This article is more than 5 years old. Information may no longer be current.
Kinase Inhibition in Rheumatology: Cutting Edge of the Brave New World of Therapeutics
Click Here to Manage Email Alerts
Yes, I started this Editorial by quoting myself — I do not think it is plagiarism as I am citing the source and I believe this is my quote. If not, then I am sorry but for all rheumatologists reading this Editorial, I don’t think this concept is earth-shattering news.
© 2017 Shutterstock.com
Think sarcoid and psoriasis from tumor necrosis factor inhibitors. Think progressive multifocal leukoencephalopathy from rituximab. Think why interleukin-17 inhibition failed rheumatoid arthritis (RA) and multiple sclerosis when all preclinical models predicted otherwise. So, the story goes with kinase inhibitors, the topic of the Cover Story in this issue of Healio Rheumatology.
Clinical Development
From the beginning, the concept of kinase inhibition as a means of treating human disease was a tough row to hoe. In the 1980s, rationally designed kinase inhibitors were born in the laboratory, but it was a long road from birth to clinical development. As Siddhartha Mukherjee, MD, recounts in his Pulitzer Prize-winning book Emperor of All Maladies, Brian J. Druker, MD, from the Oregon Health Science Center clinically pioneered the development of imatinib. Despite its initial success which he reported in 1996 in Nature Medicine, “Druker found himself inhabiting an inverted world in which an academic researcher had to beg a pharmaceutical company (Ciba-Geigy) to push its own products into clinical trials” as they told him it wouldn’t work or would be too toxic. Little did they suspect that this drug and the successful targeting of the attendant pathway would be given the “Discovery of the Decade Award” by the Prix Galien Foundation and launch a new field of small molecule discovery targeting kinase inhibitors.
Enter John O’Shea, MD, and his team of investigators and their efforts to target intracellular Janus kinases (JAK) to treat autoimmune and other inflammatory diseases. I do not think the theoretic obstacles were any less, as the conceptualization of interfering with not one but scores of cytokines were daunting in itself. No less worrisome was that this therapeutic targeting would come about via meddling with the transfer of phosphate groups from ATP, which was viewed as the fundamental “molecular unit of currency” of intracellular energy transfer. This was scary stuff. I once asked John whether at the beginning of his research in JAK targeting he would have predicted the remarkable efficacy and acceptable toxicity of these agents and my recollection was he told me, “No way.” Thus, future surprises have been shown here.
Surprises and Questions
I have outlined some of the surprises, conundrums and questions that come to mind when I think of kinase inhibition here. Consider for a moment the potency of the lead agent, tofacitinib, and its demonstrated superiority to methotrexate in a head-to-head trial. Similarly, we are seeing the same pattern for baricitinib, the agent which appears likely to be the next in line for approval in the United States. Given this potency and the status of tofacitinib and baricitinib as the only oral disease-modifying antirheumatic drugs (DMARDs) to best methotrexate, we must wonder why regulators, as well as U.S. and European RA treatment guidelines relegate tofacitinib and baricitinib, which is now approved in Europe, to patients failing previous DMARDs and not as initial DMARD therapy. One must wonder how long it will take for this to change and what burden of proof of acceptable risk-benefit will be required.
Also, consider the speed of onset. It is hard for me to imagine how these JAKATINIBS can act more quickly than anti-tumor necrosis factors, as they must shut down intracellular signaling while the monoclonals can instantaneously neutralize circulating inflammatory cytokines.
Lastly, I am intrigued and puzzled about the zoster signal that occupies space in considerations of safety for most of these agents thus far. Some risk is likely imparted via inhibition of type 1 interferon (IFN), as we are seeing dose-dependent zoster with some of the new anti-IFN agents targeting systemic lupus erythematosus. Even considering this as a likely explanation, there appears to be strong genetic effects (ie, more common in Asians) as well as a large part of the zoster risk being associated with concomitant methotrexate, an agent with low zoster risk profile. So much work remains to be done.
Future Paths
Where will kinase inhibition go? Will it go beyond JAKATINIBS? This past year, we saw data on the Bruton’s Tyrosine Kinase (BTK) inhibitor BMS-986142 in early trials. Agents targeting this pathway have been exciting in lymphoma drug development but appeared, a few years ago, to stall out in the RA space. At the minimum, stay focused on kinase inhibition in rheumatology as there are likely many more surprises to come.
Please continue to send me ideas, comments, news or anything you think we should cover in Healio Rheumatology. You can email me at calabrl@ccf.org or follow me on Twitter @LCalabreseDO. Thanks for reading.
- Reference:
- Mukherjee S. The Emperor of All Maladies: A Biography of Cancer. New York: Scribner, 2010.
- For more information:
- Leonard H. Calabrese, DO, is the Chief Medical Editor, Healio Rheumatology, and Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and RJ Fasenmyer Chair of Clinical Immunology at the Cleveland Clinic.
Disclosure: Calabrese reports he is a consultant for Genentech, Pfizer, Bristol-Myers Squibb, GlaxoSmithKline, Sanofi, Jansen and AbbVie; and is on the speakers bureau for Genentech, AbbVie and Bristol-Myers Squibb and Crescendo Bioscience.