At this year’s European Society of Cardiology Congress (ESC) in Paris, Novartis announced the results of two trials, PROVE-HF and EVALUATE-HF, assessing the benefit and long-term safety profile of Entresto (sacubitril/valsartan).

The company also gave insight into the unsuccessful results of the PARAGON-HF trial for heart failure with preserved ejection fraction (HF-PEF).

Evidence of Entresto’s benefit and long-term safety has been previously called into question by health care practitioners, so these results are paramount to the drug’s further uptake and success.

The trial results from the failed PARAGON-HF also give a clearer picture of Entresto’s future in HF-PEF patients, who desperately need new and specific treatment options for their condition. The PROVE-HF trial was a Phase IV trial demonstrating the improvement of HF biomarker N-terminal pro hormone BNP (NT-proBNP) levels in patients taking Entresto.

In PROVE-HF, Entresto was shown to reduce levels of NT-proBNP and eventually led to positive cardiac remodelling. EVALUATE-HF was a Phase IV trial investigating the effect of Entresto compared to enalapril on blood vessel remodelling and ventricular vascular coupling. The results of EVALUATE-HF showed that neither Entresto nor enalapril met the primary endpoint. However, Entresto showed positive results on the structure and function of the left ventricle, which means it could hold a benefit in reversing cardiac injury caused by HF with reduced ejection fraction (HF-REF). Safety results were comparable to those seen in all of the previous trials of Entresto.

The overall results from the PARAGON-HF trial were released in August when it was revealed that Entresto had narrowly missed statistical significance in its reduced cardiovascular death and hospitalisation endpoints.

However, the results shared at ESC 2019 showed that the drug decreased the risk of cardiovascular death by 13%. Novartis now hopes to proceed down the regulatory path with Entresto in HF-PEF, as the trial demonstrated Entresto’s favourable benefit compared to valsartan, and also highlighted that Entresto may show best results in specific patient cohorts such as women, the gender most likely to suffer from HF-PEF.

Furthermore, patients who have HF with mid-range ejection fraction (HF-mrEF) were also seen to benefit from Entresto. If trials continue in this patient subset, Novartis may have another opportunity to gain sole market share.

Both HF-PEF and HF-mrEF are huge areas of unmet need, and regulators may be more lenient when approving drugs that show overall benefit in these areas. As such, Novartis is keen to push forward with Entresto before competitors such as Astra Zeneca’s Farxiga (dapagliflozin) become major players in the HF market.

However, GlobalData has previously noted Entresto’s slow uptake in HF-REF. Although Entresto could become the only treatment option approved in the HF-PEF market, it still faces the same issues it encountered in the HF-REF market, such as its inevitably high price, lack of success on primary endpoints, and lack of evidence of use in practice, which could deter prescribers.

Forthcoming Report
GlobalData (2019) Heart Failure – Global Drug Forecast and Market Analysis to 2028, to be published.