Optimism mixed with sober analysis in Brian L. Kotzin, MD's, evening presentation to a crowd of scientific colleagues and lupus advocates in Manhattan on October 6 th. The intensive labor, immense time demands, and enormous cost in developing new lupus drugs, Dr. Kotzin explained, pose hurdles that require not only the talent of academia and the nimble approach of organizations such as the LRI, but the weighty resources of industry.
“I used to think that the universities could do it,” Dr. Kotzin explained. “But I have had a rude awakening. Now I realize this is definitely too difficult a process.” Dr. Kotzin, who has held the position of vice-president of global clinical development at the biotechnology company, Amgen, Inc., since July 2004, worked in academic medicine for 25 years on lupus pathogenesis, genetics, and immunology. He is a member of the LRI's Scientific Advisory Board.
In introducing Dr. Kotzin, the LRI Novel Research Task Force Co-Chairman, Mark Shlomchik, MD, PhD, noted how valuable it is to have such an accomplished and multitalented person as Dr. Kotzin at a global powerhouse like Amgen, where he can bring his many perspectives to bear on lupus. “He's come at the lupus problem from every aspect: clinical, basic research, and now from the drug development side.”
First Task: Examine Models of Success
To illustrate the scope of challenges ahead in lupus therapeutics, Dr. Kotzin turned to the dramatic advances of a different disease: rheumatoid arthritis (RA). For decades, scant treatment options were available for this crippling autoimmune condition. That dry spell ended with the successful development of drugs like etanercept, which transformed the playing field for RA therapeutics largely because it blazed a path to drug approvalâ€”a critical feat.
“What happened with RA and etanercept is an example of what success looks like, and all the goodies that come of that,” Dr. Kotzin said. With a model for success, the myriad challenges to drug development became manageable. Normally the complex and timely journey from concept to safe and effective therapeutic takes an average of 14 years. “I don't think were going to really know how to develop lupus drugs until we have a drug that works,” Dr. Kotzin concluded.
With the route to drug approval so daunting, it's little surprise that most proposed therapeutics flounder and fail at some point. Which is just one reason, Dr. Kotzin added, that “I'm not sure that anyone but industry should do it.”
“It takes teams of very skilled people to go through the steps in a very high quality way,” Dr. Kotzin explained. They have to select a therapeutic with optimal properties, follow through on studies that examine the drug's effects in animals and humans, find a way to adequately manufacture it, and stage clinical programs on safety and efficacy. And then there are such obstacles as cost, recruitment of patients, differences in disease manifestations, and the lack of biomarkers to signal drug effectiveness.
Moving Lupus Therapeutics Forward
Though a distance from where RA drug development stands, the outlook for lupus is positive, Dr. Kotzin said. “We're really doing well—we've got a lot of things moving forward, finally,” he explained as he projected a slide with lupus therapeutics in (or close to) clinical trials, from B cell targets to co-stimulator blockers and cytokine inhibitors. “Isn't this fabulous that we're going to be introducing so many in the near future?”
In addition to the FDA Draft Lupus Guidance Document , which provides a framework for industry in designing new medicines, lupus researchers now generally agree on how trials should look (including endpoints to measure and populations to include). Also “a big deal,” noted Dr. Kotzin, is the introduction and characterization of instruments to measure changes in overall disease activity.
Other encouraging signs include the commitment of multiple companies to develop lupus therapeutics and the current cooperation among clinical trial centers. “Only 5 years ago this was not the way it was,” Dr. Kotzin emphasized.
Strategies for Reinforcing Success
Looking forward, there need to be many “shots on goal,” Dr. Kotzin asserted—successful attempts to create new treatments, such as the LRI provides. “We need a continuous pipeline of novel targets that have incredibly strong rationale,” Dr. Kotzin continued. “And since it's unlikely we're going to have one drug that cures lupus, we have to have many drugs tested.”
The LRI provides the type of key support that keeps this pipeline open, Dr. Kotzin noted, by supporting novel ideas, drawing in new investigators, and enticing scientists from outside the traditional lupus research community.
Flexible and fast-paced organizations such as the LRI are crucial given the more risk-adverse grant review process at the NIH, which tends to fund established researchers with set track records, and favor basic and animal research over human studies. “It's great to understand the mouse,” noted Dr. Kotzin. “But we need to understand the biology of human lupus and support the clinical aspects of development.”
Collaboration with industry is vital, Dr. Kotzin continued, because this sector has the skill to navigate the development process, as well as the deep pockets to fund the staggering cost—$800 million to $1 billion—of bringing a novel therapeutic to market. The importance of such collaboration only mounts with time, Dr. Kotzin noted, as NIH research funding dwindles.
“It's a long road ahead to new lupus drugs,” Dr. Kotzin concluded, “but we'll get there.”