Drug Trials Snapshots: JESDUVROQ
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.
Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the JESDUVROQ Prescribing Information for all of the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).
Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).
JESDUVROQ (daprodustat)
jes doov' rok
GlaxoSmithKline Intellectual Property Limited
England (GlaxoSmithKline)
Original Approval date: February 1, 2023
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
JESDUVROQ is a hypoxia-inducible factor prolyl hydroxylase (HIF PH) inhibitor that treats anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least four months.
How is this drug used?
JESDUVROQ is administered orally and is taken once daily, with or without food.
Who participated in the clinical trials?
The FDA approved JESDUVROQ based on evidence from a clinical trial of 2,964 adult patients with anemia associated with chronic kidney disease who were on dialysis. The trial was conducted at 431 sites in 35 countries.
How were the trials designed?
The efficacy and safety of JESDUVROQ were evaluated in 2,964 adults with anemia due to CKD on dialysis and receiving an erythropoiesis-stimulating agent (ESA) at the time of study entry in a randomized, sponsor-blind, active-controlled, global, multicenter, event-driven clinical trial (ASCEND-D; NCT02879305). Patients were stratified by dialysis type and were required to be on dialysis for at least four months prior to the first dose of JESDUVROQ. Patients on hemodialysis (HD) were randomized 1:1 to receive oral JESDUVROQ (N=1,316) or intravenous epoetin alfa (N=1,308) while patients on peritoneal dialysis (PD) were randomized 1:1 to receive oral JESDUVROQ (N=171) or subcutaneous darbepoetin alfa (N=169).
Key exclusion criteria included: ferritin ≤100 ng/mL (≤100 µg/L), transferrin saturation ≤20% at screening; evidence of nonrenal anemia; cardiovascular abnormalities (including myocardial infarction, acute coronary syndrome, stroke or transient ischemic attack within four weeks of screening, New York Heart Association Class IV heart failure, and uncontrolled hypertension); liver disease; history of malignancy within two years of screening; current treatment of cancer; and complex kidney cyst.
The efficacy and safety of JESDUVROQ were evaluated as coprimary endpoints: the mean change in hemoglobin from baseline to the Evaluation Period (Weeks 28 to 52) and time to first adjudicated major adverse cardiovascular event (MACE; defined as all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke), using a noninferiority comparison to recombinant human erythropoietin (rhEPO) treatment (epoetin alfa and darbepoetin alfa) for both endpoints.
How were the trials designed?
Dosing in each treatment arm followed a protocol-specified adjustment algorithm to achieve and/or maintain a hemoglobin target of 10 to 11 g/dL. The starting dose of JESDUVROQ was 4 mg, 6 mg, 8 mg, or 12 mg orally once daily, based on prior ESA dose. The starting dose of either epoetin alfa (HD patients) or darbepoetin alfa (PD patients) was the same as the patient’s current dose rounded to the nearest study dose. Patients receiving other ESAs were switched to the epoetin alfa or darbepoetin alfa equivalent starting dose. The median doses at Week 52 were 6 mg per day for JESDUVROQ, 8,000 units per week for epoetin alfa, and 150 µg every four weeks for darbepoetin alfa. Most patients (86%) were exposed to randomized treatment for greater than 6 months (median 26 months for JESDUVROQ and 26 months for rhEPO). The median number of dose adjustments from Day 1 to Week 28 was 2 (interquartile range: 1 to 3) for JESDUVROQ and 2 (interquartile range: 1 to 3) for rhEPO. The median number of dose adjustments from Week 28 to Week 52 was 1 (interquartile range: 1 to 2) for JESDUVROQ and 2 (interquartile range: 1 to 3) for rhEPO.
DEMOGRAPHICS SNAPSHOT
Figure 1. Baseline Demographics by Sex
Source: Adapted from FDA Review
Figure 2. Baseline Demographics by Race
Source: Adapted from FDA Review
Figure 3. Baseline Demographics by Age
Source: Adapted from FDA Review
Figure 4. Baseline Demographics by Ethnicity
Source: Adapted from FDA Review
Who participated in the trials?
Table 1. Baseline Demographics, ITT Population, Trial ASCEND-D
|
Characteristic |
JESDUVROQ |
rhEPO |
TOTAL |
|---|---|---|---|
|
Sex, n (%) |
|||
|
Female |
636 (42.8) |
630 (42.7) |
1266 (42.7) |
|
Male |
851 (57.2) |
847 (57.3) |
1698 (57.3) |
|
Age, years |
|||
|
Mean (SD) |
57.2 (14.3) |
57.3 (14.7) |
57.2 (14.5) |
|
Median (min, max) |
58 (18, 95) |
59 (20, 94) |
58 (18, 95) |
|
Age group, years, n (%) |
|||
|
<65 |
1007 (67.7) |
978 (66.2) |
1985 (67.0) |
|
65 to <75 |
321 (21.6) |
325 (22.0) |
646 (21.8) |
|
≥75 |
159 (10.7) |
174 (11.8) |
333 (11.2) |
|
Race, n (%) |
|||
|
American Indian or Alaska Native |
19 (1.3) |
32 (2.2) |
51 (1.7) |
|
Asian |
176 (11.8) |
181 (12.3) |
357 (12.0) |
|
Black or African American |
228 (15.3) |
233 (15.8) |
461 (15.6) |
|
Native Hawaiian or Pacific Islander |
26 (1.7) |
25 (1.7) |
51 (1.7) |
|
White |
995 (66.9) |
982 (66.5) |
1977 (66.7) |
|
Multiple |
43 (2.9) |
24 (1.6) |
67 (2.3) |
|
Ethnicity, n (%) |
|||
|
Hispanic or Latino |
367 (24.7) |
371 (25.1) |
738 (24.9) |
|
Not Hispanic or Latino |
1120 (75.3) |
1106 (74.9) |
2226 (75.1) |
|
Country of participation, n (%) |
|||
|
United States |
425 (28.6) |
421 (28.5) |
846 (28.5) |
|
Rest of the world |
1062 (71.4) |
1056 (71.5) |
2118 (71.5) |
Source: Adapted from FDA Review
Abbreviations: ITT, intent-to-treat; N, number of patients in treatment group; n, number of patients with given characteristic; rhEPO, recombinant human erythropoietin; SD, standard deviation
What are the benefits of this drug?
The effectiveness of JESDUVROQ was established in a randomized study of 2,964 adults receiving dialysis. In this study, adults received either oral JESDUVROQ or injected rhEPO (a standard of care treatment for patients with anemia due to chronic kidney disease). JESDUVROQ raised and maintained the hemoglobin (the protein in red blood cells that carries oxygen and is a common measure of anemia) within the target range of 10 to 11 g/dL, similar to that of the rhEPO treatment.
What are the benefits of this drug (results of trials used to assess efficacy)?
The efficacy and safety of JESDUVROQ were evaluated in 2,964 adults with anemia due to CKD on dialysis and receiving an ESA at the time of study entry in a randomized, sponsor-blind, active-controlled, global, multicenter, event-driven clinical trial. Patients were stratified by dialysis type and were required to be on dialysis for at least four months prior to the first dose of JESDUVROQ.
The efficacy and safety of JESDUVROQ was evaluated by coprimary endpoints with the efficacy endpoint of mean change in hemoglobin from baseline to Evaluation Period (Weeks 28 to 52). The lower limit of the 95% confidence interval (CI) for the overall hemoglobin treatment difference was greater than the prespecified noninferiority margin of -0.75 g/dL, demonstrating noninferiority of JESDUVROQ to rhEPO with respect to the mean change in hemoglobin between baseline and over the Evaluation Period (see Table 2). Results were similar in patients receiving either hemodialysis or peritoneal dialysis.
Table 2. Change in Hemoglobin in Adults With Anemia Due to Chronic Kidney Disease Receiving Dialysis: ASCEND-D Trial (ITT Analysis)a
|
Assessment |
JESDUVROQ |
rhEPOb |
|---|---|---|
|
Primary endpoint: change in Hgbc |
||
|
Mean baseline Hgb, g/dL (SD) |
10.4 (1.0) |
10.4 (1.0) |
|
Hgb change, g/dL (SE)d,e |
0.3 (0.02) |
0.1 (0.02) |
|
Mean treatment difference (95% CI)e |
0.2 (0.1, 0.2) |
|
|
Change in Hgb, hemodialysis patientsf |
||
|
Number of patients |
1,316 |
1,308 |
|
Mean baseline Hgb, g/dL (SD) |
10.4 (1.0) |
10.4 (1.0) |
|
Hgb change, g/dL (SE)d,e |
0.3 (0.02) |
0.1 (0.02) |
|
Mean treatment difference (95% CI)e |
0.2 (0.1, 0.3) |
|
|
Change in Hgb, peritoneal dialysis patientsf |
||
|
Number of patients |
171 |
169 |
|
Mean baseline Hgb, g/dL (SD) |
10.3 (1.0) |
10.2 (1.0) |
|
Hgb change, g/dL (SE)d,e |
0.4 (0.1) |
0.2 (0.1) |
|
Mean treatment difference (95% CI)e |
0.2 (-0.04, 0.3) |
|
Source: JESDUVROQ Prescribing Information
a ITT analyses included observed and imputed values on and off treatment after randomization. Eight percent of patients had no observed hemoglobin during Weeks 28 to 52.
b Hemodialysis patients received epoetin alfa and peritoneal dialysis patients received darbepoetin alfa.
c Adjusted for multiplicity.
d Mean Hgb change from baseline to Evaluation Period: Weeks 28 to 52.
e Adjusted for baseline covariates.
f Not adjusted for multiplicity.
Abbreviations: CI, confidence interval; Hgb, hemoglobin; ITT, intent-to-treat; rhEPO, recombinant human erythropoietin; SD, standard deviation; SE, standard error
Were there any differences in how well the drug worked in clinical trials among sex, race and age?
- Sex: JESDUVROQ was similarly effective in males or females.
- Race: The majority of patients were White. JESDUVROQ worked similarly in White and Black or African American patients. Differences in response to JESDUVROQ among different races was not observed.
- Age: JESDUVROQ was similarly effective in patients younger than 65 years, between 65 and 75 years, and older 75 years.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
Overall, the results of the subgroup analyses were consistent with the primary efficacy analysis of change in hemoglobin from baseline with little or no heterogeneity between subgroups.
Table 3. MACE by Subgroup
|
Demographic |
JESDUVROQ |
rhEPO |
HR (95% CI) |
|---|---|---|---|
|
Sex |
|||
|
Female |
135/636 (9.2) |
149/630 (10.2) |
0.89 (0.71, 1.13) |
|
Male |
239/851 (12.6) |
245/847 (13.1) |
0.95 (0.80, 1.14) |
|
Age, years |
|||
|
<65 |
189/1007 (7.9) |
189/978 (8.2) |
0.96 (0.78, 1.17) |
|
≥65 to <75 |
114/321 (16.9) |
129/325 (18.7) |
0.92 (0.71, 1.18) |
|
≥75 |
71/159 (22.8) |
76/174 (22.2) |
1.03 (0.74, 1.42) |
|
Race |
|||
|
American Indian or Alaska Native |
4/19 (9.7) |
11/32 (17.9) |
0.51 (0.16, 1.66) |
|
Asian |
33/176 (8.4) |
44/181 (11.1) |
0.72 (0.46, 1.13) |
|
Black or African American |
57/228 (10.7) |
61/233 (11.6) |
0.89 (0.62, 1.28) |
|
White |
259/995 (11.4) |
262/982 (11.7) |
0.98 (0.83, 1.17) |
|
Other |
21/69 (14.7) |
16/49 (17.3) |
0.87 (0.45, 1.68) |
|
Region |
|||
|
United States |
137/425 (14.6) |
139/421 (15.2) |
0.96 (0.75, 1.21) |
|
Non-United States |
237/1062 (9.7) |
255/1056 (10.6) |
0.92 (0.77, 1.09) |
Source: Adapted from FDA Review
Abbreviations: CI, confidence interval; HR, hazard ratio adjusted for baseline covariates; MACE, major adverse cardiovascular event; N, number of patients in treatment group; n, number of patients matching criteria; Ns, subgroup sample size, Rate, number of events per 100 person-years; rhEPO, recombinant human erythropoietin
What are the possible side effects?
JESDUVROQ has a boxed warning for an increased risk of thrombotic vascular (blood clotting) events including death, heart attack, stroke, and blood clots in the lung, legs or dialysis access site. JESDUVROQ’s warnings and precautions include a risk of hospitalization for heart failure, worsening increase of blood pressure, stomach erosions and gastrointestinal bleeding, and may have unfavorable effects on cancer growth. JESDUVROQ is not approved for patients with anemia due to chronic kidney disease who are not on dialysis because its safety has not been established in that population.
The most common side effects of JESDUVROQ include high blood pressure, thrombotic vascular events, abdominal pain, dizziness, and allergic reactions. Patients should not use JESDUVROQ if they also take certain drugs that cause increase levels of JESDUVROQ or if they have uncontrolled high blood pressure.
What are the possible side effects (results of trials used to assess safety)?
The most common adverse reactions (≥10% of JESDUVROQ-treated patients) were hypertension, thrombotic vascular events, and abdominal pain (Table 4).
Table 4. Adverse Reactions Reported in ≥5% of Patients Treated With JESDUVROQ in the ASCEND-D Trial
|
Adverse Reaction |
JESDUVROQ |
rhEPO |
|---|---|---|
|
Hypertension |
24 |
24 |
|
Abdominal paina |
11 |
8 |
|
Dizziness |
7 |
6 |
|
Hypersensitivityb |
7 |
7 |
Source: JESDUVROQ Prescribing Information
a Includes unspecified abdominal pain, upper abdominal pain, abdominal discomfort
b Includes rash, urticaria and dermatitis.
Abbreviations: rhEPO, recombinant human erythropoietin
Adjudicated thrombotic vascular events (fatal and nonfatal) were observed in 9.8 per 100 person years (PY) of patients receiving JESDUVROQ and in 11.7 per 100 PY of patients receiving rhEPO (Table 5).
Table 5. Adjudicated Thrombotic Vascular Events (Fatal and Nonfatal) in the ASCEND D Triala
|
Event |
JESDUVROQ |
rhEPO |
|---|---|---|
|
Vascular access thrombosis |
5.0 |
6.3 |
|
Myocardial infarction |
3.4 |
4.1 |
|
Stroke |
1.2 |
1.5 |
|
Deep vein thrombosis |
0.7 |
0.6 |
|
Pulmonary embolism |
0.3 |
0.4 |
Source: JESDUVROQ Prescribing Information
a These data are not an adequate basis for comparison of rates between the study drug and the active control.
Abbreviations: PY, person years; rhEPO, recombinant human erythropoietin
MACE (defined as all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke) was evaluated as a safety coprimary endpoint along with the efficacy endpoint using a noninferiority comparison to rhEPO (epoetin alfa and darbepoetin alfa).
The hazard ratio for the time to first occurrence of MACE comparing JESDUVROQ to rhEPO was 0.93 (95% CI: 0.81, 1.07) (Table 6). Noninferiority of JESDUVROQ to rhEPO on MACE was achieved because the upper limit of the 95% CI for the MACE hazard ratio was less than the prespecified noninferiority margin of 1.25.
Table 6. Major Adverse Cardiovascular Events in the ASCEND-D Trial (ITT Analysis)a
|
|
JESDUVROQ |
rhEPOb |
|---|---|---|
|
First occurrence of MACEc, n (%) |
374 (25) |
394 (27) |
|
All‑cause mortalityd |
244 (16) |
233 (16) |
|
Nonfatal myocardial infarctiond |
101 (7) |
126 (9) |
|
Nonfatal stroked |
29 (2) |
35 (2) |
|
Hazard ratio (95% CI)e |
0.93 (0.81, 1.07) |
|
|
Incidence rate per 100 PY |
11.1 |
11.9 |
Source: JESDUVROQ Prescribing Information
a ITT analyses included events on and off treatment after randomization.
b Hemodialysis patients received epoetin alfa; peritoneal dialysis patients received darbepoetin alfa.
c Co-primary endpoint.
d Component of composite endpoint.
e Adjusted for baseline covariates.
Abbreviations: CI, confidence interval; ITT, intent-to-treat; MACE, major adverse cardiovascular events; PY, person years; rhEPO, recombinant human erythropoietin
Were there any differences in side effects of the clinical trials among sex, race, and age?
- Sex: The occurrence of MACE was similar in males or females.
- Race: The occurrence of MACE was similar in White and Black or African American patients.
- Age: The occurrence of MACE was similar in patients younger than 65 years, between 65 and 75 years, and older than 75 years.
Were there any differences in side effects of the clinical trials among sex, race, and age groups?
Results for the subgroup analysis of MACE were generally consistent with the overall study population MACE estimate.
Table 7. Overview of Side Effects by Sex, Race, and Age in Trial 200807 ASCEND-D), Safety Population
|
|
DAPRO |
rhEPO |
||||
|---|---|---|---|---|---|---|
|
Characteristic |
All Patients |
All Grades |
Grades 3 to 4 |
All Patients |
All Grades |
Grades 3 to 4 |
|
Sex, n (%) |
||||||
|
Female |
633 (42.7) |
586/633 (92.6) |
239/633 (37.8) |
630 (42.7) |
581/630 (92.2) |
248/630 (39.4) |
|
Male |
849 (57.3) |
792/849 (93.3) |
316/849 (37.2) |
844 (57.3) |
776/844 (91.9) |
336/844 (39.8) |
|
Race, n (%) |
||||||
|
White |
992 (66.9) |
920/992 (92.7) |
366/992 (36.9) |
979 (66.4) |
905/979 (92.4) |
377/979 (38.5) |
|
Black or African American |
228 (15.4) |
209/228 (91.7) |
102/228 (44.7) |
233 (15.8) |
213/233 (91.4) |
110/233 (47.2) |
|
Asian |
176 (11.9) |
167/176 (94.9) |
51/176 (29.0) |
181 (12.3) |
164/181 (90.6) |
55/181 (30.4) |
|
American Indian or Alaska Native |
19 (1.3) |
18/19 (94.7) |
9/19 (47.4) |
32 (2.2) |
28/32 (87.5) |
15/32 (46.9) |
|
Native Hawaiian or Other Pacific Islander |
25 (1.7) |
25/25 (100) |
15/25 (60.0) |
25 (1.7) |
25/25 (100) |
16/25 (64.0) |
|
Multiple |
42 (2.8) |
39/42 (92.9) |
12/42 (28.6) |
24 (1.6) |
22/24 (91.7) |
11/24 (45.8) |
|
Age group, years, n (%) |
||||||
|
<65 |
1005 (67.8) |
923/1005 (91.8) |
344/1005 (34.2) |
976 (66.2) |
884/976 (90.6) |
356/976 (36.5) |
|
65 - <75 |
318 (21.5) |
303/318 (95.3) |
135/318 (42.5) |
325 (22.0) |
310/325 (95.4) |
141/325 (43.4) |
|
≥75 |
159 (10.7) |
152/159 (95.6) |
76/159 (47.8) |
173 (11.7) |
163/173 (94.2) |
87/173 (50.3) |
Source: adae.xpt, adsl.xpt; FDA reviewer's analysis
Abbreviation: N, number of patients in the safety population; n, number of patients with given characteristic; Ns, total number of patients in each category
GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.