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The sepsis mortality rate was about 40%, and clinicians had virtually nothing to treat it (19, 20). Immunotherapy was just emerging as a promising new approach to tackle sepsis, and many companies were developing immunology-based treatments (7, 17). Some of those companies, like Immunex, had created fusion proteins by mix-and-match combinations of the p55 or p75 TNF receptor with the Fc region of IgG1 or IgG3. These fusion proteins were effective in animal models, but no one knew whether the animal results predicted efficacy in sepsis patients (14). Clinical trials for sepsis were usually completed rapidly, with a clear endpoint that required relatively few patients. If TNFR:Fc worked, it would be quickly approved (7, 17). Then, Immunex could consider clinical trials for rheumatoid arthritis, inflammatory bowel disease, and other disorders (15).

Sepsis The initial clinical results were encouraging (19). In healthy subjects, TNFR:Fc was safe at doses that were subsequently used in sepsis patients. In addition, when the subjects were challenged with endotoxin, TNFR:Fc bound to all TNF- circulating in their blood (21). Immunex’s clinical team, led by Janis Agosti, moved quickly to launch a large blinded, randomized, placebo-controlled trial (19, 21). Because sepsis is lifethreatening and progresses rapidly, the lag between enrolling and treating patients was short. Throughout the winter-summer of 1992-1993, Immunex clinical associates traveled continuously from coast to coast to monitor and support the 15 clinical sites (19). Immunex had also chartered an independent Data Monitoring Committee, which was charged with ensuring the safety of these critically ill patients and periodically reviewing the incoming trial data. The clinical investigators had enrolled about half of the targeted number of patients when the Committee became concerned (5). Immunex’s data management group was asked to decode the treatments of the patients who had died. Unfortunately, most of the deaths occurred in TNFR:Fc-treated patients. And it was a dosedependent effect (21). For the clinical team, it was “very scary to think that the drug may be causing deaths” (5). Immunex immediately stopped the trial. Steve Gillis, as acting CEO, had the unenviable task of

Reprinted from The Pharmacologist • December 2017

notifying American Cyanamid, the FDA, and the public of the results (3).

...it was “very scary to think that the drug may be causing deaths”. Through the 1990s, dozens of clinical trials of various anti-inflammatory agents failed to show a benefit in roughly 15,000 sepsis patients, despite impressive efficacy in animal models (20). It now appears that TNF’s predominant role in sepsis is protective, helping the patient combat systemic bacterial toxicity (1, 20). One by one, each of the sponsoring drug companies, including Immunex, moved away from sepsis therapeutics. At Immunex, it was a tumultuous time (6). The company had invested heavily in the sepsis trial, and its failure was an especially hard blow—more than PIXY 321 (6, 7). Further investment in TNFR:Fc did not make good business sense. “There were discussions whether to run or walk away” (17). The company decided to sell its ownership of the product, and researchers moved to more promising drug candidates (5, 22).

Limping Along Despite the company’s focus on sepsis, Craig Smith thought of TNFR:Fc as an innovative treatment for autoimmune diseases, and rheumatoid arthritis (RA) was always at the top of his list (7). He vividly remembered his Irish-Catholic grandmother, who had raised a large family in the Midwest during the Depression, despite suffering from severe rheumatoid arthritis. She made a deep impression on her young grandson, and now his TNFR:Fc might conquer the disease that had plagued her (7). Disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, sulfasalazine, and hydroxychloroquine, were available and could retard disease progression. But many patients did not adequately respond, and many stopped treatment due to toxicity (23). In parallel with the sepsis trial, Cindy Jacobs (at this time a clinical research director) oversaw small clinical trials to probe IL-1-receptor and TNFR:Fc efficacy in rheumatoid arthritis (15). Seeking interested investigators, Immunex representatives attended the

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2018 Special Compilation Issue of The Pharmacologist  

ASPET is pleased to present the second in a series of special editions of our quarterly news magazine, The Pharmacologist. This special com...

2018 Special Compilation Issue of The Pharmacologist  

ASPET is pleased to present the second in a series of special editions of our quarterly news magazine, The Pharmacologist. This special com...