Supplement: Manipulating the Mechanisms

Manipulating the Mechanisms By Mike May Andrew C. Chan, MD, PhD, vice president of research immunology and antibody engineering at Genetech, discusses the future of research on autoimmunity, and how it could lead to more precise treatments. In the pharmaceutical industry in general, what therapies look particularly promising? There is a plethora of different kinds of mechanisms that are being pursued that are, to me, very exciting. If I focus primarily on one disease, say, rheumatoid arthritis, we now have a number of anti-TNF [tumor necrosis factor] agents: Enbrel, Humira, Remicade, and now Cimzia, all of which basically target the TNF overproduction. After the anti-TNFs, there are a number of therapies for arthritis with very different mechanisms of action. There is the Orencia molecule, which targets the T cells and maybe the dendritic cells, to decrease inflammation. That's been approved this past year. Then, of course, the Roche/Genentech/Biongen Idec drug, MabThera/Rituxan, was approved - again, a totally different mechanism of action, really in the space of B-cell biology. Other things that have not been approved but are in late stages of trials include the Chugai Roche anti-IL-6 receptor antibody - another totally different mechanism of action. Just in the space of rheumatoid arthritis, we have four totally different mechanisms of action - anti-TNF, T cells, B cells, IL-6 - that we didn't have just two years ago. So I think what we're going to be seeing over the next decade is different therapies that target different types of mechanisms that are dysregulated in human rheumatoid arthritis, and the development of tests that tell us that a drug is the right drug for a particular individual. Before all these other therapies were out there, you couldn't really make a case for subsegmenting patients, because there were no therapies. In the near future, will there be autoimmune diseases that you can prevent or inhibit entirely? Just in the space of rheumatoid arthritis, we have four totally different mechanisms of action - anti-TNF, T cells, B cells, IL-6 - that we didn't have just two years ago. This is a little bit of pie-in-the-sky stuff, but I still think scientifically realistic. There's a triad of diseases: hay fever, atopic dermatitis, and allergic asthma. There have been lots of epidemiological studies that demonstrate that if you develop atopic dermatitis in your childhood, followed by hay fever, you're at a higher risk for developing severe allergic asthma as you age. With some subtle differences, it's really progressive dysregulation of a common pathway. Right now, when the kids grow up and develop asthma, we treat the asthma. If we could attack the asthma much earlier on - to reprogram the immune system or at least significantly attenuate the dysregulation of the immune system - then one might be able to decrease the incidence of severe allergic-asthma years later. What compounds could lead to new treatments? Let's take three examples. One is obviously the reopening of the understanding of B-cell biology and human disease through our drug MabThera/Rituxan. To date, it is approved for moderate-to-severe rheumatoid-arthritis patients who have failed anti-TNF. We also have studies of MabThera/Rituxan against lupus, non-anti-TNF-experienced individuals with rheumatoid arthritis, and multiple sclerosis. The second example is Xolair, an anti-IgE antibody. It's the first biologic in the space of asthma. The first demonstration in humans validated IgE as a clear and important mediator in the pathogenesis of human allergic asthma. With that knowledge base, we've gone with new early-stage agents that attack additional pathways that may contribute to asthma. Many of those studies have been opened up just by understanding human physiology in our anti-IgE experience. Courtesy of Genentech The third is Raptiva, an anti-LFA-1 [leukocyte function antigen-1] drug for psoriasis, which modulates T-cell activation. Initially (10-20 years ago), psoriasis was thought to be a purely epidermal- or keratinocyte-mediated disease. Now we know that there is a dominant autoimmune component but also a keratinocyte-epidermal biology component. Really, treatment of both, whether in a given disease or a given patient, will be required ultimately to get a remission and change the course of the disease. Utilizing the data that we have garnered from the Raptiva studies, we're actually learning more about the other pathways that are still active in people who don't respond to Raptiva. That provides additional biology and targets of human psoriasis that may provide novel pathways that we ought to be able to attack. In cases when a compound works well in patients for a period of time, but then the autoimmune disease comes back, could combination therapy help? This has been challenging in patients with rheumatoid arthritis treated with MabThera/Rituxan, some of them get very long-lasting improvement, but some patients' [disease] will recur months to years after the first treatment. Will those patients require combinations of therapies? This has been a challenging aspect in many diseases, because if you disarm many different aspects of a disease, you will increase the susceptibility to infections - because your immune system is required to combat everyday bacterial and viral infections. That doesn't mean that we may not be able to find the right combination of therapies for a given patient that will offer them better clinical benefits. The judge is the therapeutic index: the clinical benefit versus increased risk. There, the identification of patients who are most responsive to a given mechanism of action will be a huge benefit. In addition, there already are combinations that provide great benefit. In rheumatoid arthritis, for example, most therapies (biologics) are given in conjunction with another drug called methotrexate. The other aspect of combinations isn't necessarily concurrent combinations; it's the appropriate sequencing of therapies. In transplantation - not quite autoimmunity, but in essence it is because the transplanted organ becomes your own self and you want to protect it - there are induction regiments that are given and then there are maintenance regiments that are given. In many autoimmune diseases, that concept, while challenging, will likely be developed over the next decade. Eventually, if we can understand how therapies with various mechanisms of action work or don't work, we will, hopefully, be able to place appropriate mechanisms of action into a particular sequence of treatments or combination of treatments that we can pseudo-customize for a given patient.

Supplement: Manipulating the Mechanisms

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