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Five-year follow-up evaluation of nasolabial folds treated with a novel polymethylmethacrylate collagen filler (a follow up study of subjects treated in the pivotal FDA trial)
P2801
P2803
A phase III, double-blind, randomized, multicenter study evaluating the efficacy and safety of autologous human fibroblast therapy in contour deformities at 4 months David H. McDaniel, MD, Institute of Anti-Aging Research, Eastern Virginia Medical School, Virginia Beach, VA, United States
Five-year follow-up evaluation of nasolabial folds treated with a novel polymethylmethacrylate collagen filler (a follow up study of subjects treated in the pivotal FDA trial) The Artefill Study Group, Artes Medical, San Diego, CA, United States
Background: AT (Isolagen Technologies, Inc. Exton, PA) is a rejuvenation technology utilizing patient dermal fibroblasts cultured to create a biologic framework for tissue repair and regeneration. US experience (;100 clinicians and ;1000 pts) has been encouraging, with effects reported out to 24 months. Methods: A double-blind, randomized, phase III multicenter study compared the acute efficacy and safety of AT versus placebo (P) in contour deformities. Subjects over the age of 18 years indicated for cosmetic treatment for rhytids or facial scars were included in 1 of 2 strata based upon primary facial treatment area: A (rhytids) and B (scars). Subjects received 3 treatments, ;14 days apart, of AT (;2.0 3 107 cells/mL) or P. Multiple defects injected interdermally with the primary site treated first. Evaluations, performed at baseline (BL), months 1, 2, 4, and 6, included a 7point photoguide (investigator, independent blinded reviewer, and subjects) and VAS (investigator and subjects). The primary endpoint involved investigator graded response (2 point decline [BL grade 3-7], 1 point decline [BL grade 2] versus BL for the primary treatment area at month 4. The secondary endpoints involved %D vs. BL in subject VAS scores, subject scale ratings, investigator VAS scores, and independent reviewer grading of treated sites. Standard statistical methods were utilized for analysis. Safety involved collection of AEs. Results: The ITT population included 158 subjects (116 AT; 42 P): A- 109 (81 AT, 28 P) and B- 49 (35 AT, 14 P). Subjects were a mean age of 46.8 years (46.7 AT, 47.2 P), 90.5% female (94.0% AT, 81.0% P), and 91.8% white (94% AT, 85.7% P). A statistically higher proportion of investigator graded responders (P ¼.0067, CMH) at 4 months was observed with AT versus P in the primary treatment area: A- AT (43.7%), P (12.5%) and B- AT (50%), P (35.7%). Investigator graded response for the primary treated area at month 6 was significant (P ¼ .0011, CMH) for AT versus P: A- AT (53.0%), P (15.8%) and B- AT (58.6%), P (30.8%). Secondary assessments for all treated areas were significant for AT versus P. Treatment-related AEs, observed in 19.8% of AT and 5.0% of P subjects (P ¼.0409), were mild to moderate and injection siteerelated (17% AT, 2.5% P). No patients dropped out to treatment-related AEs. No SAEs were reported. Conclusions: AT was well tolerated overall and was more effective than P at month 4 visit for facial rhytids and acne scars. These effects improved further with AT versus P at month 6.
A novel soft tissue filler containing polymethylmeahacrylate (PMMA) microspheres in a collagen gel suspension with 0.3% lidocaine was recently approved in the United States for the correction of nasolabial folds. FDA approval was based upon a pivotal multicenter (8 total), randomized, double-masked, controlled study in 251 subjects comparing 128 treated with this novel PMMA based filler versus 123 control subjects using an FDA-approved bovine collagen filler. Improvement was assessed using a validated facial fold assessment (FFA) scale (a photometric grading scale from 0 [minimal] to 5 [severe]). After the 6-month evaluation, the control subjects, who lost remaining clinical benefit, were allowed to cross over to the novel PMMA collagen filler, resulting in a total of 234 subjects (128 original and 106 crossover) treated with this novel PMMA filler. At 6 months, the novel PMMA based filler showed significant improvement over control (P\.001), and at 12 months, the novel PMMA-based filler subjects showed significant improvement over baseline (P \.001), for both masked observer and investigator FFA scores. In a separate longterm follow-up study, 5 years after their last treatment, these subjects were evaluated to further substantiate safety and efficacy of this novel filler. Of the 234 subjects, 62% (145/234) of subjects responded to mail/phone requests to participate; however, 3 subjects were excluded from the efficacy analysis because their long-term follow-up period was less than 4.5 years. Of the remaining 142 subjects (83 original, 60 crossover), 15 were males and 127 females (mean age, 52.4 yrs), with a mean followup period of 5.36 years (range, 4.53-6.32 yrs). Based on FFA grading (masked observer and investigator) a significant degree of correction at the 5-year evaluation over baseline was observed (P \.001). The subjects also continued to demonstrate improvement with the 5-year evaluation of wrinkle correction statistically significant compared to that at 6 months (P ¼.002). Similarly, investigators rated treatment success; 90% of subjects receiving the top two responses (very successful or completely successful) and patients rated treatment satisfaction; with 90% receiving the top two responses (very satisfied or satisfied). The majority of adverse events reported were mild and similar to the pivotal study. A detailed listing will be presented. In summary, this is the first soft tissue filler to demonstrate a significant efficacy and safety profile over a 5-year period. Supported by Artes Medical.
100% supported by Isolagen Technologies, Inc.
P2802
P2804
A phase III, double-blind, randomized, multicenter study evaluating the efficacy and safety of autologous human fibroblast therapy in contour deformities at 6 months David H. McDaniel, MD, Institute of Anti-Aging Research, Eastern Virginia Medical School, Virginia Beach, VA, United States Background: AT (Isolagen Technologies, Inc. Exton, PA) is a rejuvenation technology utilizing patient dermal fibroblasts cultured to create a biologic framework for tissue repair and regeneration. US experience has involved ;100 clinicians and ;1000 pts; facial rhytid effects have been encouraging. One 40-subject, phase II study cited a 55.6% response rate at 4 months with few AEs. Others have observed effects out to 24 months.
Comparison of HA fragment concentration and molecular weight in various HA-based dermal filler products LiPing Yu, PhD, Genzyme Co., Cambridge, MA, United States; Laura Yang, Genzyme Co., Cambridge, MA, United States; Elizabeth Voschin, Geznyme Co., Cambridge, MA, United States; Joseph Kablik, Genzyme Co., Cambridge, MA, United States Study objective: The authors set out to quantify low molecular weight (LMW) hyaluronan (HA) fragments in commercial HA dermal fillers. The molecular weight (MW) of HA has been shown to impact the phenotypic expression of cells both in vitro and in vivo. In the literature, it can be found that high MW HA ([500 kDa) causes cells to display a normal or noninflammatory phenotype, while LMW HA (\500 kDa) has been shown to stimulate expression of a proinflammatory phenotype. Although a potential for an inflammatory response has been reported, the fleeting residence time of LMW HA fragments in normal cell conditions make the clinical impact of LMW HA fragments unclear.
Methods: A double-blind, randomized, phase III, multicenter study compared the efficacy and safety of AT and placebo (P) in contour deformities at month 6. Subjects over the age of 18 years in whom cosmetic treatment was indicated for 1 nasolabial fold (NL) and 1 glabellar line (GL) rated [2 on a 6-point Lemperle scale. Those excluded had [10 cm in total treatment length or prior treatments within 6 mo. Subjects received 3 treatments, 7 to 14 days apart, of AT (;2.0 3 107 cells/mL) or P. Up to 4 deformities (2 NL, 2 GL) were treated with intradermal injections of 0.1mL/linear cm. Two medical evaluators using a 6-point scale and subjects employing a VAS graded treated areas at baseline (BL), at 2, 4, and 6 months, then at 12 months (long-term follow up). Coprimary endpoints assessed the primary NL (worst at BL) and included investigator-graded response (2-point decrease vs. BL) and percent change (%D) in VAS vs. BL at mo 6. Secondary assessments at mo 6 were responses and %D VAS for NL, GL, and all treated areas. Cochran-Mantel-Haenszel test was used for response and ANCOVA for VAS. Safety involved reporting of AEs. Results: The intent-to-treat (ITT) population consisted of 115 subjects (AT: 58; P 57), with a mean age of 54 years (54.1 AT, 55.6 P). Subjects were 97.4% female (96.6 % AT, 98.2 % P) and 99.1% white (100% AT, 98.2% P). Primary NL response at 6 months was reported in 48.3% of AT and 26.3% of P subjects (P ¼ .0079; Cochran-MantelHaenszel). The %D VAS at month 6 for the primary NL was -26.64% for AT versus 3.92% for P (D -22.72%; P ¼ .0166). AT was significant for all secondary assessments. AEs, observed in 25.0% of AT and 13.0% of P subjects, were mildto-moderate (AT 23.1%; P 13.0%) and administration site related (17.3% AT; 3.7% P). Two SAEs (1 AT, 1 P) were documented.
Methods: Dermal filler samples were diluted, vortexed, and centrifuged to extract the soluble HA. The supernatant was filtered through a filter and injected through a size exclusion chromatograph with multi-angle laser light scattering system for MW and concentration analysis. The system provides direct MW and concentration measurement; with proper column separation conditions, the molecular weight distribution of a given HA sample can be determined. A known concentration of LMW HA was prepared as a control. Based on the calibration curve from the control, the peak ID for HA mass calculation at MW # 300 KDa and # 50 KDa were determined. The same peak ID is used to calculate the mass of HA fragments at MW # 300 KDa and # 50 KDa. Results: Eight marketed dermal fillers from 4 different companies were evaluated for HA fragment concentration. Dermal fillers were tested from Genzyme Co., Medicis Aesthetics Inc., Allergan Inc., and Mentor Co. Results show that there is a wide range of HA fragments found in commercially available dermal fillers. Concentrations ranged from 0.3 to 7.9 mg/ml for HA fragments below 300 kDa and 0.025 to 1.9 mg/ml for HA fragments below 50 kDa. All of the tested products had the average molecular weight (MW) of the soluble HA below or near 500 kDa.
Conclusions: AT was well tolerated and significant for both coprimary endpoints. These results appear consistent with prior experience. Follow up at 12 months will further characterize effects. Additional phase III studies are being conducted to further evaluate AT’s safety and effectiveness in facial rhytids.
Conclusion: The results of this study show that a wide range of LMW HA fragments are found in commercially available dermal fillers. The concentration of fragments below 300 KDa ranged from 0.3 to 7.9 mg/ml, while the concentration of fragments below 50 KDa ranged from 0.025 to 1.9 mg/ml. Although the literature indicates a potential of an inflammatory response because of the presence of these fragments, further studies are required to determine their clinical impact.
100% sponsored by Isolagen Techologies, Inc.
100% sponsored by Genzyme Co.
AB136
J AM ACAD DERMATOL
FEBRUARY 2008
P2803
A phase III, double-blind, randomized, multicenter study evaluating the efficacy and safety of autologous human fibroblast therapy in contour deformities at 4 months David H. McDaniel, MD, Institute of Anti-Aging Research, Eastern Virginia Medical School, Virginia Beach, VA, United States
Five-year follow-up evaluation of nasolabial folds treated with a novel polymethylmethacrylate collagen filler (a follow up study of subjects treated in the pivotal FDA trial) The Artefill Study Group, Artes Medical, San Diego, CA, United States
Background: AT (Isolagen Technologies, Inc. Exton, PA) is a rejuvenation technology utilizing patient dermal fibroblasts cultured to create a biologic framework for tissue repair and regeneration. US experience (;100 clinicians and ;1000 pts) has been encouraging, with effects reported out to 24 months. Methods: A double-blind, randomized, phase III multicenter study compared the acute efficacy and safety of AT versus placebo (P) in contour deformities. Subjects over the age of 18 years indicated for cosmetic treatment for rhytids or facial scars were included in 1 of 2 strata based upon primary facial treatment area: A (rhytids) and B (scars). Subjects received 3 treatments, ;14 days apart, of AT (;2.0 3 107 cells/mL) or P. Multiple defects injected interdermally with the primary site treated first. Evaluations, performed at baseline (BL), months 1, 2, 4, and 6, included a 7point photoguide (investigator, independent blinded reviewer, and subjects) and VAS (investigator and subjects). The primary endpoint involved investigator graded response (2 point decline [BL grade 3-7], 1 point decline [BL grade 2] versus BL for the primary treatment area at month 4. The secondary endpoints involved %D vs. BL in subject VAS scores, subject scale ratings, investigator VAS scores, and independent reviewer grading of treated sites. Standard statistical methods were utilized for analysis. Safety involved collection of AEs. Results: The ITT population included 158 subjects (116 AT; 42 P): A- 109 (81 AT, 28 P) and B- 49 (35 AT, 14 P). Subjects were a mean age of 46.8 years (46.7 AT, 47.2 P), 90.5% female (94.0% AT, 81.0% P), and 91.8% white (94% AT, 85.7% P). A statistically higher proportion of investigator graded responders (P ¼.0067, CMH) at 4 months was observed with AT versus P in the primary treatment area: A- AT (43.7%), P (12.5%) and B- AT (50%), P (35.7%). Investigator graded response for the primary treated area at month 6 was significant (P ¼ .0011, CMH) for AT versus P: A- AT (53.0%), P (15.8%) and B- AT (58.6%), P (30.8%). Secondary assessments for all treated areas were significant for AT versus P. Treatment-related AEs, observed in 19.8% of AT and 5.0% of P subjects (P ¼.0409), were mild to moderate and injection siteerelated (17% AT, 2.5% P). No patients dropped out to treatment-related AEs. No SAEs were reported. Conclusions: AT was well tolerated overall and was more effective than P at month 4 visit for facial rhytids and acne scars. These effects improved further with AT versus P at month 6.
A novel soft tissue filler containing polymethylmeahacrylate (PMMA) microspheres in a collagen gel suspension with 0.3% lidocaine was recently approved in the United States for the correction of nasolabial folds. FDA approval was based upon a pivotal multicenter (8 total), randomized, double-masked, controlled study in 251 subjects comparing 128 treated with this novel PMMA based filler versus 123 control subjects using an FDA-approved bovine collagen filler. Improvement was assessed using a validated facial fold assessment (FFA) scale (a photometric grading scale from 0 [minimal] to 5 [severe]). After the 6-month evaluation, the control subjects, who lost remaining clinical benefit, were allowed to cross over to the novel PMMA collagen filler, resulting in a total of 234 subjects (128 original and 106 crossover) treated with this novel PMMA filler. At 6 months, the novel PMMA based filler showed significant improvement over control (P\.001), and at 12 months, the novel PMMA-based filler subjects showed significant improvement over baseline (P \.001), for both masked observer and investigator FFA scores. In a separate longterm follow-up study, 5 years after their last treatment, these subjects were evaluated to further substantiate safety and efficacy of this novel filler. Of the 234 subjects, 62% (145/234) of subjects responded to mail/phone requests to participate; however, 3 subjects were excluded from the efficacy analysis because their long-term follow-up period was less than 4.5 years. Of the remaining 142 subjects (83 original, 60 crossover), 15 were males and 127 females (mean age, 52.4 yrs), with a mean followup period of 5.36 years (range, 4.53-6.32 yrs). Based on FFA grading (masked observer and investigator) a significant degree of correction at the 5-year evaluation over baseline was observed (P \.001). The subjects also continued to demonstrate improvement with the 5-year evaluation of wrinkle correction statistically significant compared to that at 6 months (P ¼.002). Similarly, investigators rated treatment success; 90% of subjects receiving the top two responses (very successful or completely successful) and patients rated treatment satisfaction; with 90% receiving the top two responses (very satisfied or satisfied). The majority of adverse events reported were mild and similar to the pivotal study. A detailed listing will be presented. In summary, this is the first soft tissue filler to demonstrate a significant efficacy and safety profile over a 5-year period. Supported by Artes Medical.
100% supported by Isolagen Technologies, Inc.
P2802
P2804
A phase III, double-blind, randomized, multicenter study evaluating the efficacy and safety of autologous human fibroblast therapy in contour deformities at 6 months David H. McDaniel, MD, Institute of Anti-Aging Research, Eastern Virginia Medical School, Virginia Beach, VA, United States Background: AT (Isolagen Technologies, Inc. Exton, PA) is a rejuvenation technology utilizing patient dermal fibroblasts cultured to create a biologic framework for tissue repair and regeneration. US experience has involved ;100 clinicians and ;1000 pts; facial rhytid effects have been encouraging. One 40-subject, phase II study cited a 55.6% response rate at 4 months with few AEs. Others have observed effects out to 24 months.
Comparison of HA fragment concentration and molecular weight in various HA-based dermal filler products LiPing Yu, PhD, Genzyme Co., Cambridge, MA, United States; Laura Yang, Genzyme Co., Cambridge, MA, United States; Elizabeth Voschin, Geznyme Co., Cambridge, MA, United States; Joseph Kablik, Genzyme Co., Cambridge, MA, United States Study objective: The authors set out to quantify low molecular weight (LMW) hyaluronan (HA) fragments in commercial HA dermal fillers. The molecular weight (MW) of HA has been shown to impact the phenotypic expression of cells both in vitro and in vivo. In the literature, it can be found that high MW HA ([500 kDa) causes cells to display a normal or noninflammatory phenotype, while LMW HA (\500 kDa) has been shown to stimulate expression of a proinflammatory phenotype. Although a potential for an inflammatory response has been reported, the fleeting residence time of LMW HA fragments in normal cell conditions make the clinical impact of LMW HA fragments unclear.
Methods: A double-blind, randomized, phase III, multicenter study compared the efficacy and safety of AT and placebo (P) in contour deformities at month 6. Subjects over the age of 18 years in whom cosmetic treatment was indicated for 1 nasolabial fold (NL) and 1 glabellar line (GL) rated [2 on a 6-point Lemperle scale. Those excluded had [10 cm in total treatment length or prior treatments within 6 mo. Subjects received 3 treatments, 7 to 14 days apart, of AT (;2.0 3 107 cells/mL) or P. Up to 4 deformities (2 NL, 2 GL) were treated with intradermal injections of 0.1mL/linear cm. Two medical evaluators using a 6-point scale and subjects employing a VAS graded treated areas at baseline (BL), at 2, 4, and 6 months, then at 12 months (long-term follow up). Coprimary endpoints assessed the primary NL (worst at BL) and included investigator-graded response (2-point decrease vs. BL) and percent change (%D) in VAS vs. BL at mo 6. Secondary assessments at mo 6 were responses and %D VAS for NL, GL, and all treated areas. Cochran-Mantel-Haenszel test was used for response and ANCOVA for VAS. Safety involved reporting of AEs. Results: The intent-to-treat (ITT) population consisted of 115 subjects (AT: 58; P 57), with a mean age of 54 years (54.1 AT, 55.6 P). Subjects were 97.4% female (96.6 % AT, 98.2 % P) and 99.1% white (100% AT, 98.2% P). Primary NL response at 6 months was reported in 48.3% of AT and 26.3% of P subjects (P ¼ .0079; Cochran-MantelHaenszel). The %D VAS at month 6 for the primary NL was -26.64% for AT versus 3.92% for P (D -22.72%; P ¼ .0166). AT was significant for all secondary assessments. AEs, observed in 25.0% of AT and 13.0% of P subjects, were mildto-moderate (AT 23.1%; P 13.0%) and administration site related (17.3% AT; 3.7% P). Two SAEs (1 AT, 1 P) were documented.
Methods: Dermal filler samples were diluted, vortexed, and centrifuged to extract the soluble HA. The supernatant was filtered through a filter and injected through a size exclusion chromatograph with multi-angle laser light scattering system for MW and concentration analysis. The system provides direct MW and concentration measurement; with proper column separation conditions, the molecular weight distribution of a given HA sample can be determined. A known concentration of LMW HA was prepared as a control. Based on the calibration curve from the control, the peak ID for HA mass calculation at MW # 300 KDa and # 50 KDa were determined. The same peak ID is used to calculate the mass of HA fragments at MW # 300 KDa and # 50 KDa. Results: Eight marketed dermal fillers from 4 different companies were evaluated for HA fragment concentration. Dermal fillers were tested from Genzyme Co., Medicis Aesthetics Inc., Allergan Inc., and Mentor Co. Results show that there is a wide range of HA fragments found in commercially available dermal fillers. Concentrations ranged from 0.3 to 7.9 mg/ml for HA fragments below 300 kDa and 0.025 to 1.9 mg/ml for HA fragments below 50 kDa. All of the tested products had the average molecular weight (MW) of the soluble HA below or near 500 kDa.
Conclusions: AT was well tolerated and significant for both coprimary endpoints. These results appear consistent with prior experience. Follow up at 12 months will further characterize effects. Additional phase III studies are being conducted to further evaluate AT’s safety and effectiveness in facial rhytids.
Conclusion: The results of this study show that a wide range of LMW HA fragments are found in commercially available dermal fillers. The concentration of fragments below 300 KDa ranged from 0.3 to 7.9 mg/ml, while the concentration of fragments below 50 KDa ranged from 0.025 to 1.9 mg/ml. Although the literature indicates a potential of an inflammatory response because of the presence of these fragments, further studies are required to determine their clinical impact.
100% sponsored by Isolagen Techologies, Inc.
100% sponsored by Genzyme Co.
AB136
J AM ACAD DERMATOL
FEBRUARY 2008