Heart failure therapy embarks on a new era

A host of ACE inhibitors, calcium antagonists, angiotensin receptor blockers, beta blockers and diuretics have been central to HF therapy for more than 20 years and - along with improved medical devices and surgical procedures - have been instrumental in extending survival.

HF remains an ultimately fatal condition however, with only half of patients alive five years after diagnosis. Furthermore, the disease affects millions of people around the world - it is estimated that 1-2% of all adults in industrialised countries are affected by HF at the moment - and the incidence is predicted to rise sharply by 2030.

There is no doubt that one of the most significant events to occur in HF therapy in recent memory was the launch early in 2015 of Novartis' Entresto - a drug that combines the long-established ARB valsartan with sacubitril - a first-in-class neprilysin inhibitor.

In the pivotal PARADIGM-HF trial, Entresto was shown to reduce cardiovascular death by 20% compared to standard ACE inhibitor treatment with enalapril, while cutting sudden death by 19%, death from any cause by 16% and hospitalisation by 23%.

HF treatment is likely to be transformed by Entresto thanks to the strength of its outcomes data, with analysts predicting it will eat into the prescribing of ACE inhibitors as a first-line therapy.

While Entresto has captured the headlines of late, there was another key development in HF therapy this year after Amgen secured approval in the US for Corlaner (ivabradine), a drug that has been sold for HF in Europe as Procoralan/Corlenter by originator Servier since 2012.

Ivabradine is thought to be the first drug to work by decreasing the heart rate as a consequence of its action on the If channel that controls the intrinsic pacemaker in the heart, and its proposed benefits have been backed up in clinical trials.

In the 6,500-patient SHIFT trial, for example, the drug  showed a significant reduction in the risk of the primary composite endpoint of hospitalization or cardiovascular death for worsening heart failure by 18% compared to placebo when given on top of standard HF therapy.

Both drugs will face some challenges penetrating a market populated largely by generic drugs, although Entresto received a big boost in September after the US Institute for Clinical and Economic Review (ICER) concluded its price - around $4,650 a year before discounts - is in line with the benefits it brings to patients.

Amgen chief executive Bob Bradway said earlier this year that he anticipates it will take some time to encourage cardiologists to try ivabradine in their HF patients, and that education was needed to drive home the message that a lowered heart rate is a valid therapeutic target. The treatment concept is already proving a little challenging for physicians in Europe, resulting in slow uptake.

With up to a million patients in the US eligible for treatment, he is however predicting solid sales growth for the product. Corlaner costs around the same as Entresto at around $4,500 per year.

HF affects millions of people around the world and the incidence is predicted to rise sharply by 2030

The advent of new pharmacological therapies is important, particularly because despite having robust guidelines, management of HF is 'patchy' even in developed healthcare markets like the UK, according to Satnam Singh, a cardiology registrar based in Edinburgh Heart Centre who carries out research in collaboration with the British Heart Foundation (BHF).

In particular, access to devices such as automatic implantable cardioverter/defibrillators (AICD) and left ventricular assist devices (LVADs) is variable, with better access in tertiary centres.

Meanwhile it is well established that HF nurses provide a very valuable resource to these patients – particularly in the first few months after diagnosis. Specialist nurse access “reduces re-hospitalisations and helps in controlling symptom burden,” said Singh, but access across the UK differs, possibly as a result of cost factors.

Decision Resources recently predicted that growth in sales of CHF treatments in seven countries - the US, UK, France, Germany, Italy, Spain and Japan - will increase the overall value of the market from $2.9bn in 2013 to $8.9bn in 2023. Entresto and Corlaner are expected to account for the bulk of that increase, with Entresto taking the lion's share.

HF with preserved ejection fraction still a challenge
It is also important to understand that there are different types of HF, and the picture remains pretty bleak in some cases. While new therapies have helped patients with HF and reduced ejection fraction (HFrEF), a measure of how well the blood is pumping – patients with preserved ejection fraction (HFpEF) have fared less well.

That is a big problem, as HFpEF accounts for approximately half of the overall HF burden, leaving millions of patients without effective treatment and a dismal prognosis, and is growing more quickly than HFrEF.

 “HFpEF has been neglected up until recently [and] all recent trials to manage this entity have been negative to date,” said Singh. Giving just a few examples, there have been disappointing studies involving drugs such as PDE-5 inhibitor sildenafil, ACE inhibitor perindopril and aldosterone antagonist eplerenone in this setting.

“Despite all advances in understanding the basic pathophysiology, we have failed to find a single treatment option for patients suffering from HFpEF,” he noted. “As its prevalence is rising, more clinicians are focusing on its pathophysiology in the hope of finding treatment options.”

To that end, there are some glimmers of hope for HF patients with a normal ejection fraction. Entresto is in a large-scale trial called PARAGON which aims to enrol 4,300 HFpEF patients and - if successful - could lead to regulatory filings in 2019. Ivabradine is also in a mid-stage trial being conducted by Servier in Europe - called EDIFY and involving around 500 patients with HFpEF - which should generate data in the coming months.

There are also a number of other drugs coming through the research pipelines

Pipeline growing
While Entresto and ivabradine promise to make a significant impact in HF, there are also a number of other investigational drugs coming through the research pipelines that target novel pathways to improve the prognosis of advanced HF patients.

In collaboration with Cytokinetics, Amgen is developing omecamtiv mecarbil, an activator of cardiac myosin that is designed to increase the duration of cardiac muscle contractility and improve cardiac muscle performance. Despite an early setback, the drug has cleared two phase II trials and is scheduled to start a phase III outcomes trial in 2016.

Bayer recently started three late-stage trials of its HF candidate finerenone - a mineralocorticoid drug designed as a safer replacement for older drugs in the class such as eplerenone and spironolactone, and is also developing a soluble guanylate cyclase stimulator called vericiguat in collaboration with Merck & Co.

Other candidates in mid-stage testing include: natriuretic peptide receptor agonists from Capricor Therapeutics (cenderitide) and Palatin Technologies (PL-3994); Novartis' synthetic human relaxin 2 hormone serelaxin (knocked back by regulators in the EU and US last year but still in development); Allergan/Trevena's AT1 receptor antagonist TRV207l and off-patent compound perhexiline, thought to improve the efficiency of heart muscle metabolism.

Meanwhile, further evidence for an uptick in pharma industry interest in HF is witnessed by recent licensing/acquisition deals. These include Bristol-Myers Squibb's $2bn deal to buy Cardioxyl - claiming ownership of intravenous nitroxyl donor CXL-1427 and oral follow-up CXL-1036 - and AstraZeneca's $2.7bn acquisition of ZS Pharma and ZS-9, a drug being developed to treat elevated potassium levels in HF patients.

Ultimately, the hope is that therapies can be found that, aside from relieving the pressure on the heart, can actually stop or reverse disease progression - and gene and stem cell therapies currently seem to hold the most promise in this regard.

Among these, Juventas Therapeutics' non-viral gene therapy JVS-100 - which expresses stromal cell-derived factor-1 (SDF-1) and activates the body's own tissue repair pathways - has been fast-tracked by the US FDA and is about to start phase IIb testing.

There was disappointment earlier this year however when Celladon's Mydicar gene therapy - which consists of an adeno-associated virus carrying the gene for an enzyme (SERCA 2a) that is deficient in HF - failed to show any benefit in the phase II CUPID 2 trial.

Stem cell therapy for HF is currently being led by the likes of Bioheart (recently renamed US Stem Cell), which has muscle stem cell therapy candidate Myocell in a phase III trial; Mesoblast/Teva with allogenic mesenchymal stem cell therapy Neofuse; and Celyad's C-Cure, based on autologous cardiac stem cells.

The aim of the stem cell therapies is to populate damaged regions of the heart and improve cardiac function by helping the heart muscle beat more efficiently.