Curis Hedgehog and Beyond --plus multi-targeting cancer inhibitors

Advanced Solid Tumors
http://clinicaltrials.gov/ct2/show/NCT00880308?term=LDE225 PI
This first-in-human dose-escalation study is to characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of LDE225 given orally on a daily dosing schedule in patients with advanced solid tumors.
Study Start Date: March 2009
Estimated Primary Completion Date: December 2010

Skin Basal Cell Carcinomas in Gorlin's Syndrome Patients PI / PII
http://clinicaltrials.gov/ct2/show/NCT00961896?term=LDE225
A double-blind, randomized, vehicle-controlled Proof of Concept (PoC) study to evaluate the safety, local tolerability, pharmacokinetics and pharmacodynamics of multiple topical administrations of LDE225 (a specific Smoothened inhibitor) on skin basal cell carcinomas in Gorlin's syndrome patients.

The study will consist of a 21-day screening period, a baseline period (directly before commencing the treatment period) and a treatment period of 4 weeks followed by a safety visit one week after last study drug administration (week 5) and a Study Completion evaluation 4 weeks after the last study drug administration.

Patients will be exposed to multiple doses of topically applied LDE225 twice daily for 4 weeks in a double-blind manner. LDE225 and the vehicle as a negative control, will be randomized to the test areas. Following the last application of the treatment, biopsies will be taken from the BCCs for histology, biomarker evaluation and for pharmacokinetics (skin exposure). In addition, a biopsy will be taken for pharmacokinetic evaluation of LDE225-treated uninvolved perilesional skin. In total, 4 biopsies will be taken.

Study Start Date: July 2009
Estimated Primary Completion Date: October 2009

LDE225 on Sporadic Superficial Skin Basal Cell Carcinomas(sBCC) PII
http://clinicaltrials.gov/ct2/show/NCT01033019?term=LDE225
A double-blind, randomized, vehicle-controlled Proof of Concept (PoC) study to evaluate the efficacy, safety, local tolerability, pharmacokinetics and pharmacodynamics of multiple topical administrations of LDE225 (a specific Smoothened inhibitor) on sporadic superficial skin basal cell carcinomas (superficial, sBCC) The study will consist of a 21-day screening period and a treatment period of 6 weeks ending with post treatment biopsies, followed by a safety visit one week after final drug administration (Day 50) and then by excision of the sBCC (Day 83) and a Study Completion evaluation (Day 90).

Patients will be exposed to multiple doses of topically applied LDE225 twice daily for 6 weeks in a double-blind manner. LDE225 and the vehicle as a negative control, will be randomized to the test areas. Shave biopsy may be performed pre-treatment to confirm diagnosis. Following the last application of the treatment, punch biopsies will be taken from the sBCC for biomarker and pharmacokinetics (lesional and perilesional) evaluation. In total 4 biopsies will be taken.

During treatment, the patients will return weekly for visits where each treated sBCC will be clinically evaluated and digital photographs taken. Local safety and tolerability will also be assessed.

Study Start Date: December 2009
Estimated Primary Completion Date: April 2010

http://clinicaltrials.gov/ct2/results?term=LDE225

LDE225

http://ash.confex.com/ash/2009/webprogr ... 21592.html

An oral, selective inhibitor of Smoothened
Smoothened (Smo) is a GPCR-like molecule which positively regulates Hedgehog (HH) signal transduction, a signaling pathway that plays a critical role in the development and homeostasis of many organs and tissues.1 In the absence of ligands, the HH pathway is inactive as Smo is inhibited by the receptor Patched (Ptch). This inhibition is relieved when Ptch is bound by one of the HH family of ligands including Sonic Hedgehog (SHH), Desert Hedgehog (DHH) and Indian Hedgehog (IHH).1 Active Smo signals via a cytosolic complex of proteins leading to activation of the Gli family of transcription factors. Active Gli signaling can cause cell proliferation and differentiation.1
Genetic activation of the HH pathway at or upstream of Smo is linked to tumorigenesis of several cancers.1 Activating mutations in Ptch and Smo have been identified in approximately 20% of sporadic human medulloblastoma and >70% of basal cell carcinoma.2,3 Upregulation of the HH pathway without known mutations is also linked to a number of additional tumor types, including pancreatic and lung cancer, as well as some hematological malignancies.1
LDE225 is a selective, orally bioavailable Smo antagonist from a novel structural class. It has been shown to potently inhibit HH- and Smo-dependent proliferation in vivo.
LDE225 is currently being investigated in a Phase I trial in patients with advanced solid tumors.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.
Pasca di Magliano M, Hebrok M. Hedgehog signaling in cancer formation and maintenance. Nature. 2003;3:903-911.

McMahon AP, Ingham PW, Tabin CJ. Development roles in clinical significance of hedgehog signaling. Curr Top Dev Biol. 2003;53:1-114.

Reifenberger J, Wolter M, Knobbe B, et al. Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinoma. Br J Dermatol. 2005;152:43-51