Discussion
obesity, NAFLD, nausea, death, diarrhea, fibrosis, hyperthyroidism, NASH, liver injury
OBESITY, HYPERTENSION, DISEASE, FIBROSIS, HYPERTHYROIDISM, HYPOTHYROIDISM, TYPE 2 DIABETES, DYSLIPIDEMIA
There are currently no approved pharmacological therapies for NASH. Rather, management focuses on lifestyle modification, including diet and exercise and treatment of comorbidities such as obesity, type 2 diabetes and dyslipidemia. In addition, NASH is a chronic condition which may require lifelong therapy to slow or prevent progression of the disease. The blinded, placebo-controlled data from the 52-week MAESTRO-NAFLD-1 trial reinforce the safety data reported from the 36-week resmetirom phase 2 NASH trial but in a larger population over a longer treatment period.Resmetirom was well tolerated at both 80 and 100 mg once-daily doses over 52 weeks of treatment in this trial. There were no increases in serious TEAEs or notable imbalances in specific serious TEAEs in the resmetirom arms compared to placebo. Consistent with previous data, excess TEAEs were mostly gastrointestinal in nature (diarrhea and nausea) and characterized as mild or moderate at the initiation of resmetirom treatmentIn patients with NASH, THR-β signaling within the liver is diminished, impacting lipid metabolism, fatty acid oxidation and energy production, potentially resulting in worsening NASH and liver fibrosisWhile resmetirom was specifically designed to target the liver to correct the dysfunctional THR-β signaling in patients with NASH, it is critical to ensure that resmetirom does not affect the more widely expressed THR-α receptor, which is responsible for thyroid hormone activity in the heart and bone. No signs or symptoms related to systemic hyperthyroidism or hypothyroidism, or central thyroid axis changes were noted. As shown previously, no change in heart rate was observedCV disease is the most common cause of death in patients with NASH, thus the CV effect of potential NASH therapies is to be consideredResmetirom reduced hepatic fat from baseline compared to placebo when assessed by either MRI-PDFF or CAP. The 100-mg resmetirom dose showed consistently greater reductions in hepatic fat (measured by MRI-PDFF) than 80 mg; however, patients who achieved a target level of SHBG increase (≥120% increase from baseline) on 80 or 100 mg resmetirom showed a similar reduction in hepatic fat. In the previous phase 2 trial, an MRI-PDFF reduction of ≥30% or ≥50% by resmetirom was shown to be significantly related to the magnitude of NASH reduction, including all components of NASH and fibrosis reductionThe limited number of patients who had a baseline FibroScan VCTE LSM that met the criteria for analysis precluded the ability to evaluate the effect of resmetirom on fibrosis in this patient population; however, responder analyses suggested fibrosis was improved from baseline by week 52 in the resmetirom arms compared to the placebo arm (based on reduction in either FibroScan VCTE LSM or MRE). In support of a potential improvement in fibrosis, multiple liver injury biomarkers, such as TIMP-1 (a component of the ELF score), CK-18 and adiponectin, were significantly improved compared to placebo after 52 weeks of resmetirom treatment.Limitations of the MAESTRO-NAFLD-1 trial include the impact of COVID-19-related dose interruptions on the evaluation of safety and efficacy in the DB arms. Another limitation was the early fibrosis stage of patients, which restricted evaluation of the effect of resmetirom on noninvasive measures of fibrosis, particularly VCTE and ELF score and the inability for noninvasive testing to definitively stage the disease in these patients; however, from the perspective of safety (primary end point of the study), MAESTRO-NAFLD-1 evaluated a high-risk population with significant comorbidities (almost half with type 2 diabetes; the majority with hypertension, obesity and high CV risk).In conclusion, resmetirom did not produce a difference in TEAEs relative to placebo over 52 weeks of treatment. The positive results from MAESTRO-NAFLD-1 are supportive of resmetirom’s safety and tolerability profile in patients with NAFLD.