LAV694, a new antiproliferative agent showing improved skin tolerability vs. clinical standards for the treatment of actinic keratosis

Medina, Jesús; Picarles, Valerie; Greiner, Brigitte; Elsaesser, Christian; Kolopp, Maryelle; Mahl, Andreas; Roman, Danielle; Vogel, B.; Nußbaumer, Peter; Winiski, Anthony; Meingassner, Josef G.; Fraissinette, Anne de Brugerolle de

doi:10.1016/s0006-2952(03)00369-1

Cited by 6 publications

(3 citation statements)

References 45 publications

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“…A number of literature reports have linked Src activity to the premalignant intraepithelial lesion actinic keratosis (AK) and squamous cell carcinoma (SCC) . About 65% of SCC’s arise from AK lesions. , Tubulin polymerization inhibition has also been reported to be effective in treating AK lesions . Because compound 1 has both MOAs, this opened up another clinical development opportunity.…”

Section: Resultsmentioning

confidence: 99%

Discovery of Novel Dual Mechanism of Action Src Signaling and Tubulin Polymerization Inhibitors (KX2-391 and KX2-361)

et al. 2018

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The discovery of potent, peptide site directed, tyrosine kinase inhibitors has remained an elusive goal. Herein we describe the discovery of two such clinical candidates that inhibit the tyrosine kinase Src. Compound 1 is a phase 3 clinical trial candidate that is likely to provide a first in class topical treatment for actinic keratosis (AK) with good efficacy and dramatically less toxicity compared to existing standard therapy. Compound 2 is a phase 1 clinical trial candidate that is likely to provide a first in class treatment of malignant glioblastoma and induces 30% long-term complete tumor remission in animal models. The discovery strategy for these compounds iteratively utilized molecular modeling, along with the synthesis and testing of increasingly elaborated proof of concept compounds, until the final clinical candidates were arrived at. This was followed with mechanism of action (MOA) studies that revealed tubulin polymerization inhibition as the second MOA.

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Section: Resultsmentioning

confidence: 99%

Discovery of Novel Dual Mechanism of Action Src Signaling and Tubulin Polymerization Inhibitors (KX2-391 and KX2-361)

et al. 2018

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“…Tirbanibulin is a synthetic, first-in-class, potent anti-proliferative agent that inhibits tubulin polymerization and disrupts Src kinase signaling 14 that are upregulated in AK and iSCC. [15][16][17] Tirbanibulin also promotes the induction of p53, G2/M arrest of proliferating cell populations, and subsequent apoptosis via stimulation of caspase-3 and poly (ADP-ribose) polymerase cleavage. 14 In vitro, tirbanibulin demonstrated potent inhibition of the growth of primary human keratinocytes and several melanoma cell lines (GI50 ≤50 nM).…”

Section: Introductionmentioning

confidence: 99%

Tirbanibulin Ointment 1% as a Novel Treatment for Actinic Keratosis: Phase 1 and 2 Results

Kempers¹,

DuBois²,

Forman³

et al. 2020

JDD

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Background: Current field-directed treatments of actinic keratosis (AK), a pre-malignant condition, are often limited by severe local reactions and/or complex treatment. Tirbanibulin, a novel potent anti-proliferative synthetic agent that inhibits tubulin polymerization and Src kinase signalling, is being developed as a convenient, safe, and effective field treatment of actinic keratosis. Hypothesis: A short course of tirbanibulin ointment 1% safely reduces AK lesions. Methods: In the Phase 1 study, 4 treatment cohorts with forearm lesions received tirbanibulin ointment 1% over 25 or 100 cm 2 once daily for 3 or 5 days and were evaluated through day 45. In the Phase 2 study, 2 treatment cohorts with face or scalp lesions received tirbanibulin ointment 1% once daily for 3 or 5 days over 25 cm 2 and were evaluated through day 57. Lesion reductions, clearance rates, safety, and pharmacokinetics were assessed. Results: 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. Conclusion: Tirbanibulin ointment 1% was well tolerated and active in AK reduction. Based on activity, the 5-day regimen was selected for Phase 3 development. Clinicaltrials.gov: NCT02337205; NCT02838628

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“…1991; Mortensen, Brinck, and Lichtenberg 1998; Mahl et al 2006; Makin, Mortensen, and Brock 2012). An example of an integrated assessment of a new antiproliferative drug with topical administration in comparison to marketed standard therapeutics by in vitro investigations using human reconstructed epidermis and by in vivo evaluations after dermal administration to minipigs with respect to mechanistic pathway analysis and skin tolerability is given by Medina et al (2003). A further minipig study with this drug after topical treatment over 2 weeks confirmed the results of the initial investigations with arrest of keratinocytes in the M phase of the cell cycle as demonstrated by laser scanning cytometry (Figure 3).…”

Section: The Minipig In Local Administration Of Anticancer Drugs: Topical Treatmentmentioning

confidence: 99%

The Potential of Minipigs in the Development of Anticancer Therapeutics

2015

Self Cite

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Minipigs are increasingly being used as an alternative to dog or monkey in nonclinical safety testing of pharmaceuticals since they share similar anatomical and physiological characteristics to humans. Integrative assessment of pharmacodynamic and pharmacokinetic data sets of drug candidates from in silico, in vitro, and in vivo investigations form the basis for selecting the most relevant nonrodent species for toxicology studies. Developing anticancer therapeutics represents a special challenge for species selection due to their effects on multiple organ systems. The toxicological profile of anticancer drugs can be associated with steep dose-response curves, especially due to dose-limiting toxicity on the alimentary, hematopoietic, and immune systems. Selection of an appropriate species for toxicology studies is of importance to avoid an inappropriately low (without benefit for the late-stage cancer patient) or high clinical starting dose (with a risk of unexpected adverse reactions). Although the minipig has been the preferred species to develop drugs applied topically, it is only rarely used in anticancer drug development compared to dog and monkey. In this context, we discuss the potential of minipigs in anticancer drug development with examples of programs for oral and dermal administration, intravascular application in drug-eluting stents, and local chemotherapy (chemoembolization).

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LAV694, a new antiproliferative agent showing improved skin tolerability vs. clinical standards for the treatment of actinic keratosis

Cited by 6 publications

References 45 publications

Discovery of Novel Dual Mechanism of Action Src Signaling and Tubulin Polymerization Inhibitors (KX2-391 and KX2-361)

Discovery of Novel Dual Mechanism of Action Src Signaling and Tubulin Polymerization Inhibitors (KX2-391 and KX2-361)

Tirbanibulin Ointment 1% as a Novel Treatment for Actinic Keratosis: Phase 1 and 2 Results

The Potential of Minipigs in the Development of Anticancer Therapeutics

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