Positioning JAK Inhibitors in IBD
Drs Corey Siegel, Gil Melmed, and Adam Cheifetz took to the Open Air Studio at the AIBD annual meeting to discuss an important recent change in FDA labeling for upadacitinib and the positioning of JAK inhibitors in the management of IBD.
Corey A. Siegel, MD, MS, is the Constantine and Joyce Hampers Professor of Medicine at the Geisel School of Medicine at Dartmouth and director of the Center for Digestive Health at the Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire. Gil Y. Melmed, MD, is director of Inflammatory Bowel Disease Clinical Research and codirector of the Clinical Inflammatory Bowel Disease program at Cedars-Sinai Medical Center in Los Angeles, California. Adam Cheifetz, MD, is director of the IBD Center at Beth Israel Deaconess Medical Center in Boston, Massachusetts.
TRANSCRIPT:
Dr Siegel:
Hi, I'm Corey Siegel from Dartmouth Health, coming to you from AIBD in Orlando, the largest AIBD we've ever had, on behalf of the AIBD Network here with my friends, Adam Cheifetz and Gil Melmed, talking to you about a very interesting change in our field of inflammatory bowel disease. Gil?
Dr Melmed:
Hi, I'm Gil Melmed and I direct the IBD clinical program at Cedar Sinai in Los Angeles.
Dr Cheifetz:
And I'm Adam Cheifetz. I head up the IBD Center at Beth Israel Deaconess Medical Center, big mouthful, in Boston.
Dr Siegel:
Thanks guys for taking the time out of the meeting to discuss this. What we're here to talk about is the label change for upadacitinib, which doesn't happen that often, maybe never, at least in our field when we think about the FDA changing an indication. We don't often think about the label. You guys don't pull out the label when we're talking to patients. Patients may or may not read the label, but when it comes to thinking about how we use these medications and the positioning, particularly with payers, it becomes really important. The very specific language and the label change, and we can talk about this a little bit, was the label was updated just in October, I think it was mid-October, stating that you can now use upadacitinib prior to the use of anti-TNF blocking agents. So previously it was you can only get access to upadacitinib after anti-TNFs.
So not only do they say it can be used before anti-TNFs, it says in patients for whom any use of these treatments is clinically inadvisable of anti-TNFs. So if you can come up with a clinically inadvisable reason to use anti-TNF, we'll get into what that might mean, and then who have received at least one approved systemic therapy. Again, the language is a little bit vague in all of this, but let's just start with Gil. When you heard that the FDA changed this label, what was that? That was a little surprising, I think, to many of us.
Dr Melmed:
Yeah. As you say, I don't know that this has ever been done, certainly not in our field, where the FDA becomes a little more relaxed about a safety consideration. And so seeing that to me was a little bit validating. I think this is something that many in our community have been hoping for, have been trying to show data and evidence and recognizing that we have a really terrific drug with what seems to be overall very favorable safety profile and perhaps was overly restricted in the original label that the FDA put on there. So the basis of that data and why the label was put on there, maybe we can get into, but it felt for a lot of us that it was not consistent with the evidence and safety data that we were actually seeing.
Dr Siegel:
Yeah. So Adam, why was this frustrating? The original label for upadacitinib, why was that frustrating to us as providers? What was it that your heart sank when you saw that was part of the indication?
Dr Cheifetz:
Well, I think I don't like being told what to do, as my wife will tell you. I think it was different than anywhere else, at least that I knew in the world. Canada can use it whenever you want. At Europe, same thing. So to me, particularly the basis of why they did it was a little bit disconcerting but not leaving it up to us to decide when it's best to use a particular agent, particularly where, and we'll get into it, where in certain instances we would maybe reach for UPA over an anti-TNF therapy.
Dr Siegel:
Yeah. And why? What is it about this drug that you wanted quicker access to?
Dr Cheifetz:
So look, for me, it works super quickly. I would argue, I've always said it, until UPA, infliximab has hands down been the most effective agent we have in our sickest patient population. And then you see the data for UPA and it's pretty close; it's oral, it works within days, works very quickly, and you know it works quickly. So to have to give up on that to try infliximab, which I still love, but in some of the sickest patients— low albumin, high CRP, hospitalized, severe UC—they clear the drug so quickly that it makes it harder to use and almost becomes ineffectual in some of those patients.
Dr Siegel:
Gil, can you give us the history? I'm not going to ask you to think about why the FDA had the original label, but can you remind all of us and the audience of why was there concern about upadacitinib? What prompted this unusual label, which said you had to go through another drug to get there first or another class of drugs. And let's be clear, it wasn't infliximab you had to fail. It had to fail on anti-TNF drug.
Dr Melmed:
Right. Yeah. So the history goes back, I don't know, 5 years to 2018 when tofacitinib came out. And then based on signals seen in the clinical trials, a study was done in not an IBD, in rheumatoid arthritis, the ORAL surveillance study where patients with rheumatoid arthritis over the age of 50, with a cardiovascular risk factor were followed in receiving low dose tofacitinib, high dose tofacitinib, or an anti-TNF drug. And what they saw in that study was that there was a signal for increased rates of thromboembolic events—DVTs, PEs—and even all-cause mortality. And so on the basis of that, the FDA put that warning label on tofacitinib, but also on all JAK inhibitors that came out afterwards, including upadacitinib, which is what we're talking about today. I think part of the frustration was that those signals in IBD were not that evident, were not really evident at all, even in tofacitinib and certainly not in upadacitinib in the IBD data.
And so the warning itself and the history behind that warning was derived from data from another indication, a patient population, which is perhaps not as common that we see in IBD, which is older patients with cardiovascular risk factors. And for many of our patients, for whom this drug is an incredible opportunity to get them better faster, as Adam was just saying,
It felt like a difficult situation that we were sort of forced into by these regulatory requirements.
Dr Siegel:
Yeah. And let's add on an oral daily drug that is a lot easier to take.
Dr Melmed:
Nevermind the convenience, right?
Dr Siegel:
Absolutely. Patients from a convenience standpoint. So Adam, again, before label change, after label change, how did you talk to patients about the big risks? And let's separate it into the increased risk of clotting, the increased risk of major cardiovascular events, and we should throw in shingles as well, herpes zoster infections.
Dr Cheifetz:
Yeah. I'll be honest, the label change doesn't affect how I talk to my patients. I'm going to talk to them the same way I did before and after. I think the label change makes it maybe hopefully easier for us to get it through different payers. Steve Hanauer is always the one that says, FDA doesn't tell us what we can do; it tells pharma what they can speak to us about and say. So I say the greatest risk I've seen—one, I start off that this is a very safe drug. If I'm talking about UPA, this is a sick patient with UC or Crohn's disease. So I say first and foremost, this is a safe drug. The risks of your uncontrolled disease far outweigh anything I'm going to even discuss in the next 5 minutes.
Dr Siegel:
That should always be the start of any safety discussion. The biggest risk to you is your disease not being controlled.
Dr Cheifetz:
Right, exactly. I mean, think about realistically in Crohn's, the risk of surgery—50%, right? UC, the risk of colectomy, 10%. No risk that we touch on with any of the meds, certainly any serious adverse event, comes close to that. So that's how I started because I want them to feel comfortable. I want them to know that I feel comfortable using this drug and recommending that. And then I go first into the benefits.
Dr Melmed:
You got risks of steroids too, right, if they don't get treated quickly with an effective drug.
Dr Cheifetz:
Oh God, the worst.
Dr Cheifetz:
Well, I also say you've already been on the most dangerous drug we use. Hands down, that's corticosteroids.
Dr Siegel:
And also not FDA approved for the treatment of inflammatory bowel disease.
Dr Cheifetz:
So risks I go into, again, first talk about efficacy, safety risks. I say the biggest risk that I've seen or read about is the risk of shingles. And typically in these patients, I've already made sure they've been vaccinated for shingles. And if not, it's definitely happening at that clinic. That I think is the biggest risk. And I say, we're going to know quickly if you're responding or not. If you're not better in the next few months, we're onto another drug. If you are, then we can talk about these, I would even say very rare to unclear risk of major adverse cardiovascular events and thrombosis, right?
Dr Siegel:
All right. Gil, I mean, we're lucky we have Gil to fact check us as one of the most world experts in vaccination in IBD. Do you wait to get your patients vaccinated or is that you can just go?
Dr Melmed: No.
Dr Siegel: So easy. Quick answer. Quick question.
Dr Melmed:
Get them on the drug that they need. I mean, if you think about it, the likelihood, yes, there's an elevated risk of zoster, of shingles, but that likelihood, even though it's highest in JAK inhibitors, then we have it in the other drug class that we use 5% over the course of a year. So we want to get patients better as quickly as possible. So don't delay vaccines, don't delay the Shingrix vaccine, even though they should get it, but get them onto effective therapy as quickly as possible.
Dr Cheifetz:
That was one of the best things we did is we got all these vaccines in our clinic. So they don't leave the office before they get a quick
Dr Siegel:
They can just— “go see that person on your way out.”
Dr Cheifetz:
Exactly. I really like that. Yeah.
Dr Siegel:
You're welcome to anytime. Let's break down this label change just a little bit because when we first saw it, I think we all called each other and said, "Hey, can we have a little book club about how we interpret this label?" So the specific language is that ‘who have received at least one approved systemic therapy.’ What does that mean, Gil?
Dr Melmed:
Well, there's systemic, right? So there's a few keywords there. There's approved, there's systemic and then there's therapy. Okay. Therapy we can all agree on, but does it need to be approved by whom? FDA approved, approved by our societies, by our guidelines that suggest that something could be appropriate as a used agent and systemic. So I think systemic probably excludes any topical therapies, certainly mesalamine, 5-ASAs, but I feel like there's-
Dr Cheifetz:
Can I push you on that?
Dr Melmed:
Yeah.
Dr Cheifetz:
30% of mesalamine orally is absorbed.
Dr Melmed: Oh, but come on.
Dr Cheifetz: I don't know. Okay.
Dr Siegel:
Well, all right. Well, but that's part of this is- Can you get away with that? It's vague. I don't know. And well, we don't know yet. And it depends on what you mean by getaway with. Good point. That sounds bad. I think here, we'll take a little vote with the three of us. Patient has moderate to severely active disease, ulcerative colitis. They end up taking mesalamine, 4.8 grams, they're failing. Any hesitation to go to upadacitinib?
Dr Melmed:
No.
Dr Siegel:
Personal. Don't worry about payers right now.
Dr Melmed:
No payers, no label. UPAs, I would absolutely.
Dr Siegel:
Right. So that's the point. You don't need to force yourself through another- Love it. You don't need to force yourself through ... Oh, the vote was three to nothing, by the way.
Dr Melmed:
I voted. Yeah, I didn't hear you vote.
Dr Siegel:
Yeah. Adam, I knew. He with his eyes voted and he nudged Gil. So we agree that that's clinically good enough. Whether 30% or 0% is getting absorbed, we think that for patients it's the right thing to do. So your point is valid, GIl, which is approved by who. It probably means approved by the FDA. I think that's what the language means. But then systemic therapy. So prednisone’s systemic.
Dr Melmed:
Yeah. It's not approved.
Dr Siegel:
It's confusing.
Dr Melmed:
Right.
Dr Siegel:
Yeah.
Dr Melmed:
I mean, azathioprine is not approved.
Dr Siegel:
Definitely systemic.
Dr Melmed:
Definitely systemic.
Dr Siegel:
Yeah. But again, I think there's no question moving from a thiopurine that we're not using very much these days as monotherapy anyway, but many people are, and moving from azathioprine to upadacitinib would be a very reasonable thing to do.
Dr Melmed:
Absolutely. Yeah. I think even moving from prednisone to upadacitinib. I mean, somebody being on prednisone is an indication that they need advanced therapy. And if they're not doing well enough on prednisone to get them back to normal, then they need something that's going to act quickly. And this is a perfect drug.
Dr Cheifetz:
And you can also argue, forget prednisone. One of the reasons, besides everybody's so comfortable, unfortunately with it, one of the reasons people reach for prednisone is because they can get it quickly. They can get it to the patient quickly. If we had the ability to do this with UPA, we could bypass corticosteroids altogether in some patients.
Dr Siegel:
Completely agree and think we should. I think you should have to get a prior authorization for prednisone. Then in all honesty
Dr Cheifetz:
That might change the game right there. Our
Dr Siegel:
Future would change. It's probably the best thing that could possibly happen to us. We should try to get prednisone approved and then make sure that it's really expensive.
Dr Melmed:
Exactly. You got to jack up the price.
Dr Siegel:
Jack up the price. Right. Yeah. Oh, that's good.
Dr Cheifetz:
I get it. I would argue the same for any time someone tries to write mesalamine for Crohn's disease.
Dr Siegel:
PA
Dr Cheifetz:
And extra costs.
Dr Siegel:
Or it's going to cost you a million dollars. Yes. Right. All right.
So what I'm asking you, I think is a little bit of a way around saying, is upadacitinib a reasonable first line advanced therapy? Adam?
Dr Cheifetz:
Yes. I think in the right patient population. Absolutely.
Dr Melmed:
We're talking about ulcerative colitis. Talking about Crohn's?
Dr Siegel:
We can talk about both.
Dr Melmed:
Okay. I mean, I would say for ulcerative colitis, yes. Reasonable for Crohn's, Crohn's colitis, yes. Small bowel Crohn's maybe, I'd think about.
Dr Siegel:
Yeah. Say a little more about that.
Dr Melmed:
Well, I think in general, ileal disease is harder to treat than colonic disease. I think we've seen that with a lot of our therapies, if not all of our therapies, but perhaps there may be an advantageous role to starting with an IL-23, for example, in somebody with a small bowel Crohn's disease. I think that from what we're seeing with JAK inhibitors and ulcerative colitis, hands down, there's no question this is if not one of our most effective, the most effective drug that we have for ulcerative colitis. In Crohn's disease, I'm a little less convinced, particularly in small bowel.
Dr Siegel:
All right. And then Adam, I'm going to ask you the same theme, but a little different, which is sure, we can use it first line in ulcerative colitis and maybe Crohn's disease. If a patient said to you, "Okay, thanks for telling me about your good oral drug that's really effective. I want the safest one." So what do you think is safer, upadacitinib versus an IL-23?
Dr Cheifetz:
One, I would argue whichever drug I think is going to work best and control the disease in that patient.
Dr Siegel:
Fair.
Dr Cheifetz:
Otherwise, head to head safety-wise, I think an IL-23 is safer. Yeah,
Dr Siegel:
Definitely. There's no question.
Dr Melmed:
Although I prefer the term ‘more favorable safety profile’, than ‘this is a safe drug.’
Dr Cheifetz: That's a lot more words in the mouth.
Dr Siegel:
I have a more favorable safety profile driving than my 15 ½- year old son who's learning how to drive. Something like that. Okay. Yeah. Yeah. Stay off Hanover, New Hampshire.
Dr Melmed:
But are you going to say that you are a safe driver?
Dr Siegel:
Yeah. That's actually ... It's a good point. It's not the placebo group by any stretch.
Okay. So there is some ... I just want to be clear for those listening to us that we don't think that this is a risk-free drug and everybody should just be on it, that you still have to think about it. And the risk is, in my mind, more about immune suppression and infection than it is about major cardiovascular events and clots. And in fact, our friend and colleague, Sid Singh, actually just published a couple of papers showing that the risk of MACE events, major cardiovascular events, and thrombosis looks the same compared to patients with IBD in general and patients on other drugs. So this risk that came out of the tofacitinib studies with rheumatoid arthritis probably were overrepresenting the risk in general. To be clear, this label change—class or just drug specific, Gil?
Dr Melmed: It's drug specific. So it's upadacitinib, brand name Rinvoq. I mean, this is not a class label change, and it's not even an indication label change. It's very specific to IBD and for this particular drug.
Dr Siegel:
So for sake of our argument, the sort of backend of this label change, which is about prior proved systemic therapy, I think we're going to agree that as a first-line advanced therapy, it's reasonable to use. The spirit of it probably means it's not your first advanced therapy. It's probably your second advanced therapy, meaning it opens the door to you've used vedolizumab, any of the IL-23s, 12-23s. You do not need to go to an anti-TNF before that.
Adam, I know you've worked a lot in your career talking about infliximab and optimization. The first part of the label change is talking about patients in whom these treatments are ‘clinically inadvisable.’ Tell us your thought on that and what that actually means. You alluded to it early when you were talking about a certain patient population.
Dr Cheifetz:
Yeah. When I saw this, that was what I struggled with most was this clinically inadvisable. So I agree. In my mind where that made most sense to me was in that situation where I'm fearful the patient has such high clearance of infliximab, it's not going to be the most effective agent. They're going to either have low drug concentrations, develop antibodies, lose response, or in that patient where I think they really need drug quickly, I really don't want to use prednisone. It takes, at least in my institution, upwards of 2 to 3 weeks to get them into the infusion center. I don't want to hospitalize them if they don't have to. That was sort of where my mind was sort of thinking most about this because in all honesty, most of the other relative contraindications, I don't see that different from the anti-TNFs and the upadacitinib.
Dr Melmed:
There might be some, right? I mean, MS, either a personal history. And honestly, like I see patients who are freaked out because they have a family history of MS. And even though we don't have data, I think that it's a very strong visceral reaction to something that might potentially expose to risk; CHF, advanced CHF. And I think that there's also this perception of other risks, lymphoma risk, which Corey, you've taught us a lot about, that we see with anti-TNFs in more definitive ways. I think looking to the patient and I think it's clinically inadvisable to force or really push something on a patient when they have a strong reaction against it.
Dr Siegel:
So I'm going to take it even a step further, which is patient really doesn't want IV or even injectable therapy. And I think patient preference is a huge part of what we do. And we can talk to our patients all day long about the data and label changes. And if they say, "I really don't want to sit in an infusion suite. It makes me feel like a sick patient. I don't like injections. I hate needles. I don't want any part of this. Isn't there please an oral drug that I can take?" I mean, to me, clinically inadvisable to try to convince your patient that they need to do this when there's another option. When we didn't have another option, then I think we were doing a little bit more, and I say this with all due respect to all of our patients, a little bit more arm twisting of, "I don't have a better option for you. You need this. " But in this case, we do have an option that when our patients have a really strong preference against this, we have to be thoughtful.
Dr Cheifetz: And that ties into compliance. Yeah, exactly. If your patient is going to be compliant, we know if the patient's not compliant, honestly, it doesn't matter what drug we give them, it's not going to be effective. So that was the other one I thought about was the oral.
Dr Melmed: Right. But I think if I could just say to Adam's point, we've looked at this in IBD CORUS as a multicenter collaborative. How long does it take patients to get onto drug? And we've shown and we've seen that for an IV medication, it takes over a month to get a patient onto drug from the moment you write that prescription. And so for many patients, they can't afford to wait a month. That's time that they may end up on steroids. It's time they may end up in the hospital. And so having this, I think is so critically important when we talk about this now.
Dr Siegel:
Why we tolerate this? Could you imagine going to the doctor for any other problem and they say, "Listen, I'm sorry you have pneumonia. Within the month, we'll probably get you the right treatment for it. " I mean, it's crazy that we tolerate this, but I think what we're all saying is ‘clinically inadvisable’ is a delay in therapy that our patients will take and stay on and have a high chance of getting better from.
Dr Cheifetz:
Love it. We can get quickly.
Dr Siegel:
Gil, when we think about other data in the background of upadacitinib, not just the label change and not just the clinical trials, our group that we call the BRIDGE group, we've been together for 19 years now and Adam is part of it, of course, with a number of our colleagues. We just did some work on this and we actually put together a podcast where we had a discussion and it wasn't meant to be about JAK inhibitors, but it evolved towards JAK inhibitors because there's been so many new articles coming out talking about efficacy and safety. And maybe you can just briefly touch on some of the discussion we had in this podcast called Digesting: The latest in IBD.
Dr Melmed:
Yeah, yeah, yeah. I mean, really the point of this was to look at the recent literature. And it happens to be that in the recent literature, we've got a lot about JAK inhibitors because I think maybe partly because of this FDA label that we've gone as a community to really look for evidence to teach us and help inform really what are the safety parameters and the efficacy parameters around this drug to enable us to use it in the most effective way. We talked about the fact that in most recent network meta-analyses, which are ways of comparing clinical trial data of different drugs and combining it to be able to determine the safety and efficacy of one drug relative to another, that upadacitinib rose to the top in ulcerative colitis as the most effective drug. And I think that was pretty unequivocal that this is a very potent effective drug for UC.
We talked about this thrombosis risk that's on the label that drove the label, but what about our patients who do meet the criteria of having thrombosis risk and perhaps on antithrombotic therapy? What is the safety in those patients? And we saw in the literature that upadacitinib does not increase risks in those patients. And we also talked about the use of upadacitinib because it's such a quick rapid acting drug in the most severe patients, in our hospitalized patients, the emerging data now in several studies suggesting that patients can perhaps get out of the hospital, can avoid colectomy, and can respond very favorably to the use of upadacitinib in that very sick population.
Dr Siegel:
And if I can just go to you, Adam, that group, I think is the same group that you were referring to earlier with low albumin, high CRP, that you can give infliximab all day long. And why don't patients respond in that situation?
Dr Cheifetz:
They basically, as soon as it goes into their IV, it comes out their colon.
Dr Siegel:
Yeah, it's going right through me, Doc.
Dr Cheifetz:
Right through. Yeah. And it comes right out. So this to me even, I'll say it, I think I can get away with it. Even before the label change, in those patients that they were hospitalized with severe UC, their albumin was 2 1/2,, they hadn't failed an anti- TNF therapy. I talked to them about UPA and that to me, where I in the past would've used cyclosporine, I've offered up and started using upadacitinib in this situation. And the label change just makes it that much easier.
Dr Siegel:
And then Gil, in this patient population, our sickest UC patients already have a risk of blood clots, right? A higher risk of DVTs and PEs.
Dr Melmed:
Very high risk.
Dr Siegel:
I think in Digesting, we also covered this risk of thrombosis and ways to manage that.
Dr Melmed:
Yeah. Yeah. I mean, well, for sure the patient that you're describing, just to put it out there, needs to be on a DVT prophylaxis when they're in the hospital and maybe even outside the hospital, but for short-term.
Dr Siegel:
But what if someone's had a DVT?
Dr Melmed:
So in someone who's had a DVT, the question sometimes around the use of antithrombotic agents in that patient in order to give them a JAK inhibitor, but even without the use of those agents, depending, I think, on what is the underlying risk. We know that IBD itself increases that risk. And so getting that inflammation under control with an effective drug like a JAK inhibitor, maybe all you need to mitigate that risk.
Dr Siegel:
Yeah. Okay. Fair.
Dr Cheifetz:
Let me ask you a question, Corey.
Dr Siegel:
That's not how this works, but that's okay.
Dr Cheifetz:
I know. I like to bend the rules every once in a while. So you sort of described, take it different. You see patient coming to see you in the office and we'll say BioNE, but on prednisone, when you talk to them, when you talk about the other therapies, are you going to bring up UPA as one of the choices?
Dr Siegel:
In a patient who's had ...
Dr Cheifetz:
Prednisone.
Dr Siegel:
I am, and I am talking about it with them as a reasonable alternative. What we got into earlier and never really answered the question of who it has to have been approved by. I think this gives us the flexibility to make clinical decisions that we think are right for patients. How we get this ultimately approved by payers, I think time will tell. It's been barely 2 months since this decision changed. We are already having success getting upadacitinib in our practice sooner than we did before. So let me maybe close with the same question to both of you is with this label change, Adam, how will it change your practice?
Dr Cheifetz:
So like you said, I will bring it up with patients as one of the options when I'm discussing the various therapeutic options and going over risks and benefits, and it'll become one of the choices that we get to talk about now.
Dr Siegel: Yeah. Gil?
Dr Melmed:
Yeah, same. I think that, as you say, for payers, this is going to be the most interesting way to see how this label impacts our practice because it's really been that payer situation that has, I think, gotten in the way of us prescribing this drug in a more free environment of not requiring that anti-TNF. But also, I think it's going to help the conversation with patients, because patients are going to read labels and they're very sophisticated and educated in terms of safety in particular. And I think it will really help to be able to say, "This is one of the only times the FDA has actually backed away from a safety label warning." And I think that will also go a long way to help us have an informed conversation with patients about risk.
Dr Siegel:
That's great.
Dr Cheifetz:
And let's be clear, although this label is way better than it was, we're still not up to where the rest of the world is.
Dr Siegel:
That's true. That's true. So I think what I'm taking away and learning from you guys is this is definitely a game changer in the way that we can think about using this drug in practice, but let's not be cavalier about using it. Our drugs, even our safest, safest drugs have some unexpected risks that come along with them, and we do have to be thoughtful here and use it in the right patient population, but we're getting the flexibility that if we think it's the clinically right thing to do for patients, then we should go ahead and try to do it. Agree?
Dr Melmed: Agree.
Dr Cheifetz: Agree.
Dr Siegel: Excellent. Well, coming to you from AIBD, Gil, Adam, thank you for joining me. We hope this is helpful to others too.
