Drug Trials Snapshots: REZDIFFRA
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 REZDIFFRA 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).
REZDIFFRA (resmetirom)
rez di' frah
Madrigal Pharmaceuticals, Inc
Original Approval date: March 14, 2024
DRUG TRIALS SNAPSHOT SUMMARY
What is the drug for?
REZDIFFRA is a drug that is used along with diet and exercise to treat adults with nonalcoholic steatohepatitis (NASH) with moderate to advanced liver scarring (fibrosis), but not with cirrhosis of the liver.
Some multinational liver societies recommend using the name metabolic dysfunction-associated steatohepatitis (MASH) instead of NASH; MASH and NASH are names for the same disorder.
How is this drug used?
REZDIFFRA is a tablet that is taken by mouth once daily. Based on the patient’s weight and use of certain blood thinners, the healthcare provider will recommend the appropriate dose to be taken once daily.
Who participated in the clinical trials?
The FDA approved REZDIFFRA based on evidence of efficacy from a clinical trial, Trial 1, of 888 patients who had a liver biopsy showing inflammation due to NASH with moderate or advanced liver scarring, but not with cirrhosis of the liver. The trial was conducted at 172 sites in 14 countries including Australia, Austria, Belgium, Canada, France, Germany, Hungary, Israel, Italy, Poland, Spain, Switzerland, the United Kingdom, and the United States. Approximately 66% (587) of the patients were from the United States.
The safety population for REZDIFFRA (2,019 patients) included the 888 patients from Trial 1 and two other groups of patients: an additional 162 patients from a relevant patient population enrolled in Trial 1, and 969 patients enrolled in a safety trial conducted in the United States, from a relevant patient population who received REZDIFFRA for at least one year.
The number of patients included in the efficacy findings may differ from the number of patients included in the safety findings because more patients were evaluated for safety.
How were the trials designed?
The efficacy of REZDIFFRA was evaluated based on an efficacy analysis at Month 12 in a 54-month, randomized, double-blind, placebo-controlled trial (Trial 1) in patients who have a liver biopsy showing inflammation due to NASH with moderate to advanced liver scarring, but not with cirrhosis of liver. In Trial 1, patients received placebo, REZDIFFRA 80 mg once daily, or REZDIFFRA 100 mg once daily. The primary efficacy endpoints at Month 12 were based on liver biopsy: (1) NASH resolution and no worsening of liver scarring and (2) improvement in liver scarring and no worsening of NASH.
How were the trials designed?
Trial 1 is a 54-month, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the efficacy and safety of REZDIFFRA. Patients were randomized 1:1:1 to receive placebo, REZDIFFRA 80 mg once daily, or REZDIFFRA 100 mg once daily, in addition to lifestyle counseling on nutrition and exercise. Patients were on stable doses of medications for diabetes, dyslipidemia, and hypertension. A total of 888 patients who had a baseline or recent liver biopsy showing NASH with fibrosis stage 2 or 3 and a Nonalcoholic Fatty Liver Disease Activity Score (NAS) of at least 4 contributed to the efficacy evaluation of REZDIFFRA at Month 12. The Month 12 primary endpoints were based on liver biopsy: (1) NASH resolution and no worsening of liver scarring and (2) improvement in liver scarring and no worsening of NASH.
An additional 52-week, randomized, double-blind, placebo-controlled safety trial was conducted to evaluate the safety of REZDIFFRA, which enrolled a total of 969 patients from a relevant patient population who received REZDIFFRA for at least one year. The safety population (2,019 patients) comprised of these 969 patients, 888 patients from Trial 1, and an additional 162 patients from a relevant patient population enrolled in Trial 1.
DEMOGRAPHICS SNAPSHOT
Figure 1 summarizes the percentage of male and female patients enrolled in the clinical trial that evaluated the efficacy of REZDIFFRA.
Figure 1. Baseline Demographics by Sex, Efficacy Population
Source: Adapted from FDA Review
Figure 2 summarizes the percentage of patients by race enrolled in the clinical trial that evaluated the efficacy of REZDIFFRA.
Figure 2. Baseline Demographics by Race, Efficacy Population
Source: Adapted from FDA Review
Figure 3 summarizes the percentage of patients by age enrolled in the clinical trial that evaluated the efficacy of REZDIFFRA.
Figure 3. Baseline Demographics by Age, Efficacy Population
Source: Adapted from FDA Review
Figure 4 summarizes the percentage of patients by ethnicity enrolled in the clinical trial that evaluated the efficacy of REZDIFFRA.
Figure 4. Baseline Demographics by Ethnicity, Efficacy Population
Source: Adapted from FDA Review
Other includes: Not reported (4 participants), unknown (3 participants), or not able to collect (5 participants)
Who participated in the trials?
Table 1. Baseline Demographics, Efficacy Population
| Demographic Parameters | Placebo N=294 |
REZDIFFRA 80 mg N=298 |
REZDIFFRA 100 mg N=296 |
Total N=888 |
|---|---|---|---|---|
| Sex, n (%) | ||||
| Female | 161 (54.8) | 166 (55.7) | 170 (57.4) | 497 (56.0) |
| Male | 133 (45.2) | 132 (44.3) | 126 (42.6) | 391 (44.0) |
| Age, years | ||||
| Mean (SD) | 57.2 (10.9) | 55.8 (11.4) | 57.6 (10.5) | 56.9 (11.0) |
| Median | 58.0 | 57.0 | 59.0 | 58.0 |
| Min, max | 22.0, 83.0 | 18.0, 81.0 | 22.0, 81.0 | 18.0, 83.0 |
| Age category, years, n (%) | ||||
| <65 | 215 (73.1) | 231 (77.5) | 214 (72.3) | 660 (74.3) |
| ≥65 | 79 (26.9) | 67 (22.5) | 82 (27.7) | 228 (25.7) |
| Race, n (%) | ||||
| American Indian or Alaska Native | 3 (1.0) | 4 (1.3) | 1 (<1) | 8 (<1) |
| Asian | 9 (3.1) | 9 (3.0) | 8 (2.7) | 26 (2.9) |
| Black or African American | 9 (3.1) | 5 (1.7) | 5 (1.7) | 19 (2.1) |
| Native Hawaiian or other Pacific Islander | 1 (<1) | 0 | 0 | 1 (<1) |
| White | 255 (86.7) | 268 (89.9) | 267 (90.2) | 790 (89.0) |
| Not reported | 6 (2.0) | 4 (1.3) | 10 (3.4) | 20 (2.3) |
| Other | 11 (3.7) | 8 (2.7) | 5 (1.7) | 24 (2.7) |
| Ethnicity, n (%) | ||||
| Hispanic or Latino | 46 (15.6) | 64 (21.5) | 76 (25.7) | 186 (20.9) |
| Not Hispanic or Latino | 244 (83.0) | 231 (77.5) | 215 (72.6) | 690 (77.7) |
| Other | 4 (1.4) | 3 (1.0) | 5 (1.7) | 12 (1.4) |
Source: Adapted from FDA Review
Abbreviations: SD, standard deviation
What are the benefits of this drug?
REZDIFFRA was better than placebo at achieving NASH resolution and improving liver scarring.
REZDIFFRA 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)?
Efficacy at Month 12 histology endpoints in Trial 1, (1) resolution of NASH without worsening of liver scarring and (2) improvement in liver scarring without worsening of NASH, are presented in Table 2. Two pathologists, Pathologist A and Pathologist B, independently read liver biopsies for each patient. Patients who received REZDIFFRA had a higher rate of improvement than patients who received placebo.
Table 2. Efficacy Results at Month 12, Trial 1
| Efficacy Endpoint | Placebo N=294 |
REZDIFFRA 80 mg N=298 |
REZDIFFRA 100 mg N=296 |
|---|---|---|---|
| NASH resolution without worsening of liver scarring | |||
| Response rate, Pathologist A (%) | 13 | 27 | 36 |
| Difference in response rate vs. placebo (95% CI) | NA | 14 (8, 20) | 23 (16, 30) |
| Response rate, Pathologist B (%) | 9 | 26 | 24 |
| Difference in response rate vs. placebo (95% CI) | NA | 17 (11, 23) | 15 (9, 21) |
| Improvement in liver scarring without worsening of NASH | |||
| Response rate, Pathologist A (%) | 15 | 23 | 28 |
| Difference in response rate vs. placebo (95% CI) | NA | 8 (2, 14) | 13 (7, 20) |
| Response rate, Pathologist B (%) | 13 | 23 | 24 |
| Difference in response rate vs. placebo (95% CI) | NA | 11 (5, 17) | 11 (5, 17) |
Source: Adapted from FDA Review and REZDIFFRA Prescribing Information
Abbreviations: CI, confidence interval; NA, not applicable; NASH, nonalcoholic steatohepatitis
Were there any differences in how well the drug worked in clinical trials among sex, race, and age?
- Sex: The observed effect of REZDIFFRA was similar for females and males.
- Race: The number of patients of races other than White was small; therefore, differences in how REZDIFFRA worked among races could not be determined.
- Age: The observed effect of REZDIFFRA was similar for patients younger and older than 65 years of age.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
Subgroup analyses were conducted to assess the potential for differences in the treatment effect for various demographic groups. Table 3 and Table 4 summarize efficacy results by sex, age, race, and ethnicity in Trial 1 for the endpoints of (1) resolution of NASH without worsening of liver scarring and (2) improvement in liver scarring without worsening of NASH, respectively. The subgroup analyses incorporate both pathologists’ independent readings in the results.
Overall, the treatment effect of REZDIFFRA compared to placebo appeared consistent across the demographic subgroups of sex, age, and ethnicity. However, there was an insufficient number of patients of races other than White to determine whether REZDIFFRA worked differently in different races.
Table 3. Resolution of NASH Without Worsening of Liver Scarring at Month 12 by Subgroup, Trial 1
| Subgroup | Placebo N=294 % |
REZDIFFRA 80 mg N=298 % |
REZDIFFRA 100 mg N=296 % |
REZDIFFRA 80 mg vs. Placebo Risk Difference % (95% CI) |
REZDIFFRA 100 mg vs. Placebo Risk Difference % (95% CI) |
|---|---|---|---|---|---|
| Sex | |||||
| Male | 11 | 30 | 33 | 19 (10, 28) | 23 (14, 31) |
| Female | 11 | 24 | 28 | 13 (5, 20) | 16 (9, 24) |
| Age, years | |||||
| ≥18 to <65 | 12 | 24 | 31 | 12 (6, 19) | 19 (12, 26) |
| ≥65 | 8 | 34 | 28 | 25 (13, 38) | 20 (10, 30) |
| Race1 | |||||
| American Indian or Alaska Native | 21 | 43 | NA | 21 (NA, NA) | NA |
| Asian | 12 | 56 | 31 | 37 (-14, 87) | 19 (NA, NA) |
| Black or African American | 17 | 41 | 22 | 30 (NA, NA) | 6 (NA, NA) |
| Native Hawaiian or other Pacific Islander | NA | NA | NA | NA | NA |
| White | 10 | 26 | 31 | 16 (10, 22) | 21 (15, 27) |
| Not reported | 20 | 0 | 11 | -25 (NA, NA) | -8 (NA, NA) |
| Other | 17 | 11 | 0 | -4 (-35, 27) | -17 (-47, 13) |
| Ethnicity1 | |||||
| Hispanic or Latino | 14 | 21 | 36 | 7 (-6, 20) | 22 (7, 37) |
| Not Hispanic or Latino | 11 | 28 | 28 | 17 (11, 23) | 17 (11, 23) |
| Other | 0 | 24 | 13 | 0 (-56, 56) | 13 (NA, NA) |
Source: Adapted from FDA Review
1Unable to calculate the percentage of responders or to construct the 95% CIs when the number of patients in the treatment arm in the subgroup is small.
Abbreviations: CI, confidence interval; NA, not applicable; NASH, nonalcoholic steatohepatitis
Table 4. Improvement in Liver Scarring Without Worsening of NASH at Month 12 by Subgroup, Trial 1
| Subgroup | Placebo N=294 % |
REZDIFFRA 80 mg N=298 % |
REZDIFFRA 100 mg N=296 % |
REZDIFFRA 80 mg vs. Placebo Risk Difference % (95% CI) |
REZDIFFRA 100 mg vs. Placebo Risk Difference % (95% CI) |
|---|---|---|---|---|---|
| Sex | |||||
| Male | 10 | 22 | 26 | 11 (3, 19) | 16 (7, 24) |
| Female | 17 | 25 | 27 | 8 (0, 16) | 10 (2, 18) |
| Age, years | |||||
| ≥18 to <65 | 15 | 23 | 30 | 7 (1, 14) | 15 (8, 22) |
| ≥65 | 10 | 26 | 15 | 16 (5, 28) | 5 (-4, 14) |
| Race1 | |||||
| American Indian or Alaska Native | 43 | 0 | NA | -43 (NA, NA) | NA |
| Asian | 19 | 47 | 25 | 28 (-13, 70) | 6 (NA, NA) |
| Black or African American | 33 | 9 | 0 | -14 (NA, NA) | -33 (NA, NA) |
| Native Hawaiian or other Pacific Islander | NA | NA | NA | NA | NA |
| White | 13 | 23 | 27 | 10 (4, 16) | 13 (7, 19) |
| Not reported | 10 | 0 | 32 | -13 (NA, NA) | 22 (NA, NA) |
| Other | 9 | 23 | 19 | 14 (-20, 47) | 10 (-20, 41) |
| Ethnicity1 | |||||
| Hispanic or Latino | 16 | 24 | 37 | 8 (-6, 21) | 21 (6, 36) |
| Not Hispanic or Latino | 13 | 24 | 22 | 10 (4, 16) | 9 (3, 15) |
| Other | 33 | 24 | 0 | 6 (-68, 80) | -33 (NA, NA) |
Source: Adapted from FDA Review
1Unable to calculate the percentage of responders or to construct the 95% CIs when the number of patients in the treatment arm in the subgroup is small.
Abbreviations: CI, confidence interval; NA, not applicable; NASH, nonalcoholic steatohepatitis
What are the possible side effects?
REZDIFFRA may cause serious side effects including liver toxicity and gallstone-related events (inflammation of the gallbladder or pancreas). Also, if a patient is taking statin medicines to help lower cholesterol, the dose of statin medicine may need to be adjusted while taking REZDIFFRA, to lower the risk of statin-related side effects.
The most common side effects in clinical trials included diarrhea, nausea, itching, stomach (abdominal) pain, vomiting, dizziness, and constipation.
What are the possible side effects (results of trials used to assess safety)?
Table 5 displays incidence rates (number of new cases), adjusted for duration of drug exposure, for the common adverse reactions that occurred in at least 5% of NASH patients with moderate to advanced liver scarring, but without cirrhosis, treated in either drug arm with REZDIFFRA and were greater than reported for placebo.
Table 5. Exposure-Adjusted Incidence Rates1 of Common Adverse Reactions Reported With REZDIFFRA in Adult Patients With NASH, Trial 1
| Adverse Reaction | Placebo N=294 n (EAIR) |
REZDIFFRA 80 mg N=298 n (EAIR) |
REZDIFFRA 100 mg N=296 n (EAIR) |
|---|---|---|---|
| Diarrhea | 52 (14) | 78 (23) | 98 (33) |
| Nausea | 36 (9) | 65 (18) | 51 (15) |
| Pruritus | 18 (4) | 24 (6) | 36 (10) |
| Vomiting | 15 (4) | 27 (7) | 30 (8) |
| Constipation | 18 (4) | 20 (5) | 28 (8) |
| Abdominal pain | 18 (4) | 22 (5) | 27 (7) |
| Dizziness | 6 (1) | 17 (4) | 17 (4) |
Source: Adapted from REZDIFFRA Prescribing Information
1 The EAIR per 100 person-years is the estimated number of cases of the adverse reaction if 100 patients are treated for one year
Abbreviations: EAIR, exposure-adjusted incidence rate; NASH, nonalcoholic steatohepatitis
In addition to the 888 patients enrolled in Trial 1, the safety population evaluated for safety of REZDIFFRA also included an additional 162 patients from a relevant patient population enrolled in Trial 1, and 969 patients from a relevant patient population enrolled in an additional safety trial. The baseline demographic characteristics and safety profile of this combined safety population (a total of 2,019 patients) was similar to Trial 1, other than one case of liver toxicity observed in the safety trial.
Were there any differences in side effects among sex, race, and age?
- Sex: The observed occurrence of side effects was greater for females than males. Because of limited data, this difference may be due to chance.
- Race: The number of patients of races other than White was small, therefore differences in side effects among races could not be determined.
- Age: The observed occurrence of side effects was greater for patients who were 65 years and older compared to younger adult patients. Because of limited data, this difference may be due to chance.
Were there any differences in side effects among sex, race, and age?
Table 6. Overview of Adverse Events by Demographic Subgroup, Safety Population
| Characteristic | Placebo N=349 n/Ns (%) |
REZDIFFRA 80 mg N=352 n/Ns (%) |
REZDIFFRA 100 mg N=349 n/Ns (%) |
REZDIFFRA 80 mg vs. Placebo Risk Difference % (95% CI) |
REZDIFFRA 100 mg vs. Placebo Risk Difference % (95% CI) |
|---|---|---|---|---|---|
| Sex | |||||
| Female | 181/192 (94.3) | 187/198 (94.4) | 183/197 (92.9) | 0.2 (-4.7, 5.1) | -1.4 (-6.5, 3.7) |
| Male | 143/157 (91.1) | 137/154 (89.0) | 134/152 (88.2) | -2.1 (-9.1, 4.7) | -2.9 (-10.1, 4.0) |
| Age group, years | |||||
| ≥18 to <40 | 25/27 (92.6) | 28/32 (87.5) | 21/27 (77.8) | -5.1 (-22.2, 12.9) | -14.8 (-35.0, 4.9) |
| ≥40 to <65 | 218/230 (94.8) | 215/237 (90.7) | 211/229 (92.1) | -4.1 (-9.0, 0.7) | -2.6 (-7.5, 2.0) |
| ≥65 | 81/92 (88.0) | 81/83 (97.6) | 85/93 (91.4) | 9.5 (2.1, 18.1) * | 3.4 (-5.7, 12.7) |
| ≥75 | 6/9 (66.7) | 4/5 (80.0) | 10/10 (100) | 13.3 (-38.9, 53.7) | 33.3 (-0.6, 65.3) |
| Race | |||||
| American Indian or Alaska Native | 3/3 (100) | 4/4 (100) | 1/1 (100) | 0.0 (-52.8, 59.9) | 0.0 (-83.7, 63.1) |
| Asian | 8/9 (88.9) | 8/10 (80.0) | 7/9 (77.8) | -8.9 (-43.9, 29.2) | -11.1 (-47.8, 27.8) |
| Black or African American | 9/10 (90.0) | 3/6 (50.0) | 4/5 (80.0) | -40.0 (-75.6, 5.3) | -10.0 (-56.4, 27.9) |
| Native Hawaiian or other Pacific Islander | 0/1 (0) | 0/0 (NA) | 1/1 (100) | NA | 100.0 (-58.7, 100.0) |
| White | 287/308 (93.2) | 296/319 (92.8) | 288/314 (91.7) | -0.4 (-4.5, 3.7) | -1.5 (-5.8, 2.8) |
| Not able to collect | 4/4 (100) | 4/4 (100) | 8/9 (88.9) | 0.0 (-52.3, 52.3) | -11.1 (-44.9, 42.4) |
| Other | 13/14 (92.9) | 9/9 (100) | 8/10 (80.0) | 7.1 (-24.7, 32.2) | -12.9 (-46.2, 16.7) |
| Ethnicity | |||||
| Hispanic or Latino | 53/54 (98.1) | 75/79 (94.9) | 83/89 (93.3) | -3.2 (-10.8, 5.2) | -4.9 (-12.5, 3.6) |
| Not Hispanic or Latino | 266/289 (92.0) | 243/267 (91.0) | 230/255 (90.2) | -1.0 (-5.9, 3.7) | -1.8 (-6.9, 3.0) |
| Not able to collect | 3/4 (75.0) | 3/3 (100) | 2/2 (100) | 25.0 (-43.8, 72.3) | 25.0 (-54.6, 72.8) |
| Not reported | 2/2 (100) | 2/2 (100) | 0/1 (0) | 0.0 (-71.9, 71.9) | -100.0 (-100.0, 31.5) |
| Unknown | 0/0 (NA) | 1/1 (100) | 2/2 (100) | NA | NA |
Source: Adapted from FDA Review
Abbreviations: CI, confidence interval; N, number of patients in treatment arm; n, number of patients with adverse event; NA, not applicable; Ns, total number of patients for each specific subgroup and were assigned to that specific arm
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.