Resmetirom for Nonalcoholic Fatty Liver Disease: A 2023 A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial PDF

nature medicine Article https://doi.org/10.1038/s41591-023-02603-1 Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial Received: 6 March 2023...

nature medicine Article https://doi.org/10.1038/s41591-023-02603-1 Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial Received: 6 March 2023 Stephen A. Harrison 1 , Rebecca Taub2, Guy W. Neff3, K. Jean Lucas4, Dominic Labriola2, Sam E. Moussa5, Naim Alkhouri6 & Mustafa R. Bashir7 Accepted: 20 September 2023 Published online: 16 October 2023 Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with Check for updates no approved treatment. MAESTRO-NAFLD-1 was a 52-week randomized, double-blind, placebo-controlled phase 3 trial evaluating the safety of resmetirom in adults with nonalcoholic fatty liver disease and presumed NASH. Patients were randomized to three double-blind arms (100 mg resmetirom (n = 325), 80 mg resmetirom (n = 327) or placebo (n = 320)) or open-label 100 mg resmetirom (n = 171). The primary end point was incidence of treatment-emergent adverse events (TEAEs) over 52 weeks and key secondary end points were LDL-C, apoB, triglycerides (over 24 weeks), hepatic fat (over 16 and 52 weeks) and liver stiffness (over 52 weeks). Resmetirom was safe and well tolerated. TEAEs occurred in 86.5% (open-label 100 mg resmetirom), 86.1% (100 mg resmetirom), 88.4% (80 mg resmetirom) and 81.8% (placebo) of patients. TEAEs in excess of placebo included diarrhea and nausea at the initiation of treatment. Key secondary end points included least square means difference from placebo at 80 mg, 100 mg resmetirom: LDL-C (−11.1%, −12.6%), apoB (−15.6%, −18.0%), triglycerides (−15.4%, −20.4%), 16-week hepatic fat (−34.9%, −38.6%), (P < 0.0001) and liver stiffness (−1.02, −1.70) and 52-week hepatic fat (−28.8, −33.9). These findings demonstrate resmetirom was safe and well tolerated in adults with presumed NASH, supporting a role for further clinical development. (ClinicalTrials.gov identifier NCT04197479). Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic presence of ≥5% hepatic fat (steatosis) in combination with hepatocyte dysregulation and is commonly identified in individuals with obesity, injury (ballooning) and inflammation9–11. In a subset of patients, NASH type 2 diabetes and dyslipidemia1. Overall, the global prevalence of will further progress to advanced fibrosis and cirrhosis (which can NAFLD is estimated to be approximately 25% (refs. 2–4), with higher necessitate liver transplantation), portal hypertension, hepatocellular prevalence among patients with comorbid conditions such as obesity carcinoma and death4,8. There are currently no approved treatments and type 2 diabetes5,6. In addition, the prevalence of NAFLD is projected for NASH. to increase in subsequent decades with the rising prevalence of obe- At present, a liver biopsy is needed to definitively diagnose sity7,8. In general, 25% of patients with NAFLD have NASH, defined as the NASH; however, liver biopsy is an invasive procedure with associated 1 Pinnacle Clinical Research, San Antonio, TX, USA. 2Madrigal Pharmaceuticals, Conshohocken, PA, USA. 3Covenant Metabolic Specialists, Sarasota, FL, USA. 4Lucas Research, Morehead City, NC, USA. 5University of Arizona for Medical Sciences, Tucson, AZ, USA. 6Arizona Liver Health, Tucson, AZ, USA. 7 Duke University Medical Center, Durham, NC, USA. e-mail: [email protected] Nature Medicine | Volume 29 | November 2023 | 2919–2928 2919 Article https://doi.org/10.1038/s41591-023-02603-1 morbidity. As such, noninvasive tests (biomarkers and/or imaging Access to study drug was impacted by the COVID-19 pandemic, par- techniques) that can replace serial liver biopsies in (1) identifying ticularly in the DB arms where drug kit delays occurred, but not in the patients with NASH and (2) monitoring treatment response (in the OL arm that utilized bottles of tablets. Largely due to COVID-19-related setting of an approved therapy) are urgently needed. Magnetic reso- drug kit delays in the DB arms, 86–88% of DB patients missed study nance imaging-proton density fat fraction (MRI-PDFF) is an accurate visits (inclusive of visits where no study drug was provided) and the imaging technique that quantifies hepatic fat content. A systematic average number of missed monthly visits in the DB arms was 2–3 over review and meta-analysis performed by Stine et al. showed that adults the 52-week treatment period. Only 19% of OL patients had missed with NASH who achieved a ≥30% reduction from baseline in hepatic fat study visits. Compliance was 81.2% in the OL arm and 76.4% across the (measured by MRI-PDFF) had greater odds of achieving NASH reduction three DB arms. The mean number of weeks of exposure to study drug and resolution, suggesting this threshold could be used as a marker for was 47 weeks in the OL 100 mg resmetirom arm, 45 weeks in the DB improvement in NASH12. 100 mg resmetirom arm, 43 weeks in the DB 80 mg resmetirom arm Thyroid hormone receptor (THR)-β is responsible for regulat- and 45 weeks in the placebo arm. Study drug dose adjustments (based ing metabolic pathways in the liver and is frequently impaired in on low free thyroxine (FT4) levels, defined as a ≥30% decrease from NASH13. Patients with NASH have reduced levels of thyroid hormone baseline on consecutive visits to a value of 75 μg were enrolled in the OL 100 mg resmetirom arm (to allow for open-label extension that used higher resmetirom doses of 80 and comparison with patients not on thyroxine). Patients with a diagnosis 100 mg once daily achieved a 50% and 64% relative reduction in hepatic of hypothyroidism on thyroxine doses ≤75 μg were enrolled in the DB fat, respectively15. The potential efficacy and adverse event profile arms until the protocol was amended near the end of the randomiza- of the phase 2 trials supported the selection of 80 and 100 mg res- tion period to allow patients on thyroxine doses >75 μg to enroll in metirom for phase 3 (ref. 15). MAESTRO-NAFLD-1 (NCT04951219) is the DB arms. As such, 44.4% of patients in the OL 100 mg resmetirom one of four phase 3 trials that have been initiated (MAESTRO-NASH arm were on thyroxine at baseline compared to 10.5–11.9% in the DB (NCT03900429), MAESTRO-NAFLD-1, MAESTRO-NAFLD-OLE and arms. Consistent with the higher percentage of patients on thyroxine MAESTRO-NASH-OUTCOMES (NCT05500222)) to support an indica- treatment, a higher percentage of patients in the OL arm were female. tion for the treatment of NASH with liver fibrosis. Common concomitant medications across the four arms were antidia- To increase the overall size of the safety database, MAESTRO- betes drugs (such as glucagon-like peptide-1 (GLP-1) receptor agonists NAFLD-1 was a randomized, DB, placebo-controlled phase 3 trial (RAs), metformin, pioglitazone and sodium/glucose cotransporter-2 to evaluate the safety and tolerability of 80 and 100 mg resmetirom inhibitors) and drugs to manage dyslipidemia (statins, 46%). A greater versus placebo over 52 weeks of treatment in adults with NAFLD proportion of patients in the OL arm were taking GLP-1 RAs (11.7%) and (presumed NASH) diagnosed utilizing noninvasive biomarkers and SGLT2 inhibitors (10.5%) at baseline compared to the three DB arms imaging (as opposed to an invasive diagnostic liver biopsy). Primary, (6.0–9.3% and 4.7–9.3%, respectively). Demographic and baseline key secondary and secondary end points from MAESTRO-NAFLD-1 characteristics of the modified intent-to-treat (mITT) population are reported here. (which included all randomized patients who received ≥1 dose of DB study drug and had a baseline and ≥1 post-baseline measurement) Results are shown in Extended Data Table 1. The demographic and baseline Patient disposition characteristics of the safety and mITT populations were comparable. MAESTRO-NAFLD-1 was conducted between 16 December 2019 and 13 December 2021 at 80 sites in the United States. Overall, 1,988 patients Primary outcome were screened and 1,143 patients were randomized to the trial (Fig. 1). The primary end point, incidence of TEAEs (time frame, up to 52 weeks Overall, 972 patients were randomized to the three DB arms of treatment and 4 weeks of follow-up) not being different between (100 mg resmetirom (n = 325), 80 mg resmetirom (n = 327) or placebo treatment arms was met. In total, 86.1–88.4% of resmetirom-treated (n = 320)) and 171 patients were randomized to the open-label (OL) patients and 81.8% of placebo-treated patients reported a TEAE dur- 100 mg resmetirom arm. One patient in the DB 100 mg resmetirom ing the trial (Table 2). The majority of TEAEs were mild or moderate in arm and two patients in the placebo arm were randomized but did not severity. Seventy patients experienced a serious TEAE. Approximately receive the study drug (as study sites were closed due to COVID-19). 20% of the serious TEAEs were related to either COVID-19 pneumonia As such, 969 patients randomized to DB treatment and 171 patients (n = 8, one patient in the OL arm, two in the DB 100 mg resmetirom arm, randomized to OL 100 mg resmetirom treatment were included in the three in the DB 80 mg resmetirom arm and two in the placebo arm) or a safety population. In total, 77.4% of patients (750 out of 969) across the diagnosis code for COVID-19 (n = 7, 2, 1, 1 and 3 patients, respectively). three DB arms completed the study, whereas 22.6% (219 out of 969) were No specific serious TEAEs were numerically increased in the resmetirom discontinued from the trial. Of the 171 patients randomized to the OL arms compared to placebo. TEAE rates in excess of placebo included 100 mg resmetirom arm, 89.0% (152 out of 171) completed the 52-week mild or moderate diarrhea (23.5–31.2% in the resmetirom arms versus treatment period. The percentage of patients who were discontinued 13.8% in the placebo arm) and nausea (11.9–18.2% versus 7.9%, respec- from the trial did not markedly differ among the three DB arms. Most tively). Diarrhea (or nausea) occurred more frequently in the resmeti- patients discontinued the trial due to patient withdrawal (other than rom arms than the placebo arm in the first 12 weeks of treatment and TEAEs) or were lost to follow-up (119 and 63 patients across the three the incidence was not increased in the resmetirom arms compared to DB arms, respectively). placebo after 12 weeks. The median duration of diarrhea was 15–20 d Nature Medicine | Volume 29 | November 2023 | 2919–2928 2920 Article https://doi.org/10.1038/s41591-023-02603-1 Screen 1,988 845 screen fail Pbo DB 100 mg DB 80 mg DB Open label 100 mg Randomized 320 325 327 171 (2 rand not treated) (1 rand not treated) n = 67 n = 69 n = 24 n = 83 1 sponsor 1 prot dev 10 Pt WD 48 Pt WD 39 Pt WD 32 Pt WD 3 inv Withdrawals 3 inv 3 inv 1 inv 9 LTFU (up to week 56) 23 LTFU 17 LTFU 23 LTFU 2 AE 9 AE 4 AE 10 AE 3 other 2 other Completed 52 weeks 257 (80.3) 250 (76.5) 263 (80.9) 152 (88.9) Fig. 1 | Patient composition. Pbo, placebo; rand, randomized; Pt, patient; WD, withdrew; inv, investigator decision; LFTU, lost to follow-up; AE, adverse event; prot dev, protocol deviation. in the DB resmetirom arms independent of dose. Approximately half arm, the reductions from baseline were observed in Lp(a), −28.4% of the diarrhea TEAEs were described as a single episode, worsening (3.7%), apoCIII −18.1% (3.0%) and apoB −21.3% (2.1%) and LDL-C −22.2% of underlying diarrhea or intermittent diarrhea. Diarrhea and nausea (3.0%) in patients with LDL-C ≥ 100 mg dl−1. Also, reductions were were further evaluated by sex and while the incidence of diarrhea was observed for multiple atherogenic species. For the DB 100 mg arms for similar between sexes, nausea was more common in females than males, remnant-like particle (RLP) cholesterol, −11.9% (2.6%), very low-density including in the placebo arm (Extended Data Table 2). Discontinuation lipoprotein (VLDL) cholesterol, −12.9% (5.3%) and atherogenic lipo- from the study due to TEAEs occurred in 1.2–3.1% of patients in the protein particles LDL, −16.7% (1.7%) and small LDL particles, −17.1% resmetirom arms compared to 1.3% of patients in the placebo arm. A (2.9%) were reduced compared to the placebo arm (all P < 0.0001). single patient died due to presumed cardiac arrest not related to the Data for 80 mg DB and OL are also reported (Extended Data Table 3 study drug in the 4-week follow-up period, during which, no study drug and Supplementary Table 3). had been administered. As a key secondary end point, at week 16 resmetirom treatment showed a relative reduction in hepatic fat compared to placebo treat- Secondary outcomes ment (least squares mean percent change from baseline (95% con- Key secondary end points were achieved for both the DB 100 mg and fidence interval (CI)) for OL 100 mg, −47.8% (−53.8% to −41.8%); DB 80 mg resmetirom arms. At week 24, resmetirom treatment resulted 100 mg, −45.1% (−50.3% to −39.9%); 80 mg, −41.4% (−46.6% to −36.2%); in significant reductions in atherogenic lipid levels from baseline placebo, −6.5% (−11.7% to −1.3%); P < 0.0001 versus placebo for all three compared to placebo treatment (Fig. 2a and Table 3). At 100 mg, sig- comparisons (Fig. 2b and Table 3). The significant relative reduction nificant (P < 0.0001) reductions from baseline relative to placebo were in hepatic fat achieved by week 16 was sustained over 52 weeks with observed in low-density lipoprotein cholesterol (LDL-C), −13.9% (2.0%) continued resmetirom treatment (Fig. 2b and Table 3). As an additional (least squares mean (s.e.m.)), apolipoprotein B; (apoB), −16.5% (1.6%) secondary end point, at week 52 the least squares mean relative reduc- and triglycerides (TGs), −23.4% (5.0%) (baseline TG > 150 mg dl−1). At tion from baseline (95% CI) in hepatic fat was −51.8% (−58.6% to −45.0%) 80 mg, significant (P < 0.0001) reductions from baseline relative to in the OL 100 mg resmetirom arm. Similarly, as a key secondary end placebo were observed in LDL-C, −12.4% (2.0%), apoB, −14.3% (1.6%) point, at week 52 hepatic fat as estimated by continuous attenuation and TG, −18.4% (4.8%) (baseline TG > 150 mg dl−1). In the OL 100 mg parameter (CAP) was reduced (least squares mean percent change from resmetirom arm, the reductions from baseline in LDL-C, −19.4% (2.6%), baseline (95% CI) for OL 100 mg −46.0% (−55.3% to −36.6%); DB 100 mg apoB, −21.3% (2.1%) and TG, −27.5% (4.5%) at week 24 were numerically −42.8% (−33.8% to −15.1%); 80 mg −36.7% (−27.8% to −8.9%); P < 0.0001 greater than those achieved in the DB resmetirom arms (potentially versus placebo for three comparisons (Fig. 2b and Table 3). due to more missed doses of study drug in the DB arms as a result of MRI-PDFF subgroup analyses demonstrated that resmetirom COVID-19-related drug kit delays). Effects achieved at week 24 were treatment reduced hepatic fat from baseline at week 52 in all key patient maintained over 48 weeks with continued treatment (Table 3). subgroups (Extended Data Fig. 1). In particular, weight loss ≥5% in com- Additional lipid end points reported in Table 3 in DB 100 mg, bination with resmetirom treatment or high exposure to resmetirom reductions from baseline relative to placebo at week 24 were observed measured by the sex hormone-binding globulin (SHBG) response as in Lp(a), −19.7% (4.2%) (least squares mean (s.e.m.)), apoCIII −17.6% described previously14 (defined in this study as ≥120% increase from (2.5) and apoB −16.5% (1.6%) and LDL-C −22.0% (2.4%) in patients baseline in SHBG, which corresponds to the upper two tertiles of the with LDL-C ≥ 100 mg dl−1 (P < 0.0001 for all). At 80 mg, significant SHBG response observed with 100 mg resmetirom) was associated with reductions from baseline relative to placebo were observed in Lp(a), greater reduction in hepatic fat. In contrast, weight gain ≥5% or lower −4.8% (4.1) (P = 0.0037), apoCIII −11.5% (2.4%) (P < 0.0001) and apoB exposure to resmetirom (defined as 12 weeks 8 (4.7) 20 (6.2) 16 (4.9) 16 (5.0) Nausea 24 (14.0) 59 (18.2) 39 (11.9) 25 (7.9) Onset ≤12 weeks 12 (7.0) 47 (14.5) 27 (8.3) 15 (4.7) Onset >12 weeks 12 (7.0) 12 (3.7) 12 (3.7) 10 (3.1) Abdominal pain 9 (5.3) 23 (7.1) 14 (4.3) 14 (4.4) COVID-19 21 (12.3) 27 (8.3) 27 (8.3) 27 (8.5) Urinary tract infection 9 (5.3) 20 (6.2) 21 (6.4) 23 (7.2) Arthralgia 16 (9.4) 27 (8.3) 24 (7.3) 21 (6.6) Back pain 7 (4.1) 18 (5.6) 17 (5.2) 14 (4.4) Pain in extremity 5 (2.9) 18 (5.6) 16 (4.9) 16 (5.0) Headache 13 (7.6) 27 (8.3) 22 (6.7) 24 (7.5) Type 2 diabetes 8 (4.7) 21 (6.5) 18 (5.5) 14 (4.4) Fatigue 11 (6.4) 15 (4.6) 21 (6.4) 13 (4.1) GI, gastrointestinal. fat; however, the effect of 80 mg was similar to 100 mg in females and versus 11%) and numerically fewer resmetirom-treated patients had a in patients with ≥120% increase in SHBG. ≥19% increase in MRE (Fig. 2c). In this trial, approximately one-third of randomized patients had Markers of liver injury, additional secondary end points in the a baseline liver stiffness measurement (LSM) via vibration-controlled trial, were improved with resmetirom treatment. Mean baseline liver transient elastography (VCTE) that met prespecified criteria for analysis enzymes were low in this population (mean baseline alanine ami- as a key secondary end point (≥7.2 kPa (which has been shown to notransferase (ALT), ~37 U l−1 (upper limit of normal (ULN) 41 U l−1)). In have a ≥ 90% positive predictive value for moderate fibrosis (F2)) (51 the subgroup of patients with ALT ≥ 30 IU l−1 at baseline, ALT, aspartate patients in the OL arm, 102 in the DB 100 mg resmetirom arm, 83 in aminotransferase (AST) and γ-glutamyl transferase (GGT) levels were the DB 80 mg resmetirom arm and 107 in the placebo arm). Although significantly reduced from baseline in the OL 100 mg and DB 100 mg directionally showing a treatment effect in the DB 100 mg resmetirom and 80 mg resmetirom arms compared to the placebo arm at week 52 arm, the mean change from baseline in VCTE was not significantly dif- (P < 0.05 versus placebo for all) (Table 3). Figure 3 shows mean ALT, ferent between the resmetirom and placebo arms at week 52 (Table 3). AST and GGT levels over the 52-week treatment period in patients A responder analysis was subsequently conducted to reduce the with baseline ALT ≥ 30 IU l−1. SHBG increases reflect the degree of influence of measurement variability. This analysis showed that a THR-β activation in the liver and correlate with resmetirom exposure. numerically greater percentage of patients in the resmetirom arms A time course of the level of SHBG demonstrates that SHBG gradually achieved either a ≥2 kPa reduction from baseline (32–55% in the resme- increased with a plateau at week 12 that seemed to correlate with a tirom arms versus 25% in the placebo arm) or a ≥30% reduction from plateau in ALT/AST reduction at week 24. Lower levels of SHBG were baseline (26–43% versus 21%, respectively) in VCTE at week 52 (Fig. 2c). apparent in the DB arm as compared to the OL 100-mg arm, consistent A similar responder analysis was conducted for liver stiffness measured with the COVID-19-related drug kit delays that occurred in the DB arms. by magnetic resonance elastography (MRE). The percentage of patients At week 52, biomarkers of hepatocyte injury were signifi- who achieved a ≥19% reduction from baseline in MRE at week 52 was cantly improved from baseline among resmetirom-treated versus greater in the resmetirom arms compared to the placebo arm (22–25% placebo-treated patients (Table 3). Cytokeratin-18 (CK-18) fragments Nature Medicine | Volume 29 | November 2023 | 2919–2928 2923 Article https://doi.org/10.1038/s41591-023-02603-1 a LDL-C %CFB ApoB %CFB TGs BL>150 mg dl–1 %CFB 0 –1.3 0 –3 –5 –12.4 –13.9 –14.3 –16.5 –10 –19.4 –18.4 –21.3 –23.4 –27.5 –15 %CFB –20 –25 –30 –35 100 mg OL 100 mg 80 mg Placebo b MRI-PDFF %CFB (W16) MRI-PDFF %CFB (W52) FibroScan CAP 0 –6.0 –7.9 CFB (CAP) or %CFB (MRI-PDFF) –10 –18.3 –36.6 –20 –40.8 –42.5 –42.7 –49.0 –47.7 –48.2 –47.1 –53.6 –30 –40 –50 –60 100 mg OL 100 mg 80 mg Placebo c 60 30 Percentage of paired FibroScans Percentage of paired MREs 50 25 40 20 30 15 55% 24% 20 43% 43% 22% 10 36% 32% 25% 26% 10 21% 5 11% 11% 15% 12% 12% 12% 6% 5% 8% 9% 5% 6% 0 0 Improved Worsened Improved Worsened Improved Worsened (≥2 kPa) (>2 kPa) (≥30%) (>30%) (≥19%) (≥19%) 100 mg OL 100 mg DB 80 mg DB Placebo 100 mg DB & OL 80 mg DB Placebo (n = 40) (n = 75) (n = 47) (n = 73) (n = 88) (n = 60) (n = 44) Fig. 2 | Resmetirom-mediated changes in atherogenic lipid levels and non- placebo n = 268) as well as mean CFB in FibroScan CAP at week 52 (100 mg OL invasive biomarkers. a, Least squares mean %CFB in LDL-C, apoB and TG at week n = 147; 100 mg DB n = 270; 80 mg DB n = 260; placebo n = 260). c, Percentage 24 (100 mg OL n = 169; 100 mg DB n = 314; 80 mg DB n = 320; placebo n = 309). of patients whose VCTE results improved or worsened by either ≥2 kPa or ≥30% TG reported in subgroup with baseline TG levels >150 mg dl−1 (100 mg OL n = 97; from baseline at week 52 (100 mg OL n = 50; 100 mg DB n = 102; 80 mg DB n = 83; 100 mg DB n = 169; 80 mg DB n = 166; placebo n = 163). Data are presented placebo n = 107) (left). Percent of patients whose MRE results improved or as mean ± s.e.m. b, Median %CFB in hepatic fat (measured by MRI-PDFF) at worsened by ≥19% from baseline (right). mITT population. BL, baseline. weeks 16 and week 52 (100 mg OL n = 152; 100 mg DB n = 268; 80 mg DB n = 258; were markedly reduced from baseline with resmetirom treatment metalloproteinase-1 (TIMP-1) was observed. PROs were assessed uti- (−78.4 to −87.2 U l−1) compared to an increase from baseline with lizing the chronic liver disease health questionnaire. There were no placebo (4.15 U l−1; P < 0.01 versus placebo at both doses). Adi- observed differences between the resmetirom and placebo groups ponectin levels were significantly increased from baseline among (data not shown). resmetirom-treated patients relative to placebo-treated patients (0.90–1.12 versus 0.42 μg ml−1, respectively; P < 0.05 versus placebo Exploratory outcome at both doses). Levels of reverse triiodothyronine (rT3) were reduced ALT increases of ≥3 × ULN occurred in fewer patients in the resmetirom from baseline in the resmetirom arms and increased in the placebo arm, arms compared to the placebo arm (0.5% (OL 100 mg resmetirom), resulting in a significant treatment difference at week 52 (P < 0.0001 0.3% (DB 100 mg resmetirom) and 0.6% (DB 80 mg resmetirom) versus versus placebo for both doses) (Table 3). The enhanced liver fibrosis 1.9% (placebo)). As a marker of potential efficacy, liver enzymes were (ELF) score was evaluated in a subset of patients with a baseline score reduced from baseline over time in the resmetirom arms compared of >9.8 (Extended Data Table 4). No significant difference relative to placebo. Safety observations related to potential thyroid axis or to placebo was observed for the total score but a reduction in tissue thyroid hormone effects showed no increase in signs or symptoms of Nature Medicine | Volume 29 | November 2023 | 2919–2928 2924 Article https://doi.org/10.1038/s41591-023-02603-1 Table 3 | Key secondary and secondary end points (mITT population) Resmetirom 100 mg OL Resmetirom 100 mg DB (n = 314) Resmetirom 80 mg DB (n = 320) Placebo DB (n = 169) (n = 309) Least squares 95% CI Least Least squares P value Least Least squares mean P value Least mean %CFB or squares mean difference squares difference (97.5% CI) squares CFB (s.e.m.) mean %CFB (97.5% CI) mean %CFB mean %CFB or CFB or CFB or CFB (s.e.m.) (s.e.m.) (s.e.m.) LDL-C, mg dl−1 Week 24 −19.4 (2.6) −24.5 to −14.3 −13.9 (2.0) −12.6 (−16.7 to −8.6)