Crohn's Disease: Measuring Therapeutic Response

Marla Dubinsky, MD: There has been a lot of discussion on what the endpoint is of using, for example, anti-TNF therapy. Is it symptom relief, which was originally how the drug was approved? Or do we have to go to what we believe to be the most durable response, which would be something we call “deep remission”? Deep remission means mucosal healing. We’re even dabbling with the idea that deep remission may mean that under the microscope, meaning histologically, the patient has no active inflammation.

I remember a time when if a patient presented with no chronic changes under the microscope, we were questioning whether the patient even had Crohn’s disease. That’s how much we couldn’t imagine being able to achieve histologic healing. Now, even for regulatory trials and registration trials with the FDA, we’re thinking, should histologic healing be an endpoint? Look how far we’ve come in terms of saying, “As long as your bowel habits are better and you have less pain, we’re happy. That means the drug is doing what it’s supposed to do,” to now. Our expectations are that if we are going to change someone’s natural history and restore them back to how they were predisease, we may have to get as deep as histologic remission.

Right now, while we’re dabbling in that definition of response, whether there are neutrophils in the crypt abscesses, for example, we’re talking about measuring response to a therapy at the level of the mucosa. So, yes, it is natural that if a patient has a healed lining, they should feel better. I should note that in some of our trials, we’ve shown that pain and loose stools in a patient with Crohn’s disease are not always related to Crohn’s disease. There may be an irritable bowel syndrome overlay or lactose intolerance or other reasons why patients have symptoms, which is why both at the regulatory level and even at our discussion level we feel that we need to achieve mucosal healing.

That is the definition of the ultimate response of remission. Patients who aren’t better despite healed lining need other ways of improving their symptoms, whether it’s antibiotics, whether it’s hypnotherapy, or whether it’s cognitive behavioral therapy. There are other aspects, and that’s why having a clear objective outcome is really going to move the needle and transform people’s lives. That’s where we need to get patients, all the way over here as well, recognizing that if we heal the mucosa and they want a better of quality of life, if the quality of life has not improved despite mucosal healing, we need to work on that and not just say, “I’m sorry. I’m out. I’ve achieved what I wanted to achieve by treating you.” That’s why behavioral health teams, for example, are such an important part of this.

Defining our endpoint, we’re working with the FDA and EMA and other regulatory agencies to say, “What is expected of our drug? Is it realistic? And if so, should we start applying that to regular standards of care?” If it is the endpoint for clinical trials now for Crohn’s disease, which it never has been, not 1 primary endpoint in the clinical trials to date has been mucosal healing or endoscopic remission or response. However, we’re going to define it. And now, are drugs going to be approved based on that? We better start having that as an outcome in the drugs that we’re using right now, right? Because if we’re expecting that for future drugs, we should expect that of the drugs we have now.

Anti-TNF, for example, despite it being approved based on response and remission, also has a very nice mucosal endpoint. And so right now, we are trying to get patients better and achieve their outcome of interest, which is, for us, the endoscopy.

However, what we’ve also come to realize is that while we’re chasing an endoscope or we’re chasing a stool biomarker to see if a patient is still inflamed or not, we also have drug levels. We have the ability to now know that for patients who achieve a certain drug level at their time of their infusion, when they’re sitting in the chair, for example, or when they’re getting their injection, there’s a minimum drug concentration. We call that “trough” concentration. That should be there for the patient to have a durable long-term response. And just like the reactive nature of how we used to define complicated Crohn’s disease, where we waited for patients to complicate and then validated our thoughts that they have a complication, we’ve now changed therapeutic drug monitoring away from getting a drug level when a patient is not responding to it and then saying, “Oh, you’re not responding because your drug level is too low,” or, “You’re not responding because you’ve already got antibodies against the drug, because the drug levels were too low and I never checked it,” even though the patients say, “I’m fine, I’m fine. Don’t touch me, don’t scope me, don’t measure anything. I’m fine.”

Now we’ve said, “Forget that reactive drug monitoring, let’s do proactive drug monitoring,” which means that early on when you first start the treatment, you make sure that the drug levels are adequate or else the drug levels are going to fall off and the patient’s going to develop antibodies. So, proactive therapeutic drug monitoring, proactive risk stratification, and proactive intervention with anti-TNFs. An IV patient’s life now is different than what it was before, because we understand the natural history and we’re able to actually proactively make a change in someone with Crohn’s disease’s life.

Bruce E. Sands, MD: When someone is first treated with an anti-TNF agent, we look at their response and determine whether they’re a primary responder or a nonresponder. Secondly, if a patient does respond, they may lose response. That would be a secondary nonresponder. Primary nonresponse is defined as someone who gets an adequate course of induction treatment with their anti-TNF agent and simply doesn’t have an adequate clinical response. If you want to be very rigorous about the definition, you might include measurement of drug levels and ensure that the patient had achieved adequate drug levels. If they did and still did not achieve a response, they probably are not going to respond to the TNF suppression mechanism at all. At that point, it’s best to move on to a different agent.

It’s a different matter for patients who have secondary loss of response. Those people had a primary response. Maybe they maintained it for some period of time, but over time, that response petered out. The reasons for that could be quite varied. They could include that the patient had developed antibodies against the TNF blocker, in which case switching to a second TNF blocker might be a good strategy. It could be that they have adequate levels of the anti-TNF, still but are no longer responsive to that agent. In that situation, moving to a drug with a different mechanism would be useful. It’s also possible that the patient may simply be underdosed. They don’t have antibodies against the agent, they just have low levels because of pharmacokinetics intrinsic to the person. And in that situation, simply updosing will probably bring the patient back under control.

Transcript edited for clarity.