Disclaimer
Korsuva is marketed exclusively for Fresenius Kidney Care Clinics by Fresenius Medical Care Renal Pharmaceuticals. Fresenius Medical Care Renal Pharmaceuticals and Vifor Fresenius Medical Care Renal Pharmaceuticals Ltd., a joint venture between CSL Vifor Pharma and Fresenius Medical Care AG and Company, KGaA, share marketing rights for Korsuva to health care professionals in the United States.

Dr. Michael Kraus: Welcome, everyone, to this episode of Field Notes. I'm Dr. Michael Kraus, the associate chief medical officer for Fresenius Kidney Care and your host for this discussion today. Here, we interview the experts, researchers, physicians, and caregivers who bring experience, compassion, and insight to the work we do every day.

A third of hemodialysis patients suffer from moderate to severe pruritus or itching. There have been few specific remedies for this condition that for some, can cause constant itching. Korsuva, a new FDA approved medication, can be prescribed to help hemodialysis patients who are experiencing moderate to severe pruritus associated with chronic kidney disease. Korsuva is immediately available to patients in our clinics if prescribed.

Here with me to discuss this potentially life-changing treatment is Dr. Dinesh Chatoth, associate chief medical officer and chair of Pharmacy and Therapeutics Committee at Fresenius Kidney Care.

Dr. Chatoth, welcome to Field Notes.

Dr. Dinesh Chatoth: Thank you, Dr. Kraus, for the kind introduction, and it's a pleasure to be here.

Dr. Kraus: Let's start things off, Dr. Chatoth, with a closer look at pruritus and what causes that painful condition.

Dr. Chatoth: So, pruritus, or itching, as you pointed out earlier, is actually highly prevalent in patients who have chronic kidney disease on dialysis. CKD associated pruritus was previously referred to as uremic pruritus and it's actually a distressing symptom experienced by our patients on dialysis. It was initially thought to be a result of accumulation of uremic or kidney failure related toxins under the skin.

We now know that CKD associated paralysis caused by many factors— building up of uremic toxins, but also related to neuropathy, opioid receptor activity, inflammation, and also some evidence that it's also immune mediated. So multiple ideologies.

Dr. Kraus: We've always been taught that phosphorus is the major cause of pruritus. But as you look at the literature patients with pruritus, only half of them have high phosphorus. Where do you think control of phosphorus and phosphorus exists in the world of CKD associated pruritus?

Dr. Chatoth: It is true that hyperphosphatemia or elevated phosphate levels can lead to pruritus, but that's different from CKD associated pruritus. And there's been studies shown that despite the fact that you actually control phosphate levels in patients on dialysis, patients still experience pruritus in significant numbers. Therefore, I would separate out the two. But I do want to point out an important issue which you just alluded to, which is CKD associated pruritus is a diagnosis of exclusion. So, we need to rule out typical things like elevated phosphorus, inadequate dialysis, etc. before we label a patient as having CKD associated pruritus.

Dr. Kraus: How bad is this pruritus for patients?

Dr. Chatoth: This condition actually is pretty severe. It's very debilitating for our patients and it can impact their daily activities, their sleep patterns. Patients usually present with scratch marks all over the body. But to me, CKD associated pruritus is associated with poor quality of life. So that's where it impacts me as a nephrologist when I see patients complaining of pruritus.

Let me tell you a story about a patient who was in a mid-thirties on hemodialysis, who had severe itching all day, worse at night when she sleeps. So basically, she couldn't have a good night's rest as a result of pruritus. She's been missing treatments because she associated the itching in some ways with the dialysis treatment, did not want to be around friends and family. As a result of all of this, she was very depressed. So, this nephrologist called me to tell me that basically Korsuva had made a world of difference to a patient.

Dr. Kraus: It's not just the edge, right? It is the morbidity of itching, the associated increased mortality, depression, lack of sleep.

Dr. Chatoth: Exactly. So, besides a quality of life, as you pointed out, there's been a direct link of CKD associated pruritus with hospitalization rates 20 to 24% higher risk of hospitalization, even after adjusting for the typical factors that we do, and a 20 to 21% increased risk of morbidity. So itching is no longer just a symptom in these patients. It's actually associated with poor quality of life.

Dr. Kraus: So, let's switch to Korsuva now and then we'll get back to how to decide who gets it. Exactly how does course Korsuva work?

Dr. Chatoth: Yeah. So, Korsuva is actually a kappa opioid receptor agonist, so it acts peripherally on our nerves. Typically, our peripheral nerves carry two sets of receptors—they carry kappa receptors and mu receptors. And it's the activity balance between the kappa and mu receptors that determines its signals being carried from these nerves all the way to the central nervous system.

And typically you want to see increase in kappa receptor activity and decrease in the mu receptor activity in order to turn off the signal pruritus or itch in these nerves. So, Korsuva increases the activity of the kappa receptor because it's a kappa receptor agonist and thereby literally turns off the signal of itch. And so, it doesn't really address the underlying ideology, but more so it turns off the itch signal and helps our patients manage itch, or pruritus.

Dr. Kraus: Arthritis and I heard you use the term kappa or opioid receptors, and I know that this is a concern for many of our physicians. Can you tell me why this doesn't have dependance or if I can use opioids with this drug or where that fits in, in your mind?

Dr. Chatoth: Yeah, it's a great question because typically and especially in the U.S., we're very sensitive to the word opioid given the opioid crisis we've all seen. So, although Korsuva was an opioid agonist, it does not cross the blood brain barrier and is peripherally acting. So, a typical set of symptoms we see like drowsiness in excess or dependency is not seen with Korsuva.

And actually this has been validated from the phase three studies where what we've seen is no concern for dependency and very little concern for symptoms like drowsiness or somnolence, these and other things that we would attribute opioids in general.

Dr. Kraus: Why is Korsuva such a groundbreaking treatment? What has changed now?

Dr. Chatoth: Yes, Korsuva was studied extensively in the phase three studies. And the phase three studies were actually the kalm one, kalm one and the kalm two trials. The kalm one was the was done in the U.S. and the kalm two trials were done in the rest of the world. If you look at the combined results of the phase three studies, and these were studies done— it's a placebo, controlled study, randomized controlled trial, and the study was done for 12 weeks.

At the end of 12 weeks, 51% of patients with moderate to severe pruritus actually had a pretty good response to Korsuva. So, patients actually had no itch or significant improvement in itch. And the primary endpoint, these studies was at least a three point improvement in the WINRS of the worst itch scale in the period of 12 weeks. They administered the scale at baseline. They re-administered the scale in 12 weeks and they were looking for at least a three point improvement and 51% of patients actually had at least a three point improvement and about 30% of patients had more than a four point improvement. So, to me, Korsuva really is groundbreaking because now we have a medication that can manage pruritus at least in half our patient population.

And just to add another comment there, I do want to point out that gabapentinoids, you know, Gabapentin, Pregabalin, these medications are available today and have pretty equivalent results as Korsuva to manage CKD associated pruritus. But the problem with these gabapentinoids, at least in my opinion, are these side effects. I mean, we know the patients feel drowsy, fatigued, somnolent to a point that it's the side effect and the tolerance of gabapentinoids that would actually be concerning to me, and I would favor Korsuva for that reason alone.

Dr. Kraus: In the world of CKD associated pruritus, there were prior therapies. They either A) weren't as effective or B) had more side effects in your opinion?

Dr. Chatoth: We used skin care lotions, creams, and more importantly, a lot of us prescribed antihistamines like Benadryl for our patients. Now at least six studies in one meta-analysis on Benadryl antihistamines, that I've seen, did not show much of a significant anti-pruritic activity. So, Benadryl doesn't really take care of the itch. What it really does is takes care by sedating our patients.

So, patients go to sleep and forget the itch. But remember, the itch continues for the rest of the day. So treating somebody with Benadryl during a dialysis treatment may get them through the 4 hours of dialysis, but it doesn't address the problem that exists and persist in our patients beyond the dialysis treatment. So, I don't think these are bad treatments, but may not be the only treatment that addresses the problem in our patient population.

Dr. Kraus: With that in mind, how do we determine which patients need Korsuva and how do you prescribe it?

Dr. Chatoth: Because the medications indicated for moderate to severe pruritus, we use a couple of itch scales to identify patients as candidates for Korsuva. There are two itch assessments, so, itch scales, that are out there. One is the 5-D itch scale which basically stands for five domain itch scale. It's got several questions that need to be asked and it's a little bit more quantitative.

So, for research purposes, it's a great scale, but in a clinic, to be honest, in a practical standpoint, it's not easy to administer. So, we use a different scale called the WI-NRS scale, which is the worst itch numerical rating scale. And this scale is a single question that we ask our patients. And it's basically what is the worst itch you experienced in the last 24 hours?

And so in a scale of 0 to 10, it takes 20 seconds, maybe 30 seconds to administer this. If the answer is zero, they have no itch. If they answer 1 to 3, it’s mild. If it's 4 to 6, we call that moderate and then 7 to 10 is severe. So single question. And anybody above four, I would say that you need to consider a treatment option like Korsuva to manage these patients.

Dr. Kraus: This has been validated in prior studies long before Korsuva, is that correct?

Dr. Chatoth: That is correct. I mean, the worse itch scale has been used for other dermatological conditions and so it's been validated. There are at least two or three validation studies out there saying that it's not only validated purely to assess the degree of itching in patients, but also response to therapy. So, if I'm if you ask me, it's a great skill to use. It's easy to administer and it's reliable for our patients with CKD associated pruritus

Dr. Kraus: So, let's move quickly to the side effects of Korsuva. What are the major side effects that concern you and how frequently should we expect them?

Dr. Chatoth: So, the most common side effects that we noted in the phase three studies I talked about earlier was drowsiness and dizziness, vomiting and diarrhea. Now, when we compared to placebo, there was a slightly higher incidence of vomiting and diarrhea, maybe two 1 to 2% higher risk. So, I always think about this as our patients on dialysis have significant number of symptoms and co-morbidities. So, having symptoms on dialysis is not uncommon, but I'm not as concerned about those GI complaints as drowsy and dizziness. There was slightly higher risk of drowsiness and dizziness in patients who do Korsuva, but 6 to 7% higher than the placebo group. So, there's definitely a concern about drowsiness and dizziness. And so to address this, in our patient population, we provide our patients with a one-pager that sort of explains to them some of these side effects and what to watch for, to maybe arrange for a different mode of transportation if they're driving themselves to the clinic, or to expect to be a little tired or fatigued or drowsy for the first few treatments.

So, that's something that we share with them upfront. And I know, why do we want to be concerned about this? It is a symptom. But remember, when we give a patients Benadryl, they also get drowsy. So, it's not that this is any different than what we already do for our patients. We just want to be extra careful and just advise them of these symptoms if they would experience it during dialysis.

Dr. Kraus: And many of our doctors have addressed the fact that the difelikefalin study showed us a 68% side effect profile, but they forget the placebo was 62%. What are your thoughts on that high of a side effect profile?

Dr. Chatoth: Difelikefalin have a little bit higher side effect profile. But now that we started using it in the clinics and, you know, we're not seeing that much of a side effect profile, than what is expected. So to me, our patients in general have higher side effects because everything from low blood pressure to cramping to headaches are reported as side effects.

So, a lot of the symptoms that we saw were no different than the placebo group, than we saw in the difelikefalin, or Korsuva, group. And so I would just consider them as typical side effects that patients experience on dialysis.

Dr. Kraus: Are there any limitations to the use of Korsuva?

Dr. Chatoth: Yes, there are. And most importantly, the medication is given as an intravenous bolus at the end of dialysis because it's cleared by the dialyzer with one pass through the dialyzer. So if you give it to the patient in the last 30 minutes of dialysis or during the treatment, that medication is gone, so it has to be dosed at the end of dialysis.

Our patients on home dialysis right now cannot use this medication. We've raised that as a concern because it's not like our patients who are on home therapies don't have itching or CKD associated pruritus. The company's looking into having an oral formulation available in the near future. And so I'm looking forward to having an oral formulation available that may help not only our patients on home dialysis, but also are in-center patients who rather take the medication after they go home or before they go to bed.

Dr. Kraus: And I think it's worth reinforcing that peritoneal dialysis patients have the same or higher incidence of CKD associated pruritus as home hemo patients. What have you seen from the initial roll out of Korsuva in the Fresenius Kidney Care clinics?

Dr. Chatoth: As providers, we want to make sure that we are comfortable with the medication before we get started. So there was a little bit of a slow buildup of patients going on Korsuva, and we're trying to address this, but really educating our physicians, nurses, and our providers about the medication and how to use it and be comfortable with prescribing our patients Korsuva.

So that has picked up. And over the last couple of months, we're seeing more and more patients actually being considered as candidates for Korsuva. One of the biggest issues that I'm identifying is that our patients underreport CKD associated pruritus in the clinics and by a significant amount. So if I'm itching, I just assume that's part of life and don't tell anybody about it.

And physicians as a whole, after visiting our patients and talking to them, we don't ask specifically about itching when we talk to our patients during our visits. So, it's underrecognized by us as a problem in our patients. And as a result, we feel like it's probably best for us to administer the WI-NRS scale to all patients in our facilities to identify what's the burden of moderate to severe pruritus.

So we've done that in our clinics. We know that about 10 to 15% of patients now are being identified as having moderate to severe pruritus. And so that information is going to be provided to our physicians who can then determine the best treatment option for those patients.

Dr. Kraus: I think that's an excellent point. It always amazed me because we don't see a lot of skin in dialysis clinics, as you know. You know, eventually, occasionally I take somebody’s shirt down to listen to their heart or lungs in the clinic and see just tremendous itching and scratching and skin discoloration from this dryness that they've never mentioned to me before. So, if you don't ask, you don't know.

So, with that in mind, what is your hope for our patients with the new advent and roll out of Korsuva?

Dr. Chatoth: It's an opportunity for us to address patient reported symptoms in a big way. I see patient reported outcome measures as something that's very important, and the most common one that's reported out there is post dialysis fatigue, which we all know needs to be addressed. But pruritus is a close second, and I feel like if it's a problem that's prevalent in a population, it's a patient reported symptom and we have a treatment option that's now available.

We should address this in our patient population. So I see this as an opportunity to really get in front of this patient reported symptom, identify this, and now that we have a treatment, figure out a way to treat our patients. I'm looking forward to collecting more data and our patient population as the use of Korsuva increases so we can understand the impact on hospitalization, impact on survival, impact on patients just coming to treatments regularly and staying for the full treatment.

So at least on Fresenius Kidney Care perspective, I promise you, we're going to look at the data, we're going to address all of these things and identify benefit that we can share with the physicians and nurses on what the benefit truly is in terms of overall benefit of treating CKD associated pruritus.

Dr. Kraus: What we want is better care for your patients.

Dr. Chatoth: Yeah, I agree, Mike. Our job is to make sure we provide the best care for our patients. That remains front and center for what we do, at least at Fresenius Kidney Care from the medical office. We're here to support whatever the needs of the physicians and nurses are and educate people as much as we can about the medication. But overall, I want them to address pruritus as a condition that needs to be addressed in our patient population.

Dr. Kraus: This has been a great and hopeful conversation. And to our audience, thank you for joining us. If you're new to the Field Notes podcast, you can download past episodes on the Apple Store, Google Play, or right here at FMCNA.com.

And while you're there, please subscribe to receive the very latest updates as they happen. Until next time, I'm Dr. Michael Kraus, and you've been listening to Field Notes by Fresenius Medical Care North America. Take care, everyone.