This report was reviewed for medical and scientific accuracy by Amy S. Paller, MD, Professor and Chair of Dermatology, Professor of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

This Topical Acne Treatments Express Report™ reviews data on a novel new gel formulation of clindamycin phosphate 1.2%/tretinoin 0.025% (Ziana) presented in 2007 at the 65^th Annual Meeting of the American Academy of Dermatology and the 31^st Hawaii Dermatology Seminar. According to the data presented, clindamycin phosphate 1.2%/tretinoin 0.025% gel was statistically significantly more effective than clindamycin phosphate 1.2% gel, tretinoin 0.025% gel, and vehicle gel in reducing the number of inflammatory, non-inflammatory and total lesion counts from baseline. Similarly, a subgroup analysis of patients aged 12 to 18 years demonstrated significantly greater reductions in inflammatory, non-inflammatory and total lesions compared with clindamycin phosphate 1.2% gel, tretinoin 0.025% gel, and vehicle gel for all baseline severities combined (mild, moderate, severe). The results of studies reviewed in this report suggest that the novel formulation of once-daily clindamycin phosphate 1.2%/tretinoin 0.025% gel is safe and effective for the short- and long-term treatment of acne vulgaris compared to monotherapy with clindamycin phosphate 1.2% gel or tretinoin 0.025% gel.

Expert Commentary

Provided by

Diane Berson, MD, FAAD, Assistant Professor of Dermatology at the Weill Medical College of Cornell University; Assistant Attending Dermatologist, New York-Presbyterian Hospital; New York, New York

Acne affects between 40 and 50 million individuals in the United States. ¹ Although acne is typically associated with adolescence, affecting 79% to 95% of 16- to 18-year-old adolescents, ^2-4 acne may also affect children and adults. In 10- to 12-year-old children, acne affects from 28% to 61% of individuals. ^2-4 In adults older than 25 years, 54% of women and 40% of men exhibit some degree of facial acne, with symptoms persisting into middle age. ⁵

There are many safe and effective therapeutic options to treat pediatric, adolescent, and adult patients with acne vulgaris. Topical therapies for treating acne vulgaris include benzoyl peroxide, topical retinoids (tretinoin, adapalene, and tazarotene), and topical antibiotic agents (azelaic acid, erythromycin, clindamycin, sodium sulfacetamide). Systemic therapies include systemic antibiotic agents (erythromycin, tetracycline, doxycycline, minocycline), hormonal therapy (oral contraceptives, spironolactone), and oral isotretinoin. The goal of acne therapy is to reduce the severity of disease; therefore, therapy should be individualized to the patient, with reliance on topical and systemic therapies that are prescribed based on the severity of acne.⁶ In addition, treatment should be achieved using efficacious agents offering durable therapeutic responses and a low-risk of short- and long-term adverse effects. ⁷

Because of systemic adverse effects associated with oral therapies, initial therapy for acne vulgaris typically consists of benzoyl peroxide, topical antibiotics, topical retinoids or a combination of topical agents (eg, benzoyl peroxide/clindamycin, erythromycin/tretinoin). Benzoyl peroxide is fully active against sensitive and resistant propionibacteria, thus its concomitant use with other topical agents may counteract the development of resistant bacteria. ⁷ Topical antibiotics are available in a variety of formulations (eg, lotion, cream, solution, gel) and should be tailored to the patient's skin type. Topical retinoids are appropriate for non-inflammatory comedonal acne, while patients with inflammatory lesions and comedones may respond best to a combination of topical retinoid and topical or oral antibiotic. ⁸ However, until recently, the combination of topical retinoid and topical antibiotic in a single formulation has not been commercially available.

Now that a novel formulation combining an antibiotic and a retinoid is available, dermatologists have a new way to approach the treatment of acne. The results of studies reviewed in this report suggest that the novel formulation of once-daily clindamycin phosphate 1.2%/tretinoin 0.025% gel is safe and effective for the short- and long-term treatment of acne vulgaris compared to monotherapy with clindamycin phosphate 1.2% gel or tretinoin 0.025% gel.

ANALYSIS OF PRESENTED DATA

Efficacious Novel Formulation for Treating Acne Vulgaris

The efficacy of once-daily application of clindamycin phosphate 1.2%/ tretinoin 0.025% gel was evaluated in a series of 3 randomized, double-blind, 12-week phase 3 studies in patients with mild, moderate, or severe acne vulgaris. ⁹ In Study 1 (n = 1,252) and Study 2 (n = 1,288), patients were randomized to treatment with either clindamycin phosphate 1.2%/tretinoin 0.025% gel, clindamycin phosphate 1.2% gel, tretinoin 0.025% gel, or vehicle gel. In Study 3 (n = 2, 010), patients were randomized to treatment with clindamycin phosphate 1.2%/ tretinoin 0.025% gel or clindamycin phosphate 1.2% gel.

At baseline (for all 3 studies), the patients were required to have 20-100 non-inflammatory lesions; 20-50 inflammatory lesions; and ≤2 nodules. Mandatory washout periods were prescribed for topical and systemic treatments. Patients were evaluated at baseline and Weeks 2, 4, 8, and 12. The co-primary efficacy end point was defined as 1) an Evaluator's Global Severity Scale (EGSS) assessment of "clear", "almost clear", or at least 2 grades of improvement (based on a 6-point scale); and 2) the percent improvement in 2 of 3 lesion counts (inflammatory, non-inflammatory, and total) from baseline to Week 12. Baseline demographics and disease characteristics were similar between treatments for all studies.

A combined analysis of Studies 1 and 2 demonstrated that clindamycin phosphate 1.2%/tretinoin 0.025% gel was statistically significantly more effective than clindamycin phosphate 1.2% gel, tretinoin 0.025% gel, and vehicle gel in reducing the number of inflammatory, non-inflammatory, and total lesions counts from baseline (Table 1). A summary analysis showed that therapy with clindamycin phosphate 1.2%/tretinoin 0.025% gel was associated with a 24.3% reduction in inflammatory lesions, a 19.2% reduction in non-inflammatory lesions, and a 24.3% reduction in total lesions (all P<.05). In addition, patients treated with clindamycin phosphate 1.2%/tretinoin 0.025% gel significantly improved in the overall appearance in their acne as judged by the EGSS when compared to patients treated with clindamycin phosphate 1.2% gel, tretinoin 0.025% gel, and vehicle gel (Table 1).

When assessed by baseline severity of disease (eg, mild, moderate, severe), a pooled analysis of Studies 1 and 2 demonstrated that clindamycin phosphate 1.2%/tretinoin 0.025% gel was associated with greater reductions in inflammatory, non-inflammatory, and total lesions compared with clindamycin phosphate 1.2% gel or tretinoin 0.025% gel in patients with mild, moderate, or severe acne vulgaris¹⁰ (Figure 1).

Similar efficacy results were observed in Study 3 that compared clindamycin phosphate 1.2%/tretinoin 0.025% gel and clindamycin phosphate 1.2% gel. After 12 weeks of therapy, clindamycin phosphate 1.2%/tretinoin 0.025% gel was statistically significantly more effective than clindamycin phosphate 1.2% gel for all co-primary end points. Mean percent reductions from lesion counts were significantly greater in patients treated with clindamycin phosphate 1.2%/tretinoin 0.025% gel compared with clindamycin phosphate 1.2% gel (Table 2). In addition, patients treated with clindamycin phosphate 1.2%/tretinoin 0.025% gel had significantly improved overall appearance in their acne as judged by the EGSS compared to patients treated with clindamycin phosphate 1.2% gel (Table 2).

The results of these studies demonstrate that clindamycin phosphate 1.2%/tretinoin 0.025% gel is effective in reducing inflammatory, non-inflammatory, and total lesions in acne vulgaris. In addition, the novel formulation of clindamycin phosphate 1.2%/tretinoin 0.025% gel provided greater efficacy against acne vulgaris than either monotherapy with clindamycin phosphate 1.2% gel or tretinoin 0.025% gel.

Subgroup Analysis of Patients Aged 12 to 18 Years with Acne Vulgaris

To assess the efficacy of clindamycin phosphate 1.2%/tretinoin 0.025% gel in treating acne vulgaris in patients 12 to 18 years of age, investigators performed a subgroup analysis on 1,710 patients who had participated in Studies 1 and 2 of the phase 3 studies. ¹¹ Patients were randomized to either clindamycin phosphate 1.2%/tretinoin 0.025% gel (n = 572), clindamycin phosphate 1.2% gel (n = 284), tretinoin 0.025% gel (n = 560), or vehicle gel (n = 294). Baseline demographics and disease characteristics were similar between treatment groups.

At the end of Week 12, patients treated with clindamycin phosphate 1.2%/tretinoin 0.025% gel resulted in significant reductions in inflammatory, non-inflammatory, and total lesions compared with clindamycin phosphate 1.2% gel, tretinoin 0.025% gel, and vehicle gel (P<.001 for all) (Figure 2).

In some instances, significant differences between clindamycin phosphate 1.2%/tretinoin 0.025% gel and clindamycin phosphate 1.2% gel and tretinoin 0.025% gel did not become apparent until Week 2 or Week 4 of treatment. For example, the difference in effect from clindamycin phosphate 1.2%/tretinoin 0.025% gel on total lesions did not become significantly different from clindamycin phosphate 1.2% gel and tretinoin 0.025% gel until Week 4 of treatment.

In patients aged 12 to 18 years of age, treatment with clindamycin phosphate 1.2%/tretinoin 0.025% gel was associated with significantly greater reductions in inflammatory, non-inflammatory, and total lesions compared with clindamycin phosphate 1.2% gel, tretinoin 0.025% gel, and vehicle gel for all baseline severities (mild, moderate, severe) combined (P<.001).

Demonstration of Long-term Efficacy

To assess the long-term efficacy of clindamycin phosphate 1.2%/tretinoin 0.025% gel in treating acne vulgaris, investigators conducted an open-label, 52-week safety and efficacy study following the previously described 12-week phase 3 studies. ¹² The efficacy results are reviewed here.

Patients were evaluated in 2 temporal cohorts: 0-6 months (n = 442) and 6-12 months (n = 213). Of the 442 patients beginning treatment, 225 (51%) were rated as moderate or severe at baseline. Efficacy was measured using improvements from baseline in the EGSS score: "clear", "almost clear", or ≥2 grade improvement. Baseline demographic profiles were similar between cohorts. For inclusion in the final efficacy analysis, patients had to meet the following criteria:
• completed all 12 months of the study;
• had an EGSS score of moderate or severe at baseline;
• received treatment only with clindamycin phosphate 1.2%/tretinoin 0.025% gel during the study (30% of patients used supplemental acne treatments).

At 12 months, 69 patients had met the inclusion criteria. Of the 69 patients, 56 (81%) were rated as "clear", "almost clear", or mild acne (at baseline, no patients exhibited these scores); 33 (48%) were rated as "clear" or "almost clear". No patient was rated as having severe acne at 12 months. Investigators noted that patient improvement increased with longer use of clindamycin phosphate 1.2%/ tretinoin 0.025% gel.

The results of this study demonstrate the long-term efficacy of clindamycin phosphate 1.2%/tretinoin 0.025% gel in treating acne vulgaris. Treatment with clindamycin phosphate 1.2%/tretinoin 0.025% gel was associated with significant improvement as assessed by EGSS, with continuing improvement over time.

Conclusion

Initial treatment of acne vulgaris typically consists of topical therapies including benzoyl peroxide, topical antibiotics or topical retinoids. Until recently, a formulation combining antibiotic and retinoid has not been available. The results of studies reviewed in this report suggest that the novel formulation of once-daily clindamycin phosphate 1.2%/tretinoin 0.025% gel is safe and effective for the short- and long-term treatment of acne vulgaris compared to monotherapy with clindamycin phosphate 1.2% gel or tretinoin 0.025% gel. This formulation will provide a new treatment option for acne vulgaris in patients of all ages.

References

1. White GM. Recent findings in the epidemiologic evidence, classification, and subtypes of acne vulgaris. J Am Acad Dermatol. 1998;39:S34-S37.
2. Rademaker M, Garioch JJ, Simpson NB. Acne in schoolchildren: no longer a concern for dermatologists. BMJ. 1989;298:1217-1219.
3. Kilkenny M, Merlin K, Plunkett A, Marks R. The prevalence of common skin conditions in Australian school students: 3. acne vulgaris. Br J Dermatol. 1998;139:840-845.
4. Lello J, Pearl A, Arroll B, Yallop J, Birchall NM. Prevalence of acne vulgaris in Auckland senior high school students. N Z Med J. 1995;108:287-289.
5. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol. 1999;41:577-580.
6. Smolinski KN, Yan AC. Acne update: 2004. Curr Opin Pediatr. 2004;16:385-391.
7. Tan AW, Tan HH. Acne vulgaris: a review of antibiotic therapy. Expert Opin Pharmacother. 2005;6:409-418.
8. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2003;49(1 Suppl):S1-S37.
9. Schlessinger J, Plott RT. Efficacy of a clindamycin and tretinoin combination product for acne vulgaris: results from 3 double-blind, placebo-controlled, phase 3 trials. J Am Acad Dermatol. 2007;56:AB19. Abstract P126.
10. Leyden J, Plott T, Wortzman M. A novel gel formulation of 0.025% tretinoin and 1.2% clindamycin phosphate: efficacy in patients with mild, moderate and severe baseline acne [poster]. Presented at the 31^st Hawaii Dermatology Seminar, March 3-9, 2007, Maui, Hawaii.
11. Leyden J, Eichenfield L, Plott T, Wortzman M. A novel gel formulation of 0.025% tretinoin and 1.2% clindamycin phosphate: efficacy in acne vulgaris patients aged 12 to 18 years [poster]. Presented at the 31st Hawaii Dermatology Seminar, March 3-9, 2007, Maui, Hawaii.
12. Leyden J, Wortzman M, Plott T. Efficacy of a novel gel formulation of 0.025% tretinoin and 1.2% clindamycin phosphate: efficacy results from a 52-week open-label study [poster]. Presented at the 31^st Hawaii Dermatology Seminar, March 3-9, 2007, Maui, Hawaii.

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Disclosure

Diane Berson, MD, FAAD
Honoraria/Speaker/Consultant - Medicis, Galderma, Stiefel, CollaGenex, Ortho-Neutrogena, DUSA

Amy S. Paller, MD
Grant/Research Support/Consultant/Speakers Bureau- Astellas Pharma US, Inc., Novartis

This report contains information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions; Millennium CME Institute, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients’ conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with the recommendation of other authorities. This monograph was made possible through an educational grant from Medicis, The Dermatology Company.

© 2007 Millennium CME Institute, Inc.

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