Shawn Kwatra, MD

Do each of you have some parting advice or a word of wisdom for any physicians out there taking care of patients with prurigo nodularis [PN]? Shawn, I'll start with you.

I would tell the physicians, ‘You have an opportunity to make a humongous impact on someone's quality of life.’ When we looked at the overall quality of life and how it's affected in PN patients, it's as severe as having a stroke, chronic heart failure, or being on hemodialysis. I think that's underestimated, the opportunity that any type of doctor has when you encounter a PN patient, to make a difference. At that moment, you can give folks the proper diagnosis. You can do a lab workup. You can make sure that they don't have many of these different disease comorbidities. You can also start them on therapies that are going to reduce, in my view, their likelihood of developing many different comorbidities. Sleep problems, anxiety, depression, and even worsening type 2 diabetes. I think it's a great opportunity that doctors have to intervene and make a tremendous difference. I think it's one of those conditions that has such a significant effect on quality of life. It's arguably one of the highest we see among any patients in our specialty.

How about you Sarina? Any parting thoughts?

Yes. I couldn't say it better than that. I usually say at the end of these that I advise physicians to care about their patients. I will say also to think broadly and stay up-to-date on the treatments we can offer. This is a landscape that is changing; as we mentioned, there are multiple drugs. I think there are probably going to be more that are coming online as the landscape of AD, atopic dermatitis, evolves, and the landscape of other disorders evolves. We will also learn more about prurigo nodularis. It's not just the limited few that we spoke about. I encourage everybody to really stay up-to-date and keep an eye out for things on the horizon.

I really can't put it better than both of you did. The one thing I tell my residents when it comes to any patients, but particularly these patients, is just listen. Just take a second and listen. You'll be surprised how much you figure out. How quickly you're going to change what your point of view might have been when you came into the room. Your viewpoint when you read the chief complaint or looked through the chart and saw what other notes said before the same findings you eventually get to. You'll find that perhaps you will understand why this is such an interesting and fascinating disease state and one which deserves to be treated as such. Just alongside all the other diseases that we think about potentially that are more prevalent or better understood.

With that, thank you, Shawn and Sarina, for this rich and informative discussion. This was amazing to talk to 2 world experts and get to the cutting edge of where we are and where we should be going. Thank you all for watching this HCPLive® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming peer exchanges and other great content right in your inbox. Thank you very much.

Videos

Shawn Kwatra, MD, and Sarina B. Elmariah, MD, PhD, share final pearls of wisdom for other physicians taking care of patients with prurigo nodularis (PN).

Advice for Managing Patients With PN

I'm excited that there's so much interest and so much happening as far as the space goes. That leads me to the last couple of thoughts maybe we can all share. I've learned a lot talking to you both. Maybe you can boil down what you really think are the key unmet needs in PN [prurigo nodularis]. I know that we've gone over some of these throughout, but maybe you can share from the physician’s perspective and from the patients. What do you think really needs to be the next thing that we figure out? Sarina, I'll start with you.

I think we've highlighted this a couple of times, which is the idea of how to control the itch and to do so effectively and rapidly. To allow other aspects of PN to come in line. I think that’s still, quite frankly, to me a huge unmet need with this disorder. I also think as Shawn has highlighted a couple of times, the hyperpigmentation, the potential scarring, and the nodule itself, even chronically, the other aspects of the disease still weighs heavily on patients, particularly, patients with skin of color. I think that's also another point at which we really need to focus and emphasize in our management and how we're going to conquer this disorder.

To me, what's unique about prurigo nodularis compared to atopic dermatitis and psoriasis is the fibroblast. It's fiber proliferation. It's these nodules that can be so tough and firm. I think some of the biggest questions that the patients are having is how do we get this nodule to have a resolution? What is the natural history long-term? I think we need more natural history studies to zone in on, ‘Your nodule can be expected to resolve in X amount of time.’ Is it going to leave postinflammatory hyperpigmentation? Is that going to be chronic? All those features, I think, are very important.

I think that we need more mechanistic studies because patients also ask me all the time, ‘Why?’ Why is it happening? I think for a disease like atopic dermatitis and psoriasis the why involves a lot more genetics. I think in a disease that penetrates in middle age, it's a lot more of other things too. It's the environment. It's also the social determinants of health. It's a lot of other factors. I think wrapping our minds around why that does happen. Why does it disproportionally affect patients with a skin of color? What are the factors that make folks more likely to suffer from this disease? We need to do more research on that. I think that will be able to shed greater light also as to what patients can expect in terms of the natural history of the disease.

I love it. That's a lot of food for thought. I might throw in something that you were mentioning before. It's something I've thought about a lot for atopic dermatitis. PN is a new exception as far as an inflammatory disease goes. What is going on with the heterogeneity of our patients, right? Why do we have these subsets where some people respond, and some don't? Even in targeted therapies, some people don't respond as well as others. What's going on there? Are we going to get to a point where we can figure out the right monotherapy for people? Or is it going to always be a combination-type approach, where we're going to have to have something that's targeted but also something that's more nerve-acting vs immune-acting as well? I know it's an area in which you among others are going to help us understand what's happening in the future. I think that's really, exciting.

I think from a patient’s perspective, patient education here is huge. Patients know so little about the condition because we know so little about the condition. They oftentimes are not knowing where to go when we can't tell them that it's either in their head or something is going on. They can't Google search the solution effectively. For anybody with deep pockets out there, there's a lot of health care provider education and disease state that has to happen for us. I think it's going to be equally important for patients. The ones that are out there who feel that they haven't been heard or feel like they don't know what they're going through can really feel that there is a name for what's happening to them. They can see their dermatologist in order to try to get control of their symptoms.

Experts in dermatology discuss unmet needs in prurigo nodularis (PN) and the importance of addressing those needs for disease management.

Unmet Needs in PN

That’s what excites me, and that leads into my next question. I want to bounce it back to Shawn. You mentioned nemolizumab. Can you tell me a little bit more about that? What it is? What have some of the findings shown? What does the potential hold another therapy for PN [prurigo nodularis]?

Nemolizumab is a monoclonal antibody targeting IL-31 receptor A. Phase 2 data have already been published in the 

. We know that this is a very effective agent that’s in development. We know that only a few doses of the drug can reduce itch intensity very quickly, within a matter of a few days. Also, the depth of response is also very significant. In the phase 2 trial of nemolizumab for prurigo nodularis, patients were followed, and around 10 weeks later, they had approximately a 50% reduction in their itch.

The nemolizumab clinical trial program has invested in a few things. The first thing is in addition to the 2 pivotal phase 3 trials; they’ve also invested in a multiyear extension study, a durability study. The main questions patients had are, “I’m on the therapy. I’m on a biologic. Does this mean I’m on a biologic forever? What happens if I come off?” I think that the fact that they’re investing in getting data is going to be very important for us when we’re counseling patients about if they get off therapy, what to expect. Many folks understandably are a little bit hesitant to have continuous long-term therapies. That’s 1 of the considerations I think that’s going to give us more data about the drug from the phase 2 data. The public release of some of the phase 3 data is very strong as well. It’s going to be another great option for patients with prurigo nodularis.

It’s interesting because we were looking at this drug through a very atopic dermatitis lens for a period of time, just given some of the work that had come out of the Japanese population and the approval there where it’s specifically approved for the pruritus associated with atopic dermatitis. I think that there was a little bit of reluctance among the AD [atopic dermatitis] community where they thought, OK, this seems to be a medication that’s working reasonably well for the itch, but by and large, for our conventional atopic dermatitis measures, is it really going to get us where we want it to? It’s very encouraging to see what’s happened as far as prurigo nodularis goes. I’m, personally very excited to see how this pushes the field forward in terms of a different therapeutic target, and one which I think is going to teach us a lot about IL-31, which we always talk about as the itch cytokine, but have not had any real-world practice in directly targeting, which is going to be super cool. That’s not the only new thing coming out, there are others. Sarina, I’ll pick and choose a couple that have at least some data out there. Maybe you can share your thoughts. You mentioned nalbuphine earlier, very briefly. Maybe you can tell the audience a little more about that, where you see that panning out.

Thanks Raj for that question. I mentioned before, nalbuphine is a new kappa opioid-antagonist combined medication. It is an oral extended-release medication that has been used in the past for pain, and now is being used to manage itch in prurigo nodularis. It’s in phase 2, phase 3 trials and has been showing promising results. I think that this drug and targeting this access may be helpful not just for prurigo nodularis but really thinking about how itch is involved in the process of neurosensitization and other itching disorders as well. I think it holds a lot of promise for PN but also for the broader landscape of itch.

Shawn, any thoughts on an oncostatin-M receptor beta. Since we talked about IL-31, tell me what you think of vixarelimab.

What’s fascinating is, we have a few public data releases with vixarelimab. Which targets oncostatin M receptor beta. That’s going to modulate oncostatin M signaling IL-31 as well. In atopic dermatitis, modulating oncostatin beta helped with the itch, but it didn’t necessarily help with the lesions vs prurigo nodularis. What we’re finding is it’s helping more with resolving the nodules. It comes down to more of the questions: What is dominant in atopic dermatitis? What is dominant in prurigo nodularis? Is it the itch? Is it the lesions, the subclinical inflammation? What we know in PN is the itch is truly a driver of disease severity, whereas the drug vixarelimab didn’t have much of an effect in AD, although in prurigo nodularis it seemed to work. I think that sheds light in terms of the biology of the disease as well.

Vixarelimab has some data that have been released about nodular resolution and itch. I believe Genentech acquired the compound from Kiniksa Pharmaceuticals and they’re going to be moving forward with the development for that compound. I know that Sarina talked about nalbuphine, and we had some data released that put it firmly behind the monoclonal antibodies because it was just more of a modest effect. I think the power in the study was that it had so many folks in it. If I had to look toward the future it would be more of an adjunctive therapy second-line agent.

I agree with Sarina in terms of I’m more excited about that access, especially for neuropathic pruritus, which is such a difficult problem targeting immune kappa opioid access. Also, just as an adjunctive H therapy. I think that can be a helpful option for patients. Sometimes I use the ipratropium nasal inhaler, which is a kappa opioid agonist. However, I’m always a little worried about adverse effects. Sometimes folks can have sedation or nausea or any of those types of GI [gastrointestinal] adverse effects. I think we’ll learn more from the data release. Always having new therapies is going to be helpful.

I will also mention there’s a subtype of PN that is more skewed toward neuropathic. They just don’t have any biomarkers of type 2 inflammation. I think that in that patient population, in particular, that would be a great role for nalbuphine. In addition, there are some JAK [Janus kinase] inhibitors. The insight has a JAK1 inhibitor that’s in global trials, a phase 2 dose-ranging study. As we know, our group also showed that PN IL-22 plays an important role. It’s really from CD4 [cluster of differentiation 4] and CD8 T-cells. It’s also involved in skin thickening similar to what we see in Black patients with atopic dermatitis. I think there are certainly reasons to believe a JAK1 inhibition would be an important mechanism of action. Those are the key drugs.

What I’m looking for in the future is, what about the drugs that are making their way through atopic dermatitis that may also work? We know that there are phase 2 trials that are going on with OX40 [CD134] inhibitors. We know that topical JAK inhibitors were approved for atopic dermatitis. That would be one therapy worth exploring in PN, especially from a topical level. That’s the overview of agents that we have in development right now.

Drs Raj Chovatiya, Shawn Kwatra, and Sarina B. Elmariah review exciting new therapies in the treatment landscape of PN.

Emerging Treatments for PN

I couldn’t agree more. Here’s my question to both of you then. When we started training, the idea of even a POSI [postprandial oxidative stress index] 100 was not that common. We were hoping for POSI 50 or POSI 75, and it’s taken nearly 20 years to really get there. How long do you think it’s going to take before we can get there for PN [prurigo nodularis]?

I think it’s happening very quickly, to be honest. The pipeline is expanding. I think the main hurdle here is that we need to have more investigative research. What we learn in psoriasis is, it’s the subunit that you target that can make such a big difference. You look at some of these IL-23 inhibitors like risankizumab vs Stelara and you see these giant differences in terms of efficacy. I believe we need to have more research into the pathogenesis to narrow it down and target it a little bit more. If you look at some of the agents that are coming down, like say, for nemolizumab, which is coming out very soon, some of the H data are very strong. Some of the JAK [Janus kinase] inhibitors are going to have great data. I think we’ll always have to balance how much is it going to improve the H with how much it affects the safety profile. I think that’s the most important thing. To have more target agents where we can learn a little bit more about different immune subsets that are affected in these patients.

I agree to an extent. I will say, with psoriasis, we ended up getting lucky a bit in that real time we learned about pathogenesis as we were developing therapies. What we ended up finding out was that psoriasis was probably far more homogenous than we thought as a disease in terms of the importance of IL-23 mediated skewing of Th17 [T helper 17] cells and then the pathogenic expression of IL-17A into a certain extent, IL-17F as well. It turned out that you could get to where certain drugs broadly get to a target of 100% in populations.

I’m liking this for atopic dermatitis. We’ve learned a bit since we’ve had some of our first systemic therapies and others that are far more heterogeneous as a disease. As it turns out that even with a very broadish blockade, you’re still not getting to that point that you’re getting to in psoriasis. A lot of this just comes when the drugs get there. We see what they work like in the real world. I think with PN it could go one of a couple of ways.

To Shawn’s point, I think we’re moving fast on that front. I think we’re going to learn a lot more when clinicians get these in their hands and we see what’s going on in the real world. We have more options. I’d say there’s probably a little more heterogeneity contained in this disease state. A little more on the AD [atopic dermatitis] end that’s psoriasis. We are maybe a little way off. I think we’re also going to learn that given that itch is such an important part of this disease, and that perhaps some of our agents targeting itch are really that good, will that mean that the other things we measure about the disease will catch up with PN, even more so with atopic dermatitis?

Experts in dermatology share thoughts on the need for additional investigative research of prurigo nodularis in order to better treat patients.

Shawn Kwatra, MD

Articles