A randomized, phase IIa exploratory trial to assess the safety and preliminary efficacy of LEO 43204 in patients with actinic keratosis

Abstract

SummaryBackground LEO 43204 is a novel ingenol derivative in development for the treatment of actinic keratosis. Objectives To compare the safety and preliminary efficacy of three doses of LEO 43204 with ingenol mebutate in actinic keratoses (AKs). Methods Patients with at least three visible, discrete, nonkeratotic AKs on four separate selected treatment areas on the forearms received LEO 43204 gel (0Á025%, 0Á05% and 0Á075%) and ingenol mebutate 0Á05% gel, by investigator-blinded, randomized allocation, for 2 consecutive days. Patients were assessed at 8 weeks. Primary outcomes included maximum composite local skin response (LSR) score and adverse events (AEs). Secondary outcomes included a reduction in the number of visible AKs. Results Forty patients completed the trial. For all treatments, mean LSR scores peaked at week 1, and were below baseline by week 8. Mean maximum composite LSR scores for LEO 43204 0Á025%, 0Á05% and 0Á075% were 9Á2 (Dunnett adjusted P = 0Á02), 10Á1 (Dunnett adjusted P = 0Á90) and 11Á2 (Dunnett adjusted P < 0Á01), respectively, vs. ingenol mebutate 0Á05% gel (10Á0). The most frequent AEs across all treatments were application site pruritus, burning sensation and tenderness. Mean reduction in the number of AKs was comparable for ingenol mebutate and the two lowest doses of LEO 43204 (71Á9-73Á1%), but LEO 43204 0Á075% gave a significantly larger reduction (81Á8%; Dunnett adjusted P = 0Á04). Conclusions LEO 43204 had a similar safety profile to ingenol mebutate and a dose-response relationship for LSRs was demonstrated. The highest LEO 43204 dose (0Á075%) significantly reduced the AK count when compared with ingenol mebutate.

A seamless phase I/II dose-finding trial assessing ingenol disoxate (LEO 43204) for field treatment of actinic keratosis on the scalp

“…Phase IIa data have indicated that ingenol disoxate (0Á025%, 0Á05% and 0Á075%) has comparable safety and efficacy with ingenol mebutate when applied on the forearms for two consecutive days (maximum treatment area 25 cm 2 ). 10 However, in clinical practice, the majority of patients may require treatment for skin areas > 25 cm 2 . In the pivotal ingenol mebutate trials, one dose regimen was used to treat both the face and the scalp, but lower efficacy has been observed when treating AK on the scalp compared with the face, 8,11 warranting a tailored regimen for the former.…”

“…Ingenol disoxate is a novel ingenol derivative in development for the field treatment of AK that has been selected for improved thermostability, direct cellular cytotoxicity and the ability to induce proinflammatory mediators (data on file). Phase IIa data have indicated that ingenol disoxate (0·025%, 0·05% and 0·075%) has comparable safety and efficacy with ingenol mebutate when applied on the forearms for two consecutive days (maximum treatment area 25 cm 2 ) . However, in clinical practice, the majority of patients may require treatment for skin areas > 25 cm 2 .…”

Ingenol Disoxate: A Novel 4-Isoxazolecarboxylate Ester of Ingenol with Improved Properties for Treatment of Actinic Keratosis and Other Non-Melanoma Skin Cancers

“…Although data indicated relatively higher ingenol disoxate skin exposure levels, the magnitude and temporal pattern of the local skin response (LSR) mirrored the effect of ingenol mebutate in the hairless guinea pig; an extensively used model to assess LSRs [37]. Translation to the clinical setting has subsequently been confirmed by the demonstration of a similar LSR profile of ingenol mebutate and ingenol disoxate at similar dose strengths in patients with AK [38]. …”

“…With the discovery of ingenol disoxate we have identified a molecule that fulfills our drug candidate profile criteria in terms of both chemical stability and preclinical efficacy. Ingenol disoxate is currently in Phase 3 clinical development and was recently shown to be an efficacious and well-tolerated topical field treatment for AK, further underscoring the therapeutic potential of this novel ingenol derivative in non-melanoma skin cancers [38]. …”

Treating actinic keratosis

“…In their randomized controlled phase IIa trial, Sinnya and colleagues present promising data on the efficacy and safety of a new derivate of ingenol mebutate in the treatment of AK, LEO 43204 . Patients applied different concentrations of LEO 43204 and ingenol mebutate to randomly assigned fields for 2 days.…”