Introduction Basal cell carcinoma (BCC) is a distinctive manifestation in nevoid basal cell carcinoma syndrome (NBCCS) patients. Both inherited and acquired mutations of PTCH1, a tumor suppressor gene controlling the activity of smoothened (SMO), are the primary cause of the constitutive activation of the Hedgehog (Hh) pathway leading to the emergence of BCC in NBCCS. LDE225, a novel, selective antagonist of SMO is currently being developed for the treatment of BCCs in NBCCS patients. Herein we report the results of a proof of concept study, which evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of LDE225 cream for the topical treatment of BCCs in NBCCS patients.
Methods This was a double-blind, randomized, vehicle-controlled, intra-individual study. A total of 8 NBCCS patients, presenting 27 BCCs, were treated bid with 0.75% LDE225 cream or vehicle for 4 weeks.
Results LDE225 was well tolerated and showed no skin irritation. Plasma LDE225 concentrations after 4 weeks were below detection level (0.05 ng/mL) in 4/8 patients (highest plasma level detected was 0.11 ng/mL). Mean LDE225 skin concentrations were 737 ng/g (BCC) and 605 ng/g (uninvolved skin). LDE225-treated BCCs (n=13) showed complete clinical response in 3, partial response in 9, and no response in 1 BCC. Except for one partial response, the vehicle produced no clinical response in any of the 14 treated BCCs. Mean volume reductions of 49.8% were observed in the LDE225-treated BCCs vs. 9.1% with vehicle; mean surface area reductions were 40.8% and 10.5%, respectively (3D digital photography). Biomarker analysis showed that, except for one patient, Gli 1, Gli 2, Ptch 1 and Ptch 2 mRNA level reductions correlated with the clinical outcome.
Conclusion Inhibition of hedgehog pathway with LDE225 was effective in the treatment of BCCs in NBCCS patients. Since the use of other currently available topicals for treatment of BCCs is limited by skin irritation, treatment with LDE225 cream in NBCCS patients may offer a novel therapeutic alternative.