By Ed Miseta, Chief Editor, Clinical Leader
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When Roger Mills began his career in the medical profession, he never imagined he would one day end up working for a Big Pharma company or find himself in the middle of a controversy over attempts to bring a new cardiology drug to market. That journey would see a small company teeter on the brink of bankruptcy, experience the highs of a new drug approval and acquisition by a large company, and finally, the downfall and collapse of the approved medicine. Although his time in pharma may have been shorter than some industry veterans, his experiences surpassed many. He tells the story in his recently published book, Nesiritide. The Rise and Fall of Scios.
Nesiritide (brand name Natrecor), was developed to treat acute heart failure. Prior to joining Scios, Mills had studied nesiritide in clinical trials and used it in practice. Based on his experience, it was a safe and effective short-term option for what he labeled “certain patients in certain circumstances.” Ultimately, patients receiving nesiritide had outcomes similar to those treated with intravenous nitroglycerin or nitroprusside, while requiring less complex bedside care.
The Quest For A Cure
Mills began his cardiology career in 1975 in private practice and as a clinical faculty member at the UMass Medical School. In 1988, he left private practice for a full-time academic position, and by the mid-90s, he was an established heart failure specialist at the University of Florida. In the 20-plus years he had spent in cardiology, little had changed for acute heart failure patients. When an opportunity arose to participate in a pharmaceutical clinical trial to develop a new therapy for those patients, he jumped on it.
The chain of research leading to nesiritide started in the mid-1950s. Biochemistry exploded with the unraveling of human DNA and the invention of recombinant DNA technology. Validation that human peptide hormones could be repurposed as drugs led to the spectacular success of Genentech and Amgen.
At the same time, a small biotech company, California Biotechnology, felt nesiritide might have a future for patients with heart failure. The company, kept afloat by venture funding and contract research, eventually became Scios Inc. But turning nesiritide into a multi-million dollar dream therapy would mean big-money, big-risk clinical research.
By the time Mills and the Florida clinical research team started working with nesiritide, preclinical and Phase 1 development work had been completed, as well as some limited Phase 2 work, with investigators from Columbia University and the Cleveland Clinic. A larger Phase 2b trial would be the next step.
The study, known as Scios 704.311, was completed in 1998 with 103 patients from 16 centers. All of the data were collected, including yards of Swan-Ganz pressure records. “Someone comfortable with interpreting the pressure waves recorded on those yards of paper was needed to review the data for quality and then put all of the results on the computer printouts together into a manuscript that would be suitable for scientific review and publication,” says Mills. “That someone was me.”
As the top recruiter for the study, Mills reviewed the data working with Darlene Horton, a pediatric cardiologist who had been through almost the entire drug development process at Scios. Working without interruption, the pair completed a draft of their paper in three days.
All of the patients had severe advanced heart failure as required by the protocol. After receiving nesiritide, the patients experienced rapid reductions in right heart pressures and saw an increase in forward cardiac output. Patients also maintained that improvement throughout the 24 hours of required exposure to the drug. A large percentage of patients also experienced significant dose-related reductions in their systemic blood pressure. Overall, Mills felt the results looked promising.
The next step for Scios was to discuss acceptable designs for a Phase 3 study with the FDA. If Phase 3 results looked similar to 311, the Scios team believed they had a good chance of gaining FDA approval. By the end of the FDA meeting, four trial goals were agreed upon:
- Gather and record data on cardiac filling pressure and cardiac output changes;
- Demonstrate Swan-Ganz monitoring was not required to administer the drug safely;
- Show more rapid relief of symptoms in patients receiving nesiritide;
- Substantially increase the volume of relevant safety data.
Two safety and efficacy studies, known as 325 and 326, were planned. They would eventually include 432 patients at 66 centers across the U.S.
The studies showed that, “The nesiritide infusions clearly had an impressive benefit as compared to placebo,” notes Mills. “The effect on how patients felt was essentially the same as that of widely available generic drugs. Still, nesiritide was much easier for investigators to administer and manage than the generics, like milrinone and nitroprusside. We all felt nesiritide would be a valuable addition to the initial treatment of patients admitted to a hospital for decompensated congestive heart failure.”
The trial information was sent to FDA in early 1999. As the team prepared the submission, Scios President Dick Brewer was working on a deal with Bayer to solidify the company’s finances and help move nesiritide to commercialization. The deal was contingent on a first-round FDA approval.
The Rules Change
Going into the FDA meeting, the Scios team focused on the four goals from the planning meeting. Scios would prove nesiritide reduced filling pressures measured via the Swan-Gantz catheter. Secondary endpoints were changes in cardiac output, blood pressure, and clinical status. Unfortunately, from the time the meeting started, it seemed that agreement would be hard to come by. Milton Packer, an academic, chaired the meeting. The committee had not seen an IV drug for the treatment of heart failure in 11 years, and Packer noted the committee would look at all the data. Still, it seemed bets made at the planning meeting were off.
After an intense discussion, the committee eventually voted 5-3 to recommend marketing approval. Three months later, FDA announced it would not accept the committee’s recommendation and would not approve Natrecor. The regulators wanted to see more safety data. Bayer withdrew from the planned partnering agreement, and Scios had to decide on its future direction. Brewer eventually made the decision to raise funds for another Phase 3 trial.
A New Study Gets Underway
The new Phase 3 trial was called Vasodilation in the Management of Acute Congestive Heart Failure, or VMAC. Brewer had managed to fund it, and Jim Young of the Cleveland Clinic was chosen to run it. The study would be done on a tight timetable and budget and with a new computer-generated dosing schedule. VMAC would accept patients who required hospitalization and had heart failure with shortness of breath regardless of etiology or ventricular function. Investigators would compare standard of care with one of three randomly assigned treatments — nesiritide, nitroglycerin, or placebo – used as treatments while measuring changes in filling pressure. To avoid study bias, staff members were not permitted to assist patients when completing the symptom evaluation form. The study began in October 1999. By August 2000, with 498 subjects enrolled at 55 sites, the trial completed in record time.
“The advisory committee meeting would meet for the second time on May 25, 2001,” recalls Mills. “Packer again served as chairman and was joined by four additional members from the original committee. Horton again led the Scios team and covered the trial, protocol, and goals. Young presented the trial data, which showed the use of nesiritide resulted in significant reduction in filling pressure compared to placebo. Patient reported dyspnea was also significantly improved compared to placebo.”
The meeting started at 9:00 a.m. and concluded at 5:20 p.m. with just a short break for lunch. The committee voted overwhelmingly for approval, and that approval was granted by FDA 10 weeks later. However, some on the committee still had lingering safety concerns. Dr. Steve Nissen held out for the caveat that labeling should include a hypotension warning. Packer, who also supported the warning, voted for approval. Nissan said that it would be easier to gather Phase 4 data and get a warning removed than it would be to wait for trouble and add the warning later.
Natrecor Moves To Market
The medical community initially embraced Natrecor. In the first full year on the market, it posted sales over $107 million. The small company needed a marketing partner. In early 2003, Johnson & Johnson agreed to buy Scios, which became an operating company under J&J. Later, when Brewer was diagnosed with multiple myeloma, J&J executive Jim Mitchell was brought in to run Scios, focusing on building the market for Natrecor. At that time, the prospect of doing a large and costly Phase 4 study to appease a few skeptics had no appeal in the company.
About the same time, Abbott began a Phase 3 trial for levosimendan, a cardiology drug that would certainly be a competitor to Natrecor. Milton Packer would lead Abbott’s clinical development program. Over time, problems surfaced for Natrecor with complaints about pricing and reports of hospital infusion clinics using Natrecor to treat outpatients with heart failure. In 2005, Mills accepted the position of senior director of medical affairs with Scios.
Just four days after Mills accepted his new position, the first wave of safety criticism hit Scios. Using just five of the nine nesiritide studies available, three researchers penned an article for Circulation warning of worsening renal function with the use of Natrecor. A month later, another article in the Journal of the American Medical Association (JAMA) warned of a potential for increased risk of death in patients receiving the drug. Again, the researchers did a retrospective subgroup analysis, omitting large amounts of available data. Importantly, the data used in both publications had already been reviewed by FDA. Soon the lay press, including the New York Times, picked up on the story. The media coverage gave the claims instant validity and linked the safety concerns to the outpatient treatments. For Natrecor, the coverage was disastrous.
Scios issued a press release defending the drug, and later formed a panel of experts to look into the data, in the hope the panel would recognize the flawed methods used by the authors. Although the panel clearly did not accept the findings of the two papers, it did recommend a large safety study to “assess further the benefits and risks of Natrecor compared to standard therapy.”
Things began to unravel quickly. J&J received a subpoena for documents related to sales and marketing of the drug. The company also announced it would buy back European marketing rights to the drug from GSK. Media coverage only intensified.
The End Of Scios
Over the next few months J&J conducted an intense internal review of the safety and efficacy data. Although the review found the analyses in the two journal articles flawed, the internal reviewers also favored a large-scale randomized trial that would cost millions of dollars. Unfortunately, that study would have to occur at a time when sales of the drug were plummeting. In 2006, J&J announced it would pay for a study enrolling 7,000 patients. Since Scios did not have the resources to conduct the study, it would have to partner with an academic research organization. Only a few were large enough to handle the study, and after reviewing the options, the decision was made to go with the Duke Clinical Research Institute, led by Robert Califf.
While the trial planning was ongoing, Mills was promoted to VP of medical affairs, which he calls “a true battlefield promotion if ever there was one.” J&J laid-off hundreds of Scios employees. Meanwhile, a separate trial examining the effectiveness of intermittent outpatient nesiritide infusions found they offered no benefit.
Mills conducted calls with hundreds of physicians from across the country on their experience with nesiritide. He received consistent responses. Nesiritide had helped their acute heart failure patients, but with the media uproar, they would not risk prescribing it any longer. In July 2007, hundreds more Scios employees were laid off. By the fall of that year, Scios was rapidly disappearing as a functional company. R&D personnel were long gone, as was the sales force and the medical affairs team in the field. As a company, Scios was a shell. But, as long as Natrecor was on the market, someone responsible had to mind the store. Mills was transferred to J&J’s Raritan, NJ, campus and his title was changed to “US Natrecor Medical Affairs Lead.”
The safety trial, known as ASCEND-HF, investigated 7,141 patients at 398 centers around the world. The findings, presented in the New England Journal of Medicine and at a meeting of the American Heart Association, showed no excess of safety problems with nesiritide, but the improvement in difficulty breathing with the drug was not statistically meaningful. The experts on all sides, it seemed, were wrong. But by then, no one had any appetite to continue the fight. Scios was gone, and Natrecor sales had dwindled to almost nothing.
In retrospect, what exactly went wrong? The FDA advisory committee recommended approval of Natrecor with the implied understanding that Scios would perform a large safety study. At the time, the agency had no way to enforce the bargain. The publications that raised safety questions used retrospective ad hoc pooled analyses to support their position. The press coverage certainly did not help the company, and more indepth reporting could have noted the selective data used in publications.
Still, it’s impossible to ignore the fact that Scios management stumbled at a number of key moments. Mills notes when Scios management failed to initiate the suggested safety study as soon as the drug went on the market, problems were on the horizon.
“Planning for failure is simple,” adds Mills. “It’s easy to look for the worst-case scenario. Planning for success, on the other hand, is very difficult. If you are heading for success, you will draw scrutiny and you must fulfill commitments. Crises will happen, and when they do you have to properly manage them.”
Roger Mills will be the keynote speaker at Clinical Leader Forum 2017, discussing his experiences with Scios and nesiritide. Clinical Leader Forum is a different type of conference. The focus is on issues and challenges important to you, actionable information you can immediately put to use improving your trials, and knowledgeable presenters who have faced similar challenges and overcome them. For more information or to register, please go to www.clinicalleaderforum.com.