COSMETIC The Efficacy and Safety of Liquid-Type Botulinum Toxin Type A for the Management of Moderate to Severe Glabellar Frown Lines Jung Eun Kim, Eun Jong Song, Gwang Seong Choi, Bark-Lynn Lew, Woo-Young Sim, Hoon Kang,
M.D. M.D. M.D. M.D. M.D. M.D.
Seoul and Incheon, Republic of Korea
Background: Botulinum toxin type A has been widely used to correct unwanted hyperfunctional facial lines. Most forms of botulinum toxin type A currently used require reconstitution, which is very inconvenient for users. The authors compared the efficacy and safety of a newly developed liquid-type botulinum toxin type A (MT10109L) and onabotulinumtoxinA (Botox) for moderate to severe glabellar lines. Methods: A double-blind, randomized, active drug–controlled, phase III study with 168 enrolled subjects was performed. The primary efficacy endpoint was the improvement rate at maximum frown at week 4 by the investigators’ live assessment. The secondary efficacy endpoint included the improvement rate at maximum frown at week 16 and at rest at weeks 4 and 16 by live assessment, and the improvement rate at maximum frown and at rest based on photographic assessment at week 4. Self-assessment and self-satisfaction with glabellar line improvement were also evaluated. Results: The improvement rate at maximum frown by live assessment was not significantly different between the MT10109L and Botox groups. In addition, the improvement rate of glabellar lines at rest based on the investigators’ live assessment and photographic assessment was similar in both treatment groups. However, the improvement rate at maximum frown by live assessment at week 16 was significantly higher in the MT10109L group compared with the Botox group. There were no severe adverse events. Conclusions: The efficacy and safety of MT10109L were comparable to those of Botox for the management of glabellar frown lines. MT10109L provides greater convenience because it does not require dilution and has long-lasting effects. (Plast. Reconstr. Surg. 135: 732, 2015.) CLINICAL QUESTION/ LEVEL OF EVIDENCE: Therapeutic, II.
C
hemical denervation of the corrugator and/ or procerus muscles with botulinum toxin type A was pioneered in the mid to late 1980s and meets many of the criteria of an ideal cosmetic technique for the treatment of glabellar frown lines. When carried out by experienced personnel, botulinum toxin type A injection rapidly and From the Department of Dermatology, College of Medicine, Catholic University of Korea; the Department of Dermatology, College of Medicine, Inha University; and the Department of Dermatology, College of Medicine, Kyunghee University. Received for publication December 27, 2013; accepted July 8, 2014. Presented at the Annual Meeting of the American Society for Dermatologic Surgery, in Chicago, Illinois, October 3 through 6, 2013. Copyright © 2015 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000001032
732
reversibly ameliorates or even eliminates glabellar lines, with virtually no significant adverse effects.1–3 In 2002, a decade after the first published report, the efficacy and tolerability of botulinum toxin type A for the treatment of glabellar frown lines4 were finally confirmed in two identical, large, multicenter, placebo-controlled trials.5,6 Since then, botulinum toxin type A has been widely used to temporarily treat glabellar lines and other hyperfunctional facial lines, including horizontal forehead lines (“thinker’s wrinkles”) and lateral orbital lines (“crow’s feet”).7 Commercially available botulinum toxin type A is freeze-dried and requires dilution before use.8–12 However, dilution is sometimes inconvenient and Disclosure: The authors have no financial interest to declare in relation to the content of this article.
www.PRSJournal.com
Volume 135, Number 3 • Management of Glabellar Frown Lines requires careful preparation of exact concentrations while avoiding contamination. Liquid-type botulinum toxin type A, MT10109L (Medytox, Inc., Cheonwon-gun, Republic of Korea), was therefore developed to simplify the procedure and enhance its efficacy. MT10109L does not contain any albumin or animal-derived materials. In this study, we carried out a clinical trial to investigate potential differences in efficacy and safety between the newly developed liquid-type botulinum toxin type A and the existing freeze-dried product.
PATIENTS AND METHODS This study was a prospective, randomized, double-blind, parallel, active drug–controlled, phase III clinical trial for evaluation of the efficacy and safety of MT10109L for glabellar frown line correction performed at three centers (St. Paul’s Hospital, Catholic University of Korea; Inha University Hospital; and Kyunghee University Hospital at Gangdong) in the Republic of Korea. The study and all appropriate amendments were reviewed and approved by the institutional review board at each participating center in accordance with the guidelines published in the Declaration of Helsinki (South Africa, 1996 amendment) and Good Clinical Practice guidelines. All participants provided written informed consent. Participants Male and female volunteers aged 20 to 65 years with glabellar lines were screened by investigators. Subjects with moderate to severe (severity score 2 to 3) glabellar frown lines according to the Facial Wrinkle Scale were enrolled in this study (Table 1). Exclusion criteria included any medical condition (e.g., myasthenia gravis, Lambert-Eaton syndrome, or amyotrophic lateral sclerosis) that Table 1. Scales Used to Assess the Effectiveness of MT10109L and Botox Facial Wrinkle Scale Score
Description
Maximal frown 3 Severe: lines appear clearly formed; the bottoms of the deepest lines are not visible from the surface 2 Moderate: lines appear clearly formed; the bottoms of the deepest lines are visible from the surface 1 Mild: lines noted 0 None: lines not noted Rest 3 Severe: lines readily apparent 2 Moderate: lines noticeable 1 Mild: lines somewhat noticeable 0 None: lines not noticeable
could have put the patient at risk for use of botulinum toxin, prior use of medications that could have affected the neuromuscular junction (e.g., muscle relaxants, spectinomycin hydrochloride, aminoglycosides, polypeptide antibiotics, anticholinergics, or benzodiazepines), or any allergies or hypersensitivity to the drugs or their components. Other exclusion criteria included previous treatment with botulinum toxin within 6 months, other procedures that could have affected glabellar or forehead lines within 6 months, any history of glabellar treatment (including the forehead) such as face lifting and/or permanent implants, or scars that could affect the treatment results. Patients whose glabellar lines could not be satisfactorily improved even with manual stretching were also excluded. Patients were not eligible if they had dermatologic disorders or infection at potential injection sites, or a history of facial nerve paralysis or ptosis. Pregnant or lactating women were also excluded. Study Design All eligible subjects were randomized into two groups at a 1:1 ratio and followed for 16 weeks (Fig. 1). At visit 2 (0 week, baseline), each subject received a five-point set of intramuscular injections with a total dose of 20 units (4 units/0.1 ml) of liquid botulinum toxin type A (MT10109L) or onabotulinumtoxinA (Botox; Allergan, Inc., Irvine, Calif.) in a double-blind manner. The 0.5ml total injection volume was divided into five injections: 0.1 ml (4 units) in the procerus muscle, 0.1 ml (4 units) in each medial corrugator supercilii muscle, and 0.1 ml (4 units) in the middle of each corrugator supercilii muscle (Fig. 2). For this clinical study, we used MT10109L (0.625 ml/vial; 4 units/0.1 ml) and 20 U of Botox. MT10109L did not require additional dilution, but Botox had to be dissolved in 1.25 ml of 0.9% sodium chloride to obtain a concentration of 4 units/0.1 ml. Efficacy Measures During the observation period, the subjects were assessed at 4, 10, and 16 weeks. At each visit, efficacy and safety were assessed by both the investigator and the patient. In addition, standardized digital photographs of the treated facial area were taken in the same setting using the same equipment (EOS 600d; Canon, Inc., Tokyo, Japan) to ensure reproducibility (Fig. 1). Physicians carried out live assessment of glabellar line severity at maximum frown and at rest using the Facial Wrinkle Scale. Three blinded raters assessed the photographs at maximum frown and at rest according to the Facial
733
Plastic and Reconstructive Surgery • March 2015
Fig. 1. Study design and schedule of assessments. hCG, human chorionic gonadotropin.
Fig. 2. Injection sites. Glabellar lines received a single session of either MT10109L or Botox. The 0.5-ml (20 units) total injection volume was divided into five symmetrical intramuscular injections: 0.1 ml (4 units) in the procerus muscle, 0.1 ml (4 units) in each medial corrugator supercilii muscle, and 0.1 ml (4 units) in the middle of each corrugator supercilii muscle.
Wrinkle Scale (Table 1). All investigators used the same standardized photograph grading system. The primary efficacy endpoint was the percentage of responders at maximum frown at week 4 based on the investigators’ live assessment
734
(face-to-face observation). The secondary efficacy endpoint included the following: (1) percentage of responders at maximum frown at week 16; (2) percentage of responders of glabellar lines at rest based on investigators’ live assessment at
Volume 135, Number 3 • Management of Glabellar Frown Lines weeks 4 and 16; and (3) percentage of responders at maximum frown and at rest based on photographic assessment at week 4. In accordance with previous studies for Botox, responders were defined as those who had posttreatment Facial Wrinkle Scale scores of 0 or 1 with pretreatment Facial Wrinkle Scale scores of 2 or 3. This meant an improvement of at least one point for subjects with moderate wrinkles and at least two points for subjects with severe wrinkles. In addition, we included the glabellar line improvement rates determined by self-assessment and satisfaction rates at week 4, 10, and 16 as a secondary efficacy endpoint. Subjects assessed the change in line severity using a nine-point scale from +4 (100 percent improvement) to 0 (no change) to −4 (100 percent worse), and rated their degree of satisfaction with the treatment on a seven-point scale from −3 (very unsatisfied) to +3 (very satisfied). A score of more than +2 points (moderately improved) was considered an improvement, and a score of greater than +2 points (satisfied) was considered to indicate satisfaction. Safety Measures A physical examination was carried out and vital signs were checked at each visit during the study. Investigator- and self-reported signs and symptoms, and laboratory tests (complete blood count and blood chemistry) were performed on the screening day and at week 16. Urine human chorionic gonadotropin level was determined at screening, on the treatment day, and at week 16. All adverse events that occurred after receipt of consent were summarized and analyzed. The incidence of adverse events was documented by comparing the incidence of all adverse events, drug-related adverse events, and severe adverse events. Statistical Analysis All subjects with data for primary endpoints were included in the full analysis set. The perprotocol set was the subset of subjects of the full analysis set who did not commit any major protocol violation. For the primary efficacy endpoint parameter, we calculated the lower limit of the 97.5 percent one-sided confidence interval for the difference in responder rates between two groups. The interpretation of the confidence interval was based on the null hypothesis that the expected difference in responder rates between the treatment groups was lower than the noninferiority margin of −15 percent. A lower limit of estimated confidence interval exceeding −15 percent would indicate that MT10109L was not inferior to Botox.
This confirmatory analysis was based on the perprotocol analysis. For the secondary efficacy endpoint, the paired t test, Pearson chi-square test, or Fisher’s exact test was performed. The Fisher’s exact test was used to test for between-group differences in adverse events. For laboratory variables, blood pressure, and heart rate, the Wilcoxon signed rank test was performed for within-group analyses, and the Wilcoxon rank sum test was used for between-group analyses of data at exit.
RESULTS Baseline Demographic Characteristics Of 168 subjects who were enrolled, 159 completed the study and therefore constituted the per-protocol set, of which 78 subjects were in the MT10109L group and 81 subjects were in the Botox group. Enrolled subject age ranged from 20 to 65 years. The mean age was 48.94 years in the MT10109L group and 49.86 years in the Botox group. All subjects were Korean. The demographics of the two groups were comparable, and the two groups did not differ in their pretreatment line severity, either at rest or at maximum frown. All subjects had moderate to severe glabellar frown lines at rest, and the majority of subjects had severe glabellar frown lines at maximum frown (56.41 percent for the MT10109L group and 50.62 percent for the Botox group) (Table 2). Investigator Assessment Both groups exhibited significant improvement of glabellar lines at week 4, and the improvement persisted until week 16 (Fig. 3). Four weeks after injection, the percentage of responders at maximum frown by live assessment for the perprotocol set was 87.18 percent in the MT10109L group and 87.65 percent in the Botox group. In addition, the percentage of responders in the full analysis sets in the MT10109L and Botox groups was similar to that of the per-protocol set, at 85.54 percent and 85.71 percent, respectively. The 97.5 percent confidence intervals for the difference in response between the two treatment groups (−10.79 percent for per-protocol > −15 percent; −10.47 percent for full analysis set > −15 percent) clearly supported the hypothesis that MT10109L was not inferior to Botox. The percentage of responders at maximum frown by live assessment at week 16 was significantly lower in the Botox group than in the MT10109L group. The percentage of responders in the per-protocol set was 62.34 percent in the
735
Plastic and Reconstructive Surgery • March 2015 Table 2. Subject Demographic Characteristics* Age No. of patients Mean ± SD 20–29 yr 30–39 yr 40–49 yr 50–59 yr 60–65 yr Sex No. of patients Male Female Botulinum toxin injection history No. of patients Yes No Botulinum toxin injections No. of patients Mean ± SD Elapsed time after the administration of botulinum toxin injections, mo Mean ± SD Facial Wrinkle Scale at screening, investigators’ live assessment at maximum frown (point) No. of patients 3 (severe) 2 (moderate)
MT10109L (%)
Botox (%)
78 48.94 ± 9.13 3 (3.85) 7 (8.97) 28 (35.90) 32 (41.03) 8 (10.26)
81 49.86 ± 9.13 3 (3.70) 9 (11.11) 22 (27.16) 39 (48.15) 8 (9.88)
78 19 (24.36) 59 (75.64)
81 15 (18.52) 66 (81.48)
0.3692§
78 15 (19.23) 63 (80.77)
81 12 (14.81) 69 (85.19)
0.4585§
15 1.93 ± 0.26
12 2.00 ± 0.43
0.6547§
22.18 ± 13.28
20.31 ± 16.44
0.6428§
78 44 (56.41) 34 (43.59)
81 41 (50.62) 40 (49.38)
0.4641§
p 0.5226† 0.8081§
*n = 159, per-protocol set. †Two-sample t test. ‡Wilcoxon rank sum test. §Pearson χ2 test.
MT10109L group and 40.51 percent in the Botox group (p = 0.0064) (Table 3). The percentage of responders in the full analysis set was 60.71 percent in the MT10109L group and 41.67 percent in the Botox group (Table 3). Both per-protocol and full analysis set sets showed significantly different responses between the two groups, with MT10109L being superior (Fig. 4). The percentage of responders at rest was assessed at weeks 4 and 16. There was no significant difference between the MT10109L and Botox groups at week 4 in both the per-protocol and full analysis sets. At week 16, the percentage of responders at rest in the per-protocol set was 50.00 percent in the MT10109L group and 31.58 percent in the Botox group, showing significant improvement in the MT10109L group (p = 0.0482). However, in the full analysis set, the percentage of responders in the MT10109L group (50.00 percent) was not significantly different from that of the Botox group (33.33 percent) (p = 0.0641) (Table 3). Photographic assessment by three independent, blinded raters also did not reveal any significant difference between the MT10109L and Botox groups in the responder rate at maximum
736
frown at week 4 in both the per-protocol and full analysis sets (Table 4). Self-Assessment Self-assessment of improvement of glabellar line and satisfaction yielded comparable results for the two groups. The peak improvement rate was defined as the proportion of subjects who scored more than +2 points (moderate improvement) and was assessed at weeks 4, 10, and 16. In both the per-protocol and full analysis sets, the peak improvement rate at weeks 4, 10, and 16 was not significantly different between the MT10109L and Botox groups. The subjective assessment improvement rates were 89.74 percent and 92.59 percent at week 4, 81.82 percent and 91.14 percent at week 10, and 70.13 percent and 68.35 percent at week 16 in the MT10109L and Botox groups of the per-protocol set, respectively. The satisfaction rate was defined as a patient response of “very satisfied” or “satisfied” and was also not significantly different between the MT10109L and Botox groups in the per-protocol or full analysis set, as assessed at weeks 4, 10, and 16. The satisfaction rate was 78.21 percent and 71.60 percent at week 4, 74.03 percent and 68.35 percent at week
Volume 135, Number 3 • Management of Glabellar Frown Lines
Fig. 3. Photographic assessment of treatment effects at 4 weeks and 16 weeks compared to baseline. onaBoNT/A, Botox.
10, and 58.44 percent and 48.10 percent at week 16 in the MT10109L and Botox groups of the perprotocol set, respectively (Fig. 5). Safety Comparable numbers of treatment-emergent adverse events were reported in the MT10109L group (21.43 percent) and in the control group
(16.67 percent) (Table 5). The most frequently reported treatment-emergent adverse events in patients included hypertension (2.38 percent), back pain (2.38 percent), contusion (2.38 percent), injection-site pruritus (2.38 percent), and conjunctivitis (2.38 percent). There were no treatment-related treatment-emergent adverse events in the MT10109L group. The only adverse drug
737
Plastic and Reconstructive Surgery • March 2015 Table 3. Responder Rate by Live Assessment at Maximum Frown MT10109L (%) Botox (%) PP set Week 4 No. of patients Improvement Responder Nonresponder Facial Wrinkle Scale score 3 2 1 0 Week 16 Improvement No. of patients Responder Nonresponder Facial Wrinkle Scale score 3 2 1 0 FAS set Week 4 No. of patients Improvement Responder Nonresponder Facial Wrinkle Scale score 3 2 1 0 Week 16 No. of patients Improvement Responder Nonresponder Facial Wrinkle Scale score 3 2 1 0
78
p*
81
68 (87.18) 10 (12.82)
71 (87.65) 0.9281 10 (12.35)
1 (1.28) 9 (11.54) 39 (50) 29 (37.18)
0 (0) 10 (12.35) 44 (54.32) 27 (33.33)
77 48 (62.34) 29 (37.66)
79 32 (40.51) 0.0064 47 (59.49)
8 (10.39) 21 (27.27) 36 (46.75) 12 (15.58)
8 (10.13) 39 (49.37) 25 (31.65) 7 (8.86)
84
84
71 (85.54) 12 (14.46)
72 (85.71) 0.9747 12 (14.29)
1 (1.2) 11 (13.25) 41 (49.4) 30 (36.14)
1 (1.19) 11 (13.1) 45 (53.57) 27 (32.14)
84
84
51 (60.71) 33 (39.29)
35 (41.67) 0.0135 49 (58.33)
8 (9.52) 25 (29.76) 39 (46.43) 12 (14.29)
9 (10.71) 40 (47.62) 26 (30.95) 9 (10.71)
PP, per-protocol; FAS, full analysis. *Pearson χ2 test.
reaction related to injection was one incident of facial edema reported in the control group. No severe adverse drug reactions were observed in either group. No subjects were withdrawn from the study because of adverse events. Serious adverse events occurring after the patient received the test medication were reported in 1.19 percent of the subjects (one of 84 subjects, one incident) in the MT10109L group and in 2.38 percent of the subjects (two of 84 subjects, two incidents) in the control group. Serious adverse events included a case of acute myocardial infarction and a case of peritonitis in the
738
Botox group. The patient who developed acute myocardial infarction had been previously treated for a cardiac condition in the cardiology department, suggesting that this adverse event was not related to injection of the test drug. Rotator cuff syndrome was reported in one patient of the MT10109L group after receiving the test medication. Laboratory tests and vital signs did not reveal any significant abnormal changes after test drug administration in the MT10109L or Botox group.
DISCUSSION This study demonstrated that MT10109L for the treatment of glabellar lines is safe and effective in Korean subjects. MT10109L treatment resulted in significant improvement of glabellar frown line severity at both maximal contraction and at rest by live assessment at week 4 and week 16. The results of photographic assessment by blinded raters and by self-assessment indicated that Botox and MT10109L did not differ significantly in any variable at any point. Furthermore, MT10109L may provide greater improvement than Botox at week 16. Our results suggested that the effects of MT10109L may persist longer than those of Botox. Commercially available botulinum toxin type A preparations vary widely and have different efficacies and safety concerns because of their unique biological nature.13 Of these, Botox is the best known, dominating the botulinum toxin market since it was first approved and marketed in the United States in 1989.14 As a consequence, the majority of information about handling botulinum toxin type A is associated with Botox.15 This study was therefore designed to compare the efficacy and safety of MT10109L and Botox. All botulinum toxin type A products currently used recommend that reconstitution be performed using various substances before injection, because the products are provided as freeze-dried powder formulations. The supply, dilution, and storage of these products are also inconvenient.8–12 Botox should be stored between 2° and 8°C before use and after reconstitution, and should be used within 24 hours of reconstitution.16 Botox reconstitution requires caution to obtain exact concentrations.8–12 Allergan, the manufacturer of Botox, recommends slow injection of the diluent into the Botox vial, gentle mixing of the Botox with unpreserved saline by rotating the vial, and avoidance of any vigorous agitation of the reconstituted Botox.8 It is believed that foam formation and vigorous
Volume 135, Number 3 • Management of Glabellar Frown Lines
Fig. 4. Responder rate at maximum frown by investigators’ live assessment in the (left) per-protocol set and (right) in the full analysis set. ona-BoNT/A, Botox.
Table 4. Responder Rate by Photographic Assessment (Week 4) Maximum frown PP set No. of patients Responder Nonresponder FAS set No. of patients Responder Nonresponder Resting PP set No. Responder Nonresponder FAS set No. of patients Responder Nonresponder
MT10109L (%)
Botox (%)
p*
78 74 (94.87) 4 (5.13)
81 79 (97.53) 2 (2.47)
0.4369
83 79 (95.18) 4 (4.82)
84 82 (−97.62) 0.4431 2 (−2.38)
44 25 (56.82) 19 (43.18)
47 25 (53.19) 22 (46.81)
0.7282
48 26 (54.17) 22 (45.83)
49 25(51.02) 24 (48.98)
0.7564
PP, per-protocol; FAS, full analysis. *Pearson’s χ2 test.
agitation may render the Botox solution vulnerable to surface denaturation caused by bubbles, or that bubbles may cause toxin dispersion over the surface of the vial.16–18 Furthermore, the process of dilution has the potential of introducing contamination. RimabotulinumtoxinB (Myobloc; Solstice Neurosciences, Louisville, Ky.) is the liquid injection form of botulinum toxin B, but its use is not as widespread as botulinum toxin type A and the equivalent dosage of rimabotulinumtoxinB and botulinum toxin type A has not been studied in detail.15 MT10109L, the first liquid injection form of botulinum toxin type A, was developed to reduce these inconveniences. MT10109L consists of botulinum toxin type A–type macromolecular protein
complexes with molecular weights of 900 kDa, which is similar to Botox (Table 6). Medytox, Inc., the manufacturer of MT10109L, confirmed that the diffusion capacity of MT10109L is similar to that of Botox (unpublished data). MT10109L is provided as a ready-to-use sterile liquid; no reconstitution is required and storage and reuse are more convenient than for Botox. MT10109L can be used for 22 months from the date of manufacture, and this period is expected to be prolonged by extended stability tests. During this period, MT10109L can be reused at any time, whereas Botox should be used within 4 hours to 6 weeks after reconstitution.19,20 The longer stability of MT10109L thus provides an advantage for reuse compared with reconstituted Botox. Moreover, MT10109L is currently available in small amounts (25 units/vial) suitable for treatment of glabellar lines (Table 6). The efficacy of MT10109L persisted longer than Botox in this study. The therapeutic effect of botulinum toxin type A for glabellar line improvement could be detected within 4 weeks after injection and gradually decreased between 3 and 6 months. The longer maintenance period of glabellar line improvement by MT10109L could provide a significant advantage compared with other types of botulinum toxin type A. A meta-analysis by Glogau et al. found that treatment of glabellar lines with 20 units of Botox sustained a clinical effect at week 16 in more than 50 percent of responders.21 In this study, the responder rate of Botox was lower than that of previous reports. Thus, large studies with enrollment of patients from several medical centers and with longer follow-up periods are needed to confirm this result.
739
Plastic and Reconstructive Surgery • March 2015
Fig. 5. (Left) Responder rate by self-assessment (per-protocol set) and (right) self-satisfaction rate (per-protocol set). ona-BoNT/A, Botox.
Table 5. Adverse Events (Safety Set) Adverse Events Total Treatment-emergent adverse events Adverse drug reaction Facial edema Severe adverse events Acute myocardial infarction Peritonitis Rotator cuff syndrome
MT10109L Group (n = 84) (%)
Botox (n = 84) (%)
p
19 (22.62) 18 (21.43)
15 (17.86) 14 (16.67)
0.4424 0.4319
0 (0.00)
1 (1.19)
1
0 (0.00) 0 (0.00) 1 (1.19)
1 (1.19) 1 (1.19) 0 (0.00)
1 1 1
Table 6. Characteristics of Botulinum Toxin Preparations Characteristic Manufacturer Commercial names Toxin serotype
MT10109L
Botox
Medytox, Inc. Neuranox Aqua A
Indications Active substance Complex molecular weight, kDa Units/vial
Glabellar lines Botulinum toxin type A 900 25 Methionine (0.125 mg), polysorbate Stabilizer/vial 20 (0.094 mg) Excipients/vial Sodium chloride (5.625 mg) Formulation Liquid Dilution, ml No reconstitution required Storage 2°–8°C Storage after dilution/temperature Without limitation/2°–8°C
MT10109L could also be applicable for various cosmetic uses that could take advantage of its liquid formulation. We expect that MT10109L could provide the basis for developing various cosmetic products or medical appliances containing stable liquid-type botulinum toxin type A. Whereas currently used botulinum toxin type A contains albumin or gelatin for stabilization,8–12 MT10109L eliminated albumin and other animalderived materials from the manufacturing process. Therefore, MT10109L minimizes the risk of
740
Allergan, Inc. Botox, Botox cosmetic, Vistabel, Vistabex A Blepharospasm, cervical dystonia, glabellar lines, hyperhidrosis, chronic migraine Botulinum toxin type A 900 50 Human serum albumin (0.5 mg) Sodium chloride (0.45 mg) Vacuum-dried powder 1.0–2.5 2°–8°C or < −5°C 24 hr/2°–8°C
infectious diseases, including transmissible spongiform encephalopathy. The adverse events found in our study were similar to those reported previously in the literature. No severe adverse drug reactions were observed for either toxin in this study. MT10109L is as safe as Botox. The limitations of our study included the fact that the majority of the patients were female and that all subjects were Korean; thus, the generalizability of our results may be limited in other
Volume 135, Number 3 • Management of Glabellar Frown Lines patient populations. In addition, the duration of the study was 16 weeks, and future longer term study could be useful.
CONCLUSIONS MT10109L is not inferior to Botox in the improvement of glabellar lines and is comparable in terms of safety for the treatment of relevant symptoms. With its longer maintenance period of glabellar line improvement, simple preparation, storage and reuse, and animal protein-free constituents, MT10109L may be a convenient alternative to the conventional powder formulation of botulinum toxin type A in the future. Hoon Kang, M.D. Department of Dermatology The Catholic University of Korea St. Paul’s Hospital College of Medicine 620-56, Jeonnong-dong Dongdaemoon-ku, Seoul 130-709, Republic of Korea [email protected]
PATIENT CONSENT
Patients provided written consent for the use of their images. ACKNOWLEDGMENTS
This study was supported by Medytox, Inc., Republic of Korea, and the province of Chungcheongbuk-do, Republic of Korea. Medytox, Inc., is the manufacturer of MT10109L. REFERENCES 1. Becker-Wegerich P, Rauch L, Ruzicka T. Botulinum toxin A in the therapy of mimic facial lines. Clin Exp Dermatol. 2001;26:619–630. 2. Letessier S. Treatment of wrinkles with botulinum toxin. J Dermatol Treat. 1999;10:31–36. 3. Alam M, Dover JS, Klein AW, Arndt KA. Botulinum a exotoxin for hyperfunctional facial lines: Where not to inject. Arch Dermatol. 2002;138:1180–1185. 4. Carruthers JD, Carruthers JA. Treatment of glabellar frown lines with C. botulinum-A exotoxin. J Dermatol Surg Oncol. 1992;18:17–21.
5. Carruthers JA, Lowe NJ, Menter MA, et al.; BOTOX Glabellar Lines I Study Group. A multicenter, double-blind, randomized, placebo-controlled study of the efficacy and safety of botulinum toxin type A in the treatment of glabellar lines. J Am Acad Dermatol. 2002;46:840–849. 6. Carruthers JD, Lowe NJ, Menter MA, Gibson J, Eadie N; Botox Glabellar Lines II Study Group. Double-blind, placebo-controlled study of the safety and efficacy of botulinum toxin type A for patients with glabellar lines. Plast Reconstr Surg. 2003;112:1089–1098. 7. Guyuron B, Huddleston SW. Aesthetic indications for botulinum toxin injection. Plast Reconstr Surg. 1994;93:913–918. 8. Allergan, Inc. Botox Summary of Product Characteristics. Vol. 2013. Irvine, Calif: Allergan, Inc; 2010. 9. Merz Pharma GmbH & Co. Xeomin Summary of Product Characteristics. Vol. 2013. Frankfurt, Germany: Merz Pharma GmbH & Co; 2010. 10. Beauford-Ipsen Ltda. Dysport Summary of Product Characteristics. Vol. 2013. Berkshire, UK: Beauford-Ipsen Ltd; 2009. 11. Medytox Inc. Neuronox Summary of Product Characteristics. Vol. 2013. Cheonwon-gun, Korea: Medytox, Inc. 12. Lanzhou Institute of Biological Products. BTXA Summary of Product Characteristics. Vol. 2013. Lanzhou: Lanzhou Institute of Biological Products; 2010. 13. Klein AW, Carruthers A, Fagien S, Lowe NJ. Comparisons among botulinum toxins: An evidence-based review. Plast Reconstr Surg. 2008;121:413e–422e. 14. Yang GH, Jung HH. A new botulinum toxin potentially bioequivalent to onabotulinumtoxinA: Are there any differences at all? Dermatol Surg. 2013;39:165–170. 15. Trindade De Almeida AR, Secco LC, Carruthers A. Handling botulinum toxins: An updated literature review. Dermatol Surg. 2011;37:1553–1565. 16. Huang W, Foster JA, Rogachefsky AS. Pharmacology of botulinum toxin. J Am Acad Dermatol. 2000;43:249–259. 17. Carter SR, Seiff SR. Cosmetic botulinum toxin injections. Int Ophthalmol Clin. 1997;37:69–79. 18. Fagien S, Brandt FS. Primary and adjunctive use of botulinum toxin type A (Botox) in facial aesthetic surgery: Beyond the glabella. Clin Plast Surg. 2001;28:127–148. 19. Carruthers J, Fagien S, Matarasso SL; Botox Consensus Group. Consensus recommendations on the use of botulinum toxin type a in facial aesthetics. Plast Reconstr Surg. 2004;114(Suppl):1S–22S. 20. Hexsel DM, De Almeida AT, Rutowitsch M, et al. Multicenter, double-blind study of the efficacy of injections with botulinum toxin type A reconstituted up to six consecutive weeks before application. Dermatol Surg. 2003;29:523–529; discussion 529. 21. Glogau R, Kane M, Beddingfield F, et al. OnabotulinumtoxinA: A meta-analysis of duration of effect in the treatment of glabellar lines. Dermatol Surg. 2012;38:1794–1803.
741
M.D. M.D. M.D. M.D. M.D. M.D.
Seoul and Incheon, Republic of Korea
Background: Botulinum toxin type A has been widely used to correct unwanted hyperfunctional facial lines. Most forms of botulinum toxin type A currently used require reconstitution, which is very inconvenient for users. The authors compared the efficacy and safety of a newly developed liquid-type botulinum toxin type A (MT10109L) and onabotulinumtoxinA (Botox) for moderate to severe glabellar lines. Methods: A double-blind, randomized, active drug–controlled, phase III study with 168 enrolled subjects was performed. The primary efficacy endpoint was the improvement rate at maximum frown at week 4 by the investigators’ live assessment. The secondary efficacy endpoint included the improvement rate at maximum frown at week 16 and at rest at weeks 4 and 16 by live assessment, and the improvement rate at maximum frown and at rest based on photographic assessment at week 4. Self-assessment and self-satisfaction with glabellar line improvement were also evaluated. Results: The improvement rate at maximum frown by live assessment was not significantly different between the MT10109L and Botox groups. In addition, the improvement rate of glabellar lines at rest based on the investigators’ live assessment and photographic assessment was similar in both treatment groups. However, the improvement rate at maximum frown by live assessment at week 16 was significantly higher in the MT10109L group compared with the Botox group. There were no severe adverse events. Conclusions: The efficacy and safety of MT10109L were comparable to those of Botox for the management of glabellar frown lines. MT10109L provides greater convenience because it does not require dilution and has long-lasting effects. (Plast. Reconstr. Surg. 135: 732, 2015.) CLINICAL QUESTION/ LEVEL OF EVIDENCE: Therapeutic, II.
C
hemical denervation of the corrugator and/ or procerus muscles with botulinum toxin type A was pioneered in the mid to late 1980s and meets many of the criteria of an ideal cosmetic technique for the treatment of glabellar frown lines. When carried out by experienced personnel, botulinum toxin type A injection rapidly and From the Department of Dermatology, College of Medicine, Catholic University of Korea; the Department of Dermatology, College of Medicine, Inha University; and the Department of Dermatology, College of Medicine, Kyunghee University. Received for publication December 27, 2013; accepted July 8, 2014. Presented at the Annual Meeting of the American Society for Dermatologic Surgery, in Chicago, Illinois, October 3 through 6, 2013. Copyright © 2015 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000001032
732
reversibly ameliorates or even eliminates glabellar lines, with virtually no significant adverse effects.1–3 In 2002, a decade after the first published report, the efficacy and tolerability of botulinum toxin type A for the treatment of glabellar frown lines4 were finally confirmed in two identical, large, multicenter, placebo-controlled trials.5,6 Since then, botulinum toxin type A has been widely used to temporarily treat glabellar lines and other hyperfunctional facial lines, including horizontal forehead lines (“thinker’s wrinkles”) and lateral orbital lines (“crow’s feet”).7 Commercially available botulinum toxin type A is freeze-dried and requires dilution before use.8–12 However, dilution is sometimes inconvenient and Disclosure: The authors have no financial interest to declare in relation to the content of this article.
www.PRSJournal.com
Volume 135, Number 3 • Management of Glabellar Frown Lines requires careful preparation of exact concentrations while avoiding contamination. Liquid-type botulinum toxin type A, MT10109L (Medytox, Inc., Cheonwon-gun, Republic of Korea), was therefore developed to simplify the procedure and enhance its efficacy. MT10109L does not contain any albumin or animal-derived materials. In this study, we carried out a clinical trial to investigate potential differences in efficacy and safety between the newly developed liquid-type botulinum toxin type A and the existing freeze-dried product.
PATIENTS AND METHODS This study was a prospective, randomized, double-blind, parallel, active drug–controlled, phase III clinical trial for evaluation of the efficacy and safety of MT10109L for glabellar frown line correction performed at three centers (St. Paul’s Hospital, Catholic University of Korea; Inha University Hospital; and Kyunghee University Hospital at Gangdong) in the Republic of Korea. The study and all appropriate amendments were reviewed and approved by the institutional review board at each participating center in accordance with the guidelines published in the Declaration of Helsinki (South Africa, 1996 amendment) and Good Clinical Practice guidelines. All participants provided written informed consent. Participants Male and female volunteers aged 20 to 65 years with glabellar lines were screened by investigators. Subjects with moderate to severe (severity score 2 to 3) glabellar frown lines according to the Facial Wrinkle Scale were enrolled in this study (Table 1). Exclusion criteria included any medical condition (e.g., myasthenia gravis, Lambert-Eaton syndrome, or amyotrophic lateral sclerosis) that Table 1. Scales Used to Assess the Effectiveness of MT10109L and Botox Facial Wrinkle Scale Score
Description
Maximal frown 3 Severe: lines appear clearly formed; the bottoms of the deepest lines are not visible from the surface 2 Moderate: lines appear clearly formed; the bottoms of the deepest lines are visible from the surface 1 Mild: lines noted 0 None: lines not noted Rest 3 Severe: lines readily apparent 2 Moderate: lines noticeable 1 Mild: lines somewhat noticeable 0 None: lines not noticeable
could have put the patient at risk for use of botulinum toxin, prior use of medications that could have affected the neuromuscular junction (e.g., muscle relaxants, spectinomycin hydrochloride, aminoglycosides, polypeptide antibiotics, anticholinergics, or benzodiazepines), or any allergies or hypersensitivity to the drugs or their components. Other exclusion criteria included previous treatment with botulinum toxin within 6 months, other procedures that could have affected glabellar or forehead lines within 6 months, any history of glabellar treatment (including the forehead) such as face lifting and/or permanent implants, or scars that could affect the treatment results. Patients whose glabellar lines could not be satisfactorily improved even with manual stretching were also excluded. Patients were not eligible if they had dermatologic disorders or infection at potential injection sites, or a history of facial nerve paralysis or ptosis. Pregnant or lactating women were also excluded. Study Design All eligible subjects were randomized into two groups at a 1:1 ratio and followed for 16 weeks (Fig. 1). At visit 2 (0 week, baseline), each subject received a five-point set of intramuscular injections with a total dose of 20 units (4 units/0.1 ml) of liquid botulinum toxin type A (MT10109L) or onabotulinumtoxinA (Botox; Allergan, Inc., Irvine, Calif.) in a double-blind manner. The 0.5ml total injection volume was divided into five injections: 0.1 ml (4 units) in the procerus muscle, 0.1 ml (4 units) in each medial corrugator supercilii muscle, and 0.1 ml (4 units) in the middle of each corrugator supercilii muscle (Fig. 2). For this clinical study, we used MT10109L (0.625 ml/vial; 4 units/0.1 ml) and 20 U of Botox. MT10109L did not require additional dilution, but Botox had to be dissolved in 1.25 ml of 0.9% sodium chloride to obtain a concentration of 4 units/0.1 ml. Efficacy Measures During the observation period, the subjects were assessed at 4, 10, and 16 weeks. At each visit, efficacy and safety were assessed by both the investigator and the patient. In addition, standardized digital photographs of the treated facial area were taken in the same setting using the same equipment (EOS 600d; Canon, Inc., Tokyo, Japan) to ensure reproducibility (Fig. 1). Physicians carried out live assessment of glabellar line severity at maximum frown and at rest using the Facial Wrinkle Scale. Three blinded raters assessed the photographs at maximum frown and at rest according to the Facial
733
Plastic and Reconstructive Surgery • March 2015
Fig. 1. Study design and schedule of assessments. hCG, human chorionic gonadotropin.
Fig. 2. Injection sites. Glabellar lines received a single session of either MT10109L or Botox. The 0.5-ml (20 units) total injection volume was divided into five symmetrical intramuscular injections: 0.1 ml (4 units) in the procerus muscle, 0.1 ml (4 units) in each medial corrugator supercilii muscle, and 0.1 ml (4 units) in the middle of each corrugator supercilii muscle.
Wrinkle Scale (Table 1). All investigators used the same standardized photograph grading system. The primary efficacy endpoint was the percentage of responders at maximum frown at week 4 based on the investigators’ live assessment
734
(face-to-face observation). The secondary efficacy endpoint included the following: (1) percentage of responders at maximum frown at week 16; (2) percentage of responders of glabellar lines at rest based on investigators’ live assessment at
Volume 135, Number 3 • Management of Glabellar Frown Lines weeks 4 and 16; and (3) percentage of responders at maximum frown and at rest based on photographic assessment at week 4. In accordance with previous studies for Botox, responders were defined as those who had posttreatment Facial Wrinkle Scale scores of 0 or 1 with pretreatment Facial Wrinkle Scale scores of 2 or 3. This meant an improvement of at least one point for subjects with moderate wrinkles and at least two points for subjects with severe wrinkles. In addition, we included the glabellar line improvement rates determined by self-assessment and satisfaction rates at week 4, 10, and 16 as a secondary efficacy endpoint. Subjects assessed the change in line severity using a nine-point scale from +4 (100 percent improvement) to 0 (no change) to −4 (100 percent worse), and rated their degree of satisfaction with the treatment on a seven-point scale from −3 (very unsatisfied) to +3 (very satisfied). A score of more than +2 points (moderately improved) was considered an improvement, and a score of greater than +2 points (satisfied) was considered to indicate satisfaction. Safety Measures A physical examination was carried out and vital signs were checked at each visit during the study. Investigator- and self-reported signs and symptoms, and laboratory tests (complete blood count and blood chemistry) were performed on the screening day and at week 16. Urine human chorionic gonadotropin level was determined at screening, on the treatment day, and at week 16. All adverse events that occurred after receipt of consent were summarized and analyzed. The incidence of adverse events was documented by comparing the incidence of all adverse events, drug-related adverse events, and severe adverse events. Statistical Analysis All subjects with data for primary endpoints were included in the full analysis set. The perprotocol set was the subset of subjects of the full analysis set who did not commit any major protocol violation. For the primary efficacy endpoint parameter, we calculated the lower limit of the 97.5 percent one-sided confidence interval for the difference in responder rates between two groups. The interpretation of the confidence interval was based on the null hypothesis that the expected difference in responder rates between the treatment groups was lower than the noninferiority margin of −15 percent. A lower limit of estimated confidence interval exceeding −15 percent would indicate that MT10109L was not inferior to Botox.
This confirmatory analysis was based on the perprotocol analysis. For the secondary efficacy endpoint, the paired t test, Pearson chi-square test, or Fisher’s exact test was performed. The Fisher’s exact test was used to test for between-group differences in adverse events. For laboratory variables, blood pressure, and heart rate, the Wilcoxon signed rank test was performed for within-group analyses, and the Wilcoxon rank sum test was used for between-group analyses of data at exit.
RESULTS Baseline Demographic Characteristics Of 168 subjects who were enrolled, 159 completed the study and therefore constituted the per-protocol set, of which 78 subjects were in the MT10109L group and 81 subjects were in the Botox group. Enrolled subject age ranged from 20 to 65 years. The mean age was 48.94 years in the MT10109L group and 49.86 years in the Botox group. All subjects were Korean. The demographics of the two groups were comparable, and the two groups did not differ in their pretreatment line severity, either at rest or at maximum frown. All subjects had moderate to severe glabellar frown lines at rest, and the majority of subjects had severe glabellar frown lines at maximum frown (56.41 percent for the MT10109L group and 50.62 percent for the Botox group) (Table 2). Investigator Assessment Both groups exhibited significant improvement of glabellar lines at week 4, and the improvement persisted until week 16 (Fig. 3). Four weeks after injection, the percentage of responders at maximum frown by live assessment for the perprotocol set was 87.18 percent in the MT10109L group and 87.65 percent in the Botox group. In addition, the percentage of responders in the full analysis sets in the MT10109L and Botox groups was similar to that of the per-protocol set, at 85.54 percent and 85.71 percent, respectively. The 97.5 percent confidence intervals for the difference in response between the two treatment groups (−10.79 percent for per-protocol > −15 percent; −10.47 percent for full analysis set > −15 percent) clearly supported the hypothesis that MT10109L was not inferior to Botox. The percentage of responders at maximum frown by live assessment at week 16 was significantly lower in the Botox group than in the MT10109L group. The percentage of responders in the per-protocol set was 62.34 percent in the
735
Plastic and Reconstructive Surgery • March 2015 Table 2. Subject Demographic Characteristics* Age No. of patients Mean ± SD 20–29 yr 30–39 yr 40–49 yr 50–59 yr 60–65 yr Sex No. of patients Male Female Botulinum toxin injection history No. of patients Yes No Botulinum toxin injections No. of patients Mean ± SD Elapsed time after the administration of botulinum toxin injections, mo Mean ± SD Facial Wrinkle Scale at screening, investigators’ live assessment at maximum frown (point) No. of patients 3 (severe) 2 (moderate)
MT10109L (%)
Botox (%)
78 48.94 ± 9.13 3 (3.85) 7 (8.97) 28 (35.90) 32 (41.03) 8 (10.26)
81 49.86 ± 9.13 3 (3.70) 9 (11.11) 22 (27.16) 39 (48.15) 8 (9.88)
78 19 (24.36) 59 (75.64)
81 15 (18.52) 66 (81.48)
0.3692§
78 15 (19.23) 63 (80.77)
81 12 (14.81) 69 (85.19)
0.4585§
15 1.93 ± 0.26
12 2.00 ± 0.43
0.6547§
22.18 ± 13.28
20.31 ± 16.44
0.6428§
78 44 (56.41) 34 (43.59)
81 41 (50.62) 40 (49.38)
0.4641§
p 0.5226† 0.8081§
*n = 159, per-protocol set. †Two-sample t test. ‡Wilcoxon rank sum test. §Pearson χ2 test.
MT10109L group and 40.51 percent in the Botox group (p = 0.0064) (Table 3). The percentage of responders in the full analysis set was 60.71 percent in the MT10109L group and 41.67 percent in the Botox group (Table 3). Both per-protocol and full analysis set sets showed significantly different responses between the two groups, with MT10109L being superior (Fig. 4). The percentage of responders at rest was assessed at weeks 4 and 16. There was no significant difference between the MT10109L and Botox groups at week 4 in both the per-protocol and full analysis sets. At week 16, the percentage of responders at rest in the per-protocol set was 50.00 percent in the MT10109L group and 31.58 percent in the Botox group, showing significant improvement in the MT10109L group (p = 0.0482). However, in the full analysis set, the percentage of responders in the MT10109L group (50.00 percent) was not significantly different from that of the Botox group (33.33 percent) (p = 0.0641) (Table 3). Photographic assessment by three independent, blinded raters also did not reveal any significant difference between the MT10109L and Botox groups in the responder rate at maximum
736
frown at week 4 in both the per-protocol and full analysis sets (Table 4). Self-Assessment Self-assessment of improvement of glabellar line and satisfaction yielded comparable results for the two groups. The peak improvement rate was defined as the proportion of subjects who scored more than +2 points (moderate improvement) and was assessed at weeks 4, 10, and 16. In both the per-protocol and full analysis sets, the peak improvement rate at weeks 4, 10, and 16 was not significantly different between the MT10109L and Botox groups. The subjective assessment improvement rates were 89.74 percent and 92.59 percent at week 4, 81.82 percent and 91.14 percent at week 10, and 70.13 percent and 68.35 percent at week 16 in the MT10109L and Botox groups of the per-protocol set, respectively. The satisfaction rate was defined as a patient response of “very satisfied” or “satisfied” and was also not significantly different between the MT10109L and Botox groups in the per-protocol or full analysis set, as assessed at weeks 4, 10, and 16. The satisfaction rate was 78.21 percent and 71.60 percent at week 4, 74.03 percent and 68.35 percent at week
Volume 135, Number 3 • Management of Glabellar Frown Lines
Fig. 3. Photographic assessment of treatment effects at 4 weeks and 16 weeks compared to baseline. onaBoNT/A, Botox.
10, and 58.44 percent and 48.10 percent at week 16 in the MT10109L and Botox groups of the perprotocol set, respectively (Fig. 5). Safety Comparable numbers of treatment-emergent adverse events were reported in the MT10109L group (21.43 percent) and in the control group
(16.67 percent) (Table 5). The most frequently reported treatment-emergent adverse events in patients included hypertension (2.38 percent), back pain (2.38 percent), contusion (2.38 percent), injection-site pruritus (2.38 percent), and conjunctivitis (2.38 percent). There were no treatment-related treatment-emergent adverse events in the MT10109L group. The only adverse drug
737
Plastic and Reconstructive Surgery • March 2015 Table 3. Responder Rate by Live Assessment at Maximum Frown MT10109L (%) Botox (%) PP set Week 4 No. of patients Improvement Responder Nonresponder Facial Wrinkle Scale score 3 2 1 0 Week 16 Improvement No. of patients Responder Nonresponder Facial Wrinkle Scale score 3 2 1 0 FAS set Week 4 No. of patients Improvement Responder Nonresponder Facial Wrinkle Scale score 3 2 1 0 Week 16 No. of patients Improvement Responder Nonresponder Facial Wrinkle Scale score 3 2 1 0
78
p*
81
68 (87.18) 10 (12.82)
71 (87.65) 0.9281 10 (12.35)
1 (1.28) 9 (11.54) 39 (50) 29 (37.18)
0 (0) 10 (12.35) 44 (54.32) 27 (33.33)
77 48 (62.34) 29 (37.66)
79 32 (40.51) 0.0064 47 (59.49)
8 (10.39) 21 (27.27) 36 (46.75) 12 (15.58)
8 (10.13) 39 (49.37) 25 (31.65) 7 (8.86)
84
84
71 (85.54) 12 (14.46)
72 (85.71) 0.9747 12 (14.29)
1 (1.2) 11 (13.25) 41 (49.4) 30 (36.14)
1 (1.19) 11 (13.1) 45 (53.57) 27 (32.14)
84
84
51 (60.71) 33 (39.29)
35 (41.67) 0.0135 49 (58.33)
8 (9.52) 25 (29.76) 39 (46.43) 12 (14.29)
9 (10.71) 40 (47.62) 26 (30.95) 9 (10.71)
PP, per-protocol; FAS, full analysis. *Pearson χ2 test.
reaction related to injection was one incident of facial edema reported in the control group. No severe adverse drug reactions were observed in either group. No subjects were withdrawn from the study because of adverse events. Serious adverse events occurring after the patient received the test medication were reported in 1.19 percent of the subjects (one of 84 subjects, one incident) in the MT10109L group and in 2.38 percent of the subjects (two of 84 subjects, two incidents) in the control group. Serious adverse events included a case of acute myocardial infarction and a case of peritonitis in the
738
Botox group. The patient who developed acute myocardial infarction had been previously treated for a cardiac condition in the cardiology department, suggesting that this adverse event was not related to injection of the test drug. Rotator cuff syndrome was reported in one patient of the MT10109L group after receiving the test medication. Laboratory tests and vital signs did not reveal any significant abnormal changes after test drug administration in the MT10109L or Botox group.
DISCUSSION This study demonstrated that MT10109L for the treatment of glabellar lines is safe and effective in Korean subjects. MT10109L treatment resulted in significant improvement of glabellar frown line severity at both maximal contraction and at rest by live assessment at week 4 and week 16. The results of photographic assessment by blinded raters and by self-assessment indicated that Botox and MT10109L did not differ significantly in any variable at any point. Furthermore, MT10109L may provide greater improvement than Botox at week 16. Our results suggested that the effects of MT10109L may persist longer than those of Botox. Commercially available botulinum toxin type A preparations vary widely and have different efficacies and safety concerns because of their unique biological nature.13 Of these, Botox is the best known, dominating the botulinum toxin market since it was first approved and marketed in the United States in 1989.14 As a consequence, the majority of information about handling botulinum toxin type A is associated with Botox.15 This study was therefore designed to compare the efficacy and safety of MT10109L and Botox. All botulinum toxin type A products currently used recommend that reconstitution be performed using various substances before injection, because the products are provided as freeze-dried powder formulations. The supply, dilution, and storage of these products are also inconvenient.8–12 Botox should be stored between 2° and 8°C before use and after reconstitution, and should be used within 24 hours of reconstitution.16 Botox reconstitution requires caution to obtain exact concentrations.8–12 Allergan, the manufacturer of Botox, recommends slow injection of the diluent into the Botox vial, gentle mixing of the Botox with unpreserved saline by rotating the vial, and avoidance of any vigorous agitation of the reconstituted Botox.8 It is believed that foam formation and vigorous
Volume 135, Number 3 • Management of Glabellar Frown Lines
Fig. 4. Responder rate at maximum frown by investigators’ live assessment in the (left) per-protocol set and (right) in the full analysis set. ona-BoNT/A, Botox.
Table 4. Responder Rate by Photographic Assessment (Week 4) Maximum frown PP set No. of patients Responder Nonresponder FAS set No. of patients Responder Nonresponder Resting PP set No. Responder Nonresponder FAS set No. of patients Responder Nonresponder
MT10109L (%)
Botox (%)
p*
78 74 (94.87) 4 (5.13)
81 79 (97.53) 2 (2.47)
0.4369
83 79 (95.18) 4 (4.82)
84 82 (−97.62) 0.4431 2 (−2.38)
44 25 (56.82) 19 (43.18)
47 25 (53.19) 22 (46.81)
0.7282
48 26 (54.17) 22 (45.83)
49 25(51.02) 24 (48.98)
0.7564
PP, per-protocol; FAS, full analysis. *Pearson’s χ2 test.
agitation may render the Botox solution vulnerable to surface denaturation caused by bubbles, or that bubbles may cause toxin dispersion over the surface of the vial.16–18 Furthermore, the process of dilution has the potential of introducing contamination. RimabotulinumtoxinB (Myobloc; Solstice Neurosciences, Louisville, Ky.) is the liquid injection form of botulinum toxin B, but its use is not as widespread as botulinum toxin type A and the equivalent dosage of rimabotulinumtoxinB and botulinum toxin type A has not been studied in detail.15 MT10109L, the first liquid injection form of botulinum toxin type A, was developed to reduce these inconveniences. MT10109L consists of botulinum toxin type A–type macromolecular protein
complexes with molecular weights of 900 kDa, which is similar to Botox (Table 6). Medytox, Inc., the manufacturer of MT10109L, confirmed that the diffusion capacity of MT10109L is similar to that of Botox (unpublished data). MT10109L is provided as a ready-to-use sterile liquid; no reconstitution is required and storage and reuse are more convenient than for Botox. MT10109L can be used for 22 months from the date of manufacture, and this period is expected to be prolonged by extended stability tests. During this period, MT10109L can be reused at any time, whereas Botox should be used within 4 hours to 6 weeks after reconstitution.19,20 The longer stability of MT10109L thus provides an advantage for reuse compared with reconstituted Botox. Moreover, MT10109L is currently available in small amounts (25 units/vial) suitable for treatment of glabellar lines (Table 6). The efficacy of MT10109L persisted longer than Botox in this study. The therapeutic effect of botulinum toxin type A for glabellar line improvement could be detected within 4 weeks after injection and gradually decreased between 3 and 6 months. The longer maintenance period of glabellar line improvement by MT10109L could provide a significant advantage compared with other types of botulinum toxin type A. A meta-analysis by Glogau et al. found that treatment of glabellar lines with 20 units of Botox sustained a clinical effect at week 16 in more than 50 percent of responders.21 In this study, the responder rate of Botox was lower than that of previous reports. Thus, large studies with enrollment of patients from several medical centers and with longer follow-up periods are needed to confirm this result.
739
Plastic and Reconstructive Surgery • March 2015
Fig. 5. (Left) Responder rate by self-assessment (per-protocol set) and (right) self-satisfaction rate (per-protocol set). ona-BoNT/A, Botox.
Table 5. Adverse Events (Safety Set) Adverse Events Total Treatment-emergent adverse events Adverse drug reaction Facial edema Severe adverse events Acute myocardial infarction Peritonitis Rotator cuff syndrome
MT10109L Group (n = 84) (%)
Botox (n = 84) (%)
p
19 (22.62) 18 (21.43)
15 (17.86) 14 (16.67)
0.4424 0.4319
0 (0.00)
1 (1.19)
1
0 (0.00) 0 (0.00) 1 (1.19)
1 (1.19) 1 (1.19) 0 (0.00)
1 1 1
Table 6. Characteristics of Botulinum Toxin Preparations Characteristic Manufacturer Commercial names Toxin serotype
MT10109L
Botox
Medytox, Inc. Neuranox Aqua A
Indications Active substance Complex molecular weight, kDa Units/vial
Glabellar lines Botulinum toxin type A 900 25 Methionine (0.125 mg), polysorbate Stabilizer/vial 20 (0.094 mg) Excipients/vial Sodium chloride (5.625 mg) Formulation Liquid Dilution, ml No reconstitution required Storage 2°–8°C Storage after dilution/temperature Without limitation/2°–8°C
MT10109L could also be applicable for various cosmetic uses that could take advantage of its liquid formulation. We expect that MT10109L could provide the basis for developing various cosmetic products or medical appliances containing stable liquid-type botulinum toxin type A. Whereas currently used botulinum toxin type A contains albumin or gelatin for stabilization,8–12 MT10109L eliminated albumin and other animalderived materials from the manufacturing process. Therefore, MT10109L minimizes the risk of
740
Allergan, Inc. Botox, Botox cosmetic, Vistabel, Vistabex A Blepharospasm, cervical dystonia, glabellar lines, hyperhidrosis, chronic migraine Botulinum toxin type A 900 50 Human serum albumin (0.5 mg) Sodium chloride (0.45 mg) Vacuum-dried powder 1.0–2.5 2°–8°C or < −5°C 24 hr/2°–8°C
infectious diseases, including transmissible spongiform encephalopathy. The adverse events found in our study were similar to those reported previously in the literature. No severe adverse drug reactions were observed for either toxin in this study. MT10109L is as safe as Botox. The limitations of our study included the fact that the majority of the patients were female and that all subjects were Korean; thus, the generalizability of our results may be limited in other
Volume 135, Number 3 • Management of Glabellar Frown Lines patient populations. In addition, the duration of the study was 16 weeks, and future longer term study could be useful.
CONCLUSIONS MT10109L is not inferior to Botox in the improvement of glabellar lines and is comparable in terms of safety for the treatment of relevant symptoms. With its longer maintenance period of glabellar line improvement, simple preparation, storage and reuse, and animal protein-free constituents, MT10109L may be a convenient alternative to the conventional powder formulation of botulinum toxin type A in the future. Hoon Kang, M.D. Department of Dermatology The Catholic University of Korea St. Paul’s Hospital College of Medicine 620-56, Jeonnong-dong Dongdaemoon-ku, Seoul 130-709, Republic of Korea [email protected]
PATIENT CONSENT
Patients provided written consent for the use of their images. ACKNOWLEDGMENTS
This study was supported by Medytox, Inc., Republic of Korea, and the province of Chungcheongbuk-do, Republic of Korea. Medytox, Inc., is the manufacturer of MT10109L. REFERENCES 1. Becker-Wegerich P, Rauch L, Ruzicka T. Botulinum toxin A in the therapy of mimic facial lines. Clin Exp Dermatol. 2001;26:619–630. 2. Letessier S. Treatment of wrinkles with botulinum toxin. J Dermatol Treat. 1999;10:31–36. 3. Alam M, Dover JS, Klein AW, Arndt KA. Botulinum a exotoxin for hyperfunctional facial lines: Where not to inject. Arch Dermatol. 2002;138:1180–1185. 4. Carruthers JD, Carruthers JA. Treatment of glabellar frown lines with C. botulinum-A exotoxin. J Dermatol Surg Oncol. 1992;18:17–21.
5. Carruthers JA, Lowe NJ, Menter MA, et al.; BOTOX Glabellar Lines I Study Group. A multicenter, double-blind, randomized, placebo-controlled study of the efficacy and safety of botulinum toxin type A in the treatment of glabellar lines. J Am Acad Dermatol. 2002;46:840–849. 6. Carruthers JD, Lowe NJ, Menter MA, Gibson J, Eadie N; Botox Glabellar Lines II Study Group. Double-blind, placebo-controlled study of the safety and efficacy of botulinum toxin type A for patients with glabellar lines. Plast Reconstr Surg. 2003;112:1089–1098. 7. Guyuron B, Huddleston SW. Aesthetic indications for botulinum toxin injection. Plast Reconstr Surg. 1994;93:913–918. 8. Allergan, Inc. Botox Summary of Product Characteristics. Vol. 2013. Irvine, Calif: Allergan, Inc; 2010. 9. Merz Pharma GmbH & Co. Xeomin Summary of Product Characteristics. Vol. 2013. Frankfurt, Germany: Merz Pharma GmbH & Co; 2010. 10. Beauford-Ipsen Ltda. Dysport Summary of Product Characteristics. Vol. 2013. Berkshire, UK: Beauford-Ipsen Ltd; 2009. 11. Medytox Inc. Neuronox Summary of Product Characteristics. Vol. 2013. Cheonwon-gun, Korea: Medytox, Inc. 12. Lanzhou Institute of Biological Products. BTXA Summary of Product Characteristics. Vol. 2013. Lanzhou: Lanzhou Institute of Biological Products; 2010. 13. Klein AW, Carruthers A, Fagien S, Lowe NJ. Comparisons among botulinum toxins: An evidence-based review. Plast Reconstr Surg. 2008;121:413e–422e. 14. Yang GH, Jung HH. A new botulinum toxin potentially bioequivalent to onabotulinumtoxinA: Are there any differences at all? Dermatol Surg. 2013;39:165–170. 15. Trindade De Almeida AR, Secco LC, Carruthers A. Handling botulinum toxins: An updated literature review. Dermatol Surg. 2011;37:1553–1565. 16. Huang W, Foster JA, Rogachefsky AS. Pharmacology of botulinum toxin. J Am Acad Dermatol. 2000;43:249–259. 17. Carter SR, Seiff SR. Cosmetic botulinum toxin injections. Int Ophthalmol Clin. 1997;37:69–79. 18. Fagien S, Brandt FS. Primary and adjunctive use of botulinum toxin type A (Botox) in facial aesthetic surgery: Beyond the glabella. Clin Plast Surg. 2001;28:127–148. 19. Carruthers J, Fagien S, Matarasso SL; Botox Consensus Group. Consensus recommendations on the use of botulinum toxin type a in facial aesthetics. Plast Reconstr Surg. 2004;114(Suppl):1S–22S. 20. Hexsel DM, De Almeida AT, Rutowitsch M, et al. Multicenter, double-blind study of the efficacy of injections with botulinum toxin type A reconstituted up to six consecutive weeks before application. Dermatol Surg. 2003;29:523–529; discussion 529. 21. Glogau R, Kane M, Beddingfield F, et al. OnabotulinumtoxinA: A meta-analysis of duration of effect in the treatment of glabellar lines. Dermatol Surg. 2012;38:1794–1803.
741
