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developed immunogenicity, signs of autoimmune disease, or loss of efficacy (23). To address questions about Enbrel’s long-term safety, Immunex launched an open label safety trial (34). When patients completed their 6-month blinded trial, they were invited to continue treatment in the open label trial, and most patients did. Patients who had participated in the phase 2 trial were also invited to enroll, and Elizabeth signed up (1).

Don’t Forget the Kids As soon as drug supplies became available, the team began staging expansion of Enbrel’s therapeutic indications. In parallel with the RA trials, they conducted clinical trials for psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, Crohn’s disease, and juvenile rheumatoid arthritis. Rheumatoid arthritis can affect children as young as 1 year old, and it is devastating. Inflamed joints can accelerate bone growth, leading to differences in leg length during childhood development, and consequently, to significant long-term disability. The standard of care for these children had been NSAIDs and low dose methotrexate, but they needed something better (4). The FDA encouraged all drug companies to collect pediatric data in their development programs if the medical condition affected children as well as adults. But pediatric clinical trials are quite challenging for both ethical and feasibility reasons, and most companies delayed – or even avoided – this work. As a rheumatologist who had seen juvenile RA firsthand, Barbara Finck became a strong advocate within Immunex to start the pediatric trials earlier rather than later. She succeeded in getting corporate support. It was a risky and bold management decision, given the company’s already heavy investment in Enbrel, and considering that a bad outcome in a pediatric trial could derail the entire development program (4). Daniel Lovell and Edward Giannini at the Children’s Hospital Medical Center in Cincinnati spearheaded the pediatric trial (35). The main objective was to collect pharmacokinetic data. Because the children were too small to draw multiple blood samples, the study employed a population-PK design (4, 35). The Cincinnati group saw some of the most severe cases of juvenile RA, and in the first segment of the trial, all children received Enbrel (4). Then, in the

Reprinted from The Pharmacologist • December 2017

second and blinded segment, some children received placebo injections while the rest continued taking Enbrel. If children in the placebo group experienced a flare response, they resumed Enbrel treatment (4, 35). This innovative study design had never been previously used for pediatric pharmacokinetics trials, but it is now standard (4).

The Path to Approval Enbrel faced stiff competition from other biologic drug candidates. In addition to Remicade, Abbott Laboratories was proceeding with adalimumab (Humira®), a fully humanized TNF- antibody. The Immunex team presented Enbrel data at every rheumatology-related venue – large and small – and published a steady stream of clinical study reports (6, 36). But by far, the most important document the Enbrel team prepared was the Biologics License Application (BLA), requesting market approval from the FDA. The most important presentation they made was to the FDA’s Arthritis Advisory Committee. Immunex submitted the BLA to the FDA on May 7, 1998 (33). As part of the BLA review and approval process, the FDA requested input and recommendations from its Arthritis Advisory Committee, an independent panel of experts. It was customary for the Advisory Committee to invite the sponsoring company to present summarized data and respond to their questions. For the Enbrel team, this was a critical meeting, and they did their homework. Many of them had no experience with the regulatory process, though some, including Leslie Garrison, had worked toward GMCSF’s approval. They attended Advisory Committee meetings where other products were discussed, including Centacor’s Remicade presentation in May 1998 (5, 6). Through the summer of 1998, they diligently prepared (5, 6, 36). Ann Hayes and Garrison would make the formal slide presentation and field the Advisory Committee’s questions. Many of the Advisory Committee members were rheumatologists who were familiar with Remicade and knew its problems. Their questions would reflect that experience, as well as concerns about investigational biologic drugs in general. In a series of practice sessions, the Enbrel team and their clinical consultants brainstormed every possible contingency. Sometimes, that required additional

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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...