REZDIFFRA: A NOVEL THR-BETA

AGONIST FOR METABOLIC

DYSFUNCTION-ASSOCIATED
STEATOHEPATITIS (MASH)
WITH FIBROSIS
Austin Garner, PharmD Candidate 2024
Southwestern Oklahoma State University College of Pharmacy
November 25th 2024
Objectives
■ Interpret the mechanism of action for Rezdiffra.

■ Evaluate clinical efficacy and safety data related to

Rezdiffra.

■ Examine pharmacokinetic information related to

Rezdiffra.

■ Assess the FDA approved indications and dosing for

Rezdiffra.
 Introduction
■ MASH is a severe liver disease associated with
fat accumulation and inflammation within the
liver. The consequence of this disease process
is fibrosis, loss of liver function, and potential
progression to liver cancer.

■ Before FDA approval of Rezdiffra, patients with

non-cirrhotic MASH had extremely limited
treatment options.

■ In March of 2024, Rezdiffra was approved by

the FDA for its potential to reduce liver fibrosis
and improve MASH.
 Mechanism of Action
■ Produced by Madrigal Pharmaceuticals,
Rezdiffra is a first-in-class thyroid hormone
receptor-beta (THR-β) partial agonist that
works directly in the liver. By selectively
targeting liver THR-β, this drug directly
promotes intrahepatic lipid metabolism.

■ Activation of THR-β allows intrahepatic lipid

levels to be greatly reduced, as
demonstrated by clinical trials such as
MAESTRO-NAFLD-1 and MAESTRO-NASH.

Resmetirom. In: Lexicomp Online. Hudson, OH: Wolters Kluwer; 2024. Available at:
https://online.lexi.com. Accessed November 7, 2024.
 MAESTRO-NAFLD-1 Phase
3 Trial
MAESTRO-NAFLD-1 was a 52 week, multi-center,
randomized, placebo-controlled phase 3 trial.
Rezdiffra (resmetirom) was used in conjunction with
diet and exercise.
■ Participants were randomized to receive either
resmetirom 100 mg open label, 100 mg double
blinded, 80 mg double blinded, or placebo
double blinded.
■ The primary endpoint for this study was safety,
particularly related to the number of adverse
events.
■ A key secondary endpoint in this trial was liver
fat reduction.
Harrison, S.A., Taub, R., Neff, G.W. et al.Resmetirom for nonalcoholic fatty liver disease: a randomized,
double-blind, placebo-controlled phase 3 trial. Nat Med 29, 2919–2928 (2023).
https://doi.org/10.1038/s41591-023-02603-1
 MAESTRO-NAFLD-1 Phase
3Primary
TrialOutcome
The primary outcome of this study indicated no
statistically significant difference in the rate of
adverse events when comparing resmetirom to
placebo at 52 weeks (p > 0.05).
Prevalence of Adverse Events
■ Open label 100 mg treatment arm: 86.5%
■ Double blind 100 mg treatment arm: 86.1%
■ Double blind 80 mg treatment arm: 88.4%
■ Placebo treatment arm: 81.8%

Harrison, S.A., Taub, R., Neff, G.W. et al.Resmetirom for nonalcoholic fatty liver disease: a randomized,
double-blind, placebo-controlled phase 3 trial. Nat Med 29, 2919–2928 (2023).
https://doi.org/10.1038/s41591-023-02603-1
 MAESTRO-NAFLD-1 Phase 3 Tria
Secondary Outcomes: Liver Fat Reduction
■ At week 16, a 41.4% reduction in liver fat was seen in
those receiving resmetirom 80 mg in the double
blinded treatment arm (p < 0.0001).
■ A 47.8% reduction in liver fat was shown in those who
received 100 mg in the open label arm, while a 45.1%
reduction was seen in those receiving 100 mg in the
double blinded treatment arm (p < 0.0001).
■ Only a 6.5% reduction occurred with placebo.

These findings were confirmed with non-invasive testing

via MRI-PDFF.

Harrison, S.A., Taub, R., Neff, G.W. et al.Resmetirom for nonalcoholic fatty liver disease: a randomized, double-
blind, placebo-controlled phase 3 trial. Nat Med 29, 2919–2928 (2023). https://doi.org/10.1038/s41591-023-
02603-1
 MAESTRO-NASH Phase
3 Trial
A biopsy confirmed, double blinded, placebo controlled
study conducted in patients with NASH fibrosis (F2-F3).
Patients were randomized to receive either 80 mg or 100 mg
for a total of 52 weeks.
Primary outcomes
• NASH resolution without worsening fibrosis: 30% in
100mg group (p<0.0001), 26% in 80mg group (p <
0.0001), 10% with placebo.
• >1 stage fibrosis improvement: 26% in 100mg group
(p<0.0001), 24% in 80 mg group (p < 0.0002), 14% with
placebo.
Secondary outcomes
• Liver fat reduction from baseline: -42% in 80 mg
treatment arm; -51% in 100 mg treatment arm; -
10% in placebo treatment arm.
Harrison SA, Bedossa P, Guy CD, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver
Fibrosis. N Engl J Med. 2024;390(6):497-509. doi:10.1056/NEJMoa2309000
 Ongoing Clinical Trials
MAESTRO-NASH-OUTCOMES is an ongoing trial being
conducted in patients who have well compensated NASH
cirrhosis (Stage F4). This trial seeks to evaluate the long
term impact of resmetirom on clinical outcomes in this
patient population.
Primary outcome
Prevention of hepatic decompensation events in early
cirrhosis patients.
Secondary outcomes
- Liver stiffness reduction
- Liver enzyme levels
- Lipid markers
 Pharmacokinetics
■ Rezdiffra undergoes hepatic metabolism by enzyme
CYP2C8.
■ Rezdiffra acts as an inhibitor of BCRP/ABCG2 and
OATP1B1/1B3.
■ Time to peak is approximately 4 hours. Steady state
is achieved after 3 to 6 days of repeated dosing.
■ Excretion occurs primarily in the feces (67%) but a
smaller portion is also excreted in the urine (23%).
■ This drug exhibits a high degree of protein binding
(99%).

Resmetirom. In: Lexicomp Online. Hudson, OH: Wolters Kluwer; 2024. Available at:
https://online.lexi.com. Accessed November 7, 2024.
 Pharmacoeconomics
The Wholesale Acquisition Cost (WAC) for Rezdiffra:
■ 60 mg tablets (30 day supply): $3,950
■ 80 mg tablets (30 day supply): $3,950
■ 100 mg tablets (30 day supply): $3,950

Rezdiffra is a LDD (Limited Distribution Drug) and can

only be found in specialty pharmacies. Unfortunately,
GoodRx does not cover this kind of medication.
Medicare Part D plans generally do not cover this
medication.
Commercial insurance patients may be eligible for the
Rezdiffra Copay Savings Card, which can reduce the
cost of the medication to as little as $10.
IBM Micromedex REDBOOK. Resmetirom (Rezdiffra) Pricing Information. IBM Corporation. Accessed
November 8, 2024.
 Dosing and
Administration
Dosage Form:
This drug is available only as an oral tablet.

Recommended Dose:
■ <100 kg: 80 mg by mouth once daily
■ ≥100 kg: 100 mg by mouth once daily

If Rezdiffra is concomitantly taken with a moderate

CPY2C8 inhibitor such as clopidogrel, a dosage
adjustment is required:
■ <100 kg: 60 mg by mouth once daily
■ ≥100 kg: 80 mg by mouth once daily
Madrigal Pharmaceuticals, Inc. Resmetirom prescribing information. 2024. Available at:
https://www.madrigalpharma.com. Accessed November 7, 2024.
 Safety Profile
Common Adverse Reactions
Diarrhea, nausea, and dermatologic reactions such as
itching or erythema are common side effects. In clinical
trials, these adverse events were often detected in early
treatment and often lasted no longer than 3 to 4 weeks in
duration.
Serious Risks
■ Hepatotoxicity: Monitor liver enzymes, discontinue if
significant elevations in liver enzymes are observed.
■ Gallbladder Events: Risk for cholelithiasis and
cholecystitis requires close monitoring.
■ Drug Interactions: CYP2C8 substrates and inhibitors
impact resmetirom levels and efficacy, with dosage
adjustments recommended.

Madrigal Pharmaceuticals, Inc. Resmetirom prescribing information. 2024. Available at:

https://www.madrigalpharma.com. Accessed November 7, 2024.
 Limitations of Use
This medication should be avoided in patients with
decompensated cirrhosis (consistent with moderate
to severe hepatic impairment, Child-Pugh class B or
C).
Avoid use with strong CYP2C8 inhibitors such as
gemfibrozil.
Avoid use with OATP1B3 or OATP1B1 inhibitors such
as cyclosporine.

Madrigal Pharmaceuticals, Inc. Resmetirom prescribing information. 2024. Available at:

https://www.madrigalpharma.com. Accessed November 7, 2024.
Place in Therapy
Advantages Over Standard Care
This drug utilizes a unique mechanism which
targets underlying disease processes, offering long-
term benefits in the management of this condition.

Guideline Positioning
Rezdiffra serves as a first-in-class option for NASH
with liver fibrosis stages F2-F3, suitable for those
without decompensated cirrhosis. Pending studies
will assess the application of this medication in
those who have well compensated NASH cirrhosis
(Stage F4).
Counseling and Monitoring
Parameters
Patient Counseling
Patients should be aware of potential GI
disturbances and signs of hepatotoxicity (dark
urine, jaundice, clay-colored stools), as well as signs
of gallbladder problems (steady gripping or
gnawing pain in the RUQ).
If the patient is concomitantly on a statin, they may
be more prone to statin related side effects such as
myalgia, elevated LFTs, and rhabdomyolysis.
Monitoring
Regular liver enzyme and gallbladder assessments
are required to detect adverse effects early.
Key Takeaways
■ Rezdiffra is a breakthrough therapy that
addresses an unmet need in MASH and MASLD
with fibrosis, offering a novel approach through
THR-β receptor targeting.
■ Monitoring is essential for safety. Monitor for
potential liver, gallbladder, GI issues, and drug
interactions.
■ Rezdiffra may reshape treatment for MASH and
MASLD if ongoing confirmatory trials such as
MAESTRO-NASH-OUTCOMES show sustained
benefits.
Questions?
REZDIFFRA: A NOVEL THR-BETA
AGONIST FOR METABOLIC
DYSFUNCTION-ASSOCIATED
STEATOHEPATITIS (MASH)
WITH FIBROSIS
Austin Garner, PharmD Candidate 2024
Southwestern Oklahoma State University College of Pharmacy
November 25th 2024