- Approval Id
- f6a9674d94a5242f
- Drug Approval Emc Name
- Rezdiffra 80 mg film-coated tablets
- Drug Name
- Rezdiffra 80 mg film-coated tablets
- Company Name
- Madrigal Pharmaceuticals UK Limited
- Company Address
- c/o Fora, 3rd Floor, 20 Eastbourne Terrace, Paddington, London, W2 6LG
- Company Website
- www.madrigalpharma.co.uk
- Company Medical Info Direct Line
- 0800 031 8910
- Company Medical Info Email
- [email protected]
- Atc Code
- A05BA11
- Legal Category
- Prescription only medicine
- Authorisation Holder
- 7. Marketing authorisation holder Madrigal Pharmaceuticals EU Limited 1 Castlewood Avenue Dublin D06 H685 Ireland
- Authorisation Number
- 8. Marketing authorisation number(s) PL 51531/0002
- Authorisation Date
- 9. Date of first authorisation/renewal of the authorisation 03/06/2026
- Instruction Authorisation Holder
- 7. Marketing authorisation holder Madrigal Pharmaceuticals EU Limited 1 Castlewood Avenue Dublin D06 H685 Ireland
- Instruction Authorisation Number
- 8. Marketing authorisation number(s) PL 51531/0002
- Instruction Authorisation Date
- 9. Date of first authorisation/renewal of the authorisation 03/06/2026
- Instruction Composition
- 2. Qualitative and quantitative composition Each film-coated tablet contains 80 mg of resmetirom. For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- 3. Pharmaceutical form Film-coated tablet (tablet). Yellow, oval film-coated tablets with “P80” debossed on one side and plain on the other side. Approximate tablet dimensions 7.1 mm x 13.5 mm.
- Instruction Clinical Particulars
- 4. Clinical particulars 4.1 Therapeutic indications Rezdiffra is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis (consistent with fibrosis stages F2 to F3). 4.2 Posology and method of administration Posology The posology is based on the patient's body weight (see section
- Instruction Pharmacology
- 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Bile and liver therapy, liver therapy, ATC code: A05BA11. Mechanism of action Resmetirom is a liver-directed partial agonist for the thyroid hormone receptor beta (THR-β). Resmetirom produced 83.8% of the maximum response compared to triiodothyronine (T3), with an EC50 of 0.21 μM in an in vitro functional assay for THR-β activation. The same functional assay for thyroid hormone receptor alpha (THR-α) agonism showed 48.6% efficacy for resmetirom relative to T3, with an EC50 of 3.74 μM. THR-β is the predominant form of THR in the liver. Stimulation of THR-β in the liver improves mitochondrial function and lipid metabolism, and increases fatty acid β-oxidation, thereby reducing lipotoxic liver fat, inflammation and liver fibrosis. Resmetirom's liver directed THR-β agonism is particularly relevant in the treatment of MASH and leads to minimal off-target activity on THR-α in tissues such as heart and bone. Pharmacodynamic effects Liver fat content Resmetirom decreases liver fat content as measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) or FibroScan controlled attenuation parameter (CAP). Reductions in liver fat content by MRI-PDFF were observed at 16 (the first assessment) and 52 weeks of treatment. Reductions in liver fat content by CAP were observed at 52 weeks of treatment. Reductions in lipids Resmetirom reduces blood low density lipoprotein (LDL) cholesterol, apolipoprotein B, lipoprotein (a) and triglyceride levels. Reductions in all lipid endpoints were observed initially after 4 weeks (the first assessment) and sustained at 24 and through 52 weeks of treatment. Prohormone FT4 Decreased concentrations of prohormone FT4 were observed at the first assessment at 4 weeks of treatment. Similar decreases in FT4 were observed during treatment. Sex hormone binding globulin (SHBG) Resmetirom increased concentrations of sex hormone binding globulin (SHBG) at the first assessment at 4 weeks of treatment and at longer durations of treatment; by week 52, SHBG increased from baseline 145% (95% CI: 128, 160%) for 80 mg, 205% (95% CI: 182, 229%) for 100 mg and -0.4% (95% CI: -4, 2%) for placebo. No known adverse reactions were associated with SHBG elevations.. Cardiac electrophysiology At a dose of 200 mg given for 7 days, resmetirom did not prolong the QT interval, PR interval, QRS interval, or alter heart rate in a study in healthy subjects. Clinical efficacy and safety The efficacy of resmetirom was studied in one multicentre, randomised, double-blind, placebo-controlled, clinical study in patients with MASH with liver fibrosis (MAESTRO-NASH). The 54-month outcomes portion of MAESTRO-NASH remains ongoing. The dual primary endpoints of the 52-week analysis were the effects of resmetirom versus placebo on: 1) the percentage of patients with resolution of NASH (ballooning 0, inflammation 0,1) associated with at least a 2-point reduction in NAFLD Activity Score (NAS) and without worsening of fibrosis by liver biopsy, and 2) the histological improvement from baseline demonstrated by at least a 1-point improvement in fibrosis (NASH Clinical Research Network [CRN] system) by liver biopsy with no worsening of NAS (total of three NAS components: ballooning, inflammation and steatosis). Patients with metabolic risk factors were included in MAESTRO-NASH who had a baseline or recent historic liver biopsy showing NASH with a NAS of at least 4 and fibrosis stage 2 or 3. The 52-week assessment included 917 patients with F2 or F3 fibrosis who received resmetirom 80 mg (n=306), resmetirom 100 mg (n=308), or placebo (n=303) once daily, in addition to lifestyle counselling on diet and exercise. Patients were on stable doses of medicinal products for diabetes, dyslipidaemia and hypertension. Patients were stratified by baseline type-2 diabetes status (present/absent) and fibrosis stage. Demographics and baseline disease characteristics were balanced between treatment arms. The mean (SD) age at baseline was 57 (11) years. 25% of patients were older than 65 years, and 2% of patients were 75 years of age or older. Overall, 56% were female, ethnicity was 21% Hispanic, and races included 89% White, 3% Other, 3% Asian and 2% Black. The mean BMI was 36 (7) and mean body weight was 101 (23) kg. The baseline disease and comorbidity characteristics are shown in Table 2. Table 2: Baseline disease and comorbidity characteristics in F2 and F3 patients enrolled in MAESTRO-NASH Overall (N=917) Type 2 diabetes, n (%) 614 (67) Hypertension, n (%) 715 (78) Dyslipidaemia, n (%) 652 (71) Statin use, n (%) 441 (48) Thyroxine use, n (%) 124 (14) FibroScan VCTE (kPa), median (Q1, Q3) 12 (10, 15) FibroScan CAP (dB/m), median (Q1, Q3) 350 (321, 378) MRI-PDFF (% ), median (Q1, Q3) 17 (13, 22) Fibrosis stage F2, n (%) 319 (35) F3, n (%) 583 (64) NAS at Screening ≥ 5, n (%) 770 (84) ELF score (n = 905), median (Q1, Q3) 9.7 (9.2, 10.4) Fib-4 index (n = 915), median (Q1, Q3) 1.3 (1.0, 1.8) Note: Patients who were rescored F4 at baseline were considered F3 for the purposes of stratification and analysis and are included in F3 numbers. The 80 and 100 mg doses of resmetirom achieved both primary endpoints with statistically significant improvement relative to placebo in NASH resolution and fibrosis improvement (by 1 stage) (Table 3). Confidence intervals for other study endpoints were not controlled for multiple determinations. NASH resolution and fibrosis improvement were consistent regardless of age, gender, diabetes status, and baseline fibrosis stage. NASH resolution and fibrosis improvement (combined) and 2-stage reduction in fibrosis also improved with both doses of resmetirom relative to placebo. Table 3: Effect of resmetirom in F2/F3 patients at week 52 on the primary liver biopsy endpoints of MAESTRO-NASH Week 52 Endpoint Resmetirom 80 mg (N=300) Resmetirom 100 mg (N=306) Placebo (N=300) NASH Resolution (%) 26 30 10 % difference vs placebo (95% CI) 16 (11, 22) 21 (15, 26) p-value < 0.0001 < 0.0001 Fibrosis Improvement (%) 27 29 17 % difference vs placebo (95% CI) 9 (4, 15) 12 (6, 18) p-value 0.0017 < 0.0001 Note: Missing data were considered as non-responders. Additionally, 11 patients whose biopsies were delayed outside of the analysis window due to COVID-related issues were excluded. Decreases from baseline in liver enzymes in resmetirom versus placebo-treated patients were observed at week 12 and continued to decline over 1 year (Table 4). Table 4: Mean percent change from baseline to week 48 in liver enzymes in F2-F3 patients – ANCOVA with Placebo-based (-CR) Multiple Imputation (Week 52 Modified Intent-to-Treat Population – F2/F3) Parameter Resmetirom 80 mg N = 305 Resmetirom 100 mg N = 308 Placebo N = 303 ALT (% CFB) -17.2 -22.5 1.0 Relative to placebo (95% CI) -18.2 (-27.0, -9.5) -23.6 (-32.5, - 14.7) AST (% CFB) -13.8 -18.7 3.6 Relative to placebo (95% CI) -17.4 (-25.7, -9.1) -22.2 (-30.7, - 13.8) GGT (% CFB) -21.8 -27.4 5.7 Relative to placebo (95% CI) -27.5 (-3
- Instruction Pharmaceutical Particulars
- 6. Pharmaceutical particulars 6.1 List of excipients Tablet core Microcrystalline cellulose Mannitol Croscarmellose sodium Colloidal anhydrous silica Magnesium stearate Tablet coating Poly(vinyl alcohol) Titanium dioxide (E171) Macrogol Talc Yellow iron oxide (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Store below 30 °C 6.5 Nature and contents of container Rezdiffra film-coated tablets are supplied in PVC/PCTFE blisters with aluminium foil lidding. Pack size of 28 film-coated tablets. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
- Instruction Content
- ## Composition
2. Qualitative and quantitative composition Each film-coated tablet contains 80 mg of resmetirom. For the full list of excipients, see section 6.1.
## Pharmaceutical Form
3. Pharmaceutical form Film-coated tablet (tablet). Yellow, oval film-coated tablets with “P80” debossed on one side and plain on the other side. Approximate tablet dimensions 7.1 mm x 13.5 mm.
## Clinical Particulars
4. Clinical particulars 4.1 Therapeutic indications Rezdiffra is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis (consistent with fibrosis stages F2 to F3). 4.2 Posology and method of administration Posology The posology is based on the patient's body weight (see section
## Pharmacological Properties
5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Bile and liver therapy, liver therapy, ATC code: A05BA11. Mechanism of action Resmetirom is a liver-directed partial agonist for the thyroid hormone receptor beta (THR-β). Resmetirom produced 83.8% of the maximum response compared to triiodothyronine (T3), with an EC50 of 0.21 μM in an in vitro functional assay for THR-β activation. The same functional assay for thyroid hormone receptor alpha (THR-α) agonism showed 48.6% efficacy for resmetirom relative to T3, with an EC50 of 3.74 μM. THR-β is the predominant form of THR in the liver. Stimulation of THR-β in the liver improves mitochondrial function and lipid metabolism, and increases fatty acid β-oxidation, thereby reducing lipotoxic liver fat, inflammation and liver fibrosis. Resmetirom's liver directed THR-β agonism is particularly relevant in the treatment of MASH and leads to minimal off-target activity on THR-α in tissues such as heart and bone. Pharmacodynamic effects Liver fat content Resmetirom decreases liver fat content as measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) or FibroScan controlled attenuation parameter (CAP). Reductions in liver fat content by MRI-PDFF were observed at 16 (the first assessment) and 52 weeks of treatment. Reductions in liver fat content by CAP were observed at 52 weeks of treatment. Reductions in lipids Resmetirom reduces blood low density lipoprotein (LDL) cholesterol, apolipoprotein B, lipoprotein (a) and triglyceride levels. Reductions in all lipid endpoints were observed initially after 4 weeks (the first assessment) and sustained at 24 and through 52 weeks of treatment. Prohormone FT4 Decreased concentrations of prohormone FT4 were observed at the first assessment at 4 weeks of treatment. Similar decreases in FT4 were observed during treatment. Sex hormone binding globulin (SHBG) Resmetirom increased concentrations of sex hormone binding globulin (SHBG) at the first assessment at 4 weeks of treatment and at longer durations of treatment; by week 52, SHBG increased from baseline 145% (95% CI: 128, 160%) for 80 mg, 205% (95% CI: 182, 229%) for 100 mg and -0.4% (95% CI: -4, 2%) for placebo. No known adverse reactions were associated with SHBG elevations.. Cardiac electrophysiology At a dose of 200 mg given for 7 days, resmetirom did not prolong the QT interval, PR interval, QRS interval, or alter heart rate in a study in healthy subjects. Clinical efficacy and safety The efficacy of resmetirom was studied in one multicentre, randomised, double-blind, placebo-controlled, clinical study in patients with MASH with liver fibrosis (MAESTRO-NASH). The 54-month outcomes portion of MAESTRO-NASH remains ongoing. The dual primary endpoints of the 52-week analysis were the effects of resmetirom versus placebo on: 1) the percentage of patients with resolution of NASH (ballooning 0, inflammation 0,1) associated with at least a 2-point reduction in NAFLD Activity Score (NAS) and without worsening of fibrosis by liver biopsy, and 2) the histological improvement from baseline demonstrated by at least a 1-point improvement in fibrosis (NASH Clinical Research Network [CRN] system) by liver biopsy with no worsening of NAS (total of three NAS components: ballooning, inflammation and steatosis). Patients with metabolic risk factors were included in MAESTRO-NASH who had a baseline or recent historic liver biopsy showing NASH with a NAS of at least 4 and fibrosis stage 2 or 3. The 52-week assessment included 917 patients with F2 or F3 fibrosis who received resmetirom 80 mg (n=306), resmetirom 100 mg (n=308), or placebo (n=303) once daily, in addition to lifestyle counselling on diet and exercise. Patients were on stable doses of medicinal products for diabetes, dyslipidaemia and hypertension. Patients were stratified by baseline type-2 diabetes status (present/absent) and fibrosis stage. Demographics and baseline disease characteristics were balanced between treatment arms. The mean (SD) age at baseline was 57 (11) years. 25% of patients were older than 65 years, and 2% of patients were 75 years of age or older. Overall, 56% were female, ethnicity was 21% Hispanic, and races included 89% White, 3% Other, 3% Asian and 2% Black. The mean BMI was 36 (7) and mean body weight was 101 (23) kg. The baseline disease and comorbidity characteristics are shown in Table 2. Table 2: Baseline disease and comorbidity characteristics in F2 and F3 patients enrolled in MAESTRO-NASH Overall (N=917) Type 2 diabetes, n (%) 614 (67) Hypertension, n (%) 715 (78) Dyslipidaemia, n (%) 652 (71) Statin use, n (%) 441 (48) Thyroxine use, n (%) 124 (14) FibroScan VCTE (kPa), median (Q1, Q3) 12 (10, 15) FibroScan CAP (dB/m), median (Q1, Q3) 350 (321, 378) MRI-PDFF (% ), median (Q1, Q3) 17 (13, 22) Fibrosis stage F2, n (%) 319 (35) F3, n (%) 583 (64) NAS at Screening ≥ 5, n (%) 770 (84) ELF score (n = 905), median (Q1, Q3) 9.7 (9.2, 10.4) Fib-4 index (n = 915), median (Q1, Q3) 1.3 (1.0, 1.8) Note: Patients who were rescored F4 at baseline were considered F3 for the purposes of stratification and analysis and are included in F3 numbers. The 80 and 100 mg doses of resmetirom achieved both primary endpoints with statistically significant improvement relative to placebo in NASH resolution and fibrosis improvement (by 1 stage) (Table 3). Confidence intervals for other study endpoints were not controlled for multiple determinations. NASH resolution and fibrosis improvement were consistent regardless of age, gender, diabetes status, and baseline fibrosis stage. NASH resolution and fibrosis improvement (combined) and 2-stage reduction in fibrosis also improved with both doses of resmetirom relative to placebo. Table 3: Effect of resmetirom in F2/F3 patients at week 52 on the primary liver biopsy endpoints of MAESTRO-NASH Week 52 Endpoint Resmetirom 80 mg (N=300) Resmetirom 100 mg (N=306) Placebo (N=300) NASH Resolution (%) 26 30 10 % difference vs placebo (95% CI) 16 (11, 22) 21 (15, 26) p-value < 0.0001 < 0.0001 Fibrosis Improvement (%) 27 29 17 % difference vs placebo (95% CI) 9 (4, 15) 12 (6, 18) p-value 0.0017 < 0.0001 Note: Missing data were considered as non-responders. Additionally, 11 patients whose biopsies were delayed outside of the analysis window due to COVID-related issues were excluded. Decreases from baseline in liver enzymes in resmetirom versus placebo-treated patients were observed at week 12 and continued to decline over 1 year (Table 4). Table 4: Mean percent change from baseline to week 48 in liver enzymes in F2-F3 patients – ANCOVA with Placebo-based (-CR) Multiple Imputation (Week 52 Modified Intent-to-Treat Population – F2/F3) Parameter Resmetirom 80 mg N = 305 Resmetirom 100 mg N = 308 Placebo N = 303 ALT (% CFB) -17.2 -22.5 1.0 Relative to placebo (95% CI) -18.2 (-27.0, -9.5) -23.6 (-32.5, - 14.7) AST (% CFB) -13.8 -18.7 3.6 Relative to placebo (95% CI) -17.4 (-25.7, -9.1) -22.2 (-30.7, - 13.8) GGT (% CFB) -21.8 -27.4 5.7 Relative to placebo (95% CI) -27.5 (-3
## Pharmaceutical Particulars
6. Pharmaceutical particulars 6.1 List of excipients Tablet core Microcrystalline cellulose Mannitol Croscarmellose sodium Colloidal anhydrous silica Magnesium stearate Tablet coating Poly(vinyl alcohol) Titanium dioxide (E171) Macrogol Talc Yellow iron oxide (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Store below 30 °C 6.5 Nature and contents of container Rezdiffra film-coated tablets are supplied in PVC/PCTFE blisters with aluminium foil lidding. Pack size of 28 film-coated tablets. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
