"This remarkably insightful book gives true meaning to the apocryphal moan from the pharmaceutical CEO as he traveled home after an FDA slap down: 'Drug development ain't for sissies'." Peter Kowey, MD, author of LETHAL RHYTHM, DEADLY RHYTHM and THE EMPTY NET When Roger Mills, a medical school professor, made a late-career move from academic cardiology to the pharmaceutical industry, he had no idea what the next decade would bring. At the University of Florida in the late 1990s, he had been a clinical investigator in a phase 2 trial studying the dosing and efficacy of nesiritide, which Scios Inc. was attempting to bring to the market. He joined the company in 2005, and soon became its vice president for medical affairs. Nesiritide was the biotechnology company's only product in clinical development, and after a stunning turn of events at a Food and Drug Administration meeting in 1999, company president Dick Brewer had to use all his smarts to keep the company together and reverse its fortunes.Johnson & Johnson would eventually acquire the company in 2003 for $2.4 billion, but then found it would have to decide how to deal with safety concerns raised about the drug after two scientific publications claimed it could cause kidney failure and death. Get a revealing look at what it really takes to develop and introduce a drug to market and all the things that can go wrong in Nesiritide. Nesiritide The Rise and Fall of Scios By Roger M. Mills iUniverse Copyright © 2016 Roger M. Mills, MD All rights reserved. ISBN: 978-1-4917-9764-8 Contents Preface, ix, Introduction, xiii, Chapter 1 Eddy Buczynski, 1, Chapter 2 From the Dog Lab to Molecular Structure, 6, Chapter 3 Biotechnology, 11, Chapter 4 Early Clinical Trials, 14, Chapter 5 The First Rough Times, 20, Chapter 6 Brewer on the Road, 31, Chapter 7 Approval, Not Unconditional Love, 36, Chapter 8 Dancing on the Tables, 47, Chapter 9 Change, and More Change, 49, Chapter 10 The Bigger They Are, 53, Chapter 11 The Wise Men Meet, 62, Chapter 12 Folding the Tent, 75, Chapter 13 Life in the Penalty Box, 83, Chapter 14 Never Fall in Love with a Molecule, 86, Chapter 15 Consequences, Foreseeable and Not, 93, Chapter 16 The Short, Sad Story of Stresscopin, 96, Chapter 17 A New Oral Drug — Natriuretic Peptides Vindicated, 100, Chapter 18 Getting Involved in Drug Safety, 104, Chapter 19 Risk-Benefit — Another FDA Advisory Committee, 109, Afterword, 115, References, 117, CHAPTER 1 EDDY BUCZYNSKI In 1975, as a newly minted cardiologist fresh from Harvard's Peter Bent Brigham Hospital, I started into private solo practice in Worcester, Massachusetts. From my small office on the fourth floor of a relatively new medical office building, I could look directly across busy Belmont Street, Route 9, to the Memorial Hospital emergency department. As part of my staff appointment at Memorial, I was the director of the new coronary care unit. If I walked briskly, and traffic was not too heavy, I could make the journey from the office to the emergency room in roughly two and a half minutes, depending on the traffic coming down the hill. I consulted on a lot of patients with new onset or rapidly worsening ( acute ) heart failure for the ER team. Heart failure ( HF ) is not a specific disease. HF is what medical doctors call a syndrome, a collection of various patient complaints ( symptoms ), evidence on physical examination ( signs ), and laboratory abnormalities (on blood tests, electrocardiogram, and imaging studies) that cluster together. The HF syndrome includes a broad spectrum of clinical problems that plague individuals who have impaired heart function. The heart is a pump; its mechanical functions are limited to filling and emptying. Nonetheless, a long list of specific diseases can cause impairment of either its filling, its emptying, or both. If and when the consequences of that reduced cardiac function come to dominate a patient's life, then he or she has the heart failure syndrome. The 1970s and 1980s saw great progress in heart failure research. Laboratory and then clinical data established compelling evidence that the same physiological responses that are activated to retain salt and water under a variety of circumstances like dehydration, gastrointestinal fluid loss (vomiting or diarrhea), or bleeding are also highly activated in heart failure. Collectively, those responses are known as the renin-angiotensin-aldosterone system ( RAAS ). This occurs because the heart is not adequately filled or emptied, and the systemic arterial circulation is underfilled. The relative underfilling that occurs with heart failure stimulates the same RAAS responses that depletion of the circulating blood volume from dehydration or bleeding does. Think of it this way: it's as if you set your home thermostat on the living room wall to a comfortable seventy degrees. Then, when the house temperature was steady at seventy degrees, you take th