Efficacy and Safety of Tapencarium (RZL-012) in Submental Fat Reduction
Efficacy and Safety of Tapencarium (RZL-012) in Submental Fat Reduction
Abstract
novel injectable synthetic molecule with cytolytic properties, capable of reducing subcutaneous fat volume.
Objectives: The goal of this 3-armed, randomized, double-blind, placebo-controlled phase 2b study was to determine the
safety and efficacy of low- and high-dose RZL-012 vs placebo on submental fat (SMF) reduction.
Methods: Patients (n = 151, age 18-65 years) with excess SMF received a single treatment session of RZL-012 or placebo in
the submental area, after which they were monitored for 84 days. SMF was assessed at baseline and after dosing with newly developed scales, namely the Clinician Chin Assessment Tool (C-CAT) and Subject Chin Assessment Tool (S-CAT). SMF
was also assessed by magnetic resonance imaging (MRI) at screening and on Day 84 after treatment.
Results: The proportion of patients who had a 1-grade or 2-grade improvement in C-CAT and/or S-CAT on Day 84 vs baseline was significantly higher in the high-dose RZL-012 group vs the placebo group (P < .002). The relative percentage reduction in MRI-measured SMF volume (Day 84 vs screening) was significantly greater in the high-dose RZL-012 group vs the
low-dose RZL-012 or the placebo group (P < .0001). Local injection site reactions were the most common adverse events
(AEs).
Conclusions: A single administration of RZL-012 into SMF resulted in significant improvement in submental appearance as
assessed by clinicians, patients, and MRI. From a safety perspective, there were no serious AEs and no clinically significant
changes in vital signs or laboratory tests over the course of the study.
Accumulation of submental fat (SMF) represents a common aesthetic concern that appears in people of all age groups. Colloquially referred to as a “double-chin,” SMF can occur regardless of body mass due to genetics or lifestyle factors, contributing to the loss of normal chin and jawline definition.1 Accumulation of SMF can have a significant negative impact on affected individuals, resulting in lowered self-esteem and social activity and causing many to seek medical attention.2 Data collected from 3527 consumers through a blinded online survey on aesthetic procedures found that 70% of patients were most bothered by excessive fat under the chin or neck.3
Treatments of excess SMF can be managed by invasive or noninvasive procedures. Invasive surgical procedures such as liposuction or fat excision carry the risks associated with surgery and may not be a practical option for all patients. In view of these risks as well as extended patient recovery time, there is a large demand for nonsurgical alternatives.4 Noninvasive or minimally invasive options include cryolipolysis (CoolSculpting, Allergan Aesthetics, Irvine, CA) and sodium deoxycholate (KYBELLA, Allergan Aesthetics, Irvine, CA) injections, both of which require more than 1 treatment session. Raziel Therapeutics, a company based in Rehovot, Israel, is developing a novel cytolytic drug (designated RZL-012) that effectively reduces SMF after a single treatment session.
The proposed mechanism of action by which RZL-012 reduces fat volume is through induction of rapid fat cell death at the injected area by irreversibly rupturing cell membrane integrity. Such local elimination of adipocytes results in an improved appearance of the submental area after a single injection cycle, through both reduction of localized subcutaneous fat deposits and formation of firm fibrotic tissue.5
METHODS
Study Design and Demographics
This was an institutional review board–approved, phase 2B double-blind, randomized, dose-ranging, placebo-controlled study. Male and female patients with excess SMF, ages 18 to 65, with BMIs between 22 and 40 were included in the study. Major inclusion criteria were the presence of a visible or large pocket of SMF according to physician global assessment, grade 3 to 4 as rated by both the Clinician Chin assessment Tool (C-CAT) and the Subject Self-Chin Assessment Tool (S-CAT). Each patient was randomized to either active treatment (high- or low-dose RZL-012) or placebo at a ratio of 1:1:1 per group.
Investigational Procedures
The study consisted of a screening period, baseline day during which the injection session was performed, and a posttreatment follow-up period. Patients received a single treatment session that consisted of multiple injections (28-36 injections) of RZL-012 or placebo into the submental area under the chin, after which they were monitored for safety and efficacy over 84 days. Patients were injected with RZL-012 or placebo perpendicular (at 90°) to the skin. An ice pack was placed on the treated area for pain relief immediately after dosing and patients remained seated for an additional 10 minutes after dosing. The injection pattern was based on a submental area shaped grid in which the distance between rows and columns was 1 cm, as seen in Figure 1. The investigator chose 32 ± 4 sequential points on the grid that marked the injected area according to SMF fullness and convexity. The treatment area was bounded superiorly by a line 1 cm inferior to the mandibular margin, laterally by the sternocleidomastoid muscles, and inferiorly by the hyoid bone.
Each patient was randomized to either active treatment (high- or low-dose RZL-012) or placebo at a ratio of 1:1:1 per group and received 1 of the following:
- Low dose: 28 to 36 injections of 5.1 mg/injection point, resulting in an average dose of 166 mg/patient (n = 53)
- High dose: 28 to 36 injections of 7.5 mg/injection point, resulting in an average dose of 244 mg/patient (n = 50)
- Placebo: 28 to 36 injections of vehicle, resulting in a dose of 0 mg/patient (n = 48)
Study Objectives and Endpoints
The objectives of this study were to determine the safety of submental RZL-012 injection and the efficacy of RZL-012 vs placebo treatments on SMF reduction as measured on Day 84 vs baseline.
Safety Endpoints
Safety was monitored by the collection of adverse events (AEs), physical examinations, vital sign measurements, and laboratory testing. All data were evaluated and compared with baseline medical data. AEs were assessed for severity and relation to investigational product. AE monitoring was conducted throughout patients’ participation up to 84 days after injection or until resolution for AEs that were not resolved at 84 days.
Predefined Efficacy Endpoints
The primary endpoint was the proportion of patients who had at least a 1-grade improvement in C-CAT on Day 84 vs baseline in the RZL-012 high-dose group compared with the placebo group. The secondary endpoints were (1) the proportion of patients who had at least a 2-grade improvement in both C-CAT and S-CAT on Day 84 vs baseline in the RZL-012 high-dose group compared with the placebo group; and (2) the reduction in SMF volume as measured by magnetic resonance imaging (MRI) (Day 84 vs screening) in both RZL-012 groups vs the placebo group.
Clinical Measurements and Assessment Tools
Chin Assessment Tools
The chin assessment tools included both a clinician-reported outcome measure (C-CAT) and patient-reported outcome measure (S-CAT). The scales were developed according to PRO (patient-reported outcome) and ClinRO (clinician-reported outcome) guidelines to rate the severity of SMF in adult patients.6-8
The C-CAT and S-CAT scales are proprietary, 5-point validated scales (scored 0-4). The grading system categorizes 3 aspects of SMF: bulge (size of the SMF bulge), neck (extension of the bulge into the neck, downward and lateral), and jawline (the appearance of the jawline, presence of fat, and definition of the jawline). Each grade includes a description and a line drawing. Each grade is distinct and nonoverlapping. SMF ratings with the C-CAT and S-CAT scales were conducted by the treating clinicians’ (C-CAT) and by patients’ (S-CAT) live assessments at screening and baseline and at study visits on Days 28, 56, and 84 to assess the change in SMF area following treatment. Grades 0 to 4 were analogous in the C-CAT and S-CAT tools. A comprehensive training guide was provided to the clinicians and patients.
Magnetic Resonance Imaging (MRI)
MRI was conducted at screening to establish a baseline objective quantitative measurement for assessment of treatment efficacy. Posttreatment MRI was completed at 84 days (±14 days) after dosing. This objective measurement provided a quantitative parameter assessment of SMF reduction following treatment. All SMF MRI measurements were performed in a blinded manner, without the assessor knowing whether they were pretreatment or posttreatment MRIs.
Standardized Photography
Standardized 2-dimensional photography of the submental area (lateral, oblique, and frontal views) was carried out at screening to establish baseline images before treatment. Additional photographs were taken on Days 1, 7, 28, 56, and 84 to evaluate qualitative changes in the SMF area. Photographs were taken with a digital camera according to photography standards employed in practice for the face/neck area.
Statistical Analysis
Primary Endpoint
The chi-square test was applied to test the statistical difference in responder (patients achieving at least a 1-grade improvement in C-CAT score) rate on Day 84 between the placebo group and the high-dose RZL-012 group. The statistical difference between the placebo and low-dose RZL-012 group was also calculated.
Secondary Endpoint 1
The chi-square test was applied to test the statistical difference in responder (patients achieving at least a 2-grade improvement in both C-CAT and S-CAT scores) rate on Day 84 between the placebo group and the RZL-012 high-dose group. The statistical difference between the placebo and RZL-012 low-dose groups was also calculated.
Secondary Endpoint 2
The 2-sample t test for independent samples was applied to test the statistical significance of the percentage change from screening to Day 84 in SMF volume, as measured by MRI, between each of the RZL-012 dose groups and the placebo group. All endpoints were tested with a 2-sided test at the α = 0.05 level of significance. All measured variables and derived parameters were listed individually and, if appropriate, tabulated by descriptive statistics. A patient with missing primary endpoint data was imputed as treatment failure.
Ethics
The study protocol, related documents, and amendments were reviewed and approved by the Advarra Institutional Review Board (NCT04867434). Patients provided written informed consent, by which the patients agreed to the use and analysis of their data, before participating in any study-related activities and were advised that they could voluntarily withdraw from the study at any time. The trial was carried out in accordance with the International Conference on Harmonization Good Clinical Practice and the United States Code of Federal Regulations (CFR) applicable to clinical studies (21 CFR 50 and 56, and 45 CFR 46).
RESULTS
A total of 151 eligible and consenting patients were enrolled in the study. The majority of patients were female (80.1%), white (74.2%), and Fitzpatrick skin type I to III (68.9%), with an average age in all groups between 41.6 and 44.6 years (range, 20 to 65). Table 1 shows the gender, race, and ethnicity distribution of study patients.
Demographic Data—Gender, Race, and Ethnicity
| RZL-012 high dose | RZL-012 low dose | Placebo | |
|---|---|---|---|
| n (%) | n (%) | n (%) | |
| Gender | |||
| Male | 8 (16) | 8 (15.1) | 14 (29.2) |
| Female | 42 (84) | 45 (84.9) | 34 (70.8) |
| Race | |||
| White | 37 (74) | 39 (73.6) | 36 (75.0) |
| Black or African American | 5 (10) | 4 (7.5) | 5 (10.4) |
| American Indian or Alaska Native | 1 (2) | 3 (5.7) | 1 (2.1) |
| Native Hawaiian or other Pacific | 0 (0) | 1 (1.9) | 1 (2.1) |
| Asian | 4 (8) | 5 (9.4) | 5 (10.4) |
| Not reported or unknown | 3 (6) | 1 (1.9) | 0 (0) |
| Ethnicity | |||
| Not Hispanic or Latino | 39 (78) | 37 (69.8) | 38 (79.2) |
| Hispanic or Latino | 11 (22) | 16 (30.2) | 10 (20.8) |
| Country | |||
| USA | 50 (100) | 53 (100) | 48 (100) |
All randomized patients were included in the efficacy analysis set. One patient from the placebo group and 4 patients treated with low-dose RZL-012 were lost to follow-up and did not complete the Day 84 visit. Those patients were included in the C-CAT and S-CAT primary and secondary efficacy analyses by setting their Day 84 scores equal to their baseline scores and defining them as treatment failures.
The primary endpoint achieved statistical significance. Eighty-six percent (86%) of patients in the high-dose RZL-012 group, 73.7% in the low-dose group, and 56.3% of the patients in the placebo group had at least a 1-grade improvement in the C-CAT score (from baseline to Day 84). The difference in proportion of patients between the RZL-012 high-dose and placebo groups was statistically significant at P = .0011. The difference in proportion of patients between the RZL-012 low-dose and placebo groups trended but was not statistically significant (P = .0675). Subgroup analyses determined that there was no significant difference in results on the basis of BMI (≤30 and >30), gender, age (≤30, 30 to ≤40, 40 to ≤50, >50), or Fitzpatrick skin type (types I to III and types IV to VI).
Secondary endpoint 1 also achieved statistical significance. Thirty-four percent (34%) of patients in the high-dose RZL-012 group, 17% in the low-dose group, and 6.3% of the patients in the placebo group had at least a composite 2-grade improvement in both C-CAT and S-CAT scores (from baseline to Day 84). The difference in proportion of patients between the RZL-012 high-dose and placebo groups was statistically significant at P = .0007. The difference in proportion of patients between the RZL-012 low-dose and placebo groups trended but was not statistically significant (P = .0960). Figures 2, 3 are pictures of 2 patients treated with high-dose RZL-012 who met the secondary composite endpoint of improving by at least 2 grades in both C-CAT and S-CAT between baseline and Day 84 visits.
Secondary endpoint 2 MRI analysis was performed on a total of 130 patients, 45 patients in the placebo group, 44 in the low-dose group, and 41 in the high-dose group. Percentage reduction in SMF volume was evaluated by MRI (Day 84 vs screening) in the RZL-012 groups vs placebo group as illustrated in Figure 4. The percentage change in SMF volume on Day 84 vs screening was −14.9% in the high-dose RZL-012 group vs +1.5% in the placebo group (P < .0001). In the low-dose RZL-012 group the change was −8.3% vs +1.5% in the placebo group (P < .0001). A responder analysis demonstrated robust, dose-related differences between the treatment groups, with 68% of high-dose patients, 32% of low-dose patients, and only 2% of placebo patients passing a threshold of at least a 10% reduction in SMF volume measured by MRI. Figures 2, 3 also show before and after MRI scans taken at screening and on Day 84 following treatment.
| MedDRA system organ class/preferred term | Placebo (n = 48) |
RZL-012 low dose (34 mg/mL) (n = 53) | RZL-012 high dose (50 mg/mL) (n = 50) | ||||
|---|---|---|---|---|---|---|---|
| n | % | n | % | n | % | ||
| Gastrointestinal disorders | Dysphagia | 2 | 4.2 | 21 | 39.6 | 15 | 30.0 |
| Odynophagia | 0 | 0 | 5 | 9.4 | 6 | 12.0 | |
| General disorders and administration site conditions | Injection site mass | 1 | 2.1 | 4 | 7.5 | 5 | 10.0 |
| Injection site induration | 0 | 0 | 7 | 13.2 | 7 | 14.0 | |
| Pain | 0 | 0 | 4 | 7.5 | 4 | 8.0 | |
| Injection site bruising | 20 | 41.7 | 17 | 32.1 | 18 | 36.0 | |
| Injection site erythema | 3 | 6.3 | 4 | 7.5 | 7 | 14.0 | |
| Injection site hemorrhage | 7 | 14.6 | 10 | 18.9 | 6 | 12.0 | |
| Injection site hypesthesia | 12 | 25.0 | 15 | 28.3 | 15 | 30.0 | |
| Injection site swelling | 16 | 33.3 | 18 | 34.0 | 17 | 34.0 | |
| Injection site edema | 27 | 56.3 | 27 | 50.9 | 21 | 42.0 | |
| Injection site pain | 23 | 47.9 | 31 | 58.5 | 34 | 68.0 | |
| Injection site pruritus | 6 | 12.5 | 5 | 9.4 | 5 | 10.0 | |
| Respiratory, thoracic, and mediastinal disorders | Oropharyngeal pain | 0 | 0 | 3 | 5.7 | 4 | 8.0 |
| Nervous system disorders | Facial paralysis | 0 | 0 | 1 | 1.9 | 3 | 6.0 |
| Facial nerve disorder | 0 | 0 | 0 | 0 | 1 | 2.0 | |
| Injury, poisoning, and procedural complications | VIIth nerve injury | 0 | 0 | 0 | 0 | 1 | 2.0 |
DISCUSSION
People with excess SMF desire reduction of fat volume and subsequent improvement in chin, jawline, and neck contour aesthetics.2,9 The improvement in submental fullness is associated with an overall improved self-perception, whereas there are significant negative attitudes and perceptions of individuals with a “double chin” and poor neckline contour.10 Options for treating chin, jawline, and neck include both surgical and nonsurgical treatments, both with pros and cons. Although surgical procedures such as liposuction have significant efficacy, people who are naive to aesthetic procedures often seek nonsurgical therapy to improve submental fullness as their primary entry point into aesthetics because they do not desire surgical intervention. Despite desiring a nonsurgical treatment, they want a robust, surgical-like outcome.11 Patients also desire a single treatment and may be dissatisfied with the multiple treatments required for SMF reduction in comparison to the results seen with a single toxin or filler treatment, and be unwilling or unable to undergo multiple treatments, even when followed for over 1 year.10,12
Interestingly, although most aesthetic surgical procedures are primarily performed on females, males had a 29% increase in minimally invasive aesthetic procedures and a 27% decrease in aesthetic surgical procedures from 2000 to 2020.13 A real-world experience study of nonsurgical contouring of the neck and jawline with an injectable included 39% men; this demonstrated the ability of nonsurgical procedures to transcend gender and typical aesthetic norms.14 Furthermore, a study of 600 aesthetically aware but treatment-naive men found that double chin was the top treatment priority for 70% of them.15
RZL-012 is a clinical stage product being developed for fat-related disorders such as Dercum’s disease and aesthetic applications.5,16 The compound is administered by a single injection session into subcutaneous fat deposits, resulting in reduction of fat tissue volume. This phase 2b study met the primary endpoint, namely the proportion of patients who had at least a 1-grade improvement in C-CAT (Day 84 vs baseline) showed statistically significant differences between the high-dose RZL-012 and placebo treatment groups (P = .0011). The low-dose RZL-012 group showed a nonsignificant trend for difference from the placebo group. Analysis of the proportion of patients with at least a 2-grade improvement on both C-CAT and S-CAT scales also favored high-dose RZL-012 treatment vs placebo (P = .00007), whereas the low-dose RZL-012 group showed a nonsignificant beneficial trend compared with the placebo group. A clear dose response was also seen in the 130 patients on whom MRI was performed, demonstrating that both doses had a positive effect of SMF reduction.
Of note is the placebo effect (about 50%) seen at the 1-grade improvement primary endpoint, despite objective MRI data that demonstrated no actual improvement in SMF of the placebo group. The placebo was formulated with the same nonactive components as those utilized in the RZL-012 drug product, namely propylene glycol, Tween-80, benzyl alcohol, and water and was associated with some of the same initial local adverse reactions as the RZL-012 drug product, such as injection site bruising, injection site edema or swelling, injection site hypesthesia, and injection site pain. This may have led patients and clinicians to believe that the patient had received active treatment, and therefore increased the placebo effect. See Figure 6 for an example of a placebo group patient who showed 1-grade improvement for the primary endpoint with MRI confirmation of no actual change. This high placebo effect supports the conclusion that blinding was maintained during the study.
Local injection site reactions were the most common AEs associated with the RZL-012 drug product. Dysphagia was also commonly reported in patients in the RZL-012 treatment groups. Rates of some of these AEs were similarly reported across all groups but were judged as more severe in the RZL-012 groups. Although these AEs should be carefully monitored, it is noted that there were no serious outcomes to any of these events, and all AEs resolved without sequelae. The transient increase in D-dimer values may be related to tissue trauma due to cell lysis.
Although the KYBELLA phase 3 studies employed different scales and allowed for up to 6 monthly treatments, results for RZL-012 high-dose group compared favorably with those for KYBELLA: 86% vs 79% with ≥1 grade improvement on the clinician rating scale, 34% vs 13% with composite ≥2 grade improvement, and 68% vs 46% responders on MRI measurement of SMF volume reduction.17 Limitations of the study included inclusion of patients with BMIs between 22 and 40 only, and lack of long-term follow-up.
CONCLUSIONS
This clinical trial met both primary and secondary endpoints, and results demonstrated the robust, significant, dose-related efficacy of RZL-012 as a minimally invasive treatment to reduce subdermal fat after a single dosing session. No serious AEs were associated with either of the 2 tested doses. Based on available safety and efficacy data, RZL-012 may provide a safe and effective nonsurgical alternative, dosed in a single treatment session, for focal fat reduction and sculpting of the chin and jawline. Phase 3 clinical trials are under way to further characterize the mechanism of action and provide longer follow-up.
Disclosures
Drs Shridharani, Dayan, Biesman, Cohen, Downie, Jones, Shamban, Fabi, Yoelin, Fagien, Ablon, Gold, and Walker serve as consultants to Raziel Therapeutics Ltd. (Rehovot, Israel). Dr Gueta is an employee of Raziel Therapeutics Ltd (Santa Barbara, CA).
Funding
The study was sponsored by Raziel Therapeutics Ltd (Santa Barbara, CA).
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14 Shridharani SM. Real-world experience with 100 consecutive patients undergoing neck contouring with ATX-101 (deoxycholic acid): an updated report with a 2-year analysis. Dermatol Surg. 2019;45(10):1285–1293. doi: 10.1097/DSS.0000000000001811
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Author notes
Dr. Shridharani is a plastic surgeon in private practice in New York City, NY, USA and is a Cosmetic Surgery section editor for Aesthetic Surgery Journal.
Dr Dayan is the director of Denova Research, Chicago, IL, USA and is an interspecialty consulting editor for Aesthetic Surgery Journal.
Dr Biesman is an oculofacial plastic surgeon in private practice in Nashville, TN, USA.
Dr Cohen is the director of a private practice in Greenwood Village, CO, USA and is a clinical editor for Aesthetic Surgery Journal.
Dr Downie is the director of a private practice in Montclair, NJ, USA.
Dr Jones is a dermatologist in private practice in Los Angeles, CA, USA.
Dr Shamban is a dermatologist in private practice in Santa Monica, CA, USA.
Dr Fabi is a dermatologist in private practice in San Diego, CA, USA.
Dr Yoelin is the director of a private practice in Newport Beach, CA, USA.
Dr Fagien is the director of a private practice in Boca Raton, FL, USA.
Dr Ablon is a principal investigator, Ablon Skin Institute and Research Center, Manhattan Beach, CA, USA.
Dr Gold is the medical director, Tennessee Clinical Research Center, Nashville, TN, USA and is an interspecialty consulting editor for Aesthetic Surgery Journal.
Dr Gueta is the clinical development director, Raziel Therapeutics Ltd., Rehovot, Israel.
Dr Walker is the chief medical officer (consultant), Raziel Therapeutics Ltd., Santa Barbara, CA, USA.
