Black Box Warning on JAK Inhibitors: Implications for Rheumatology

In this podcast, 3 prominent rheumatologists—Neal Birnbaum, MD, Leonard Calabrese, DO, and Vikas Majithia, MD—discuss the implications of the recent 'black box' warning required for JAK inhibitors used in treating inflammatory conditions and their own experience in treating patients with this drug class. 

Neal Birnbaum, MD, is director of the Division of Rheumatology at California Medical Center in San Francisco, California, and a clinical professor of medicine at the University of California San Francisco.

Leonard Calabrese, DO, is a professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and the RJ Fasenmyer Chair of Clinical Immunology at the Cleveland Clinic in Cleveland, Ohio.

Vikas Majithia, MD, is a professor of internal medicine and division director and fellowship program director of rheumatology at the University of Mississippi Medical Center in Jackson, Mississippi.

TRANSCRIPT:

Hello, everyone, and welcome to another podcast from Rheumatology & Arthritis Learning Network. I'm your moderator, Rebecca Mashaw.

I am here today with 3 leading rheumatologists in the United States who are going to be talking to us about the use of JAK inhibitors in rheumatology and the FDA's recent decision to put a black box warning on all JAK inhibitors because of the results of a recent postmarketing study on tofacitinib.

Gentlemen, would you introduce yourselves for us please?

Dr. Leonard Calabrese:  I'm Dr. Len Calabrese. I'm a clinical immunologist and rheumatologist and do some infectious diseases at the Cleveland Clinic.

Dr. Neal Birnbaum:  Dr. Neal Birnbaum, practicing rheumatologist in San Francisco, where I'm chief of rheumatology at California Pacific Medical Center and clinical professor of medicine at UCSF.

Dr. Vikas Majithia:  Vikas Majithia. I'm a professor of internal medicine at University of Mississippi School of Medicine, where also, I'm division director for rheumatology.

Rheumatology and Arthritis Learning Network:  Thank you for joining us this afternoon to talk about this. Let's start off with a brief overview of JAK inhibitors as a class, what their mechanism of action is, how they function in the practice of rheumatology, and overall risks and benefits.

Dr. Calabrese, we'll start with you again. What have you found?

Dr. Calabrese:  This is a very exciting class of drugs, small molecules that we've had around for a decade. The lead compound is tofacitinib. Rheumatologists are now very conversant with this class, but they're also being studied and indications are spreading into dermatology, inflammatory bowel disease, and other specialties.

As a class, we recognize them as compounds that are capable of inhibiting the signal transduction of over 50 different cytokines and chemokines. We have an armamentarium of 3 currently approved agents: tofacitinib, baricitinib, and upadacitinib.

Varying, in terms of their specificity for JAK inhibition, but by and large, have a lot of overlying properties and a lot of overlying indications. They were the original oral targeted therapy. We called them targeted synthetic therapies. They're quite potent as a class and have been growing.

We've known for many years that they are potent immunomodulators and immunosuppressives. They carry with them a number of adverse events in their safety profile, including serious and opportunistic infections and association with venous thromboembolic disease and cardiovascular events.

They carry the traditional biologic malignancy warning and they also cause perturbations of laboratory studies such as leukopenia, variable effects on hemoglobin, minor effects on creatinine, CK, and dyslipidemia. A strong class of agents.

RALN:  Dr. Majithia, what have you found in your practice? What's your experience been like?

Dr. Majithia:  As Dr. Calabrese very, very well put, the mechanism, I feel they are wonderful drugs. Ever since tofacitinib has been approved, it's been one of the medications which is a go-to medication for me regarding rheumatoid arthritis.

Again, the use has expanded to psoriatic arthritis. We have a very big number of inflammatory bowel disease patients where it's one of the agents that our gastroenterology colleagues use frequently. I'm also very excited about their potential for use in spondyloarthridities, and especially axial spondyloarthridities. They are showing significant promise.

Personally, I feel that they're a very, very convenient form of medication. We've always had biologics, but none of them was an oral small molecule in the past. Their efficacy is good. They are easier to take. I think the patients do have some preference towards taking these medications. The payers love them because of their lack of administration costs with the number of IV medications and some of the other things which come from that.

They are one of the preferred medications that that I'm using, especially when upadacitinib has been approved. I have not used much baricitinib, but tofacitinib and baricitinib are one of the agents I use frequently, even as a first-line agent after failure of methotrexate in patients with rheumatoid arthritis.

RALN:  Dr. Birnbaum, what about you? Have you had a good bit of experience with these drugs, and what has that been like for you and your patients?

Dr. Birnbaum:  I would echo the comments of my colleagues, that they have been growing in their use, both within their regional use in RA, but also in other indications.

Initially, we were used to having very effective drugs. The biologics, the anti-TNFs have been around now for 20-plus years and we were comfortable using those. The original growth of tofacitinib was slow, but as physicians tried it in their more difficult patients and found that it worked well and was generally well tolerated, that the use began to expand as an agent, that would be used after methotrexate failures as an equal alternative to traditional biologic therapy. I would agree they've been very effective and generally well tolerated.

RALN:  In inflammatory bowel disease, it appears that patients who are anti-TNF-naive have actually had greater success when they've used tofacitinib as a first-line agent rather than waiting until that TNF failure. Have you seen something like that in your own practices?

Dr. Calabrese:  In general, these drugs have been mostly used in patients who have failed a biologic. Only up until this year has ACR RA treatment recommendations endorsed putting them on a level plane with other biologics. I think a lot of us have done that.

There's a lot of pushback on payers. But they had moved from a third-line drug to a second-line drug, increasingly to a first-line drug in people who wanted oral options.

Dr. Majithia:  I would like to echo what Lenny just said, but also point out that the question you are asking about them being more effective if the patients are biologics-naive, I don't know for sure that I would agree with that. By and large, we use them or have used them in the past after failure of one of the other biologic agents. I think if the patient population is different, that's where you see a better effect if you're going to use them earlier.

But I also do feel one benefit we do have with these agents is that they are almost equally efficacious whether we use them with another traditional DMARD, especially methotrexate, or without it. So where it has helped me is if a patient has methotrexate intolerance, either initially or during treatment, then I do feel that these medications are reasonable options for these patients.

RALN:  So this is a good monotherapy for rheumatology patients?

Dr. Majithia:  The evidence suggests that their efficacy is not lost if they are not given with a traditional DMARD. The number of other biologics seem to work better when they are given in a combination with a traditional DMARD, particularly methotrexate, and particularly in rheumatoid arthritis patients.

Dr. Birnbaum:  One of the issues when I have discussions with a patient, there is some trade-off with most the biologics, with the exception of the IL-6 inhibitors. You don't have mandatory quarterly lab work, whereas with the JAK inhibitors, you do.

You get a pill, that's great, but you have to come in quarterly to get your lab work done, which you don't have to do with a lot of the other agents. It is a trade-off.

RALN  Have you seen any adverse effects in your patients, Dr. Birnbaum, who are on tofacitinib?

Dr. Birnbaum:  In general, they have been very well tolerated. Is there the occasional patient who says they're nauseated? Sure, but I would say we personally have not seen serious side effects. I've seen virtually no serious lab adverse events that we monitor for. I've had 1 or 2 people I had to put on a statin because their lipids went up. By and large, very, very well tolerated.

I think that's why this additional warning from the FDA was a surprise to a lot of people. Obviously, we've not had access to that data. That was a large study. We in our individual practices are seeing smaller numbers of patients, so we don't know what that really means. I think people don't know yet whether the FDA is showing an abundance of caution or an overabundance of caution.

RALN:  Dr. Calabrese, what's your take on the FDA action?

Dr. Calabrese:  To set the stage, that we're all talking around this, the FDA has released top-line results, but not detailed results, of a Phase 4 study that was mandated that compared tofacitinib in 2 doses, 1 approved dose and secondly, a higher dose, 10 milligrams twice a day, which we know has carried toxicity to TNF inhibitors, etanercept and adalimumab, and had coprimary endpoints of looking at cardiovascular outcomes, including death and malignancies. It was set up with a noninferiority treatment target.

At the end of the day, tofacitinib failed to achieve both coprimary endpoints, in terms of cardiovascular events, death, and malignancies. Now much has been said by many smart people who have looked at what data is available and looked at this as kind of yin and yang. The cardiovascular events were increased in the tofacitinib group, but not statistically significantly so, but did not meet the noninferiority predetermined endpoints.

There were more malignancies, particularly lymphoma, with tofacitinib, yet the number of malignancies in the TNF group was very small, looking at historical trials. All we know is that there will be warnings, not only for tofacitinib, particularly in high-risk people—his trial was done in people over the age of 50. —but there will be warnings in the other 2 drugs, which were not included in this trial.

Neal had said, is this a cautious reaction or overreaction to this? This is a single trial, and it missed its endpoints, and it deserves attention. I'm not surprised to see tofacitinib's labeling change to be more rigorous.

I do question 2 things. One, this nonstatistical, at least significant difference, that was seen. If this trial was repeated again, would we see the same results? I don't have firm faith in that, and there are other long-term safety studies done in CORONA and other databases that have been very reassuring in the real world.

The last point, and get my colleagues' take on this, is whether baricitinib and upadacitinib deserve the smack down that tofacitinib's getting because they weren't studied. They have their own long-term extension studies that have been quite reassuring. We respect the toxicity of this.

I've commented this publicly in the last few weeks that our regulatory agency, the FDA, has been very harsh on this class of drugs. We threw filgotinib out the window. Baricitinib did not get the indication that they had requested, nor the dose that they wanted. Both of those drugs are fully approved in Europe by the EMA.

It's not like a slam dunk that we have this terrible toxic class of drugs. There's room for discussion here. It's going to make it very difficult for patient conversations. Although, the ones that I've had in the past few weeks, nobody seems to be too worked up over this once this is explained.

RALN:  Dr. Majithia, what's your take on this?

Dr. Majithia:  I don't think I can add a whole lot more than what Dr. Calabrese just said. Tofacitinib was the first drug in this class, and we needed to look at these additional information for this new class of drugs.

This particular trial deserved all the attention that it is getting but a whole lot more, because as Neal has pointed out, the difference is not statistically significant and the prevalence of malignancy in the TNF group is not usually reproduced in long-term trials.

I completely agree, I don't think baricitinib as well as upadacitinib deserved this additional black box at this point. Again, they have ongoing trials, and if we had waited it out, looked at those results, we don't necessarily know whether there are truly any differences within the class or the doses.

Yet, I do think that it's important to inform public about results of these particular trials. Again, we do not have access to the whole data.

RALN:  Do you think this is likely to change your practice?

Dr. Majithia:  It brings up a point to discuss. Again, we really have to think about what the evidence is. These are high-risk patients above the age of 50. A number of our patients do not fall into this category, yet a number of others do.

It is important to discuss this potential for increased toxicity, possibly, without raising panic. There is a signal which needs to be looked at and watched over.

As with Dr. Calabrese, most patients have taken in stride, and then if you look at the numbers, the numbers are fairly small. I have not had as much of a pushback as I've had in the past with some of the other medications or as much as I expected.

Dr. Birnbaum:  I don't think this has gotten out to the general public that much yet. Certainly, the patients aren't calling the office saying, "Should I be off this drug?"

The sense I have in talking to patients is that most, if not all of them, will choose to stay on drug because these were generally difficult patients who had failed anti-TNFs and other biologics in the past.

I think going forward, there will be issues and longer discussions until we have the data that we've all said that everybody wants. Should these warnings apply to all patients, or are there certain subsets with age and predisposing conditions? Should it apply to all the drugs in the class, and should it apply to all the doses that are available? The brush painted so far by the FDA is a very, very broad one.

Also, we'll be facing issues about payers. What will happen if a doctor has an informed consent discussion with a patient and decides they don't want to go through a biologic first and they want to go to one of these drugs? Will there be difficulty getting approval?

The other that always lurks in the background is, what if you decide to use one of these drugs and there is an adverse event? What are the lawyers going to say about it?

RALN:  In closing, what would you advise your colleagues in rheumatology to do from this point forward?

Dr. Majithia: I'll start by saying that at this point, I think we need to look further into the data as it will become available. Having this discussion is reasonable, but not making significant changes on the basis of the information available at this point is needed.

It is important to give the patients the right medicine as it is appropriate, because most of them are taking it after they have failed a number of those other biologics. It is very reasonable to keep them on it, or consider starting in the lower-risk patients.

Dr. Calabrese:  I agree with that.

Dr. Birnbaum:  We're looking for the details from this study and we're also looking for information from manufacturers of the other drugs and their long-term safety observations to see, is there a difference?

I don't think we've seen yet what the package inserts are going to look like. The negotiations that'll be held between the manufacturers and the FDA—will they all look identical, or will they negotiate some individuality that we know that that has occurred in the past?

It's an important piece of information, but I don't think it's something that we're going to rely on completely until we have supporting data from other trials, one way or the other.

RALN:  Thank you all very much for spending some time with us today to talk about this. It's a very interesting subject. Certainly, this discussion will continue. I look forward to talking to you all again. Thanks a lot.

Dr. Calabrese:  Thank you.

Dr. Birnbaum:  Thank you.

Dr. Majithia: Thank you all. Good seeing you all.