Optimizing IBD therapies may depend on positioning, dosing, targeting new pathways

Stephen B. Hanauer

BOSTON – Given the numerous biologic pathways targeted by inflammation, the future development of new therapies for inflammatory bowel disease will need to focus on optimizing outcomes, and on individual patient and disease features, according to a presentation given at the Interdisciplinary Autoimmune Summit.

Stephen B. Hanauer, MD, medical director of the Digestive Health Center at Northwestern Medicine, said the IBD community has had a wealth of success in the development of new drugs over the last 5 or so years, but the success of any single therapy has been limited because of the complex pathophysiology of the disease.

“We have a number of different targets. We have too many targets,” he said. “The number of targets will tell us why were only getting 30% to 40% efficacy in any of these drugs.”

Hanauer said better efficacy could come down to position or dosing. However, the nature of the disease and its ability to affect many different immune receptors makes it inherently difficult to treat. If one receptor is blocked, Hanauer said the disease can find a route around it.

New drugs, new pathways

Recently, new therapeutic targets like interleukin (IL)-12 and IL-23 have become relevant in the setting of Crohn’s disease and show potential efficacy in ulcerative colitis, Hanauer said.

While IL-12 tends to be upregulated early in CD, upregulation of IL-23 occurs once the disease is established, he explained.

Emerging therapies that target these pathways include Stelara (ustekinumab, Janssen), which was recently approved by the FDA for Crohn’s disease. This agent targets both IL-12 and IL-23, and showed significantly greater efficacy vs. placebo in the UNITI studies. Other earlier phase investigational agents include MEDI2070 (Amgen/AstraZeneca), which specifically targets IL-23. In a study presented at ECCO, the agent demonstrated a significant clinical effect, and led to more than a 50% reduction from baseline in fecal calprotectin and C-reactive protein in 42.6% of patients compared with just 10% for placebo. Yet another investigational IL-23 inhibitor, risankizumab (AbbVie), induced clinical remission at week 12 in 30.5% of patients with Crohn’s disease vs. 15.4% in the placebo group, according to data shared at DDW 2016.

Janus kinase (JAK) inhibition is another emerging pathway implicated in the pathogenesis of ulcerative colitis. Xeljanz (tofacitinib, Pfizer), for example, is an oral small molecule JAK inhibitor that demonstrated efficacy for ulcerative colitis in the OCTAVE trials. It is currently approved for rheumatoid arthritis and psoriatic arthritis, and the FDA is expected to make a decision on approval for UC in June 2018. Other JAK inhibitors in development include filgotinib (Gilead) and upadacitinib (AbbVie), Hanauer noted.

As more of these drugs are developed, Hanauer argued there is a need for comparative effectiveness studies between new drugs and established therapies, because changes in regulatory requirements will make it difficult to make comparisons using network meta-analysis.

The number of new drugs has also made things difficult for researchers, Hanauer said.

“There’s a simple problem to this,” he said. “We don’t have the patients to study all these agents. We’re starting to have to prioritize based on very limited data.” – by Alex Young

Reference:

Hanauer SB. “Managing IBD with Targeted Pathophysiologic Strategies.” Presented at: Interdisciplinary Autoimmune Summit; April 27-29, 2018; Boston, Mass.

Disclosures: Hanauer reports that he conducts clinical research for AbbVie, Amgen, Celgene, Genentech, GSK, Janssen, Lilly, Luitpold/American Regent, Novartis, Novo Nordisk, Pfizer, Prometheus, Receptos, Sanofi-Aventis, Takeda, UCB Pharma, and Luitpold/American Regent; consulting for AbbVie, Actavis, Amgen, Arena, Astellas Pharma Global, Astra Zeneca, Baxter, Boehringer Ingelheim, Bristol-Myers Squibb, Catabasis, Celgene, Celltrion, Cellceutix, Cubist, Ferring, Forest Labs, Genentech, Glenmark, GSK, Hospira, Janssen, Lilly, Luitpold/American Regent, Meda, Merck, Nestle, Novartis, Novo Nordisk, Pfizer, Prometheus, Receptos, Salix, Sanofi-Aventis, Seattle-Genetics, Seres Health, Shire, Sun Pharmaceuticals, Takeda, Theradiag, TiGenix, UCB Pharma, VHsquared; performs data and safety monitoring for Bristol-Myers Squib; and he is a speaker for AbbVie, Janssen, and Takeda.