Therapeutic Optimization in Crohn's Disease - Episode 17
William J. Sandborn, MD: Where is the field going? I see several things, the real application of treat-to-target in clinical practice. I anticipate we’ll see some precision medicine, where the knowledge about genetics and inflammation pathways might be applied to choose particular patients whose inflammation is more susceptible to drugs that target the abnormal pathway that they have. Right now, that’s all empiric, and we just guess. I see an evolution towards more combination therapy, but with an emphasis on finding components of the combination therapy that are acceptably safe to mix together. We also recognize that many patients with Crohn’s disease who were treated with biologics didn’t get sufficient personalized dosing. So, I anticipate that we’ll see more and more therapeutic drug monitoring and personalized dosing of biologics. That tends to drive up response and remission rates. And the sum total of all these things could really make the world look different in 5 years from what it does today.
Marla Dubinsky, MD: I think one of the most exciting aspects of IBD is that we never utter the word prevention, other than to say we want to prevent complications. And that’s more tertiary prevention. That means you have a patient who is already diagnosed, talking about all of the things that we talked about in terms of risk stratification and predicting complication. That’s tertiary prevention. Imagine that we’re actually, right now, studying something called secondary prevention, where you’re looking at those people, for example, siblings, who are genetically at highest risk, or family structures.
We’re working closely with the Orthodox Jewish community, because they have a significant genetic risk load in multiple family members, or other families who are not Orthodox Jewish but have multiple first-degree relatives diagnosed. We are looking at those siblings who don’t have disease yet and following them closely, following their microbiome every 3 to 4 months and seeing whether or not there’s a switch in their microbiome right before they get disease and saying, “Wow, when they have this microbiome pattern, there’s no disease. When they switch to this microbiome profile or this metabolite,” meaning what the bacterial byproduct is, “they develop disease.” So, why don’t we develop a cocktail that looks more like the state where the patients didn’t have disease and create a true targeted microbial therapy to that patient’s microbial profile?
Fecal microbial transplant, albeit exciting and considered curative by some, is really in the C difficile, or clostridium difficile, space. The IBD space has really conflicting evidence and merits further investigation for sure. However, one thing we understand is that you maybe shouldn’t just give a single transplant from a mystery donor who has a whole bunch of different pathogens. Maybe it will become targeted fecal transplant or it will be a pill, because I don’t think that’s a sustainable model. But a pill, for example, that gives you or me the right microbial pattern is filling in for what I was missing, because I realize I was missing bacteria that made short-chain fatty acids. Short-chain fatty acids are anti-inflammatory, protect the gut, and make the mucous layer work better so that you don’t have bacteria crossing into the lining. Maybe that magic pill or diet food or whatever it is will have bacteria or short-chain fatty acids themselves to help repopulate the gut in that individual.
Imagine we’re using targeted microbial therapy in people with IBD, with the idea that we’re going to perhaps create microbial therapies for people who don’t have avert evidence of disease but look like they’re headed in that direction, to reverse their microbial pattern back to a healthy fate.
Never did we utter the word prevention. We always uttered cure, but I think, to me, prevention is the new cure. I think with trillions of bacteria and 200 and some-odd genes, how exactly are we going to be cured unless we feel that there’s 1 trigger? Of course not, or else it would have been done by now.
William J. Sandborn, MD: Another question is, what else is new? What’s coming in terms of Crohn’s disease? There’s a number of interesting molecules. One is called mongersen. It’s an antisense administered orally that blocks SMAD7 and is a pro-mucosal healing drug with a very good side effect profile because of its local delivery system. So, that’s looked very interesting in phase II trials in Crohn’s disease and is being tested in phase III. There are several Janus kinase, or JAK, inhibitors, upadacitinib and filgotinib, that are being investigated in Crohn’s disease. These are relatively JAK1, or Janus kinase 1, selective. They’re orally administered. They have some incidence of herpes zoster and you can see infection, but they’re relatively well tolerated, at least as good as other drugs that we use like steroids and azathioprine from a tolerance standpoint. And they are effective, particularly in the patients who failed on anti-TNF therapy. Some of the clinical trials will have enrolled patients who have failed 2 or 3 anti-TNF drugs and vedolizumab, and despite that, they will respond to oral Janus kinase 1 inhibition. So, I think that’s very interesting. We can see colonoscopy healing with that class of drugs in the refractory patients.
Another class that’s interesting are the patients with pure interleukin-23. Recall that with ustekinumab, you block p40, which is shared by interleukin-12 and interleukin-23. By contrast, the anti-p19 drugs block the other subunit of interleukin-23 that is not shared by additional cytokines, and that’s p19. So, there’s a number of anti-p19 or anti—interleukin-23 antibodies in development, including brazikumab, risankizumab, and mirikizumab in the Crohn’s disease setting. And the plenary results show that this particular class of monoclonal antibodies is highly effective in Crohn’s disease. You can see colonoscopy healing and it seems to work in patients that have failed anti-TNF drugs, which is a big unmet need. So, I think that’s quite exciting. We’re applying all the principles of more intensive dosing, learning the lessons that we learned in the anti-TNF years to optimize the dosing of these newer drugs, and those look very promising.
Another drug class that is being tested in Crohn’s disease is sphingosine 1-phosphate, or S1P1, receptor modulation. This basically results in the trapping of a subset of lymphocytes in lymph nodes, so it’s a selective lymphocyte reduction. It’s worked very well in ulcerative colitis. More recently, including a pilot study in Crohn’s disease, the drug that is in clinical trials is ozanimod. That’s going into phase III now in Crohn’s disease as well. So, there is a lot of cause for optimism with the future pipeline.
Transcript edited for clarity.