Exploring the Food and Drug Administration's review and approval of Entresto (sacubitril/valsartan)

Abstract

Federal regulatory agencies such as the United States Food and Drug Administration review pharmacological evidence to ensure the safety and efficacy of new and repurposed pharmaceuticals prior to market approval. The discussions, disagreements and procedural decisions contained within such reviews offer unique insight into a pharmaceutical's strengths, weaknesses and opportunities, yet are often overlooked as a significant source of pharmacological information for research and development. To highlight the value of such resources, we present a case study on Entresto, a first-in-class angiotensin receptor-neprilysin inhibitor for the treatment of heart failure with reduced ejection fraction, and explore the regulatory rationale underlying its market approval. Using information extracted from Entresto's online approval package at Drugs@FDA, we explore some of the procedural complexities underlying market approval of new pharmaceuticals, discuss the broad pharmacological implications contained within regulatory agency grey literature, and highlight opportunities for future therapeutic development.

Keywords: NT-proBNP; PARADIGM-HF; PARAGON-HF; pediatric heart failure; postmarketing requirements; sex differences.

FIGURE 1

Entresto's mechanism of action. Entresto is a combination drug composed of sacubitril (a neprilysin inhibitor) and valsartan (an angiotensin receptor blocker). Neprilysin is responsible for the degradation of natriuretic peptides ANP and BNP, as well as bradykinin. ANP reduces blood pressure and prevents cardiac hypertrophy, whereas BNP reduces cardiac fibrosis. Bradykinin regulates blood vessel dilation through smooth muscle relaxation. The binding of angiotensin II to the angiotensin II receptor type I increases cardiac workload from sympathetic drive and increased blood pressure, however chronic activation of the receptor can lead to increased cardiac fibrosis, inflammation, oxidative stress, and programmed cell death. Angiotensin II levels are increased in heart failure due to reductions in renal blood flow resulting from reduced cardiac output, as well as from the increased mechanical load placed on surviving cardiac cells. ANP, atrial natriuretic peptide; AT₁R, angiotensin II receptor type I; B₁, bradykinin receptor; BNP, B‐type natriuretic peptide; NPR‐A, natriuretic peptide receptor type A. Created with BioRender.com

FIGURE 2

Retrieval of regulatory approval documents via the Drugs@FDA database. (A) Approval dates, letters, labels, and reviews were obtained from https://www.accessdata.fda.gov/scripts/cder/daf/ using the search term “Entresto”. (B) Search results revealed links to Entresto's original application documents, (C) including approval letters, memorandums, reviews, and correspondences

FIGURE 3

Timeline for the approval of Entresto (sacubitril/valsartan) compiled from FDA documentation. Major milestones are presented. Clinical trials and milestones relating to the FDA approval of Entresto (or valsartan) are highlighted in blue. Milestones relating to post‐marketing requirements are highlighted in purple. CV, cardiovascular; FDA, Food and Drug Administration; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IND, investigational new drug; NDA, new drug application; PDUFA, Prescription Drug User Fee Act; PMR, post‐marketing requirements; RPM, Regulatory Project Manager; sNDA, supplemental new drug application. Created with Vizzlo