ESC preview – Novartis seeks Paradigm change and patients take neurostimulation to heart


Novartis will draw back the curtain on its heart failure project LCZ696 while Sanofi and Regeneron Pharmaceuticals will present data from the lipid-lowering antibody alirocumab when specialists gather next week at the world’s largest cardiology conference in Barcelona.

The European Society of Cardiology meeting will also see Boston Scientific and Cyberonics release data on the seemingly counterintuitive use of neurostimulation for heart failure. Trophos, meanwhile, has been selected to discuss its TRO40303 as a therapy to prevent reperfusion injury in heart attack patients who are having stents implanted in coronary arteries.

Looking for clarity

Novartis has said very little about LCZ696, a potential blockbuster that combines Diovan with a molecule known generically as sacubitril, since announcing the early termination of the Paradigm-HF trial for clear evidence of positive efficacy (Novartis gets surprise heart failure win as ACC data roll in, March 31, 2014). Congestive heart failure has seen little in the way of innovation for more than a decade, and most of the leading therapies have lost patent exclusivity; sales of branded drugs used to treat heart failure have more than halved over the past decade.

LCZ696 is a dual-action pill that contains Diovan’s active ingredient, valsartan, which inhibits angiotensin II and reduces blood pressure, making it easier for the heart to pump blood. The second active ingredient is AHU377, which inhibits neprilysin, an enzyme that breaks down a vasodilator called C-type natriuretic peptide.

Since announcement of the Paradigm trial’s termination, forecasts for LCZ696 have skyrocketed and stand at nearly $2bn in 2020, according to EvaluatePharma’s consensus. But without complete data it is hard to say what the pill’s ultimate potential is. For one, Novartis released no safety data in March, although Diovan’s long usage and an unambiguous decision by the Paradigm trial’s data-monitoring committee strongly hints that this will not be a problem.

In Paradigm-HF LCZ696 was tested against the ACE inhibitor Vasotec in 8,442 patients, with the primary endpoint a composite of time to first occurrence of cardiovascular death or heart failure hospitalisation.

The consensus forecast for the project could change based on the data that will be disclosed in a hotline session August 31. UBS analyst Alexandra Hauber puts 2020 sales at $5.4bn, suggesting that a stellar mortality benefit and, equally important to payers, a reduction in hospitalisation, could drive a migration to the new pill. Cardiologists will also look for a consistency of benefit in various subpopulations, Ms Hauber wrote.

Shocking stuff

On the medtech side, a surprising amount of work is going into vagus nerve stimulation (VNS) for heart failure, with both Cyberonics, a neurostimulation specialist, and Boston Scientific presenting initial data from mid-stage trials. The technique is used to treat epilepsy and depression, but companies are now looking beyond the central nervous system as evidence suggests that stimulating the peripheral nerves can have broader effects throughout the body.

Initial data are expected from Boston Scientific’s phase II Nectar-HF trial, assessing stimulation of the right vagal nerve in 250 moderate to severe heart failure patients. Importantly, the study was sham controlled: patients randomised to the control arm had the device implanted but did not receive right vagal nerve stimulation for the first six months. After that, they received therapy.

Cyberonics is the doyen of vagal nerve stimulation. Its device, the VNS System, has been available in Europe since 1995 and in the US since 1997 (Therapeutic focus – Responsive neurostimulator technology shocks epilepsy market, December 10, 2013). Anthem-HF, a phase I/II trial in 60 heart failure patients, has no sham group but has instead compared six months of VNS implantation on the left side to that on the right side.

The company plans a European CE mark submission for fiscal 2015. The VNS System is forecast to have global sales for all its indications of $518m in 2020.

VNS as a technique has a drawback in that it involves an invasive procedure compared with other devices such as stents, and its novelty – even if the trials are successful – will also be a mark against it. Boston appears to be aiming its device at patients who are currently not candidates for heart failure device therapy, meaning that VNS will occupy the same niche in the treatment sequence as it does in epilepsy and depression.

Over to you, alirocumab

Sanofi and Regeneron’s alirocumab is in a neck-and-neck race with Amgen’s evolocumab to become the first PCSK9 antibody to come to the market; positive data from nine phase III trials were recently released, and the companies paid for priority review with the FDA (Down to the wire in the PCSK9 class, July 31, 2014).

At an ESC hotline session on August 31 data from four of the trials in the Odyssey programme in patients with high levels of low-density lipoprotein cholesterol (LDL-C) will be detailed – Combo II in patients inadequately controlled on maximum statin doses, FH I and II in heterozygous familial hypercholesterolaemia, and the most important from a commercial standpoint, Long Term, in high-risk patients unable to control their LDL-C levels.

Other than the 18,000-patient Odyssey Outcomes trial, which will not report until 2018, Long Term is the biggest in the pivotal programme and applies to the largest patient group. Sanofi and Regeneron have disclosed that alirocumab met its primary endpoint at 24 weeks, a reduction in LDL-C versus placebo, and a post-hoc analysis showed a lower rate of cardiovascular events and deaths.

A third experimental drug that will be in the spotlight at ESC will be Trophos’s TRO40303, which was selected to be used in the European Union-supported Mitocare study of ischaemia-reperfusion injuries, or tissue damage caused by the return of blood after surgical intervention.

Trophos, a private French group, has disclosed little about the trial beyond news that the final patient had completed it last October. As with Trophos’s lead candidate olesoxime, TRO40303 is a mitochondrial pore modulator that helps cells survive under stress.

Cardiovascular research has in many ways migrated to better use of existing interventions. Yet with so many patients unable to achieve treatment goals with current drugs and technologies, there is still room for innovation.

Study name Trial ID
Paradigm-HF NCT01035255
Nectar-HF NCT01385176
Anthem-HF NCT01823887
Odyssey Combo II NCT01644188
Odyssey FH I NCT01623115
Odyssey FH II NCT01709500
Odyssey Long Term NCT01507831
Mitocare NCT01374321

To contact the writers of this story email Jonathan Gardner or Elizabeth Cairns at or follow @EPVantage on Twitter

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