IBD Drive Time: Sunanda Kane, MD, on JAK Inhibitors

Sunanda Kane, MD, and host Raymond Cross, MD, discuss JAK inhibitors in the treatment of inflammatory bowel disease in this IBD Drive Time podcast.

Sunanda Kane, MD, is a professor of medicine at the Mayo Clinic in Rochester, Minnesota, where she specializes in the care of patients with IBD. Raymond Cross, MD, is a professor of medicine and director of the IBD Program at the University of Maryland School of Medicine.

TRANSCRIPT:

 Raymond Cross:  Welcome, everyone, to "IBD Drive Time." I'm Raymond Cross from the University of Maryland School of Medicine. I'm delighted to have my colleague and friend Susie Kane, from Mayo Clinic, on our podcast to talk about JAK/STAT inhibitors. Susie, welcome to IBD Drive Time.

Sunanda Kane:  Thank you. It's great to be here. Thanks for asking me.

Dr Cross:  Susie, let's just jump right in. Can you explain to our listeners some of the differences between how these JAK/STAT inhibitors work compared to our conventional anti-TNF and novel biologic therapies?

Dr Kane:  Sure. At this point, most gastroenterologists feel pretty comfortable with understanding different parts of the immune system and where we have targeted previously with our biologics.

JAK/STAT inhibitors are just another means for inhibiting activity of another pathway of our immune system. These, collectively, are the JAK kinase cytokines. We know that JAK kinase is an important pathway for inflammation and that if you inhibit these pathways, that you can actually then downregulate that pathway and treat different autoimmune diseases.

It's important that people understand that JAK kinases are a family and that there are at least 3 JAK kinases, maybe 4. Ray, you may have a better sense of this than me, with your background.

It's important that people understand that the first drug that we're going to talk about that has FDA approval in this class, which is tofacitinib, is an inhibitor of all 3 of the important JAK kinase pathways. It's nonselective.

Why does that become important? Because there are other JAK kinase inhibitors that are coming down the pike, that are already FDA-approved for other indications, that are more selective. That's where the differentiation comes in for these different agents.

Dr Cross:  I'm going to come back and ask you about those more selective JAKS in a minute. The pivotal trials, Susie, for tofacitinib were OCTAVE 1 and 2. There's so many endpoints for that trial. Can you just briefly summarize the high-level findings from OCTAVE 1 and 2 that led to approval by the FDA?

Dr Kane:  Yeah, absolutely. I just want to mention, really important — it was so important that I forgot to mention it because it seemed so obvious — that the JAK/STAT inhibitors are oral medications.

That's just another big differentiator between these class of agents and our other biologics. These are oral therapies. They're not biologics because they are not antibodies. They are called small molecules, as opposed to biologics. That's where the nomenclature changes...

Dr Cross:  And no immunogenicity...

Dr Kane:  Which is great. OCTAVE 1 and 2 were published in the New England Journal of Medicine, back in 2017. These agents are new to us but not necessarily new to the autoimmune world. In OCTAVE 1 and 2, these were the trials for looking at short-term response and remission.

Patients were given 10 mg BID or placebo for 8 weeks. The endpoint was clinical remission for moderate ulcerative colitis. There was OCTAVE Sustain, which were the patients who initially responded to that 8 weeks, then were randomized to either 5 or 10 mg BID for 52 weeks.

What were the main results? At week 8, for the OCTAVE 1 study, 18.5% of patients were in clinical remission at 8 weeks versus only 8% in the placebo trial.

In OCTAVE 2, it was 16% versus 3.5. There was clearly a benefit here for a hard endpoint of clinical remission, as soon as 8 weeks, for these patients who were biologic naive or biologic exposed. This was a population that was particularly ill, so some very impressive results, very early on, for that 8 week.

Maybe we're going to get there. You're going to ask me about safety. Maybe I'm stealing your thunder [laughs] with the next question. Obviously, we want to know about efficacy. Again, the primary endpoint was clinical remission, a much harder endpoint than clinical response.

If you look at response, which is what patients are interested in as well, the rates were well over this 18 to 16 percent. We're talking about 35 to 40%. Endoscopically, we were seeing, at the end of 8 weeks, some very impressive endoscopic healing as well.

Dr Cross:  Susie I'm going to come back to safety. Just quickly, with the novel biologics we have, there's this sense that perhaps their onset of action is a bit slower. Maybe that's been overplayed a little bit. How fast is the onset of action with this drug, or how fast can it be, should we say?

Dr Kane:  There's been a lot of slicing and dicing of the OCTAVE data since that 2017 paper. We know, now in published studies, that as soon as 2 weeks, patients can see a significant decrease in stool frequency as well as absence of bleeding. Pretty important to patients that they can feel better really pretty quickly.

Dr Cross:  It's real too. I've had 2 patients tell me that after 2 doses, they've had complete resolution of their rectal bleeding. It can be fairly impressive, although it doesn't mean we don't give them a full 8 weeks to see if they're going to respond. That's why I try to emphasize there's a subset that respond pretty quickly with this drug.

Dr Kane:  I will tell my patients as well that yes, this is fairly rapid onset, akin to even steroids. You will start to feel better and see a difference within just a few days, yes.

Dr Cross:  Let's come back to safety. Let's focus on what we've seen in our ulcerative colitis study. What are the key safety concerns with this drug that we need to communicate to our patients?

Dr Kane:  Out of those OCTAVE trials that were published in the New England Journal paper, if you go back to it, they do talk about the signal of herpes zoster infection being higher in the treated patients versus placebo, and the nonmelanoma skin cancers as well as the cardiovascular events.

There were signals back then that perhaps we needed to pay attention to what was happening in these patients given these JAK kinases. Where are we sitting? About a 5% increased risk for shingles. It's hard to know what to tell patients about nonmelanoma skin cancer risk, but the frequency in the trials for exposed patients was higher.

As you know, we just recently had the FDA with the black box warning about tofacitinib and significant cardiovascular events, including stroke and myocardial ischemia leading to death even. Having said that, that's pretty scary, but it's really been seen in our rheumatoid arthritis patients who are on tofacitinib, not the ulcerative colitis population.

There's been a lot of going back and looking and slicing and dicing of all of the data available in the OCTAVE trials, in the Sustain and then also in just post-marketing. We're just not seeing the same type of elevation in risk in our all ulcerative colitis patients.

Bill Sandborn presented...It was ACG, where he presented individual patient data for who had developed venous thrombus embolus events. The N back then was 7. All of these patients had other risk factors for why they would have VTE.

Really, while we do have to talk about this and keep our eyes and ears open, this is not something that would keep me from prescribing this class of therapy to a patient.

Dr Cross:  I agree, Susie. What's really interesting is it's not like tofacitinib...It's a new kid in ulcerative colitis, but it's been around for a decade in rheumatoid arthritis. This wasn't a signal that was seen in that population until this 1 trial.

For the listeners, this was an observational cohort study of patients treated with either low-dose tofacitinib plus methotrexate, high-dose plus methotrexate, or an anti-TNF plus methotrexate. All of us are struggling to apply that data. By the way, they had to be 50 and over with at least 1 risk factor for cardiovascular disease, so it was a unique population.

I agree with Susie. I haven't really seen this in my population. With the high risk of thromboembolic disorders in our flaring patients, you'd think that we would see a signal, but to see some of the other events, like malignancy and cardiovascular events, we'd have to give this to hundreds, if not thousands, of patients through OAC and follow them in the long term to see a signal.

Dr Kane:  Again, I just want to emphasize for our listeners that rheumatoid arthritis patients don't look like ulcerative colitis patients. They're older. They have other comorbidities. They're on other therapies, other medications, as well. I don't think that it's fair to lump our IBD patients in with the rheumatoid arthritis ones.

Dr Cross:  Before we move to our final set of questions, I just want to remind everyone that IBD Drive Time is sponsored by the Gastroenterology Learning Network and AIBD. Speaking of AIBD, I want to promote the national meeting, which will be in Orlando, December 9th to December 11th. Please join us there, where you're going to learn more, I'm sure, about JAK/STAT inhibitors and other drugs.

Susie, big question as a clinician. Given what we know about the efficacy, onset of action, oral agent, and safety, how do you position this drug in your practice?

Dr Kane:  It's a great question. Like you have already pointed out, JAK kinase inhibitors have been around, clinically, for other indications for a long time but relatively new to the IBD space. As an academician, I am an early adopter. I have patients who have already been on multiple biologics and have failed those.

I'm seeing top-of-the-pyramid sick patients. It's easy for me to say, "OK, you've already been on 2 different classes of biologics. Let's give you something that's new." My patients definitely appreciate that it's oral. Right now, realistically, for my practice, it is the patient coming to me who has already been exposed to other agents.

Where do I put this in the future as we get more and more clinical data on these agents is that it will move, you know, up in the armamentarium, meaning that I'll turn to it sooner, but you know, Ray, just like everybody else, that a lot of our decisions are driven by what's going to get covered by insurance.

Dr Cross:  Indeed.

Dr Kane:  What's going to happen with it in the Medicare and Medicaid space, if patients are government-insured, is it's a hard sell because it's not cheap. Just because it's oral doesn't mean that it's cheap. People need to understand that. For a patient who has already failed 2 different classes, it's a no-brainer for me to think about tofacitinib.

What am I concerned about for them? If they do have other risk factors for a thromboembolic event or for a cardiovascular event, so if they're over 50, if there's a family history for cardiac events, if they are significantly hypertensive, if they have metabolic syndrome, if it's a female who is on oral contraceptives, if she has liver disease, then that's maybe somebody that I'm giving pause.

Certainly, I think that more and more of our ulcerative colitis patients who have already been on, say, an injectable anti-TNF, maybe even vedolizumab because of what insurance is driving them towards, who are now showing up in our clinics, this is a really nice option for them.

Dr Cross:  I agree. For me, it's biologic-exposed patients and particularly those that are sicker, the more severe as opposed to moderate patients. This is a good drug. I forgot to ask about women of childbearing age and pregnancy with this drug, Susie. I don't think we know much, but what do we know?

Dr Kane:  Actually, you didn't forget. That was a question that was going to come up as we talked about who potentially is a good or bad candidate for this and special considerations.

I will tell you — this is where some people's eyes are going to start to glaze over — that JAK kinases are actually very important for placental health. If you start to inhibit these pathways in a very nonselective manner, you are putting at risk an early pregnancy because you need the placenta to develop and grow and to form those attachments to a zygote.

For right now, we are recommending that any woman who is contemplating starting a family but sick with ulcerative colitis that we not choose this. If it's that she wants to eventually get pregnant but is sick and is thinking "I want to get better" and tofacitinib is an appropriate agent for her, we will start this. We will get her well.

Then if she gets pregnant while she is well on this agent, we will enroll her in the PIANO study and probably also the OTIS study, which is another birth defect national registry that is run out of San Diego.

Right now, we are not recommending that women who are interested, actively, in childbearing, that this may not be a good medicine for them because of that very specific interaction between JAK kinases and a placenta.

The data that we do have, which of course is very small and very early, suggests that if women who are well, who are on tofacitinib, we will continue it through pregnancy to maintain that remission and that they do OK. Again, it's a placental issue, not a fetal one or with DNA or congenital anomalies.

Dr Cross:  There's been some emerging data from Michigan and other places, given the rapid onset of action, of using this potentially in the inpatient with acute severe colitis. Have you tried to use it for this indication, Susie?

Dr Kane:  We have not. Our group here at Mayo Clinic, we're intrigued by that data, but we have not bought into it such that we're willing to do it for our patients. Some of it is just logistic. Tofacitinib will not be covered in our hospital as an oral therapy. There's just not enough data yet.

As you can imagine, like at the University of Michigan, the patients who are sent here, who are hospitalized with acute severe ulcerative colitis, are just really sick. They have been on multiple medications already. It's just not something we're willing to mess around with.

These were patients who were bridged to other therapies. Most of the patients who we see have already failed those other medications. No, we have not done this yet.

Dr Cross:  It helps sometimes if they have it approved as an outpatient. They can get it with them to the hospital. I've done that once. It was successful, but I agree. Many of these patients needed a colectomy 2 drugs ago. We're just prolonging the inevitable.

How do you monitor these patients? For safety monitoring and health maintenance, Susie, what type of things do you do with these patients, maybe different perhaps than what you would do with other immunosuppressive or biologics, if anything?

Dr Kane:  Not necessarily a lot different. Now, it's really important that people understand that the brand name Shingrix, the nonlive-attenuated zoster vaccine, is now FDA-approved for high-risk patients. You don't have to be 50 anymore. Absolutely anybody who's going to start on tofacitinib, I get them vaccinated first.

Then I will also do a baseline cholesterol level. We do know that their cholesterol levels, at least transiently, will go up and if they're starting with a cholesterol of 250, I'm certainly going to take pause. I'm going to monitor.

How do I do that? I will do it again in a month. If, at 3 months, it's still significantly elevated, I may think about whether to stop this. Again, we see this elevation in lipids is relatively transient and doesn't translate into anything clinical. At baseline and then 1 month and, if still elevated, again at 3 months.

I will send the patients, if they have not been to a dermatologist, for a skin check and then for annual skin checks, but I'll do that for anybody who is on a biologic or on a thiopurine. I've just added them now to that population.

Dr Cross:  I guess from my perspective, with the new malignancy signal, make sure they have all their routine health maintenance, mammograms, etc., which they should be doing anyway. That's not unique to this drug.

We mentioned payers. Interesting happening in the Mid-Atlantic, we're now getting pressure from payers to dose-reduce 10 BID or from 22 once a day to 5 BID or 11 once a day. Susie, is that a good strategy? What are you doing in your practice? If you do do this, is there a subset of patients that you do it on?

Dr Kane:  Yeah. Great question. If I go back to citing the OCTAVE Sustain trial, remember that those patients were randomized to 5 BID or 10 BID. At week 52, there were still patients on the 5 BID that did great.

Using that information, somebody who is at 10 BID, who is well and has had a good response at 8 weeks, I might, because of the population that I see, give them probably at least another month at 10 BID.

Yes, I do try to dose reduce. It's not from an insurance pressure I do it. I just feel better if they're at a lower dose. We will try actively to reduce to 5 BID. I would say that about, anecdotally, 30 to 40% of the time, we end up going back to the 10 BID because they just start to have symptoms again at that lower dose.

If I recapture that response and remission at 10 BID, I leave them there. I just will have a shorter leash for them, meaning that I definitely want to monitor them for any kind of safety events, but I feel pretty comfortable leaving them at that if they don't have a lot of other risk factors for safety events.

Dr Cross:  If I remember right, David Rubin presented a subanalysis from that dose reduction in maintenance. It was about a third, like you said, would have worsening symptoms. He quoted, if I'm remembering right, about 50% did not recapture. They presented RIVETING at UEGW last year. They showed something similar, not quite 30%.

I've been waiting to get to the post-3, -6-month endoscopy. I guess if it looked completely normal, I might talk to him about it. I actually haven't been dose reducing because I'm afraid that I'm going to lose 1 in 6 refractory people. This highlights the art of taking care of IBD patients and how everyone manages patients just a little bit differently.

Two more questions, Susie. One is you talked about more selective JAKs. Are they going to be safer than what we have?

This is a crystal ball. What do you think?

Dr Kane:  Again, we have to take our clues from the rheumatologists and what's happening out there. Upadacitinib is a selective JAK kinase. In theory, when you select, you are going to decrease the risk for some of these events.

Which ones really are truly mitigated by the selection has yet to really be announced. In theory, it's the cardiovascular ones which would be decreased with the selectivity.

I've been using upadacitinib off-label for my Crohn's patients right now. I've been very impressed with how well-tolerated it is. I'm not seeing the cholesterol elevations. I'm still sending patients for skin checks and vaccinating them for herpes zoster. Otherwise, I think that the selectivity is going to be a real thing.

Dr Cross:  Last question, the fun question. Susie, tell the audience something about yourself that they may not now.

Dr Kane:  I will tell you we're at week 4 now of the NFL season. I am the commissioner of 2 different fantasy football leagues here in the GI division. I was so successful in recruiting to 1 league that we had to start a second. I'm the commissioner. Every week, I write a summary newsletter about how the teams did.

This year, what I'm doing for that newsletter is I'm picking different themes. We've done an homage to The Beatles. I've just finished a celebration of The Who. Because the Eagles are coming to Minneapolis this week and I'm going to go see them, next week's newsletter is going to highlight themes from Eagles songs.

Dr Cross:  I knew that you were a football fanatic. I knew that. I did not know you were a commissioner of 2 leagues, though. Susie, thank you for joining us. You were wonderful. I'm sure everyone has learned a lot. We hope to have you back sometime soon.

Dr Kane:  I would love to come back. Thanks, Ray, for having me.