phase 2 and phase 3 studies.13,14 Other CCH studies have reported that patients with PD and DC have reduced levels of anti—AUX I and anti—AUX-II antibodies at 5 years posttreatment,9,12 and the presence of neutralizing antibodies does not affect clinical response or the frequency of AEs.8,9
In preclinical rat studies, repeat-dose IV administration at ≥43× the proposed therapeutic human dose (on a mg/kg basis) was reasonably well tolerated. The repeated systemic administration (QOD; 8 IV injections) in this animal study supports the presumption that inadvertent IV administration of CCH as a treatment for cellulite on the thighs or buttocks in women would likely not have a substantial negative impact on patient safety and tolerability. Additionally, the dosing technique for CCH administration involves 12 separate SC injections in a treatment area, thus effectively eliminating the risk of inadvertently administering the full CCH dose of 0.84 mg intravenously in any one particular treatment area.
The data described in the current manuscript support the clinical safety and benign immunogenicity profile of CCH, when administered into the thigh or buttock in women with cellulite. Limitations of the studies are the small sample size of the human PK studies in which to gain additional safety information, evaluation of only single-dose (1 session) SC administration, and use of animal data alone to evaluate inadvertent IV dosing. In conclusion, no quantifiable circulating CCH levels were observed in humans after a single SC dose of CCH up to 3.36 mg, and CCH was generally well tolerated, supporting a lack of systemic exposure after injection of CCH. These data add to the overall favorable safety and tolerability profile of CCH injection.
In preclinical rat studies, repeat-dose IV administration at ≥43× the proposed therapeutic human dose (on a mg/kg basis) was reasonably well tolerated. The repeated systemic administration (QOD; 8 IV injections) in this animal study supports the presumption that inadvertent IV administration of CCH as a treatment for cellulite on the thighs or buttocks in women would likely not have a substantial negative impact on patient safety and tolerability. Additionally, the dosing technique for CCH administration involves 12 separate SC injections in a treatment area, thus effectively eliminating the risk of inadvertently administering the full CCH dose of 0.84 mg intravenously in any one particular treatment area.
The data described in the current manuscript support the clinical safety and benign immunogenicity profile of CCH, when administered into the thigh or buttock in women with cellulite. Limitations of the studies are the small sample size of the human PK studies in which to gain additional safety information, evaluation of only single-dose (1 session) SC administration, and use of animal data alone to evaluate inadvertent IV dosing. In conclusion, no quantifiable circulating CCH levels were observed in humans after a single SC dose of CCH up to 3.36 mg, and CCH was generally well tolerated, supporting a lack of systemic exposure after injection of CCH. These data add to the overall favorable safety and tolerability profile of CCH injection.
DISCLOSURES
ACB reports being a consultant and clinical advisor for Endo Pharmaceuticals Inc.
SV and MPM are employees of Endo Pharmaceuticals Inc.
TP is a former employee of Endo Pharmaceuticals Inc.
MKG reports serving in the speakers’ bureau for Endo Pharmaceuticals Inc., and serving as a consultant for BioSpecifics Technologies Corporation.
Funding: Supported by Endo Pharmaceuticals Inc., Malvern, PA.
SV and MPM are employees of Endo Pharmaceuticals Inc.
TP is a former employee of Endo Pharmaceuticals Inc.
MKG reports serving in the speakers’ bureau for Endo Pharmaceuticals Inc., and serving as a consultant for BioSpecifics Technologies Corporation.
Funding: Supported by Endo Pharmaceuticals Inc., Malvern, PA.
ACKNOWLEDGMENT
Technical editorial and medical writing assistance were provided,
under the direction of the authors, by Mary Beth Moncrief, PhD,
and Julie B. Stimmel, PhD, Synchrony Medical Communications,
LLC, West Chester, PA. Funding for this support was provided by
Endo Pharmaceuticals Inc., Malvern, PA.
REFERENCES
1. Rudolph C, Hladik C, Hamade H, et al. Structural gender dimorphism and the biomechanics of the gluteal subcutaneous tissue: implications for the pathophysiology of cellulite. Plast Reconstr Surg. 2019;143(4):1077-1086.
2. Rossi AB, Vergnanini AL. Cellulite: a review. J Eur Acad Dermatol Venereol. 2000;14(4):251-262.
3. Nürnberger F, Müller G. So-called cellulite: an invented disease. J Dermatol Surg Oncol. 1978;4(3):221-229.
4. Mlosek RK, Woźniak W, Malinowska S, Lewandowski M, Nowicki A. The effectiveness of anticellulite treatment using tripolar radiofrequency monitored by classic and high-frequency ultrasound. J Eur Acad Dermatol Venereol. 2012;26(6):696-703.
5. DiBernardo BE. Treatment of cellulite using a 1440-nm pulsed laser with oneyear follow-up. Aesthet Surg J. 2011;31(3):328-341. 6. Piérard GE, Nizet JL, Piérard-Franchimont C. Cellulite: from standing fat herniation to hypodermal stretch marks. Am J Dermatopathol. 2000;22(1):34- 37.
7. Luebberding S, Krueger N, Sadick NS. Cellulite: an evidence-based review. Am J Clin Dermatol. 2015;16(4):243-256.
8. Xiaflex® (collagenase clostridium histolyticum) for injection, for intralesional use [package insert]. Malvern, PA: Endo Pharmaceuticals Inc; 2018.
9. Peimer CA, Blazar P, Coleman S, Kaplan FT, Smith T, Lindau T. Dupuytren contracture recurrence following treatment with collagenase clostridium histolyticum (CORDLESS [Collagenase Option for Reduction of Dupuytren Long-Term Evaluation of Safety Study]): 5-year data. J Hand Surg Am. 2015;40(8):1597-1605.
10. Peimer CA, Wilbrand S, Gerber RA, Chapman D, Szczypa PP. Safety and tolerability of collagenase Clostridium histolyticum and fasciectomy for Dupuytren's contracture. J Hand Surg Eur Vol. 2015;40(2):141-149.
11. Carson CC, III, Sadeghi-Nejad H, Tursi JP, et al. Analysis of the clinical safety of intralesional injection of collagenase Clostridium histolyticum (CCH) for adults with Peyronie's disease (PD). BJU Int. 2015;116(5):815-822.
12. Goldstein I, Lipshultz LI, McLane M, et al. Long-term safety and curvature deformity characterization in patients previously treated with Collagenase clostridium histolyticum for Peyronie's disease. J Urology. 2020;203(6):1191- 1197.
13. Sadick NS, Goldman MP, Liu G, et al. Collagenase clostridium histolyticum for the treatment of edematous fibrosclerotic panniculopathy (cellulite): a randomized trial. Dermatol Surg. 2019;45(8):1047-1056.
14. Kaufman J, Joseph JH, Kaminer MS, et al. Two randomized, doubleblind, placebo-controlled, phase 3 trials of collagenase clostridium histolyticum (CCH) for the treatment of cellulite (edematous fibrosclerotic panniculopathy). Presented at American Academy of Dermatology Annual Meeting; March 1-5, 2019; Washington, DC.
2. Rossi AB, Vergnanini AL. Cellulite: a review. J Eur Acad Dermatol Venereol. 2000;14(4):251-262.
3. Nürnberger F, Müller G. So-called cellulite: an invented disease. J Dermatol Surg Oncol. 1978;4(3):221-229.
4. Mlosek RK, Woźniak W, Malinowska S, Lewandowski M, Nowicki A. The effectiveness of anticellulite treatment using tripolar radiofrequency monitored by classic and high-frequency ultrasound. J Eur Acad Dermatol Venereol. 2012;26(6):696-703.
5. DiBernardo BE. Treatment of cellulite using a 1440-nm pulsed laser with oneyear follow-up. Aesthet Surg J. 2011;31(3):328-341. 6. Piérard GE, Nizet JL, Piérard-Franchimont C. Cellulite: from standing fat herniation to hypodermal stretch marks. Am J Dermatopathol. 2000;22(1):34- 37.
7. Luebberding S, Krueger N, Sadick NS. Cellulite: an evidence-based review. Am J Clin Dermatol. 2015;16(4):243-256.
8. Xiaflex® (collagenase clostridium histolyticum) for injection, for intralesional use [package insert]. Malvern, PA: Endo Pharmaceuticals Inc; 2018.
9. Peimer CA, Blazar P, Coleman S, Kaplan FT, Smith T, Lindau T. Dupuytren contracture recurrence following treatment with collagenase clostridium histolyticum (CORDLESS [Collagenase Option for Reduction of Dupuytren Long-Term Evaluation of Safety Study]): 5-year data. J Hand Surg Am. 2015;40(8):1597-1605.
10. Peimer CA, Wilbrand S, Gerber RA, Chapman D, Szczypa PP. Safety and tolerability of collagenase Clostridium histolyticum and fasciectomy for Dupuytren's contracture. J Hand Surg Eur Vol. 2015;40(2):141-149.
11. Carson CC, III, Sadeghi-Nejad H, Tursi JP, et al. Analysis of the clinical safety of intralesional injection of collagenase Clostridium histolyticum (CCH) for adults with Peyronie's disease (PD). BJU Int. 2015;116(5):815-822.
12. Goldstein I, Lipshultz LI, McLane M, et al. Long-term safety and curvature deformity characterization in patients previously treated with Collagenase clostridium histolyticum for Peyronie's disease. J Urology. 2020;203(6):1191- 1197.
13. Sadick NS, Goldman MP, Liu G, et al. Collagenase clostridium histolyticum for the treatment of edematous fibrosclerotic panniculopathy (cellulite): a randomized trial. Dermatol Surg. 2019;45(8):1047-1056.
14. Kaufman J, Joseph JH, Kaminer MS, et al. Two randomized, doubleblind, placebo-controlled, phase 3 trials of collagenase clostridium histolyticum (CCH) for the treatment of cellulite (edematous fibrosclerotic panniculopathy). Presented at American Academy of Dermatology Annual Meeting; March 1-5, 2019; Washington, DC.
AUTHOR CORRESPONDENCE
Ashish C. Bhatia MD FAAD ashish@oakderm.com
