Glasdegib
| Evidence Level: L2 | Predicted Indications: 10 |
Table of Contents
Glasdegib: From Acute Myeloid Leukemia to Myelodysplastic/Myeloproliferative Disease
One-Sentence Summary
Glasdegib is a Smoothened (SMO) / Hedgehog pathway inhibitor originally developed and approved (in combination with low-dose cytarabine) for acute myeloid leukemia (AML). The TxGNN model predicts it may also be effective for myelodysplastic/myeloproliferative disease (MDS/MPN), with 3 clinical trials and 1 publication currently supporting this direction.
(Note: The single highest-scoring TxGNN hit, “bulbar polio,” and several other top-ranked outputs were flagged by the evidence engine itself as biologically implausible / likely model noise — see “Why is This Prediction Reasonable?” below for how the MDS/MPN candidate was selected instead.)
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Acute Myeloid Leukemia (AML), in combination with low-dose cytarabine (not TFDA-approved / not marketed in Taiwan) |
| Predicted New Indication | Myelodysplastic/Myeloproliferative Disease (MDS/MPN) |
| TxGNN Prediction Score | 96.76% |
| Evidence Level | L2 |
| Taiwan Market Status | Not marketed (Not Marketed) |
| Number of Authorizations | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism-of-action documentation is not yet available for this evidence pack (marked as a High-severity data gap). Based on information embedded in the evidence itself, glasdegib (PF-04449913) is a Smoothened (SMO) receptor antagonist that inhibits Hedgehog pathway signaling — a pathway implicated in the self-renewal and chemoresistance of leukemic stem cells. It is already approved (in combination with low-dose cytarabine) for AML.
MDS/MPN and AML sit on the same myeloid stem-cell malignancy spectrum, sharing overlapping pathobiology (clonal hematopoietic stem/progenitor cell disorders with Hedgehog-pathway involvement in leukemic stem cell survival). This mechanistic continuity is why glasdegib’s known AML activity plausibly extends to MDS/MPN, and it is reflected in real clinical development: glasdegib has been directly studied — alone and combined with azacitidine — in MDS and CMML populations.
By contrast, several other high-TxGNN-score outputs (bulbar polio, 5q35 microduplication syndrome, neuralgic/amyotrophic neuralgia, ganglioneuroblastoma) were assessed by the evidence pack’s own rationale as having no known biological link to SMO/Hedgehog inhibition and are treated as likely model noise (Hold). Two AML/MDS subtypes related to prior alkylating-agent or radiation exposure, plus acute panmyelosis with myelofibrosis and bilineal AML, are mechanistically consistent with glasdegib’s known biology but currently lack any subtype-specific trial or literature evidence (Research Question stage) — these are worth monitoring but are not yet actionable.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01842646 | Phase 2 | Completed | 35 | Single-arm study of oral SMO inhibitor glasdegib (PF-04449913) in relapsed/refractory MDS or CMML; evaluates safety and efficacy. |
| NCT04842604 | Phase 3 | Completed | 14 | Open-label continuation study of azacitidine with or without glasdegib in previously untreated AML, MDS, or CMML patients continuing from prior studies. |
| NCT02367456 | Phase 1 | Completed | 73 | Phase 1b study of glasdegib combined with azacitidine in previously untreated higher-risk MDS, AML, or CMML; evaluates safety, efficacy, PK and PD via a safety lead-in and expansion cohorts. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 31030089 | 2019 | Phase 2 Trial | Leukemia Research | Phase 2 trial of glasdegib in HMA-failure MDS (n=35, median age 73); Hedgehog pathway upregulation implicated in leukemic stem cell survival, with 54–77% of patients classified high-risk by IPSS/MD Anderson Global Risk Model. |
EU Market Information
Glasdegib is currently not marketed in Taiwan (0 authorizations, market status: Not marketed). No license or approved-indication data is available to tabulate.
Cytotoxicity
Glasdegib is an antineoplastic agent (approved for AML, a hematologic malignancy).
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (SMO/Hedgehog pathway inhibitor); typically administered with a conventional cytotoxic backbone (e.g., low-dose cytarabine or azacitidine) |
| Myelosuppression Risk | High — expected when combined with cytotoxic backbone therapy in myeloid malignancies; please refer to the SmPC for confirmed grading |
| Emetogenicity Classification | Low (oral small-molecule targeted agent); please refer to the SmPC for confirmed classification |
| Monitoring Items | CBC with differential, liver and renal function; ECG/QTc monitoring is a class consideration for SMO inhibitors and should be confirmed against the SmPC |
| Handling Protection | As an antineoplastic agent, handling should follow institutional hazardous-drug protocols; refer to SmPC/safety data sheet for specifics |
Safety Considerations
Please refer to the SmPC for safety information. (Key warnings, contraindications, and drug interaction data are not currently available in this evidence pack; the DDI query returned no results.)
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Glasdegib’s approved AML mechanism (SMO/Hedgehog inhibition targeting leukemic stem cells) extends plausibly to MDS/MPN, and this is supported by three completed early-phase trials and one published Phase 2 study — but none are confirmatory randomized Phase 2/3 trials, and safety/label data remain unavailable.
To proceed, the following is needed:
- TFDA label warnings/contraindications (currently a Blocking data gap — required before any S1 safety assessment)
- Verified mechanism-of-action documentation (High-severity data gap)
- A confirmatory randomized trial in MDS/MPN specifically (existing trials are single-arm or small continuation studies)
- Drug-drug interaction data (current DDI query returned no results)
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.