Understanding the Black Box Warnings for JAK Inhibitors - Episode 3

Reviewing Clinical Trial Data for JAK Inhibitors

,

Matthew Zirwas, MD, breaks down the safety of JAK inhibitors based on clinical trial data.

Linda Stein Gold, MD: We did mention that this is a twice a day drug. It was used twice a day for 8 weeks in the phase 3 clinical trial, and then we allowed patients to go on a long-term safety study. That safety study is not included in the package insert at this point, but we do have experience with patients using this drug for longer periods of time. One thing that I really liked about the clinical trials was that it included 2 sister studies: 2 studies done by different investigators, different patients, different places, but are almost mirror images of each other. That, to me, as a clinical investigator, and I’m sure to you also Matt, is when you see reproducible data and it really helps you to believe in the data that we’re getting. I agree with you, the itch data was really impressive in that, as you mentioned, within the first day, you start to see a reduction in itch. That high bar, the 4-point reduction, was also statistically significant really early on in the clinical trials. We talked about the fact that it kicks in pretty quickly, can be used anywhere on the body, is a nice cream formulation, rapidly reduces itch and does so efficacy. Let’s talk a little bit about the safety profile in terms of the clinical trials. In terms of tolerability, Matt, what did you see, both in your clinical trials experience, as well as what you see in the clinic?

Matthew Zirwas, MD: I love that you separated tolerability from safety because I think of those things as 2 totally different issues. We know, for example, that the PDE4 [phosphodiesterase 4] inhibitor has been on the market for a while, and is extremely safe, but doesn’t always have the best tolerability. I have not seen any tolerability issues, so I’ve yet to have either a trial patient, or somebody that I’ve prescribed it in “real life.” I haven’t had anybody complain of any burning, stinging, or any kind of application site reactions or any tolerability issues.

Linda Stein Gold, MD: Yes. That’s really important because, as you mentioned, this is not a steroid, and often when we think about a nonsteroidal product, we think about a tradeoff. It’s safe, but it might have a little bit of stinging and burning. I think we’ve seen that with our other nonsteroidals, both in atopic dermatitis, as well as psoriasis. This is one where we really don’t see that stinging and burning that we might expect with a nonsteroidal. It’s pretty well tolerated, even at day 1. So let’s go on and talk a little about the safety overall. What about the safety? Were there any significant signals that were seen?

Matthew Zirwas, MD: There weren’t a ton. There were a couple of cases of thrombosis. I think there were also a couple of cases of shingles that happened, but there were such small numbers that you really don’t know if they were triggered by the drug or not. This wasn’t a statistically significant increase in the number of cases. It is a really difficult thing now because we have the box warning, as you mentioned, that kind of looks the same as with the orals, but we know you’ve got this dramatically lower systemic absorption, although it’s not 0. That’s the thing that makes it difficult. When we look back at things like the tacrolimus box warning or the pimecrolimus box warning, we knew that there was 0 systemic absorption. You couldn’t even detect it in the blood unless somebody had Netherton syndrome. There is some systemic absorption here. It’s low. It’s 6%, but we know that the side effects of JAK [Janus kinase] inhibitors are dose related, so it is conceivable that there’s a little bit of immunosuppression. Do I personally think there is? Probably not. In fact, I’d be really surprised if there was. It is conceivable that there is a tiny increase in the risk of venous thromboembolic events. Do I think that there is? Probably not because the systemic exposure is so low, but it’s possible. I can’t say to a patient, “Look, this doesn’t even get into your blood, so you don’t need to worry about any of that.” A little bit of it does get into your blood. I don’t think these are significant risks, but they could be. We don’t have big enough numbers of patients to be 100% sure whether there is risk here or not. We just don’t know.

Linda Stein Gold, MD: I think that’s such a good point. It’s important to state that in the clinical trials, they only went up to 20%, when we can contrast this to crisaborole [Eucrisa] where patients went up to 95% BSA [body surface area]. This is not that kind of a drug. Matt, you went over the maximum use studies, and I think that was important because here they looked at patients who had much larger body surface areas than what we saw in the clinical trials. In fact, the average BSA and the maximum use was about 37%. They weren’t between 25% to 90%. So here, they did push the envelope and as you mentioned, there were some systemic levels that were seen with the steady state plasma concentrations for sure. It’s low, and it’s below the oral levels absolutely, but as you apply it to larger body surface areas and you push that envelope, you do see some systemic levels.

Transcript edited for clarity.