Treating AD: Discussing a Phase 3 Trial on Ruxolitinib

Lawrence Eichenfield, MD, is chief of pediatric and adolescent dermatology at Rady Children's Hospital-San Diego in San Diego, CA, and professor of dermatology and pediatrics and vice-chair of the department of dermatology at UC San Diego School of Medicine. He is board certified in dermatology, pediatric dermatology, and pediatrics. Dr Eichenfield’s expertise is in atopic dermatitis (AD), acne, psoriasis, other inflammatory skin conditions, and more. He met to discuss one of his most recent studies, “Efficacy and Safety of Ruxolitinib Cream for the Treatment of Atopic Dermatitis: Results From Two Phase 3, Randomized, Double-blind Studies.”¹

Regarding the earlier data, what types of AD patients may be good candidates for being treated with ruxolitinib cream?
Ruxolitinib cream is the first topical Janus kinase (JAK) inhibitor that we're getting a lot of experience with for AD. It is technically a JAK1/JAK2 inhibitor. We know that the JAK pathway is important in mediating inflammation in eczema.

In the clinical studies, it has shown very good efficacy associated with an anti-inflammatory effect, as well as a marked antipruritic effect. It does this as a noncorticosteroid. It can be niched anywhere in clinical practice where someone would like a nonsteroid anti-inflammatory/antipruritic, so it can be broadly used throughout AD care.

Patients who were treated in the studies had body surface area involvement that ranged from 3% up to 20% (excluding the scalp). So, even with the limitation of 20% body surface area, the study allowed a significant amount of the body being treated.

Patients with active AD often have involvement in delicate skin areas (potentially face, neck, body folds). These are sites where we get concerned about atrophy with topical corticosteroids, so the use of ruxolitinib has great potential. 

For patients who have very persistent AD, or frequently recurrent AD, that can't be well-maintained with intermittent topical corticosteroids, ruxolitinib may be quite useful.

Looking at the evidence basis of the use of the drug, topical ruxolitinib was studied twice a day for active AD for an 8-week period in the core phase 3 studies. There was also an extension study, assessing the use of the drug for up to 1 year.

In that week 8 to 1-year use, the study design was such that people could use their medicine when they had active disease but stop it if they didn't. There was a desire, of course, to get experience with long-term use because this was the long-term safety study for the development of the drug. However,  the study didn’t require people to use the medication all the time during the year of use, and it was withheld they had no active clinical disease

In the initial part of the study, patients were randomized to either lower strength ruxolitinib, 0.75%, or 1.5%, or vehicle, using their study medication twice a day for 8 weeks. They didn't know, at that point, what their study medication was, as both patients and investigators were blinded. At the conclusion of the 8-week period, if they entered the extension study, they remained on their active medication strength, unless they were on the vehicle, in which case they randomly received either the higher strength or lower strength cream for the up to 1-year period. If they had active eczema, then they used the medicine twice a day to the involved areas. When they cleared, they were treated 3 days beyond lesion clearance and then stopped medication. Patients could restart medication if there was a recurrence. So, the study design is really quite “real-world use-like.”

Patients were evaluated every 4 weeks with traditional assessment for safety, as well as a lesional scoring.

The long-term data showed continued efficacy with our standard outcome measures. My overall perspective was that the topical ruxolitinib  showed excellent objective measures of disease control as well as impressive impact on  itch.

So, who might be a target patient for topical ruxolitinib? Patients who are trying to avoid topical corticosteroids, patients who could use it in regimens with topical corticosteroids, or patients who are on systemic therapy but have remnant AD. There are a set of patients on dupilumab, for instance, who have persistent facial dermatitis despite the systemic medication. Topical ruxolitinib might be highly useful for these patients.

High disease burden due to itch and pain impacts patients' quality of life (QOL). In what ways can ruxolitinib cream improve patients QOL?
First, itch is highly associated with AD. It is associated with inflammations in the skin, but we have increasing information about neural mechanisms at play with the sensation of itch. For instance, we know that patients with atopic eczema have “twitchier skin.” If you take coarse fabric fibers and rub them on a patient with AD, as compared to someone without AD, the sensation that comes from that, the pruritus level, is much higher in a patient with AD.

Probably, the example in clinical practice that is most impressive, is what we see in some younger children when a parent takes the child’s clothes off in the office, and the child immediately starts “working at their skin,” scratching away.  This shows that air on the skin is perceived as an itchy sensation.

Itch is very much tied to eczema presentation but also incredibly tied to the impact on QOL. In some cases, that's direct because the itch and the response to itch, which is scratching, makes the rash worse which cycles up the amplification of inflammation.

There's also a very important impact on sleep. Itch is highly associated with sleep disturbance, and sleep disturbance clearly impacts so many aspects of life. When we've had a bad night of sleep, we're grumpy. We're not as alert, we may not go to work or be as present at work. It may, also, impact on our interrelationships with other people.

When we're doing QOL testing, there are several parameters of symptoms and life that are being assessed. Skin pain is now also  appreciated to be part of the impact of AD on the individual.

The question is, can ruxolitinib help heal AD by improving itch and quality of life? The answer is yes. In the clinical studies, they did a deep dive on itch. One of the things we see is that the itch response with ruxolitinib is very quick. Within hours, and in the measured studies within days, you see a very rapid separation from vehicle in reported itch.

Moisturizer helps AD, but not very rapidly or profoundly with itch. A variety of scores are used in the study. The classic score is the Numerical Rating Score score, which asks "What is the worst issue you had over the last 24 hours?". It's a 0 to 10 score; the baseline could be 4 or it could be 8. It depends, of course, on the severity of the group in the clinical study. One standard endpoint used in studies is what percentage of patients will have at least a 4-point reduction in their baseline itch score. Ruxolitinib showed very nice separation from vehicle in that worst daily itch early on. In fact, significant itch reductions vs vehicle were seen within 12 hours of the first application of 1.5% ruxolitinib (P<.05).

When you get to the end of the 8-week study, you have about 50% of patients, 42% with the lower strength and 52% with the higher strength, who had at least a 4-point reduction in the daily itch score. The number of days of itch that patients reported was markedly decreased.

Part of the data that was presented at the AAD Virtual Meeting Experience² (VMX) discussed the proportion of the adolescent and adult patients treated with topical ruxolitinib who had 0 to 2 days of itching the past week as compared to those having 5 to 7 days of itch. With the higher strength topical ruxolitinib, almost 70% of patients reported having 0 to 2 days of itchy skin at the end of the study compared with only 10% at baseline.   

Analyses also looked at sleep disturbance, assessed by evaluating sleep scores that are embedded in other outcomes measures as well as an independent sleep score.

The Scoring Atopic Dermatitis (SCORAD) tool is a mixture of an objective measure of the extent and severity of rash on the skin, as well as subjective measures on itch and sleep. An analysis presented by Dr Eric Simpson at the AAD VMX³ discussed sleep disturbance and how ruxolitinib performed in that SCORAD sleep score. In addition, a relatively new AD score, a Patient-reported Outcome Measures Information System (PROMIS) sleep disturbance score, was presented. PROMIS is an initiative attempting to create consistent outcome measures across disease states rather than having specific scores for each disease.  Thus, the PROMIS tool assessing AD sleep disturbance isn’t specific to AD, but more like a registered tool to assess sleep in general. There are questions about sleep disturbance in the Patient Oriented Eczema Measure (POEM) score. The POEM assesses the impact of AD by quantifying effects over the past week.

Ruxolitinib performed well with this analysis of  the core studies, showing reduction in the sleep disturbance based on both the PROMIS tool and the POEM, while the sleeplessness score decreased significantly. Using multiple instruments, it looked like there is significant improvement in sleep issues with the use of the topical medication.

Long-winded answer, there are very nice data on decreased itch and decreased pain. We know these are highly important in terms of our quality-of-life scores.

How could ruxolitinib cream reduce the treatment burden for patients with AD?
Part of the treatment burden of AD relates to the core issues of the disease. A lot of AD skin is very dry. There are people who are innately dry, and they may have deficiencies in filaggrin expression or have no filaggrin in their body, which makes them this fundamentally dry.

We know that inflammation in the skin further compromises the skin barrier. The active eczema causes problems both in terms of itch, rash, and changes in microbiome, etc. All of this is tied to the disease. Of course, part of the burden of AD is caring for the skin. We see this very commonly in pediatric dermatology where patients come in and they were told to emphasize moisturizers. They're doing 6- to 8-times per day application with total body moisturizers, and the eczema is in terrible shape because the inflammation has outstripped the ability of the moisturizer to heal the skin. They're working towards minimizing the xerosis component but not necessarily controlling the inflammation. What we need to do is to do both. Ruxolitinib brings a potent nonsteroidal anti-inflammatory into the armamentarium.

It's probably a good time to discuss a little bit about how strong ruxolitinib is. It's always a difficult question to answer directly, but it does harken back to the phase 2 study of ruxolitinib, which also studied the 1.5% ruxolitinib cream.

In the phase 2 trial, ruxolitinib was compared to triamcinolone 0.1%, a standard mid-strength topical corticosteroid. Ruxolitinib did comparable or better, depending upon which week is analyzed, and at the end of  the study looked superior in efficacy to triamcinolone 0.1%. If this is what we observe in practice, as well as in studies, this would be a huge boon to us. Other nonsteroidals have associated issues over time, such as calcineurin inhibitors (pimecrolimus, tacrolimus) and our approve phosphodiesterase 4 inhibitor, crisaborole, and these do not seem to have the efficacy of a mid-strength topical corticosteroid.

What people want is to be able to clear their skin quickly and then to keep it under control. For some patients, it could be that they're going to be using ruxolitinib as needed every now and then. For other people, it could be that they will use ruxolitinib a few times a week for the hotspots and prevention. In others, it will be mixing and matching with topical corticosteroids.

Treatment burden can be reduced if people can get to a regular standard regimen that's needed proportionate to their disease to get them essentially symptom-free and rash-free.

When it comes to AD, are there any pearls of wisdom you’d like to share?
One of my biggest takeaways is that we used to talk about trying to minimize flares and increase the number of days between flares. I've been a big proponent for changing the verbiage. It's about long-term disease control. We would like to bring the greatest number of people to minimal rash, minimal itch, and minimal sleep disturbance.

My message to health care providers is that this is what they should communicate to their patients, because it brings them along into a different way. Many times, patient understand it better when I parallel it to asthma. I'll see a patient who has had persistent eczema. When I ask them the last time their skin was totally clear, they giggle when they say, "Never." The analogy is that if they had asthma, they would be wheezing all the time. They treat when they worry about the disease, or they start to treat it when it gets really bad. That's not what we're going for!

We want long-term disease control because that is going to minimize the comorbidities and the QOL impact. It is much easier to do that with different tools. Topical ruxolitinib can be a different tool as a nonsteroid, bringing excellent efficacy to AD care. Sometimes you need more than one tool to fix things.

Is there anything else you’d like to share regarding ruxolitinib cream or AD?
It's been an exciting last few years in AD and will continue to be very exciting going forward. Hopefully, we'll have topical ruxolitinib, systemic IL-4 and IL-13 blockers with dupilumab, other topical nonsteroids, our oral JAK inhibitors, and several other biologics well along the way in their clinical studies or under review at the time that we're doing this interview.

Having different kinds of tools and multiple tools will help us assist our patients. It will also help us to get the message out to patients because we still see so many patients with AD who haven't been back to the dermatologist recently. We're going to continue to have this explosion of information to go along with our new resources clinically. It will allow us to improve their lives.

References
1. Papp K, Szepietowski JC, Kircik L, et al. Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: results from two phase 3, randomized, double-blind studies. J Am Acad Dermatol. Published online May 3, 2021. doi:10.1016/j.jaad.2021.04.085

2. Blauvelt A, Szepietowski JC, Papp K, et al. Ruxolitinib cream rapidly decreases pruritus in atopic dermatitis: pooled results from two phase 3 studies. Presented at: AAD VMX 2021; April 23-25, 2021. Poster 26884.

3. Simpson EL, Boguniewicz M, Thaçi D, et al. Effect of ruxolitinib cream on sleep disturbance and sleep impairment: pooled analysis from two randomized phase 3 studies. Presented at: AAD VMX 2021; April 23-25, 2021. Poster 26887.