Bayer AG and Merck & Co. Inc. took Wall Street by surprise in November with their phase III success testing vericiguat in heart failure (HF), such that the guanylate cyclase stimulator’s odds not only have improved significantly but also in a different way than imagined before.
Leverkusen, Germany-based Bayer and Merck, of Kenilworth, N.J., tested vericiguat in a study called Victoria, and the once-daily drug met its primary efficacy endpoint in patients suffering from worsening chronic HF with reduced ejection fraction (HFrEF). Enrolled were 5,050 HFrEF patients who had a decompensation event/heart failure hospitalization or who were taking an intravenous diuretic for HF. As a bonus, the trial had enrolled patients more briskly than expected and the efficacy/safety interim analyses were put off, so the favorable readout came early.
Vericiguat had failed to meet its primary biomarker endpoint in a phase II trial, so expectations for the phase III effort were low. And the companies seemed to further stack the deck against themselves by designing Victoria in such a way that patients could sign up even if they were taking background standard-of-care therapy, including Entresto (sacubitril/valsartan, Novartis AG).
But it worked. That transformed the vericiguat scenario from one of would-be competition with Entresto to a possible combination setup with the approved drug. How feasible the combo setup could be will depend on the size of the subgroup of Victoria patients on Entresto, and Wall Street won’t find that out until later this year. Trial details are due at a scientific meeting, and observers will be particularly keen on finding out – along with the subgroup’s magnitude – the number of hospitalizations in the trial, as a way of further figuring out how the drug might ultimately fit into the treatment paradigm.
Quality of life (QoL) measures, also part of Victoria, will be important as well. Results are coming soon from Bayer/Merck from the phase II Vitality trial in HF with preserved ejection fraction (HFpEF), which uses patient-reported QoL as the primary endpoint, and a positive outcome from Vitality could have an effect on how doctors approach HFpEF, given that Entresto didn’t show benefit in that segment.
In HFpEF, also called diastolic HF, the heart muscle contracts normally but the ventricles do not relax as they should during ventricular filling (when the ventricles relax). In HFrEF, or systolic HF, the heart does not contract effectively, so that less oxygen-rich blood is pumped out to the body. In the U.S., HF affects 6.5 million patients, and 40% to 50% fall into the HFrEF category. About 30% of people with symptomatic chronic HF experience worsening of the disease annually, with 50% rehospitalized within 30 days of the worsening event, and an estimated one in five patients dead within two years.
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Other HF players could benefit from the attention gained by Bayer and Merck, including South San Francisco-based Cytokinetics Inc., which has cardiac myosin activator omecamtiv mecarbil in a phase III trial. In November, with partner Amgen Inc., of Thousand Oaks, Calif., and Les Laboratoires Servier SAS, of Suresnes, France, Cytokinetics offered a comprehensive post-hoc analysis of the phase II Cosmic-HF trial that showed, not for the first time, the upside of omecamtiv in HFrEF patients. The findings bolstered confirmed previous results that proved omecamtiv beneficial in improving left ventricular systolic function and size by improving cardiac contractility. The results significantly reduced any potential concerns over omecamtiv’s possible negative impact on diastolic function, which made sense given the mechanism of action. Because the compound tampers with the cardiac cycle and ups systolic ejection time, it might – some feared – hurt diastolic filling and lead to side effects. But diastolic function in Cosmic-HF came out no different from placebo.
Up next is the second interim peek at phase III data from the GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) experiment, due in the first quarter of this year. Underway by partner Amgen, the study enrolled patients in 35 countries: about 40% in the U.S. and Canada, Western Europe, South Africa and Australasia; 33% in Eastern Europe and Russia; 19% in Latin America and 8% in Asia. About 25% of patients in GALACTIC-HF were hospitalized at the time of randomization, and enrollment completed last summer.
Wainwright analyst Joseph Pantginis said in a Jan. 17 report that “visibility around the drug and the study should increase significantly as investors should progressively see and value the clinical endgame.” He conceded that no data were disclosed in the first interim look, though an analysis was performed that supported the continuation of the trial. “We highlight that an unprecedented number of patients have been treated with the drug, and some of them for a long period of time (over two years) adding further confidence” in the program. Piper Sandler analyst Edward Tenthoff said in a Jan. 21 dispatch to investors that he “believe[s] positive data would propel Cytokinetics’ shares, as omecamtiv mecarbil represents a novel mechanism with blockbuster sales potential in HF patients with reduced ejection fraction.”
The second phase III trial with omecamtiv, METEORIC-HF (Multicenter Exercise Tolerance Evaluation of Omecamtiv Mecarbil Related to Increased Contractility in Heart Failure), is testing the candidate in improving exercise capacity in patients with HF, is expected to complete enrollment in 2020 with data readouts in 2021, maybe setting the stage for a label expansion.
As well-characterized as HF is, along with cardiovascular difficulties generally, discoveries continue to roll out. Not all are not encouraging. HF has been found to be independently associated with end-stage renal disease, according to a publication recently in the Journal of the American Society of Nephrology. A study by researchers at the University of Bergen in Belgium, published in Nature Medicine, found that about 50% of women with HF are given inappropriate treatment because, unlike men, their disease doesn’t mainly manifest as a heart attack.