Efficacy and Tolerability of a New Facial 2-Mercaptonicotinoyl Glycine-Containing Depigmenting Serum Versus Hydroquinone 4% over 3-Month Treatment of Facial Melasma

Abstract

Introduction

Topical treatment with hydroquinone 4% and hydroquinone-based preparations is the gold standard of care for melasma; however, it is limited by complications. 2-Mercaptonicotinoyl glycine (Melasyl™) is a new active ingredient targeting melanin synthesis without impairing the tyrosinase enzyme, with proven efficacy and safety. This study assessed the non-inferiority of a new facial depigmenting serum Mela B3^® (MB3), containing 0.5% 2-mercaptonicotinoyl glycine, versus hydroquinone 4%.

Methods

This comparative, non-inferiority, randomized, investigator-blind, parallel-group investigation included adult women with mild-to-severe epidermal or mixed facial melasma. Patients received 3-month treatment with MB3 (twice daily) or hydroquinone 4% (once daily) and applied a broad spectrum SPF 50+/UVA tinted sunscreen (twice daily). Evaluations were conducted at day (D) 0, D28, D56, and D84 of treatment by a dermatologist and the patients. Non-inferiority analysis was performed at D84 on the Modified Melasma Area and Severity Index (mMASI) (non-inferiority margin 1.3). Efficacy assessments included mMASI, Melasma Quality of Life questionnaire (MELASQoL), and Patient Unique Stigmatization Holistic tool in Dermatology (PUSH-D) scores at each visit. Safety and tolerance were evaluated.

Results

The study included 109 women (phototypes I–IV; > 80% had phototypes III–IV). At D84, the estimated difference in mMASI score between MB3 and hydroquinone 4% was 0.46 (95% confidence interval − 0.25–1.17). Both groups demonstrated statistically significant improvements on mMASI from D28 versus baseline. The MELASQoL and PUSH-D scores decreased significantly from D28 in both groups (no difference between the groups). Nevertheless, a significant difference in the PUSH-D score was observed at D28 and D56 in favor of MB3. MB3 showed better tolerability versus hydroquinone 4% at D28 with fewer local skin reactions (6.0% versus 21.4%, respectively; p = 0.0286).

Conclusion

MB3 shows non-inferior efficacy and better tolerability compared with hydroquinone 4%. MB3 is an effective and well-tolerated alternative option for the topical treatment of melasma.

Clinical Trial Registration

NCT06787846.

Key Summary Points

Why carry out this study?

Melasma is a chronic, acquired disorder negatively affecting the quality of life of patients.

Although hydroquinone 4% and hydroquinone-based preparations are the gold standard of care for melasma, they are limited by complications.

This study assessed the non-inferiority of a new facial depigmenting serum Mela B3® (MB3), containing 0.5% 2-mercaptonicotinoyl glycine, versus hydroquinone 4%.

What was learned from the study?

MB3 shows non-inferior efficacy and better tolerability compared with hydroquinone 4%.

Treatment with MB3 overcomes the limitation of hydroquinone 4% regarding its duration of use.

MB3 is an effective and well-tolerated alternative option for the topical treatment of melasma.

Introduction

Melasma is a chronic, acquired disorder clinically presenting as hyperpigmented patches of the face. It most often develops in women and individuals with darker skin tones [1, 2]. Melasma in women accounts for approximately 80% of cases [3–5]. In Latin America, melasma affects up to 10% of the population [6].

The pathogenesis of melasma is complex, including chronic exposure to sun radiation, hormonal factors in women (i.e., pregnancy and use of oral contraceptive drugs), and a genetic predisposition [7–9]. Data strongly suggest that melasma is a photoaging disorder affecting genetically predisposed individuals [8, 9].

This disorder is associated with a significant psychosocial impact and poses challenges to patients and physicians in the long term [1, 2]. Studies conducted worldwide have shown that melasma reduces the quality of life (QoL) of patients [3, 6, 10–13]. Morgaonkar et al. demonstrated that, despite its asymptomatic and benign nature, melasma exerts a moderate effect on the QoL of patients [3]. Furthermore, a recent investigation almost exclusively involving women revealed that melasma negatively affects the QoL of patients, regardless of its severity [10]. A previous Brazilian study investigated the impact of melasma on the QoL of 51 adult women. The analysis demonstrated that melasma has a marked emotional effect on QoL, as a consequence of feelings regarding skin appearance. The emotional impact was more pronounced in older individuals who experienced a longer duration of this disease [6]. The impact of melasma on the emotional status of patients may, in turn, have negative consequences on social functioning or productivity, as well as reduce self-esteem [4]. This evidence emphasizes the need for effective treatments to mitigate the negative effects of this disorder.

Currently, topical treatment with hydroquinone 4% and hydroquinone-based preparations is the gold standard of care for melasma [1, 11, 14–16]. Research has demonstrated that the use of high protection factor sunscreen lessens the severity of melasma and decreases its rate of occurrence by more than 90%. Thus, the application of sunscreen is included in the gold standard therapeutic regimen for melasma [4]. Visible light plays a major role in the pathophysiology of melasma. Therefore, the use of tinted sunscreens is recommended, as pigments can protect from visible light [17].

The usefulness of hydroquinone as a depigmenting agent was discovered almost a century ago. This compound has been utilized in numerous trials as a comparator to evaluate the efficacy and safety profiles of novel agents [1, 11]. Nevertheless, the use of hydroquinone frequently results in irritant and allergic contact dermatitis, and long-term use exposes patients to exogenous ochronosis [7, 18, 19]. Thus, there is room for alternatives to hydroquinone in the management of chronic long-lasting pigmentary disorders, including melasma.

Unlike other conventional agents, 2-mercaptonicotinoyl glycine (2-MNG; Melasyl™; L’Oreal, Clichy, France) binds to certain melanin precursors (dopaquinone, 5,6-dihydroxyindole, or 5,6-dihydroxyindole-2-carboxylic acid). This leads to a balanced inhibition of eumelanin and pheomelanin synthesis, without compromising the integrity of melanocytes. This molecule has exhibited efficacy against major depigmented molecules [20, 21].

The objective of this study was to assess the non-inferiority of a new facial depigmenting serum, Mela B3^® (MB3; La Roche-Posay Laboratoire Dermatologique, Levallois-Perret, France), containing 0.5% 2-MNG, versus hydroquinone 4% in patients with facial melasma.

Methods

Study Design

This was a comparative, non-inferiority, randomized, investigator-blind, parallel-group investigation conducted in a single center in Brazil. The planned duration of the study was a 3-month treatment period, which included four visits.

Ethical Approval

The protocol of this study was approved by an independent ethics committee from the Pró-Cardíaco Hospital, Rio De Janeiro, Brazil. The investigation was conducted in accordance with the principles of Resolution 466/2012 of the Conselho Nacional de Saúde do Brazil, ethical principles stipulated in the Declaration of Helsinki of 1964 (and its subsequent amendments), and Good Clinical Practice defined by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. The patients provided consent for the publication of patient images. ClinicalTrials.gov identifier NCT06787846.

Patients

The criteria for inclusion in this study were as follows: female patients with skin phototypes I–IV; patient age > 18 years; and diagnosis of mild-to-severe epidermal or mixed facial melasma.

All patients received verbal and written information concerning the study in accordance with the applicable local regulations and guidelines. This information explained the nature, purpose, and risks of the study. In addition, it emphasized that participation is voluntary and that the patient may withdraw from the study at any time and for any reason. The patients provided written informed consent for their participation in the study.

Treatment

MB3 is a new facial depigmenting serum containing 0.5% 2-MNG, 10% niacinamide, Cystoseira tamariscifolia extract, lipohydroxy acid, carnosine, retinyl palmitate, and dipotassium glycyrrhizate.

The patients were randomized to receive treatment at home with MB3 or hydroquinone 4% (registered as a cosmetic standard of care in Brazil) for 3 months. The treatment involved facial application of MB3 twice daily (morning and evening) or hydroquinone 4% cream once daily (evening).

In both groups, patients also applied a tinted sun protection factor (SPF) 50+ with high ultraviolet A-protection factor (UVA-PF) sunscreen with good visible light protection (Anthelios UVMUNE 400 tinted cream; La Roche-Posay Laboratoire Dermatologique) to the area of treatment twice daily (morning and midday with a minimum of a 10-min interval between applications).

Study Endpoints and Assessments

Evaluations of the application area were conducted at day (D) 0, D28, D56, and D84 of treatment by a dermatologist (clinical scores) or by the patients (self-assessment).

The primary endpoint was the non-inferiority analysis at D84 based on the mean change from baseline of Modified Melasma Area and Severity Index (mMASI). The mMASI is a modified version of the MASI (the most common outcome measure used for studies on melasma) after eliminating homogeneity measurement [22]. This measure was employed to assess the area and darkness of the melasma on three areas of the face (i.e., forehead, right and left cheeks, and chin) (score range 0–24). The mMASI score has previously demonstrated excellent reliability and good validity for assessing the severity of melasma [23]. Thus, it is commonly used for the evaluation of efficacy in clinical trials [24]. In the absence of a published minimal clinically important difference (MCID) for mMASI, we decided to set 1.3 as the non-inferiority margin, representing approximately 50% of the difference versus placebo at D84 in this study [25].

The secondary efficacy endpoints included mMASI, Melasma Quality of Life questionnaire (MELASQoL), and Patient Unique Stigmatization Holistic tool in Dermatology (PUSH-D) scores at each visit. The MELASQoL is a dermatology-specific instrument used to assess the impact of melasma on health-related QoL [26]. The instrument includes 10 questions, which are evaluated by the patients using a scale ranging from 1 (not bothered at all) to 7 (bothered all the time). The total MELASQoL score ranges from 7 to 70, with a higher score signifying worse QoL. This instrument has been validated in clinical trials and translated in numerous languages [10]. PUSH-D is a 17-item questionnaire offering a comprehensive view of the degree of stigmatization in visible skin disorders, as well as the comparability of stigmatization levels across various skin conditions [27]. It measures two pertinent dimensions, namely felt stigma (eight items; range 0–32) and enacted stigma (nine items; range 0–36). The stigmatization total score ranges from 0 (no stigma) to 68 (high stigma).

Safety was evaluated by the investigator and the patients.

Statistical Analysis

All statistical analyses were performed with SAS^® version 9.4 or higher (SAS institute, Cary, NC, USA) at the 5% significance level using a two-sided test. Normality was evaluated by the Kolmogorov–Smirnov test at the 1% threshold.

Quantitative efficacy variables were analyzed by an analysis of covariance (ANCOVA). Non-inferiority was achieved if the upper bound of the two-sided 95% confidence interval (CI) was < 1.3. For the mMASI analyses, missing values were imputed using the last observation carried forward (LOCF) method. All quantitative efficacy parameters were analyzed using an ANCOVA or by the Mann–Whitney test if normality was rejected. Non-quantitative parameters were analyzed using the chi-squared test.

Results

Patients

This study was performed from August to December 2023. A total of 151 women were screened in this investigation and 109 were randomized (54 in the MB3 group and 55 in the hydroquinone 4% group). The safety set included all randomized patients who applied the study product at least once during the study. Safety data after D0 were not available for seven patients. These patients were excluded from the safety set, which included 102 patients (52 in the MB3 group and 50 in the hydroquinone 4% group). Figure 1 presents the disposition of patients in this study, and Table 1 provides demographic and baseline data.

Fig. 1.

Patient disposition.  

Table 1.

Demographics and baseline characteristics

Variable	MB3 group	Hydroquinone 4% group
Analysis population (N = 109)	54	55
Sex (%)
Female	100%	100%
Male	0%	0%
Mean age, years (range)	43.0 ± 4.6 (30–51)	43.4 ± 5.0 (31–50)
Phototypes (%)
I	1.9%	1.8%
II	14.8%	16.4%
III	37.0%	21.8%
IV	46.3%	60.0%
Ethnicity (%)
Caucasian	29.6%	23.6%
African	9.3%	16.4%
Asian	9.3%	3.6%
Hispanic	27.8%	29.1%
Other	24.1%	27.3%
Modified Melasma Area and Severity Index	7.57	7.43
Type of melisma
Epidermal	31.5%	50.9%
Mixed	68.5%	49.1%

The mean age of patients was similar between the two groups (approximately 43 years; range 30–51 years). In addition, more than 80% of all patients had phototypes III–IV; specifically, more than half of the patients (53.2%) had phototype IV with a slight difference observed between groups (i.e., 46.3% in the MB3 group vs. 60% in the hydroquinone 4% group). Moreover, 29.4% and 17.4% of patients had phototype III and phototypes I/II, respectively. The groups were also similar in terms of ethnic composition (26.6% Caucasian, 12.8% African, 6.4% Asian, 28.4% Hispanic, and 25.7% Other). Among all patients, 58.7% and 41.3% were diagnosed with mixed and epidermal melasma, respectively. In the MB3 group, 68.5% and 31.5% of patients were diagnosed with mixed and epidermal melasma, respectively. In the hydroquinone 4% group, these rates were 49.1% and 50.9%, respectively. The differences in the rates of mixed and epidermal melasma were not considered clinically relevant for this study. According to the investigator, approximately 53%, 41%, and 6% of patients in both groups had mild, moderate, and severe melasma, respectively.

mMASI Score (LOCF Analysis)

At baseline, the average mMASI score was 7.57 for the MB3 group and 7.43 for the hydroquinone 4% group. The estimated mean difference between the groups at D84 was 0.46 (95% CI − 0.25–1.17). Non-inferiority was achieved as the upper bound of the CI was strictly < 1.3. Both products showed significant decreases in mMASI scores: MB3 showed a reduction of 2.16 (95% CI − 1.52 to − 2.80; p < 0.0001) and hydroquinone 4% showed a reduction of 2.56 (95% CI − 1.86 to − 3.25; p < 0.0001); these values correspond to − 29% and − 34% decreases from baseline, respectively (Fig. 2). This decrease reached statistical significance as early as D28, showing an early onset of action. Notably, there was no difference observed between the two groups at any visit (Fig. 3).

Fig. 2.

Non-inferiority of MB3 versus hydroquinone 4% at D84 (mMASI score). CI confidence interval, D day, MB3 Mela B3^®, mMASI Modified Melasma Area and Severity Index

Fig. 3.

Clinical evaluation (mMASI score) at each visit. CI confidence interval, D day, MB3 Mela B3^®, mMASI Modified Melasma Area and Severity Index. *p < 0.05 versus baseline. S indicates significant difference from baseline

MELASQoL and PUSH-D Scores

At baseline, stigmatization assessed by the PUSH-D questionnaire was low (average 18.4; range 0–54) without any relevant difference between the groups. The average scores for felt stigma and enacted stigma were 13.5 (range 0–31) and 4.8 (range 0–27), respectively. The impact on the QoL assessed by the MELASQoL was noteworthy with an average score of 48 (range 11–70), without any relevant difference between the groups.

The analysis revealed that the MELASQoL and PUSH-D scores decreased significantly as early as D28 in both groups, without statistically significant difference recorded at D84. Nevertheless, a significant difference in the PUSH-D score was observed at D28 (− 5.64 [− 29.6%] vs. − 1.71 [− 9.7%], respectively) and D56 (− 6.79 [− 35.7%] vs. − 3.31 [− 18.7%], respectively) in favor of MB3 (Fig. 4).

Fig. 4.

PUSH-D: total stigma score at each visit. CI confidence interval, D day, MB3 Mela B3^®, PUSH-D Patient Unique Stigmatization Holistic tool in Dermatology. *p < 0.05 versus baseline. *indicates significant difference from baseline. S indicates significant difference between the two groups

Safety Analysis

Between D0 and D84, 23.1% and 36.0% of patients in the MB3 and hydroquinone 4% groups, respectively, developed at least one local intolerance.

Global tolerance was evaluated by the patients and the investigator. These evaluations demonstrated that both products were well tolerated. According to the investigator, the incidence rates of signs/symptoms of intolerance in the MB3 and hydroquinone 4% groups were 6.0% versus 21.4% (D28) (p = 0.0286), 8.3% versus 11.7% (D56), and 4.2% versus 6.8% (D84), respectively. According to the patients, the rates of good/very good tolerance for MB3 and hydroquinone 4% were 96% versus 90.5% (D28), 95.9% versus 88.4% (D56), and 100% versus 90.9% (D84), respectively.

Discussion

In this study, MB3 demonstrated comparable efficacy with hydroquinone 4%, as well as better tolerance and a significant improvement of QoL and stigmatization. Considering the major impact that melasma has on the physical appearance and emotional status of patients, assessment of health-related QoL is crucial [4, 6, 10, 13].

The therapeutic approach should combine a clinical examination with a thorough evaluation of the psychological status of the patient [12]. Such a multidisciplinary approach to the management of melasma may assist in achieving better outcomes [13]. During the diagnosis and treatment of this disorder, MELASQoL can help the treating physician to assess the disease and determine its impact on patients’ well-being, in turn assisting in the provision of timely and appropriate counseling [13]. The importance of MELASQoL in the evaluation of the impact of melasma on patients’ QoL has been confirmed by a systematic review of 14 studies involving almost 1400 patients. A subsequent meta-analysis of data from four of those studies (including a total of 522 patients) revealed that melasma negatively affects emotional well-being, social life, recreation, and leisure, thereby impairing the QoL of patients [13].

The present evidence indicates that, under similar conditions of use (i.e., season, location, sunscreen), MB3 shows efficacy and better tolerability than the reference cosmetic product hydroquinone 4%. Figure 5 shows two patients treated with MB3 and followed up from D0 to D84. Importantly, patients with many different ethnic backgrounds were included in this study. The findings demonstrated that MB3 is effective and well tolerated in all ethnicities.

Fig. 5.

Photographs of the faces of two patients after treatment. From left to right, panels show the face at D0, D28, D56, and D84, respectively. D day

The evaluations carried out by a dermatologist (i.e., mMASI) and patients’ self-assessments yielded consistent findings. This was reflected on improved QoL, as captured by a non-specific measure (PUSH-D) and a specific measure (MELASQoL).

Moreover, the statistically significant difference in the rate of local intolerance perceived by the investigator at D28 indicated better tolerance for MB3 compared with hydroquinone 4%. The patients did not perceive differences in tolerance between the groups at any visit.

This study was characterized by certain limitations. Firstly, the investigation was conducted in a single center. Hence, the generalizability of these findings may be limited. Therefore, additional multicenter studies are warranted to confirm the current data. Secondly, this was a single-blind study, as MB3 was applied twice daily and hydroquinone 4% was applied once daily. Finally, this analysis included patients with skin phototypes I–IV. A systematic review revealed that patients with darker phototypes are at a higher risk of developing ochronosis versus those with lighter phototypes [18]. Hence, patients with phototypes I–IV were selected to avoid the risk of ochronosis, as patients with melasma might have been treated with hydroquinone.

On the basis of the present evidence, the new MB3 joins thiamidol in a small group of cosmetic products exhibiting similar efficacy to that of hydroquinone 4% [1, 25, 28–34].

Moreover, treatment with MB3 is not associated with exogenous ochronosis, as 2-MNG is not a tyrosinase inhibitor. Importantly, in patients in whom treatment with hydroquinone 4% beyond 3 months should be avoided, MB3 can be used for longer periods of treatment and potentially lead to better outcomes. This overcomes the limitation of hydroquinone 4% regarding its duration of use. Recently, it was stated that novel topical treatments may be utilized in patients who are intolerant, do not respond to first-line therapy, have contraindications, or plan to receive maintenance therapy [1]. Therefore, MB3 holds great promise for the effective and safe treatment of melasma.

Conclusion

Melasma continues to negatively affect the well-being of patients. In this study, we assessed the non-inferiority of a new depigmenting 2-MNG-containing serum versus hydroquinone 4% in patients with facial melasma. According to the data, MB3 shows non-inferior efficacy and better tolerability compared with hydroquinone 4%. Moreover, treatment with MB3 overcomes the limitation of hydroquinone 4% regarding its duration of use. Thus, MB3 is a safe and effective alternative option for the topical treatment of melasma.

Author Contributions

Conceptualization: Guénaëlle Le Dantec, Delphine Kerob; Methodology: Guénaëlle Le Dantec, Thierry Passeron; Formal analysis and investigation: Guénaëlle Le Dantec, Alessandro R. do Nascimento and Renato Moura, Samir Salah; Writing—original draft preparation: Anne-Laure Demessant-Flavigny; Writing—review and editing: Delphine Kerob, Thierry Passeron, Andrew Alexis; Funding acquisition: Delphine Kerob; Resources: Mariana Feiges and Erika Fernandez; Supervision: Anne-Laure Demessant-Flavigny.

Funding

Sponsorship for this study was funded by La Roche-Posay Laboratoire Dermatologique. The Rapid Service Fee was provided by La Roche-Posay Laboratoire Dermatologique.

Data Availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Thierry Passeron has received honoraria from ACM, Beiersdorf, Galderma, L’Oréal, Hyphens, ISIS Pharma, ISDIN, NAOS, Pierre Fabre, SUN Pharma, SVR, and Symrise. Delphine Kerob, Guénaëlle Le Dantec, Anne-Laure Demessant-Flavigny, and Samir Salah are employees of La Roche-Posay Laboratoire Dermatologique. Alessandro R. do Nascimento and Renato Moura have no conflict of interest to declare. Mariana Feiges and Erika Fernandez are employees of L’Oreal. Andrew Alexis has received honoraria from Leo, Galderma, Pfizer, Sanofi-Regeneron, Dermavant, Beiersdorf, Ortho, L’Oreal, BMS, Bausch health, UCB, Vyne, Arcutis, Janssen, Allergan, Almirall, Abbvie, Sol–Gel, Amgen, VisualDx, Eli Lilly, Swiss American, Cutera, Cara, EPI, and Incyte.

Ethical Approval

The protocol of this study was approved by an independent ethics committee from the Pró-Cardíaco Hospital, Rio De Janeiro, Brazil. The investigation was conducted in accordance with the principles of Resolution 466/2012 of the Conselho Nacional de Saúde do Brazil, ethical principles stipulated in the Declaration of Helsinki of 1964 (and its subsequent amendments), and Good Clinical Practice defined by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. The patients provided consent for the publication of patient images.