Sonidegib

證據等級: L5

預測適應症: 10 個

Sonidegib: From Basal Cell Carcinoma to Broader Skin Cancer Indications

One-Sentence Summary

Sonidegib is an oral Smoothened (SMO)/Hedgehog-pathway inhibitor whose approved use for advanced basal cell carcinoma (BCC) is documented in the literature evidence collected here, though structured regulatory license data is not present in this dataset. TxGNN’s highest-evidenced prediction extends this into the broader Skin Cancer category, backed by 10 clinical trials (including the pivotal BOLT study) and 20 publications. Nine additional candidates were also predicted by the model, but only one — Xeroderma Pigmentosum-associated BCC — has any supporting evidence (a single case report); the rest are score-only (L5) and should be treated as hypotheses, not findings.

Quick Overview

Item	Content
Original Indication	Advanced Basal Cell Carcinoma (per literature evidence, e.g. PMID 26323341, 31545507; no structured regulatory record available in this dataset)
Predicted New Indication	Skin Cancer (broader NMSC category, encompassing locally advanced/metastatic BCC)
TxGNN Prediction Score	99.76% (rank 6553/full candidate list)
Evidence Level	L2 (multiple completed Phase 2 RCTs, including the registrational BOLT trial; no completed Phase 3)
US Market Status	Not Marketed (per this dataset; no license record captured)
Number of NDAs	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Structured mechanism-of-action data is not available in this evidence pack (original_moa: [Data Gap]). However, the literature evidence collected under this candidate independently confirms the mechanism: sonidegib is described as “an orally bioavailable, small molecule, Smoothened (SMO) receptor antagonist” that blocks Hedgehog pathway signalling (PMID 26323341), and multiple reviews confirm its established role in locally advanced and metastatic BCC via this mechanism (PMID 31545507 — BOLT study, PMID 27636236, PMID 33888008).

Because BCC is a form of skin cancer, TxGNN’s prediction of “skin cancer” as a repurposing target largely reflects and extends an indication the drug already addresses, rather than identifying a mechanistically distant new disease. This is analogous to a fluoropyrimidine predicted to work in a related GI tumour type: the underlying pathway (aberrant Hedgehog/SMO signalling) is shared across BCC and other cutaneous malignancies with similar oncogenic drivers, which is why multiple trials have also explored sonidegib combinations (with buparlisib, pembrolizumab, photodynamic therapy) across a wider range of advanced solid/skin tumours (NCT02303041, NCT06623201, NCT04007744).

A second, more genuinely novel signal in this dataset is Xeroderma Pigmentosum (XP) (rank 2, score 99.87%). XP patients have defective DNA repair and develop multiple BCC lesions; a 2026 case report (PMID 41862093) describes sonidegib successfully treating multiple BCCs in an XP patient. The mechanistic link here is indirect — sonidegib treats the BCC complication of XP, not the underlying DNA-repair defect — but it represents a plausible, evidence-anchored label-extension use case within a rare, high-need population.

Clinical Trial Evidence

(for the primary predicted indication: Skin Cancer)

Trial Number	Phase	Status	Enrollment	Key Findings
NCT01327053	Phase 2	Completed	230	BOLT study — efficacy/safety of two sonidegib doses in locally advanced or metastatic BCC; basis for regulatory approval
NCT00961896	Phase 2	Completed	18	Topical LDE225 (sonidegib) in Gorlin syndrome-associated BCC; PoC safety/PK/PD
NCT03534947	Phase 2	Completed	16	Neoadjuvant sonidegib before surgery/imiquimod for BCC in cosmetically sensitive sites
NCT01576666	Phase 1	Completed	120	Dose-escalation of sonidegib + buparlisib in advanced solid tumours (breast, pancreatic, colorectal, glioblastoma)
NCT01033019	Phase 2	Terminated	25	Topical sonidegib cream in sporadic superficial/nodular BCC
NCT02303041	Phase 2	Terminated	10	Sonidegib + buparlisib in metastatic/advanced BCC
NCT04007744	Phase 1	Active, not recruiting	36	Sonidegib + pembrolizumab in advanced solid tumours
NCT06623201	Phase 1	Recruiting	20	Sonidegib combined with blue-light photodynamic therapy for multiple BCC lesions
NCT05463757	N/A (registry)	Recruiting	80	Real-world Netherlands registry comparing vismodegib vs. sonidegib in advanced/multiple BCC
NCT01757327	Phase 2	Withdrawn	0	Planned study of Hedgehog inhibitor on disseminated tumour cells in ER-negative/HER2-negative breast cancer (never enrolled)

Literature Evidence

PMID	Year	Type	Journal	Key Findings
31545507	2020	RCT (long-term follow-up)	Br J Dermatol	42-month BOLT study analysis confirming durable efficacy/safety of sonidegib in advanced BCC
37604067	2023	Guideline	Eur J Cancer	European interdisciplinary consensus guideline on BCC diagnosis/treatment (2023 update)
31288208	2019	Guideline	Eur J Cancer	European consensus-based guidelines on BCC diagnosis and treatment
37326221	2023	Drug safety review	Expert Opin Drug Saf	Efficacy and safety evaluation of sonidegib for BCC management
26323341	2015	Drug profile	Drugs	“Sonidegib: First Global Approval” — SMO antagonist mechanism, Swiss approval for advanced BCC
33888008	2021	Expert opinion	Expert Opin Drug Saf	Sonidegib efficacy, safety and tolerability review
27636236	2016	Review	Expert Rev Anticancer Ther	Safety and efficacy of sonidegib in locally advanced BCC
32759706	2020	Review	Int J Mol Sci	Comprehensive review of BCC biology and treatment resistance mechanisms
33725197	2021	Review	Curr Treat Options Oncol	Neoadjuvant sonic hedgehog inhibitor use in locally advanced/multiple BCC
26566923	2016	Review	Int J Dermatol	Oral hedgehog inhibitors (vismodegib, sonidegib) for advanced non-melanoma skin cancer

Other TxGNN-Predicted Candidates (Exploratory, Low Evidence)

This evidence pack contained 10 predicted indications in total. Aside from Skin Cancer above, only one has any literature support:

Rank	Disease	TxGNN Score	Evidence Level	Recommendation	Note
2	Xeroderma Pigmentosum	99.87%	L4	Research Question	Single 2026 case report (PMID 41862093) treating XP-associated multiple BCC with sonidegib
1	Medulloblastoma with extensive nodularity	99.90%	L5	Hold	Strong mechanistic rationale (SHH-driven medulloblastoma) but zero sonidegib-specific trials/literature in this pack
3	Annular epidermolytic ichthyosis	99.83%	L5	Hold	Keratin-gene disorder; no known Hedgehog-pathway link
4	Epidermolysis bullosa simplex w/ mottled pigmentation	99.79%	L5	Hold	No mechanistic or evidentiary link identified
5	Trichothiodystrophy, photosensitive	99.77%	L5	Hold	Theoretical link via shared photosensitivity/DNA-repair biology with XP; unproven
7	Cutaneous adenocystic carcinoma	99.75%	L5	Hold	No supporting data
8	Benign neoplasm of sweat gland	99.74%	L5	Hold	No supporting data
9	Eccrine carcinoma	99.72%	L5	Hold	No supporting data
10	“Obsolete” cataract–microcephaly–failure to thrive–kyphoscoliosis syndrome	99.71%	L5	Hold	Obsolete disease ontology term; recommend excluding from further review

These L5 candidates should not be advanced without new evidence — high TxGNN scores here likely reflect topological/embedding similarity rather than validated pharmacology.

US Market Information

No license records are present in this dataset (total_licenses: 0). Sonidegib’s known first global approval (Switzerland, per PMID 26323341) and subsequent BCC indications elsewhere are documented only through the literature evidence above, not through a structured regulatory record in this pack. This is itself a data gap that should be closed before any regulatory-facing decision (see Next Steps).

Cytotoxicity

Sonidegib qualifies as antineoplastic based on its established use in advanced/metastatic basal cell carcinoma (per literature evidence) and its classification as a Hedgehog-pathway/Smoothened inhibitor.

Item	Content
Cytotoxicity Classification	Targeted therapy (Smoothened/Hedgehog pathway inhibitor) — not a conventional cytotoxic chemotherapeutic
Myelosuppression Risk	Low — SMO inhibitors are not characteristically myelosuppressive; no hematologic toxicity data present in this pack
Emetogenicity Classification	Low, consistent with the targeted-therapy drug class
Monitoring Items	Creatine kinase (musculoskeletal adverse effects are class-characteristic), renal function, pregnancy status (embryo-fetal toxicity is a known class warning for Hedgehog inhibitors)
Handling Protection	No cytotoxic-handling data in this pack; as a class, Hedgehog pathway inhibitors carry embryo-fetal toxicity warnings requiring exposure precautions for pregnant staff/patients — confirm against the actual package insert before implementing handling protocols

Safety Considerations

Please refer to the package insert for safety information.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: The Skin Cancer prediction is supported by a robust body of completed Phase 2 clinical trials (including the pivotal BOLT study) and 20 publications, but this largely confirms/extends an already-known mechanism of action (BCC treatment) rather than revealing a mechanistically novel indication. The remaining 9 predicted indications lack sufficient evidence (8 are L5, score-only; 1 is a single case report) and must remain in a research/monitoring status.

To proceed, the following is needed:

Structured regulatory data (FDA/EMA license records) to resolve the “Not Marketed” data gap, since literature evidence indicates the drug does have approvals elsewhere
Structured DrugBank MOA field to replace the current data gap
TFDA/FDA package insert warnings and contraindications (currently a Blocking data gap per DG001)
For Xeroderma Pigmentosum: additional case reports or a small case series before elevating beyond “Research Question”
For all L5 candidates: no action beyond periodic literature monitoring until new evidence emerges
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.