Restoring MAPK signalling in the skin: pharmaceutical development and non-clinical evaluation of a topical BRAF inhibitor gel for EGFR inhibitor induced acneiform rash

EGFR-targeted therapies are frequently limited by the development of acneiform skin toxicities resulting from inhibition of MAPK/ERK signalling in the epidermis. Paradoxical RAF activation in BRAF wild-type keratinocytes provides a mechanistic opportunity to locally counteract this effect. This study aimed to develop a topical formulation of a BRAF inhibitor and to conduct its pharmaceutical and non-clinical evaluation for the treatment of EGFR inhibitor-induced skin toxicities. In the EpiDerm™ Full Thickness reconstructed human skin model, the BRAF inhibitor induced MAPK/ERK pathway activation with a bell-shaped concentration-response profile and restored ERK signalling in the presence of the EGFR inhibitor afatinib. To translate this effect into a topical treatment, gels containing 0.1% and 1% (w/w) BRAF inhibitor were developed using a low-water-content, co-solvent-rich vehicle. Both formulations exhibited suitable rheological properties, showed no detectable recrystallisation by XRPD, and provided sustained in vitro diffusion across Strat-M^® membranes. As part of a two-year stability study, three-month results showed that the physicochemical parameters of the gels met internal specifications and European Pharmacopoeia requirements. Finally, the activity of the BRAF inhibitor on the MAPK/ERK pathway was maintained following incorporation into the gel. In mice, topical administration favoured cutaneous exposure while reducing systemic exposure compared with oral administration at the same nominal dose, with an approximately 16-fold lower plasma Cmax and a 3-fold lower AUClast. Repeated topical administration for 28 days showed a favourable local tolerability profile. No agonist activity at MRGPRX2 was detected, whereas in vitro phototoxic potential was identified, requiring appropriate risk-mitigation measures during clinical development. Overall, these findings provide a pharmaceutical and non-clinical basis for the clinical evaluation of a topical BRAF inhibitor as a targeted treatment for EGFR inhibitor-induced acneiform skin toxicities.