Stephen B. Hanauer, MD, on Improvements in Targeted IBD Therapies

Dr Hanauer discusses his presentation from the Interdisciplinary Autoimmune Summit on the advances and improvements made — and coming in the future —in targeted biologic and small molecule therapeutics for the management of inflammatory bowel disease.

Stephen B. Hanauer, MD, is the Clifford Joseph Barborka Professor of Medicine at the Feinberg School of Medicine at Northwestern University in Chicago, Illinois.

TRANSCRIPT

Hello, I'm Steve Hanauer from Northwestern University in Chicago. During my presentation in the Interdisciplinary Autoimmune Summit, I was discussing small molecules and other new advances in the treatment for patients with inflammatory bowel disease.

Over the past 20 years, we have primarily focused on advances related to biologic therapies including the development of a series of tumor necrosis factor inhibitors; other cytokine inhibitors, at the present time ustekinumab, which targets both interleukin-12 and interleukin-23; as well as antiadhesion molecules, previously natalizumab and more recently, the gut-specific vedolizumab.

All of these have provided significant advances for patients with both ulcerative colitis and Crohn's disease while none of them have actually impacted a large percentage of patients. Approximately 40% to 60%of patients have significant clinical improvement or clinical remissions with any of these biologic agents.

Unfortunately, in patients who have failed one group, such as TNF inhibitors, responses to the next agent have been further sublimated. Over the past several years, we've had the introduction of a first oral therapy for moderate to severe ulcerative colitis, that being tofacitinib.

Tofacitinib has been very effective for patients with moderate to severe ulcerative colitis, but its use has recently been limited by the Food and Drug Administration to patients who have had an inadequate response to tumor necrosis factor agents.

Unfortunately, because patients who have failed TNF inhibitors have a sublimated response; it somewhat limits patients with treatment for tofacitinib to those who are likely not to have the best response because the best response to any of these therapies, be it biologic or small molecule, is as a first-line agent.

With the advent of tofacitinib, the first oral JAK inhibitor for ulcerative colitis, this has opened the door in both rheumatology, dermatology, and gastroenterology for more focused Janus kinase oral inhibitors. The tofacitinib is a less specific JAK inhibitor, and there are some off-target impacts including immune suppression but also potential impacts on cholesterol.

With the more specific JAK inhibitors, it appears that we can potentially improve efficacy as well as reduce some of the risks of infection, which primarily involve a risk of reactivation of herpes zoster infections. Tofacitinib and subsequent JAK inhibitors that are currently under development for ulcerative colitis and Crohn's disease looked to be very promising as oral agents.

Now, indeed, oral agents have a number of advantages compared to biologics. Firstly, they're pills rather than injections or infusions, but they are also not associated with immunogenicity. Patients do not develop antidrug antibodies to these oral agents, so they can be stopped, for instance, perhaps for pregnancy, and then restarted without the concern for infusion or injection site reactions.

Now along with a series of more specific Janus kinase inhibitors, another class of oral agents has been coming into play in the setting of inflammatory bowel disease. This class are known as S1P modulators or sphingosine-1-phosphate modulators.

Sphingosine is a chemical that is present in lymph nodes and allows or prevents the egress of lymphocytes out of the lymph nodes based on the gradient of sphingosine. By modulating this process, a number of agents such as ozanimod actually trap lymphocytes in the lymph nodes so they're not able to circulate and cannot get into the tissue. It's another form of lymphocyte or leukocyte-trafficking agent.

Ozanimod has already been approved for the treatment of multiple sclerosis and has been submitted for approval for the treatment of ulcerative colitis. Additional S1P modulators that are even more specific than ozanimod are also under development. These agents appear to be both safe and effective. There is a potential for immune suppression. S1P modulators can also affect cardiac rhythms. For some of these agents, it may be necessary to exclude prior cardiovascular disease or any particular rhythm abnormalities before instituting and possibly immediately after starting one of these agents.

Nevertheless, another class of oral agents that can inhibit lymphocyte and leukocyte-trafficking appears to be promising in the setting of inflammatory bowel disease as well as in the setting of other conditions such as multiple sclerosis.

Again, these oral agents have the advantage of being able to stop and restart without the issues of immunogenicity, and they can be temporarily halted in case of side effects or any intervening illnesses.

Now, where these new classes are going to enter into the therapeutic armamentarium remains a bit to be determined. Of course, we are missing head-to-head studies of these agents versus one another or versus any of our biologic classes of agents. Comparative effectiveness remains to be established as does comparative safety.

Finally, as all of the clinicians understand, many of these therapies are going to be prioritized by insurance companies who are ultimately going to make the decision of access for individual patients, but these along with a number of new biologic agents are going to significantly expand our armamentarium in the options for patients with ulcerative colitis and Crohn's disease. Thank you.