Primary • Complete clearance (AKCLEAR 100), defined as a 100% reduction from baseline in the number of clinically visible AK lesions, at Week 8 Secondary • Partial clearance (AKCLEAR 75), defined as ≥75% reduction from baseline in the number of clinically visible AK lesions, at Weeks 4 and 8 • Percent reduction in AK lesion count from baseline at Week 8 Safety • Local skin responses (LSRs) and adverse events (AEs), assessed by investigators on Days 1 and 4, and Weeks 1, 2, 4, and 8, respectively Physician- and patient-reported outcomes • Global photo-damage outcome assessment by investigator at Week 8 • Patient Treatment Satisfaction Questionnaire for Medication (TSQM) v.1.4, and cosmetic outcome at Week 8 • Ingenol mebutate (IngMeb; Picato®) is indicated for the topical treatment of actinic keratosis (AK) in areas of skin up to 25 cm21 • Two or three consecutive days of treatment with IngMeb provides clinically relevant clearance of AK lesions on the face/scalp (0.015% gel) and trunk/extremities (0.05% gel) when compared with vehicle gel;2 in addition, treatment effects of IngMeb gel are maintained long term3 • However, some patients may require treatment of AK over areas of skin larger than 25 cm2 Background Methods • Phase III, randomized, parallel-group, double-blind, vehicle-controlled, eight-week trial in patients with AK (Figure 1) • Patients were eligible if they had 5–20 clinically typical, visible and discrete AK lesions within a selected treatment area of sun-damaged skin on either the full face, full balding scalp (>25 cm2–250 cm2) or a contiguous area of (~250 cm2) on the chest Table 1. Baseline demographics and disease characteristics • AKCLEAR 100 (non-site-specific score) at Week 8 was 21.4% (95% CI, 18.0–24.9) for IngMeb 0.027% gel vs 3.4% (95% CI, 0.7–6.1) for vehicle gel (p<0.001). Efficacy at Week 8 differed according to anatomical site: o For IngMeb, AKCLEAR 100 was 23.8% (95% CI, 19.7–27.8) for the face/chest (n=435) and 12.5% (95% CI, 6.4–18.6) for the scalp (n=114); respective values in the vehicle group were 3.5% (95% CI, 0.5–6.5; n=144) and 3.1% (95% CI, 0.0–9.2; n=32) • AKCLEAR 75 (non-site-specific score) at Week 4 was 59.8% (95% CI, 55.7–63.9) for IngMeb 0.027% gel vs 9.2% (95% CI, 4.8–13.5) for vehicle (p<0.001, Figure 2) • At Week 8, AKCLEAR 75 was 59.4% (95% CI, 55.2–63.5) for IngMeb 0.027% gel vs 8.9% (95% CI, 4.6–13.2) for vehicle gel (p<0.001); both values were similar to those observed at Week 4 (Figure 2) Conclusions • IngMeb 0.027% gel was superior to vehicle as a field treatment on full face, balding scalp or ~250 cm2 on the chest in patients with AK, although it was less efficacious for the treatment of AK on the scalp • AKCLEAR 75 and 100, and percent reduction in lesion count were similar at Weeks 4 and 8, suggesting a maximal treatment effect of IngMeb by Week 4 • The safety profile of IngMeb, for both LSRs and AEs, was as expected • IngMeb was also associated with higher levels of patient treatment satisfaction and cosmetic outcomes compared with vehicle 1. PICATO® (ingenol mebutate) prescribing information https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202833lbl.pdf. Last accessed October 2017 2. Lebwohl M, et al. New England Journal of Medicine 2012;366(11):1010–9 3. Lebwohl M, et al. JAMA Dermatol 2013;149:666–70 References Figure 1. Trial design • Treatment-related AEs (TRAEs) were experienced by 73.8% and 9.1% of patients in the IngMeb and vehicle groups, respectively. Serious AEs occurred in 1.5% vs 1.1% of patients receiving IngMeb or vehicle, respectively; none were treatment related • The most frequently reported AEs (occurring in ≥2% patients receiving IngMeb 0.027% gel) included application-site pain and application-site pruritus (Table 2) Figure 4. Composite LSR profile Study endpoints Results • In total 729 patients were randomized to receive IngMeb 0.027% gel (n=552) or vehicle gel (n=177). The median age was 67.5, most patients were male (73.4%), all were white and 95.6% of patients had Fitzpatrick skin type I–III (Table 1). Median AK count at baseline was 12 (range 5–56) Efficacy Patient population Figure 2. AKCLEAR 75 by visit • The trial was sponsored by LEO Pharma A/S. The authors would like to acknowledge Ailsa Dermody, PhD, of iMed Comms, an Ashfield Company, part of UDG Healthcare plc for medical writing support that was funded by LEO Pharma in accordance with Good Publication Practice (GGP3) guidelines Acknowledgments Limitations • Since LSRs were observed during the study, with early onset and rapid resolution, those receiving active treatment could potentially be identified Efficacy and safety of ingenol mebutate gel in field treatment of actinic keratosis on full face, balding scalp or approximately 250 cm2 on the chest: a Phase III, randomized, controlled trial C. William Hanke,1 Lorne Albrecht,2 Laerke Kristine Kyhl,3 Thomas Larsson,3 Marie Louise Oesterdal,3 Lynda Spelman4 1Laser and Skin Surgery Center of Indiana, Indiana, USA; 2Enverus Medical, Surrey, British Columbia, Canada; 3LEO Pharma A/S, Ballerup, Denmark; 4Veracity Clinical Research, Queensland, Australia All randomized (N = 729) Median (Range) Age (years) 67.5 (38-91) N % Sex Male 535 73.4% Female 194 26.6% Race White 729 100.0% Ethnicity Not hispanic or latino 726 99.6% Hispanic or latino 3 0.4% Skin type I Always burns easily, never tans 138 18.9% II Always burns easily, tans minimally 359 49.2% III Burns moderately, tans gradually (light brown) 200 27.4% IV Burns minimally, always tans well (moderate brown) 31 4.3% V Rarely burns, tans profusely (dark brown) 1 0.1% IngMeb 0.027% (n=549) Vehicle (n=176) General disorders and administration-site conditions Application-site pain 350 63.8% 4 2.3% Application-site pruritus 202 36.8% 7 4.0% Application-site discomfort 28 5.1% 2 1.1% Application-site paresthesia 14 2.6% 2 1.1% Nervous system disorders Headache 22 4.0% 4 2.3% Eye disorders Eyelid edema 14 2.6% 0 0.0% Study objective • To compare the efficacy and safety of IngMeb 0.027% gel with vehicle gel, as a field treatment in patients with AK, when applied once daily for three consecutive days on the full face, balding scalp or ~250 cm2 on the chest (clinical trial identifier: NCT02361216) Safety • Mean composite LSR scores peaked at Day 4 (IngMeb 0.027% gel, 10.8; vehicle, 1.6), rapidly declined and returned to minimal levels by Week 4 (Figure 4) • The lower efficacy of IngMeb observed on the scalp vs face/chest corresponded with lower LSR scores in this area o Mean LSR scores for face, chest and scalp groups were 11.7, 9.5 and 8.8, respectively Figure 3. Reduction in AK lesion count by visit Table 2. Most frequent AEs Figure 5. TSQM scores Physician- and patient-reported outcomes • Investigators reported that 80% of patients receiving IngMeb experienced minor, moderate or marked improvements in the global photo-damage outcome at Week 8, vs 18% in the vehicle group • TSQM global satisfaction score, driven by patients’ perceptions of Effectiveness, was significantly higher for IngMeb vs vehicle (41.0-point difference; p<0.001, Figure 5). No differences were reported for the Side Effects or Convenience domains AEs were classified according to MedDRA version 15.1 • Cosmetic outcomes: o Overall feel: ‘much improved’ or ‘somewhat improved’ reported by 92% patients receiving IngMeb vs 18% for vehicle o Overall appearance: ‘much improved’ or ‘somewhat improved’ reported by 94% patients receiving IngMeb vs 19% for vehicle o For IngMeb, AKCLEAR 75 was 63.4% (95% CI, 58.8–67.9) for the face/chest (n=435) and 44.1% (95% CI, 35.0–53.3) for the scalp (n=114) at Week 8; respective values in the vehicle group were 9.5% (95% CI,4.6–14.4; n=144) and 6.3% (95% CI, 0.0–14.7; n=32). The breakdown by anatomical location at Week 4 was similar to these Week 8 values • Reduction in AK lesion count from baseline at Week 8 with IngMeb was 75.7% (95% CI, 73.9–77.3) vs 12.7% (95% CI, 3.0–21.4) with vehicle. A similar effect was observed at Week 4 (Figure 3) o For IngMeb, reduction in AK lesion count from baseline at Week 8 was 76.8% (95% CI, 74.7–78.6) for the face/chest (n=435) and 64.3% (95% CI, 59.1–68.8) for the scalp (n=114); respective values in the vehicle group were 15.5% (95% CI, 3.4–26.1; n=144) and 8.2% (95% CI, -14.9–26.6; n=32) Placeholder For Figure 1 d, day; w, week; mo, month IngMeb 0.027% gel Vehicle gel Treatment period Follow-up period 552 patients 177 patients 1d 4d 1w 2wTime Visit no. 1 4w 8w 5mo 8mo 11mo 14mo 2 3 4 5 6 7 8 9 10 11 Screening period Extended follow-up period IngMeb 0.027% gel Vehicle gel LSR assessment AK lesion count pcg-workstation-2 Sticky Note Marked set by pcg-workstation-2