The Development of ARNI: An example of Academic Industry Collaboration
BRIGHAM AND WOMEN’S TRANSATLANTIC DIALOGUES ON CONTROVERSIES IN CONTEMPORARY CARDIOLOGY
Eugene Braunwald set out to illustrate the necessity and possible achievements of good collaboration between academia and industry, by taking the physiologic and clinical advances that led to the development of the first angiotensin-receptor blocker (ARB)-neprilysin inhibitor (ARNi) as an example.
The PARADIGM-HF trial, evaluating ARNi in patients with congestive heart failure (HF), was stopped early in 2014, due to overwhelming efficacy. In this trial, as compared with treatment with enalapril, treatment with the ARNi sacubitril/valsartan had a beneficial effect on mortality (CV and any cause), clinical worsening of HF and the need for urgent medical care. In May 2016, both the American and European cardiology societies published focused updates on therapy for HF, recommending for sacubitril/valsartan to replace treatment with an ACE-inhibitor (ACEi) or ARB in HF with reduced ejection fraction (HFrEF, NYHA class II or III).
The start of the development of this ARNi dates back to an experiment published in 1896, when the Finnish Professor of Physiology Robert AA Tigerstedt demonstrated that pulverised and dissolved rabbit kidney induced a rapid rise in mean arterial pressure after being injected in the jugular vein1. This was the first step on the way to deciphering the renin-angiotensin system, although Tigerstedt did not continue this work. Harry Goldblatt later created experimental hypertension, which led to the understanding that the kidney must release substances that influence blood pressure (BP).2 Subsequent work by various academic scientists culminated into the discovery of an enzyme derived from snake venom that not only potentiates the vasodilator bradykinin, but also inhibits the peptidase that converts angiotensin I to angiotensin II. This is when industry entered the scene, by designing the first orally active inhibitor of this enzyme with dual action (captopril).3 A similar compound, enalapril, was shown to reduce mortality as compared with placebo in patients with congestive HF.3
The development of sacubitril/valsartan has been a fruitful interaction between academic and industry efforts
The pathologist Alfredo J de Bold discovered atrial natriuretic peptide (ANP)4, and an enzyme (later called neprilysin) that rapidly hydrolyses ANP was identified in the kidney.5 Subsequently, industry developed an inhibitor of this enzyme.6
These insights together yielded a better understanding of the natriuretic peptide system. A concept arose that patients with HF have atrial distension, and they release high levels of ANP. But the enzyme neprilysin, due to its ANP hydrolysing activity, prevents a strong vasodilatory, diuretic and natriuretic effect of ANP. Omapatrilat was a combined inhibitor of ACE and neprilysin (and aminopeptidase), member of the class of vasopeptidases. This class was extremely effective at lowering BP, but associated with serious adverse effects such as angioedema and issues in the upper airway. Hence, development of these bradykinin-increasing agents was discontinued.
Combining inhibition of neprilysin with an ARB instead of ACEi proved to solve these issues, as ARB does not affect bradykinin. This is what we now know as the ARNi sacubitril (the neprilysin-inhibitor)/valsartan (ARB). This combined approach gives additional BP-lowering as compared with valsartan alone.7
Overall, the development of this drug class has been a fruitful interaction between academic and industry efforts. Braunwald credits academia for its creativity and experimental excellence, which led to the discovery of two important physiologic systems and elucidation of their function. He praises industry for its ingenuity and resources for the development and application of the most advanced technology to develop safe drugs. Braunwald concluded that both parties have been essential for the development of the first ARNi, and the whole is much greater than the sum of its parts.