Marla C. Dubinsky, MD: The Next Revolution for IBD Treatments

Mirikizumab might soon become a top treatment option for patients with ulcerative colitis.

The treatment continues to garner praise with new data in favor of its efficacy and safety being presented at virtually every recent gastroenterology conference.

During 2022 Digestive Disease Week Annual Meeting in San Diego, investigators led by Marla C. Dubinsky, MD, Icahn School of Medicine at Mount Sinai, explained the promise of mirikizumab and how it could usher in a new revolution of treatments.

The data was presented as a late-breaking abstract.

HCPLive: Can you give an overview on your late-breaking abstract being presented at DDW 2022?

Dubinsky: I am presenting the LUCENT 2 study, which is the safety and efficacy of mirikizumab, which is a p-19, IL-23 monoclonal antibody. I'm presenting the maintenance data, which is LUCENT 2, my colleague, Dr. Bruce Sands, is going to be presenting the induction study, which is LUCENT 1.

So particularly the study I'm presenting is all patients who responded to mirikizumab at 12 weeks.

I'm now going to be presenting those that actually respond at week 12, who are then re-randomized into either receiving or continuing mirikizumab in a subcutaneous formulation versus placebo.

I'm presenting the primary and key secondary outcomes related to the safety and efficacy of mirikizumab in the maintenance population. And what I'm going to be presenting on is the fact that mirikizumab was superior to placebo at all of the key primary and key secondary endpoints.

Specific data included clinical remission, which was the primary endpoint at week 52 was superior to placebo, also looking at maintenance of clinical remission, which is those who are in remission at week 12.

How many were able to maintain out to week 52 and data also showed significance over placebo.

Other endpoints such as response and 1 of the outcomes which is near and dear to my heart, which you and I have talked about before is bowel urgency. Showing that there was a persistent change in bowel urgency, which is a symptom that is probably the most important patient reported outcome for UC patients.

That is very exciting as well.

We also talked about the safety because you can't talk about efficacy without talking about safety. And again, the safety that we saw in the phase 2 studies as well as in the induction study continues to show that this drug has a consistent safety profile and there was no safety signal compared to placebo that rendered this drug to not be able to be both effective and safe for patients with IBD, for UC in particular.

HCPLive: How important is it to talk to patients about the aspects of the disease that might directly impact the quality of their lives, including bowel urgency?

Dubinsky: We've asked them in the CONFIDE (Communicating Needs and Features of IBD Experiences) study, which is a survey based study where we asked sort of patients versus healthcare providers What are the symptoms that a patient says most impacts their quality of life?

Urgency ranks very high, if not the top on their list of things that keep them from having relationships, engaging in intimate relationships, having a social life, being able to go to work on time.

Imagine that 46% of patients that were surveyed said that they have to think about or actually use a diaper due to urgency or incontinence.

Imagine that as a patient and being able to say that we have a therapy that specifically looked at that and targeted that and be able to bring urgency to the conversation for both providers and patients because we have a therapy that actually specifically looked at it in their trial.

Now there's other trials and other drugs that have used other types of patient reported outcomes where urgency is one of the questions.

The beauty about the urgency, numeric rating scale, which was specifically developed in the context of the mirikizumab program, it's an 11 point scale zero to 10.

Looking at an average of seven day’s worth of monitoring or tracking or urgency, and be able to show in a clinical trial that the drug not only address common symptoms that people look at in all trials, which is rectal bleeding and stool frequency that remains in every trial, but the fact that this was called out as a specific endpoint.

That's really just a really advanced in our field for patients with ulcerative colitis.

HCPLive: Is bowel urgency generally something that worsens over time?

Dubinsky: There's a few things that result in urgency. There's actual inflammation of the rectum for example, since that sort of irritability or inflammation renders the rectum sometimes not able to function correctly and this urge to go even resulting as I noted and having accidents.

The ability to heal that inflammation definitely is why bowel urgency responds when you heal the intestinal lining. However, what we've also learned is that there are patients who have had long standing rectal inflammation who sort of lose compliance in their rectum that even if their lining is healed, so we call that the mucosa.

Even if the mucosa is healed, even down to the cells under the microscope, they may not be any. There could be because the rectum is a muscle. And it could be that if you leave inflammation untreated for a very long time, we're not talking just within the constructs of one year trial, but years of suffering years of uncontrolled inflammation, that your muscle may not work as well.

We also saw that in patients even if they're healed on the inside, there is still patients who may suffer from urgency and require more pelvic floor therapy or a different approach.

But it is tied to the fact that you have long standing untreated or inadequately treated inflammation, which is why having therapies that target these symptoms specifically getting the dialogue with providers to include urgency as a question even in our note.

Now it's going to raise to the attention of providers and patients and be able to talk about it openly. It's often an embarrassing topic. Do you make it to the toilet in time? Have you had an accident? Do you have to wear or bring a diaper with you to work that has never been asked? Yeah, this survey allowed us to actually understand that we need to start asking this question because this is what keeps patients up at night.

HCPLive: Do you think mirikizumab will be one of the big drugs in the space in the coming years?

Dubinsky: If you take the journey with me on IBD and think about in the late 90s When infliximab first came out, and we focused on what I call the anti TNF revolution and then we had two sometimes three other anti-TNF that were developed over time, mainly due to different delivery mechanisms, the target remained the same.

And then in 2014, for UC we had vedolizumab or a new integrin base type of monoclonal antibody. In 2019, we had ustekinumab which has the IL-1223. But now we see a revolution in understanding the importance of blocking IL-23, not just tumor necrosis factor.

So I call this the next revolution in immune disease management such as IBD, which is targeting IL-23.

You've heard a lot in the Crohn’s space, we have rizakinumab which are waiting for approval for that and this will be the first IL-23 targeted for ulcerative colitis if and when it gets approved. And the idea that we are now entering into a new revolution is really exciting and why you've heard a lot about it.

HCPLive: So you think this will spawn many other drugs targeting IL-23?

Dubinsky: I think we already know there's a lot of others in the pipeline. I think the fact that hopefully shortly for Crohn's and hopefully in the not too distant future for UC, we're going to have two really great options that is amazing for patients, because there's a lot of patients who don't respond to all the other therapies that have come to market, particularly anti-TNF.

It is not the right choice for many patients, yet it became a default because we didn't have this understanding of a whole other pathway or immune system pathway that we need to attack

Now where I think the next five years is going to be, I view it in sort of two different ways is that you have patients where we need to get to precision medicine where we can say based on clinical characteristics or biomarkers or genetics are however trying to get as close to oncology as we can, where we can actually go to the tissue and say this patient needs this pathway.

This patient needs this pathway. And I think the 23 blockade is going to be a major part of that dialogue, because we may figure out that there's a certain group of patients where sequencing of drugs will matter.

And your first sequence is best served by targeting IL-23 or your best sequences going to TNF first or an integrin base.

I view this as just the tip of the iceberg of what the next five years are going to look like. And there's other writers s-p receptor modulators, there's JAK's.

So it is an incredible time in for IBD patients. I never thought I would say that we would have this many targets for ulcerative colitis, it's almost sort of unbelievable from when I started my practice.

It was infliximab, that was all we had. And now we have, you know, a treasure trove of options but we need to know how to actually use them correctly. And understand which patient benefits from which therapy because the first one you try is the one that's going to have the most impact. So you got to get it right. And I think the l 23. Revolution, as I call it is really going to help us get it right.