Stephen Hanauer, MD, on Beyond TNFis: Optimizing IL-12/23 and IL-23 Inhibitors in IBD

Dr Hanauer reviews his presentation at the Interdisciplinary Autoimmune Summit on the use of interleukin 12/23 and interleukin 12 inhibitors in the treatment of inflammatory bowel disease.

Stephen Hanauer, MD, is the Clifford Joseph Barborka Professor of Medicine at the Feinberg School of Medicine and medical director of the Digestive Health Center at Northwestern University in Chicago, Illinois.

TRANSCRIPT:

Hello. I'm Dr. Steve Hanauer, professor of medicine and medical director of the Digestive Health Center at Northwestern University Feinberg School of Medicine, and Northwestern Medicine, in Chicago. I am one of the 3 senior advisors for the Interdisciplinary Autoimmune Summit, and I have provided a discussion regarding interleukin 12 and interleukin 23 pathways in the setting of inflammatory bowel disease.

The discussion included the role of IL-12 and 23 in the inflammatory pathways, how our treat-to-target strategy has been evolving to incorporate newer therapies, including IL-12 and IL-23 inhibitors, and I also described the key efficacy and safety data for ustekinumab and several of the interleukin 23 inhibitors in the treatment of inflammatory bowel disease.

While we have been using tumor necrosis factor inhibitors or blockers over the past 25 years for the treatment of IBD, as well as many other immune-mediated inflammatory diseases, we continue to learn about the role of different cytokine pathways and networks in the treatment of these various immune-mediated diseases. And as we've recently learned, while TNF is a central mediator, there are a number of other very relevant cytokines that have different roles in different tissues, such as the gut, the joints, as well as the skin. And there has been a diversity of cytokine inhibition studies in and amongst these immune-mediated inflammatory diseases.

We've learned that TNF inhibition is very effective, but there remain significant therapeutic gaps as our goals of therapy continue to evolve, and go deeper and deeper into the achievement of not only clinical but also biologic remissions. So over the past several decades, our treatment goals or endpoints in clinical trials have evolved, in both ulcerative colitis and Crohn's disease, from clinical remission and steroid-free remissions to endoscopic improvement, and most recently histologic improvement and histologic remissions, based on the absence of neutrophils in tissues after treatment with therapies for inflammatory bowel disease.

Our treatment targets have continued to narrow to include both clinical improvement and resolution of symptoms, as well as normalization of biomarkers, such as C-reactive protein or fecal calprotectin. in inflammatory bowel disease, and in children, improvement in growth. We also have been able to achieve mucosal healing, now termed mucosal improvement, which is a return to a normal mucosal vascular pattern and intact mucosa when we examine the bowel endoscopically. And as I mentioned, most recently, histology has been incorporated into our therapeutic goals, as improvement in endoscopic and histologic findings have correlated with improvements in outcomes, such as sustained remissions clinically, the reduction in hospitalizations and surgery, with an ultimate goal in the future for disease modification and preventing progression of ulcerative colitis or Crohn's disease.

Utilizing this treat-to-target strategy, we have identified that utilizing biomarkers, in addition to symptoms, can add additional important endpoints such as endoscopic healing in patients that have been presented in what's known as the CALM, C-A-L-M, study, reported by Jean-Fred Colombel in Lancet in 2017. So all of our societies have begun to assimilate the treat-to-target strategy, which offers improved long-term outcomes compared to treating symptoms alone.

At the same time, we've begun to dissect the underpinnings of the immunopathogenesis of inflammatory bowel disease and other immune-mediated diseases. And as I've mentioned, we recognized a variety of inflammatory mediators, including cytokines, that have been quite relevant in both the pathogenesis, and served as excellent treatment targets, with primarily biologic therapies in the setting of the immune-mediated diseases.

Cytokines have also had a very prominent role in the differentiation of lymphocytes and inflammatory cells in different tissues. As I mentioned, TNF is a relatively central mediator that has a role in skin, joint, as well as the gut. But on the other hand, inhibition of TNF may have bad effects in central nervous system disease, such as multiple sclerosis. We've also identified more recently that interleukin 23 has a very prominent role in the skin in patients with psoriasis, and in the gut in patients with ulcerative colitis and Crohn's disease.

IL-12 and IL-23 share the p40 subunit in the receptors. And by inhibiting p40, we get inhibition of both interleukin 12 and interleukin 23. And a very relevant inhibitor of IL-12 and 23 is ustekinumab. That's been demonstrated to be effective in the treatment of both ulcerative colitis and Crohn's disease and has achieved these deeper goals of clinical steroid-free remissions, as well as endoscopic improvement, and in the setting of ulcerative colitis, improvement in the histology as well as endoscopy.

Most recently, however, specific IL-23 inhibitors, based on inhibition of the p19 subunit, which is unique to interleukin 23 and not present in interleukin 12 receptors, has also been effective in a variety of immune-mediated diseases, including psoriasis and psoriatic arthritis. And most recently a series of anti-p19 monoclonal antibodies, including brazikumab, risankizumab, mirikizumab, and guselkumab have been studied in different settings of immune-mediated diseases, including ulcerative colitis, and also in the setting of Crohn's disease.

The advantage of interleukin 23 inhibition is based on both efficacy and safety. We've learned from ustekinumab, the IL-12 and 23 inhibitor, that we can achieve clinical endoscopic and histologic improvement in patients with both ulcerative colitis and Crohn's disease, with a very excellent safety profile and a very low incidence of serious infections and absence of significant neoplasia outside of the setting of nonmelanomic skin cancers, which can occur in the setting of psoriasis, that have not been seen yet in the setting of ulcerative colitis or Crohn's disease.

We have also seen presentations already of clinical studies looking at risankizumab in the setting of Crohn's disease, in both patients who have been biologic naive as well as biologic exposed. And in these publications that are going to lead to the approval of risankizumab for the setting of Crohn's disease, probably in the next several months, we've seen coprimary endpoint improvements at week 12 extending out to week 52, in both patients who are biologic naive, as well as patients who have been bio-exposed. So it looks like this class of medications, including a variety of subsequent to come IL-23 inhibitors, are going to offer improved benefits as well as improved safety. And as we've seen with ustekinumab, which starts with an intravenous infusion and then is followed by subcutaneous injections every 8 weeks, a very efficient and very tolerable administration profile for patients, who would only need 6 subcutaneous doses in 1 year.

What we've learned with all of these agents is that the earlier within the course of Crohn's disease that we treat, the better the outcomes are going to be, and this is the potential area for disease modification in the setting of Crohn's disease. When we administer these effective and safe therapies too late, while patients already have the complications of strictures or fistula, we can't prevent these transmural complications. So both the safety and the efficacy of IL-23 inhibitors and IL-12/23 inhibitors, such as ustekinumab, risankizumab and others to follow, will offer earlier intervention of patients in a very safe and convenient manner. Thank you.