Sacubitril
| Evidence Level: L5 | Predicted Indications: 5 |
Table of Contents
- Sacubitril
- Pharmacist Assessment Report
- Sacubitril: Brain small vessel disease 1 with or without ocular anomalies
- One-Sentence Summary
- Quick Overview
- Why is This Prediction Reasonable?
- Clinical Trial Evidence
- Literature Evidence
- Australia Market Information
- Safety Considerations
- Conclusion and Next Steps
- Disclaimer
Sacubitril: Brain small vessel disease 1 with or without ocular anomalies
One-Sentence Summary
Sacubitril is a neprilysin inhibitor supplied in Australia as a fixed-dose tablet with valsartan (Entresto). The licence record compiled for this report does not state an approved indication. The TxGNN model predicts it may be effective for diabetic nephropathy, the most credible of its top five predictions, with 1 clinical trial (Phase 4, status unknown) and 15 publications, most of them preclinical or reviews.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in the local data |
| Predicted New Indication | Brain small vessel disease 1 with or without ocular anomalies |
| TxGNN Prediction Score | 0.9958 |
| Evidence Level | L5 |
| Australia Market Status | Listed on the PBS Schedule (1 of 1 items) – TGA (ARTG) registration status is not included in this data |
| Number of PBS Items | 1 (valid: 1) |
| Recommended Decision | Hold (research question; see conclusion) |
The top-ranked prediction by score was brain small vessel disease 1 with or without ocular anomalies (0.9958). It has no supporting mechanism or evidence (L5, Hold). Diabetic nephropathy is the only prediction with a clinical trial and a plausible mechanism, so this report focuses on it. Rankings 1, 2, 4 and 5 have little or no evidence:
| Rank | Predicted Indication | Score | Evidence Level | Comment |
|---|---|---|---|---|
| 1 | Brain small vessel disease 1 (COL4A1-related) | 0.9958 | L5 | The only paper retrieved concerns systemic right ventricular failure, which is unrelated. No mechanistic link is evident. |
| 2 | Autosomal dominant familial haematuria-retinal arteriolar tortuosity-contractures syndrome | 0.9957 | L5 | No trials or literature. Computational prediction only. |
| 4 | Rheumatoid arthritis | 0.9935 | L5 | The only paper is a case report of golimumab-associated myocarditis. It is not evidence of efficacy. |
| 5 | Haemoglobinopathy | 0.9918 | L5 | No trials or literature. Any hypothesis is speculative. |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. From general pharmacology, sacubitril is a prodrug whose active metabolite inhibits neprilysin, an enzyme that degrades natriuretic peptides. Inhibition raises natriuretic peptide levels, which promotes vasodilation and natriuresis and has anti-fibrotic effects. In the marketed tablet it is combined with valsartan, an angiotensin II receptor blocker.
Blocking the renin-angiotensin system is a cornerstone of diabetic kidney disease management. The neprilysin inhibitor adds a complementary pathway. Preclinical studies in rats and db/db mice report reduced oxidative stress, NF-κB-mediated inflammation, glomerular and tubular injury, and gut microbiota changes. A secondary analysis of the PARADIGM-HF trial (Lancet Diabetes Endocrinol, 2018) examined renal function in patients with type 2 diabetes and heart failure.
An important caveat is that the benefit of sacubitril beyond valsartan alone on renal outcomes has not been established. The prediction is plausible but unconfirmed.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT06501651 | Phase 4 | Unknown | 297 | Hyper-Save: randomised, controlled, multicentre comparison of sacubitril/valsartan with valsartan over 12 weeks (2:1 allocation) in essential hypertension with type 2 diabetic nephropathy. No results available. Planned dates were August 2024 to April 2025. |
No ANZCTR trials were identified in the data compiled for this report.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 37549515 | 2023 | Clinical study (randomised groups, n=112) | Int Immunopharmacol | Nifedipine controlled-release plus sacubitril/valsartan versus plus valsartan in diabetic nephropathy with hypertension. |
| 29661699 | 2018 | Secondary analysis of RCT | Lancet Diabetes Endocrinol | PARADIGM-HF secondary analysis of neprilysin inhibition and renal function in type 2 diabetes with heart failure. |
| 40416927 | 2025 | Clinical imaging study | Diabetes Metab Syndr Obes | BOLD-MRI evaluation of renal effects of sacubitril/valsartan in diabetic nephropathy. |
| 37625003 | 2023 | Review | Diabetes Care | Update on the pillars of therapy slowing diabetic nephropathy progression. |
| 35165832 | 2022 | Review | Curr Hypertens Rep | Newer drugs for blood pressure lowering and hypertensive organ damage. |
| 35992034 | 2022 | Preclinical (rat) | Diabetes Metab Syndr Obes | Sacubitril/valsartan slowed early diabetic nephropathy via NLRP3 inflammasome inhibition. |
| 36589853 | 2022 | Preclinical (mouse) | Front Endocrinol | Improved diabetic kidney disease and modulated gut microbiota. |
| 32596035 | 2020 | Preclinical (rat) | PeerJ | LCZ696 reduced oxidative stress, inflammation and glomerulosclerosis. |
| 33870733 | 2021 | Preclinical (mouse) | Am J Physiol Renal Physiol | Differential effects versus valsartan in db/db and KKAy mice. |
| 30909895 | 2019 | Preclinical (rat) | Cardiovasc Diabetol | Attenuated glomerular and tubular injury in Zucker obese rats. |
Five further publications (reviews, a podocyte cell study and a mouse study) were retrieved but are not listed here.
Australia Market Information
| ARTG Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| ARTG 11122J | Entresto | Tablet containing sacubitril 97.2 mg with valsartan 102.8 mg | Not stated in the data compiled |
Safety Considerations
Drug Interactions (6 moderate-level interactions recorded):
- Nitisinone
- Rosuvastatin
- Simvastatin
- Cobicistat
- Revefenacin
- Alpelisib
For other warnings and contraindications, please refer to the TGA-approved Product Information (PI). The label-based safety data was not available for this report.
Conclusion and Next Steps
Decision: Hold
Rationale: The TxGNN score is very high, but the evidence is early. There is one Phase 4 trial of unknown status, preclinical data, and no completed Phase 3 renal outcome trial. The other four predictions have no meaningful support. Blocked safety screening (no label data) is also a reason to wait. Diabetic nephropathy remains a reasonable research question, and could move to Proceed with Guardrails if the evidence below is obtained.
To proceed, the following is needed:
- Results and current status of NCT06501651, including eGFR and albuminuria endpoints
- Evidence that sacubitril adds renal benefit beyond valsartan alone
- The TGA Product Information, including approved indications, warnings and contraindications
- Mechanism of action data confirmed from DrugBank
- A safety plan for patients with diabetic kidney disease, covering renal function, potassium and blood pressure monitoring
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.