Playing the field: Introducing tirbanibulin for actinic keratosis therapy

By Warren R. Heymann, MD
January 27, 2021
Vol. 3, No. 4

Field therapy is a cornerstone of actinic keratosis (AK) management. Two years ago, a New England Journal of Medicine article demonstrated that 5-fluorouracil (5-FU) was the best among inadequate therapies (compared to imiquimod, MAL-PDT, and ingenol mebutate). (1) This was discussed in DWI&I (2); a new product is on the horizon that warrants readdressing AK therapy.

During the past two years, the landscape of AK field therapy has changed for three reasons: 1) Leo Pharma recalled ingenol mebutate (Picato) on precautionary grounds, after concerns about the possible risk of skin malignancy; 2) Evidence that 5-FU combined with calcipotriene may give satisfactory results in days rather than weeks (3); and 3) the announcement by Almirall of FDA approval of tirbanibulin (Klisyri) for a 5-day course of topical AK therapy of the face and scalp, anticipated to be available this year. This commentary will focus on tirbanibulin.

According to Liu et al, tirbanibulin is as a non-ATP-competitive inhibitor of SRC proto-oncogene nonreceptor tyrosine kinase (SRC) that is being clinically investigated for the management of various cancers and AK. Tirbanibulin strongly inhibits tubulin by inducing tubulin depolymerization and G₂/M phase cell cycle arrest at low nanomolar concentrations, similar to colchicine. It has been demonstrated that tirbanibulin reversibly binds to the colchicine-binding site on β-tubulin. The reversible binding may be responsible for the drug’s low toxicity. (4) Tirbanibulin also promotes the induction of p53 and subsequent apoptosis via stimulation of caspase-3 and poly (ADP-ribose) polymerase cleavage. (5)

Out of curiosity, if this drug works by binding to the colchicine-binding site on β-tubulin, why not try topical colchicine for AK? It is not an original idea. In 1968, Marshall reported his experience utilized either N-desacetyl thiocolchine (Thiocolciran) or N-desacetyl methylcolchicine (Colcémide) in 104 and 40 patients, respectively; 75 of 104 patients had a good response to Thiocolciran while 15 of 40 patients had a good response to Colcémide. (6) Other studies noted complete resolution of AKs with 1% colchicine cream in 7 of 10 patients (7) and a comparable response of colchicine cream 0.5% to photodynamic therapy with methylaminolevulinate for field cancerization therapy on the forearms, with total clearance of 6 of 36 (17%) of colchicine-treated forearms compared to 7 of 36 (19%) PDT-treated forearms. (8) Faghihi et al performed a randomized double-blind study of 70 patients receiving either 1% colchicine gel or 3% diclofenac sodium cream twice a day for 6 weeks. The mean of changes in the size was significant in both groups both before and after treatment (<0.001). The mean lesion size before treatment and at 30, 60, and 120 days was not different between the two groups (p > 0.05). No case of erythema was seen in the colchicine group, while erythema was seen in 22.9% (eight cases) of patients in the diclofenac sodium group (p = 0.005), allowing the authors to conclude that 1% colchicine gel was a safe and effective medication with fewer side effects than diclofenac. (9)

To date (Jan. 8, 2020), my PubMed search revealed only a single published study on the use of tirbanibulin for the treatment of AK. Kempers et al performed Phase 1 and Phase 2 studies using tirbanibulin 1% ointment. In the Phase 1 study, four treatment cohorts with forearm lesions received tirbanibulin ointment 1% over 25 or 100 cm² once daily for 3 or 5 days and were evaluated through day 45. In the Phase 2 study, two treatment cohorts with face or scalp lesions received tirbanibulin ointment 1% once daily for 3 or 5 days over 25 cm² and were evaluated through day 57. Lesion reductions, clearance rates, safety, and pharmacokinetics were assessed. Forearm AK lesions were reduced by day 45 in all Phase 1 cohorts (N=30). Complete AK clearance at day 57 for face/scalp AK lesions in Phase 2 cohorts (N=168) was demonstrated in 43% and 32% of participants of the 5-day and 3-day cohorts, respectively. Adverse reactions were mainly transient mild local erythema and flaking/scaling, pruritus, and pain. Tirbanibulin plasma concentrations were low or undetectable. The authors concluded that tirbanibulin ointment 1% was well tolerated and active in AK reduction. Based on activity, the 5-day regimen was selected for Phase 3 development. (5)

The only Phase 3 data that I can find was included in the press release from Almirall on Dec. 15, 2020 — as it was not listed in PubMed, I will not provide that information or comment on it.

Tirbanibulin’s short course of application is appealing, but its bottom line will be based on how its efficacy compares to the long-reigning champion, 5-fluorouracil. Experience has taught us that post-marketing analysis may remove AK treatments from our therapeutic options. Regardless, any novel therapy for AK that is safe and effective is welcome. We will soon determine if tirbanibulin has expanded the field of AK field therapy.

Point to Remember: Tirbanibulin, a tubulin-inhibitor, has been approved for the topical treatment for actinic keratoses. Further studies will determine its precise role in the management of AKs compared to other options.

Our Expert’s Viewpoint

Ashley Decker, MD
Assistant Professor of Medicine
Cooper University Health Center

Actinic keratoses (AK) are one of the most common diagnoses made by dermatologists. In addition to deleterious effect on quality of life, AKs are a large financial burden to our health care system. As Dr. Heymann discussed in his thoughtful commentary, field therapy is preferred in widespread involvement with 5-FU being the most effective field treatment available (compared to imiquimod, MAL-PDT, and ingenol). Despite its efficacy, the prolonged treatment regimen combined with moderate to severe application site reactions, make this treatment unappealing to many patients. Based on the results of phase 1 and 2 trials, tirbanibulin does appear to be a promising new treatment options but will require head-to-head comparison to other established treatment options to determine its true potential.

1. Jansen MHE, Kessels JPHM, Nelemans PJ, Kouloubis N et al. Randomized Trial of Four Treatment Approaches for Actinic Keratosis. N Engl J Med. 2019 Mar 7;380 (10):935-946.

2. Connolly D, Lawrence N. Is there a best approach to widespread actinic keratosis? Dermatology World Insights and Inquiries. 2019; Vol. 1, No. 5.

3. Heymann WR. Calcipotriene and 5-fluorouracil: Dermatology’s new dynamic duo? Dermatology World Insights and Inquiries 2019; Vol 1, No. 28.

4. Niu L, Yang J, Yan W, Yu Y, Zheng Y, Ye H, Chen Q, Chen L. Reversible binding of the anticancer drug KXO1 (tirbanibulin) to the colchicine-binding site of β-tubulin explains KXO1's low clinical toxicity. J Biol Chem. 2019 Nov 29;294(48):18099-18108.

5. Kempers S, DuBois J, Forman S, Poon A, Cutler E, Wang H, Cutler D, Fang J, Kwan R. Tirbanibulin Ointment 1% as a Novel Treatment for Actinic Keratosis: Phase 1 and 2 Results. J Drugs Dermatol. 2020 Nov 1;19(11):1093-1100.

6. Marshall J. Treatment of solar keratoses with topically-applied cytostatic agents. Br J Dermatol. 1968 Aug;80(8):540-2.

7. Grimaître M, Etienne A, Fathi M, Piletta PA, Saurat JH. Topical colchicine therapy for actinic keratoses. Dermatology. 2000;200(4):346-8.

8. Miola AC, Ferreira ER, Lima TRR, Schmitt JV, Abbade LPF, Miot HA. Effectiveness and safety of 0·5% colchicine cream vs. photodynamic therapy with methyl aminolaevulinate in the treatment of actinic keratosis and skin field cancerization of the forearms: a randomized controlled trial. Br J Dermatol. 2018 Nov;179(5):1081-1087.

9. Faghihi G, Elahipoor A, Iraji F, Behfar S, Abtahi-Naeini B. Topical Colchicine Gel versus Diclofenac Sodium Gel for the Treatment of Actinic Keratoses: A Randomized, Double-Blind Study. Adv Med. 2016;2016:5918393.

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