Forum for Discovery 2003

Unique Symposium Stimulates Out-of-the-Box Thinking on Therapies

Dr. Peter LipskyLRI Taskforce Co-Chairman and NIAMS Scientific Director Peter Lipsky, MD, moderated a lively forum, BioDrug Symposium, that provided an opportunity to learn about the hottest new ideas for lupus treatments. Six of the country's leading scientists presented their proposed target in a forum chaired by Dr. Lipsky, who took the role of Vice President of Research and Development at BioDrug, a fictitious biotechnology company.

The presentations emphasized the importance of reining in tissue damaging immune responses in lupus. The following approaches were championed by the experts.

Replace Inactive Tregs . . . Jeffrey Bluestone, PhD, of the University of California-San Francisco Hormone Research Institute and the NIH Immune Tolerance Network, proposed a clinical trial in which Tregs – T lymphocytes that dampen down the immune response – are taken from lupus patients, grown in a laboratory, and then reintroduced into these patients.

Dr. Brian KotzinTarget Interferons – a group of proteins important in regulating the immune response . . . Jacques Banchereau, PhD, of the Baylor Institute of Immunology Research, proposed developing agents that would block the formation or action of interferon-alpha, while Brian L. Kotzin, MD of the University of Colorado Health Sciences Center, proposed blocking another type of interferon, interferon-gamma.

Dr. Betty DiamondFocus on B Lymphocytes – immune system cells that mature into antibody-producing cells . . . Betty Diamond, MD, of Albert Einstein College of Medicine, proposed administering potential treatments to remove self-reactive B lymphocytes during periods of disease remission to prevent these cells from surviving and maturing into cells that produce self-destructive antibodies.

Andrew C. Chan, MD, PhD, of Genentech, Inc., proposed combining rituximab, an engineered antibody designed to attack certain B cells, with another antibody to remove the self-reactive B cells and also to cause other B cells to self-destruct.

Target Signaling Molecules . . . Anthony L. DeFranco, PhD, of the University of California-San Francisco, proposed developing drugs enhancing a protein called Syk that signals antibody production to stop, thus reining in the production of self-reactive antibodies.

A panel of “BioDrug” consultants consisting of Robert B. Jackson of Deerfield Partners (financial analyst); David Wofsy, MD, of the University of California, San Francisco; Lee S. Simon, MD (FDA representative); and Ingrid Wickelgren (contributing correspondent to Science), raised a number of issues including the need to bring lupus trials to more rapid conclusions, and to carefully consider which subsets of patients would most likely benefit from the proposed intervention.

Dr. Jeffrey A. BluestoneJeffrey A. Bluestone, PhD, is recognized internationally as an immunobiologist who has made a significant contribution toward understanding of the biological basis for immune tolerance – the blocking of unwanted immune responses by reprogramming the body's immune system. Dr. Bluestone, Director of the Immune Tolerance Network and the Diabetes Center at UCSF, told conference participants, "Lupus therapies focus on dampening down the entire immune system. With our present understanding of immune reactions we should be able to tweak parts of the system without having to sledgehammer it."

Overcoming Barriers to Lupus Drug Development

How can we tell if a medication is really helping people who suffer from lupus? How can we measure if the patient is really improving on a particular drug? These and other complex questions were addressed in a panel discussion, FDA Guidance Document: Its Role in Lupus Drug Development.

Dr. Lee S. SimonLee S. Simon, MD, then Director of the FDA's Division of Anti-inflammatory, Analgesic and Ophthalmologic Drug Products, reported that the FDA's Guidance Document intended to help pharmaceutical companies with lupus clinical trial designs, is now under internal review.

Because clinical trials in lupus can take a long time, drug companies may choose to put their efforts into other immune disorders where a speedier answer is possible. Dr. Simon suggested that one way to overcome this barrier is the development of surrogate endpoints, laboratory or other clinical biomarkers (predictors) that are reasonably likely to be associated with clinical benefit to lupus patients. "Surrogates could be considered as endpoints for trials to seek FDA approval, although clinical benefit would have to be shown in trials after approval," Dr. Simon said.

Designing Clinical Trials

David Wofsy, MD, of the University of California, discussed ethical concerns about lupus clinical trials. "In a lupus trial where there are already approved treatments, a placebo should be used with close monitoring in patients who have very well controlled disease," Dr. Wofsy said.

Dan Wallace, MD, of Cedar Sinai/UCLA School of Medicine, provided the practicing clinician's view on lupus trials, suggesting that patient enrollment would be improved by involving qualified private practitioners in trials.

Dr. Susan ManziPanel participant Susan Manzi, MD, of the University of Pittsburgh School of Medicine, discussed what clinical trials should be measuring, including reduced mortality, reduced disease activity, and disease or treatment damage. She also described typical complications, such as patient flares, in setting up lupus trials.

Echoing the complexity of developing drugs for lupus, Jill P. Buyon, MD, of New York University School of Medicine emphasized that no one set of outcomes can be useful for all lupus trials. Dr. Buyon described her study demonstrating two surrogate markers that may be useful predictors to determine a need for treatments even before clinical signs of a flare.

Promoting the discovery of surrogate markers to speed lupus drug development is a priority for the LRI.

 

The Lupus Research Institute thanks the following companies for their support of the LRI Scientific Conference: Amgen, Inc., Aspreva Pharmaceuticals Corp., Bristol-Myers Squibb Co., IDEC/Genentech, La Jolla Pharmaceutical Co., Medarex, Inc., and Protein Design Labs, Inc.