Heart Failure Pipeline Review: Amgen's Omecamtiv And Merck's Vericiguat Step Up To Plate

In addition to small molecules, stem cell therapies promise to help rejuvenate the chronic heart failure pipeline, but high prices and invasive procedures may limit their use to end-stage patients, and skepticism about efficacy persists.

Merck & Co. Inc./Bayer AG's soluble guanylate cyclase stimulator vericiguat and Amgen Inc.'s novel inotropic molecule omecamtiv mecarbil, both in Phase III, are each projected to bring in over $1bn in chronic heart failure drug sales in major markets in 2026, accounting for more than one-fifth of total revenue for that year, according to a new pipeline review from Datamonitor Healthcare.

The chronic heart failure (CHF) market is dominated by generics; angiotensin receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors are widely available.

Despite demonstrating an impressive cardiovascular (CV) outcomes benefit with very high statistical significance, Novartis AG's Entresto (valsartan/sacubitril) has had a tough time breaking into the market, but is starting to make headway, aided by strong guideline recommendations in the US and EU. (See sidebar.)

In its Jan. 24 fourth quarter and year-end earnings report, Novartis said that Entresto's performance improved for every quarter in 2017, with sales surpassing $500m, up 195%, for the year.

In the US, Japan and five major European markets (France, Germany, Italy, Spain and the UK), Datamonitor projects the CHF market will grow at a compound annual growth rate of 9.1% from 2017 to 2026 – taking sales from about $4.7bn to $10.1bn.

Drug development for chronic heart failure (CHF) has been more focused on patients who have reduced ejection fraction, and the market for patients with preserved ejection fraction represents a tough-to-target area of unmet medical need in the space. About half of chronic heart failure patients have reduced ejection fraction (see box).

Heart Failure Terminology

The ejection fraction is a measurement that shows how well the heart is pumping out blood and is used for diagnosing and monitoring heart failure.

Preserved ejection fraction (HFpEF): Also called diastolic heart failure. The heart muscle contracts normally but the ventricles do not relax as they should during ventricular filling. Prevalence: 3.3m US, 3.1m top five EU markets.

Reduced ejection fraction (HFrEF). Also called systolic heart failure. The heart muscle does not contract effectively and less oxygen-rich blood is pumped out to the body. Prevalence: 3.3m US, 3m top five EU markets.

Source: American Heart Association, Novartis

Growth of the chronic heart failure market will be fueled by Entresto's continued success, but also by a range of pipeline candidates including new molecules, greater use of marketed drugs in heart failure and emerging stem cell therapies.

"Traditional treatment pathways for CHF consist of combinations of highly genericized classes, and so pipeline therapies will either need to be priced competitively, or show remarkable efficacy in order to drive uptake by physicians and gain favorable formulary coverage from insurers," Datamonitor analyst Sita Indrakumar said in a Dec. 11 report reviewing the CHF pipeline.

Datamonitor projects that the two biggest new Phase III drugs lined up to refuel the CHF pipeline between 2017 and 2026 are Amgen's omecamtiv mecarbil and Merck/Bayer's vericiguat, both of which are small molecules and are set to bring in sales of $1.3bn and $1.1bn, respectively, in 2026 (see chart).

Indrakumar explained that the novel modes of action for both omecamtiv mecarbil and vericiguat compared with traditional CHF treatment will spur utilization of these drugs as add-on therapies and that high prices will mean significant revenues even if uptake is modest.

Omecamtiv, which is partnered with Cytokinetics Inc., has clear benefits over inotropic agents such as Aspen Global Inc./Covis Pharmaceuticals Inc.'s genericized Lanoxin (digoxin) and may find a role as an add-on treatment in CHF. (Also see "Amgen, Cytokinetics Checked With Payers Before Taking Omecamtiv Into Phase III" - Scrip, 2 Sep, 2016.) Digoxin used to be a mainstay of CHF treatment but became associated with serious safety issues – notably increased mortality in patients who had had a recent heart attack – so use has been restricted.

"Omecamtiv mecarbil’s ability to increase cardiac contractility without impacting intracellular calcium places it at a clear advantage to other inotropic agents, as changes in intracellular calcium are associated with safety issues with current inotropic agents. The benefit of omecamtiv mecarbil increasing cardiac output could provide an attractive edge over current CHF treatment, which focuses on reducing the strain on the failing heart as opposed to actively improving cardiac function," the Datamonitor report explains.

Usage of omecamtiv mecarbil will be highest in the US, which is expected to account for 98% of sales, Datamonitor analysts predict.

Meanwhile, Datamonitor expects that Merck/Bayer's soluble guanylate cyclase stimulator vericiguat will be approved initially for HFrEF but will also be used in HFpEF.

Vericiguat did not demonstrate significant improvements in Phase II studies – SOCRATES-PRESERVED or SOCRATES-REDUCED – but this could have been due to incorrect dosing, that is, higher levels might have worked better.

The Phase III VICTORIA cardiovascular outcomes study is testing vericiguat in HFrEF; the primary completion date is January 2020.

"Although there has been no announcement with regards to any further plans to move to Phase III with HFpEF, it is likely that a label expansion will be pursued at a later date. Given the prescribing trends currently seen in HFpEF, it is probable that this drug will experience some off-label use in this patient population even if it is only approved for HFrEF," Indrakumar said.

Projected Sales For Phase III Drugs In CHF: US, Japan & Five Major EU Markets
Sponsor & Drug	Description	First year projected sales or 2018 sales (for drugs already used in CHF)	2026 projected sales
Amgen/Cytokinetics's omecamtiv mecarbil	Small molecule directly stimulates activation of the myosin ATPase enzyme, resulting in increased cardiac contractility without increasing stimulation of beta-adrenergic receptors or inhibiting phosphodiesterase activity, which may cause adverse events	$25.4m, 2022	$1.3bn
Merck/Bayer's vericiguat (BAY-1021189)	Small molecule, soluble guanylate cyclase (sGC) stimulator increases levels of cyclic guanosine monophosphate (cGMP) via the nitric oxide-sGCcGMP pathway	$16m, 2021	$1.1bn
Mesoblast's MPC-150-IM (rexlemestrocel-L)	Intravenous allogeneic stem cell product based on adult-derived mesenchymal precursor cells (MPCs)	$2.3m, 2019	$753m
Boehringer Ingelheim/Lilly's Jardiance (empagliflozin)	Small molecule sodium-glucose cotransporter-2 (SGLT-2) inhibitor, eliminates excess sugar in the urine in diabetes patients, mechanism in heart failure still being studied	$74.4m, 2018	$596m
J&J/Bayer's Xarelto (rivaroxaban)	Small molecule inhibits free Factor Xa and prothrombinase activity	$459.9m, 2018	$550m
AstraZeneca/Bristol-Myers Squibb's Farxiga (dapagliflozin)	Small molecule, SGLT-2 inhibitor	$11.5m, 2018	$408.6m
Celyad/Medisun Holdings' C-Cure	Personalized, bone marrow-derived I.V. stem cell therapy aimed at regenerating cardiac tissue following severe damage due to heart attacks	$0.4m, 2022	$244.7m
Source: Datamonitor Healthcare, Biomedtracker

New Uses For Marketed Drugs

Marketed drugs are also expected to come into greater use with new indications for chronic heart failure.

Datamonitor expects Johnson & Johnson/Bayer AG's novel oral Factor Xa anticoagulant Xarelto (rivaroxaban), for example, will add a CHF indication in 2020.

"The drug already experiences significant off-label use in this indication, and Xarelto’s expected label expansion in CHF in 2020 will allow it to compete more strongly with warfarin for share of the CHF market. Xarelto will reach peak sales of $833m in 2024, before the arrival of generics results in rapid erosion," the report states.

Xarelto is being tested in a large outcomes study called COMMANDER HF in heart failure patients with significant coronary disease, and Datamonitor analysts note positive results would enhance uptake.

Warfarin is currently used in heart failure patients who have atrial fibrillation (irregular heart rate), but not in patients without atrial fibrillation. The COMMANDER HF study examines Xarelto in patients without atrial fibrillation and, if positive, will show the value of anticoagulants in this population. Consequently, some key opinion leaders expect the trial could have a big impact on clinical practice. The primary completion date is May 2018.

Members of the class of sodium-glucose cotransporter-2 (SGLT-2) inhibitors are also poised to play a greater role in the treatment of heart failure patients. The class is approved for diabetes and results from outcomes trials have shown benefits in subsets with heart failure.

In 2016, Boehringer Ingelheim GMBH/Eli Lilly & Co.'s Jardiance (empagliflozin) became the first SGLT-2 inhibitor to get a US FDA labeling claim for cardiovascular mortality risk reduction in patients with type 2 diabetes, based on results from the EMPA-REG study. In that trial, the drug demonstrated a 14% reduction in a composite of major adverse cardiovascular events, the primary endpoint. Furthermore, there was a 38% reduced risk of CV death and a 32% reduced risk of all-cause mortality. (Also see "Boehringer/Lilly's Jardiance Wows With CVOT Data" - Scrip, 18 Sep, 2015.) The benefit in heart failure patients was an important contributing factor to the results, as the hazard ratio for reduction in risk of hospitalization was 0.65, whereas a significant improvement for stroke and heart attack individually was not reported.

In 2017, Johnson & Johnson reported that its SGLT-2 inhibitor Invokana (canagliflozin) demonstrated a significant 14% reduction in major cardiovascular events in the CANVAS outcomes program, including a rate of heart failure hospitalizations that was 33% lower for the test drug arm, though there was no significant improvement in mortality and a risk for amputation surfaced. (Also see "CANVAS Trial Results: Better For Janssen, Lilly Or the SGLT2 Class?" - Scrip, 13 Jun, 2017.)

A 2017 analysis ofAstraZeneca PLC's retrospective, observational CVD-REAL study showed that rates of heart failure and death were halved in type 2 diabetes patients taking three marketed SGLT-2 inhibitors – Boehringer's Jardiance, AstraZeneca's Farxiga (dapagliflozin) and J&J's Invokanacompared with other diabetes therapies. (Also see "Entresto Facing Pressure From Diabetes Drugs" - Scrip, 15 May, 2017.) Results were not broken down for individual SGLT-2 inhibitors.

"Jardiance is being tested in two large-scale trials targeting both preserved and reduced ejection fraction, whereas Farxiga is only being tested in patients with reduced EF. This may have been a strategy by AstraZeneca to capitalize on the class-effect hypothesis by utilizing any positive data in HFpEF from Jardiance. However, physicians may be reluctant to prescribe Farxiga to patients with HFpEF without clinical data in this specific patient population," Datamonitor's Indrakumar said.

Data reported out so far have impressed the cardiology community. For example, the European Society of Cardiology meeting in August 2017 featured numerous sessions about changes in the paradigm of heart failure treatment and the SGLT-2 inhibitors had a high profile. In one session on the SGLT-2 inhibitors' potential to change the heart failure landscape, the University of Glasgow's John McMurray noted that there has been an "explosion" in the volume of published research for the class in recent years.

In the EMPA-REG study of Jardiance, the reduction in heart failure events appears to have driven the reduction in cardiovascular mortality, said McMurray, deputy director of the Institute of Cardiovascular and Medical Sciences.

The treatment effect for heart failure looked too good to be true, but it was repeated in the CANVAS study of canagliflozin, which showed an almost identical reduction in risk for heart failure hospitalization, he said.

The mechanism for the "remarkable benefit" is unclear, McMurray said. Patients had not been diagnosed at baseline and it's unclear if they had HFrEF or HFpEF. The benefit for preventing heart failure events was rapid and dramatic, whereas the traditional glucose-related metabolic effect takes decades to affect atherothrombosis, the clinician said.

"We just don't have the answers yet" about the connections in heart failure and diabetes, McMurray said. "There are probably hundreds of groups of researchers around the world all scrambling to try and better understand what is going on in the heart of patients with both of these conditions," the clinician added.

The DECLARE-TIMI 58 CV outcomes study of AstraZeneca's Farxiga in type 2 diabetes is due to report in 2019 and may help shed some light on some of the lingering questions, as this study was done later than the others and may have more data collection on heart failure.

One big question going forward is whether SGLT-2 inhibitors can prevent heart failure, in addition to preventing incidents of heart failure. Another question is whether SGLT-2 inhibitors could be used broadly in heart failure, or whether they will just play a role in those with diabetes.

Trials are under way of Jardiance and Farxiga that include heart failure patients without diabetes. Data from the pivotal PARADIGM-HF study of Novartis' Entresto suggests that diabetes is very common in heart failure patients – 36% have it, but another 13% have undiagnosed diabetes and 25% have prediabetes, McMurray noted.

"The SGLT-2 inhibitors will have to provide data illustrating significant benefits over standard-of-care CHF treatment before these drugs are utilized outside of the diabetes subpopulation. The proposed mode of action of the SGLT-2 inhibitors and the availability of low-cost generic ACE inhibitors, beta blockers, and diuretics may significantly limit uptake in the wider CHF population," Datamonitor's Indrakumar concluded.

Novartis is testing an inhibitor of SGLT-1 and SGLT-2 called LIK066 against empagliflozin in a large Phase II study (n=496) for patients with diabetes and heart failure. During its fourth-quarter earnings call, Novartis execs said that the study was one of the fastest enrolling trials they could recall; recruitment is complete and the results should be out in 2018.

Stem Cell Therapies Face Test

Stem cell therapies are another source of reinvigoration for the CHF pipeline. Celyad SA has developed C-Cure, which is designed to regenerate cardiac tissue following damage caused by heart attacks. Therapy involves taking patients' own cells from bone marrow, treating them with Celyad's proprietary cell culture to develop autologous heat muscle cells. The treated cells are then re-injected into scar tissue in the heart.

In the CHART-1 study, C-Cure failed the primary endpoint but showed benefits in a subgroup with baseline left ventricular end-diastolic volumes between 200 mL and 370 mL, Datamonitor analysts noted. Consequently, FDA granted the drug fast track designation for the subgroup of patients who benefited from treatment. The company has not secured a strategic partner yet, so a Phase III study in the US is on hold.

"C-Cure will need to demonstrate strong long-term safety and efficacy results in order to gain regulatory approval for the treatment of advanced stage chronic heart failure and compete effectively against its rival late-stage stem cell treatments. Celyad’s competitors have substantially larger resources, and given the large cost and unreliability of the manufacturing process (a viable product is only produced for 70% of patients), it is unlikely C-Cure will be commercialized unless another commercial partnership is made," Datamonitor analysts said in a market forecast report accompanying the CHF pipeline review.

C-Cure is expected to launch in 2022.

That means competitor Mesoblast Ltd. will have a three-year timing edge for its MPC-150 IM (rexlemestrocel-L) stem cell therapy, built upon the company's proprietary mesenchymal precursor cell platform, with an expected launch date of 2019. The Phase III therapy involves extraction of cells from the bone marrow of donors, which are then expanded into therapeutic quantities. So unlike C-Cure, there is potential for an off-the-shelf therapeutic. The company lost its partner Teva Pharmaceutical Industries Ltd. in 2016 but it is still working with Lonza Group Ltd. as a manufacturing partner, per a 2011 deal. (Also see "Mesoblast Seeks New Partner In Chronic Heart Failure, To Replace Teva" - Scrip, 14 Jun, 2016.)

"While other stem cell therapies also display regeneration potential, Mesoblast’s strategic partnership for manufacturing with Lonza provides a clear commercial edge, given the cost and difficulties associated with the manufacturing of stem cells," the Datamonitor report states.

Many unrelated recipients could be treated and unlike other types of stem cells, mesynchymal precursor cells do not initiate an immune response, it notes. Furthermore, a Phase III study has passed its interim futility analysis, which "will place greater confidence in the efficacy of the treatment," the report says.

While stem therapies show promise in end-stage disease due to regenerative potential, high prices and invasiveness of the procedures involved will limit use in the wider CHF population. Treatment options at the end stage of disease are currently very limited, she added.

There is also a lot of skepticism about the efficacy of stem cell therapies in the community, as trials to date have not consistently shown a benefit, so positive results in Phase III studies will need to confirm their value and safety. Physicians will be looking for studies showing efficacy on mortality and hospitalization rates.

Despite the challenges, stem cell therapies are expected to add "sizable revenue to the CHF market even at modest uptake, contributing a forecasted $997m in 2026," the Datamonitor report concluded.