A promising new treatment for solar lentigines

Journal of Drugs in Dermatology, April, 2003 by SI Colby, EH Schwartzel, FJ Huber, A Highton, DJ Altman, WW Epinette, E Lyon

Abstract

The purpose of this open-label study was to determine the adverse event rate of topical 4HA/tretinoin when used twice daily for up to 24 weeks with concomitant sunscreen in the treatment of solar lentigines and related hyperpigmented lesions. There were two treatment areas: bilateral dorsal forearms, including the back of the hands; and the face, including the forehead and cheek areas. Each treatment area had a target lesion at least 5mm in diameter and was moderately darker than the surrounding skin. A nine-point bipolar scale was used for evaluation of Target Lesion Pigmentation (0 = extremely lighter than pigment of the surrounding skin, 4 = equal with pigment of surrounding skin, 8 = extremely darker than pigment of surrounding skin). The other solar lentigines present in the treatment areas also had to have an overall pigmentation grade of at least Grade 6. Twice daily applications to individual lesions in each treatment area were made for up to 24 weeks followed by a 4-week follow-up phase. Sunscreen applications (sunscreen with sun protection factor (SPF) 25 or greater) were made every morning and reapplied after six hours if additional sun exposure was expected. Clinical evaluations were performed at weeks 0, 4, 8, 16, 24 and 28. The clinical signs of Target Lesion Pigmentation and Overall Lesion Pigmentation were evaluated at each visit.

A total of 96 subjects were enrolled at four study centers; 77 (80%) subjects completed the study. Treatment-related adverse events (AEs) for 4HA/tretinoin included erythema, burning/stinging/tingling, desquamation, pruritus, skin irritation, halo hypopigmentation and hypopigmentation. Five (5%) subjects discontinued from the study due to adverse events considered to be related to study medication. When used with sunscreen of SPF 25 or greater, 4HA/tretinoin was safe and well tolerated and did not produce any unexpected or unusual adverse events.

Purpose

BMS 181158/181159 ethanolic solution is a combination product of 2% 4-hydroxyanisole (4HA, also known as Mequinol) and 0.01% tretinoin for the treatment of solar lentigines. The purpose of this open-label study (DE132-011) was to evaluate the safety of using BMS-181158/181159 with concomitant sunscreen in the treatment of solar lentigines and related hyperpigmented lesions.

Background

Solar lentigines are lesions of excessive skin pigmentation which are very common, manifesting as localized, pigmented, macular lesions on sun-exposed parts of the body. This is a melanocytic disorder characterized by increased numbers of active melanocytes and increased melanin production, induced by ultraviolet radiation (1).

BMS-181158/181159 (4HA/tretinoin combination) demonstrated a reversible depigmentation when assessed in an animal model of hyperpigmentation (Yucatan pig) (2) and in two double-blind clinical trials. The depigmentation observed was greater for the 4HA/tretinoin combination than for either component alone. The mechanism of the synergistic activity of BMS-181158/181159 observed in the animal model is not known.

Materials and Methods

* Subjects with solar lentigines on both forearms/back of hands and face at least moderately darker than normal surrounding skin (Grade 6).

* Subjects: Men and Women (non-childbearing capacity: surgically sterile or postmenopausal).

* Target enrollment of 100 subjects; 96 subjects received study medication of BMS-181158/181159.

* Two treatment sites: face (at least three lesions) and arms (at least five lesions on each forearm and back of hand).

* Twice-daily treatment of BMS-181158/181159 for up to 24 weeks to individual lentigines. Daily use of sunscreen (SPF 25 or greater) following morning application of study medication.

* Daily use of sunscreen during follow-up phase of four weeks.

* Physician's evaluation of two Target Lesions (one on face, one on forearm) at each visit: nine-point (0-8) bipolar ordinal scale.

* Physician's evaluation of Overall Lesion Pigmentation (all treated lesions within the treatment areas) at each visit: nine-point bipolar ordinal scale.

* Subjects were evaluated at Week O, 4, 8, 12, 16, 20 and 24 weeks of treatment and four weeks post-treatment.

Results

A total of 96 subjects were enrolled into the study; 77 (80%) subjects completed the study.

Demographics

* Enrolled subjects: 15% males; 85% females

* Caucasian 88; Hispanic 8; Mean Age (Range) 64.2 years (39-85).

* Reasons for subject discontinuation were: Subject request: 3 (3%); Adverse event: 10 (10%); Noncompliance: 2 (2%); Other reasons: 4 (4%).

Safety Results

Laboratory Tests

* Clinical laboratory tests were not associated with any treatment-related changes.

Adverse Events

* The most frequently reported adverse events that were related to treatment were erythema, burning/stinging/tingling, pruritus, skin irritation and desquamation (Table 1).

* Most treatment-related adverse events were reported as mild.

* Halo hypopigmentation (defined as hypopigmentation of the skin surrounding the treated solar lentigines) related to study treatment was reported for 3 (3%) subjects. One subject had two occurrences of this AE, while two other subjects had one occurrence each. Two occurrences were reported as mild and two were reported as moderate. Study medication applications were interrupted for two of the subjects. These AEs resolved by the end of the study.