worse No change Somewhat improved Improved Much improved

Procedures During the initial screening visit, the treatment areas of each subject were assessed using the IGA-LCL Severity Scale. After confirmation of study participation, subjects were randomized to receive RT001 or placebo in double-blind fashion at baseline (Day 0). The investigator applied RT001 or placebo (which are indistinguishable once reconstituted) to the LCA on each side of the face and then covered the area with a nonadhesive occlusive dressing to prevent the subject from inadvertently touching the gel. The gel was removed after 30 minutes. This procedure was repeated at week 4. Subjects were followed at weeks 2, 4, 6, and 8.

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Statistical Methods The primary efficacy end point was the proportion of LCA responders at week 8 defined as 2-point or more improvement in baseline IGA-LCL Severity Scale scores. Secondary efficacy end points included the proportion of LCA responders at weeks 2, 4, and 6, defined as 2-point or more or 1-point or more improvement in baseline IGA-LCL Severity Scale scores and the proportion of subjects with a SGA Questionnaire response of somewhat improved, improved, or much improved. All between-group responder rates were compared using Pearson chisquare or Fisher exact tests if 25% or more of expected cell frequencies were less than 5. Other efficacy end points analyzed were the proportion of responders at weeks 2, 4, 6, and 8, defined as 1-point or more improvement in baseline IGA-LCL Severity Scale score in either or both LCAs or 2-point or more improvement from baseline IGA-LCL Severity Scale score in either LCA. Multiple occurrences of the same adverse event (AE) were counted only once for each subject. AEs and the demographic characteristics of enrolled subjects were summarized using descriptive statistics.

TABLE 3. Subject Demographics (N = 36)

Characteristic Age, mean 7 standard deviation (range) Sex, n (%) Male Female White, n (%) Hispanic or Latino, n (%) RT001 (n = 19) 50.2 7 7.4 (38­60) 1 18 19 16 (5.3) (94.7) (100.0) (84.2) Placebo (n = 17) 56.3 7 3.8, (49­60) 3 14 17 16 (17.6) (82.4) (100.0) (94.1)

scores of at least 1 point, versus five (14.7%) placebo-treated subjects (po.001). Improvement of 1 point or more has been shown to be clinically meaningful to subjects and investigators, consistent with similar scales in the literature. SGA Questionnaire responses at week 8 were significantly higher (p = .007) for subjects treated with RT001 (Figure 3) at both time points than for placebo controls.

Safety Two subjects treated with RT001 (10.5%) and three treated with placebo (17.6%) reported AEs. None were considered to be treatment related, and all were mild or moderate in severity. No clinically significant changes in laboratory or ECG parameters were observed. Skin erythema assessments revealed mild, one-sided post-treatment skin erythema in one subject at the baseline visit; this erythema was localized and transient. Ocular irritation assessments revealed mild, bilateral erythema in one subject in each

TABLE 4. Subjects with Moderate or Severe Lateral Canthal Lines (LCLs) at Rest at Baseline

n (%) LCL Severity Both moderate Both severe One moderate, one severe RT001 (n = 19) 5 (26.3) 11 (57.9) 3 (15.8) Placebo (n = 17) 3 (17.6) 9 (52.9) 5 (29.4)

Results The study enrolled 36 subjects who were randomized to receive treatment with RT001 (n = 19) or placebo (n = 17). Demographic information is provided in Table 3. Evaluable subjects included all subjects who received treatment. Efficacy Baseline IGA-LCL Severity Scale scores are summarized in Table 4. The results of the primary efficacy measure are shown in Figure 1. At week 8, 19 (50%) RT001-treated LCAs demonstrated 2-point or more improvement in baseline IGA-LCL Severity Scale, versus none (0%) of the placebo-treated subjects (po.001). Furthermore, as shown in Figure 2, 36 (94.7%) RT001-treated LCAs demonstrated an improvement in baseline IGA-LCL Severity Scale

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RT001 (n=19)

100 80 % Subjects 60 40 20 0

Figure 1. At each time point, subjects treated with topical RT001 demonstrated significantly greater improvement in lateral canthal areas than placebo-treated subjects based on a 2-point or more improvement in Investigator's Global Assessment of Lateral Canthal Line at Rest Severity Scale score. P-values based on Fisher exact test.

Placebo (n=17)

84.2* 73.7

41.2

41.2

Week 4

Week 8

Figure 3. Response to the Subject Global Assessment Questionnaire indicates that a substantially greater number of RT001-treated subjects rated their lateral canthal areas were improved at 4 weeks and 8 weeks than of those treated with placebo. ÃP = .007, Fisher exact test.

treatment group at the baseline visit before and after treatment; this erythema was localized and transient. Cranial nerve assessments revealed no abnormalities and showed no evidence of any weakening of muscles other than orbicularis oculi.

Discussion The data from the present study indicate that RT001 Topical Gel provides sufficient penetration of BoNTA to weaken the orbicularis oculi muscle to produce a treatment effect on lateral canthal lines with no evidence of adverse ocular, neurologic, or other

systemic effects. By doing so, RT001 achieved significantly greater improvement in LCLs (crow's feet) than control as defined by the primary and secondary end points. A single topical administration of RT001 in the lateral canthal area resulted in significant diminution of LCLs at the 4-week time point as rated by the investigator and the subject. Specifically, 81.6% of LCAs achieved improvement over baseline at 4 weeks according to investigator assessment after treatment with RT001 as demonstrated by 1-point or greater improvement, and 73.7% showed improvement according to subject assessment. A second application of RT001 was administered to the same subjects to evaluate the safety of repeat dosing, with safety results described below. At the 8-week time point (4 weeks after the second application), RT001 again achieved significant improvement from baseline according to investigator and subject assessments. At 8 weeks, improvement was observed in 94.7% of RT001-treated LCA according to investigator assessment ( 1-point improvement) and 84.2% according to subject assessment, both greater than the 4-week results with visible improvements (Figures 4 and 5). Prior RT001 studies (data on file) have suggested that continued improvement may occur beyond 4 weeks after a single administration of RT001. Thus, the

100 80 % LCAs 60 40 20 0

2.9 8.8 p<0.0001 76.3 p<0.0001 81.6

p<0.0001 94.7

p<0.0001 94.7 n=38

14.7

14.7

n=34

Week 2

Week 4

RT001

Week 6

Placebo

Week 8

Figure 2. At each time point, subjects treated with topical RT001 demonstrated significantly greater improvement in lateral canthal areas than placebo-treated subjects based on a 1-point or more improvement in Investigator's Global Assessment of Lateral Canthal Line at Rest Severity Scale scores. P-values based on Fisher exact test.

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Figure 4. Representative subject photographs showing brow lift with shorter and shallower LCLs. (A) Screening, (B) 4 weeks post first application of RT001, and (C) 8 weeks post first application of RT001 (4 weeks post second application of RT001).

contribution of an additive effect from a second dose versus continued improvement from the initial dose cannot be distinguished in the present work. Future studies will be required to fully understand the relative contribution of each dose, although the week 4 data suggest that the majority of the improvement occurs after the first application. Several studies have assessed LCLs at rest using scales similar to the one employed here. Nearly all (81.6­94.7%) subjects attained improvement at rest in the severity of their LCAs after RT001 treatment under this protocol. Although difficult to compare with other routes of administration, these rates are consistent with the 53% to 84% rates of improvement at rest encountered in prior studies 4 weeks after treatment with various injectable BoNTA for LCLs.9,14 There are fundamental differences between glabellar lines and LCLs even from an anatomic perspective. Scales that measure maximum

expression (frown) are often used to measure paralysis in the glabellar and corrugator muscle groups, but an at-rest evaluation is the most direct assessment of paralysis of the target muscle orbicularis oculi for LCLs. At rest, LCLs are primarily caused by a chronic spasm in the orbicularis oculi muscle. At maximum expression (smile), other muscle groups (zygomaticus and levators of the corner of the mouth), which are not the target of treatment, make a significant contribution. Based upon increasing concern about unintended spread of BoNTA outside of the target muscle, resting assessment for this end point may represent not only the most direct measure of paralysis for the target muscle, but also the most prudent from a safety perspective. An encouraging overall safety profile as well accompanies these efficacy results. There was no greater frequency, severity, or duration of AEs or other safety parameters than in placebo-treated

Figure 5. Representative subject photographs showing shorter and shallower LCLs. (A) Screening, (B) 4 weeks post first application of RT001, and (C) 8 weeks post first application of RT001 (4 weeks post second application of RT001).

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subjects. There were no treatment-related AEs. All AEs were mild, local, and transient. Of particular importance, there was no evidence of regional weakness in muscles other than the orbicularis oculi. Additionally, there was no evidence of systemic exposure, and there were no clinically significant changes in laboratory values or ECGs related to treatment. This is the first reported randomized, blinded, controlled clinical study to demonstrate safe transcutaneous delivery of a macromolecule of this size (150 kDa) and complexity after topical administration. Future work to evaluate delivery of other large, complex therapeutics may be warranted based upon the results observed here.

6. Blitzer A, Binder W, Aviv J, et al. The management of hyperfunctional facial lines with botulinum toxin. A collaborative study of 210 injection sites in 162 patients. Arch Otolaryngol Head Neck Surg 1997;123:389­92. 7. Ellis D, Tan A. Cosmetic upper-facial rejuvenation with botulinum. J Otolaryngol 1997;26:92­6. 8. Fagien S. Botox for the treatment of dynamic and hyperkinetic facial lines and furrows: adjunctive use in facial aesthetic surgery. Plast Reconstr Surg 1999;103:701­13. 9. Lowe N, Lask G, Yamauchi P, Moore D. Bilateral, double-blind, randomized comparison of 3 doses of botulinum toxin type A and placebo in patients with crow's feet. J Am Acad Dermatol 2002;47:834­40. 10. Baumann L, Slezinger A, Vujevich J, et al. A double-blinded, randomized, placebo-controlled pilot study of the safety and efficacy of Myobloc (botulinum toxin type B)-purified neurotoxin complex for the treatment of crow's feet: a double-blinded, placebo-controlled trial. Dermatol Surg 2003;508­15. 11. Guerrissi J. Intraoperative injection of botulinum toxin A into the orbicularis oculi muscle for the treatment of crow's feet. Plast Reconstr Surg 2003;112:161­3S. 12. Levy J, Servant J, Jouve E. Botulinum toxin A: a 9-month clinical and 3D in vivo profilometric crow's feet wrinkle formation study. J Cosmet Laser Ther 2004;6:16­20. 13. Lowe N, Ascher B, Heckmann M, et al. Double-blind, randomized, placebo-controlled, dose-response study of the safety and efficacy of botulinum toxin type A in subjects with crow's feet. Dermatol Surg 2005;31:257­562. 14. Ascher B, Rzany B, Grover R. Efficacy and safety of botulinum toxin type A in the treatment of lateral crow's feet: double-blind, placebo-controlled, dose-ranging study. Dermatol Surg 2009;35:1478­86. 15. Cote T, Mohan A, Polder J, et al. Botulinum toxin type A injec´ tions: adverse events reported to the US Food and Drug Administration in therapeutic and cosmetic cases. J Am Acad Dermatol 2005;53:407­15. 16. Pena M, Alam M, Yoo S. Complications with the use of botulinum toxin type A for cosmetic applications and hyperhidrosis. Semin Cutan Med Surg 2007;26:29­33. 17. Matarasso S, Matarasso A. Treatment guidelines for botulinum toxin type A for the periocular region and a report on partial upper lip ptosis following injections to the lateral canthal rhytids. Plast Reconstr Surg 2001;108:208­14. 18. Matarasso S. Decreased tear expression with an abnormal Schirmer's test following botulinum toxin type A for the treatment of lateral canthal rhytides. Dermatol Surg 2002;28:149­52. 19. Arat Y, Yen M. Effect of botulinum toxin type A on tear production after treatment of lateral canthal rhytids. Ophthal Plast Reconstr Surg 2007;23:22­4. 20. Racette B, Lopate G, Good L, et al. Ptosis as a remote effect of therapeutic botulinum toxin B injection. Neurology 2002;59:1445­7. 21. Rowe F, Noonan C. Botulinum toxin for the treatment of strabismus. Cochrane Database Syst Rev 2009:CD006499.

Conclusions The topical application of a novel product containing BoNTA achieved primary and secondary efficacy end points. RT001 significantly reduced the severity of LCLs or crow's feet wrinkles after each of two applications 4 weeks apart. There was no greater frequency, severity, or duration of AEs or other safety parameters in subjects treated with RT001 than in placebo-treated subjects after either application. Based on these promising results, larger clinical studies for assessing the safety and efficacy of RT001 for the treatment of LCLs are warranted.

References

1. Carruthers J, Carruthers J. Treatment of glabellar frown lines with C. botulinum-A exotoxin. J Dermatol Surg Oncol 1992;18:17­21. 2. Botoxs Cosmetic (onabotulinumtoxinA) for injection Prescribing Information. Allergan 2009. 3. Dysportt for Injection (abobotulinumtoxinA) Prescribing Information. Medicis Aesthetics 2009. 4. ASAPS. Cosmetic Procedures in 2009. American Society for Aesthetic Plastic Surgery 2010; Available at: http://www. surgery.org/consumers/consumer-resources/news-and-trends/ 117-cosmetic-procedures-in-2007 Accessed April 2010. 5. Keen M, Blitzer A, Aviv J, et al. Botulinum toxin A for hyperkinetic facial lines: results of a double-blind, placebo-controlled study. Plast Reconstr Surg 1994;94:94­9.

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22. Dutton J, Fowler A. Botulinum toxin in ophthalmology. Surv Ophthalmol 2007;52:13­31. 23. Sarifakioglu N, Sarifakioglu E. Evaluating the effects of ice application on the pain felt during botulinum toxin type-a injections: a prospective, randomized, single-blind controlled trial. Ann Plast Surg 2004;53:543­6. 24. Wollina U, Konrad H. Managing adverse events associated with botulinum toxin type A: a focus on cosmetic procedures. Am J Clin Dermatol 2005;6:141­50. 25. Carruthers A, Carruthers J. Single-center, double-blind, randomized study to evaluate the efficacy of 4% lidocaine cream versus vehicle cream during botulinum toxin type A treatments. Dermatol Surg 2005;31:165­9. 26. Bates B. A Guide to Physical Examination and History Taking. 6th ed. Philadelphia: Lippincott; 1997.

27. Yen T, Driscoll C, Lalwani A. Significance of House-Brackmann facial nerve grading global score in the setting of differential facial nerve function. Otol Neurotol 2003;24:118­22. 28. Dykes P, Marks R. An evaluation of the irritancy potential of povidone iodine solutions: comparison of subjective and objective assessment techniques. Clin Exp Dermatol 1992;17:246­9. 29. Food and Drug Administration. Guidance for Industry. Skin Irritation and Sensitization Testing of Generic Transdermal Drug Products. US Department of Health and Human Services, Center for Drug Evaluation and Research; 1999, Rockville, MD.

Address correspondence and reprint requests to: Fredric Brandt, MD, Dermatology Research Institute, LLC, 4425 Ponce de Leon Boulevard, Suite 200, Coral Gables, FL 33146, or e-mail: [email protected]

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Efficacy and Safety Evaluation of a Novel Botulinum Toxin Topical Gel for the Treatment of Moderate to Severe Lateral Canthal Lines