Drug Trials Snapshot: VANRAFIA
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 VANRAFIA Prescribing Information for all 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).
VANRAFIA (atrasentan)
van rah’ fee ah
Novartis Pharmaceuticals
Original Approval date: April 2, 2025
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
VANRAFIA is an endothelin type A receptor antagonist that is indicated to reduce proteinuria in adults with primary immunoglobulin A (IgA) nephropathy at risk of rapid disease progression, generally a urine protein-to-creatinine ratio (UPCR) ≥1.5 g/g.
How is this drug used?
VANRAFIA is an oral tablet that is taken once daily.
Who participated in the clinical trials?
FDA granted accelerated approval to VANRAFIA based on evidence from a clinical trial (ALIGN/NCT04573478) in adult patients with primary immunoglobulin A nephropathy (IgAN). The trial was conducted at 99 sites in 18 countries in Asia, Europe, North America, Latin America and the Caribbean, and Oceania (including Australia and New Zealand).
The same trial was used to assess both efficacy and safety. The efficacy analyses were based on an interim analysis of 270 patients (135 on VANRAFIA and 135 on placebo) who reached Week 36 in the trial. Of these 270 patients, 35 were from the United States. The safety analyses were based on 403 patients (201 on VANRAFIA and 202 on placebo) who received at least one dose of drug or placebo and standard of care during the trial.
How were the trials designed?
VANRAFIA was evaluated in a randomized, double-blind, placebo-controlled, trial (ALIGN) in adults with IgAN. Patients with IgAN and protein in the urine were randomly assigned to receive either VANRAFIA or placebo once daily. The trial also included a subset of subjects on sodium-glucose cotransporter-2 inhibitors (SGLT2i) at baseline who were excluded from the primary efficacy analysis. The primary endpoint for accelerated approval was the percent reduction in urine protein at Week 36 compared to baseline.
How were the trials designed?
VANRAFIA was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial in adults with biopsy-proven IgAN (ALIGN). Patients with IgAN, eGFR (a measure of kidney function) ≥30 mL/min/1.73 m2, and total urine protein ≥1.0 g/day on a maximally-tolerated stable dose of renin-angiotensin system (RAS) inhibitor treatment were enrolled. Patients were randomized (1:1) to either VANRAFIA (0.75 mg) or a matched placebo taken orally once daily. The trial also included a subset of patients on SGLT2i at baseline who were not included in the primary efficacy analysis. Rescue immunosuppressive therapy could be initiated during the trial, per investigator discretion. The primary endpoint in the trial was the relative change from baseline in UPCR (the amount of protein in the urine) at Week 36.
DEMOGRAPHICS SNAPSHOT
Figure 1 summarizes how many male and female patients were enrolled in the clinical trial used to evaluate the efficacy of VANRAFIA.
Figure 1. Baseline Demographics by Sex, Interim Analysis Set
Source: Adapted from FDA Review
Figure 2 summarizes how many patients by race were enrolled in the clinical trial used to evaluate the efficacy of VANRAFIA.
Figure 2. Baseline Demographics by Race, Interim Analysis Set
Source: Adapted from FDA Review
* Other includes 10 (<1%) other race, 2 (<1%) multiple race, and 2 (<1%) patients with no race data reported. There were no Native Hawaiians or other Pacific Islanders in the study.
Figure 3 summarizes how many patients by age were enrolled in the clinical trial used to evaluate the efficacy of VANRAFIA.
Figure 3. Baseline Demographics by Age, Interim Analysis Set
Source: Adapted from FDA Review
Figure 4 summarizes how many patients by ethnicity were enrolled in the clinical trial used to evaluate the efficacy of VANRAFIA.
Figure 4. Baseline Demographics by Ethnicity, Interim Analysis Set
Source: Adapted from FDA Review
Who participated in the trials?
Table 1. Baseline Demographics, Trial ALIGN
| Subgroup | VANRAFIA n (%) |
Placebo n (%) |
Total n (%) |
|---|---|---|---|
| All | 135 (100) | 135 (100) | 270 (100) |
| Sex | |||
Female |
81 (60) | 78 (58) | 159 (59) |
Male |
54 (40) | 57 (42) | 111 (41) |
| Age group, years | |||
<65 |
124 (92) | 129 (96) | 253 (94) |
≥65 |
11 (8) | 6 (4) | 17 (6) |
| Race | |||
White |
49 (36) | 48 (36) | 97 (36) |
Asian |
75 (56) | 79 (59) | 154 (57) |
Black or African American |
4 (3) | 1 (1) | 5 (2) |
Other |
3 (2) | 7 (5) | 10 (4) |
Multiple |
2 (1) | NA | 2 (1) |
Not reported |
2 (1) | NA | 2 (1) |
| Ethnicity | |||
Hispanic or Latino |
32 (24) | 24 (18) | 56 (21) |
Not Hispanic or Latino |
98 (73) | 110 (81) | 208 (77) |
Not reported |
5 (4) | 1 (1) | 6 (2) |
Source: Adapted from FDA Review
Abbreviations: NA, not applicable
What are the benefits of this drug?
In a trial comparing VANRAFIA to placebo, the benefit of VANRAFIA was evaluated using the mean reduction of protein in the urine compared to baseline after 36 weeks of treatment. Compared to baseline, there was a 38% reduction in the mean urine protein (assessed as UPCR) for VANRAFIA compared to a 3% reduction for placebo.
VANRAFIA was approved under FDA’s accelerated approval program, which provides earlier patient access to a promising new drug while the company continues to conduct clinical trials to confirm that the drug works well.
What are the benefits of this drug (results of trials used to assess efficacy)?
Compared to baseline, the interim analysis for the ALIGN trial showed that participants treated with VANRAFIA in addition to a stable dose of background therapy had a 38% reduction in the mean urine protein compared with 3% reduction in mean urine protein in participants treated with placebo.
Percentage reductions from baseline in urine protein measured using urine protein to creatinine ratio are provided in Table 2.
Table 2. Efficacy Results, Trial ALIGN
| Parameter | VANRAFIA N=135 |
Placebo N=135 |
|---|---|---|
| % reduction in UPCR (95% CI) at Week 36 relative to baseline | 38 (32, 44) | 3 (-7, 12) |
| % difference (95% CI)* | 36 (26, 45) |
|
| p-value | <0.0001 |
|
Source: Adapted from FDA Review
* Confidence interval nominal by arm.
Abbreviations: CI, confidence interval; UPCR, urine protein to creatinine ratio
Were there any differences in how well the drug worked in clinical trials among sex, race, and age?
- Sex: The observed effect of VANRAFIA was similar for females and males.
- Race: The observed effect of VANRAFIA was similar for Asian and White patients. The number of patients of other races was small; therefore, differences in how VANRAFIA worked among other races could not be determined.
- Age: The observed effect of VANRAFIA was similar in patients younger than 65 and in patients 65 years of age and older.
- Ethnicity: The observed effect of VANRAFIA was similar for patients who were Hispanic or Latino and not Hispanic or Latino.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
Table 3 presents analyses of the primary endpoint according to sex, race, age, and ethnicity.
Table 3. Efficacy Results by Subgroup, Interim Analysis Set
| Subgroup | % Reduction in UPCR (95% CI) at Week 36 Relative to Placebo* |
|---|---|
| Sex | |
Male |
27 (11, 40) |
Female |
42 (28, 55) |
| Age, years | |
<65 |
34 (23, 43) |
≥65 |
28 (-26, 50) |
| Race | |
Asian |
36 (23, 47) |
White |
29 (9, 42) |
| Ethnicity | |
Hispanic or Latino |
34 (15, 49) |
Not Hispanic or Latino |
34 (22, 44) |
Source: Adapted from FDA Review
* Treatment differences and credible intervals may not match values of (treatment - control) since estimates include the relevance of outcomes from other subgroups.
CI, confidence interval; UPCR, urine protein to creatinine ratio
What are the possible side effects?
VARANFIA may cause harm to an unborn baby and should not be given to pregnant individuals.
VARANFIA can cause changes in liver tests. Some medicines that are like VARANFIA can cause liver failure. Patients should undergo testing to monitor their liver before starting VARANFIA, then periodically during treatment with VARANFIA.
VARANFIA may cause decreased sperm counts in males and may affect their ability to father a child.
VARANFIA may cause decreases in blood pressure.
In the ALIGN trial, the most common side effects of VARANFIA were fluid retention (swelling) and low red blood cell levels (anemia).
What are the possible side effects (results of trials used to assess safety)?
Table 4 summarizes common side effects reported in ≥2% of adult patients with IgAN treated with VANRAFIA and higher than placebo.
Table 4. Side Effects Reported in ≥2% of Adult Patients With IgAN Treated With VANRAFIA and Higher Than Placebo, Trial ALIGN, Safety Population
| Side Effect | VARANFIA N=201 n (%) |
Placebo N=202 n (%) |
|---|---|---|
| Fluid retention | 21 (10) | 14 (7) |
| Anemia | 12 (6) | 2 (1) |
| Liver enzyme elevation | 4 (2) | 2 (1) |
Source: Adapted from FDA Review
Abbreviations: IgAN, immunoglobulin A neuropathy
Were there any differences in side effects among sex, race, and age?
- Sex: The occurrence of anemia was greater in females than males. Because of limited data, this difference may be due to chance.
- Race: The occurrence of side effects was similar in White and Asian patients. The number of patients of all other races was small; therefore, differences in side effects in other races could not be determined.
- Age: The occurrence of edema was greater in patients 45 years of age and older. Because of limited data, this difference may be due to chance.
Were there any differences in side effects of the clinical trials among sex, race, and age groups?
Table 5 summarizes adverse reactions (edema/fluid retention and anemia) by subgroups.
Table 5. Side Effects by Subgroup, Safety Population
| Subgroup | Edema/Fluid Retention | Anemia | ||
|---|---|---|---|---|
| VARANFIA n/N (%) |
Placebo n/N (%) |
VARANFIA n/N (%) |
Placebo n/N (%) |
|
| Sex | ||||
Female |
10/77 (13) | 10/92 (11) | 9/77 (12) | 1/92 (1) |
Male |
11/124 (9) | 4/110 (4) | 3/124 (2) | 1/110 (1) |
| Age group, years | ||||
<45 |
5/90 (6) | 7/110 (6) | 7/90 (8) | 1/110 (1) |
≥45 |
16/111 (14) | 7/92 (8) | 5/111 (5) | 1/92 (1) |
| Race | ||||
Asian |
8/101 (8) | 6/111 (5) | 6/101 (6) | 2/111 (2) |
Black or African American |
0/5 (0) | 0/1 (0) | 2/5 (40) | 0/1 (0) |
Native Hawaiian or other Pacific Islander |
1/4 (25) | 0/1 (0) | 0/4 (0) | 0/1 (0) |
Not reported |
1/6 (17) | 0/1 (0) | 0/6 (0) | 0/1 (0) |
Other |
1/7 (25) | 1/12 (8) | 2/7 (29) | 0/12 (0) |
White |
10/78 (13) | 7/76 (9) | 2/78 (3) | 0/76 (0) |
| Ethnicity | ||||
Hispanic or Latino |
4/41 (10) | 3/40 (8) | 4/41 (10) | 0/40 (0) |
Not Hispanic or Latino |
14/153 (9) | 10/157 (6) | 7/153 (5) | 2/157 (1) |
Not reported |
3/7 (43) | 1/5 (20) | 1/7 (14) | 0/5 (0) |
Source: Adapted from FDA Review
Abbreviations: N, total number in the subgroup; n, number who experienced the side effect
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 used in clinical trials 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.
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