PowerPoint Presentation Andrew Blauvelt1, Steven Kempers2, Seth Forman3, Edward Lain4, Suzanne Bruce5, Glynis Ablon6, Abel Jarell7, Michael Bukhalo8, Robert Lieberman9, Jane Fang10, Tirbanibulin Phase III Study Group 1Oregon Medical Research Center, Portland, OR, USA; 2Associated Skin Care Specialists, Fridley, MN, USA; 3Forward Clinical Trials, Tampa, FL, USA; 4Austin Institute for Clinical Research, Pflugerville, TX, USA; 5The Center for Skin Research, Houston, TX, USA; 6The Ablon Skin Institute Research Center, Manhattan Beach, CA, USA; 7ActivMed Practices & Research, Portsmouth, NH, USA; 8Arlington Dermatology, Arlington Heights, IL, USA; 9Henderson Dermatology Research, Henderson, NV, USA; 10Athenex, Inc., Buffalo, NY, USA TIRBANIBULIN OINTMENT 1%, A NOVEL INHIBITOR OF TUBULIN POLYMERIZATION AND SRC KINASE SIGNALING, FOR THE TREATMENT OF ACTINIC KERATOSIS (AK): RESULTS FROM TWO PIVOTAL PHASE III STUDIES Table 3. Maximal post-baseline severe (Grade 3) LSRs (Safety Population) • Actinic keratosis (AK) are precancerous lesions that if left untreated may lead to invasive squamous cell carcinoma1 • Tirbanibulin (KX2-391, KX01) is a synthetic, highly selective, novel inhibitor of tubulin polymerization and Src kinase signaling developed as a first-in-class topical formulation for the treatment for AK2 • Previous Phase I and II studies demonstrated that tirbanibulin ointment 1% was active against AK lesions on the forearm and face or scalp, respectively. Local skin reactions (LSRs) were mostly transient and mild- to-moderate in severity, and tirbanibulin was well tolerated3,4 • This poster presents results from two Phase III, double-blinded, vehicle- controlled, randomized, parallel-group, multicenter studies (KX01-AK- 003 [NCT03285477]; KX01-AK-004 [NCT03285490]) that evaluated the efficacy and safety of tirbanibulin versus vehicle in adults with AK lesions on the face or scalp SYNOPSIS Tirbanibulin Phase III Study Group: of KX01-AK-003 (NCT03285477) and KX01-AK-004 (NCT03285490): Jerry Bagel, Joshua Berlin, Norman Bystol, Anne Chapas, Joel Cohen, J Clay Davis, Jess DeMaria, Sunil Dhawan, Janet Dubois, Robert Fixler, Joseph Fowler Jr, Scott Fretzin, David Greenstein, Scott Guenthner, Fashat Hamzavi, George Han, C William Henke III, Catherine Hren, John Humeniuk, Stephen Huang, Sarah Jackson, Sasha Jazayeri, Peter Jenkin, Timothy Jochen, Terry Jones, Debra Liu, Keith Loven, Kappa Meadows, Adnan Nasir, Terri Nutt, Maureen Olivier, James Pehoushek, Catherine Pointon, Edward Primka, Marta Rendon, Jeffrey Rosen, Todd Schlesinger, Joel Schlessinger, James Solomon, Kenneth Stein, Melody Stone, Dow Stough, Leonard Swinyer, Jens Thiele, Douglas Thomas, Aldo Trovato, Anne Truitt, Eduardo Tschen, John Tu, Stephen Tyring, Darryl Wong, Martin Zaiac, Matthew Zook. Editorial support, under the direction of the authors, was provided by Gemma McGregor, PhD, of CMC AFFINITY, a division of McCann Health Medical Communications Ltd, Glasgow, UK, in accordance with Good Publication Practice (GPP3) guidelines and was funded by Almirall SA. ACKNOWLEDGMENTS ‒ KX01-AK-003: 44% vs 5% (complete clearance); 68% vs 16% (partial clearance), respectively ‒ KX01-AK-004: 54% vs 13% (complete clearance); 76% vs 20% (partial clearance), respectively • Significantly higher complete and partial clearance rates for tirbanibulin compared with vehicle were also demonstrated in subgroup analyses for age, baseline AK lesion count, gender, skin type, and treatment location (face or scalp) in both studies (p<0.001) • To assess the efficacy and safety of tirbanibulin compared with vehicle in participants with AK lesions on the face or scalp OBJECTIVE • Adult participants with 4–8 typical, visible AK lesions in a 25 cm2 treatment area on the face or scalp were enrolled (2:1) in the study • Participants were randomized to receive either tirbanibulin ointment 1% or vehicle (1:1); treatment was self-applied once-daily for 5 consecutive days and left in place for ~12 hours • The primary efficacy endpoint was complete (100%) clearance of AK lesions at Day 57 • Partial (≥75% reduction of AK lesions) clearance was a secondary efficacy endpoint • Safety assessments included adverse events (AEs) and monitoring of LSRs including erythema, flaking/scaling, crusting, swelling, vesicles/pustules, and erosions/ulcers as graded on a 4-point scale (0 [absent] to 3 [severe]); composite LSR score was the sum of all six LSR grades (possible range: 0–18) METHODS This study was sponsored by Athenex, Inc. Authors are either investigators (AB, SK, SF, EL, SB, GA, AJ, MB, RL) or consultants (SK, SF, JF) of Athenex, Inc. DISCLOSURES 1. Fernandez Figueras MT. J Eur Acad Dermatol Venereol. 2017;31 Suppl 2:5-7 2. Smolinksi, MP, et al. J Med Chem. 2018;61:4707-4719 3. DuBois J, et al. Phase I study of tirbanibulin ointment 1%, a novel Src phosphorylation and tubulin polymerization inhibitor, in subjects with actinic keratosis. Poster presented at the 6th Annual Practical Symposium, Beaver Creek, CO, USA, August 8–11, 2019 4. DuBois J, et al. Phase II study of tirbanibulin ointment 1%, a novel Src phosphorylation and tubulin polymerization inhibitor, for actinic keratosis. Poster presented at the 6th Annual Practical Symposium, Beaver Creek, CO, USA, August 8–11, 2019 REFERENCES CONCLUSIONS • Tirbanibulin ointment 1% once-daily for 5 days resulted in higher overall complete AK clearance rates at Day 57 than vehicle in two Phase III studies (KX01-AK-003: 44% vs 5%; KX01-AK-04: 54% vs 13%, respectively; p<0.0001) • Statistically significant differences were demonstrated in all subgroups analyzed for the face and scalp • Most treatment-related TEAEs were mild-to-moderate, transient application site pruritus, or pain that did not require treatment • Mean composite LSR scores were low and peaked at Day 8 before resolving by Day 29 • Over 99% of participants completed the full 5-day self-application of tirbanibulin Study participants • Overall 702 participants were enrolled from 62 study sites in the US (n=351 from 31 sites per study where each site participated in only one study); over 99% of participants were treatment compliant • Demographics and baseline characteristics were similar between treatment groups; most participants were White males (mean age, 70 years) and had a Fitzpatrick Skin Type of I–II (Table 1) • The Intent-to-Treat and Safety Population were the same for both studies and included all randomized participants who were dosed. Participants who discontinued early were considered non-responders RESULTS Table 1. Demographics and baseline characteristics (ITT population) KX01-AK-003 (n=351) KX01-AK-004 (n=351) Tirbanibulin (n=175) Vehicle (n=176) Tirbanibulin (n=178) Vehicle (n=173) Mean age, years 69.5 70.2 69.1 70.2 Male, n (%) 147 (84) 154 (88) 158 (89) 150 (87) White, n (%) 175 (100) 175 (99) 177 (99) 173 (100) Fitzpatrick Skin Type I-II, n (%) 123 (70) 142 (81) 126 (71) 120 (69) Median baseline AK lesion count 6 6 6 6 Treatment area face:scalp ratio 119:56 121:55 119:59 118:55 Safety • Treatment-related treatment-emergent AEs (TEAEs) were reported in 56 participants receiving tirbanibulin (KX01-AK-003, n=20 [11%]; KX02-AK- 004, n=36 [20%]) and 35 participants treated with vehicle (KX01-AK-003, n=16 [9%]; KX02-AK-004, n=19 [11%]) ‒ Most treatment-related TEAEs were mild-to-moderate, transient application site pruritus or pain that did not require treatment • Two tirbanibulin-treated participants did not complete treatment for reasons unrelated to study drug but remained in the study • In the vehicle-treated group, two participants discontinued early from the study for reasons unrelated to treatment • No discontinuations or serious AEs related to tirbanibulin were reported • No ocular exposure led to ocular AEs, and there were no clinically significant abnormal electrocardiograms, laboratory findings, physical examinations, or vital signs Local skin reaction assessments • LSRs were mostly mild-to-moderate erythema and flaking/scaling • Mean composite LSR scores were low for tirbanibulin, peaked on Day 8 and were resolved by Day 29 (Figure 1) • The most common maximal post-baseline severe (Grade 3) LSRs were erythema and flaking/scaling (Table 3) Table 2. Complete (100%) and partial (≥75%) clearance rates of AK lesions (ITT population) KX01-AK-003 (n=351) KX01-AK-004 (n=351) Tirbanibulin (n=175) Vehicle (n=176) p-value Tirbanibulin (n=178) Vehicle (n=173) p-value 100% clearance, n (%) 77 (44%) 8 (5%) <0.0001 97 (54%) 22 (13%) <0.0001 Face 50% 6% <0.0001 61% 14% <0.0001 Scalp 30% 2% <0.0001 41% 11% 0.0003 ≥75% clearance, n (%) 119 (68%) 29 (16%) <0.0001 136 (76%) 34 (20%) <0.0001 Subgroup analysis Age <65 years old 45% 2% <0.0001 63% 10% <0.0001 ≥65 years old 44% 5% <0.0001 51% 13% <0.0001 Gender Female 61% 14% 0.0007 85% 13% <0.0001 Male 41% 3% <0.0001 51% 13% <0.0001 Baseline AK lesion count 4–6 AK lesions 49% 6% <0.0001 61% 13% <0.0001 7–8 AK lesions 31% 2% <0.0001 42% 11% 0.0002 Fitzpatrick Skin Type I or II 45% 5% <0.0001 54% 13% <0.0001 III, IV, V, or VI 42% 3% <0.0001 56% 13% <0.0001 AK actinic keratosis; ITT, intent-to-treat AK actinic keratosis; ITT, intent-to-treat KX01-AK-003 (n=351) KX01-AK-004 (n=351) n (%) Tirbanibulin (n=175) Vehicle (n=176) Tirbanibulin (n=178) Vehicle (n=173) Erythema 5 (3) 0 17 (10) 0 Flaking/scaling 11 (6) 0 20 (11) 1 (<1) Crusting 2 (1) 0 5 (3) 0 Swelling 1 (<1) 0 1 (<1) 0 Vesicles/pustules 1 (<1) 0 1 (<1) 0 Erosions/ulcers 0 0 0 0 LSRs, local skin reactions 0 2 4 6 8 10 12 14 16 18 1 5 8 15 29 57 M e a n c o m p o s it e L S R Study Day 0 2 4 6 8 10 12 14 16 18 1 5 8 15 29 57 M e a n c o m p o s it e L S R Study Day Tirbanibulin Vehicle KX01-AK-003 (n=351) KX01-AK-004 (n=351) LSRs were graded on a 4-point scale (0=absent; 1=mild [slightly or barely perceptible]; 2=moderate [distinct presence]; 3=severe [marked/intense]). Composite LSR score is the sum of all six LSR (erythema, flaking/scaling, crusting, swelling, vesicles/pustules, erosions/ulcers) grades with a possible range of 0–18 LSR, local skin reaction Figure 1. Mean composite LSR scores (Safety Population) Presented at the Fall Clinical Dermatology Conference®, October 17–20, 2019, Wynn Hotel, Las Vegas, NV, USA Efficacy • Complete (100%) and partial (≥75%) clearance rates were significantly higher in participants administered tirbanibulin compared with vehicle in both studies (p<0.0001) (Table 2)