Alpelisib

證據等級: L5

預測適應症: 1 個

A quick note before the report: drug.original_indications is empty and taiwan_regulatory.licenses is empty (drug not marketed in Finland), so the "Original Indication" cannot be sourced from the regulatory license text as the template default rule specifies. I've inferred it from the clinical-trial/literature context in the evidence pack itself (HR+/HER2− advanced breast cancer), which is clearly labeled below as inferred rather than regulatory-confirmed.

Alpelisib: From Breast Cancer to Pulmonary Hypertension

One-Sentence Summary

Alpelisib is a PI3Kα inhibitor used in HR+/HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer. The TxGNN model predicts it may be effective for Pulmonary Hypertension, but this prediction is currently supported by 0 relevant clinical trials and 0 supportive publications — the only clinical trial retrieved is a drug/indication mismatch, and the only literature retrieved actually documents alpelisib-induced lung and cardiac toxicity, which runs counter to the predicted benefit.

Quick Overview

Item	Content
Original Indication	Breast cancer (HR+/HER2-negative, PIK3CA-mutated advanced/metastatic BC) — inferred from trial/literature context; not confirmed by Finnish/Fimea regulatory data
Predicted New Indication	Pulmonary Hypertension
TxGNN Prediction Score	99.03%
Evidence Level	L5
Finland Market Status	未上市 (Not Marketed)
Number of Authorizations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Detailed mechanism-of-action data for alpelisib is currently a data gap in this evidence pack (DG002). Based on known pharmacology, alpelisib is a selective PI3Kα (p110α) inhibitor approved for PIK3CA-mutated breast cancer, where it blocks aberrant PI3K/AKT/mTOR signaling driving tumor cell proliferation.

The TxGNN model's rationale for linking alpelisib to pulmonary hypertension rests on a mechanistic hypothesis: in preclinical animal models, PI3Kα signaling has been implicated in pulmonary artery smooth muscle cell proliferation and anti-apoptotic signaling, and selective p110α inhibition has been shown to prevent or reverse experimental pulmonary hypertension and right ventricular hypertrophy. This provides a theoretical basis for repurposing.

However, this mechanistic hypothesis has not been validated in human pulmonary hypertension populations by any trial or study in this evidence pack. On the contrary, the two literature reports retrieved describe alpelisib-associated interstitial lung disease (ILD) and PI3Kα-pathway-inhibition-associated cardiac atrophy/right ventricular dysfunction — adverse effects that point in the opposite direction of the intended therapeutic benefit for a patient population that, by definition, has compromised pulmonary and right-heart function. The mechanistic plausibility therefore coexists with a real safety signal that argues for caution rather than support.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT06705504	N/A	Completed	435	Real-world retrospective study of ribociclib (not alpelisib) in HR+/HER2- advanced/metastatic breast cancer. Flagged by relevance review as Grade C — not relevant: wrong drug, wrong indication (breast cancer, not pulmonary hypertension); appears to be a drug-name co-occurrence mismatch and does not support this indication.

No clinical trial in this evidence pack actually studies alpelisib in pulmonary hypertension.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
35730191	2023	Case Report	J Oncol Pharm Pract	Reports alpelisib-induced interstitial lung disease in a patient with advanced breast cancer — a pulmonary adverse-effect signal, not supportive efficacy evidence.
31039672	2019	Preclinical/Mechanistic	J Am Heart Assoc	PI3Kα pathway inhibition (with doxorubicin) causes biventricular cardiac atrophy and right ventricular dysfunction in animal models — a cardiotoxicity signal relevant to right-heart function, which is already compromised in pulmonary hypertension.

Neither publication provides direct evidence of efficacy in pulmonary hypertension; both instead flag lung and cardiac safety concerns relevant to this candidate indication.

Finland Market Information

Alpelisib is currently not marketed in Finland (market_status: 未上市), with 0 authorizations on record. No Fimea/marketing-authorization license data is available to summarize.

Cytotoxicity (Antineoplastic Drug)

Alpelisib is classified here as antineoplastic because its known original indication is breast cancer and it belongs to a targeted oncology drug class (PI3Kα inhibitor).

Item	Content
Cytotoxicity Classification	Targeted therapy (PI3Kα / p110α inhibitor) — not a conventional cytotoxic agent
Myelosuppression Risk	Not established in this evidence pack (DrugBank toxicity data not retrieved). Please refer to the package insert warnings and precautions.
Emetogenicity Classification	Please refer to the package insert warnings and precautions
Monitoring Items	Given the literature signals above: pulmonary function/imaging (ILD risk), cardiac function assessment (right ventricular function, given documented biventricular atrophy/dysfunction in PI3Kα-pathway inhibition), blood glucose (class-associated hyperglycemia), liver and renal function, CBC
Handling Protection	Oral antineoplastic small molecule; institutional hazardous/antineoplastic drug handling precautions should be followed pending confirmation from the TFDA/Fimea package insert

Safety Considerations

All formal safety fields in this evidence pack (key_warnings, contraindications, ddi) are data gaps. Please refer to the package insert for safety information.

Important signal from the literature review (not part of the formal safety dataset, but material to this decision): the only two publications identified for this candidate describe alpelisib-associated interstitial lung disease and PI3Kα-pathway-related cardiac dysfunction — both directly relevant risks for a pulmonary hypertension population, which typically has reduced pulmonary and right-ventricular reserve.

Conclusion and Next Steps

Decision: Hold

Rationale: The TxGNN score is high, but it is unsupported by any direct human evidence — the single clinical trial retrieved is a drug/indication mismatch, and the only literature retrieved reports adverse pulmonary and cardiac effects rather than therapeutic benefit. Combined with a Blocking data gap on TFDA/Fimea labeling (DG001) and the drug not being marketed in Finland, there is currently no basis to advance this candidate beyond model prediction (evidence level L5, decision stage S0).

To proceed, the following is needed:

TFDA/Fimea package insert with confirmed warnings, contraindications, and DDI data (DG001, Blocking)
Verified mechanism-of-action documentation from DrugBank or another primary source (DG002, High)
A trial or study that directly evaluates alpelisib (or PI3Kα inhibition) in human pulmonary hypertension patients
Targeted pulmonary/cardiac safety assessment to reconcile the mechanistic hypothesis against the documented ILD and cardiotoxicity signals before any further evaluation
Disclaimer

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