Stephen Hanauer, MD, on Positioning JAK Inhibitors in IBD
Stephen Hanauer, MD, reviews his presentation on positioning Janus kinase inhibitors in the treatment of inflammatory bowel disease, which he made at the virtual Advances in Inflammatory Bowel Disease 2020 regional meeting July 25.
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Stephen Hanauer, MD, is the Clifford Joseph Barborka Professor of Medicine and the medical director of the Digestive Disease Center at Northwestern Medicine in Chicago, Illinois.
Dr. Stephen Hanauer: Hello, I'm Steve Hanauer from Northwestern University in Chicago. I hope you've enjoyed my presentation on positioning JAK inhibitors in the setting of inflammatory bowel disease.
I discussed the rationale for using JAK inhibitors, a small molecule that is important in the activation of cytokines and downstream cytokines that are very important in the pathogenesis of inflammatory bowel disease. Janus kinase pathways are intimately activated in IBD patients.
There are a number of potential advantages of small molecules compared to biologic therapies. We've learned, over the past several years, that as effective as biologic therapies are, up to two‑thirds or more patients treated with TNF inhibitors lose response over a period of time.
Small molecules are very different than biologics. Biologic agents actually work outside of the cell or extracellularly. Small molecules including Janus kinase inhibitors work internally within the cell.
Small molecules do not have the issues of immunogenicity and can be started and stopped in short periods of time without worrying about the development of antidrug antibodies.
Given the gaps in our effectiveness in treating both ulcerative colitis and Crohn's disease, it's clear that novel mechanisms of action are needed in addition to our other conventional agents: TNF inhibitors, other side kinase inhibitors, and lymphocytes trafficking agents.
Tofacitinib was the first oral JAK inhibitor approved for moderate to severe ulcerative colitis after undergoing a number of clinical trials. The clinical trials enrolled patients that were either unresponsive to conventional agents or TNF inhibitors.
Tofacitinib was effective in moderate to severe patients, whether or not they had previously been exposed to TNF inhibitors, but as with other agents that we've seen, patients who were TNF naive had an absolute numerical advantage over patients who had failed TNF inhibitors.
While personally, I believe there is a role for JAK inhibitors earlier in the treatment due to the potential risk of thromboembolic events that were identified in rheumatologic population of older individuals, the FDA has restricted the use of tofacitinib and probably other JAK inhibitors to be determined later, for patients who have failed or not responded to TNF inhibitors.
In this situation, we've identified that tofacitinib works very quickly. Clinical responses can be seen as early as three days with reductions in bowel frequency and rectal bleeding.
Tofacitinib has also had very good long-term results in patients who have been transitioned from the 10‑milligram twice daily dose to the five‑milligram twice daily dose.
Nevertheless, we still need to be aware of potential risks that primarily include infections in these patients, and reactivation of herpes zoster has been a pretty common side effect in patients treated with Janus kinase inhibition.
Now, there are also a number of other JAK inhibitors that are currently under development. There are a number of different JAK receptors. Depending on the individual receptor, there may be more or less peripheral effects, instead of just the unique effects on inflammatory cascades.
Whether or not these more selective JAK inhibitors will offer more efficacy or safety will remain to be determined based on Phase III studies that are underway and eventually head‑to‑head comparisons.
Conventional agents that are nonbiologic certainly have potential advantages and dosing flexibility for IBD patients. Tofacitinib has been the first representative of this new class utilized in patients with ulcerative colitis.
We look forward to additional phase 3 data and eventual approval of other more selective JAK inhibitors in the next several years.