Novartis' Heart Failure Blockbuster Entresto Misses Primary Endpoint in Phase III PARADISE-MI Trial

Compiled by Keke

Recently, Novartis quietly revealed in its Q1 2021 financial report that the Phase III clinical trial Paradise-MI showed that Entresto missed the primary endpoint of reducing the risk of cardiovascular death and heart failure after acute myocardial infarction.

In this study, the data trends of the trial results consistently favored the standard-of-care drug ramipril, and Entresto failed to meet its primary endpoint.

Novartis initiated the Paradise-MI clinical study in 2016 to evaluate whether Entresto could surpass the widely used ACE inhibitor ramipril in reducing cardiovascular mortality and heart failure among patients who had suffered a myocardial infarction. The study enrolled 5,669 participants and compared 200 mg doses of Entresto with 5 mg doses of ramipril. In addition to receiving standard post-myocardial infarction care, participants in both groups administered their respective medications twice daily.

Despite the unsatisfactory study results, Entresto’s first-quarter sales rose 39% to $789 million, helping Novartis offset the decline in sales caused by competition in its generics business.

The trial failure of Entresto occurred shortly after the drug achieved a major victory in its heart failure indication. In February, the U.S. FDA approved Entresto for the treatment of patients with heart failure with preserved ejection fraction (HFpEF) characterized by a left ventricular ejection fraction (LVEF) below normal values.

In addition to existing studies on Entresto for chronic heart failure and patients with reduced ejection fraction, this approval positions the drug as the first and only medication approved for both indications. Novartis stated that this new indication also paves the way for the company to target approximately 5 million of the 6 million Americans with chronic heart failure who are eligible for the drug.

Peter Welford, an analyst at the prominent Wall Street investment bank Jefferies, wrote in 2020, when an independent FDA panel supported the use of the drug in patients with HFpEF, that the peak sales forecast for Entresto had been raised by an additional $1 billion. Regarding the failed trial, Welford noted that the post-heart-attack patient market accounted for only $525 million of the projected $5.1 billion in global peak sales for Entresto. Reportedly, Entresto generated $2.5 billion in sales in 2020, making it Novartis’ third-largest revenue source that year.

Furthermore, Novartis’s Q1 2021 financial report showed a 2% decline in net sales to $12.411 billion, attributable to forward purchases related to COVID-19 in the prior year (approximately $400 million). Sales in the Pharmaceuticals division remained flat year-over-year at $10.1 billion, driven by continued strong growth of Entresto (+34% cc), Zolgensma (+81% cc), and Cosentyx (+11% cc); Kesimpta sales reached $50 million. Driven by Kymriah (+55% cc), Promacta/Revolade (+13% cc), Kisqali (+19% cc), and Jakavi (+8% cc), sales in the Oncology division increased by 1%, with Adakveo sales reaching $37 million. Sales in the Generics division, Sandoz, declined by 13% to $2.3 billion, with retail sales down 18% and biopharmaceutical sales up 7%. COVID-19 had a negative impact on sales, particularly in dermatology, ophthalmology, the breast cancer portfolio, Sandoz’s retail business, and anti-infectives.

Reference Source:

1. Novartis Financial Report

2.Amid impressive growth, Novartis' blockbuster Entresto falls short in post-heart attack trial