This phase 2a trial investigated the efficacy of NFX-179 Topical Gel, a metabolically labile MEK inhibitor, in the treatment of cutaneous neurofibromas (cNFs) in neurofibromatosis type 1. Forty-eight participants were randomized to four treatment arms: NFX-179 Topical Gel 0.05%, 0.15%, and 0.5% or vehicle applied once daily to five target cNFs for 28 days. Treatment with NFX-179 Topical Gel resulted in a dose-dependent reduction in p-ERK levels in cNFs at day 28, with a 47% decrease in the 0.5% NFX-179 group compared to the vehicle ( P = 0.0001). No local or systemic toxicities were observed during the treatment period, and systemic concentrations of NFX-179 remained below 1 ng/ml. In addition, 20% of cNFs treated with 0.5% NFX-179 Topical Gel showed a ≥50% reduction in volume compared to 6% in the vehicle group by ruler measurement with calculated volume ( P = 0.021). Thus, NFX-179 Topical Gel demonstrated significant inhibition of MEK in cNF with excellent safety and potential therapeutic benefit.

Common Warts: A Noninterventional, Observational Study Stuart D. Shanler, MD, FAAD, FACMS1; Chris Powala1; Alan Shields, PhD2; Mark Bradshaw, PhD3 ; Judith Schnyder, MBA1 1Aclaris Therapeutics, Inc., Wayne, PA; 2Adelphi Values, Boston, MA; 3GCP-MB, LLC, Asbury Park, NJ CONCLUSIONS 1Inter-rater agreement was substantial to excellent based on 2 separate assessments, indicating PWA scores were reproducible and consistent across independent raters 2 Intra-rater agreement was excellent between assessments at 2 separate time points using the PWA, indicating findings were consistent over time among individual raters 3These findings establish the usefulness and reliability of the PWA, and support use of the tool in clinical trials designed to evaluate the efficacy and safety of HP45 in patients with common warts

Treatment of Common Warts: 8-Week Results From the Phase 2 WART-203 Trial Stephen K. Tyring, MD, PhD1; Stacy R. Smith, MD2; Michael H. Gold, MD3; Mark Bradshaw, PhD4; Stuart D. Shanler, MD, FAAD, FACMS5 1Houston Skin Associates, Houston, TX; 2California Dermatology & Clinical Research Institute, Encinitas, CA; 3Tennessee Clinical Research Center, Nashville, TN; 4GCP-MB, LLC, Asbury Park, NJ; 5Aclaris Therapeutics, Inc., Wayne, PA CONCLUSIONS 1Treatment with HP45 was safe and well tolerated and resulted in a statistically significantly greater reduction from baseline in target wart PWA score compared with vehicle as early as week 3 after treatment initiation 2 Compared with vehicle, HP45 led to the clearance of more target warts by week 4 and resulted in the clearance of all treated warts in more patients by week 6 3This study provides supportive evidence for the safety and efficacy of HP45 topical solution in the treatment of common warts; a Phase 3 clinical program is under way

Seborrheic Keratoses on the Trunk, Extremities, and Face: Results of a Phase 2, Randomized, Double-Blind, Vehicle-Controlled, Parallel-Group Study Janet DuBois, MD1; Kimberly Grande, MD, FAAD2; Mark Bradshaw, PhD3; Judith Schnyder, MBA4 1DermResearch Inc., Austin, TX; 2The Skin Wellness Center, Knoxville, TN; 3GCP-MB, LLC, Asbury Park, NJ; 4Aclaris Therapeutics, Inc., Wayne, PA CONCLUSIONS 1Over the 15-week study, both HP40 and HP45 were well tolerated and associated with a favorable safety profile 2 Most patientand investigatorreported LSRs that occurred during treatment with HP40 and HP45 had resolved by the end of the study 3Only minimal changes in skin pigmentation were observed at the end of the study compared with earlier time points

BACKGROUND Seborrheic keratosis (SK) is a common benign skin tumor, yet no topical treatments are approved in the United States. OBJECTIVE To evaluate the proprietary, stabilized, high-concentration hydrogen peroxide–based topical solution A-101 (32.5% and 40% concentrations) for treatment of facial SK lesions. MATERIALS AND METHODS In this multicenter, double-blind, vehicle-controlled study, eligible subjects were randomly assigned to receive up to 2 treatments of A-101 40%, A-101 32.5%, or vehicle solution applied to a single facial SK lesion. The primary efficacy assessment was the Physician's Lesion Assessment (PLA), a validated 4-ordinal scale. RESULTS The primary end point, the mean reduction in PLA grade from baseline to Day 106 was 1.7 for A-101 40%, 1.4 for A-101 32.5%, and 0.1 for vehicle (p < .001, both concentrations vs vehicle). Lesions for 68%, 62%, and 5% of subjects, respectively, were judged to be clear or near clear (p < .001, both concentrations vs vehicle). Local skin reactions were predominantly mild and transient. No subjects discontinued because of treatment-related adverse events. CONCLUSION A-101 solution demonstrated efficacy in treating SKs on the face. Greater magnitude of effect was seen with the 40% concentration than the 32.5% concentration. A-101 solution had a favorable safety and tolerability profile at both concentrations.

Background: Approved topical treatments for seborrheic keratoses (SKs) are an unmet need. Objective: To evaluate the safety and efficacy of 40% hydrogen peroxide topical solution (HP40) versus vehicle for the treatment of SKs (A-101-SEBK). Methods: A total of 937 patients with 4 SKs each (>= 1 lesion each on the face and on the trunk and/or an extremity) were randomized 1:1 to HP40 or vehicle. At each visit, SKs were graded using the Physician's Lesion Assessment (PLA) scale (0, clear; 1, nearly clear; 2, <= 1 mm thick; and 3, [1 mm thick). After 1 treatment, SKs with a PLA score higher than 0 were re-treated 3 weeks later. Results: At day 106, significantly more patients treated with HP40 than with vehicle achieved a PLA score of 0 on all 4 SKs (study 1, 4% vs 0%; study 2, 8% vs 0% [both P < .01]) and on 3 of 4 SKs (study 1, 13% vs 0%; study 2, 23% vs 0% [both P < .0001]). A higher mean per-patient percentage of SKs were clear (study 1, 25% vs 2%; study 2, 34% vs 1%) and clear or nearly clear (study 1, 47% vs 10%; study 2, 54% vs 5%) with HP40 than with vehicle. Local skin reactions were largely mild and resolved by day 106. Limitations: The optimal number of treatment sessions was not evaluated. Conclusion: Application of HP40 was well tolerated and effective in the removal of SKs.

Abstract Not Available Disclosures: Study supported by Alcaris.

Background: Previous studies showed that adjunctive subantimicrobial dose doxycycline (SDD; 20 mg, twice daily) provides significant clinical benefits to scaling and root planing (SRP). A modified‐release SDD formulation containing 40 mg doxycycline (SDD‐40) to be taken once daily has been developed. The aim of this study was to investigate the efficacy of SDD‐40 when used as an adjunct to SRP for the treatment of periodontitis. Methods: A 9‐month, double‐masked, randomized, placebo‐controlled, multicenter study was conducted to test the efficacy of adjunctive SDD‐40 in 266 subjects with periodontitis. Subjects were treated by SRP and randomized to receive SDD‐40 or placebo for 9 months with evaluations at 3, 6, and 9 months. Results: Adjunctive SDD‐40 provided significantly greater clinical benefits than placebo at all time points. At month 9, at sites with baseline probing depths (PD) ≥6 mm, 72% to 76% of sites in the SDD‐40 group demonstrated clinically significant PD reductions and clinical attachment level (CAL) gains ≥2 mm compared to 56% to 58% of sites in the placebo group ( P <0.0001); 48% to 52% of sites in the SDD‐40 group demonstrated PD reductions and CAL gains ≥3 mm compared to 32% of sites in the placebo group ( P <0.0001). In moderate sites (baseline PD 4 to 6 mm), adjunctive SDD‐40 provided significant clinical benefits compared to placebo for mean CAL (all time points: P <0.05), PD (3 months: P = 0.002; 6 and 9 months: P = 0.001), and bleeding on probing (BOP) (3 months: P <0.01; 6 months: P <0.02; 9 months: P <0.05). In deep sites (baseline PD ≥7 mm), SDD‐40 provided significant benefits over control for mean CAL (3 months: P <0.05; 6 and 9 months: P <0.01), PD (all time points: P <0.001), and BOP (3 months: P <0.05; 6 months: not statistically significant; 9 months: P <0.05). Compliance with study medication was high (>92%) with no significant differences in adverse events between groups and no evidence of microbiologically significant changes or development of antibiotic resistance in the subgingival flora in either group. Conclusion: SDD‐40 used as an adjunct to SRP resulted in significantly greater clinical benefits than SRP alone in the treatment of periodontitis.

BACKGROUND Previous studies showed that host modulation therapy (HMT) or topical antimicrobial therapy (TAT) provided significant adjunctive benefits to scaling and root planing (SRP) in the treatment of chronic periodontitis (CP). The purpose of this study was to evaluate a combination therapy involving SRP, HMT, and TAT in the treatment of moderate to severe CP. METHODS A 6-month, randomized, multicenter, placebo-controlled, examiner-masked study was undertaken to evaluate the clinical usefulness of a combination treatment of systemically delivered doxycycline hyclate (HMT; 20 mg, twice a day) plus locally delivered doxycycline hyclate gel (TAT; 10%, in pockets > or =5 mm) in combination with SRP versus SRP plus placebo. Clinical outcomes included mean changes in probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), and gingival index (GI) at baseline and at 3 and 6 months. RESULTS In 171 subjects, combination therapy provided significantly greater clinical benefits than control therapy for all clinical measures at 3 and 6 months. In moderate CP (PD of 4 to 6 mm), combination therapy provided significant benefits over control for PD (3 and 6 months: P <0.01), CAL (3 months: P <0.01; 6 months: P <0.03), BOP (3 months: P <0.02; 6 months: P <0.05), and GI (3 months: P <0.01; 6 months: P <0.03). In severe CP (PD > or =7 mm), combination therapy provided significant benefits over control for PD (3 and 6 months: P <0.01), CAL (3 months: P <0.01; 6 months: P <0.02), BOP (3 months: P <0.01; 6 months: P >0.05), and GI (3 months: P <0.01; 6 months: P <0.01). CONCLUSION Combination therapy, including SRP, HMT, and TAT, provided significantly greater clinical benefits than SRP alone in the treatment of moderate to severe CP.

BACKGROUND Recurrent oral aphthous ulceration (ROAU) is a common problem that can result in considerable pain and distress for patients. The aim of this pilot study was to evaluate the role of subantimicrobial dose doxycycline (SDD - 20 mg doxycycline twice daily) in the management of patients with ROAU. METHODS 50 patients with ROAU were randomly allocated to treatment with SDD or placebo for 90 days. Daily ulcer diaries were completed by the participants to record the number of new ulcers and the pain associated with the ulcers. RESULTS There were significantly more days with no new ulcers in the SDD group (80.4 +/- 5.9) than the placebo group (69.8 +/- 18.7; P=0.04). Strong trends were observed towards fewer new ulcers per day, fewer new ulcers over the 90-day period, and more days with no pain in the SDD group compared with the placebo group (P=0.06-0.08). CONCLUSION SDD shows promise as potential therapy in the management of ROAU, though this needs to be confirmed in further studies.

Background. Two large clinical trials have recently demonstrated the efficacy of a 40‐mg controlled‐release formulation of doxycycline in the treatment of rosacea, a dose well below the conventional level of 100 to 200 mg/d. Since no formal dose‐response studies have been conducted, the authors analyzed phase 3 data to determine whether a dose‐efficacy relationship exists. Methods. Standard parametric regression analyses were used to estimate the correlations between dose (mg/kg body weight) and overall drug exposure (area under the curve [AUC]) in a phase 1 pharmacokinetic study and between dose and efficacy (mean change from baseline in total inflammatory lesion count at week 16) in 2 pooled phase 3 clinical efficacy studies. Additional regressions were run at each visit for the clinical efficacy studies to determine whether results differed across visits. A regression analysis was also performed in a subset of patients who showed a greater efficacy response. Results. We found overall drug exposure (AUC) to have a highly significant correlation with dose (mg/kg) (r=0.49; P=.006). In contrast, clinical efficacy did not correlate with dose at any of the visits at week 3 (r=0.01; P=.85), week 6 (r=0.04; P=.53), week 12 (r<0.01; P=.98), and week 16 (r=0.03; P=.64) or among the subset of patients who showed greater clinical benefit. Conclusions. Higher mg/kg doses led to higher plasma concentrations but did not lead to increased clinical efficacy. Anti‐inflammatory dose doxycycline (40‐mg controlled‐release formulation) conferred peak anti‐inflammatory efficacy in the treatment of rosacea. (SKINmed. 2007;6:221–226)

Background: Doxycycline monotherapy at antimicrobial doses has been shown to be effective for the treatment of rosacea.Objective: To evaluate the efficacy and safety of once-daily anti-inflammatory dose doxycycline for the treatment of rosacea.Methods: In two phase III, parallel-group, multicenter, randomized, double-blind, placebo-controlled studies (studies 301 and 302), patients received 40-mg of controlled-release doxycycline (n = 269) or placebo (n = 268) for 16 weeks. The primary efficacy end point was the mean change from baseline in facial inflammatory lesion count.Results: The mean lesion count at baseline was approximately 20 in each study arm. At week 16, the mean change from baseline in lesion count in the active-treatment groups was -11.8 in study 301 and -9.5 in study 302 compared with -5.9 and -4.3, respectively, in the placebo groups (P < .001 for both comparisons). Anti-inflammatory close doxycycline was well tolerated; the most common adverse events were nasopharyngitis (4.8%), diarrhea (4.4%), and headache (4.4%).Limitations: In both studies, the reduction of inflammatory lesion counts did not plateau within the 16-week time frame in either treatment group. Rosacea is often treated for a period of months or years. The duration of the studies did not allow for assessment of safety beyond 16 weeks or whether the progressive improvement seen with active treatment would continue beyond 16 weeks. Neither study assessed the effect of treatment in patients with only erythematotelangiectatic (subtype 1) rosacea.Conclusion: Once-daily anti-inflammatory dose doxycycline appears to be effective and safe for the treatment of rosacea.

OBJECTIVE:To assess the efficacy of subantimicrobial dose doxycycline (SDD; 20 mg doxycycline twice daily) as an adjunct to scaling and root planing (SRP) in the treatment of moderate-severe chronic periodontitis (CP) in institutionalised elderly patients aged 65 years or older.BACKGROUND:Previous studies have shown that SDD is of clinical benefit in the treatment of CP. However, the benefits of SDD in geriatric populations (65+ years) have not been determined.MATERIAL AND METHODS:A 9-month, double-blind, randomised, placebo-controlled pilot study was conducted. 24 institutionalised geriatric patients (65 years or older) with evidence of CP manifested by baseline clinical attachment levels (CAL) 5-9 mm, probing depths (PD) 4-9 mm and bleeding on probing (BOP) were recruited. At baseline, patients were treated by a standardised episode of SRP, and randomised to receive either adjunctive SDD or placebo. Full mouth PD and CAL were measured using the manual UNC-15 periodontal probe at 3, 6, and 9 months post-baseline to assess the response to treatment. Periodontal sites were stratified by baseline PD value: sites with PD 4-5 mm were considered moderately diseased and sites with PD > or = 6 mm severely diseased.RESULTS:The SRP + placebo resulted in PD reductions similar to those reported previously in the literature. At all time-points and in both moderate and deep sites, SRP + SDD resulted in significantly greater PD reductions relative to baseline than SRP + placebo. At month 9, in moderate sites, mean PD reductions of 1.57 +/- 0.11 mm were reported in the adjunctive SDD group, compared with 0.63 +/- 0.11 mm in the adjunctive placebo group (p < 0.001). In deep sites at month 9, mean PD reductions of 3.22 +/- 0.29 mm were reported in the adjunctive SDD group, compared with 0.98 +/- 0.31 mm in the adjunctive placebo group (p < 0.05). Similar improvements were observed for CAL in the SDD group compared with the placebo group. Significantly lower BOP scores were also recorded at month 9 in the SDD group (7.5%) compared with the placebo group (71.2%) (p < 0.01).CONCLUSION:SDD used as an adjunct to SRP provides significant benefit for elderly patients with CP compared with SRP alone.

BACKGROUND Subantimicrobial dose doxycycline (SDD--20 mg doxycycline twice daily) is indicated as an adjunctive treatment for periodontitis. Doxycycline downregulates the activity of matrix metalloproteinases (MMPs), key destructive enzymes in periodontal disease. Current understanding of periodontal pathogenesis suggests that MMPs play a major role in the destruction of periodontal tissues, leading to the clinical signs of periodontitis. Research supports that downregulation of MMPs by SDD confers benefit to patients with periodontitis. METHOD We review the clinical, microbiological and safety data relating to the use of SDD in patients with periodontitis, and consider the historical events that led to the development of adjunctive SDD as a treatment for periodontitis. RESULTS Studies have shown that SDD, when prescribed as an adjunct to scaling and root planing (SRP), results in statistically and clinically significant gains in clinical attachment levels and reductions in probing depths over and above those that are achieved by SRP alone. SRP must be thorough and performed to the highest standard to maximise the benefits of adjunctive SDD. SDD does not result in antibacterial effects, or lead to the development of resistant strains or the acquisition of multiantibiotic resistance. The frequency of adverse events is low, and does not differ significantly from placebo. CONCLUSIONS Adjunctive SDD confers clinical benefit to patients with periodontitis. A comprehensive treatment strategy is suggested, involving patient education and motivation, reduction of the bacterial burden by SRP, host response modulation with SDD, and periodontal risk factor modification.

Background: Subantimicrobial doses of doxycycline may improve outcomes in rosacea when combined with topical metronidazole and used as maintenance monotherapy.Objective: The purpose of this Study was to evaluate the safety and efficacy of doxycycline hyclate 20 mg (subantimicrobial dose doxycycline) administered twice daily as an adjunct to metronidazole 0.75% topical lotion in the treatment of rosacea.Methods: Patients received subantimicrobial doses of doxycycline twice daily Plus metronidazole (n = 20) or placebo plus metronidazole (n = 20) for 12 weeks. Subantimicrobial-dose doxycycline or placebo monotherapy continued for 4 weeks. The primary efficacy measure was change from baseline in total inflammatory lesions at weeks 2 and 16.Results: Total inflammatory lesions were reduced significantly (P =.048) by week 4 and by all subsequent visits in the subantimicrobial-dose doxycycline/metronidazole group compared with placebo/ metronidazole. Changes from baseline increased over time and were maintained during subantimicrobialdose doxycycline monotherapy.Conclusion: Adjunctive use of subantimicrobial dose doxycycline significandy reduced the clinical signs of rosacea compared with metronidazole alone and may be useful maintenance monotherapy.

Objective To determine if treatment with subantimicrobial-dose (SD) doxycycline hyclate (20-mg tablets taken twice daily) improved clinical outcome, had any detectable effect on skin flora, led to overgrowth or colonization of skin by opportunistic pathogens, or resulted in an increase in antibiotic resistance by the surface skin microflora in patients with moderate acne compared with placebo. Design Multicenter, double-blind, randomized, placebo-controlled, parallel-group trial. Setting Two university-based clinics. Subjects Adults (N = 51) with moderate facial acne. Interventions Patients were randomized to receive SD doxycycline (Periostat; CollaGenex Pharmaceuticals Inc, Newtown, Pa) or placebo twice daily for 6 months. Main Efficacy Outcomes Primary: changes from baseline in numbers of inflammatory, noninflammatory, and total lesions. Secondary: changes from baseline of individual counts of papules, pustules, and nodules and global assessments of clinical improvement by patient and physician. Results Forty patients completed 6 months of treatment. At 6 months, the SD doxycycline group had a significantly greater percent reduction in the number of comedones (P<.01), inflammatory and noninflammatory lesions combined (P<.01), and total inflammatory lesions (P<.05) than did the placebo group. They also had significantly greater improvement according to the clinician's global assessment (P= .03). There were no significant differences in microbial counts between groups and no evidence of change in antibiotic susceptibility or colonization by potential pathogens. The treatment was well tolerated. Conclusions Twice-daily SD doxycycline treatment significantly reduced the number of inflammatory and noninflammatory lesions in patients with moderate facial acne, was well tolerated, had no detectable antimicrobial effect on the skin flora, and did not result in any increase in the number or severity of resistant organisms.

BACKGROUND:Severe, generalized periodontitis is a form of chronic periodontitis that appears to be associated with an exaggerated host response. Little information is available on the benefits of using adjunctive host modulation in the management of this form of periodontal disease. METHODS:Thirty subjects < or = 45 years of age with severe, generalized periodontitis received subgingival debridement and oral hygiene instructions each week for 4 weeks, plus 6 months of adjunctive subantimicrobial doxycycline (SDD) or placebo. Periodontal status was monitored at baseline, and at 1, 3, 5.25, and 8.25 months following completion of the hygiene sessions. Maintenance therapy was performed at 3, 5.25, and 8.25 months for both groups. RESULTS:Ten subjects in each group completed all phases of the study. Subgingival debridement plus adjunctive SDD reduced deep pockets (> or =7 mm at baseline) by an average of 3.02 mm after 9 months versus 1.42 mm for the placebo group. A significant clinical response was seen in both groups as soon as 1 month, but the response was always clinically and statistically greater in the SDD group. In the SDD group, nearly 40% of 237 pockets > or =7 mm were reduced by > or =4 mm, and 55% were reduced by > or =3 mm. In addition, only 2 pockets deepened by > or =4 mm in the SDD group versus 10 in the placebo group. CONCLUSIONS:The supplementation of hygienist-delivered full mouth subgingival and supragingival debridement with a host-modulating agent, SDD, provides clinically and statistically significant benefits in the reduction of deep pockets in patients with severe, generalized periodontitis. In addition, adjunctive SDD is more effective than a placebo in preventing further increases in probing depth.