Tirbanibulin

1 INDICATIONS AND USAGE KLISYRI is indicated for the topical field treatment of actinic keratosis on the face or scalp. KLISYRI is a microtubule inhibitor indicated for the topical treatment of actinic keratosis of the face or scalp. ( 1 )

2 DOSAGE AND ADMINISTRATION For topical use only; not for oral or ophthalmic use. Apply KLISYRI evenly to cover up to 100 cm 2 treatment field on the face or balding scalp once daily for 5 consecutive days using 1 unit-dose packet per application. Wash hands immediately with soap and water after application. Avoid washing and touching the treated area for approximately 8 hours after application of KLISYRI. Following this time, the area may be washed with a mild soap. Avoid transfer of KLISYRI to the periocular area [see Warnings and Precautions ( 5.1 )] . Avoid application near and around the mouth and lips. For topical use; not for oral or ophthalmic use. ( 2 ) Apply KLISYRI to the treatment field on the face or scalp once daily for 5 consecutive days using 1 unit-dose packet per application. ( 2 )

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥2%) are local skin reactions, application site pruritus, and application site pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Almirall, at 1-866-665-2782 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Two double-blind, vehicle-controlled clinical trials were conducted in 702 adult subjects with actinic keratosis on the face or scalp. Subjects were randomized 1:1 to KLISYRI or vehicle. Subjects enrolled in the trials had 4 to 8 clinically typical, visible, and discrete AK lesions in a contiguous area of 25 cm 2 on the face or scalp. Subjects’ average age was 70 years (range 45 to 96 years) and they were predominantly White (99%), male (87%), with Fitzpatrick skin types I or II (72%) and actinic keratosis on the face (68%) or scalp (32%). Treatment groups were comparable across all demographics and baseline characteristics, including AK lesion count and distribution on the face or scalp. In the controlled trials, local skin reactions (LSRs) were collected independent of adverse events. Local skin reactions including erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, erosions/ulcerations were assessed by the investigators using a grading scale of 0 = absent, 1 = mild (slightly, barely perceptible), 2 = moderate (distinct presence), and 3 = severe (marked, intense). The percentages of subjects with the maximal post-baseline grades for each local skin reaction (LSR) greater than baseline by treatment group are provided in Table 1 . LSRs were mostly mild to moderate in severity ( Table 1 ). Table 1 Post-Baseline Local Skin Reactions in the Treatment Area (face or scalp) - Pooled Data from 2 Controlled Clinical Phase 3 Trials KLISYRI N = 353 Vehicle N = 349 Local Skin Reactions Mild n (%) Moderate n (%) Severe n (%) Mild n (%) Moderate n (%) Severe n (%) Erythema 76 (22%) 223 (63%) 22 (6%) 98 (28%) 20 (6%) 0 Flaking/ Scaling 92 (26%) 166 (47%) 31 (9%) 86 (25%) 33 (9%) 1 (<1%) Crusting 107 (30%) 50 (14%) 7 (2%) 31 (9%) 8 (2%) 0 Swelling 102 (29%) 32 (9%) 2 (<1%) 15 (4%) 1 (<1%) 0 Vesiculation/ Pustulation 25 (7%) 2 (<1%) 2 (<1%) 3 (<1%) 0 0 Erosion/ Ulceration 32 (9%) 9 (3%) 0 10 (3%) 0 0 Table 2 presents the adverse reactions experienced in ≥2% of subjects participating in the controlled clinical trials with KLISYRI. No subject withdrew from the trials due to adverse reactions. Table 2 Adverse Reactions Occurring in ≥2% of Subjects in 2 Controlled Clinical Trials– Pooled Safety Population a Application site pain includes pain, tenderness, stinging, and burning sensation at the application site. Adverse Reaction System Organ Class KLISYRI N = 353 Vehicle N = 349 Number of Subjects (%) with any adverse reaction (possibly related to treatment) 56 (16%) 35 (10%) Application site pruritus 32 (9%) 21 (6%) Application site paina 35 (10%) 11 (3%) For the 51 subjects (45 KLISYRI, 6 vehicle) who maintained complete clearance through the 12-month follow-up period, no additional local adverse reactions were reported. In a multicenter, open-label safety trial of 105 subjects where KLISYRI was applied to a treatment field of 100 cm 2 on the face or balding scalp, the results were comparable to the safety profile established by the controlled trials in subjects with a 25 cm 2 treatment area. Dermal Safety Studies Clinical studies in healthy subjects demonstrated KLISYRI did not cause contact sensitization (261 subjects), phototoxic skin reactions (31 subjects), or photoallergic skin reactions (64 subjects).

12.3 Pharmacokinetics Absorption Following topical treatment of a mean daily dose of 348 mg (range: 224 to 435 mg) of KLISYRI to a 100 cm 2 contiguous area of the face or balding scalp, once daily for 5 consecutive days. On Day 5, systemic exposure to tirbanibulin had a mean±SD maximum plasma concentration (C max ) of 1.32±0.74 ng/mL and 0.71±0.31 ng/mL, and a mean±SD area under the plasma concentration from time zero to 24 hours (AUC 24 ) of 19.6±8.1 h∗ng/mL and 11.7±4.4 h∗ng/mL, in subjects who received the face and scalp topical treatment, respectively. The median time to reach C max (T max ) was ~6 hours. Distribution Plasma protein binding of tirbanibulin is 88% and is independent of concentrations in the range of 0.01 to 10 µg/mL. Elimination Metabolism Following topical treatment with KLISYRI to adult subjects with actinic keratosis, the plasma concentrations of KX2-5036, KX2-5163, and KX2-5180, three pharmacologically inactive metabolites, were detectable with the highest plasma concentrations of 0.36 ng/mL, 0.42 ng/mL, and 1.70 ng/mL, respectively. The in vitro study indicated that incubation of 1 or 10 µM tirbanibulin with human hepatocytes generated KX2-5036, KX2-5162 and other unidentified metabolites. In vitro, tirbanibulin is mainly metabolized by CYP3A4, and to a lesser extent, CYP2C8. Excretion Excretion of tirbanibulin has not been fully characterized in humans. Drug Interactions Clinical Studies No clinical studies evaluating the drug interaction potential of KLISYRI have been conducted. In Vitro Studies CYP Enzymes: Tirbanibulin and the metabolite KX2-5036 directly or time-dependently inhibited CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 with an IC 50 value of >17 µM. Tirbanibulin up to 1 µM (431.5 ng/mL) and the metabolite KX2-5036 up to 3 µM (1024 ng/mL) did not induce CYP 1A2, 2B6, or 3A4. The metabolite KX2-5180 was neither an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4 with an IC 50 value of > 225 nM (85 ng/mL) nor an inducer of CYP1A2, 2B6, and 3A4 at a concentration of 225 nM (85 ng/mL). These findings suggest that KLISYRI has no clinically meaningful effect on the PK of drugs metabolized by CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4. Drug Transporters: Neither tirbanibulin nor the metabolite KX2-5036 was a substrate of MDR1, BCRP, BSEP, MRP2, MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1 or OCT2. The metabolite KX2-5180 was a substrate of BCRP, but not a substrate for other transporters. Tirbanibulin and the metabolites of KX2-5036 and KX2-5180 inhibited MDR1, BCRP, MRP2, BSEP, MATE1, MATE2-K, OAT1, OTA3, OATP1B1, OATP1B3, OCT1 and/or OCT2 with an IC 50 50 value of >1 µM. The results suggest that KLISYRI has no clinically meaningful effect on the PK of drugs mediated by MDR1, BCRP, MRP2, BSEP, MATE1, MATE2-K, OAT1, OTA3, OATP1B1, OATP1B3, OCT1 and OCT2.