Future Therapies May Come from Modulation of Cell Signaling in Rheumatic Disease

VBCR - February 2014, Volume 3, No 1 - Personalized Medicine in Rheumatology
Phoebe Starr

By Phoebe Starr

San Diego, CA—“This is an exciting time for treatment of rheumatoid arthritis [RA], with many new therapies. But the question is where do we go from here for future therapies, and what have we learned from past failures,” Arthur F. Kavanaugh, MD, Director, Center for Innovative Therapy, University of California, San Diego, La Jolla, told listeners at the 2013 American College of Rheumatology meeting.

Rheumatic diseases are considered auto­immune conditions as a consequence of a dysregulated immune system that attacks the body’s own tissues. Potential therapeutic targets, including T-cells, B-cells, and macrophages, are thought to drive immune response and inflammatory mediators that sustain the ongoing dynamic autoimmune process, he said.
Immunotherapeutic approaches can help dissect out various rheumatic diseases, because some therapies work better in one disease, for example, psoriatic arthritis than in RA. Autoimmune diseases are multigenetic, heterogeneous, and complex, and developing new therapies is therefore also complex.

“As we think about responders and nonresponders, we have to consider different layers of response. This speaks to the difficulty of picking a single target that will work across all patients. We would like to have personalized medicine, but we need to learn which patients need to have a specific pathway blocked versus a different pathway,” Dr Kavanaugh said.

Large- and Small-Molecule Inhibitors
Currently, 5 tumor necrosis factor (TNF) inhibitors are approved by the US Food and Drug Administration; these agents have revolutionized the treatment of RA and other rheumatic diseases. But they are composed of large molecules, which means they are administered either parenterally or subcutaneously, they are expen­sive to produce, and are difficult
to replicate.

“Maybe there is another way to inhibit kinases. One alternative is to look into individual cells, to allow the use of smaller and potentially more precise molecules,” he noted. “This involves transcription, translation, and the protein. Small molecules would be orally available, less expensive to make, and different in selectivity.”

Several small-molecule inhibitors are currently available, and others are in late-phase development for various rheumatic diseases. Kinases that regulate signaling pathways that modulate transcription, translation, and mRNA stability have emerged as the next generation of therapeutic targets.

A decade ago, sights were set on developing a P38 MAP kinase inhibitor, based on promising experimental data. “A decade later, we found that they don’t work. Clinical trials showed significant toxicity due to lack of specificity,” Dr Kavanaugh said. “There are many possible reasons for this failure, including lack of inhibition of cytokines, affecting counter-regulatory pathways, and other complex and chaotic undefined interactions.”

Experience has shown that a small molecule can inhibit one pathway, and then downstream can inhibit other unintended pathways, giving rise to toxicity. Cyclooxygenase-2 inhibitors are such an example.

“This is not a simple question. The more questions you ask, the more answers you get. Mainly, these studies reveal lack of specificity,” he said.

A Closer Look at More Complex Pathways
Affecting counterregulation pathways is a major hurdle in the treatment of patients with autoimmune disease. Proinflammatory cytokines drive autoimmune diseases, but they also drive anti-inflammatory processes. Anti-inflammatory cytokines drive anti-inflammatory and proinflammatory pathways to achieve homeostasis, which is the ultimate goal for regulatory processes. “Clearly we need more complex approaches, and more complex approaches are being tried,” he said.

The signaling protein Janus kinase (JAK), one such approach, has 4 isoforms, including JAK1, JAK2, JAK3, and TYK2. Different JAK inhibitors target separate pathways. Tofacitinib targets JAK1 and JAK2. This agent has exerted faster and more effective disease control compared with methotrexate in clinical trials thus far, but it also has more safety concerns, including changes in cholesterol, liver enzymes, hemoglobin, and serum cre­atinine, and like many biologics, tofacitinib increases the risk of serious infection.
“We will need to monitor carefully for side effects with tofacitinib and other JAK inhibitors,” Dr Kavanaugh commented.

Another potential approach in RA and other rheumatic diseases is targeting the B-cell receptor pathway downstream. Rituximab is effective in some of these diseases, and drugs that target the downstream B-cell receptor pathway, such as the Bruton’s tyrosine kinase inhibitor idelalisib and the spleen tyrosine kinase (STK) fostamatinib, are under study.
Early data suggested that fostamatinib has good activity in patients with RA receiving background methotrexate, but studies to date are equivocal, and hypertension is a big issue with this drug.

“It is not clear if STK is still a viable target, but studies of more specific STK inhibitors may have better results. The debate is ongoing. STK inhibitors are still in development, but the P38 story is still fresh in our minds,” Dr Kavanaugh noted.

Although TNF inhibitors are effective across the spectrum of rheumatic diseases, separate pathways are of research interest in specific rheumatic diseases. For psoriatic arthritis, there is interest in interleukin (IL)-12/23 and IL-17 inhibitors, phosphodiesterase (PDE)-4 inhibitors, and JAK/signal transducer and activator of transcription inhibitors. A PDE-4 inhibitor was also found effective in Behçet’s disease in a paper presented at this meeting.

“Personalized medicine has always been our goal. We have 12 therapies to offer a patient, but it is not clear which one is the best for which patient. The hope is that personal omics profiles will pay off in this regard, but this is still expensive and not feasible in every patient,” Dr Kavanaugh said. “We need to replicate the successes in oncology, where inhibitors are available for specific mutations. There are many questions to address in rheumatology. Maybe in 6 to 8 years we will have more to talk about.”

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