Novartis’ Entresto Produces Mixed Results in Two Clinical Trials

Novartis reported results from two clinical trials evaluating improvements in heart structure and function, as well as long-term safety for Entresto (sacubitril/valsartan). The drug was being evaluated in patients with heart failure with reduced ejection fraction (HFrEF). Both trials were presented at the ESC Congress 2019 held in Paris. The company also presented data from a third trial of Entresto, compared to valsartan.

The trials were the PROVE-HF and EVALUATE-HF trials. PROVE-HF was a Phase IV, 52-week, single-arm, open-label trial. This trial showed that patients receiving Entresto had significantly improved levels of an important biomarker, N-terminal pro-B-type natriuretic peptide (NT-proBNP). The study showed an association between improvement in this biomarker and positive changes related to reversal of cardiac remodeling at six months and one year.

The safety and tolerability data of the trial was consistent with the pivotal PARADIGM-HF trial except more patients reported dizziness in the PROVE-HF trial.

EVALUATE-HF is a Phase IV, multicenter, randomized, double-blind, active-controlled trial to evaluate Entresto’s effect on remodeling of the blood vessels of the heart and ventricular-vascular coupling. Ventricular-vascular coupling is a way of determining the mechanical efficiency of the heart. Cardiac remodeling, or sometimes ventricular remodeling, refers to changes in the size, shape, structure and function of the heart.

This study compared Entresto to enalapril.

The EVALUATE-HF trial, however, showed that neither Entresto nor enalapril improved the primary endpoint, change in aortic impedance, which is a way of measuring vascular stiffness. The company notes that because the trial was relatively short, and the patient population may already have experienced some improved aortic impedance, that this may have affected the outcomes. But the findings were consistent with those seen in PROVE-HF and safety was comparable to the PARADIGM-HF trial.

Entresto is approved for patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction to reduce the risk of cardiovascular death and heart failure-related hospitalization.

“The PROVE-HF and EVALUATE-HF studies provide the first evidence that Entresto may help reverse the damage to the heart caused by HFrEF, which could lead to improved clinical outcomes,” stated Marcia Kayath, global head Medical Affairs and chief medical officer, Novartis Pharmaceuticals. “As part of our commitment to reimagining heart failure treatment, we conducted these studies to more deeply understand Entresto’s impact on heart structure and function in HFrEF patients. For the first time, an association was shown between a biomarker and cardiac remodeling improvement in patients treated with Entresto.”

Novartis has projected Entresto’s peak sales at $5 billion annually. However, while also releasing data from PROVE-HF and EVALUATE-HF, the company also presented data from its Phase III PARAGON-HF trial, which evaluated Entresto compared to active comparator valsartan in heart failure with HFpEF. The drug decreased the composite primary endpoint of total heart failure hospitalizations and cardiovascular death by 13%, which the company is calling a “near miss” for statistical significance.

“While the reduction in the primary endpoint was not statistically significant, the totality of evidence from PARAGON-HF suggests potential overall benefit of sacubitril/valsartan compared with valsartan in HFpEF, particularly in patients with ejection fraction below normal,” said Scott Solomon, director of Noninvasive Cardiology at Brigham and Women’s Hospital, professor, Harvard Medical School, and PARAGON-HF executive committee co-chair. “It also highlights the complexity of HFpEF and may suggest that some treatments have a more pronounced impact in certain patient groups, including women, who are more likely to suffer from this condition than men.”