Tirbanibulin (Klisyri®): A Comprehensive Monograph on its Pharmacology, Clinical Efficacy, and Therapeutic Role in Dermatology

Executive Summary

Tirbanibulin is a first-in-class topical medication approved for the treatment of actinic keratosis (AK) on the face or scalp. Marketed under the brand name Klisyri®, it represents a significant advancement in dermatological therapy, distinguished by a novel, dual-action mechanism of action that inhibits both tubulin polymerization and Src kinase signaling.[1] This unique molecular activity allows for the targeted disruption of key pathways involved in the proliferation and survival of neoplastic keratinocytes characteristic of AK.[3]

The most notable clinical feature of Tirbanibulin is its remarkably short treatment duration, requiring only a once-daily application for five consecutive days.[5] This abbreviated regimen contrasts sharply with the weeks or months of therapy required for many established topical agents, addressing a critical unmet need for treatments that enhance patient adherence and satisfaction.[7] Its clinical profile is further defined by a favorable safety and tolerability profile. Adverse events are almost exclusively localized to the application site, consisting of predictable, transient, and manageable local skin reactions (LSRs) such as erythema and scaling, which typically resolve within a few weeks of treatment completion.[9]

Pivotal Phase 3 clinical trials demonstrated statistically significant and clinically meaningful efficacy, with complete clearance of AK lesions observed in 44% to 54% of patients at day 57, compared to 5% to 13% with vehicle.[10] Post-marketing studies have corroborated these findings in real-world settings and have highlighted high levels of patient satisfaction, particularly regarding treatment convenience.[7] The drug's clinical utility was recently broadened by a U.S. Food and Drug Administration (FDA) label expansion, which increased the approved treatment area fourfold to 100 cm², solidifying its role as a true field therapy for patients with more extensive disease.[12] Tirbanibulin is thus positioned as a valuable therapeutic option in the management of AK, offering an effective balance of efficacy, safety, and unparalleled convenience.

Molecular Profile and Physicochemical Characteristics

A comprehensive understanding of Tirbanibulin's chemical and physical properties is fundamental to appreciating its formulation, biological activity, and clinical application.

Chemical Identity and Nomenclature

Tirbanibulin is a small molecule drug belonging to the class of pyridines.[1] Its identity is established through a variety of internationally recognized names and identifiers.

• Primary Name: The adopted nonproprietary names are Tirbanibulin (USAN, INN).[1]
• Systematic (IUPAC) Name: The formal chemical name is N-benzyl-2-[4-(2-morpholin-4-ylethoxy)phenyl]pyridin-2-yl]acetamide.[1] Various synonyms and alternative nomenclatures appear in scientific literature, including N-Benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide and N-benzyl-5-(4-(2-morpholinoethoxy)phenyl)picolinamide.[14]
• Registry Numbers: The primary Chemical Abstracts Service (CAS) Registry Number is 897016-82-9.[1] A deprecated CAS number, 1248514-68-2, is also on record.[1]
• Database Identifiers: To facilitate cross-referencing across major pharmacological and chemical databases, Tirbanibulin is assigned several unique identifiers, including DrugBank ID: DB06137, ChEMBL ID: CHEMBL571546, and UNII: 4V9848RS5G.[1]
• Synonyms and Developmental Codes: During its development, the compound was known by the codes KX-01 and KX2-391.[1] Commercially, it is marketed under the brand names Klisyri® and Onakta®.[21]

Structural and Formulaic Data

• Molecular Formula: The molecular formula for Tirbanibulin is consistently reported as C26​H29​N3​O3​.[1] One source lists an alternative formula ( C25​H27​N3​O3​), which appears to be an error given the consensus across multiple official and scientific databases.[15]
• Molecular Weight: The average molecular weight is approximately 431.54 g/mol, with a monoisotopic mass of 431.2209 g/mol.[18]
• Chemical Structure: Tirbanibulin is structurally characterized as a pyridine ring substituted at position 2 with a 2-(benzylamino)-2-oxoethyl group and at position 5 with a 4-[2-(morpholin-4-yl)ethoxy]phenyl group.[1]
• Canonical Representations: For computational and database purposes, the structure is represented by the following:
• SMILES: C1COCCN1CCOC2=CC=C(C=C2)C3=CN=C(C=C3)CC(=O)NCC4=CC=CC=C4.[1]
• InChIKey: HUNGUWOZPQBXGX-UHFFFAOYSA-N.[1]

Physicochemical Properties

The physicochemical properties of Tirbanibulin are critical determinants of its formulation as a topical ointment and its pharmacokinetic behavior.

• Solubility: The molecule exhibits poor aqueous solubility, being practically insoluble in water (<1 mg/mL). In contrast, it is highly soluble in organic solvents such as dimethyl sulfoxide (DMSO) at a concentration of 80 mg/mL.[20] This lipophilic character necessitates its formulation in a non-aqueous base for effective topical delivery.
• Storage and Stability: Tirbanibulin is stable enough for shipping under ambient temperatures. For long-term preservation, the powder form should be stored at -20°C, where it maintains stability for over five years. The commercially prepared ointment is stored at controlled room temperature.[15]
• Drug-likeness Properties: Computational analysis reveals that Tirbanibulin adheres to Lipinski's Rule of Five, with zero violations, suggesting properties favorable for oral bioavailability, although its clinical application is topical.[18] Key calculated parameters include an AlogP of 3.32, nine rotatable bonds, a polar surface area of 63.69 A˚2, and a basic pKa​ of 6.63.[18]

The molecule's design and physicochemical characteristics appear deliberately optimized for its intended clinical use. The poor water solubility and lipophilic nature are not limitations but rather key features that ensure the drug remains localized within the epidermis upon topical application. This property is essential for its mechanism of action against superficial keratinocytes and directly contributes to its favorable safety profile by minimizing systemic absorption. The commercial formulation as an ointment, containing excipients like propylene glycol and mono- and di-glycerides, is a direct consequence of these properties and serves as an effective vehicle to deliver the active compound to its target site while limiting its entry into systemic circulation.[22]

---

Table 1: Drug Identification and Chemical Properties of Tirbanibulin

Property	Value	Source(s)
IUPAC Name	N-benzyl-2-[4-(2-morpholin-4-ylethoxy)phenyl]pyridin-2-yl]acetamide	1
DrugBank ID	DB06137	1
CAS Number	897016-82-9	1
Molecular Formula	C26​H29​N3​O3​	18
Molecular Weight	431.54 g/mol (Average)	18
Solubility (Water)	<1 mg/mL (insoluble or slightly soluble)	20
Solubility (DMSO)	80 mg/mL	20
AlogP	3.32	18
Basic pKa​	6.63	18
Lipinski's Rule Violations	0	18

---

Comprehensive Pharmacological Profile

Tirbanibulin exerts its therapeutic effects through a novel and synergistic mechanism of action, which translates into a distinct pharmacodynamic profile characterized by potent local antiproliferative activity and minimal systemic impact.

Mechanism of Action (MoA)

Tirbanibulin is the first clinical agent in its class with a dual mechanism of action, simultaneously targeting two separate and critical pathways involved in neoplastic cell growth and survival: tubulin polymerization and Src kinase signaling.[1]

Tubulin Polymerization Inhibition

The primary antimitotic effect of Tirbanibulin stems from its activity as a microtubule inhibitor.[4] Microtubules are dynamic polymers of tubulin protein that form the cellular cytoskeleton and are indispensable for the formation of the mitotic spindle, the apparatus that segregates chromosomes during cell division.

• Molecular Target: Tirbanibulin binds directly to tubulin, specifically at or near the colchicine-binding site on the β-tubulin subunit.[19] This interaction disrupts the dynamic process of tubulin polymerization, preventing the assembly of functional microtubules.[4]
• Cellular Consequence: The disruption of the microtubule network leads to a halt in the cell cycle at the G2/M transition phase. This cell cycle arrest is particularly effective against rapidly dividing cells, such as the atypical keratinocytes that constitute AK lesions.[4] Unable to complete mitosis, the arrested cells are ultimately driven into apoptosis (programmed cell death).[26]
• Reversibility: A key feature of this interaction is its reversibility. The binding of Tirbanibulin to tubulin is concentration-dependent, and its effects can be reversed upon removal of the drug.[26] This reversibility is thought to contribute significantly to the drug's favorable toxicity profile, as it may allow normal, slower-dividing cells that are transiently affected to recover, thereby localizing the cytotoxic effect primarily to the hyperproliferative target cells.

Src Kinase Inhibition

In addition to its antimitotic activity, Tirbanibulin acts as a potent inhibitor of Src kinase, a non-receptor tyrosine kinase.[3]

• Molecular Target: Tirbanibulin is a non-ATP competitive inhibitor that binds to the peptide substrate binding site of Src kinase.[3] This mode of inhibition confers a higher degree of specificity compared to inhibitors that compete with ATP.
• Cellular Consequence: Src kinase is a crucial node in intracellular signaling pathways that regulate cell proliferation, survival, migration, and invasion. Its expression and activity are frequently upregulated in precancerous conditions like AK and in various epithelial tumors.[1] By blocking Src kinase, Tirbanibulin effectively shuts down these pro-survival and pro-proliferative signals, further contributing to its antineoplastic effect and inducing apoptosis.[1]

The combination of these two distinct mechanisms provides a powerful, two-pronged attack on the pathogenesis of AK. By simultaneously arresting the machinery of cell division (via tubulin inhibition) and cutting off essential survival signals (via Src kinase inhibition), Tirbanibulin creates a synergistic effect that enhances its overall efficacy.[4] This dual-targeting strategy makes it more difficult for neoplastic cells to develop resistance compared to agents that act on a single pathway.

Pharmacodynamics

The molecular actions of Tirbanibulin translate into specific, observable effects on tissues and cells.

• Antiproliferative Effect: The primary pharmacodynamic outcome is the potent and selective inhibition of proliferation in the atypical, hyperproliferative keratinocytes of AK lesions, leading to their clinical resolution.[19] Preclinical studies have confirmed that Tirbanibulin is more effective at inducing cell death in fast-growing cells compared to their slower-growing counterparts, highlighting its selectivity for neoplastic tissues.[27]
• Anti-inflammatory Properties: Beyond its direct cytotoxic effects, Tirbanibulin has been noted to possess anti-inflammatory properties. This may contribute to the clinical outcome by reducing the erythema, swelling, and general inflammation associated with AK, which is itself a contributing factor to disease progression.[4]
• Broad Preclinical Antitumor Activity: The fundamental nature of Tirbanibulin's targets—tubulin and Src kinase—suggests its potential utility beyond dermatology. This is supported by preclinical studies where it demonstrated efficacy in animal models of various solid tumors, including breast, colon, pancreatic, and prostate cancer.[19] It has also been investigated in early-phase clinical trials for advanced malignancies.[30]

Pharmacokinetics (ADME)

The pharmacokinetic profile of topically applied Tirbanibulin is defined by its extensive local action and minimal systemic exposure, which is a cornerstone of its safety.

• Absorption: Following the topical application of Tirbanibulin 1% ointment to the face or scalp, systemic absorption is very low.[1] Plasma concentrations reach a steady state by 72 hours of daily application. After five days, the mean maximum plasma concentration ( Cmax​) was measured to be only 0.34 ng/mL for facial application and 0.18 ng/mL for scalp application. The median time to reach this peak concentration (Tmax​) was approximately 7 hours.[1]
• Distribution: There is limited information on the volume of distribution in humans. The drug is highly bound to plasma proteins (88%), a factor that further restricts the amount of free, pharmacologically active drug available in the systemic circulation.[13] This high degree of protein binding, coupled with low absorption, ensures the drug's effects remain predominantly localized to the skin.
• Metabolism: In vitro studies have shown that Tirbanibulin is primarily metabolized by the cytochrome P450 enzyme CYP3A4, with a minor contribution from CYP2C8.[19] The two main metabolites detected in human plasma, KX2-5036 and KX2-5163, are pharmacologically inactive and are present at negligible concentrations.[19]
• Elimination: Comprehensive data on the route of elimination and clearance rate in humans are limited.[1] The plasma half-life is estimated to be approximately 4 hours, suggesting that the small amount of drug that does enter systemic circulation is cleared relatively quickly.[19]

Clinical Development and Efficacy in Actinic Keratosis

The approval of Tirbanibulin for AK was based on a robust clinical development program, highlighted by two large, well-controlled Phase 3 trials that demonstrated its superior efficacy over vehicle, which was subsequently supported by real-world evidence.

Pivotal Phase 3 Trial Analysis (KX01-AK-003 & KX01-AK-004)

The core evidence for Tirbanibulin's efficacy comes from two identically designed, pivotal Phase 3 studies, the results of which were published in the New England Journal of Medicine.[10]

• Study Design: The trials were randomized, double-blind, and vehicle-controlled, enrolling a total of 702 adult subjects with AK on the face or scalp. Eligible participants had between four and eight clinically typical AK lesions within a contiguous 25 cm² treatment area. Subjects self-applied either Tirbanibulin 1% ointment or a matching vehicle ointment once daily for five consecutive days.[10]
• Patient Population: The study population was representative of individuals at high risk for AK. The average age was 70 years, 87% were male, 99% were Caucasian, and 72% had sun-sensitive Fitzpatrick skin types I or II.[6]
• Primary Endpoint: The primary measure of efficacy was the percentage of subjects achieving complete (100%) clearance of all AK lesions within the treatment area at Day 57. Tirbanibulin demonstrated a highly statistically significant superiority over vehicle in both trials.
• In trial KX01-AK-003, 44% of patients in the Tirbanibulin group achieved complete clearance, compared to only 5% in the vehicle group (p<0.0001).[10]
• In trial KX01-AK-004, 54% of patients in the Tirbanibulin group achieved complete clearance, versus 13% in the vehicle group (p<0.0001).[10]
• Secondary Endpoint: A key secondary endpoint was the rate of partial clearance, defined as a reduction of at least 75% in the number of lesions at Day 57. Tirbanibulin was also significantly superior for this outcome.
• In trial KX01-AK-003, 68% of the Tirbanibulin group achieved partial clearance, compared to 16% of the vehicle group (p<0.0001).[10]
• In trial KX01-AK-004, 76% of the Tirbanibulin group achieved partial clearance, versus 20% of the vehicle group (p<0.0001).[10]

---

Table 2: Summary of Pivotal Phase 3 Efficacy Results (Day 57)

Trial ID	Endpoint	Tirbanibulin Group (%)	Vehicle Group (%)	p-value
KX01-AK-003	Complete Clearance (100%)	44	5	<0.0001
	Partial Clearance (≥75%)	68	16	<0.0001
KX01-AK-004	Complete Clearance (100%)	54	13	<0.0001
	Partial Clearance (≥75%)	76	20	<0.0001
Data sourced from.10

---

Long-Term Efficacy and Recurrence

While Tirbanibulin is highly effective for initial lesion clearance, the durability of the response is an important consideration. In a follow-up analysis of patients who had achieved complete clearance in the pivotal trials, the estimated rate of lesion recurrence at one year was 47%.[6] This rate is consistent with the chronic nature of AK and the underlying field cancerization of sun-damaged skin, indicating that, like other field therapies, Tirbanibulin treats existing lesions effectively but does not permanently cure the underlying predisposition.

Efficacy on Larger Treatment Areas

Recognizing that AK often affects large areas of skin, a subsequent Phase 3 open-label safety study was conducted in over 100 U.S. patients to evaluate the application of Tirbanibulin over a larger surface area of approximately 100 cm².[7] The study's primary endpoints were safety and tolerability, which were found to be consistent with the results from the original pivotal trials on the smaller 25 cm² area.[12] This successful demonstration of safety over a four-fold larger area supported the FDA's decision in 2024 to approve the expanded use, significantly enhancing the drug's clinical utility for patients with more extensive disease.[12]

Post-Marketing and Real-World Evidence

Data from routine clinical practice has become crucial for validating the results of controlled trials. Post-registration studies, such as the PROAK and TirbaSkin prospective cohort studies, have provided valuable real-world insights.[7] A pooled analysis of 606 patients from these studies confirmed the drug's effectiveness outside of a trial setting, with 74.3% of patients achieving either complete or partial (≥75%) clearance of their AK lesions.[7]

Perhaps more importantly, these studies quantified the high level of patient satisfaction associated with Tirbanibulin treatment. Using the validated Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9), patients reported high mean scores for Effectiveness (73.5), Convenience (83.8), and Global Satisfaction (74.7).[7] The exceptionally high score for convenience underscores the clinical impact of the short, 5-day treatment regimen. This strong patient-reported outcome is not merely a secondary benefit but a core component of Tirbanibulin's value proposition. The historical challenge with topical AK therapies has been poor patient adherence due to long, arduous treatment courses and severe, prolonged skin reactions.[5] By offering a regimen that is easy to complete and has manageable, transient side effects, Tirbanibulin directly addresses this barrier, increasing the likelihood that patients will complete the therapy and thereby achieve effective clinical outcomes in a real-world setting.

Safety, Tolerability, and Risk Management

The safety profile of Tirbanibulin is well-characterized and is a key factor in its favorable clinical positioning. Due to its topical application and minimal systemic absorption, adverse events are predominantly localized, predictable, and self-limiting.

Profile of Adverse Events

The most frequently reported adverse events in clinical trials were local skin reactions (LSRs) at the site of application. These reactions are considered an extension of the drug's pharmacodynamic effect on proliferating keratinocytes.

• Local Skin Reactions (LSRs): The vast majority of patients experience some form of LSR.
• Incidence and Nature: The most common reactions were erythema (redness), reported in 91% of patients, and flaking/scaling, reported in 82%. Other common reactions included crusting and swelling.[6] Vesiculation/pustulation (blistering) and erosion/ulceration were less common.[6]
• Severity: Crucially, most of these reactions were mild to moderate in intensity. Severe reactions were infrequent, underscoring the treatment's tolerability.[10]
• Timeline: The LSRs typically follow a predictable course, increasing in intensity during the 5-day treatment period, peaking approximately three days after treatment completion (Day 8), and then resolving spontaneously within two to three weeks.[40]
• Application Site Symptoms: In addition to visible skin changes, patients also reported application site pain (10% of patients) and pruritus (itching) (9% of patients).[6]
• Systemic Safety: Consistent with its low systemic absorption, Tirbanibulin has a very favorable systemic safety profile. Systemic adverse events were not significantly different from vehicle in clinical trials. Notably, no patients withdrew from the pivotal Phase 3 studies due to treatment-related adverse events, a testament to the drug's high tolerability.[10]

---

Table 3: Incidence and Severity of Common Local Skin Reactions (LSRs) in Pivotal Trials

Local Skin Reaction	Mild (%)	Moderate (%)	Severe (%)
Erythema	22	63	6
Flaking/Scaling	26	47	9
Crusting	30	14	2
Swelling	29	9	<1
Vesiculation/Pustulation	7	<1	<1
Erosion/Ulceration	9	3	0
Data represents maximal post-baseline severity in subjects treated with Tirbanibulin (N=353).32

---

Warnings, Precautions, and Contraindications

The prescribing information for Tirbanibulin highlights several key points for safe use.

• Contraindications: There are no absolute contraindications listed in the FDA-approved label.[39] A general precaution against use in patients with known hypersensitivity to the active substance or excipients applies.[24]
• Ophthalmic Irritation: A primary warning relates to the risk of eye irritation. The ointment should not be applied in, near, or around the eyes. Patients must wash their hands thoroughly after application to avoid accidental transfer to the periocular area. If exposure occurs, the eyes should be flushed immediately with copious amounts of water, and the patient should seek medical care.[23]
• Use on Compromised Skin: Application is not recommended on open wounds or on skin that has not fully healed from any previous drug, surgical, or other procedure.[9]
• Occlusion: The use of occlusive dressings or bandages over the treated area should be avoided, as this may increase the severity of local skin reactions.[6]

Use in Special Populations

• Geriatric Population: In clinical trials, 70% of subjects were 65 years of age or older. No overall differences in safety or effectiveness were observed between this group and younger subjects. However, the possibility of greater sensitivity in some older individuals cannot be entirely ruled out.[32]
• Pregnancy and Lactation: There are no adequate and well-controlled studies in pregnant women. Animal reproduction studies involving oral administration at high systemic exposures (at least 74 times the maximum recommended human dose) showed evidence of fetal harm.[32] For breastfeeding mothers, systemic absorption of topical Tirbanibulin is very low and the drug is highly protein-bound, making significant excretion into breast milk unlikely. Therefore, it is not considered a reason to discontinue breastfeeding, provided that direct contact between the infant's skin and the mother's treated skin areas is strictly avoided.[13]
• Pediatric Population: The safety and efficacy of Tirbanibulin have not been established in children.[41]

Regulatory and Commercial Landscape

Tirbanibulin's journey from development to market has been marked by key regulatory milestones in major global markets and a strategic partnership between its developer and a commercializing entity.

Global Regulatory Approvals

Tirbanibulin has secured marketing authorization from the primary regulatory bodies in North America and Europe.

• United States (Food and Drug Administration - FDA):
• Initial Approval: The FDA first approved Klisyri® on December 14, 2020. This approval was for the topical treatment of AK on the face or scalp, limited to a treatment area of up to 25 cm².[11]
• Label Expansion: On June 10, 2024, the FDA approved a supplemental New Drug Application (sNDA) that significantly expanded the approved treatment area to up to 100 cm². This decision was based on a Phase 3 safety study demonstrating a consistent safety profile over the larger area.[12]
• European Union (European Medicines Agency - EMA):
• A marketing authorization valid throughout the European Union was granted for Klisyri® on July 16, 2021. The indication is for the field treatment of non-hyperkeratotic, non-hypertrophic (Olsen grade 1) AK of the face or scalp in adults.[9]
• Other Regions: The global reach of Tirbanibulin is expanding through strategic partnerships. Licensing agreements have been established with Avir Pharma, Inc. for Canada and with PharmaEssentia Corp. for other territories including Australia, New Zealand, Japan, and South Korea, indicating that regulatory submissions are either underway or planned in these markets.[43]

The 2024 label expansion by the FDA is a particularly important strategic development. It transformed the clinical positioning of Tirbanibulin from a therapy suitable for limited, localized disease to a true field therapy capable of addressing the more common clinical scenario of widespread field cancerization. By validating its safety over a four-fold larger area, regulators have enabled clinicians to align the treatment footprint with the underlying pathology of sun-damaged skin, thereby increasing the drug's utility and making it a more direct competitor to established field therapies like topical 5-fluorouracil.

Manufacturer and Market Presence

The successful development and commercialization of Tirbanibulin is the result of a collaboration between a research and development firm and a global dermatology-focused pharmaceutical company.

• Development and Commercialization: The drug was discovered and advanced through all preclinical and clinical studies required for its initial FDA approval by Athenex, Inc..[10] Almirall, S.A., a company with a strong global presence in medical dermatology, partnered with Athenex to lead the commercialization efforts in the United States and Europe, as well as the regulatory process with the EMA.[46]
• Brand Names: The product is marketed primarily as Klisyri® in the United States and the European Union.[11] The brand name Onakta® is used in other regions.[19]
• Formulation and Packaging: Tirbanibulin is available as a 1% (10 mg/g) ointment. It is supplied in single-dose packets to ensure proper dosing and prevent contamination. Initially, it was available in a 250 mg packet designed for treating up to 25 cm². Following the label expansion, a larger 350 mg packet was introduced to facilitate treatment of areas up to 100 cm².[12]

Dosing, Administration, and Patient Guidance

Proper administration and patient education are essential for achieving optimal outcomes and ensuring the safe use of Tirbanibulin.

Dosage Regimen

The recommended dosage regimen is straightforward and designed for ease of use: apply a thin layer of Tirbanibulin 1% ointment to the affected area once daily for five consecutive days.[24] This 5-day treatment course constitutes a single, complete cycle of therapy.

Treatment Area and Application Instructions

• Treatment Area: The ointment should be applied to evenly cover the entire treatment field where AK lesions are present, up to a maximum area of 100 cm² on the face or scalp.[12]
• Step-by-Step Application Guide:

1. Preparation: Wash hands thoroughly with soap and water before starting. The skin area to be treated should be gently washed with a mild soap and water and then patted dry.[40]
2. Dosing: Open a new single-dose packet for each application. Squeeze a sufficient amount of ointment onto a fingertip.[40]
3. Application: Apply a thin, even layer of the ointment over the entire treatment field.
4. Post-Application: Immediately wash hands again with soap and water to remove any residual ointment and prevent accidental transfer.[23]
5. Disposal: Each packet is intended for single use only. Any remaining ointment in an opened packet should be discarded.[23]

Critical Patient Counseling Points

Effective patient counseling is crucial for managing expectations and ensuring adherence. The following points should be emphasized:

• The 8-Hour Rule: Patients must be instructed to avoid washing or touching the treated area for approximately 8 hours after applying the ointment. After this period has passed, the area may be washed with mild soap and water.[23]
• Managing Expectations for LSRs: It is vital to inform patients that local skin reactions (redness, scaling, crusting) are an expected and normal part of the treatment process. These reactions indicate the medicine is working. Patients should be reassured that these reactions typically peak a few days after the 5-day treatment course is finished and will gradually resolve over the following two to three weeks.[40]
• Avoidance of Sensitive Areas: Patients must be strictly warned to avoid applying the ointment in or near the eyes, mouth, lips, or inside the nostrils or ears, due to the risk of severe irritation.[24]
• Sun Protection: Since AK is caused by chronic sun exposure, ongoing sun protection is essential. Patients should be advised to minimize exposure to sunlight and artificial UV sources (e.g., tanning beds) and to consistently use broad-spectrum sunscreen and protective clothing on treated areas.[24]

Comparative Therapeutic Analysis

Tirbanibulin enters a well-established therapeutic landscape for AK, which includes a variety of topical medications and office-based procedures. Its clinical value is best understood through a comparative analysis that weighs its efficacy, safety, and convenience against these alternatives.

Comparison with Topical Therapies

Tirbanibulin's primary differentiators are its short treatment duration and favorable tolerability profile.

• 5-Fluorouracil (5-FU): This topical chemotherapeutic agent is a long-standing first-line therapy. It generally demonstrates higher complete clearance rates (often cited as 70-75%) than Tirbanibulin. However, this efficacy comes at the cost of a much longer treatment course, typically lasting several weeks, and is associated with more severe and prolonged local skin reactions, which frequently lead to poor patient adherence.[6]
• Imiquimod: An immune response modifier, imiquimod also boasts high efficacy rates comparable to 5-FU. Its treatment regimen is also lengthy, often requiring application over a period of up to 16 weeks. The mechanism induces a significant inflammatory response, leading to considerable skin irritation that can be difficult for patients to tolerate.[6]
• Diclofenac Sodium: This topical nonsteroidal anti-inflammatory drug (NSAID) is generally better tolerated than 5-FU or imiquimod. However, its efficacy is generally considered lower, and it requires a very long treatment duration of two to three months to achieve its effect.[49]
• Ingenol Mebutate: This agent was notable for its short 2- to 3-day treatment course, but it has been withdrawn from the market in several regions due to long-term safety concerns regarding an increased risk of skin cancer. Tirbanibulin now effectively occupies the "short-course therapy" niche that ingenol mebutate once held, but with a more robust long-term safety profile to date.

Comparison with Procedural Therapies

• Cryotherapy: The application of liquid nitrogen is highly effective for treating one or a few discrete, individual AK lesions. However, it is not suitable for field therapy to address widespread AKs and carries a risk of side effects such as blistering, pain, and permanent hypopigmentation (lightening of the skin).[50]
• Photodynamic Therapy (PDT): PDT is an effective in-office procedure for field treatment. It involves the application of a photosensitizing agent followed by exposure to a specific wavelength of light. While effective, it can be quite painful during light activation and requires patients to strictly avoid sunlight for 24-48 hours post-treatment to prevent severe phototoxic reactions.[50]

In synthesis, Tirbanibulin is strategically positioned to fill a specific gap in the AK treatment paradigm. While some older agents may offer marginally higher absolute clearance rates, Tirbanibulin's distinct advantage lies in its unique combination of clinically meaningful efficacy, an unprecedentedly short 5-day treatment course, and a predictable and transient side effect profile. This profile makes it an excellent option for patients who prioritize convenience and tolerability, or for those who have previously failed to adhere to the longer, more arduous regimens of other topical therapies.

---

Table 4: Comparative Analysis of Topical Treatments for Actinic Keratosis

Attribute	Tirbanibulin (Klisyri®)	5-Fluorouracil (e.g., Efudex®)	Imiquimod (e.g., Aldara®)	Diclofenac (Solaraze®)
Mechanism of Action	Tubulin & Src Kinase Inhibitor	Antimetabolite (Chemotherapy)	Immune Response Modifier (TLR7 Agonist)	NSAID (COX Inhibitor)
Typical Duration	5 days	2-4 weeks	Several weeks (up to 16)	2-3 months
Complete Clearance Rate	~45-55%	~70-75%	~70-75%	Lower than other agents
Key Side Effects	Mild-moderate, transient erythema, scaling, crusting	Severe, prolonged erythema, erosion, crusting	Severe inflammation, erythema, erosion, flu-like symptoms	Mild skin irritation, dryness, photosensitivity
Convenience/Adherence	Very High	Low to Moderate	Low to Moderate	Moderate
Data synthesized from.6 Clearance rates are approximate and can vary by study and formulation.

---

Emerging Research and Future Outlook

Since its approval, a growing body of real-world evidence and exploratory research has begun to shape the future trajectory of Tirbanibulin, suggesting potential new applications and confirming its value in clinical practice.

Real-World Effectiveness and Patient-Centered Outcomes

Post-marketing studies have been crucial in confirming that the efficacy and safety observed in controlled trials translate to routine clinical practice. More importantly, this research has highlighted the central role of patient-centered outcomes in the drug's success. Studies have consistently shown high rates of patient satisfaction, driven by the short treatment course and manageable side effects.[7] This has led to an emerging expert consensus that Tirbanibulin should be considered a first-line treatment option for many patients with AK, particularly because its user-friendly profile directly addresses the historical challenge of non-compliance with other topical therapies.[52]

Novel Applications and Off-Label Use

The unique mechanism and favorable safety profile of Tirbanibulin have prompted investigation into its use beyond the approved indications.

• Expanded Anatomical Areas: Case reports are emerging on the off-label use of Tirbanibulin on other chronically sun-damaged areas, such as the décolleté (upper chest). While showing potential efficacy, these reports also caution that such use can be associated with more severe local reactions, including bullous eruptions, in some individuals.[53]
• High-Risk Populations: There is preliminary evidence of Tirbanibulin's effectiveness in treating field cancerization in solid organ transplant recipients.[54] This is a significant area of unmet need, as these immunosuppressed patients are at a much higher risk of developing aggressive squamous cell carcinomas from AK lesions.
• Other Dermatological Conditions: Early reports have also explored its potential use for other hyperproliferative skin conditions, such as porokeratosis, though this remains highly experimental.[54]

Unexplored Mechanisms and Secondary Benefits

One of the most intriguing areas of emerging research involves the observation of potential secondary benefits beyond the clearance of AK. A recent real-life study reported that patients treated with Tirbanibulin not only had their precancerous lesions resolved but also showed marked improvement in the overall appearance of their photodamaged skin. These "anti-aging" effects included a noticeable improvement in skin texture, a reduction in fine wrinkles, and, most strikingly, a significant lightening of mottled hyperpigmentation and solar lentigines (sun spots).[55] This cosmetic benefit appears to be unique among AK therapies and suggests that Tirbanibulin may have effects on melanocytes or other aspects of skin biology that are not yet fully understood.

If these observations are validated in controlled clinical trials, they could fundamentally reshape the drug's clinical profile and commercial potential. The patient population treated for AK is the same demographic that actively seeks cosmetic treatments for photoaging. The ability to offer a therapy that addresses a medical necessity (precancer prevention) while simultaneously providing a desirable cosmetic outcome would create a powerful dual-value proposition. This could dramatically increase patient demand and physician adoption, potentially elevating Tirbanibulin from a standard medical treatment to a novel dermo-cosmetic agent.

Future Research Trajectory

The current body of evidence provides a strong foundation for the use of Tirbanibulin but also points toward several key areas for future investigation.

• Comparative Trials: Experts have called for larger, longer-term, head-to-head clinical trials comparing Tirbanibulin directly with other first-line therapies like 5-FU and imiquimod. Such studies are needed to more definitively establish its relative long-term efficacy, particularly concerning recurrence rates and the prevention of progression to invasive squamous cell carcinoma.[33]
• Mechanism of Cosmetic Effects: The biological mechanisms underlying the observed improvements in skin photoaging require dedicated investigation. Research into Tirbanibulin's effects on melanogenesis, collagen remodeling, and other pathways related to skin aging could unlock new therapeutic potential.[55]
• Flexible Dosing Regimens: Given its excellent safety profile, research into the use of repeated treatment cycles for patients with recurrent disease is warranted to establish optimal long-term management strategies.[52]

Synthesis and Strategic Insights

The introduction of Tirbanibulin (Klisyri®) to the therapeutic armamentarium for actinic keratosis represents more than just the addition of a new drug; it signals a strategic evolution in the management of the disease. Its primary innovation is not necessarily a superior rate of lesion clearance compared to all existing therapies, but rather its ability to achieve clinically robust outcomes through a regimen that prioritizes patient experience. By offering a uniquely short 5-day treatment course with a predictable and manageable safety profile, Tirbanibulin directly confronts and overcomes the long-standing clinical barrier of patient non-adherence that has historically undermined the real-world effectiveness of topical AK field therapies.

The recent regulatory expansion to a 100 cm² treatment area has solidified its role as a true field therapy, allowing clinicians to treat extensive areas of sun damage in a manner that is both effective and highly tolerable for the patient. This, combined with strong post-marketing data confirming high levels of patient satisfaction, positions Tirbanibulin as a compelling first-line option, particularly for patients who value convenience or have struggled with the prolonged and arduous regimens of older agents. Furthermore, the intriguing preliminary evidence of secondary anti-aging benefits suggests a potential future trajectory that could expand its clinical utility into the dermo-cosmetic space. In conclusion, Tirbanibulin's well-balanced profile of efficacy, safety, and unparalleled convenience marks a significant, patient-centered advancement in dermatology, making it a versatile and increasingly vital tool for the modern clinician.

Works cited

1. Tirbanibulin | C26H29N3O3 | CID 23635314 - PubChem, accessed August 29, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Tirbanibulin
2. go.drugbank.com, accessed August 29, 2025, [https://go.drugbank.com/drugs/DB06137#:~:text=Tirbanibulin%20is%20a%20tyrosine%20kinase,on%20the%20face%20or%20scalp.&text=Tirbanibulin%20(KX%2DO1%20or%20KX2,of%20Src%20Kinase%20and%20tubulin.](https://www.google.com/url?q=https://go.drugbank.com/drugs/DB06137%23:~:text%3DTirbanibulin%2520is%2520a%2520tyrosine%2520kinase,on%2520the%2520face%2520or%2520scalp.%26text%3DTirbanibulin%2520(KX%252DO1%2520or%2520KX2,of%2520Src%2520Kinase%2520and%2520tubulin.&sa=D&source=editors&ust=1756476947636885&usg=AOvVaw0JdXM0MV4c6WuiWoiG8zEU)
3. go.drugbank.com, accessed August 29, 2025, https://go.drugbank.com/drugs/DB06137#:~:text=Tirbanibulin%20is%20a%20non%2DATP,migration%2C%20proliferation%2C%20and%20survival.
4. What is the mechanism of Tirbanibulin? - Patsnap Synapse, accessed August 29, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-tirbanibulin
5. Tirbanibulin 1% Ointment for Actinic Keratosis: Results from a Real-Life Study - MDPI, accessed August 29, 2025, https://www.mdpi.com/1648-9144/60/2/225
6. Tirbanibulin (Klisyri) for the Treatment of Actinic Keratosis - AAFP, accessed August 29, 2025, https://www.aafp.org/pubs/afp/issues/2021/1100/p519.html
7. Tirbanibulin Reduces Actinic Keratosis Lesions, Achieves High Patient Satisfaction, accessed August 29, 2025, https://www.hcplive.com/view/tirbanibulin-reduces-actinic-keratosis-lesions-achieves-high-patient-satisfaction
8. Clinicians and Patients Report Treatment of Pre-Skin Cancer with Tirbanibulin to be Effective and Tolerable - FirstWord Pharma, accessed August 29, 2025, https://firstwordpharma.com/story/5743676
9. Klisyri (tirbanibulin) - European Medicines Agency, accessed August 29, 2025, https://www.ema.europa.eu/en/documents/overview/klisyri-epar-medicine-overview_en.pdf
10. Almirall announces New England Journal of Medicine publication of Phase III data demonstrating efficacy and safety of Klisyri (tirbanibulin), accessed August 29, 2025, https://www.almirall.com/newsroom/news/almirall-announces-new-england-journal-of-medicine-publication-of-phase-iii-data-demonstrating-efficacy-and-safety-of-klisyri-tirbanibulin
11. Klisyri (tirbanibulin) FDA Approval History - Drugs.com, accessed August 29, 2025, https://www.drugs.com/history/klisyri.html
12. FDA approves Almirall's Klisyri® (tirbanibulin) for the treatment of actinic keratosis on expanded area of face or scalp up to 100 cm2, accessed August 29, 2025, https://www.almirall.com/newsroom/news/fda-approves-almirall-s-klisyri-tirbanibulin-for-the-treatment-of-actinic-keratosis-on-expanded-area-of-face-or-scalp-up-to-100-cm2
13. Tirbanibulin - Drugs and Lactation Database (LactMed®) - NCBI Bookshelf, accessed August 29, 2025, https://www.ncbi.nlm.nih.gov/books/NBK565965/
14. Tirbanibulin | CAS No: 897016-82-9 - Cleanchem Laboratories LLP, accessed August 29, 2025, https://www.cleanchemlab.com/Tirbanibulin
15. Tirbanibulin | CAS#897016-82-9 | Src kinase inhibitor | MedKoo Biosciences, accessed August 29, 2025, https://www.medkoo.com/products/5569
16. Tirbanibulin | C26H29N3O3 - ChemSpider, accessed August 29, 2025, https://www.chemspider.com/Chemical-Structure.24633341.html
17. TIRBANIBULIN - precisionFDA, accessed August 29, 2025, https://precision.fda.gov/ginas/app/ui/substances/4V9848RS5G
18. Compound: TIRBANIBULIN (CHEMBL571546) - ChEMBL - EMBL-EBI, accessed August 29, 2025, https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL571546
19. Tirbanibulin: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 29, 2025, https://go.drugbank.com/drugs/DB06137
20. Tirbanibulin | Src | Microtubule Associated - TargetMol, accessed August 29, 2025, https://www.targetmol.com/compound/tirbanibulin
21. Tirbanibulin - Wikipedia, accessed August 29, 2025, https://en.wikipedia.org/wiki/Tirbanibulin
22. HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use KLISYRI safely and effec - accessdata.fda.gov, accessed August 29, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213189s001s003s005lbl.pdf
23. Tirbanibulin: uses, dosing, warnings, adverse events, interactions - MedCentral, accessed August 29, 2025, https://www.medcentral.com/drugs/monograph/180579-321001/tirbanibulin-topical
24. Klisyri® (tirbanibulin) PRESCRIBING INFORMATION - Dermatology, accessed August 29, 2025, https://dermatology.almirallmed.co.uk/wp-content/uploads/sites/16/2023/11/pi-klisyri-aug2021.pdf
25. tirbanibulin - Drug Central, accessed August 29, 2025, https://drugcentral.org/drugcard/5431
26. Tirbanibulin as a Novel Treatment in Actinic Keratosis: A Literature Review - ResearchGate, accessed August 29, 2025, https://www.researchgate.net/publication/384311478_Tirbanibulin_as_a_Novel_Treatment_in_Actinic_Keratosis_A_Literature_Review
27. [Translated article] Tirbanibulin: review of its novel mechanism of action and how it fits into the treatment of actinic keratosis, accessed August 29, 2025, https://www.actasdermo.org/es-withdrawn-tirbanibulin-review-its-novel-avance-S1578219021003140
28. INDIVIDUAL ARTICLE: Tirbanibulin 1% Ointment: The Mechanism of Action of a Novel Topical Therapy for Actinic Keratosis - JDDonline, accessed August 29, 2025, https://jddonline.com/articles/individual-article-tirbanibulin-1-ointment-mechanism-of-action-of-novel-topical-therapy-actinic-keratosis-S1545961625S19913X/
29. Tirbanibulin: review of its novel mechanism of action and how it fits into the treatment of actinic keratosis - Elsevier, accessed August 29, 2025, https://www.elsevier.es/es-revista-vacunas-72-articulo-translated-article-tirbanibulin-review-its-S0001731022000217
30. Tirbanibulin Completed Phase 1 Trials for Lymphoma / Solid Tumors Treatment - DrugBank, accessed August 29, 2025, https://go.drugbank.com/drugs/DB06137/clinical_trials?conditions=DBCOND0006647%2CDBCOND0029860&phase=1&purpose=treatment&status=completed
31. Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis - Uniformed Services University of the Health Sciences - Ex Libris, accessed August 29, 2025, https://usuhs.primo.exlibrisgroup.com/discovery/fulldisplay?docid=cdi_proquest_journals_2488212937&context=PC&vid=01USUHS_INST:01USUHS_INST&lang=en&search_scope=Main_and_CI&adaptor=Primo%20Central&tab=Everything&query=sub%2Cexact%2C%20Face%20-%20pathology%20%2CAND&mode=advanced&offset=0
32. 213189Orig1s000 - accessdata.fda.gov, accessed August 29, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213189Orig1s000lbl.pdf
33. Tirbanibulin ointment effective in actinic keratosis of face, scalp for short period: NEJM, accessed August 29, 2025, https://medicaldialogues.in/dermatology/news/tirbanibulin-ointment-effective-in-actinic-keratosis-of-face-scalp-for-short-period-nejm-74508
34. Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis | Request PDF - ResearchGate, accessed August 29, 2025, https://www.researchgate.net/publication/349214804_Phase_3_Trials_of_Tirbanibulin_Ointment_for_Actinic_Keratosis
35. Almirall announces New England Journal of Medicine publication of Phase III data demonstrating efficacy and safety of Klisyri® (tirbanibulin) - PR Newswire, accessed August 29, 2025, https://www.prnewswire.com/news-releases/almirall-announces-new-england-journal-of-medicine-publication-of-phase-iii-data-demonstrating-efficacy-and-safety-of-klisyri-tirbanibulin-301226367.html
36. Topical Tirbanibulin Under Study for the Treatment of Actinic Keratosis - JNCCN 360, accessed August 29, 2025, https://jnccn360.org/advanced-skin-cancers/medical-literature/topical-tirbanibulin-under-study-for-the-treatment-of-actinic-keratosis/
37. Almirall's Klisyri gains approval for larger area of actinic keratosis, accessed August 29, 2025, https://www.pharmaceutical-technology.com/news/almirall-klisyri-actinic-keratosis/
38. Study Details | Patient and Clinician Reported Outcomes for Tirbanibulin Effectiveness and Safety in Actinic Keratosis | ClinicalTrials.gov, accessed August 29, 2025, https://clinicaltrials.gov/study/NCT05260073?term=Klisyri&rank=3
39. 1 HIGHLIGHTS OF PRESCRIBING ... - accessdata.fda.gov, accessed August 29, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213189s000lbl.pdf
40. Package leaflet: Information for the patient Klisyri 10 mg/g ointment tirbanibulin This medicine is subject to additional monito, accessed August 29, 2025, https://www.medicines.org.uk/emc/files/pil.12932.pdf
41. Tirbanibulin (topical application route) - Side effects & dosage - Mayo Clinic, accessed August 29, 2025, https://www.mayoclinic.org/drugs-supplements/tirbanibulin-topical-application-route/description/drg-20506427
42. Klisyri, INN-tirbanibulin, accessed August 29, 2025, https://ec.europa.eu/health/documents/community-register/2021/20210716152138/anx_152138_en.pdf
43. In which countries is Tirbanibulin approved? - Patsnap Synapse, accessed August 29, 2025, https://synapse.patsnap.com/article/in-which-countries-is-tirbanibulin-approved
44. FDA Approves Expanded Use of Almirall's Klisyri for the Treatment of Actinic Keratosis, accessed August 29, 2025, https://www.pharmexec.com/view/fda-approves-expanded-use-of-almirall-s-klisyri-for-the-treatment-of-actinic-keratosis
45. Klisyri | European Medicines Agency (EMA), accessed August 29, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/klisyri
46. Almirall announces FDA approval of Klisyri® (tirbanibulin), a new innovative topical treatment for actinic keratosis, accessed August 29, 2025, https://www.almirall.com/newsroom/news/almirall-announces-fda-approval-of-klisyri%C2%AE-tirbanibulin-a-new-innovative-topical-treatment-for-actinic-keratosis
47. Almirall Presents Early-Stage Pipeline Progress for Tirbanibulin - - PracticalDermatology, accessed August 29, 2025, https://practicaldermatology.com/news/Almirall-Presents-Early-Stage-Pipeline-Progress-Tirbanibulin/2471540/
48. Tirbanibulin Topical Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed August 29, 2025, https://www.drugs.com/dosage/tirbanibulin-topical.html
49. How to Remove Actinic Keratosis at Home: 5 Options - Healthline, accessed August 29, 2025, https://www.healthline.com/health/skin-cancer/how-to-remove-actinic-keratosis-at-home
50. Treating Actinic Keratosis and Bowen Disease - American Cancer Society, accessed August 29, 2025, https://www.cancer.org/cancer/types/basal-and-squamous-cell-skin-cancer/treating/actinic-keratosis.html
51. Actinic Keratosis Treatment - The Skin Cancer Foundation, accessed August 29, 2025, https://www.skincancer.org/skin-cancer-information/actinic-keratosis/actinic-keratosis-treatment-options/
52. Real-World Efficacy of Tirbanibulin in Actinic Keratosis Treatment: Expert Consensus and Clinical Insights - PMC, accessed August 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12339078/
53. Exploring New Frontiers: Off-Label Use of Tirbanibulin 1% Ointment for Actinic Keratosis on the Décolleté | Request PDF - ResearchGate, accessed August 29, 2025, https://www.researchgate.net/publication/390457916_Exploring_New_Frontiers_Off-Label_Use_of_Tirbanibulin_1_Ointment_for_Actinic_Keratosis_on_the_Decollete
54. Efficacy and safety of tirbanibulin 1% ointment in actinic keratoses: Data from two phase-III trials and the real-life clinical practice presented at the European Academy of Dermatology and Venereology Congress 2022 - PubMed, accessed August 29, 2025, https://pubmed.ncbi.nlm.nih.gov/38116638/
55. Anti-aging Effects of Tirbanibulin 1% Ointment: A Real-Life Experience - PMC, accessed August 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11169325/