Full Text :COPYRIGHT 2008 Journal of Drugs in Dermatology, Inc.

Abstract

Azelaic acid (AzA) 15% gel is approved for the treatment of rosacea in the US, but also has approval for the treatment of acne vulgaris in many European countries where it has demonstrated success. Two randomized, multicenter, controlled clinical trials compared the effects of AzA 15% gel with those of topical benzoyl peroxide 5% or topical clindamycin 1%, all using a twice-daily dosing regimen. The primary endpoint in the intent-to-treat analysis was a reduction in inflammatory papules and pustules. AzA 15% gel resulted in a 70% to 71% median reduction of facial papules and pustules compared with a 77% reduction with benzoyl peroxide 5% gel and a 63% reduction with clindamycin. AzA 15% gel was well-tolerated. In addition, a 1-year European observational study conducted by dermatologists in private practice evaluated the safety and efficacy of AzA 15% gel used as monotherapy or in combination with other agents in more than 1,200 patients with acne. Most physicians (81.9%) described an improvement in patients' symptoms after an average of 34.6 days, and 93.9% of physicians reported patient improvement after an average of 73.1 days. Both physicians and patients assessed AzA 15% gel to be effective with 74% of patients being "very satisfied" at the end of therapy. AzA 15% gel was considered "well-tolerated" or "very well-tolerated" by 95.7% of patients. The majority of patients were more satisfied with AzA than with previous therapies. AzA 15% gel represents a new therapeutic option for the treatment of acne vulgaris.

Introduction

Acne vulgaris is a common polymorphic disease with a multi-factorial pathophysiology. (1,2) There are 4 essential pathogenetic factors in acne that affect the pilosebaceous unit: increased sebum production, follicular hyperkeratosis, proliferation of Propionibacterium acnes (P. acnes), and reactive inflammation. (1,2)

The goal of treatment for both inflammatory and non-inflammatory lesions is to address as many pathophysiologic factors as possible while maintaining tolerability. (3) Several topical and oral drugs are recommended for the treatment of mild to moderate acne vulgaris. (1,2) Due to their efficacy and tolerability, topical agents have been considered the foundation of a therapeutic approach to both inflammatory and non-inflammatory acne lesions. (1,2) Agents that address more than one factor in the multifaceted pathophysiology of acne are generally preferred. (1-3) A combination of agents with complementary mechanisms of action can also address more pathophysiologic factors. (2,3) Many studies have shown that combination treatment may provide additive efficacy without a significant increase in adverse events. (3-5) While not FDA approved in the US for this indication, AzA 15% gel is frequently used abroad for the treatment of acne vulgaris. In the US, AzA is indicated for the treatment of rosacea.

AzA is a naturally occurring, saturated, straight-chain 9-C dicarboxylic acid with antimicrobial, anti-inflammatory, and antikeratinizing properties that address 3 of the 4 pathophysiologic mechanisms in acne vulgaris: follicular hyperkeratosis, P. acnes proliferation, and inflammation. (6-8)

AzA was first available in a cream formulation, which is less than optimal in patients with severe seborrhea and patients who live in warm climates. (6) Subsequently, a nonalcoholic hydrogel formulation containing 15% AzA was developed.

This article will review the clinical efficacy of AzA 15% gel for the treatment of acne vulgaris using evidence from 2 phase III clinical trials and one observational study conducted in several European countries.

Controlled Clinical Trials

Two multicenter, randomized, controlled clinical trials were conducted from 1997 to 2000 in Germany, Holland, Norway, and Greece. (7) The first study was a double-blind, randomized, multicenter, controlled phase III study with group comparison of AzA 15% (n=176) against benzoyl peroxide (BPO) 5% (n=175), both in a hydrogel base. The second was a single-blind, randomized, multicenter, controlled phase III trial comparing AzA 15% (n=114) with clindamycin sulfate (clindamycin) 1% (n=115), both in a hydrogel base. All therapies were used in a twice-daily dosing regimen. Patients in both studies had mild to moderate inflammatory (papulopustular) acne vulgaris, with an average of 10 to 50 papules/pustules on the face, and an average disease duration of more than 50 months. The primary objective of these clinical trials was to determine efficacy as defined by the primary end-point: percentage reduction in the number of papules and pustules from baseline. Secondary endpoints included the comparative reductions in open and closed comedones and efflorescence (ie, rash or eruption, any skin lesion) at the end of treatment, as well as the subjective assessment by both the physician and the patient of the therapeutic result, including tolerance and overall cosmetic acceptance. The demographic characteristics of both studies were comparable, with more females than males participating (Table 1).

Both studies used an intent-to-treat trial design. Statistical analysis of the reduction in papules and pustules compared with baseline involved the use of the one-sided Mann-Whitney U test with a level of significance set at 0.05. Statistical analysis of secondary endpoints involved the 2-sided Mann-Whitney U test and the Fisher exact test with a significance level set at 0.05.

Results

AzA 15% gel proved effective in meeting the primary end-point of studies 1 and 2, producing a 70% to 71% median reduction in facial papules and pustules compared with a 77% reduction with BPO 5% gel and a 63% reduction with clindamycin (Figure 1). These differences were not statistically significant. However, significantly greater reductions in closed and open comedones were observed with AzA 15% gel than with topical clindamycin (P=0.031). AzA provided efficacy comparable to that of BPO. Physician assessments of the therapeutic effects of the treatments based on the percentage of patient ratings of "good" or "very good" were similar among agents: 63.6% and 65.1% with AzA in studies 1 and 2, respectively; 77.6% with BPO; and 71.9% with clindamycin. Patient evaluations of efficacy produced similar results. The cosmetic acceptance was positive, with each of the 3 agents in both studies producing "good" or "very good" results in 82% to 90% of patients. AzA was well-tolerated in both studies. Skin irritation was much lower with AzA than with BPO. Five patients in the AzA group discontinued treatment because of skin irritation compared with 10 patients in the BPO group. In the second study, 5 patients in the AzA group discontinued treatment because of skin irritation compared with one patient in the clindamycin group. Although skin irritation occurred more frequently with AzA than with clindamycin, this irritation occurred mainly during the first month of treatment. BPO 5% gel was associated with the greatest incidence and severity of irritation, including xerosis, erythema, and desquamation. No severe side effects occurred with any of the products in either study. (7)

Observational Study

A 1-year European observational study was conducted by dermatologists in private practice. (8) The purpose of the observational study was to evaluate the safety and efficacy of 15% AzA in a hydrogel formulation. This observational study included 1,243 patients (66% women, 34% men) with a mean age of 22.1 ([+ or -]9.6) years. More than half of the patients (57%) who participated in the study were younger than 20 years old. Patients participating in the survey experienced varying degrees of acne for a median of 4 years. A majority of patients (72%) had been pretreated with other agents before participating in the study. Of those who were pretreated, 69% were treated with other topical therapies and 25% with systemic therapy.

AzA 15% gel was given as monotherapy in 64.9% of patients (n=804) and in combination with another topical or oral acne drug in the remaining 35.1% of patients (n=435) (Table 2). Duration of treatment varied from 9 to 210 days (median, 69 days). Two follow-up evaluations were performed during the study to gauge the improvement of symptoms based on a scale of "slight" to "very good" improvement. The first follow-up visit was conducted after an average of 34.6 days (4-6 weeks) and the second after an average of 73.1 days (8-12 weeks) after administration of the first medication. Both physicians and patients were asked to assess the onset of action and the overall efficacy of AzA 15% gel at the end of the observational period. Patients rated efficacy as satisfaction with treatment on a scale of 0 (dissatisfied) to 10 (very satisfied).

Results

Physician documentation of symptom improvement in a majority of patients occurred between 5 and 10 weeks and no more than 12 weeks after the beginning of therapy (mean, 5.2 weeks) (Table 3). Most physicians (81.9%) described an improvement in patients' symptoms after an average of 34.6 days, and 93.9% of physicians reported patient improvement after an average of 73.1 days. Both physicians and patients assessed therapy to be effective with 74% of patients being "very satisfied" (median score, 8; mean score, 7.3) at the end of therapy. This is in contrast to patients' experiences with previous therapy, with 36% of patients rating their satisfaction between 2 and 3, and 35% of patients rating their satisfaction between 4 and 5 (median, 4; mean, 3.9). The patients' assessment of their self-confidence also improved during therapy with AzA. (8)

AzA 15% gel was considered "well-tolerated" or "very well-tolerated" by 95.7% of patients. Minor side effects (mainly local irritation) occurred in only 11 patients. A large percentage of patients (86.5%) continued to use AzA as maintenance therapy after the observational period. (8)

Discussion

These studies demonstrate that AzA 15% gel is effective and well-tolerated in the treatment of both inflammatory and non-inflammatory acne vulgaris. The multiple mechanisms of action of AzA make it a particularly attractive addition to the acne armamentarium. The efficacy of AzA in the treatment of acne may be due to its antikeratinizing, antibacterial, and anti-inflammatory actions. At high concentrations (>250 mmol/L), AzA is bacteriostatic against Staphylococcus epidermidis (S. epidermidis) and P. acnes and has been shown to produce marked inhibition of protein synthesis by S. epidermidis and P. acnes at concentrations comparable to those required for inhibition of microbial growth. (6,9) Like BPO, AzA does not appear to promote bacterial resistance. (6) AzA has also been shown to decrease the generation of reactive oxygen species by neutrophils, thus suggesting anti-inflammatory and antioxidant effects. (10)

Within the range of established antiacne agents, AzA provides antikeratinizing effects and has demonstrated efficacy comparable to that of erythromycin, BPO, and oral tetracycline in reducing comedonal and papulopustular lesions. (6,8) Administration of AzA was shown to be well-tolerated. It does not induce allergic sensitization and is associated with less overall cutaneous irritation than BPO. (6,7) AzA does not induce antibiotic resistance, which is seen with oral and topical antibiotics. (6) It is also devoid of adverse systemic effects and is safe to use during pregnancy (AzA is designated as Pregnancy Category B in product labeling). (6,7)

Conclusions

The results of both randomized, controlled trials and the observational trial demonstrate that AzA 15% gel is an effective and well-tolerated topical treatment for mild to moderate inflammatory acne vulgaris, showing clinical efficacy that is equal to or better than that of topical BPO or clindamycin. Findings from the studies have also demonstrated that AzA is effective and well-tolerated as a single agent or in combination with other agents. Furthermore, it has a clinical profile that is compatible with long-term use including sustained efficacy, lack of microbial resistance, tolerability, and patient acceptance. AzA is also not teratogenic or mutagenic, and consequently can be used safely during pregnancy. In summary, AzA is a rational choice in the therapy of papulopustular acne vulgaris.

Disclosure

Dr. Thiboutot has participated in clinical trials and has been a consultant for Intendis, Inc, Galderma Laboratories, LP, CollaGenex, Inc, Allergan, Inc, Stiefel Laboratories, Inc, and QLT, Inc.

References

1. Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of care for acne vulgaris management. J Am Acad Dermatol. 2007;56:651-663.

2. Gollnick H, Cunliffe W. Management of acne. A report from a Global Alliance to improve outcomes in acne. J Am Acad Dermatol. 2003;49:S1-38.

3. Leyden JJ. Acne vulgaris is a multifactorial disease. J Am Acad Dermatol. 2003;49:S199.

4. Lookingbill DP, Chalker DK, Lindholm JS, et al. Treatment of acne with combination clindamycin/benzoyl peroxide gel compared with clindamycin, benzoyl peroxide gel and vehicle gel: combined results of two double-blind investigations. J Am Acad Dermatol. 1997; 37:590-595.

5. Leyden JJ, Hickman JG, Jarrat MT, Stewart DM, Levy SF. The efficacy and safety of a combination benzoyl peroxide/clindamycin topical gel compared with benzoyl peroxide alone and benzoyl peroxide/erythromycin combination product. J Cutan Med Surg. 2001; 5:37-42.

6. Fitton A, Goa KL. Azelaic acid. A review of its pharmacological properties and therapeutic efficacy in acne and hyperpigmentary disorders. Drugs. 1991;41:780-798.

7. Gollnick HPM, Graupe K, Zaumseil R-P. Azelaic acid 15% gel in the treatment of acne vulgaris. Combined results of two double-blind clinical comparative studies [in German]. J Dtsch Dermatol Ges. 2004;10:841-847.

8. Jansen T, Zaumseil R-P, Grabbe S. Azelaic acid 15% gel in the treatment of acne vulgaris. Akt Dermatol. 2006;32:382-387.

9. Bojar RA, Holland KT, Lemming JP, Cunliffe WJ. Azelaic acid: its uptake and mode of action in Staphylococcus epidermidis NCTC 11047. J Appl Bacteriol. 1988;64:497-504.

10. Akamatsu H, Miyachi Y, Komura J. Effects of azelaic acid on neutrophil function: a possible cause for its efficacy in treating pathogenetically unrelated diseases. Arch Dermatol Res. 1991;283:162-166.

ADDRESS FOR CORRESPONDENCE

Diane Thiboutot MD

Professor of Dermatology

Pennsylvania State University

College of Medicine

The Milton S. Hershey Medical Center

500 University Drive

Hershey, PA 17033-0850

Phone: 717-531-6820

Diane Thiboutot MD

Professor of Dermatology, Department of Dermatology, Pennsylvania State University College of Medicine, Hershey, PA

Table 1. Patient demographics of 2 randomized clinical trials. (5)
 
                                          AzA       BPO         Total
Study 1                                   (n=176)   (n=175)     (N=351)
 
Male                                       68        67         135
Female                                    108       108         216
Age, mean/median, y (range)                21/20     20.9/19     21/19
                                          (13-45)   (11-42)     (11-45)
Duration of acne, mean/median, mo          55.0/36   56.2/42     55.6/38
  (range)                                  (2-300)   (3-264)     (2-300)
Acne only on face, No.                    126       125         351
Also on chest and back, No.                50        50         100
 
                                          AzA       Clindmycin  Total
Study 2                                   (n=114)   (n=115)     (N=229)
 
Male                                       47        55         102
Female                                     67        60         127
Age, mean/median, y (range)                22.1/19   20.1/19     21.1/19
                                          (14-50)   (13-38)     (13-50)
Duration of acne, mean/median, y (range)   56.9/36   51.5/36     54.2/36
                                           (1-384)   (2-300)     (1-384)
Acne only on face, No.                     86        87         173
Also on chest and back, No.                28        28          56
 
Table 2. Observational study: therapy regimen. (6)
 
AzA 15 % Gel Regimen   Patients, %
 
Monotherapy            65
Combination Therapy    35
 
As Combination Therapy with
 
Another Topical Agent  58
A Systemic Drug        24
Oral Contraceptives    18
 
Table 3. Patient reports of onset of action in 1,173 patients
(100%).* (6)
 
Time After Therapy          Patients, No. (%)
 
Immediately                  11 (0.9)
1 to 2 weeks                 64 (5.5)
2 to 3 weeks                395 (33.7)
5 to 10 weeks               629 (53.6)
>10 weeks                    11 (0.9)
No breakthrough              63 (5.4)
 
Onset of Action ([dagger])  Weeks
 
Mean [+ or -] SD              5.2 [+ or -] 2.1
Median                        5
 
*71 patients reported no data on onset of action.
([dagger]) Only patients in whom onset of action occurred.

Disclaimer:This information is not a tool for self-diagnosis or a substitute for professional care.