Daprodustat (Jesduvroq)

Number: 1044

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 daprodustat (Jesduvroq) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

1. Criteria for Initial Approval

   Note: Requirements regarding pretreatment hemoglobin level exclude values due to a recent transfusion. All members must be assessed for iron deficiency anemia and have adequate iron stores (defined as a serum transferrin saturation [TSAT] level greater than or equal to 20% within the prior 3 months) or are receiving iron therapy before continuation of treatment with Jesduvroq. Members may not use Jesduvroq concomitantly with other erythropoiesis stimulating agents.

   Aetna considers daprodustat (Jesduvroq) medically necessary for treatment of anemia due to chronic kidney disease (CKD) when both of the following criteria are met:

   1. The member has been receiving dialysis for at least four months; and
   2. The member’s pretreatment hemoglobin level is less than or equal to 11 g/dL.

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Note: Requirements regarding current hemoglobin level exclude values due to a recent transfusion. All members must be assessed for iron deficiency anemia and have adequate iron stores (defined as a serum transferrin saturation [TSAT] level greater than or equal to 20% within the prior 3 months) or are receiving iron therapy before continuation of treatment with Jesduvroq. Members may not use Jesduvroq concomitantly with other erythropoiesis stimulating agents. 
   
   For continuation of therapy after at least 12 weeks of Jesduvroq treatment, all members (including new members) must show a response with a rise in hemoglobin of greater than or equal to 1 g/dL. Members who completed less than 12 weeks of Jesduvroq treatment and have not yet responded with a rise in hemoglobin of greater than or equal to 1 g/dL may continue Jesduvroq therapy for up to 12 weeks to allow for sufficient time to demonstrate a response.
   
   Aetna considered continuation of daprodustat (Jesduvroq) therapy medically necessary for treatment of anemia due to CKD in adult members receiving dialysis with current hemoglobin less than 12 g/dL.

3. Related Policies 

   1. CPB 0195 - Erythropoiesis Stimulating Agents
   2. CPB 0541 - Dialysis
   3. CPB 0575 - Intravenous Iron Therapy

Dosage and Administration

Jesduvroq is supplied as 1 mg, 2 mg, 4 mg, 6 mg, and 8 mg tablets. Below include FDA-approved labeled recommendations.

• Individualize dosing and use the lowest dose of Jesduvroq sufficient to reduce the need for red blood cell transfusions. Do not target a hemoglobin higher than 11 g/dL.
• Jesduvroq can be taken with or without food, and without regard to concomitant administration of iron or phosphate binders.
• Jesduvroq should be swallowed whole. Tablets should not be cut, crushed, or chewed.
• Jesduvroq can be administered without regard to the timing or type of dialysis.
• See Full Prescribing Information for starting dosage based on hemoglobin level, liver function and concomitant medications, and for dose titration and monitoring recommendations. 

Adults with Anemia Due to CKD Receiving Dialysis for at Least 4 Months:

Adults Not Being Treated with an Erythropoiesis Stimulating Agent (ESA)

The starting dose of Jesduvroq is based on the hemoglobin level (see Table 1). Dose modifications are needed for persons receiving concomitant treatment with a moderate CYP2C8 inhibitor or moderate hepatic impairment (see Full Prescribing Information).

Table 1: Starting Dose for Adults on Dialysis not Receiving an ESA

Pre-Treatment Hemoglobin Level (g/dL)	Starting Dose of Jesduvroq (once daily oral dosingFootnote*)
Less than 9	4 mg
9 to 10	2 mg
greater than 10	1 mg

Adults Being Switched from an ESA

For adults being switched from an ESA to Jesduvroq, the starting dose of Jesduvroq is based on the dose regimen of the ESA at the time of substitution (see Table 2). Dose modifications are needed for persons receiving concomitant treatment with a moderate CYP2C8 inhibitor or moderate hepatic impairment.

Table 2: Starting Dose for Adults on Dialysis Switching from an ESA

Current Dose of ESA		Dose of JesduvroqFootnote2**
Epoetin AlfaFootnote3*** Intravenous (units/week)	Darbepoetin Alfa Subcutaneous /Intravenous (mcg/4 weeks)	Methoxy PEG-Epoetin Beta Subcutaneous /Intravenous (mcg/month)	Once Daily Oral Dosing
Less than or equal to 2,000	20 to 30	30 to 40	4 mg
Greater than 2,000 to less than 10,000	Greater than 30 to 150	Greater than 40 to 180	6 mg
Greater than or equal to 10,000 to less than 20,000	Greater than 150 to 300	Greater than 180 to 360	8 mg
Greater than or equal to 20,000	Greater than 300	Greater than 360	12 mg

Source: GSK, 2023

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
90935 - 90999	Dialysis
HCPCS codes covered if selection criteria are met:
J0889	Daprodustat, oral, 1 mg, (for ESRD on dialysis)
ICD-10 codes covered if selection criteria are met:
D63.1	Anemia in chronic kidney disease

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Background

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

• Jesduvroq is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least four months.

Daprodustat, branded as Jesduvroq (GlaxoSmithKline), is a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) that stimulates endogenous erythropoietin production via HIF activation; thus, inducing erythropoiesis. Although, erythropoiesis-stimulating agents (ESA), in conjunction with iron supplementation, has been the mainstay of treatment for anemia in chronic kidney disease (CKD), concerns of increased risk for cardiovascular events has prompted interest in the developement of an alternative therapeutic strategy. Clinical trials suggest that HIF-PHIs are as effective as ESAs in increasing hemoglobin levels (Singh et al., 2021; Sugahara et al., 2022).

Singh and colleagues (2021) state that oral HIF-PHI (daprodustat) is an effective alternative to injectable recombinant human erythropoietin (ESAs) in treating anemic patients with CKD who are undergoing dialysis. In their open-label, global, multicenter, phase 3 trial (ASCEND-D), 2694 adult patients with CKD who had a hemoglobin level of 8 to 11.5 grams per deciliter (g/dL) (mean [±SD; standard deviation] baseline hemoglobin level was 10.4±1.0 g/dL overall) and undergoing dialysis for at least 4 months were randomized to receive daprodustat or ESA. Patients on hemodialysis (HD) were randomized 1:1 to receive oral daprodustat (n = 1316) or intravenous epoetin alfa (n = 1308), while patients on peritoneal dialysis (PD) were randomized 1:1 to receive oral daprodustat (n = 171) or subcutaneous darbepoetin alfa (n = 169). "Key exclusion criteria included: ferritin ≤100 ng/ml (≤100 mcg/L), transferrin saturation ≤20% at screening; evidence of non-renal anemia; cardiovascular abnormalities (including myocardial infarction, acute coronary syndrome, stroke or transient ischemic attack within 4 weeks of screening, New York Heart Association (NYHA) Class IV heart failure, and uncontrolled hypertension); liver disease; history of malignancy within 2 years of screening; current treatment of cancer and complex kidney cyst." Ther study included two primary outcomes: (i) mean change in the hemoglobin level from baseline to weeks 28 through 52 (noninferiority margin, -0.75 g per deciliter); and (ii) the first occurrence of a major adverse cardiovascular event (a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), with a noninferiority margin of 1.25. The authors found that the mean (±SE; standard error) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.28±0.02 g/dL in the daprodustat group and 0.10±0.02 g/dL in the ESA group (difference, 0.18 g/dL; 95% confidence interval [CI], 0.12 to 0.24), which met the prespecified noninferiority margin of -0.75 g/dL. During a median follow-up of 2.5 years, a major adverse cardiovascular event occurred in 374 of 1487 patients (25.2%) in the daprodustat group and in 394 of 1477 (26.7%) in the ESA group (hazard ratio, 0.93; 95% CI, 0.81 to 1.07), which also met the prespecified noninferiority margin for daprodustat. The percentages of patients with other adverse events were similar in the two groups. The authors concluded that daprodustat was noninferior to ESAs in regards to change in the hemoglobin level from baseline and cardiovascular events in patients with CKD undergoing dialysis. 

In February 2023, the FDA approved Jesduvroq tablets as the first oral treatment for anemia caused by CKD in adults who have been receiving dialysis for at least four months. Approval was based on the ASCEND-D study, which found that Jesduvroq raised and maintained the hemoglobin within the target range of 10-11 g/dL, similar to that of the recombinant human erythropoietin (FDA, 2023). 

Jesduvroq is contraindicated in persons with uncontrolled hypertension and those on a strong cytochrome P450 2C8 (CYP2C8) inhibitor such as gemfibrozil. 

Jesduvroq label carries a black box warning for increased risk of death, myocardial infarction, stroke, venous thromboembolism, and thrombosis of vascular access. Targeting a hemoglobin level greater than 11 g/dL is expected to further increase the risk of death and arterial venous thrombotic events, as occurs with ESAs, which also increase erythropoietin levels. No trial has identified a hemoglobin target level, dose of Jesduvroq, or dosing strategy that does not increase these risks. Thus, the recommendation is to use the lowest dose of Jesduvroq sufficient to reduce the need for red blood cell (RBC) transfusions.

Labeled warnings and precautions for Jesduvroq include the following:

• Risk of hospitalization for heart failure, which is increased in patients with a history of heart failure. 
• Hypertension: worsening hypertension, including hypertensive crisis may occur. 
• Gastrointestinal erosion: gastric or esophageal erosions and gastrointestinal bleeding have been reported. 
• Not indicated for treatment of anemia of CKD in patients who are not dialysis-dependent
• Malignancy: may have unfavorable effects on cancer growth. Thus, not recommended if there is active malignancy.

Jesduvroq may cause fetal harm. Breastfeeding is not recommended until one week after the final dose of Jesduvroq. 

Jesduvroq is not recommended in severe hepatic impairment (Child-Pugh Class C). Starting dose should be reduced in patients with moderate hepatic impairment (Child-Pugh Class B).

The most common adverse reactions (incidence of 10% or more) include hypertension, thrombotic vascular events, and abdominal pain (GSK, 2023).

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References