Unmet Needs of Therapy for Crohn's Disease

JANUARY 17, 2018
MD Magazine Staff

Marla Dubinsky, MD: When you think about where our field is going, about the research that we know is happening over the next 5 years, and about what the unmet needs are, we need to merge them together so that we’re ready for when new treatments come out. I think we only had a few classes of therapies since 1998. Between 1998 and 2014, we just had the anti-TNF class of therapy, really. All that happened was we went from an IV formulation to a self-injectable formation, then a self-injectable formulation that’s every month as opposed to every 2 weeks. So, we weren’t changing paradigms of the immune system for a long time, and then we had a new class of therapy called the integrins, of which vedolizumab is a member. And then last year, we had ustekinumab, which is the IL-12/23 inhibitor. So, we now have 3 classes.

I have a patient sitting in front of me. I have no way of knowing right now, with the developments or news we have, to say, “You should get an anti-TNF, you should an IL-23 or IL-12/23 inhibitor, or you could get an integrin-based therapy.” I’m not very good at telling a patient which one. All I can talk about is how long they were on market, what the 1-year clinical trial data look like, or what our off-label experience is. So, imagine how complicated it’s going to get over the next few years. We’re actually going to have even more targets. Imagine the idea that we need to be ready, let’s say in 2022, 5 years from now, to be able to say, “You should get an anti-TNF, you should get an IL-12/23 inhibitor, you should get an IL-23 inhibitor, you should get a JAK kinase inhibitor, you should get a JAK 1/3 inhibitor, and you should get a JAK 1 or JAK 2 inhibitor.” You could see the confusion that will ensue both on the patient’s side and on the physician’s side.

Our responsibility on the research side is to try and develop tools that will help the physician dictate what therapy would best work for that patient. Because one thing we know is that the first therapy is the most important. What we’ve learned so far is that the sequence of therapy is also going to be important, but our second drug doesn’t work as well as the first, and it’s the same with the third. Besides, by that time we’re saying, “Sorry, you need surgery.” This also brings in the idea that we need to figure out who should go to surgery first and then what the post-operative maintenance strategy would be. Because you don’t want to wait until 5 years later and maybe ruin the chance of using that drug again in the future, when the patient needed surgery.

A real unmet need will be to look at the tissue itself, going to the colon or ileal biopsy and saying, “Wow, you are a predominant IL-23 maker, and I’m going to use this drug.” We need to personalize our precision medicine, take a page out of the oncology space, use the platforms that they’ve used to figure out, for example, that there are 5 kinds of lymphoma. You knew that by going to the tissue and genetically understanding the treatment strategies.

That is happening in the background right now because we know that by 2022 we have to be ready or else there’s going to be mass chaos. You’ll have all these targets, patients aren’t going to know what to do, and physicians are going to be either resorting back to their original anti-TNF agent and then, if that doesn’t work, going to an innovative therapy. There are also biosimilars that are just going to complicate the space, because the cost of those may, I hope not, mandate that we need to go down the anti-TNF route first. So, of course we’ll be tracking that closely.

William J. Sandborn, MD: A really critical issue is, what are the unmet needs in Crohn’s disease? I would say there are several. We need some additional first-line therapies that are quite safe in patients with mild to moderate Crohn’s disease. And then, in the patients with moderate to severe disease, our best outcomes right now come with the early introduction of an anti-TNF agent plus an immune suppressive. But the problem is from a toxicity standpoint, because with the immune suppressive part of that, you end up with an increased risk of non-Hodgkin’s lymphoma, skin cancer, and serious opportunistic infections. All of those are undesirable. And if you don’t give the combination therapy, the remission rates are lower, the endoscopic healing rates are lower, and the ability to stay off steroids and prevent disease progression is lower. So, what I think we need more of in the years to come is additional, precision drugs that are not heavily immune suppressive and, ideally, that could be co-administered. So, you’d have 2 or 3 highly effective drugs that, from a safety profile, would be acceptable to give as double or triple combination therapy. We’re not yet at that utopia, so we’re looking to see 50% to 60% or more of patients have complete remission and healing with a favorable side effect profile.

Stephen B. Hanauer, MD: There are multiple unmet needs regarding Crohn’s disease treatment. We need to be able to treat the disease early in the patients with high-risk disease with effective therapies. At the present time, because of third party payer and insurance concerns, we often need to go through corticosteroids or immunosuppressives to move on to more effective therapy. A second important need is to replace corticosteroids. Steroids are cheap, they’re effective at controlling symptoms, but they really do not impact on the long-term course of the disease. And steroids are associated with the largest number of side effects, both systemic side effects as well as risks of infection and even the risk of death.

Bruce E. Sands, MD: As agents with newer mechanisms become available, I think we’re going to see a shift in the role of TNF blockers. TNF blockers have been around now for nearly 20 years. We have a wealth of experience with them. They are still viewed as our most effective agents. We know a whole lot about how to tune their utilization to improve their efficacy. We know how to bring patients back from loss of response. So, there’s a lot that we need to learn about those same points with the newer agents.  

Transcript edited for clarity.

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