Targeting IL-12/IL-23 in Crohn's Disease

DECEMBER 27, 2017
MD Magazine Staff

Stephen B. Hanauer, MD: Ustekinumab has been tested in 2 patient populations: those who have failed prior biologics, primarily TNF inhibitors, and also in biologic-naïve patients. As we’ve seen with all therapies, in the earlier patients, the less refractory patients, the biologic-naïve patients, we actually get better outcomes than we get in patients who are more refractory and experienced with biologics. But nevertheless, the outcomes are significantly superior to placebo in both groups of patients.

We also have a long safety experience with ustekinumab. It has been on the market for psoriasis for over 8 years, so we have many thousands of patient-years’ experience. There is a small risk of infection, but that really hasn’t been identified in the Crohn’s disease populations. In these individuals with Crohn’s disease, they’re not just treated with ustekinumab, as many have been on corticosteroids or immunosuppressives as well. So, any of the side effects need to be discriminated from ustekinumab versus the other concomitant agents. But overall, ustekinumab has been very safe. In the psoriatic population that has been exposed to ultraviolet light, there has been an increased risk of non-melanotic skin cancers, but we have yet to see that in the Crohn’s disease population. The induction dose of ustekinumab is 6 mg/kg administered intravenously, then maintenance is with 90 mg subcutaneously every 8 weeks.

Bruce E. Sands, MD:  The biologic rationale for blocking interleukin-12 and interleukin-23 in Crohn’s disease harkens back to the genetics of these diseases. Actually, if you look at genetic risk factors for both Crohn’s disease and ulcerative colitis, you find many loci that involve the IL-12 and IL-23 pathway. That includes the IL-23 receptor gene. And, quite interestingly, there’s 1 polymorphism that is actually protective for the development of Crohn’s disease, which suggests that if you block IL-23, that may be beneficial. Aside from that, we’ve learned from many animal models of inflammatory bowel disease that IL-12 and IL-23 are elevated, and that if you block those cytokines, the inflammation in those models actually goes away.

Finally, in human tissues, if you measure interleukin-12 and interleukin-23, you’ll find that those cytokines are elevated. So, altogether, this provides very strong rationale for wanting to block these very important cytokines that are involved in adaptive immune responses in IBD. The last thing to say is that these cytokines have a lot in common. They’re both heterodimer molecules. They share 1 component, which is the p40 compound. So, when you have an antibody, such as ustekinumab, that blocks p40, you’re actually blocking both IL-12 and IL-23.

William J. Sandborn, MD: One question that comes up is how long you can continue ustekinumab therapy, and how long the remission might last. It’s really quite a highly durable drug. It’s interesting. It has a half-life of about 25 days, so the doses are long lasting. You can dose the patients every 8 weeks during the maintenance phase with subcutaneous dosing, and what we saw was that the maintenance effect in the clinical trials was really solid over time. You didn’t see a lot of loss. So, I found this in the clinical trials, and in practice, to be a very useful maintenance agent.

Transcript edited for clarity.
 

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