Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Almirall, S.A., Ronda General Mitre 151, 08022 Barcelona, Spain
Pharmacotherapeutic group: Antibiotics and chemotherapeutics for dermatological use, other chemotherapeutics
ATC code: D06BX03
Tirbanibulin disrupts microtubules by direct binding to tubulin, which induces cell cycle arrest and apoptotic death of proliferating cells, and is associated with disruption of Src tyrosine kinase signalling.
The efficacy and safety of tirbanibulin applied on the face or scalp for 5 consecutive days was studied in 2 pivotal randomised, double-blind, vehicle-controlled Phase III studies (KX01-AK-003 and KX01-AK-004) including 702 adult patients (353 patients treated with tirbanibulin and 349 patients treated with vehicle).
Patients had 4 to 8 clinically typical, visible, discrete, non-hyperkeratotic, non-hypertrophic, actinic keratosis lesions within a contiguous 25 cm² treatment field on the face or scalp. On each scheduled dosing day, the ointment was applied to the entire treatment field. In the tirbanibulin group, the mean age was 69 years (range 46 to 90 years) and 96% of patients had Fitzpatrick skin type I, II, or III. Efficacy, measured as complete (primary endpoint) and partial clearance rate, was assessed at day 57.
At day 57, patients treated with tirbanibulin had statistically significantly higher complete and partial clearance rates than patients treated with vehicle (p <0.0001) (see Table 2). Efficacy was less in scalp lesions compared to facial lesions, though still statistically significant (see Table 3).
Table 2. Complete and partial clearance rates at day 57, ITT population (pooled data KX01-AK-003 and KX01-AK-004):
| Overall (face and scalp) | ||
|---|---|---|
| Tirbanibulin 10 mg/g ointment (N=353) | Vehicle (N=349) | |
| Complete (100%) clearance ratea | 49%c | 9% |
| Partial (≥75%) clearance rateb | 72%c | 18% |
ITT=Intent-to-Treat
a Complete clearance rate was defined as the proportion of patients with no (zero) clinically visible actinic keratosis lesions in the treatment field.
b Partial clearance rate was defined as the percentage of patients in whom 75% or more of the number of baseline actinic keratosis lesions in the treatment field were cleared.
c p <0.0001; compared to vehicle by Cochran-Mantel-Hansel stratified by anatomical location and study.
Table 3. Complete and partial clearance rates at day 57 by anatomical location, ITT population (pooled data KX01-AK-003 and KX01-AK-004):
| Location | Complete (100%) Clearance Rate | Partial (≥75%) Clearance Rate | ||
|---|---|---|---|---|
| Tirbanibulin 10 mg/g ointment (N=353) | Vehicle (N=349) | Tirbanibulin 10 mg/g ointment (N=353) | Vehicle (N=349) | |
| Face n/N | 133/238 | 23/239 | 185/238 | 49/239 |
| % | 56% | 10% | 78% | 21% |
| (95% CI) | (49% - 62%)a | (6% - 14%) | (72% - 83%)a | (16% - 26%) |
| Scalp n/N | 41/115 | 7/110 | 70/115 | 14/110 |
| % | 36% | 6% | 61% | 13% |
| (95% CI) | (27% - 45%)a | (3% - 13%) | (51% - 70%)a | (7% - 20%) |
CI=confidence interval; ITT=Intent-to-Treat
a p <0.0001; compared to vehicle by Cochran-Mantel-Haenszel stratified by study.
In the individual studies, total and partial clearance rates at day 57 (the primary and key secondary endpoints in these studies) were statistically significantly higher in the group treated with tirbanibulin compared with the vehicle group (p ≤0.0003), both overall and by treatment location (face or scalp).
A total of 204 patients achieved complete clearance of actinic keratosis lesions in the treatment field at day 57 (174 treated with tirbanibulin and 30 treated with vehicle) and were eligible for a 1-year follow-up period for safety monitoring and to evaluate sustained efficacy by assessing actinic keratosis lesions in the treatment field.
After one year, the recurrence rate in patients treated with tirbanibulin was 73%. There was a higher recurrence rate for scalp lesions compared to facial lesions. Of the patients who developed recurrences, 86% had either 1 or 2 lesions. Furthermore, 48% of patients developing recurrences reported at least 1 lesion that was not identified at the time of the initial treatment (i.e., newly occurring lesions counted as recurrences).
By day 57, there were no reports of SCC in the treatment field in patients treated with tirbanibulin (0 of 353 patients) or vehicle (0 of 349 patients). One isolated SCC in the treatment field was reported in 1 patient following the day 57 assessment; this event was considered by the investigator not to be related to treatment with tirbanibulin.
Of the 353 patients treated with tirbanibulin in the 2 randomised, double-blind, vehicle-controlled Phase III studies conducted, 246 patients (70%) were 65 years of age or older. No overall differences in safety or efficacy were observed between younger and older patients.
The European Medicines Agency has waived the obligation to submit the results of studies with Klisyri in all subsets of the paediatric population in the treatment of actinic keratosis (see section 4.2 for information on paediatric use).
Tirbanibulin ointment was minimally absorbed in 18 patients with actinic keratosis after topical application once daily for 5 consecutive days over an area of 25 cm². Tirbanibulin plasma concentrations were low at steady state (mean maximum concentration [Cmax] of 0.258 ng/mL or 0.598 nM and AUC0-24h of 4.09 ng∙h/mL).
The protein binding of tirbanibulin to human plasma proteins is approximately 88%.
In vitro, tirbanibulin is mainly metabolised by CYP3A4, and to a lesser degree by CYP2C8. The main metabolic pathways are N-debenzylation and hydrolysis reactions. The most relevant metabolites were characterised in patients with actinic keratosis in a maximal use pharmacokinetic study and showed minimal systemic exposure.
In vitro studies show that tirbanibulin does not inhibit or induce cytochrome P450 enzymes and it is not an inhibitor of efflux and uptake transporters at maximum clinical exposures.
Elimination of tirbanibulin has not been fully characterized in humans.
No formal studies of tirbanibulin ointment in patients with hepatic or renal impairment have been conducted. Due to the low systemic exposure to tirbanibulin after topical application of tirbanibulin ointment once daily for 5 days, changes in hepatic or renal function are unlikely to have any effect on the elimination of tirbanibulin. Therefore, no dose adjustments are considered needed (see section 4.2).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity. Tirbanibulin was a moderate contact sensitiser in animals but this was not confirmed in humans.
Tirbanibulin was not mutagenic but induced chromosomal damage and micronuclei in genotoxicity studies. Detailed testing suggested that tirbanibulin is clastogenic/aneugenic and associated with a threshold, below which there is no induction of genotoxic events. In vivo, genotoxicity occurred at plasma levels >20 times higher than the human exposure in the maximal use pharmacokinetic study. In embryo-foetal development studies in rats and rabbits, embryonic and foetal toxicity, including foetal malformations, occurred at multiples of 22 times and 65 times greater than human exposure in the maximal use pharmacokinetic human study. In a pre- and postnatal development study in rats, reductions in fertility and increased embryo-foetal lethality were seen in the offspring of treated females.
In a fertility and early embryonic development study in rats, decrease in testes weight which correlated with decreased sperm count, decreased sperm motility, increased incidences of abnormal sperm, and increased incidence of degeneration of the seminiferous epithelium, considered indicative of male fertility toxicity, occurred at multiples of 58 times greater than human exposure in the maximal use pharmacokinetic human study. However, there were no changes in male mating or fertility indices.
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