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The Impact of JAK Inhibitors in AD Treatment


A dermatology expert highlights the role JAK inhibitors play in AD therapy, from mechanism of action to ruxolitinib and the TrUE AD1 and -2 trials.

Neal Bhatia, MD: The mechanism of action of a Janus kinase [JAK] inhibitor starts with what a kinase does, which is develop phosphorylation with its target. If you think about the processes needed in cytokine intake and processing into the immune system and how it works, you have to think of the simple steps that are in play: the amortization of the cytokine receptor, the actual binding of the cytokine to that receptor, the docking of the STAT [signal transducer and activator of transcription] protein, then the carriage of that information on the STAT protein to the nucleus. Those several steps are very important. They also involve phosphorous. It’s like the passage of a battery when you think about where that phosphorous comes from. It has to be there to make the receptor come together to allow cytokine binding to allow for the STAT protein to dock and carry the inflammation down as well to go to the nucleus. All of those steps are essential.

When we think about what Janus kinase inhibitors do, they’re very specific to binding that enzyme so that those processes don’t receive that necessary phosphorous and therefore can’t continue. That’s some of the essential equations vs the biologic therapies that are readily available. For example, the interleukin-4 and interleukin-13 receptor blockade by dupilumab [Dupixent] is dupilumab blocking the receptor binding of those cytokines, but it isn’t depleting their population or affecting the cells. It’s just preventing the exertion of interleukin-4 and interleukin-13 to doing their job of making the pathogenesis of atopic dermatitis. Whereas tralokinumab [Adtralza] is going right after interleukin-13 itself. It has a significant impact on the cytokine, basically destroying it rather than going after the receptor. There a lot of variations in the approach. But as you see from all of them, they’re much more targeted and developed to stop the process of the disease rather than just mopping up the mess of inflammation that’s downstream.

We’ve learned [a lot] in the past couple of years with the development of Janus kinase inhibitors, starting with the original molecules, such as tofacitinib [Xeljanz] and a few others that were used in rheumatology and other disciplines. Now we have topical delivery of ruxolitinib [Jakafi] with the ruxolitinib 1.5% cream indicated for atopic dermatitis, which is a great asset. Because for one, it doesn’t have the steroid consequences, so we can use it head to toe. We can use it on the eyelids, in the intertriginous areas and not worry about any atrophic or absorption potential. It’s well suited for that patient who has 3% to 12% body surface area [BSA] affected. But even more so, we can use it with a lot of flexibility because of its speed of onset and the lack of any steroid-type effects.

The best part about what we’re learning about the flexibility of ruxolitinib cream is the long-term safety data, not just at 8 weeks but also at 52 weeks with how patients can use this and basically continue on with their daily lives. They can use it when things flare up and stop it or take holidays as they need to and keep moving. Obviously, there’s development of ruxolitinib cream in other disease states. But when we focus on atopic dermatitis, there are significant advantages obviously over triamcinolone, which has been studied head-to-head. But even more so, it’ll reduce our reliance on steroids. It’ll allows us to use steroids properly but without the consequences or steroid phobia in the world today.

The studies that brought topical ruxolitinib cream to the market were known as TRuE-AD1 and TRuE-AD2. The design was a dose-ranging study where 1.5% cream and .75% cream were studied [twice a day] head-to-head as well as against the vehicle. Remember, in dermatology, we don’t say placebo. We always say vehicle because we want to see the vehicle do something. There was basically a 2:2:1 ratio. Four out of 5 subjects got at least some active treatment in the trial design. But it was standard in terms of who was in the trial. Patients were 12 years of age and older. They all had to have a history of atopic dermatitis. Most of them were mild, but there were some moderate patients. There were a lot of different skin and color types as well as gender and age. But the vast majority were considered moderate. There were a few mild patients as well.

What’s interesting is the average BSA in those trials was about 10%. If you look at the data, they looked at the sprint effect compared with the vehicle of how many patients got better within 2 weeks, at 4 weeks, and then at 8 weeks. There were close to about 53% of the patients in each study by 8 weeks achieving that 2-grade improvement. Those are significant numbers of those who achieved success.

What they found that made an impact was the sprint effect of how fast things were getting better in a lot of patients. The flatter vehicle numbers were obvious in terms of the separation of the trial. But even more so what they found with safety. There’s no atrophogenic potential, so they can use it on different areas. In that 12%, there was nothing that would be considered to be excluded. But even more so, the NRS [numerical rating scale] data. Remember the rating scale numbers? Those who achieved 4-point improvement was also pretty significant. That’s where we’re going to see the test of these patients, how fast they’re going to get better within several days and even up to 8 weeks.

Finally, there was very little in terms of application site reactions, and very little in terms of anything that was of concern for permeation and such. Because everyone is asking you about black box warnings, you have to remember that a lot of these black box warnings were developed in patients with rheumatoid arthritis aged 50 and older on concomitant medications or had significant comorbidity. Those patients unfortunately also had other risks, but it affected the entire class of Janus kinase inhibitors. It’s very important to keep all of that in mind as well.

This transcript has been edited for clarity.

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