ADMINISTRATION OF ADAPALENE AND BENZOYL PEROXIDE FOR THE LONG-TERM TREATMENT OF ACNE VULGARIS

Abstract

A regimen for the safe and effective long-term treatment of acne vulgaris entails topically applying onto the affected skin area of a subject afflicted therewith, for a period of time of at least four (4) months, e.g., for at least twelve (12) months and advantageously on a daily basis and preferably once a day, a thus effective amount of a topical medicament containing adapalene and benzoyl peroxide, formulated into a pharmaceutically acceptable medium therefor.

Claims

1.-19. (canceled)

20. A regimen for safe and effective long-term treatment of acne vulgaris, comprising topically applying onto an affected skin area of a subject afflicted therewith, at least once every two days for a period of time of 9 to 12 months, a thus effective amount of a topical medicament which comprises a fixed-dose combination of 0.01% to 0.5% by weight of adapalene and 2.5% to 5% by weight of benzoyl peroxide, formulated into a pharmaceutically acceptable medium therefor, the percentages by weight being relative to the total weight of the topical medicament, wherein said adapalene and said benzoyl peroxide are the only active ingredients in said fixed-dose combination, and wherein a percent reduction in each of total, inflammatory and non-inflammatory lesion counts after at least 9 months is at least 65%.

21. The regimen for long-term treatment of acne vulgaris as defined by claim 20, comprising administering said topical medicament once a day.

22. The regimen for long-term treatment of acne vulgaris as defined by claim 20, comprising administering said topical medicament every two days.

23. The regimen for long-term treatment of acne vulgaris as defined by claim 20, comprising administering said topical medicament in evening after washing said affected skin area.

24. The regimen for long-term treatment of acne vulgaris as defined by claim 20, said topical medicament comprising a gel composition.

25. The regimen for long-term treatment of acne vulgaris as defined by claim 20, wherein the topical medicament comprises 0.1% to 0.5% by weight of adapalene and 2.5% by weight of benzoyl peroxide, relative to the total weight thereof.

26. The regimen for long-term treatment of acne vulgaris as defined by claim 20, said affected skin area containing from 20 to 100 non-inflammatory lesions, 20 to 50 inflammatory lesions, and no active nodules or cysts.

27. A regimen for safe and effective long-term treatment of acne vulgaris, comprising topically applying onto an affected skin area of a subject afflicted therewith, at least once every two days for a period of time of 10 to 12 months, a thus effective amount of a topical medicament which comprises a fixed-dose combination of 0.01% to 0.5% by weight of adapalene and 2.5% to 5% by weight of benzoyl peroxide, formulated into a pharmaceutically acceptable medium therefor, the percentages by weight being relative to the total weight of the topical medicament, wherein said adapalene and said benzoyl peroxide are the only active ingredients in said fixed-dose combination, and wherein a percent reduction in each of total, inflammatory and non-inflammatory lesion counts after at least 10 months is at least 68%.

28. The regimen for long-term treatment of acne vulgaris as defined by claim 27, comprising administering said topical medicament once a day.

29. The regimen for long-term treatment of acne vulgaris as defined by claim 20, comprising administering said topical medicament every two days.

30. The regimen for long-term treatment of acne vulgaris as defined by claim 27, comprising administering said topical medicament in evening after washing said affected skin area.

31. The regimen for long-term treatment of acne vulgaris as defined by claim 27, said topical medicament comprising a gel composition.

32. The regimen for long-term treatment of acne vulgaris as defined by claim 27, wherein the topical medicament comprises 0.1% to 0.5% by weight of adapalene and 2.5% by weight of benzoyl peroxide, relative to the total weight thereof.

33. The regimen for long-term treatment of acne vulgaris as defined by claim 27, said affected skin area containing from 20 to 100 non-inflammatory lesions, 20 to 50 inflammatory lesions, and no active nodules or cysts.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0055] FIG. 1 shows a time course of median percentage change in lesion counts.

[0056] Median Percent Change in Lesion Counts (ITT Population, Observed Data, and Month 12 LOCF)

[0057] Endpoint: the last available data observed during the study. Baseline value was used if no post-Baseline data were available.

[0058] FIG. 2 shows time course of local cutaneous irritation (worse than baseline, observed data, and final score). Percentages of subjects with scores worse than baseline at each time point with endpoint.

[0059] FIG. 3 shows the local Tolerability with representation of the Final Score and Worst Score (Safety Population).

[0060] “Final” means the last available data observed during the post-baseline period.

[0061] “Worst” means the data observed with the highest severity during the post-baseline period.

[0062] The present invention provides a regimen for the long-term treatment of acne vulgaris by the use of a gel composition containing 0.1 by weight of adapalene and 2.5% by weight of Benzoyle Peroxide. Such product is described in WO 03/055472. The following details a study that clearly demonstrates the clinical benefit of long-term treatment of acne with the above mentioned composition.

[0063] To further illustrate the present invention and the advantages thereof, the following specific examples are given, it being understood that same are intended only as illustrative and in nowise limitative. In said examples to follow, all parts and percentages are given by weight, unless otherwise indicated.

EXAMPLE

Clinical Test of Long-Term Treatment of Acne Vulgaris with a Fixed-Dose Combination Gel Containing Adapalene 0.1% to BPO 2.5% by Weight/Total Composition weight

[0064] Study Design and Subjects:

[0065] The long-term safety and efficacy of a fixed combination gel of adapalene-BPO were evaluated in a multicenter, open-label, single-arm study conducted at 28 centers in the United States. Subjects with acne vulgaris applied once-daily adapalene-BPO to the face for up to 12 months. Safety and efficacy evaluations were performed at baseline, week 1, week 2, and at months 1, 2, 4, 6, 8, 10, and 12. A urine pregnancy test was required at baseline and at the final study visit for all females of childbearing potential. Subjects were free to withdraw from the study at any time and for any reason. Subjects not completing the entire study were to be fully evaluated when possible.

[0066] A total of 452 subjects enrolled in 28 study centers in the United States. All 452 subjects applied study medication at least once, and were analyzed in both the Safety and Efficacy (ITT) populations. Male and female subjects, 12 years of age or older, with 30 to 100 non-inflammatory facial lesions, 20 to 50 inflammatory facial lesions, and no active nodules or cysts were enrolled in the study. Specified washout periods were required for subjects taking certain topical and systemic treatments. Exclusion criteria prohibited enrollment of subjects with severe acne requiring isotretinoin therapy or other dermatologic conditions requiring interfering treatment. Women were excluded if they were pregnant, nursing, or planning a pregnancy as were men with facial hair that would interfere with the assessments.

TABLE-US-00001 TABLE 1 Summary of Subject Demographics and Baseline Characteristics (ITT Population): Variable Total (N = 452) Gender Male 222 (49.1%) Female 230 (50.9%) Total  452 (100.0%) Age (Years) N 452 Mean 18.3 S.D. 6.62 Median 16.0 Min, Max 12, 50 Age Category (Years) 12 to 17 299 (66.2%) 18 to 64 153 (33.8%) 65 and Above 0 Total  452 (100.0%) Race Caucasian 345 (76.3%) Black  53 (11.7%) Asian 10 (2.2%) Hispanic 31 (6.9%) Other 13 (2.9%) Total  452 (100.0%) Skin Photo Type I 12 (2.7%) II 105 (23.2%) III 162 (35.8%) IV  87 (19.2%) V  61 (13.5%) VI 25 (5.5%) Total   452 (100.0%)

[0067] Safety and Efficacy Assessments:

[0068] Safety and tolerability were assessed through evaluations of local facial tolerability and adverse events. At each visit, the investigator rated erythema, scaling, dryness, stinging/burning on a scale ranging from 0 (none) to 3 (severe). Adverse events were evaluated at each visit. Routine laboratory data (hematology, blood chemistry, and urinalysis) were collected at screening, month 6, and month 12.

[0069] The efficacy variables were percent lesion count reduction from baseline (total, inflammatory, and non-inflammatory) and subject's assessment of acne (on a scale from 0 [complete improvement] to 5 [worse]). Lesion counts were assessed on the face only, excluding the nose.

[0070] Efficacy and Safety Variables:

[0071] Table 2 is a flow chart of assessed measurements during this study.

TABLE-US-00002 TABLE 2 Flow Chart of Efficacy and Safety Measurements: Month 12/ Early Wk Months Month Termination Parameter Screening Baseline 1 & 2 1, 2 & 4 Month 6 Month 8 10 Visit Efficacy Lesion Counts X X X X X X X X Subject's X X Assessment of Acne Safety Local X X X X X X X Tolerability Adverse Events X X X X X X X Blood & Urine X X X Sampling Wk = Week M = Month

[0072] The Investigator (or responsible designee) conducted efficacy evaluations consisting of non-inflammatory lesion counts (open and closed comedones) and inflammatory lesion counts (papules and pustules) and nodules/cysts. Lesion counts were taken from the face only. Subject's assessment of acne was also documented.

[0073] Non-inflammatory and inflammatory lesions were counted on the forehead, left and right cheeks, and chin above the jaw line (excluding the nose). Total lesion counts were calculated by the Sponsor. The following definitions were used:

[0074] Non-Inflammatory Lesions:

[0075] Open Comedone: A mass of sebaceous material that is impacted behind an open follicular orifice (blackhead).

[0076] Closed Comedone: A mass of sebaceous material that is impacted behind a closed follicular orifice (whitehead).

Inflammatory Lesions

[0077] Papule: A small, solid elevation less than one centimeter in diameter.

[0078] Pustule: A small, circumscribed elevation of the skin that contains yellow-white exudate.

[0079] Nodule/Cyst: A circumscribed, elevated lesion generally more than 1.0 cm in diameter.

[0080] Subjects evaluated their facial acne at the Month 6 and Month 12/Early Termination Visit, as compared to the Baseline Visit, according to the following scale:

TABLE-US-00003 TABLE 3 1 Marked Improvement 2 Moderate Improvement 3 Minimal Improvement 4 No Change 5 Worse

[0081] The safety variables evaluated were: local tolerability (erythema, scaling, dryness, and stinging/burning), Adverse Events (AEs), and routine laboratory data (hematology, blood chemistry, and urinalysis). Side effects expected during treatment with topical retinoids include erythema, scaling, dryness, and stinging/burning. During the study, the course of these expected events was assessed as local tolerability.

[0082] Erythema, scaling, dryness, and stinging/burning were rated on the following scales:

TABLE-US-00004 TABLE 4 Erythema: abnormal redness of the skin: None 0 No erythema Mild 1 Slight pinkness present Moderate 2 Definite redness, easily recognized Severe 3 Intense redness

TABLE-US-00005 TABLE 5 Scaling: abnormal shedding of the stratum corneum: None 0 No scaling Mild 1 Barely perceptible shedding, noticeable only on light scratching or rubbing Moderate 2 Obvious but not profuse shedding Severe 3 Heavy scale production

TABLE-US-00006 TABLE 6 Dryness: brittle and/or tight sensation: None 0 No dryness Mild 1 Slight but definite roughness Moderate 2 Moderate roughness Severe 3 Marked roughness

TABLE-US-00007 TABLE 7 Stinging/Burning: prickling pain sensation immediately after (within 5 minutes of) dosing: None 0 No stinging/burning Mild 1 Slight warm, tingling/stinging sensation; not really bothersome Moderate 2 Definite warm, tingling/stinging sensation that is somewhat bothersome Severe 3 Hot, tingling/stinging sensation that has caused definite discomfort

[0083] Erythema, scaling, and dryness were evaluated by the Investigator. Stinging/burning was recorded by the Investigator after discussion with the subject.

[0084] Local tolerability measures of the signs and symptoms of skin irritation were considered adverse effects only if the severity of the expected signs and symptoms was such that an interruption of the subject's participation in the study, at his/her request or at the Investigator's discretion, had occurred. Altered dosing regimens (such as every other day dosing) to manage irritation were not considered to be an interruption of the subject's participation in the study.

[0085] Adverse Events (AEs):

[0086] An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the investigational product. Any new sign, symptom or disease, or clinically significant increase in the intensity of an existing sign, symptom or disease, was considered an AE. This included any new signs or symptoms suffered by the subject after accidental or intentional overdose or misuse. Lack of efficacy of the study drug was not considered an AE unless it led to other unfavorable medical occurrences. However, clinically significant worsening of the treated disease was considered an AE.

[0087] Pregnancy was not considered an AE but was an important medical event.

[0088] Severity of an AE was rated as mild, moderate, or severe. Relationship of an AE to study drug was rated as: related (possibly, probably or definitely related) or unrelated (unlikely or definitely unrelated).

[0089] Serious Adverse Events (SAEs):

[0090] An SAE was defined as any untoward medical occurrence that at any dose:

[0091] Resulted in death

[0092] Was life-threatening (i.e., the subject was at risk of death at the time of the event, but not an event which hypothetically might have caused death if it were more severe)

[0093] Required inpatient hospitalization or prolongation of an existing hospitalization (hospitalization solely for diagnostic tests, even if related to an adverse event, elective hospitalization for any intervention planned before subject entered the study, or admission to a day-care facility did not themselves constitute an SAE)

[0094] Resulted in persistent or significant disability/incapacity or

[0095] Resulted in a congenital anomaly/birth defect, or

[0096] other important medical events that jeopardized the subject or required intervention to prevent one of the outcomes listed above.

[0097] Routine Laboratory Tests:

[0098] Blood and urine samples were obtained according to the schedule specified in the study flow chart of Table 1. The following blood chemistries were evaluated: protein, albumin, globulin, A/G ratio, bilirubin (total), alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphate, gamma-glutamyl transferase GGT, lactic dehydrogenase (LDH), blood urea nitrogen (BUN), creatinine, uric acid, cholesterol (total), triglycerides, and glucose.

[0099] The following hematology parameters were evaluated: hematocrit, hemoglobin, red cell count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), white cell count, and platelet count.

[0100] A routine urinalysis for the following was performed: color, appearance, specific gravity, urine reaction pH, glucose, protein (qualitative.), ketones, occult blood, bilirubin, nitrite, and leukocytes.

[0101] Statistical analyses:

[0102] As this was an open-label study, only descriptive data presentations were made. No formal statistical hypotheses were tested. Descriptive statistics were used to summarize all data. For continuous variables, the number of subjects (N), mean, standard deviation (SD), median, minimum and maximum are provided for the data collected at each visit and the changes/percent changes from baseline at each post-baseline visit. For categorical variables, frequencies and percentages for each category are provided.

[0103] All summaries for subject characteristics and efficacy data were based on the Intent to Treat (ITT) population (this population consisted of all subjects enrolled, to whom study medication was dispensed). All safety data is based on the safety population (all subjects who applied study drug at least once).

[0104] Analysis visits were imputed according to an algorithm to summarize data by the treatment duration. If multiple measurements were present within the same interval, the measurement closest to the target study day was used for analysis. If two measurements were taken with equal differences in timing compared with the target day, data from the nominal visit number (recorded on the case report form) was used for analysis. For example, if measurements were collected on Day 360 and Day 367, the data collected at Day 360 was used for analysis at Month 12 while data collected at Day 367 was used in analysis for endpoint. Although all data were used in imputing the visits for analysis, some data were not used for analysis due to multiple observations within a visit window.

[0105] Subject data for all treated subjects were summarized by four quarters of the study: “Baseline to <3 months”, “3 months to <6 months”, “6 months to <9 months”, and “9 months to 1 year.” The number of subjects at risk for each period (i.e., subjects available at beginning of each period) was tabulated. The number of subjects at risk is determined based on each subject's treatment duration. Each month was considered to be 30 days for these calculations, and a 7-day visit window was used. Thus, “Baseline to <3 months” is Day 1 through Day 82, “3 months to <6 months” is Day 83 through Day 172, “6 months to <9 months” is Day 173 through Day 262, “9 months to <1 year” is Day 263 through Day 352, and “1 year and above” is Day 353 and above.

[0106] By the same principle, subject completion/discontinuation was summarized by subjects and by four quarters. The discontinuation rate for each quarter was calculated by the number of subjects who discontinued within the period divided by the number of subjects at risk for the given period.

[0107] The planned safety variables to be analyzed were as follows: [0108] 1. Local Tolerability Assessment (Erythema, Scaling, Dryness, Stinging/Burning) was to be evaluated at Baseline and each post-Baseline visit on a “0” (=None) to “3” (=Severe) scale. [0109] 2. AEs were to be assessed at each visit. [0110] 3. Routine laboratory data (haematology, blood chemistry, urinalysis) were to be collected at Screening, Month 6 and Month 12/Early Termination Visit.

[0111] The planned efficacy variables to be analyzed were: [0112] 1. Percent change from Baseline in facial Inflammatory, Non-inflammatory, and Total Lesion Counts at scheduled post-Baseline visits. [0113] 2. Subject's Assessment of Acne on a “5” (Worse) to “0” (Complete Improvement) scale at Month 6 and Month 12/Early Termination Visit.

[0114] The Non-inflammatory Lesion Count was the sum of open comedones and closed comedones. The Inflammatory Lesion Count was the sum of papules and pustules. The other Lesion Count was the sum of nodules and cysts. The Total Lesion Count was the sum of Inflammatory, Non-inflammatory, and other Lesions. Subject's Assessment of Acne was evaluated on a 5 (Worse) to 0 (Complete Improvement) scale.

[0115] The intent-to-treat (ITT) population was defined as all subjects enrolled, to whom medication was dispensed. The safety population was defined as all subjects enrolled who had applied study medication at least once. Subjects with major protocol deviations were to be tabulated. No per-protocol (PP) population was defined for this study.

[0116] All data analyses were carried out according to a pre-established analysis plan. The sample size of 450 was selected to ensure approximately 300 subjects would be exposed to adapalene-BPO for at least 6 months and 100 subjects would be exposed for up to 1 year. All safety data were summarized based on the safety population. Adverse events were tabulated in frequency tables and summarized by quarters to evaluate the adverse event profile over time. Tolerability variables (erythema, scaling, dryness, stinging/burning) were summarized by severity score. A shift table for the laboratory data at screening versus last post-baseline visit was tabulated for each laboratory parameter. All efficacy data were summarized based on the ITT population. Lesion count data collected at each visit and the changes and percent changes from baseline at post-baseline visits were summarized. Subject's assessment of acne was tabulated. Descriptive statistics were used to summarize the data. No formal statistical hypotheses were tested.

[0117] The safety population was defined as all patients randomized and treated at least once. The intent-to-treat (ITT) population included all randomized subjects who were dispensed study medication. At each time point, efficacy assessments were evaluated using observed data as well as using last observation carried forward methodology (LOCF). Subjects with major protocol deviations were to be tabulated. No per-protocol (PP) population was defined for this study.

[0118] Results:

[0119] Subject Disposition and Baseline Characteristics:

[0120] A total of 452 subjects were enrolled in the study (table 1). All 452 subjects applied study medication at least once and were analyzed in the ITT and safety populations. A total of 397 (87.8%) subjects were evaluated for 3 months or more, 366 (81.0%) were evaluated for 6 months or more, and 334 (73.9%) were evaluated for 9 months or more. Overall, 327 (72.3%) of subjects completed the 12-month study. The mean(±SD) extent of exposure was 294.6 days (±117.7). No subjects discontinued due to lack of efficacy and discontinuations due to adverse events were low (2.0%). The baseline characteristics of the ITT population are summarized in Table I.

[0121] Efficacy Evaluation:

[0122] The results for percent change in lesion counts in the ITT Population are shown in FIG. 1 and table 8.

TABLE-US-00008 TABLE 8 Summary of Inflammatory, Non-inflammatory, and Total Lesion Counts: Median Counts at Baseline and Median Percent Change from Baseline at Each Visit and at Month 12 LOCF (ITT Population): Inflam- matory Non- Total Lesion inflammatory Lesion Time-point N Count N Lesion Count N Count Baseline 452 27.0 452 42.0 452 72.0 Count Week 1 423 −21.9% 423 −19.3% 423 −19.4% Week 2 429 −32.1% 429 −31.7% 429 −31.0% Month 1 415 −42.5% 415 −43.3% 415 −43.2% Month 2 426 −53.7% 426 −54.0% 426 −53.7% Month 4 390 −69.3% 390 −64.8% 390 −65.4% Month 6 361 −69.4% 361 −61.9% 361 −64.8% Month 8 341 −74.1% 341 −70.6% 341 −70.1% Month 10 329 −74.4% 329 −68.8% 329 −69.4% Month 12 327 −76.0% 327 −70.0% 327 −70.8% Month 12 452 −69.5% 452 −65.7% 452 −64.9% LOCF

[0123] For the 327 subjects who remained in the study until Month 12 visit (observed data), the percent reductions in total, inflammatory and non-inflammatory lesion counts were 70.8%, 76% to 70% respectively. When ITT LOCF data are considered, the median percent reductions from baseline in total, inflammatory, and non-inflammatory lesion counts were 64.9%, 69.5%, and 65.7% at Month 12, respectively. Reductions in inflammatory, non-inflammatory, and total lesions were observed starting as early as Week 1. For patients remaining in the study, lesion counts continued to decrease through the initial 4 months of the study and the reductions were maintained for the duration of the study.

[0124] The subject assessment demonstrated a clinical improvement with 12 months of adapalene-BPO treatment. At the end of the study, 330 subjects (330/411, 80.3%) reported a moderate, marked, or complete improvement, 45 subjects (45/411, 10.9%) reported a minimal improvement, and 36 subjects (36/411, 8.8%) reported no change or worsening. The results were similar regardless of age, gender, or race.

[0125] FIG. 1 illustrates the effect of adapalene-BPO combination therapy on facial acne during the course of the 12-month study.

TABLE-US-00009 TABLE 9 Summary of Subject's Assessment of Acne (ITT Population, Month 12 Observed Data, and Month 12 LOCF): Subjects Assessment of Acne Month 6 Month 12 Month 12 LOCF 0 = Complete Improvement 17 (4.7%) 40 (12.2%) 43 (10.5%) 1 = Marked Improvement 149 (41.5%) 164 (50.2%) 193 (47.0%) 2 = Moderate Improvement 147 (40.9%) 77 (23.5%) 94 (22.9%) 3 = Minimal Improvement 31 (8.6%) 37 (11.3%) 45 (10.9%) 4 = No Change 11 (3.1%) 6 (1.8%) 20 (4.9%) 5 = Worse 4 (1.1%) 3 (0.9%) 16 (3.9%) Total 359 (100.0%) 327 (100.0%) 411 (100.0%) Month 12 LOCF: the last available data observed during the study carried forward. Baseline value was used if no post-Baseline data were available.

[0126] Safety Evaluation:

[0127] Local Tolerability Assessment:

[0128] Local tolerability variables (erythema, scaling, dryness, and stinging/burning) were summarized by a severity score on a 4-point scale at each visit (0=none to 3=severe). Each subject's “Worst” score and the “Final” score were summarized where “Worst” was the highest score and “Final” was the last observation during the post-baseline period.

[0129] The number of subjects whose local tolerability data were worse (higher score) than their Baseline score was tabulated at each post-baseline visit. The “Worst” and “Final” scores for each subject, if higher than Baseline were tabulated.

[0130] Overall, treatment with adapalene-BPO was safe and well-tolerated when used for up to 12 months in subjects with acne vulgaris. The scores for the severity of erythema, scaling, dryness, and stinging/burning after study treatment are summarized in FIG. 2. Local cutaneous tolerability of the study treatment was good throughout the study, with mean tolerability scores for erythema, dryness, scaling, and burning/stinging all less than 1 (mild) at each study visit. The mean worst scores of all subjects were consistent with mild irritation. The highest mean cutaneous tolerability scores were recorded in the first post-baseline study visit (week 1) and then decreased to levels similar to baseline scores.

[0131] Erythema, Scaling, Dryness, and Stinging/Burning were graded at Baseline and each post-Baseline visit on a scale of “0” (=None) to “3” (=Severe) scale. The results were similar for each of the signs and symptoms. The worst severity scores were generally mild or moderate, and rarely severe.

[0132] A summary of the worst severity scores in the subjects with Local Tolerability Assessments worse than baseline is provided in Table 10. Incidences for severe Local Tolerability scores ranged from 0.4% to 3.3% overall signs and symptoms.

TABLE-US-00010 TABLE 10 Summary of Local Tolerability Assessment - Percentages of Subjects with Scores Worse than Baseline (Safety Population): Stinging/ Timepoint N Erythema N Scaling N Dryness N Burning Week 1 423 29.3% 423 40.2% 423 45.2% 423 50.8% (observed) Week 2 429 19.8% 429 29.4% 429 31.5% 429 24.0% (observed) Month 1 415 16.1% 415 20.5% 415 25.5% 415 19.3% (observed) Month 2 426 13.4% 426 16.4% 426 21.6% 426 11.5% (observed) Month 4 389 4.6% 389 8.0% 389 11.8% 389 5.9% (observed) Month 6 361 7.8% 361 7.8% 361 9.1% 361 6.4% (observed) Month 8 341 7.9% 341 10.0% 341 13.8% 341 8.2% (observed) Month 10 329 7.0% 329 9.1% 329 11.9% 329 7.3% (observed) Month 12 327 5.5% 327 4.6% 327 9.2% 327 5.8% (observed) Final 448 7.4% 448 9.4% 448 14.1% 448 8.5% Worst 448 48.0% 448 61.8% 448 65.2% 448 66.1% Final: The last available data observed during the post-Baseline period. Worst: The data observed with the highest severity during the post-Baseline period.

[0133] The majority of Local Tolerability Assessment scores which were worse than the baseline scores were reported during the first week of treatment with Adapalene/Benzoyl Peroxide Gel for 29.3% of subjects for Erythema, 40.2% for Scaling, 45.2% for Dryness, and 50.8% for Stinging/Burning (Table 10). However, the incidence of Erythema, Scaling and Stinging/Burning decreased rapidly, and were reported by 10% or less subjects by Month 4. Incidences of Dryness were less than 12% by Month 4, and following Month 4 fluctuated from 9% to 14% for the remainder of the study.

[0134] Expected signs and symptoms of local cutaneous irritation were mild to moderate in severity. Very few subjects had severe scores. (Table 11).

TABLE-US-00011 TABLE 11 Summary of Local Tolerability Assessment Worse than Baseline - Worst Scores (Safety Population): Local Tolerability Worse than Baseline - Worst Score.sup.a (N = 448).sup.b Worst Severity Score in these Subjects Number of Mild Moderate Severe Variable Subjects N (%) N (%) N (%) Erythema 215 (48.0%) 151 61 (13.6%) 3 (0.7%) (33.7%) Scaling 277 (61.8%) 225 50 (11.2%) 2 (0.4%) (50.2%) Dryness 292 (65.2%) 230 57 (12.7%) 5 (1.1%) (51.3%) Stinging/Burning 296 (66.1%) 185 96 (21.4%) 15 (3.3%)  (41.3%) .sup.aThe data observed with the highest severity during the post-Baseline period for the subjects with data worse than Baseline. .sup.bN = 448 is the number of subjects with local tolerability data available at Baseline and at least one post-baseline data point.

[0135] Adverse Events:

[0136] All AEs recorded on the case report forms (CRFs) are displayed in data listings.

[0137] AEs were also summarized for all subjects. A subject was counted only once per body system, even if more than one event was reported, and only once per COSTART (Coding Symbols for Thesaurus of Adverse Reaction Terms), even if more than one occurrence was reported.

[0138] The AE incidence by quarter was summarized for “Baseline to <3 months”, “3 months to <6 months”, “6 months to <9 months”, and “9 months to 1 year.” The AE incidence for each period was calculated as the number of subjects with AE onset dates within the period divided by the number of subjects at risk per period.

[0139] AE summary tables are listed in the Statistical Analysis Plan (SAP).

[0140] A summary of adverse events over the course of the study is shown in Table 12. Overall, 288 subjects (63.7%) experienced adverse events during the study. A total of 147 subjects (32.5%) had treatment-related adverse events (i.e., adverse event relationship to study drug assessed as “possible”, “probable” or “definitely related”). The most common treatment-related adverse event was dry skin (17.3%) (table 13). The majority of adverse events were mild or moderate in severity. Most adverse events occurred within the first 3 months of therapy and the incidence dropped at subsequent visits. Only 19 subjects (4.2%) had severe adverse events and, of these, 10 subjects (2.2%) had severe adverse events deemed at least possibly related to study treatment. During the 12-month course of the study, only 9 subjects had 10 adverse events leading to discontinuation. Out of these 10 adverse events, 7 were related to study treatment.

TABLE-US-00012 TABLE 12 Overall Summary of Adverse Events (Safety Population): Baseline Month 3 Month 6 Month 9 to to to to <Month 3 <Month 6 <Month 9 Year Total Category (N+ = 452) (N+ = 397) (N+ = 366) (N+ = 334) (N = 452) Subjects With At Least One AE 195 79 83 82 288 (43.1%) (19.9%) (22.7%) (24.6%) (63.7%) Dermatological AE 104 13 12 11 131 (23.0%) (3.3%) (3.3%) (3.3%) (29.0%) Non-Dermatological AE 139 72 77 78 243 (30.8%) (18.1%) (21.0%) (23.4%) (53.8%) Subjects With At Least One AE 127 16 11 5 147 Related To Study Drug (28.1%) (4.0%) (3.0%) (1.5%) (32.5%) Dermatological AE 94 8 8 4 110 (20.8%) (2.0%) (2.2%) (1.2%) (24.3%) Non-Dermatological AE 66 8 4 2 78 (14.6%) (2.0%) (1.1%) (0.6%) (17.3%) Subjects With At Least One SAE 1 2 1 1 5 (0.2%) (0.5%) (0.3%) (0.3%) (1.1%) Dermatological AE 0 0 0 0 0 Non-Dermatological AE 1 2 1 1 5 (0.2%) (0.5%) (0.3%) (0.3%) (1.1%) Subjects With At Least One AE 7 1 0 1 9 (1.5%) (0.3%) (0.3%) (2.0%) Leading to Disc. Dermatological AE 6 1 0 0 7 (1.3%) (0.3%) (1.5%) Non-Dermatological AE 1 0 0 1 2 (0.2%) (0.3%) (0.4%)

[0141] Subjects may be counted twice, once in Dermatological category and once in Non-dermatological category for having more than one AE.

[0142] Related to study drug means that AE relationship to study drug was assessed as ‘possible’, ‘probable’ or ‘definitely related’.

[0143] Subjects may be counted in more than one period due to multiple AEs.

[0144] AE(s) with incomplete onset date(s) or onset date(s) prior to the first application are only included in the Total column.

[0145] N+=N at risk, the number of subjects at the beginning of each period.

TABLE-US-00013 TABLE 13 Most Frequent Adverse Events, Reported by at Least 1% of Total Subjects by System Organ Class and Preferred Term (Safety Population): Baseline Month Month Month to 3 to 6 to 9 to <Month 3 <Month <Month 9 1 Year Total System Organ Class/Preferred (N+ = 6 (N+ = (N+ = (N+ = (N = Term* 452) 397) 366) 334) 452) Total Number of AE(s) 405 113 125 108 766 Total Number (%) of Subjects 195 79 83 82 288 with AE(s) (43.1%) (19.9%) (22.7%) (24.6%) (63.7%) Infections and Infestations 48 33 39 49 135 (10.6%) (8.3%) (10.7%) (14.7%) (29.9%) Nasopharyngitis 14 7 9 8 30 (3.1%) (1.8%) (2.5%) (2.4%) (6.6%) Upper Respiratory Tract 7 0 11 9 26 Infection (1.5%) (3.0%) (2.7%) (5.8%) Influenza 4 2 2 10 18 (0.9%) (0.5%) (0.5%) (3.0%) (4.0%) Sinusitis 6 3 3 5 15 (1.3%) (0.8%) (0.8%) (1.5%) (3.3%) Pharyngitis Streptococcal 5 2 3 3 13 (1.1%) (0.5%) (0.8%) (0.9%) (2.9%) Urinary Tract Infection 1 3 0 4 8 (0.2%) (0.8%) (1.2%) (1.8%) Gastroenteritis Viral 2 1 2 3 7 (0.4%) (0.3%) (0.5%) (0.9%) (1.5%) Bronchitis 0 3 1 3 7 (0.8%) (0.3%) (0.9%) (1.5%) Skin and Subcutaneous Tissue 104 13 12 11 131 Disorders (23.0%) (3.3%) (3.3%) (3.3%) (29.0%) Dry Skin 71 5 6 3 80 (15.7%) (1.3%) (1.6%) (0.9%) (17.7%) Erythema 22 1 2 1 25 (4.9%) (0.3%) (0.5%) (0.3%) (5.5%) Skin Desquamation 22 0 1 0 23 (4.9%) (0.3%) (5.1%) Contact Dermatitis 12 1 2 2 17 (2.7%) (0.3%) (0.5%) (0.6%) (3.8%) Pruritus 4 0 2 1 7 (0.9%) (0.5%) (0.3%) (1.5%) Acne 3 2 0 0 5 (0.7%) (0.5%) (1.1%) Swelling Face 4 0 1 1 5 (0.9%) (0.3%) (0.3%) (1.1%) Skin Discomfort 5 0 0 0 5 (1.1%) (1.1%) General Disorders and 63 5 7 2 74 Administration Site Conditions (13.9%) (1.3%) (1.9%) (0.6%) (16.4%) Application Site Burning 57 3 4 1 64 (12.6%) (0.8%) (1.1%) (0.3%) (14.2%) Application Site Irritation 16 1 0 1 18 (3.5%) (0.3%) (0.3%) (4.0%) Injury, Poisoning and 21 18 5 4 47 Procedural Complications (4.6%) (4.5%) (1.4%) (1.2%) (10.4%) Sunburn 11 8 1 2 21 (2.4%) (2.0%) (0.3%) (0.6%) (4.6%) Joint Sprain 2 1 0 1 5 (0.4%) (0.3%) (0.3%) (1.1%) Respiratory, Thoracic and 9 6 13 3 29 Mediastinal Disorders (2.0%) (1.5%) (3.6%) (0.9%) (6.4%) Pharolaryngeal Pain 4 4 5 1 14 (0.9%) (1.0%) (1.4%) (0.3%) (3.1%) Nasal Congestion 1 1 2 1 5 (0.2%) (0.3%) (0.5%) (0.3%) (1.1%) Gastrointestinal Disorders 14 8 6 4 28 (3.1%) (2.0%) (1.6%) (1.2%) (6.2%) Vomiting 4 1 2 0 6 (0.9%) (0.3%) (0.5%) (1.3%) Nausea 1 1 3 1 6 (0.2%) (0.3%) (0.8%) (0.3%) (1.3%) Nervous System Disorders 16 5 1 5 25 (3.5%) (1.3%) (0.3%) (1.5%) (5.5%) Headache 16 4 1 3 21 (3.5%) (1.0%) (0.3%) (0.9%) (4.6%) *Multiple occurrences within a System Organ Class (SOC) by a subject were counted once per SOC. Multiple occurrences of a Preferred Term by a subject were counted once per Preferred Term. A subject was counted once even if the subject experienced more than one AE during the study. Subjects may be counted in more than one period due to multiple AEs. AE(s) with incomplete onset date(s) or onset date(s) prior to the first application are only included in the Total column. N+ = N at risk, the number of subjects at the beginning of each period.

[0146] Five subjects (5/452, 1.1%) had a total of 6 serious adverse events (depression, staphylococcal infection, clavicle fracture, syncope, bipolar disorder and drug abuse), all of which were non-dermatologic and unrelated to the study drug. There were no deaths during the study and no confirmed cases of sensitization occurred in the study. Over the course of the one year, no clinically relevant drug-related changes in routine laboratory parameters (clinical chemistry, hematology and urinalysis) were observed. Ten subjects (10/452, 2.2%) had clinically significant post-baseline laboratory assessments reported as adverse events, although these were not considered treatment-related.

[0147] This study is the first long-term clinical evaluation of the safety and efficacy of a unique fixed-dose combination of a retinoid (adapalene 0.1%) and BPO 2.5%. This once-daily combination addresses multiple pathogenic factors of acne, providing prompt and sustained efficacy with no risk for antibiotic resistance. Overall, the results of the study support the safe and effective use of the fixed-dose combination gel of adapalene and BPO for the long-term management of subjects with acne vulgaris. In terms of safety, most adverse events and symptoms of skin irritation were mild-to-moderate, occurred early in the study, and were transient. The use of a daily moisturizer when starting therapy may help to avoid the most common adverse events, like dry skin. Importantly, there was a low rate of discontinuation due to adverse events (2.0%) and no subjects discontinued due to lack of efficacy. Clinically significant inflammatory and non-inflammatory lesion count reductions were observed as early as week 1 and were sustained for up to 1 year. Eighty percent (80%) of subjects reported moderate, marked, or complete improvement of their acne. Results of this study are consistent with a previous 12-week, double-blind controlled study, which showed the adapalene-BPO combination produced significantly greater lesion reductions and had a quicker onset of action relative to corresponding monotherapies, with a comparable safety profile to adapalene.

[0148] Since acne is a chronic disease, its management often requires a long-term therapeutic strategy to control acne and maintain improvements. For all but the most severe acne, combination therapy with agents with complementary mechanisms of action should be utilized as early as possible and then followed with a maintenance therapy. As observed in this study, the use of the adapalene-BPO fixed-dose combination can be use for both initiation and long-term therapy for moderate to severe acne.

[0149] Previous studies have shown that the use of combination therapy with adapalene gel 0.1° A may be more tolerable and associated with a lower rate of adverse events relative to the other topical retinoids..sup.25-29 Consistent with these prior experiences, adapalene when combined with BPO in a fixed-dose formulation was well tolerated in pre-clinical studies, a large double-blind controlled clinical study, and in the current long-term study, with a similar safety and tolerability profile as adapalene monotherapy. Furthermore, a well-tolerated fixed-dose combination therapy may also be more convenient and simplify a acne treatment regimen, thereby potentially improving treatment adherence.

[0150] The results of this study are compatible with those reported in recently published acne maintenance studies. Acne lesions have been shown to return after discontinuing a combination treatment regimen and therefore long-term therapy is necessary for many acne patients. In this study, acne lesions continued to decrease from baseline to approximately month 4 and the therapeutic effect was sustained throughout the year. There are several published studies demonstrating the value of long-term treatment following successful initial therapy to help limit the development of subclinical microcomedones and thereby prevent the recurrence of the disease after initial improvement. For example, Thiboutot et al assessed the maintenance effect of adapalene 0.1° A gel relative to gel vehicle in 253 subjects successfully treated in a previous adapalene-doxycycline combination therapy study. This 16-week study demonstrated a significant clinical benefit of continued treatment with adapalene 0.1% gel relative to vehicle. Although future studies will be needed to properly evaluate adapalene-BPO as a maintenance therapy, the long-term safety and efficacy results of the current study suggest that expanding the armamentarium available for acne management with this fixed-dose combination will provide greater flexibility for customizing both short- and long-term care.

[0151] Each patent, patent application, publication, text and literature article/report cited or indicated herein is hereby expressly incorporated by reference in its entirety.

[0152] While the invention has been described in terms of various specific and preferred embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims, including equivalents thereof.