Difelikefalin Injection (Korsuva)

Number: 1028

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses difelikefalin Injection (Korsuva) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of difelikefalin Injection (Korsuva) is required of all Aetna participating providers and members in applicable plan designs. For precertification of difelikefalin Injection (Korsuva), call (866) 752-7021, or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.  

1. Exclusions

   Coverage will not be provided for members on peritoneal dialysis, as difelikefalin injection has not been studied for use in this population.

2. Prescriber Specialties

   This medication must be prescribed by or in consultation with a nephrologist.

3. Criteria for Initial Approval

   Aetna considers difelikefalin intravenous injection (Korsuva) medically necessary for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis when all criteria are met:

   1. Member is 18 years of age or older; and
   2. Member is currently undergoing hemodialysis (HD); and
   3. Member has moderate-to-severe pruritus associated with chronic kidney disease (CKD) (also known as uremic pruritus) supported by a baseline scoring system (e.g., Worst Itching Intensity Numerical Rating Scale [WI-NRS], visual analog scale [VAS]/numeric rating scale [NRS]); and
   4. Pruritus is not associated with non-uremic causes (e.g., primary dermatologic conditions [e.g., drug-induced hypersensitivity, allergies, dermatitis, psoriasis] or systemic conditions [e.g., liver disease, malignancy/lymphoma, post-herpetic neuralgia, HIV]); and
   5. Pruritus is not limited to occurring only during the dialysis session; and
   6. Member has tried and failed, or has a contraindication to other pruritus treatments (e.g., antihistamines, gabapentin, pregabalin, topical emollients / analgesics); and
   7. Dosage will not exceed 0.5 mcg/kg per HD treatment, not to exceed three doses per week.

   Aetna considers all other indications as experimental and investigational. 

4. Continuation of Therapy

   Aetna considers continuation of difelikefalin (Korsuva) therapy medical necessary for treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis when all criteria are met:

   1. Member meets all initial criteria; and
   2. There is documentation of a positive clinical response in pruritus symptoms (e.g., improvement of at least 4 points from baseline on the WI-NRS).

5. Related Policies 

   1. CPB 0205 - Phototherapy and Photochemotherapy (PUVA) for Skin Conditions
   2. CPB 0541 - Dialysis

Dosage and Administration

Korsuva is supplied as 65 mcg/1.3 mL (50 mcg/mL) of difelikefalin. 

The recommended dosage of Korsuva is 0.5 mcg/kg administered by intravenous bolus injection into the venous line of the dialysis circuit at the end of each hemodialysis (HD) treatment. Per labeling, if a regularly scheduled HD treatment is missed, resume Korsuva at the end of the next HD treatment. Korsuva is to be administered within 60 minutes of syringe preparation.

Korsuva has not been studied in persons on peritoneal dialysis and is not recommended for use in this population.

Source: Cara Therapeutics, 2021

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
96374 - 96379	Therapeutic, prophylactic, or diagnostic injection; intravenous push
HCPCS codes covered if selection criteria are met:
J0879	Injection, difelikefalin, 0.1 microgram, (for esrd on dialysis)
ICD-10 codes covered if selection criteria are met:
L29.0 - L29.9	Pruritus
Z99.2	Dependence on renal dialysis [must be billed with code from L29.0-L29.9]

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Korsuva is indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis (HD).

  Limitation of Use: Korsuva has not been studied in patients on peritoneal dialysis and is not recommended for use in this population.

Difelikefalin injection is available as Korsuva (Cara Therapeutics, Inc.). Difelikefalin is a kappa opioid receptor (KOR) agonist. The relevance of KOR activation to therapeutic
effectiveness is not known. 

Korsuva carries labeled warnings and precautions for dizziness, somnolence, mental status changes and gait disturbances.  In clinical trial, 17.0% of patients randomized to receive difelikefalin reported at least one of these adverse reactions, compared to 12.0% of patients who received placebo. The incidence of somnolence was higher in difelikefalin-treated subjects 65 years of age and older (7.0%) than in difelikefalin-treated subjects less than 65 years of age (2.8%). Concomitant use of centrally-acting depressant medications, sedating antihistamines and opioid analgesics may increase the likelihood of these adverse reactions and should be used with caution during treatment with difelikefalin. Because of these risks, the label also includes risk of driving and operating machinery, as Korsuva may impair mental or physical abilities. The most common adverse reactions (incidence ≥2% and ≥1% higher than placebo) were diarrhea, dizziness, nausea, gait disturbances, including falls, hyperkalemia, headache, somnolence, and mental status change (Cara Therapeutics, 2021).

Chronic Kidney Disease (CKD)-Associated Pruritus (CKD-aP)

Chronic kidney disease (CKD)–associated pruritus (CKD-aP), also known as uremic pruritus, is a common and distressing condition in patients with CKD and has a serious negative impact on quality of life (QOL). High-quality evidence on which to base recommendations for the treatment of uremic pruritus has been limited. Most recommendations have been based on anecdotal reports and small, uncontrolled clinical trials. Further complicating the interpretation of the studies that address management include the use of different scoring systems for the intensity of pruritus and a lack of head-to-head comparisons among different agents. Treatment has generally involved a stepwise approach that depends upon the severity of symptoms and the response to initial therapies. Treatment for uremic pruritus has included optimizing dialysis sessions, treating for hyperparathyroidism/hyperphosphatemia/hypermagnesemia to accepted target values, using emollients and/or topical analgesics, oral antihistamines, and gabapentin or pregabalin (Kobrin, 2022).

In August 2021, the U.S. FDA approved Korsuva for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis (HD). Korsuva is administered by intravenous bolus injection into the venous line of the dialysis circuit at the end of each HD treatment. FDA approval is based on positive outcomes from the KALM-1 and KALM-2 pivotal trials.

The KALM-1 trial was a 12-week, randomized, multicenter, double-blind, placebo-controlled, phase 3 study that evaluated difelikefalin in HD patients with moderate-to-severe pruritus. Patients (n=378) from 56 sites in the United States were randomly assigned to receive either intravenous difelikefalin (at a dose of 0.5 μg per kilogram of body weight) or placebo three times per week for 12 weeks. The primary outcome was the percentage of patients with an improvement (decrease) of at least 3 points from baseline at week 12 in the weekly mean score on the 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS; scores range from 0 to 10, with higher scores indicating greater itch intensity). The secondary outcomes included the change from baseline in itch-related quality-of-life measures, the percentage of patients with an improvement of at least 4 points in the WI-NRS score at week 12, and safety. A total of 82 of 158 patients (51.9%) in the difelikefalin group had a decrease of at least 3 points in the WI-NRS score, as compared with 51 of 165 (30.9%) in the placebo group. The imputed percentage of patients with a decrease of at least 3 points in the WI-NRS score was 49.1% in the difelikefalin group, as compared with 27.9% in the placebo group (p<0.001). Difelikefalin also resulted in a significant improvement from baseline to week 12 in itch-related quality of life as measured by the 5-D itch scale and the Skindex-10 scale. The imputed percentage of patients with a decrease of at least 4 points in the WI-NRS score at week 12 was significantly greater in the difelikefalin group than in the placebo group (p<0.001). Diarrhea, dizziness, and vomiting were more common in the difelikefalin group than in the placebo group. The investigators of the trial concluded that patients treated with difelikefalin had a significant reduction in itch intensity and improved itch- related quality of life as compared with those who received placebo. The trial enrolled patients who were undergoing HD; the effect of treatment in patients with CKD who are not undergoing HD requires evaluation. A phase 2 trial evaluating an oral formulation of difelikefalin in this population is under way (Fishbane et al., 2020).

The KALM-2 trial is a multicenter, double-blind, randomized, placebo-controlled, phase 3, international study that evaluated the safety and efficacy of difelikefalin in 473 patients 18 years of age and older undergoing HD who had moderate-to-severe pruritus. Patients were randomized to receive intravenous bolus injections of difelikefalin 0.5 mcg per kilogram of dry body weight into the venous line of the HD circuit at the end of each HD session or placebo three times per week for 12 weeks. In both the KALM-1 and KALM-2 trials, a 7-day run-in period prior to randomization was used to confirm that each subject had moderate-to-severe pruritus and to establish a baseline itch intensity, as measured by the patient-reported daily 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS) scores (0 “no itch” to 10 “worst itch imaginable”). The mean (SD) baseline WI-NRS score was 7.2 (1.4) in the KALM-2 trial. Efficacy was assessed based on the proportion of patients achieving a 4-point or greater improvement (reduction) from baseline in the weekly mean of the daily 24-hour WI-NRS score at Week 12. Percentage of patients with a 4-point or greater from baseline in WI-NRS score was 37% in the difelikefalin group and 26% in the placebo group. Itch reduction was seen by Week 4 and sustained through Week 12 (Cara Therapeutics, 2021).

Topf et al (2022) report on a pooled analysis that evaluated the efficacy of difelikefalin on the itch-related quality of life (QoL) from the KALM-1 and KALM-2 trials. The combined trials included 851 randomized participants (difelikefalin, n = 426; placebo, n = 425). The authors state that the pooled analysis demonstrated early (week 1), sustained difelikefalin efficacy, with significantly greater achievement of greater than or equal to 3-point WI-NRS reduction with difelikefalin (51.1%) versus placebo (35.2%; p< 0.001). Achievement of a greater than or equal to 4-point WI-NRS reduction was significantly greater with difelikefalin (38.7%) versus placebo (23.4%; p < 0.001). The authors found that difelikefalin reduced itch intensity in subgroups based on age, sex, anti-itch medication use, the presence of specific medical conditions, and gabapentin or pregabalin use. More participants receiving difelikefalin versus placebo achieved clinically meaningful decreases of greater than or equal to 15 points on the Skindex-10 scale (55.5% vs 40.5%, respectively; p < 0.001) and greater than or equal to 5 points on the 5-D Itch scale (52.1% vs 42.3%, respectively; p = 0.01), with sustained 5-D Itch effects up to 64 weeks. The authors concluded that difelikefalin demonstrated rapid, sustained efficacy, with consistent results in diverse populations of patients treated by HD. The authors acknowledge the limitations of this analysis includes small subgroup samples, and that the WI-NRS, Skindex-10, and 5-D Itch are not used in routine clinical care of dialysis patients; therefore, findings may not reflect the real-world effectiveness of difelikefalin.

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Appendix

The 5-D Itch Scale

For the 5-D Itch Scale: A Measure of Pruritus, see The 5-D Itch Scale.

The 5-D itch scale was developed as a brief but multidimensional questionnaire designed to be useful as an outcome measure in clinical trials. The five dimensions are degree, duration, direction, disability and distribution (Elman et al, 2010). The 5-D itch scale is considered a reliable and multidimensional measure of uremic pruritus that has been validated in hemodialysis patients. Multidimensional scales, such as the 5-D itch scale, not only assess pruritus intensity but measure the impact of pruritus on patients’ quality of life (Lai et al, 2017). Scores on the 5-D itch scale range from 5 to 25, with higher scores indicating worse itch-related quality of life (Fishbane et al, 2020).

The Skindex-10 Scale

The Skindex-10 Scale is a multidimensional questionnaire which assesses itch-related quality of life (QOL) over the past week. The questions cover 3 domains: disease, mood/emotional distress, and social functioning domain. Individual complete one of seven bubbles (“0 [never bothered], 1, 2, 3, 4, 5, and 6 [always bothered]”) for each of the questions. The total score is the sum of the numeric value of each answered question. The domain scores are sums of the following: disease domain (questions 1 to 3), mood/emotional distress domain (questions 4 to 6), and social functioning domain (questions 7 to 10). A lower total score represents better QOL. 

Source: Mathur et al (2010)

Visual Analog Scale (VAS)/Numeric Rating Scale (NRS) 

The visual analog scale (VAS) is a 10-cm long line that patients mark by crossing the line that corresponds to the severity of experienced itching. VAS should start with ‘no itch’ (0) and finish with ‘worst imaginable itch’ (10). The numeric rating scale (NRS) is very similar to the VAS. It provides numerical values of pruritis severity from 0 (no pruritus) to 10 (most severe pruritus) in which the patient must indicate a number that corresponds to the perceived intensity.

• Mild pruritus: 0.1 to 3.9 points
• Moderate pruritus: 4 to 6.9 points
• Severe pruritus: 7 to 8.9 points
• Very severe pruritus: 9 to 10 points

Source: Reich and Szepietowski (2013)

Worst Itching Intensity Numerical Rating Scale (WI-NRS) in Chronic Kidney Disease Associated Pruritus (CKD-aP)

The WI-NRS is a validated 11-point scale ranging from 0 to 10 which indicates the intensity of the worst itching the individual experienced over the past 24 hours. This patient-reported scale has been used in clinical trials to assess individuals with CKD-aP. Reduction of 3 or more points on the NRS is associated with clinically meaningful change in itch severity for persons with moderate-to-severe CKD-aP.

• Mild: 0 (no itching) to 3
• Moderate: 4 to 6
• Severe: 7 to 10 (worst itching imaginable).

Source: Combs et al, 2015; Vernon et al (2020); Wooldridge et al (2020)

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References