The failure of Novartis AG's Entresto in a phase III clinical trial staggered the stock (NASDAQ:NVS) somewhat Monday, down just 1.14%, but the real trauma may well be the loss of roughly $2.5 billion in anticipated sales.
While Novartis didn't release specific numbers, the pharma giant said the Paragon-HF clinical trial "narrowly" missed its composite primary end point in reducing cardiovascular death and total heart failure hospitalizations in patients with preserved ejection fraction. The study was an investigation into the safety and efficacy of sacubitril/valsartan, a combination ACE/neprilysin inhibitor, vs. the active comparator valsartan in patients with heart failure with preserved ejection fraction (HFpEF).
There currently is no approved treatment for these patients.
In January 2018, Novartis CEO Paul Hudson predicted wider use of Entresto had potential to rake in $4 billion to $5 billion a year. It's not his problem anymore though; Hudson is leaving Novartis to become CEO at Sanofi SA on Sept. 1.
Analysts at Jefferies viewed the phase III failure as a mere stumble and took a long view. The company shares can further appreciate, they noted, especially should optimistic sales figures for Novartis' Cosentyx and possible boosts from two debuts hold true.
"We still view Novartis as a quality EU Pharma growth story, with potentially exciting Mayzent and Zolgensma launches, plus ongoing Cosentyx momentum together driving consensus EPS upgrades," they wrote Monday.
Mayzent (siponimod) recently was given the nod for adults with relapsing forms of multiple sclerosis that include secondary progressive multiple sclerosis (SPMS) – where it's the first and only therapy – as well as relapsing remitting disease. Basel, Switzerland-based Novartis won Mayzent's approval based on the phase III trial called Expand, the largest-ever controlled clinical experiment of SPMS patients, which proved that the treatment significantly reduced the risk of disease progression, including impact on physical disability and cognitive decline. Jefferies analysts predict a $1.25 billion worldwide peak in Mayzent sales. (See BioWorld, March 28, 2019)
Even more recent is Novartis' Zolgensma (onasemnogene neparvovec), which received FDA approval for its Avexis Inc. unit. Zolgensma is a new gene therapy designed to treat all types of spinal muscular atrophy (SMA) in children under 2 with biallelic mutations in the survival motor neuron 1 gene. Jefferies weighed in again by predicting a rapid adoption of the treatment of infants with the most common and severe variant of the disease, type 1, and as much as $2.6 billion in peak worldwide sales. After Biogen Inc.'s Spinraza (nusinersen), Zolgensma becomes the second FDA-approved therapy for SMA in an active corner of rare disease drug development. (See BioWorld, May 28, 2019)
The way is cleared now for Boehringer Ingelheim GmbH and Eli Lilly and Co.'s empagliflozin for the reduction of the risk of cardiovascular death and hospitalization for heart failure in people with chronic heart failure. Empagliflozin, marketed as Jardiance in the U.S., is a once-daily tablet used along with diet and exercise to lower blood sugar in adults with type 2 diabetes and to reduce the risk of cardiovascular death in adults with type 2 diabetes and known cardiovascular disease. The FDA fast tracked empagliflozin for the ongoing Emperor clinical trial, which will evaluate the effect of empagliflozin on cardiovascular death and hospitalization for heart failure in adults with chronic heart failure with reduced or preserved ejection fraction, respectively. The study is set to conclude next year.
Novartis still holds out hope for the heart of the Paragon-HF study. The company was heartened to see that safety and tolerability were consistent with previously reported sacubitril/valsartan data.
"The totality of evidence from the trial suggests that treatment with sacubitril/valsartan may result in clinically important benefits in HFpEF. We will be discussing potential next steps with clinical experts and regulators while we prepare to present the full results at the ESC Congress 2019 in September," said John Tsai, Novartis' global drug development and chief medical officer.
HFpEF is a distinct type of heart failure where the heart muscle contracts normally but the ventricles do not relax as they should during ventricular filling or when the ventricles relax. An estimated 13 million people, half of all heart failure patients, globally suffer from it.
The FDA approved Entresto a little over five years ago. The nod came less than five months after the agency granted priority review and ahead of its anticipated PDUFA date. Entresto, formerly known as LCZ-696, demonstrated an ability to reduce the rate of cardiovascular death and hospitalization related to heart failure in pivotal trials. (See BioWorld, July 9, 2015.)