Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist

Pan, Shifeng; Wu, Xu; Jiang, Jiaoyang; Gao, Wenqi; Wan, Yufeng; Dai, Cheng; Han, Dong Hoon; Li, Jun; Englund, Nathan; Wang, Yan; Peukert, Stefan; Miller‐Moslin, Karen; Yuan, Jing; Guo, Ribo; Matsumoto, Melissa; Vattay, Anthony; Jiang, Yun; Tsao, Jeffrey; Sun, Fangxian; Pferdekamper, AnneMarie Culazzo; Dodd, Stephanie; Tuntland, Tove; Maniara, Wieslawa; Kelleher, Joseph F.; Yao, Yung-Mae; Warmuth, Markus; Williams, Juliet; Dorsch, Marion

doi:10.1021/ml1000307

Cited by 293 publications

(248 citation statements)

References 18 publications

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“…Sonidegib does not exhibit a time-dependent pharmacokinetic profile. The drug accumulation pattern over time and extent of accumulation at steady state are consistent with in vitro data showing lack of induction or timedependent inhibition of CYP enzymes (10). Sonidegib displayed nonlinear pharmacokinetics at higher doses, likely because of solubility-limited absorption, and not because of dose-dependent metabolism as shown by parallel decline of the plasma concentration profile across the dose range.…”

Section: Discussionsupporting

confidence: 81%

“…S1; ref. 10). Sonidegib demonstrated high tissue penetration (including blood-brain barrier) and good oral bioavailability in preclinical studies (10).…”

Section: Introductionmentioning

confidence: 99%

“…10). Sonidegib demonstrated high tissue penetration (including blood-brain barrier) and good oral bioavailability in preclinical studies (10). Oral administration of sonidegib in mouse medulloblastoma models Ptch þ/À p53 À/À and Ptch þ/À Hic1 þ/À (hypermethylated in cancer 1) resulted in complete suppression of glioma-associated oncogene homolog 1 (GLI1) and tumor regression, suggesting targeted inhibition of hedgehog signaling (11).…”

Section: Introductionmentioning

confidence: 99%

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A Phase I, Multicenter, Open-Label, First-in-Human, Dose-Escalation Study of the Oral Smoothened Inhibitor Sonidegib (LDE225) in Patients with Advanced Solid Tumors

Rodón

Tawbi

Thomas

et al. 2014

Clinical Cancer Research

205

216

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Purpose: This phase I trial was undertaken to determine the maximum tolerated dose (MTD), doselimiting toxicities (DLT), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog signaling, in patients with advanced solid tumors.Experimental Design: Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma and basal cell carcinoma (BCC), at doses ranging from 100 to 3,000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose pharmacokinetics run-in period. Dose escalations were guided by a Bayesian logistic regression model. Safety, tolerability, efficacy, pharmacokinetics, and biomarkers in skin and tumor biopsies were assessed.Results: The MTDs of sonidegib were 800 mg daily and 250 mg twice daily. The main DLT of reversible grade 3/4 elevated serum creatine kinase (18% of patients) was observed at doses ! the MTD in an exposuredependent manner. Common grade 1/2 adverse events included muscle spasm, myalgia, gastrointestinal toxicities, increased liver enzymes, fatigue, dysgeusia, and alopecia. Sonidegib exposure increased dose proportionally up to 400 mg daily, and displayed nonlinear pharmacokinetics at higher doses. Sonidegib exhibited exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed in patients with medulloblastoma and BCC were associated with evidence of hedgehog pathway activation.Conclusions: Sonidegib has an acceptable safety profile in patients with advanced solid tumors and exhibits antitumor activity in advanced BCC and relapsed medulloblastoma, both of which are strongly associated with activated hedgehog pathway, as determined by gene expression.

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Section: Discussionsupporting

confidence: 81%

“…S1; ref. 10). Sonidegib demonstrated high tissue penetration (including blood-brain barrier) and good oral bioavailability in preclinical studies (10).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Phase I, Multicenter, Open-Label, First-in-Human, Dose-Escalation Study of the Oral Smoothened Inhibitor Sonidegib (LDE225) in Patients with Advanced Solid Tumors

Rodón

Tawbi

Thomas

et al. 2014

Clinical Cancer Research

205

216

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“…Surgery, the primary course of treatment for most BCCs, and radiotherapy are often not viable options in advanced BCC 1, 2, 3. In recent years, hedgehog (Hh) pathway inhibitors (HPIs) were developed to block aberrant Hh signalling that is found in most sporadic BCCs; HPIs have demonstrated efficacy in patients with laBCC and those with mBCC 4, 5, 6, 7, 8, 9, 10, 11, 12, 13…”

Section: Introductionmentioning

confidence: 99%

Long‐term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30‐month analysis of the randomized phase 2 BOLT study

Lear

Migden

Lewis

et al. 2017

Acad Dermatol Venereol

166

183

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BackgroundPatients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difficult‐to‐treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in laBCC based on results from the BOLT trial.ObjectiveTo evaluate long‐term efficacy and safety of sonidegib in laBCC and mBCC in the BOLT 18‐ and 30‐month analyses.MethodsBOLT (NCT01327053, ClinicalTrials.gov), a double‐blind phase 2 study, enrolled patients from July 2011 until January 2013. Eligible HPI‐treatment–naïve patients with laBCC not amenable to curative surgery/radiotherapy or mBCC were randomized 1 : 2 to sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC, n = 23). Tumour response was assessed per central and investigator review.ResultsWith 30 months of follow‐up, among patients treated with sonidegib 200 mg (approved dose), objective response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and 15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients with laBCC and three with mBCC in the 200‐mg arm died. Median overall survival was not reached in either population; 2‐year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efficacy was similar regardless of aggressive or non‐aggressive histology. Sonidegib 200 mg continued to have a better safety profile than 800 mg, with lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs. 40.0%).ConclusionSonidegib continued to demonstrate long‐term efficacy and safety in these populations. These data support the use of sonidegib 200 mg per local treatment guidelines.

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“…Sonidegib (LDE225) is a potent and selective SMO inhibitor that has demonstrated dose-dependent tumor regression in ) mouse medulloblastoma models (13,14). In recent phase I studies testing single-agent sonidegib in adult and pediatric patients with advanced solid tumors, antitumor activity was demonstrated in several patients with medulloblastoma (15,16).…”

Section: Introductionmentioning

confidence: 99%

A Five-Gene Hedgehog Signature Developed as a Patient Preselection Tool for Hedgehog Inhibitor Therapy in Medulloblastoma

Shou¹,

Robinson²,

Amakye

et al. 2015

Clinical Cancer Research

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Purpose: Distinct molecular subgroups of medulloblastoma, including hedgehog (Hh) pathway–activated disease, have been reported. We identified and clinically validated a five-gene Hh signature assay that can be used to preselect patients with Hh pathway–activated medulloblastoma. Experimental Design: Gene characteristics of the Hh medulloblastoma subgroup were identified through published bioinformatic analyses. Thirty-two genes shown to be differentially expressed in fresh-frozen and formalin-fixed paraffin-embedded tumor samples and reproducibly analyzed by RT-PCR were measured in matched samples. These data formed the basis for building a multi-gene logistic regression model derived through elastic net methods from which the five-gene Hh signature emerged after multiple iterations. On the basis of signature gene expression levels, the model computed a propensity score to determine Hh activation using a threshold set a priori. The association between Hh activation status and tumor response to the Hh pathway inhibitor sonidegib (LDE225) was analyzed. Results: Five differentially expressed genes in medulloblastoma (GLI1, SPHK1, SHROOM2, PDLIM3, and OTX2) were found to associate with Hh pathway activation status. In an independent validation study, Hh activation status of 25 medulloblastoma samples showed 100% concordance between the five-gene signature and Affymetrix profiling. Further, in medulloblastoma samples from 50 patients treated with sonidegib, all 6 patients who responded were found to have Hh-activated tumors. Three patients with Hh-activated tumors had stable or progressive disease. No patients with Hh-nonactivated tumors responded. Conclusions: This five-gene Hh signature can robustly identify Hh-activated medulloblastoma and may be used to preselect patients who might benefit from sonidegib treatment. Clin Cancer Res; 21(3); 585–93. ©2014 AACR.

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Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist

Cited by 293 publications

References 18 publications

A Phase I, Multicenter, Open-Label, First-in-Human, Dose-Escalation Study of the Oral Smoothened Inhibitor Sonidegib (LDE225) in Patients with Advanced Solid Tumors

A Phase I, Multicenter, Open-Label, First-in-Human, Dose-Escalation Study of the Oral Smoothened Inhibitor Sonidegib (LDE225) in Patients with Advanced Solid Tumors

Long‐term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30‐month analysis of the randomized phase 2 BOLT study

A Five-Gene Hedgehog Signature Developed as a Patient Preselection Tool for Hedgehog Inhibitor Therapy in Medulloblastoma

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