Conflict of interest:
Catherine Zip has served as a speaker and consultant for Bausch Health and Galderma.

Abstract:
Topical retinoids are recommended as first line therapy for the treatment of acne. Despite this recommendation, topical retinoids are underutilized, in part because of their tendency to cause cutaneous irritation. Tazarotene 0.045% lotion was developed using polymeric emulsion technology to provide an effective, well tolerated topical retinoid for the treatment of acne.

Key Words:
tazarotene, retinoid, acne, topical, facial

Introduction

Acne is a common chronic inflammatory disease of the pilosebaceous unit. Although its prevalence is highest in adolescence, acne often persists into adulthood, especially in women. In fact, more than 50% of women in their 20s and more than 35% in their 30s experience acne.¹ As long-term treatment is frequently required, topical therapy plays a pivotal role in its management. Topical retinoids are recommended as first line therapy for most acne patients by evidence-based guidelines in the US, Europe and Canada.^2-4 Although utilization of retinoids has increased over time, a claims-based study of data obtained from a large US database indicated that of all patients seen by a dermatologist for acne, only 59% were prescribed either an oral or topical retinoid. Nondermatologist physicians prescribed a retinoid to 32% of acne patients.⁵ Novel retinoid formulations may improve tolerability and increase use.

Background

Topical retinoids improve acne by normalizing follicular keratinization and reducing keratinocyte cohesiveness, thereby decreasing follicular occlusion and comedone and microcomedone formation. As well, retinoids have antiinflammatory effects.⁶ In addition, they may improve acne indirectly by enhancing penetration of other topicals, reducing postinflammatory hyperpigmentation, and improving acne scarring.⁷

Four topical retinoids have been approved by the United States Food and Drug Administration (FDA) for the treatment of acne: adapalene, tazarotene, tretinoin and trifarotene. Although retinoid effects are likely mediated by multiple pathways, retinoids bind with varying affinity to retinoic acid receptor (RAR) isotypes alpha, beta and gamma. Binding of the retinoid receptor to its agonist leads to modulation of gene transcription. RAR-gamma is the dominant subtype of RAR in the epidermis and hence believed to be a key mediator of retinoid effects in keratinocytes.⁸

Tazarotene, a third generation synthetic retinoid, is a prodrug which is rapidly converted in the skin to its active form, tazarotenic acid. Tazarotenic acid binds to all 3 RAR isotypes but shows relative selectivity for RAR-beta and RAR-gamma.

Studies comparing the efficacy and tolerability of tretinoin, adapalene and tazarotene have shown mixed results.^9-12 Whereas some of these studies have shown comparable efficacy and tolerability, others have demonstrated greater efficacy but lower tolerability with tazarotene 0.1% cream, gel or foam. Studies comparing trifarotene to other topical retinoids have not yet been published.

Tazarotene 0.1% gel, cream and foam are FDA approved for the treatment of acne, initially in 1997. Although effective, cutaneous irritation has limited their clinical use.¹³ In an effort to improve tolerability and maintain efficacy, tazarotene has been reformulated at a lower concentration into a non-greasy lotion vehicle. Tazarotene 0.045% lotion was approved for the treatment of acne for patients 9 years and older by the FDA in 2019 and by Health Canada for those 10 years and older in 2021. This new formulation utilizes polymeric emulsion technology, which solubilizes tazarotene in an oil-in-water emulsion containing hydrating ingredients that are trapped within a honeycomb matrix. This allows for a uniform distribution of tazarotene and moisturizing excipients on the skin, which should lead to more efficient drug delivery into the epidermis and reduced irritation.¹⁴

Phase 2 Data Comparing Different Formulations of Tazarotene

A phase 2 multicenter, double-blind, randomized, vehicle-controlled study compared tazarotene 0.045% lotion and tazarotene 0.1% cream to their respective vehicles.¹⁴ A total of 210 patients 12 years and older were enrolled in the 12 week trial. Tazarotene 0.045% lotion showed statistically significant superiority in reducing both inflammatory and noninflammatory lesion counts compared to its vehicle. The mean percentage changes in inflammatory lesion counts from baseline to week 12 were 63.8% with tazarotene lotion versus 51.4% with vehicle, and in noninflammatory lesion counts 56.9% versus 35.2% with vehicle. Tazarotene lotion showed a numerically greater reduction in both inflammatory and noninflammatory lesions than tazarotene cream but the differences were not statistically significant. Both formulations of tazarotene were well tolerated, although more treatmentrelated adverse effects were reported with tazarotene cream (5.6% versus 2.9%). The only treatment-related adverse effect with tazarotene lotion was application site pain, reported in 2 patients.

Phase 3 Data on the Efficacy and Safety of Tazarotene Lotion in Acne Treatment

Two phase 3 multicenter, double-blind, randomized, vehicle-controlled trials studied the efficacy, safety and tolerability of tazarotene 0.045% lotion in the treatment of acne.¹⁵ A total of 1614 subjects with moderate to severe facial acne aged 9 years or older were enrolled. Subjects were randomized 1:1 to receive tazarotene 0.045% lotion or vehicle once daily for 12 weeks. The co-primary efficacy endpoints were inflammatory and noninflammatory lesion counts and facial Evaluator Global Severity Score (EGSS). Treatment success was defined as a minimum 2-grade improvement in EGSS and achievement of either clear or almost clear. Demographic data were comparable across the two studies, with a mean age of 20 in both studies. Overall, 66% of subjects were female and 74% were Caucasian.

Tazarotene 0.045% lotion showed statistically significant superiority to vehicle in reducing both inflammatory and noninflammatory lesions in both trials (P<0.001). The mean percent reductions in inflammatory and noninflammatory lesions from baseline were 55.5% and 51.4% with tazarotene lotion in Study 1 (versus 45.7% and 41.5% with vehicle) and 59.5% and 60.0% with tazarotene lotion in Study 2 (versus 49.0% and 41.6% with vehicle). Tazarotene lotion was also significantly more likely than vehicle to achieve treatment success (P<0.001). Treatment success was achieved by 25.5% in Study 1 and 29.6% in Study 2 of subjects treated with tazarotene lotion, compared with 13.0% and 17.3% receiving vehicle in the respective studies.

Treatment-related adverse effects were reported in 11.3% (88/779) of subjects receiving tazarotene lotion. The most common were application site pain (5.3%), dryness (3.6%), exfoliation (2.1%) and erythema (1.8%). Most adverse effects were mild, peaked at week 2 and returned to baseline by week 12. The authors commented that application site reactions were less common than those reported previously with tazarotene 0.1% gel, cream and foam, which may be due to the formulation of the lotion and its lower concentration of tazarotene.

Sensitization and Tolerability Studies

In two phase 1 dermal safety studies of tazarotene lotion conducted in healthy adults, no participants developed dermal sensitization.¹⁶ Likewise, no cases of allergic contact dermatitis were reported in tazarotene-treated subjects in the phase 2 and 3 trials. In the phase 1 cumulative irritation patch test study which compared tazarotene 0.045% lotion to vehicle lotion, saline solution, and sodium lauryl sulfate (SLS), tazarotene lotion was deemed to be “slightly irritating”. Although the mean irritation score for tazarotene lotion was statistically greater than that of the SLS positive control, this was felt to be due to the exaggerated dosing conditions employed. The authors commented that the cumulative irritancy score for tazarotene 0.045% lotion was less than half of those reported in previous studies with tazarotene 0.1% cream, gel and foam.

Clinical Use

Topical tazarotene is contraindicated in pregnancy. Although pharmacokinetic studies show low systemic exposure with use of topical tazarotene, exposure levels that could lead to teratogenicity in humans are unknown and there is currently very limited data regarding pregnancy outcomes after in utero exposure.¹⁷

Based on a small study done with tazarotene 0.1% foam, topical tazarotene has a low potential to cause phototoxicity and has not been reported to cause photoallergic reactions.¹⁸ However, as with all retinoids, sun protective measures are recommended with its use. Concomitant application of oxidizing agents such at benzyl peroxide is not recommended to avoid potential degradation of the retinoid.¹⁹

When prescribing a topical retinoid, patients should be counselled regarding the use of mild cleansers and emollients, as the large variation in patient usage of topical retinoids may be an important determinant of tolerability.²⁰

Conclusion

Topical retinoids are recommended as first line therapy for most patients with acne. Despite strong data supporting their pivotal role in acne management, they continue to be underutilized. Although comparative studies have shown similar or better efficacy of tazarotene compared to other retinoids, higher rates of irritation have limited use of older formulations of topical tazarotene. Tazarotene 0.045% lotion is a novel formulation which utilizes polymeric emulsion technology to improve tolerability and epidermal penetration. Despite the lower concentration of tazarotene in the lotion formulation, which likely also contributes to improved tolerability, tazarotene 0.045% lotion is at least as effective as tazarotene 0.1% cream. Given its effectiveness and improved tolerability, tazarotene 0.045% lotion is a useful addition to our armamentarium of topical retinoids for the treatment of acne.

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¹Center for Clinical Studies, Webster, TX, USA
²Meharry Medical College, Nashville, TN, USA
³Department of Dermatology, University of Texas Health Science Center, Houston, TX, USA

Conflict of interest:
Stephen Tyring received grant support, paid to the Center for Clinical Studies, from Athenex. The other authors have no conflicts of interest.

Abstract:
Actinic keratosis (AK) is a common precancerous condition found on chronically sun-damaged skin, particularly on the face, scalp, arms, and legs. Early and effective treatment of AKs is important to prevent progression to squamous cell carcinoma. Many topical treatments for AKs are often limited because of poor tolerability, prolonged treatment duration, and reduced adherence. Tirbanibulin 1% ointment, a new topical field therapy for AKs, reduces these issues. It requires a consecutive 5-day application period and is effective, demonstrating complete (100%) clearance of AK lesions in 49% of patients, partial (>75%) clearance in 72%, and a median reduction in lesion count of 87.5% while exhibiting a favorable safety profile, mild adverse events, improved tolerability, and long-term results.

Key Words:
tirbanibulin; actinic keratosis, field therapy, 5-fluorouracil, diclofenac, imiquimod, face, scalp

Introduction

Actinic keratosis (AK) is a common, recurrent precancerous condition found on chronically sun-damaged skin, particularly on the face, scalp, arms, and legs.¹ Clinically AKs appear as macules, papules, or hyperkeratotic plaques with an erythematous background.² Its prevalence steadily increases with age and prolonged sun-exposure. The American Academy of Dermatology (AAD) notes that approximately 60% of predisposed individuals over the age of 40 are diagnosed with at least one AK.³ Other risk factors include male gender, fair skin (Fitzpatrick type I-II), ultraviolet (UV) exposure, immunosuppression, previous history of AKs or skin cancer, human papillomavirus (HPV) infection, and genetic diseases.³

Cumulative UV exposure is considered a major risk factor for AK development because of the resultant modification of cellular repair mechanisms in keratinocytes.⁴ UVB irradiation causes the formation of thymidine dimers in DNA and mutations of the telomerase gene, whereas UVA indirectly induces DNA mutation through photo-oxidative stress.³ The clinical significance of AKs is secondary to the associated discomfort, cosmetic burden, and the possibility of progression to invasive squamous cell carcinoma (SCC).⁵ Rates of malignant transformation vary from 0.025% to 16%, and the risk of progression increases in patients with multiple AKs (more than five).³ While AKs are a risk factor for the development of SCC, it is impossible to predict which lesions will transform, therefore treatment of all AKs is recommended.³

Many treatments exist for AKs. Single or few discrete AKs are typically treated with cryosurgery.¹ Treatment of multiple lesions and surrounding photo-damaged skin (field cancerization) includes topical agents and photodynamic therapy (Table 1).¹ These treatments may be associated with local skin reactions of pain, irritation, redness, flaking, erosions, ulcerations, and irreversible skin changes of pigmentation and scarring.¹ Furthermore, some treatments have to be administered over periods of weeks or months, which may reduce adherence and undermine treatment success.¹

Table 1

More recently, the role of the Src kinase in carcinogenesis has shed light on an alternative therapeutic option. In UV damaged skin, a cascade of events activates peroxisome proliferator activated receptor (PPAR) beta/delta which stimulates the Src oncogene expression, increases Src kinase activity and enhances the EGFR/Erk1/2 signaling pathway, resulting in increased epithelial-to-mesenchymal transition (EMT) marker expression.⁶ Elevated levels of Src have been linked to AKs and SCCs, and play a role in both primary tumor growth and metastases.⁷ Therefore, Src inhibitors were viewed as a plausible therapeutic option and many have since been developed. Tirbanibulin is a novel compound that inhibits Src kinase signaling and tubulin polymerization in rapidly dividing cells. It has shown promise as a new therapeutic agent for the treatment of AKs on the face or scalp.

Background

Mechanism of Action

The chemical name of tirbanibulin is N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridine-2-yal) acetamide (Figure 1).⁴ It is a synthetic, first-in-class, anti-proliferative agent that disrupts Src kinase signaling and inhibits tubulin polymerization (Figure 2).⁸ Through these mechanisms, it also promotes the induction of p53, G2/M arrest of proliferating cell populations, and subsequent apoptosis.⁸

Clinical Trials

Phase I⁸

The Phase I trial was an open-label, single-center study in subjects aged ≥18 years with clinically typical AKs on the forearm. Thirty participants were enrolled into 4 sequential cohorts (n=4, 10, 8, and 8 in each cohort, respectively): Cohort 1 received tirbanibulin ointment 1% 50 mg/day once daily for 3 days over 25 cm² treatment area with 4-8 AK lesions; Cohort 2 received 200 mg/day once daily for 3 days over 100 cm² treatment area with 8-16 AK lesions; Cohort 3 and Cohort 4 were similar to Cohort 1 and Cohort 2, respectively, but treatment was for 5 days. The follow-up period was through day 45.

To assess tirbanibulin activity, AK lesion numbers at baseline (day 1), days 10, 17, 31, and 45 were collected. Complete (100%) and partial (≥75%) AK clearance rates (defined by the reduction in AK lesions in the treatment area at day 45 compared with baseline) were evaluated for each cohort.

Twenty-nine participants completed the study with one participant withdrawing consent on day 2. Reductions in lesion counts from day 1 to 45 were observed in all cohorts. On day 45, Cohorts 1-4 demonstrated 25%, 0%, 50%, and 12.5% of complete AK clearance in the treatment area, respectively.

Dermal safety clinical studies in healthy subjects demonstrated that tirbanibulin 1% ointment did not cause contact sensitization, phototoxic skin reactions, or photoallergic skin reactions.⁴

Phase II⁸

The Phase II trial was an open-label, uncontrolled, dose-regimen- finding, multicenter study in subjects aged ≥18 years with clinically typical AKs on the face or scalp. One hundred and sixty-eight participants were enrolled into 2 sequential cohorts (n=84 in each cohort): Cohort 1 received 50 mg/day tirbanibulin ointment 1% once daily for 3 days over 25 cm² treatment area with 4–8 AK lesions; Cohort 2 received the same treatment for 5 days.

AK lesion counts at baseline (day 1), 8, 15, 29, and 57 were collected, with a 12-month follow-up period for participants that achieved complete AK clearance to monitor for recurrence. All 168 participants completed the trial. Extensive overall AK clearance on the face or scalp was demonstrated in both cohorts. More participants had 100% clearance at day 57 in the 5-day (43% [95% Confidence Interval (CI) = 32, 54]) vs. the 3-day cohort (32% [95% CI = 22, 43]). Partial clearance rates were also slightly higher in the 5-day (56% [95% CI = 45, 67]) vs. the 3-day cohort (52% [95% CI = 41, 63]). There was a consistent decrease in lesion counts across all visits from baseline to day 57 for both cohorts.

All 63 participants who had 100% clearance at day 57 in the Phase 2 study were included in the Recurrence Follow-up Set. At 12 months post-day 57, recurrence rates for the 5-day cohort (57% [95% CI = 41, 73]) were lower than the 3-day cohort (70% [95% CI = 51, 87]). Most recurrence occurred within 6 months post-day 57.

Phase III¹

The Phase III trial was a randomized, double-blind, parallel-group, vehicle-controlled, multicenter (62 US centers) trial in subjects aged >18 years with 4-8 clinically typical AKs on the face or scalp within a contiguous area measuring 25 cm². A total of 702 participants, divided among two identical trials (n=351 at each site), were randomly assigned in a 1:1 ratio to receive either tirbanibulin 1% ointment for 5 days self-administered to a 25 cm² contiguous area or vehicle ointment (placebo). Enrollment across patients was controlled to achieve a 2:1 ratio of facial: scalp treatment areas. The primary outcome was the percentage of patients with a complete reduction in the number of lesions in the application area at day 57. The secondary outcome was the percentage of patients with a partial reduction in the number of lesions within the application area at day 57. The incidence of recurrence was evaluated at 1 year.

Tirbanibulin demonstrated higher complete clearance levels in trial 1 (44% [95% CI = 32, 47]; P<0.001) and trial 2 (54% [95% CI = 33, 51]; P<0.001) compared to the vehicle groups (5% and 13% in trials 1 and 2, respectively). Pooled data from both trials demonstrated complete clearance in 49% ([95% CI = 35, 47]; P<0.001) of patients in the tirbanibulin groups and in 9% of the vehicle groups.

Partial clearance was significantly higher in both tirbanibulin groups at 68% (trial 1) and 76% (trial 2) than in the vehicle groups. Pooled data revealed partial clearance in 72% ([95% CI = 48, 60]; P<0.001) of patients in the tirbanibulin groups and in 18% of the vehicle groups. At 1 year, 47% of patients with complete clearance experienced recurrence of AKs.

Median reduction in AK lesion count in patients received tirbanibulin was 87.5% vs. 20% for vehicle (P<0.0001).¹

Safety and Tolerability

Throughout all phases, no serious adverse events (AEs) were reported secondary to tirbanibulin.^1,8 Local skin reactions (LSRs) consisted mostly of mild-moderate erythema, flaking or scaling, application-site pruritus, and application-site pain.¹ Erythema (93%) and flaking (82%) were most common.¹ Severe LSRs (all types) were observed in <10% of patients, with severe erythema in 6% of patients.¹ Other LSRs included crusting, swelling, scaling, vesiculation or pustulation, and ulcerations or erosions.⁴ LSRs typically appeared on treatment day 2 and peaked on treatment day 8, before spontaneously resolving in ~2 weeks-1 month.^1,8 No participants were withdrawn from the clinical trials due to AEs or LSRs.

Laboratory evaluation of blood chemistry, hematology, urine analysis, vital signs, electrocardiograms, and physical examinations in association with the phase III trials were not indicative of any systemic side effects.¹ Tirbanibulin produces adverse ophthalmic reactions, and therefore, patients must be careful not to transfer the drug into the periocular area or eyes.

There has been no data on possible birth defects and/or adverse fetal/maternal outcomes during pregnancy with the use of tirbanibulin.⁴ However, extremely high doses were noted to cause birth defects in rats and rabbits (more than 70 and 159 times the recommended human dose, respectively).⁴

Regulatory Approval

The topical 1% ointment formulation of tirbanibulin was approved by the US FDA in December 2020 for the treatment of AKs on the face and scalp.⁷ One packet of ointment (250 mg) contains 2.5 mg (1%) of tirabanibulin.⁴ The medication is applied on the affected area of the face or scalp once a day for 5 consecutive days.⁴ Each packet will cover up to 25 cm² on the face or scalp and is disposed of after its one-time use.⁴

There are no contraindications listed in the FDA-approved prescribing information.⁴

Discussion

Compared to other older topical treatments for AKs, tirbanibulin demonstrates several advantages. Tirbanibulin effectively and completely cleared AK lesions with a 5-day application while demonstrating a favorable safety profile and long-term results. The most common AEs for tirbanibulin were mild and included erythema, flaking, pruritus and pain at the application site. Unlike most other topical treatments for AKs, severe local
reactions, including vesiculation or pustulation and erosion or ulceration, were infrequent.¹ The favorable tolerability is attributed to tirbanibulin mechanism of action in which it induces apoptosis rather than necrosis. Apoptosis is associated with little or no inflammation.¹⁰

Treatment adherence and patient satisfaction has shown to be significantly better with shorter duration topical treatments for AK.¹¹ Current first-line topical field therapies for AKs include 5-fluorouracil (5-FU), imiquimod, and diclofenac gel, all of which have unfavorable aspects undermining compliance and thus successful treatment (Table 1).¹² These therapies more frequently result in AEs, severe LSRs, and prolonged patient discomfort, at times necessitating a pause in treatment until the healthy skin has healed.¹² In addition, each requires an extended period of application ranging from 3-4 weeks to 8-12 weeks with more than one application daily and/or a second cycle.¹² Ingenol mebutate, a promising short duration (3-day) AK treatment, recently lost its first-line status after being discontinued in 2020 secondary to increased risk of skin malignancy.

A combination of 5% 5-FU cream plus 0.005% calcipotriol ointment has been used off-label to treat AKs with variable results.¹³ The evidence was based on a single center study using the combination topical treatment twice daily for 4 days applied to 25 cm² area.¹³ Twenty-seven percent of patients achieved complete clearance of AK lesions on the face, and <20% on the scalp at week 8.¹³ Severe erythema on the face was observed in 80% of patients.¹³

The incidence of recurrence with conventional treatments has ranged from 20% to 96%.¹ However, owing to the chronic nature of AKs, recurrence of lesions in sun-damaged areas is expected.¹ With tirbanibulin, 47% of patients with complete clearance experienced a recurrence at 1 year in the phase III trials. Despite the apparent benefits of tirbanibulin, no direct comparisons have been made with other AK treatments.¹ Ultimately, head-to-head studies will be needed to determine true superiority/inferiority.

Other uses of tirbanibulin are being explored. Phase I trials are underway in Taiwan to investigate its potential as a treatment for psoriasis.⁷ Tirbanibulin was noted to successfully eradicate periungual SCC in a patient that failed to clear with imiquimod 5% in combination with monthly cryotherapy, suggesting its potential as a nonsurgical therapeutic option for SCC.¹⁴

Conclusion

Early and effective treatment of AKs is important to prevent progression to SCC.⁴ Many topical treatments for AKs are often limited because of patient tolerability, treatment duration, and adherence. Tirbanibulin effectively and completely cleared AK lesions with a 5-day application period while demonstrating a favorable safety profile, mild AEs, improved tolerability, and long-term results, making it a promising field therapy for AKs.

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