Tirbanibulin

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 )

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 )

Ointment: 1% white to off-white ointment supplied in a unit-dose packet (2.5 mg tirbanibulin in 250 mg or 3.5 mg tirbanibulin in 350 mg). Ointment: 1% tirbanibulin supplied in unit-dose packets. ( 3 )

None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Ophthalmic Adverse Reactions: May cause eye irritation upon ocular exposure. Avoid transfer of the drug into the eyes and to the periocular area. If accidental exposure occurs, flush eyes with water and seek medical care. ( 5.1 ) Local Skin Reactions: Local skin reactions can occur including severe reactions (e.g., vesiculation/pustulation, erosion/ulceration) in the treated area. Avoid use until skin is healed from any previous drug or surgical treatment. ( 5.2 )

5.1 Ophthalmic Adverse Reactions KLISYRI may cause eye irritation. Avoid transfer of the drug into the eyes and to the periocular area during and after application. Wash hands immediately after application. If accidental exposure occurs, instruct patient to flush eyes with water and seek medical care as soon as possible.

5.2 Local Skin Reactions Local skin reactions, including severe reactions (erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation and erosion/ulceration) in the treated area can occur after topical application of KLISYRI [see Adverse Reactions ( 6.1 )] . Occlusion after topical application of KLISYRI is more likely to result in irritation. Avoid use until skin is healed from any previous drug, procedure, or surgical treatment.

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).

8.1 Pregnancy Risk Summary There are no available data with KLISYRI use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of tirbanibulin to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal deaths and malformations at a systemic exposure that was at least 19 times the exposure associated with the maximum recommended human dose (MRHD). Oral administration of tirbanibulin to pregnant rabbits during the period of organogenesis resulted in reduced mean fetal weight and size at a systemic exposure that was 41 times the exposure associated with the MRHD ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Tirbanibulin induced fetal deaths and external, visceral, and skeletal malformations when administered orally to pregnant rats during the period of organogenesis at doses greater than or equal to 1.25 mg/kg/day, which resulted in systemic exposures at least 19 times the exposure associated with the MRHD on an Area Under the Curve (AUC) comparison basis. Tirbanibulin had no apparent effects on fetal development in rats at a dose of 0.5 mg/kg/day, which resulted in systemic exposures 5 times the exposure associated with the MRHD. Tirbanibulin reduced mean fetal weight and size (crown-rump length) when administered orally to pregnant rabbits during the period of organogenesis at a dose of 3 mg/kg/day, which resulted in a systemic exposure 41 times the exposure associated with the MRHD on an AUC comparison basis. Tirbanibulin had no apparent effects on fetal development in rabbits at a dose of 1 mg/kg/day, which resulted in systemic exposures 14 times the exposure associated with the MRHD. Tirbanibulin was assessed for effects on peri- and post-natal development of rats in a study that involved oral administration to pregnant rats during the period of organogenesis through lactation at dosages up to 1.25 mg/kg/day. These dosages resulted in systemic exposures up to 19 times the exposure associated with the MRHD on an AUC comparison basis. No adverse effects on maternal function or developmental, neurobehavioral, or reproductive performance of offspring were observed.

8.2 Lactation Risk Summary There are no data on lactational transfer of KLISYRI to human or animal milk. The effects of KLISYRI on the breastfed infant, or its effects on milk production, are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KLISYRI and any potential adverse effects on the breastfed child from tirbanibulin or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of KLISYRI for actinic keratosis in subjects less than 18 years of age have not been established. Actinic keratosis is not a condition generally seen within the pediatric population.

8.5 Geriatric Use Of the 353 subjects with AK treated with KLISYRI in the 2 controlled Phase 3 trials, 246 (70%) were 65 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Risk Summary There are no available data with KLISYRI use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of tirbanibulin to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal deaths and malformations at a systemic exposure that was at least 19 times the exposure associated with the maximum recommended human dose (MRHD). Oral administration of tirbanibulin to pregnant rabbits during the period of organogenesis resulted in reduced mean fetal weight and size at a systemic exposure that was 41 times the exposure associated with the MRHD ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Tirbanibulin induced fetal deaths and external, visceral, and skeletal malformations when administered orally to pregnant rats during the period of organogenesis at doses greater than or equal to 1.25 mg/kg/day, which resulted in systemic exposures at least 19 times the exposure associated with the MRHD on an Area Under the Curve (AUC) comparison basis. Tirbanibulin had no apparent effects on fetal development in rats at a dose of 0.5 mg/kg/day, which resulted in systemic exposures 5 times the exposure associated with the MRHD. Tirbanibulin reduced mean fetal weight and size (crown-rump length) when administered orally to pregnant rabbits during the period of organogenesis at a dose of 3 mg/kg/day, which resulted in a systemic exposure 41 times the exposure associated with the MRHD on an AUC comparison basis. Tirbanibulin had no apparent effects on fetal development in rabbits at a dose of 1 mg/kg/day, which resulted in systemic exposures 14 times the exposure associated with the MRHD. Tirbanibulin was assessed for effects on peri- and post-natal development of rats in a study that involved oral administration to pregnant rats during the period of organogenesis through lactation at dosages up to 1.25 mg/kg/day. These dosages resulted in systemic exposures up to 19 times the exposure associated with the MRHD on an AUC comparison basis. No adverse effects on maternal function or developmental, neurobehavioral, or reproductive performance of offspring were observed.

The safety and effectiveness of KLISYRI for actinic keratosis in subjects less than 18 years of age have not been established. Actinic keratosis is not a condition generally seen within the pediatric population.

Of the 353 subjects with AK treated with KLISYRI in the 2 controlled Phase 3 trials, 246 (70%) were 65 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

KLISYRI (tirbanibulin) ointment is a microtubule inhibitor for topical use. The chemical name of tirbanibulin is N -benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl) acetamide. The molecular weight is 431.4 and the molecular formula is C 26 H 29 N 3 O 3 . Tirbanibulin’s structural formula is: Tirbanibulin ointment 1% contains 10 mg tirbanibulin per gram of white to off-white ointment containing mono- and di-glycerides and propylene glycol. Chemical Structure

12.1 Mechanism of Action Tirbanibulin is a microtubule inhibitor. The mechanism of action of KLISYRI for the topical treatment of actinic keratosis is unknown.

12.2 Pharmacodynamics The pharmacodynamics of tirbanibulin in the treatment of actinic keratosis is unknown.

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.

Tirbanibulin is a microtubule inhibitor. The mechanism of action of KLISYRI for the topical treatment of actinic keratosis is unknown.

The pharmacodynamics of tirbanibulin in the treatment of actinic keratosis is unknown.

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.

, Mutagenesis, Impairment of Fertility No studies have been performed to evaluate the potential of tirbanibulin to induce carcinogenesis. Tirbanibulin was negative in an in vitro bacterial reverse mutation (Ames) assay. Tirbanibulin was positive in an in vitro chromosomal aberration assay with Chinese hamster ovary (CHO) cells, an in vitro mouse lymphoma assay with L5178/TK +/- cells, and an in vivo micronucleus assay in rats. Tirbanibulin was assessed for effects on fertility or reproductive function in rats. Reproductive performance of rats was unaffected by oral doses of tirbanibulin up to 4 mg/kg/day (24 times the MRHD on an AUC comparison basis) in males and 1 mg/kg/day (15 times the MRHD on an AUC comparison basis) in females. However, oral administration of 4 mg/kg/day of tirbanibulin to male rats adversely affected spermatogenesis, including reduced sperm count and motility, and increased observations of morphologically abnormal sperm. No effects on sperm were observed in males treated at 2 mg/kg/day (12 times the MRHD on an AUC comparison basis).

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use). Ophthalmic Adverse Reactions Advise patients that KLISYRI is not for ophthalmic use. Advise patients to avoid application around the eyes, and transfer of the drug into the eyes and to the periocular area. If accidental exposure occurs, advise patients to flush eyes with water and seek medical care [see Warnings and Precautions ( 5.1 )] . Local Skin Reactions Inform patients that treatment with KLISYRI may lead to local skin reactions [see Warnings and Precautions ( 5.2 )] . Important Administration Instructions Advise patients that KLISYRI is for topical use only. Advise patients to avoid application near and around the eyes, mouth and lips. Instruct patients to: Wash hands well after applying KLISYRI to avoid transfer of the drug into the eyes and to the periocular area after application. Avoid washing and touching the treated area for 8 hours after treatment. Following this time, patients may wash the area with a mild soap and water [see Dosage and Administration ( 2 )]. Avoid inadvertent transfer of KLISYRI to other areas, or to another person. Manufactured for: Almirall, LLC Malvern, PA. 19355, USA

Store at 20°C-25°C (68°F-77°F), excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Do not refrigerate or freeze.