Delving into the Latest Updates on Sacubitril with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Sacubitril, Sacubitril (JAN/USAN/INN), AHU-377

Target

CD10

Action

inhibitors

Mechanism

enkephalinase inhibitors(Neprilysin inhibitors)

Therapeutic Areas

Cardiovascular Diseases

Active Indication

Heart FailureLeft ventricular systolic dysfunction

Inactive Indication

Chronic heart failureErectile DysfunctionEssential Hypertension+ [3]

Originator Organization

Novartis Pharma AG

Active Organization

Novartis Pharmaceuticals Corp.

Inactive Organization

Novartis Pharmaceuticals Canada, Inc.

License Organization-

Drug Highest PhasePhase 3

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC24H29NO5

InChIKeyPYNXFZCZUAOOQC-UTKZUKDTSA-N

CAS Registry149709-62-6

Sub-analyses of key trials suggest a preferential benefit for specific heart failure with preserved ejection fraction (HFpEF) therapies in women. This work investigated treatment effects between women and men in the PARAGLIDE-HF (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF) trial.

METHODS:

In this prespecified subgroup analysis, we examined outcomes according to sex in the PARAGLIDE-HF trial. The primary endpoint was time-average proportional change in amino terminal pro-B type natriuretic peptide (NT-proBNP) from baseline through Weeks 4 and 8. We also examined secondary outcomes and tolerability.

RESULTS:

Overall, 242 women (52%) and 224 men (48%) were randomized. Women had significantly higher LVEF, worse renal function, and less comorbidities than men. In the overall population, the time-averaged reduction in NT-proBNP was significantly greater for sacubitril/valsartan (sac/val) than valsartan (ratio of change 0.85, 95% CI, 0.73-0.999). When examined according to sex, the time-averaged reduction in NT-proBNP was numerically greater with sac/val in both women (ratio of change = 0.86, 95% CI, 0.69-1.070) and men (ratio of change 0.84, 95% CI, 0.67-1.05) with no differential treatment effect (P interaction = .91). Similarly, the secondary hierarchical endpoint favored sac/val over valsartan in both women and men but was not statistically significant. Study drug dosage levels were similar across women and men and there were no sex-specific differences in the incidence of adverse events.

CONCLUSIONS:

In patients with mildly reduced or preserved EF >40% and a recent worsening HF event, the efficacy, safety and tolerability of sac/val vs valsartan were similar in both women and men, suggesting consistent effects across appropriately selected patients regardless of sex. Future prospective studies are needed to further evaluate sex-specific differences in treatment response of HFpEF therapies.

TRIAL REGISTRATION:

Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF; NCT03988634; https://www.

CLINICALTRIALS:

gov/study/NCT03988634.

01 Sep 2025·HEART & LUNG

Clinical outcomes of sacubitril-valsartan versus angiotensin converting enzyme inhibitor or angiotensin receptor blocker among patients with heart failure and ejection fraction at/less than 60 %: A retrospective, observational, parallel cohort, multi-group study

Article

Author: Albert, Nancy M ; Bena, James F ; Martyn, Trejeeve ; Khairnar, Rahul ; Faulkenberg, Kathleen ; Williams, J Bradley ; Morrison, Shannon L

BACKGROUND:

Real-world heart failure (HF) and all-cause hospitalization, HF-related emergency care visits, all-cause mortality and the composite of all-cause or HF hospitalization or HF-related emergency visit remain high, due to underuse of core HF medications.

OBJECTIVES:

A better understanding of real-world clinical outcomes is needed based on sacubitril-valsartan vs. angiotensin converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) use among patients with HF and a wide range of ejection fractions.

METHODS:

Data retrieved from a multi-center, multi-state healthcare system database of patients prescribed sacubitril-valsartan were matched to those on ACEI/ARB based on age, sex, EF, comorbidity status, systolic blood pressure and index date site (hospital or ambulatory). Six- and 12-month outcomes based on sacubitril-valsartan vs. ACEI/ARB were assessed using linear, logistic, and Poisson models with generalized estimating equations.

RESULTS:

Patients (N = 4188; 2094/cohort) were well matched based on characteristics; 29.8 % were female, mean (SD) age was 64.3 (13.1) years, systolic blood pressure was 122.0 (16.2) mmHg, EF% was 29.1 (9.9); nearly half were in NYHA FC II and 422 (10.1 %) had EF of 41-60 %. Frequency of non-study medications at baseline was 92.6 % beta-blocker, 43.2 % mineralocorticoid receptor antagonist and 64.2 % loop diuretic. Compared to ACEI/ARB, all 6 and 12-month clinical outcomes were improved among patients using sacubitril-valsartan (all 12-month p<.001).

CONCLUSIONS:

Among patients with HF and EF up to 60 %, sacubitril-valsartan use was associated with lower 12-month morbidity and mortality. Providers and clinicians need to advocate for use of sacubitril-valsartan per hierarchical renin angiotensin system inhibitor national guideline recommendations.

01 Aug 2025·JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS

Early metabolomics revealed the sensitivity of sacubitril/valsartan to person with end-stage renal disease accompanied by heart failure

Article

Author: Yang, Weiyu ; Song, Lili ; Wei, Jinxia ; Liu, Huimin ; Lin, Jiayi ; Li, Yubo ; Zhang, Lijuan

Heart failure (HF) is a major complication in patients with end-stage renal disease (ESRD) and is the leading cause of death in this high-risk population. Sacubitril/Valsartan is an angiotensin receptor-neprilysin inhibitor (ARNI) that has been shown to improve treatment outcomes in patients with ESRD accompanied by HF. Unfortunately, in clinical practice, some patients who received sacubitril/valsartan treatment not only did not show a good therapeutic effect, but also got worse with the passage of time. To explore potential biomarkers for predicting the clinical efficacy of sacubitril/valsartan, serum samples were prospectively collected upon admission and again collected after sacubitril/valsartan treatment was completed. Patients were divided into good response group (GR) and poor response group (PR). At the same time, samples before treatment were divided into GR group and PR group by sample tracing and matching, and metabolomics analysis was conducted. In the end, a total of 9 different metabolites were identified between patients in the early GR and PR groups. In order to find more effective biomarkers, two algorithms, random forest (RF) and support vector machine (SVM), were used for metabolite selection and performance evaluation, and three kinds of Lysophosphatidylcholine (LysoPC) metabolites showed good predictive effect, and the expression of the enzyme phospholipase A2 group IVA (PLA2G4A), associated with this metabolite was significantly elevated in the PR group. The disordered metabolism may reduce the sensitivity of patients to sacubitril/valsartan treatment, and PLA2G4A targeted inhibitors may be a promising therapeutic strategy to improve the sensitivity of patients with ESRD and HF to sacubitril/valsartan treatment.

30

News (Medical) associated with Sacubitril

24 Jan 2025

·pharma.economictimes.indiatimes.com

Novartis Entresto to face another generic challenge as FDA gives nod to Lupin's version

Mumbai: After a series of courtroom heats between Novartis and generics maker MSN, the Swiss giant blockbuster heart failure drug Entresto is set to face challenge from another generic version by Lupin as the Indian generics maker has secured approval for Sacubitril and Valsartan Tablets from the FDA. Making the announcement, Lupin said, it has received approval from the United States Food and Drug Administration (U.S.FDA) for its Abbreviated New Drug Application (ANDA), Sacubitril and Valsartan Tablets, which are the generic version of Entresto marketed by Novartis. The tablets are indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure and reduced ejection fraction and for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older. Entresto is one of the best-selling drugs of Novartis and in the last annual year till November the drug generated more than $6 billion in the US drug market , in 2023 it also generated $6,035 million ($6 billion). In 2022, Novartis filed a lawsuit in a Delaware federal court against MSN Pharmaceuticals and others, accusing them of infringing the combination patent by launching generic versions of Entresto. Novartis also sued the FDA, challenging the agency's "unlawful" approval of MSN generic heart failure drug. In August 2023, U.S. District Judge Richard Andrews rejected Novartis’ request for a preliminary injunction, ruling that the company was unlikely to succeed on its infringement claims. However, the judge temporarily halted MSN generic launch while Novartis appealed the decision to the Federal Circuit. As reported by a wire service, last week the Washington, D.C. federal judge refused Novartis' eleventh-hour bid to block drugmaker MSN Pharmaceuticals from launching a generic version of Novartis' blockbuster heart-failure drug Entresto. The decision by the U.S. District Judge Dabney Friedrich clears a hurdle for MSN to introduce the first U.S. generic version. By Online Bureau ,

Drug ApprovalPatent Infringement

24 Jan 2025

·pharma.economictimes.indiatimes.com

US Court upholds Novartis’ blockbuster drug Entresto patent

Basel: Swiss pharmaceutical giant Novartis has announced that the US Court of Appeals for the Federal Circuit (CAFC) has upheld the combination patent for its blockbuster heart failure drug, Entresto (sacubitril/valsartan). In 2022, Novartis filed a lawsuit in a Delaware federal court against MSN Pharmaceuticals and others, accusing them of infringing the combination patent by launching generic versions of Entresto. Novartis also sued the FDA last year, challenging the agency's "unlawful" approval of MSN’s generic heart failure drug. In August 2023, U.S. District Judge Richard Andrews rejected Novartis’ request for a preliminary injunction, ruling that the company was unlikely to succeed on its infringement claims. However, the judge temporarily halted MSN’s generic launch while Novartis appealed the decision to the Federal Circuit. The Federal Circuit has now reversed the Delaware court’s earlier judgment, upholding Novartis’ combination patent for Entresto. The combination patent for Entresto is set to expire in July 2025, while the individual patents for its components—sacubitril and valsartan—will remain valid until 2033 and 2036, respectively. Following the ruling, Novartis stated it would enforce the combination patent through its pediatric exclusivity period, which ends in July 2025. The company also reaffirmed its commitment to defending its intellectual property and regulatory rights related to Entresto. Entresto, a first-in-class Angiotensin Receptor Neprilysin Inhibitor (ARNI), reduces strain on the failing heart. The twice-daily tablet enhances the heart’s protective neurohormonal systems (NP system) while suppressing harmful ones. According to analytics firm GlobalData, Entresto generated $6.035 million in net sales in 2023 and $3.8 million in the first half of 2024, underscoring its significant impact on the cardiovascular drug market. By Online Bureau ,

Patent Infringement

24 Jan 2025

·www.pharmaceutical-technology.com

FDA approves drug application for Lupin’s heart failure therapy

The approval covers dosages of the medicine comprising 24 mg/26 mg, 49 mg/51 mg and 97 mg/103 mg. Credit: Shidlovski/Shutterstock. The US Food and Drug Administration (FDA) has approved the abbreviated new drug application (ANDA) of Lupin ’s Sacubitril and Valsartan tablets for heart failure patients. Sacubitril and Valsartan tablets are the generic equivalent of Novartis ‘ Entresto, used to reduce cardiovascular risks in adults with chronic heart failure and decreased ejection fraction. The approval covers dosages of 24 mg/26 mg, 49 mg/51 mg and 97 mg/103 mg. They are also used for treating symptomatic heart failure with systemic left ventricular systolic dysfunction in paediatric patients aged one year and older. The tablets are expected to tap into a market with annual US sales of $6.06bn. The company has also announced the receipt of tentative approval from the US regulator under the US President’s Emergency Plan for AIDS Relief (PEPFAR) for its Abacavir, Dolutegravir and Lamivudine tablets for oral suspension. This generic equivalent of ViiV Healthcare’s Triumeq PD tablets for oral suspension is set to be manufactured at the company’s Nagpur facility in India. The tablets are for distribution in low and middle-income nations. The Abacavir 60 mg/Dolutegravir 5 mg/Lamivudine 30 mg fixed-dose combo is intended for the treatment of human immunodeficiency virus (HIV)-1 infection in children aged three and above weighing at least 6kg, and is a once-a-day single-pill regimen. Lupin API Plus SBU head, global chief financial officer and executive director Ramesh Swaminathan stated: “We are committed to providing affordable and high-quality treatments for patients worldwide. The tentative approval from the US FDA for our Abacavir, Dolutegravir and Lamivudine tablets enables us to improve the well-being of paediatric patients with HIV-1, thereby significantly boosting our HIV medication portfolio.” In September 2024, the company entered a non-exclusive patent licence agreement with Takeda Pharmaceutical for the commercialisation of Vonoprazan tablets in India.

Drug ApprovalLicense out/in

100 Deals associated with Sacubitril

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External Link

KEGG	Wiki	ATC	Drug Bank
D10225	Sacubitril	C09DX04	DB09292

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Heart Failure	Phase 3	United States	Novartis Pharmaceuticals Corp.	02 May 2019
Heart Failure	Phase 3	Japan	Novartis Pharmaceuticals Corp.	02 May 2019
Heart Failure	Phase 3	Argentina	Novartis Pharmaceuticals Corp.	02 May 2019
Heart Failure	Phase 3	Austria	Novartis Pharmaceuticals Corp.	02 May 2019
Heart Failure	Phase 3	Bulgaria	Novartis Pharmaceuticals Corp.	02 May 2019
Heart Failure	Phase 3	Canada	Novartis Pharmaceuticals Corp.	02 May 2019
Heart Failure	Phase 3	Croatia	Novartis Pharmaceuticals Corp.	02 May 2019
Heart Failure	Phase 3	Czechia	Novartis Pharmaceuticals Corp.	02 May 2019
Heart Failure	Phase 3	Finland	Novartis Pharmaceuticals Corp.	02 May 2019
Heart Failure	Phase 3	France	Novartis Pharmaceuticals Corp.	02 May 2019

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Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03785405 (CTgov)	Phase 3	Heart Failure \| Left ventricular systolic dysfunction	216	valsartan+sacubitril (Age Group 1)	uxwxhnyfeo = ldbbbbzgre ngqsgoupue (xailvwqbeg, kwroqzdsms - qzomzdpmth) View more	-	16 Jul 2024
				valsartan+sacubitril (Age Group 2)	uxwxhnyfeo = uiuwdbqcud ngqsgoupue (xailvwqbeg, seeakuyplm - yafldacusj) View more
ESH2024	Phase 3	Essential Hypertension	1,197	Sacubitril/allisartan 240 mg	tsvgixqhlg(buqjtmjdyj) = tcvlvbckbn rddierlbvi (wwvcsiincj, -4.2 to 0.4)	Positive	01 May 2024
				Sacubitril/allisartan 480 mg	tsvgixqhlg(buqjtmjdyj) = prnmhxuhxr rddierlbvi (wwvcsiincj, -7.3 to -2.8)
NCT03917459 (CONFIDENCE-HF, CTgov)	Phase 3	Heart Failure, Systolic \| Erectile Dysfunction	27	LCZ696 matching placebo+LCZ696 (LCZ696)	kikapnvpuo(kfrsxahdek) = xpldakgptn nhkcehozzp (cmfeovsbju, 2.15) View more	-	08 Jan 2024
				Enalapril matching placebo+enalapril (Enalapril)	kikapnvpuo(kfrsxahdek) = yxfmoerzhu nhkcehozzp (cmfeovsbju, 2.00) View more
ESC2022	Not Applicable	-	25	Sacubitril	hpebdtbhly(jcutfrlxtm) = aatmygqddy yfginglouu (gjqhzqyoba )	-	29 Aug 2022
				Sotalol	wtiuhoqmar(osiqnutwvn) = mkigcwbcyc hvgsmiawdk (ehvwinbgxc ) View more
ESC2020	Not Applicable	Arrhythmias, Cardiac	-	Sacubitril	geavqnjseh(geztpywnaj) = kytevlnfuc jnumcydhhp (jlljkpvzqa ) View more	-	28 Aug 2020
NCT01281306 (RATIO, CTgov)	Phase 2	Hypertension	910	Valsartan+AHU377 (VAL + AHU 400 mg)	qxlgzdyzph(symnazlnkl) = ppuvkjbcsn neqovfyebs (wldxviszfu, 1.22) View more	-	18 Aug 2015
				Valsartan+AHU377 (VAL + AHU 200 mg)	qxlgzdyzph(symnazlnkl) = yhkzuartib neqovfyebs (wldxviszfu, 1.21) View more
NCT00549770 (CTgov)	Phase 2	Essential Hypertension	1,334	Placebo+LCZ696 (LCZ696 100 mg)	yyuwmgljdt(aaizahvjvi) = uviuipiett epvnqwqyhu (rulgfadpos, 0.73) View more	-	10 Aug 2015
				Placebo+LCZ696 (LCZ696 200 mg)	yyuwmgljdt(aaizahvjvi) = xvxgqpzawq epvnqwqyhu (rulgfadpos, 0.70) View more