Topical Tirbanibulin, a Dual Src Kinase and Tubulin Polymerization Inhibitor, for the Treatment of Plaque-Type Psoriasis: Phase I Results

Jin-Bon Hong, Po-Yuan Wu, Albert Qin, Yi-Wen Huang, Kuan-Chiao Tseng, Ching-Yu Lai, Wing-Kai Chan, Jane Fang, David L Cutler, Tsen-Fang Tsai, Jin-Bon Hong, Po-Yuan Wu, Albert Qin, Yi-Wen Huang, Kuan-Chiao Tseng, Ching-Yu Lai, Wing-Kai Chan, Jane Fang, David L Cutler, Tsen-Fang Tsai

Abstract

Plaque-type psoriasis is a common skin disorder. Tirbanibulin (KX01) is a new Src kinase inhibitor with potent antiproliferative activity against keratinocytes and has been approved for treatment of actinic keratosis. This Phase I study investigates the safety and activity of KX01 ointment in patients with plaque-type psoriasis. We recruited 28 patients from two medical centers in Taiwan. This study was performed in four stages. Double-blind treatments were randomized in stages I (KX01 0.01% + placebo, two rounds of two-week treatment) and II (KX01 0.1% + placebo, four weeks) and open-labelled in stages III (KX01 1%, five days) and IV (KX01 1%, five days weekly for four weeks). The safety, tolerability, KX01 concentration, target area score, physician global assessment, and disease relapse were determined. Most treatment-emergent adverse events were mild-to-moderate application site reactions. Three (50.0%) subjects from the stage IV group showed ≥50% reduction in the target area score (TAS50), while two subjects (33.3%) showed a clinically meaningful improvement in the physician global assessment score. KX01 0.01%, 0.1%, and 1% were safe and well-tolerated. KX01 1% at four weeks showed a promising activity for the treatment of plaque-type psoriasis.

Keywords: KX01; clinical trial; psoriasis; tirbanibulin.

Conflict of interest statement

TFT has conducted clinical trials or received honoraria for serving as a consultant for AbbVie, AnaptysBio, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galderma, GSK-Stiefel, Janssen-Cilag, Leo-Pharma, Merck, Novartis, Pfizer Inc., PharmaEssentia, and UCB Pharma. AQ, KCT, CYL, and TFT own stocks in PharmaEssentia. WKC, JF, and DLC own stocks in Athenex. INC. The other authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
The study design and flow chart of the patient enrollment. (a) The study design. (b) Stage I: KX01 0.01% or placebo administered topically twice daily for two weeks, followed by one week of wash-out, then twice daily for two weeks. (c) Stage II: KX01 0.1% or placebo administered topically twice daily for four weeks. (d) Stage III: KX01 1% administered topically once daily over five consecutive days. (e) Stage IV, KX01 1% administered topically over four cycles of five-day treatments followed by two days of rest each.
Figure 1
Figure 1
The study design and flow chart of the patient enrollment. (a) The study design. (b) Stage I: KX01 0.01% or placebo administered topically twice daily for two weeks, followed by one week of wash-out, then twice daily for two weeks. (c) Stage II: KX01 0.1% or placebo administered topically twice daily for four weeks. (d) Stage III: KX01 1% administered topically once daily over five consecutive days. (e) Stage IV, KX01 1% administered topically over four cycles of five-day treatments followed by two days of rest each.
Figure 2
Figure 2
(a) The TAS scores of the target lesions in the single-arm KX01 1% group in stage IV. (b) The PGA scores of the target lesions in the single-arm KX01 1% group in stage IV.
Figure 3
Figure 3
Representative photographs of two participants treated with topical KX01 at stage IV.

References

    1. Michalek I.M., Loring B., John S.M. A systematic review of worldwide epidemiology of psoriasis. J. Eur. Acad. Dermatol. Venereol. 2017;31:205–212. doi: 10.1111/jdv.13854.
    1. Kim W.B., Jerome D., Yeung J. Diagnosis and management of psoriasis. Can. Fam. Physician. 2017;63:278–285.
    1. Rachakonda T.D., Schupp C.W., Armstrong A.W. Psoriasis prevalence among adults in the United States. J. Am. Acad. Dermatol. 2014;70:512–516. doi: 10.1016/j.jaad.2013.11.013.
    1. Armstrong A.W., Mehta M.D., Schupp C.W., Gondo G.C., Bell S.J., Griffiths C.E.M. Psoriasis prevalence in adults in the United States. JAMA Dermatol. 2021;157:940–946. doi: 10.1001/jamadermatol.2021.2007.
    1. Chang Y.T., Chen T.J., Liu P.C., Chen Y.C., Chen Y.J., Huang Y.L., Jih J.S., Chen C.C., Lee D.D., Wang W.J., et al. Epidemiological study of psoriasis in the national health insurance database in Taiwan. Acta Derm. Venereol. 2009;89:262–266. doi: 10.2340/00015555-0642.
    1. Tsai T.F., Wang T.S., Hung S.T., Tsai P.I., Schenkel B., Zhang M., Tang C.H. Epidemiology and comorbidities of psoriasis patients in a national database in Taiwan. J. Dermatol. Sci. 2011;63:40–46. doi: 10.1016/j.jdermsci.2011.03.002.
    1. World Health Organization Global Report on Psoriasis. [(accessed on 30 May 2022)]. Available online: .
    1. Boehncke W.-H., Schön M.P. Psoriasis. Lancet. 2015;386:983–994. doi: 10.1016/S0140-6736(14)61909-7.
    1. Parisi R., Iskandar I.Y.K., Kontopantelis E., Augustin M., Griffiths C.E.M., Ashcroft D.M., Global Psoriasis Atlas National, regional, and worldwide epidemiology of psoriasis: Systematic analysis and modelling study. BMJ. 2020;369:m1590. doi: 10.1136/bmj.m1590.
    1. Wang T.S., Hsieh C.F., Tsai T.F. Epidemiology of psoriatic disease and current treatment patterns from 2003 to 2013: A nationwide, population-based observational study in Taiwan. J. Dermatol. Sci. 2016;84:340–345. doi: 10.1016/j.jdermsci.2016.08.535.
    1. Lowes M.A., Suárez-Fariñas M., Krueger J.G. Immunology of psoriasis. Annu. Rev. Immunol. 2014;32:227–255. doi: 10.1146/annurev-immunol-032713-120225.
    1. Albanesi C., Madonna S., Gisondi P., Girolomoni G. The interplay between keratinocytes and immune cells in the pathogenesis of psoriasis. Front. Immunol. 2018;9:1549. doi: 10.3389/fimmu.2018.01549.
    1. Rendon A., Schäkel K. Psoriasis pathogenesis and treatment. Int. J. Mol. Sci. 2019;20:1475. doi: 10.3390/ijms20061475.
    1. Tsai T., Ho J., Chen Y., Hsiao P., Lee W., Chi C., Lan C., Hui R.C., Lin Y., Yang K., et al. Health-related quality of life among patients with moderate-to-severe plaque psoriasis in Taiwan. Dermatol. Sin. 2018;36:190–195. doi: 10.1016/j.dsi.2018.06.006.
    1. Samarasekera E.J., Sawyer L., Wonderling D., Tucker R., Smith C.H. Topical therapies for the treatment of plaque psoriasis: Systematic review and network meta-analyses. Br. J. Dermatol. 2013;168:954–967. doi: 10.1111/bjd.12276.
    1. Devaux S., Castela A., Archier E., Gallini A., Joly P., Misery L., Aractingi S., Aubin F., Bachelez H., Cribier B., et al. Topical vitamin D analogues alone or in association with topical steroids for psoriasis: A systematic review. J. Eur. Acad. Dermatol. Venereol. 2012;26((Suppl. 3)):52–60. doi: 10.1111/j.1468-3083.2012.04524.x.
    1. Weger W. Current status and new developments in the treatment of psoriasis and psoriatic arthritis with biological agents. Br. J. Pharmacol. 2010;160:810–820. doi: 10.1111/j.1476-5381.2010.00702.x.
    1. Strober B., Stein Gold L., Bissonnette R., Armstrong A.W., Kircik L., Tyring S.K., Piscitelli S.C., Brown P.M., Rubenstein D.S., Tallman A.M., et al. One-year safety and efficacy of tapinarof cream for the treatment of plaque psoriasis: Results from the PSOARING 3 trial. J. Am. Acad. Dermatol. 2022;87:800–806. doi: 10.1016/j.jaad.2022.06.1171.
    1. Lebwohl M.G., Papp K.A., Stein Gold L., Gooderham M.J., Kircik L.H., Draelos Z.D., Kempers S.E., Zirwas M., Smith K., Osborne D.W., et al. ARQ. 151 201 Study investigators. Trial of Roflumilast cream for chronic plaque psoriasis. New Engl. J. Med. 2020;383:229–239. doi: 10.1056/NEJMoa2000073.
    1. Weinstein G.D., Krueger G.G., Lowe N.J., Duvic M., Friedman D.J., Jegasothy B.V., Jorizzo J.L., Shmunes E., Tschen E.H., Lew-Kaya D.A., et al. Tazarotene gel, a new retinoid, for topical therapy of psoriasis: Vehicle-controlled study of safety, efficacy, and duration of therapeutic effect. J. Am. Acad. Dermatol. 1997;37:85–92. doi: 10.1016/S0190-9622(97)70216-0.
    1. Tsai T.-F., Lee C.-H., Huang Y.-H., Chi C.-C., Chang Y.-T., Wong T.-W., Yang C.-H., Wang L.F. Taiwanese Dermatological Association consensus statement on management of psoriasis. Dermatol. Sin. 2017;35:66–77. doi: 10.1016/j.dsi.2017.01.002.
    1. Kragballe K., Austad J., Barnes L., Bibby A., De La Brassinne M., Cambazard F., Fleming C., Heikkilä H., Jolliffe D., Peyri J., et al. A 52-week randomized safety study of a calcipotriol/betamethasone dipropionate two-compound product (Dovobet/Daivobet/Taclonex) in the treatment of psoriasis vulgaris. Br. J. Dermatol. 2006;154:1155–1160. doi: 10.1111/j.1365-2133.2006.07236.x.
    1. Papp K., Reich K., Leonardi C.L., Kircik L., Chimenti S., Langley R.G., Hu C., Stevens R.M., Day R.M., Gordon K.B., et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1) J. Am. Acad. Dermatol. 2015;73:37–49. doi: 10.1016/j.jaad.2015.03.049.
    1. Smolinski M.P., Bu Y., Clements J., Gelman I.H., Hegab T., Cutler D.L., Fang J.W.S., Fetterly G., Kwan R., Barnett A., et al. Discovery of novel dual mechanism of action Src signaling and tubulin polymerization inhibitors (KX2-391 and KX2-361) J. Med. Chem. 2018;61:4704–4719. doi: 10.1021/acs.jmedchem.8b00164.
    1. Liu T., Hu W., Dalton H.J., Choi H.J., Huang J., Kang Y., Pradeep S., Miyake T., Song J.H., Wen Y., et al. Targeting SRC and tubulin in mucinous ovarian carcinoma. Clin. Cancer Res. 2013;19:6532–6543. doi: 10.1158/1078-0432.CCR-13-1305.
    1. Anbalagan M., Carrier L., Glodowski S., Hangauer D., Shan B., Rowan B.G. KX-01, a novel Src kinase inhibitor directed toward the peptide substrate site, synergizes with tamoxifen in estrogen receptor alpha positive breast cancer. Breast Cancer Res. Treat. 2012;132:391–409. doi: 10.1007/s10549-011-1513-3.
    1. Kim S., Min A., Lee K.-H., Yang Y., Kim T.-Y., Lim J.M., Park S.J., Nam H.-J., Kim J.E., Song S.-H., et al. Antitumor Effect of KX-01 through Inhibiting Src Family Kinases and Mitosis. Cancer Res. Treat. 2017;49:643–655. doi: 10.4143/crt.2016.168.
    1. Anbalagan M., Ali A., Jones R.K., Marsden C.G., Sheng M., Carrier L., Bu Y., Hangauer D., Rowan B.G. Peptidomimetic Src/pretubulin inhibitor KX-01 alone and in combination with paclitaxel suppresses growth, metastasis in human ER/PR/HER2-negative tumor xenografts. Mol. Cancer Ther. 2012;11:1936–1947. doi: 10.1158/1535-7163.MCT-12-0146.
    1. Blauvelt A., Kempers S., Lain E., Schlesinger T., Tyring S., Forman S., Ablon G., Martin G., Wang H., Cutler D.L., et al. Phase 3 trials of tirbanibulin ointment for actinic keratosis. N. Engl. J. Med. 2021;384:512–520. doi: 10.1056/NEJMoa2024040.
    1. 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;19:1093–1100. doi: 10.36849/JDD.2020.5576.
    1. Yavel R., Overcash J.S., Cutler D., Fang J., Zhi J. Phase 1 maximal use pharmacokinetic study of tirbanibulin ointment 1% in subjects with actinic keratosis. Clin. Pharmacol. Drug Dev. 2022;11:397–405. doi: 10.1002/cpdd.1041.
    1. Athenex . Global Investigator’s Brochure. 3rd ed. Athenex; Buffalo, NY, USA: 2017.
    1. Patel R.V., Tsui C.L. Evaluating psoriasis: A review of the assessments most commonly used in clinical trials. Psoriasis Forum J. Psoriasis Psoriatic Arthritis. 2011;17:259–266. doi: 10.1177/247553031117a00403.
    1. Pascoe V.L., Enamandram M., Corey K.C., Cheng C.E., Javorsky E.J., Sung S.M., Donahue K.R., Kimball A.B. Using the physician global assessment in a clinical setting to measure and track patient outcomes. JAMA Dermatol. 2015;151:375–381. doi: 10.1001/jamadermatol.2014.3513.
    1. Robinson A., Kardos M., Kimball A.B. Physician global assessment (PGA) and psoriasis area and severity index (PASI): Why do both? A systematic analysis of randomized controlled trials of biologic agents for moderate to severe plaque psoriasis. J. Am. Acad. Dermatol. 2012;66:369–375. doi: 10.1016/j.jaad.2011.01.022.
    1. Traulsen J., Hughes-Formella B.J. The atrophogenic potential and dermal tolerance of calcipotriol/betamethasone dipropionate ointment compared with betamethasone dipropionate ointment. Dermatology. 2003;207:166–172. doi: 10.1159/000071788.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere