{"id":49407,"date":"2023-05-19T17:14:02","date_gmt":"2023-05-19T16:14:02","guid":{"rendered":"https:\/\/www.touchendocrinology.com\/?p=49407"},"modified":"2023-06-02T16:30:59","modified_gmt":"2023-06-02T15:30:59","slug":"resmetirom-an-orally-administered-small-molecule-liver-directed-%ce%b2-selective-thr-agonist-for-the-treatment-of-non-alcoholic-fatty-liver-disease-and-non-alcoholic-steatohepatitis","status":"publish","type":"post","link":"https:\/\/www.touchendocrinology.com\/liver-disorders\/journal-articles\/resmetirom-an-orally-administered-small-molecule-liver-directed-%ce%b2-selective-thr-agonist-for-the-treatment-of-non-alcoholic-fatty-liver-disease-and-non-alcoholic-steatohepatitis\/","title":{"rendered":"Resmetirom: An Orally Administered, Small-molecule, Liver-directed, \u03b2-selective THR Agonist for the Treatment of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis"},"content":{"rendered":"

Non–<\/span>alcoholic fatty liver disease (NAFLD<\/span>) encompasses a spectrum of fatty liver diseases<\/span>, including non–<\/span>alcoholic fatty liver<\/span><\/span>\u00a0(NAFL)\u00a0<\/span>and non–<\/span>alcoholic steatohepatitis (NASH<\/span>)<\/sup>.1<\/sup><\/span>\u00a0NAFLD is associated with\u00a0<\/span>metabolic\u00a0<\/span>disorders<\/span>,<\/span>\u00a0including obesity, hypertension, dyslipida<\/span>emia, type\u00a02<\/span><\/span>\u00a0diabetes mellitus (T2DM), hypothyroidism and metabolic syndrome.2<\/sup><\/span>\u00a0The diagnosis of NAFLD requires\u00a0<\/span>\u2265<\/span><\/span>5%<\/span>\u00a0histologic or imaging evidence of hepatic steatosis,<\/span>\u00a0<\/span>with\u00a0<\/span>exclusion of secondary causes of\u00a0<\/span>hepatic steatosis<\/span>, such as significant alcohol consumption, hereditary disorders and steatogenic medications.1<\/sup><\/span>\u00a0NASH, the more severe and progressive form of\u00a0the\u00a0<\/span>disease, is characterized by inflammation and hepatocyte injury (ballooning) with or without hepatic fibrosis<\/sup>.1<\/sup><\/span><\/p>\n

Our understanding of the natural history of NAFLD\u00a0and\u00a0<\/span>NASH continues to evolve. In a seminal paired liver biopsy study with a\u00a0mean <\/span>follow-up of\u00a013.7<\/span><\/span>\u00a0years<\/span>,<\/span>\u00a0Ekstedt\u00a0et al.<\/span>\u00a0conducted a biopsy study\u00a0<\/span>found\u00a0<\/span>that\u00a016<\/span>%<\/span>\u00a0of patients\u00a0with NAFLD<\/span>\u00a0showed improvement in<\/span>\u00a0fibrosis<\/span>, 43<\/span>%<\/span>\u00a0remained<\/span>\u00a0stable,\u00a041<\/span>%<\/span>\u00a0showed\u00a0<\/span>fibrosis progression and 5<\/span>% <\/span>developed <\/span><\/span>cirrhosis-related complications, thus\u00a0providing relevant insight into the natural history of NASH with no intervention<\/span><\/span><\/span><\/span>.3 <\/sup><\/span>NASH is a heterogenous disease,\u00a0so\u00a0<\/span>multiple factors,<\/span>\u00a0including genetic determinants, environmental factors and comorbidities,<\/span>\u00a0interact\u00a0<\/span>to promote fibrosis progression in specific individuals<\/span><\/span>.<\/span>\u00a0Ultimately, fibrosis is the most important predictor of clinical outcomes4<\/sup><\/span>\u00a0and thus represents an important endpoint in clinical trials,<\/span>\u00a0while longer-term follow-up can be done to assess clinical outcomes.<\/p>\n

The global prevalence of NAFLD is estimated to be 25<\/span>%, with\u00a0the highest prev<\/span><\/span>alence in the Middle East and South America and the lowest in Africa.<\/span><\/span><\/span><\/span>5<\/sup><\/span>\u00a0<\/span><\/span>It\u00a0<\/span><\/span><\/span>is thought to affect\u00a0<\/span>55.5<\/span><\/span><\/span><\/span>%\u00a0<\/span><\/span><\/span>of individuals<\/span>\u00a0with T2DM6<\/sup><\/span>\u00a0and\u00a0<\/span>70<\/span>\u2013<\/span>80<\/span>%<\/span>\u00a0of\u00a0<\/span>patients with obesity\u00a0<\/span>worldwide<\/span>.7<\/sup><\/span>\u00a0The global prevalence of NASH is about\u00a05<\/span>%,<\/span><\/span>\u00a0and among those with T2DM,<\/span>\u00a0the prevalence is estimated at 37.3<\/span>%6<\/sup><\/span>\u00a0and 33.5% among individuals who are <\/span>overweight or <\/span>obese.8<\/sup><\/span>\u00a0In\u00a0<\/span>USA<\/span><\/span>North America<\/span>, the prevalence of\u00a0<\/span>NAFLD is estimated to be about\u00a02<\/span>4.13<\/span>%<\/span>\u00a0<\/span>in the adult population,<\/span>\u00a0while N<\/span>ASH is estimated to affect\u00a05<\/span>\u2013<\/span>6<\/span>%<\/span>\u00a0of adults<\/span>.5,9,10<\/sup><\/span>\u00a0B<\/span>ased on data from the Scientific Registry of Transplant Recipients (2002\u2212<\/span>2019), NASH\u00a0was\u00a0<\/span>the leading cause\u00a0of\u00a0<\/span>liver transplantation in\u00a0women<\/span> and the second most common indication overall in waitlisted transplant candidates without hepatocellular carcinoma<\/span><\/span>\u00a0in the USA<\/span><\/span>.11<\/sup><\/span>\u00a0Markov model<\/span>ling suggests that by 2030, <\/span><\/span>approximately\u00a0100.9<\/span><\/span>\u00a0million<\/span>\u00a0people\u00a0<\/span>will have NAFLD, <\/span>and 27.0<\/span><\/span>\u00a0million<\/span>\u00a0people\u00a0<\/span>will have NASH with varying stages of fibrosis.9<\/sup><\/span>\u00a0The latter<\/span>\u00a0represents a\u00a063<\/span>%<\/span>\u00a0increase\u00a0in NASH cases <\/span>from\u00a02015<\/span>. Of those with NASH,\u00a0<\/span>14<\/span>\u00a0million<\/span><\/span>\u00a0are projected to have\u00a0a\u00a0<\/span>fibrosis\u00a0score of F2<\/span>\u00a0or higher (i.e. moderate-to-high fibrosis),<\/span> which\u00a0<\/span><\/span>may represent the eligible population for treatment should a drug be approved for therapy.9<\/sup><\/span>\u00a0Despite the increasing prevalence of NASH with\u00a0the increase <\/span><\/span>in<\/span>\u00a0obesity,10 <\/sup><\/span>no treatment has been\u00a0<\/span>approved\u00a0by the\u00a0<\/span>European Medicines Agency<\/span><\/span>\u00a0or\u00a0the\u00a0<\/span>US\u00a0<\/span>Food and Drug Administration<\/span>\u00a0(FDA<\/span>).<\/p>\n

Lipotoxicity as a key driver in the pathogenesis of\u00a0non–<\/span>alcoholic steatohepatitis<\/span><\/span><\/span><\/h1>\n

The pathogenesis of hepatic steatosis is extremely complex but is thought to be conceptionally driven by\u00a0the\u00a0<\/span>excess delivery<\/span>\u00a0of free fatty acids to the liver,<\/span>\u00a0coupled\u00a0with<\/span>\u00a0increased\u00a0de novo <\/em>lipogenesis<\/span><\/span>\u00a0fuell<\/span>ed\u00a0with<\/span> excess carbohydrates, particularly fructose.12,13<\/sup><\/span> The two major fates of fatty acids in hepatocytes are mitochondrial \u03b2<\/span>-oxidation and re-esterification to form triglycerides<\/span>.13 <\/sup><\/span>Triglycerides<\/span>\u00a0can be exported into the blood as\u00a0very-low-density lipoproteins<\/span><\/span>\u00a0or stored in lipid droplets.14<\/sup><\/span>\u00a0Lipid–<\/span>droplet triglyceride undergoes regulated lipolysis to release fatty acids back into the hepatocyte<\/span>\u00a0<\/span>free fatty acid<\/span>\u00a0pool.14<\/sup><\/span>\u00a0When the disposal of fatty acids through\u00a0\u03b2<\/span>-oxidation or\u00a0the\u00a0<\/span>formation of triglyceride is overwhelmed, fatty acids can contribute to the formation of lipotoxic species that lead to\u00a0endoplasmic reticulum<\/span>\u00a0<\/span>stress, oxidant stress and inflammasome activation.14<\/sup><\/span>\u00a0Insulin resistance and hyperinsulina<\/span>emia further fuel lipid accumulation by not only diverting glucose from glycogen synthesis to\u00a0de novo<\/em>\u00a0lipogenesis\u00a0<\/span>in the liver but also impacting peripheral lipolytic pathways<\/span><\/span><\/span>.13<\/sup><\/span><\/p>\n

When the hepatocytes<\/span>‘<\/span>\u00a0ability to handle this stress is overwhelmed, hepatocyte injury and apoptosis result in the recruitment and activation of inflammatory cells and\u00a0the\u00a0<\/span>activation of hepatic stellate cells, which are the predominant cellular source of collagen\/fibrosis in response to any chronic liver injury.15<\/sup><\/span>\u00a0The activation of these repair pathways moves\u00a0diagnosis<\/span>\u00a0from\u00a0<\/span>simple<\/span>\u00a0steatosis (NAFL<\/span>)<\/span>\u00a0to<\/span>\u00a0the\u00a0the\u00a0<\/span>more active progressive form of\u00a0NAFLD,\u00a0<\/span>steatohepatitis (NASH<\/span>).<\/span>15<\/sup><\/span><\/p>\n

In its quiescent state, the hepatic stellate cell is\u00a0v<\/span>itamin<\/span>\u00a0<\/span>rich\u00a0and<\/span>\u00a0<\/span>produces predominantly type IV collagen. With injury, it undergoes phenotypic changes,<\/span> including increased proliferation and<\/span>\u00a0contractility and a shift towards <\/span>producing type I and III collagens,\u00a0which are\u00a0<\/span>characteristic of the cirrhotic liver.16<\/sup><\/span>\u00a0<\/span>Progressive fibrosis is often defined histologically on a scale ranging from F0 to F4,<\/span>\u00a0as shown in\u00a0Table 1<\/span><\/em>.<\/span>15<\/sup><\/span><\/span>\u00a0<\/span>As fibrosis is the most important predictor of clinical outcomes,<\/span>17,18<\/sup><\/span>\u00a0<\/span>improvement in fibrosis has become the most important surrogate endpoint in NASH clinical trials while awaiting longer–<\/span>term follow-up for clinical outcomes.<\/p>\n

\"\"<\/p>\n


\n<\/span><\/span>In the USA, a<\/span>pproximately\u00a0<\/span><\/span>20<\/span>%<\/span>\u00a0of patients with NAFLD have disease progression to NASH,<\/span>\u00a0and up to\u00a020<\/span>%<\/span>\u00a0of patients with NASH may develop cirrhosis within their lifetime<\/span>\u00a0(Figure 1<\/span><\/em>).19<\/sup><\/span>\u00a0While the most common cause of death in patients with NASH is cardiovascular disease,20<\/sup><\/span>\u00a0the risk of liver-related mortality increases exponentially with fibrosis stage\u00a0increase<\/span>,17<\/sup><\/span><\/span>\u00a0and liver fibrosis is the most important predictor of liver-related mortality in\u00a0patients with <\/span>NAFLD.18<\/sup><\/span> Patients with advanced fibrosis are at an increased risk of morbidity and mortality due to the<\/span>\u00a0<\/span>disease\u00a0progressing\u00a0<\/span>to liver failure, cirrhosis and hepatocellular carcinoma<\/span>.15,17,18<\/sup><\/span>\u00a0In addition to obesity and T2DM, other conditions associated with NAFLD include dyslipida<\/span>emia, polycystic ovary syndrome, metabolic syndrome, obstructive sleep apno<\/span>ea and endocrine disorders<\/span>\u00a0including hypogonadism, hypopituitarism and hypothyroidism<\/sup>.1<\/sup><\/span>\u00a0This review will focus on the role of thyroid hormone signal<\/span>ling in NASH pathogenesis and the potential role of\u00a0thyroid hormone receptor (THR)<\/span>–\u03b2<\/span> agonists as a treatment strategy.<\/p>\n

\"\"<\/h1>\n

Thyroid hormone-mediated regulation of lipid metabolism and mitochondrial activity in the context of <\/span>non–<\/span>alcoholic fatty liver disease<\/span><\/span>\/non–<\/span>alcoholic steatohepatitis<\/span><\/span><\/span><\/h1>\n

Low serum thyroid hormone levels are associated with\u00a0non–<\/span>alcoholic fatty liver disease<\/span><\/span><\/h2>\n

<\/span>The hypothalamus produces\u00a0t<\/span>hyroid-r<\/span>eleasing\u00a0h<\/span>ormone<\/span>,<\/span>\u00a0which stimulates\u00a0the<\/span>\u00a0production\u00a0of\u00a0thyroid-stimulating hormone<\/span>\u00a0(TSH)\u00a0<\/span><\/span>from the pituitary gland.21<\/sup><\/span>\u00a0TSH promotes\u00a0the\u00a0<\/span>secretion of prohormone\u00a0<\/span>thyroxine (T4)\u00a0<\/span>and triiodothyronine (T3)\u00a0<\/span><\/span>from the thyr<\/span>oid gland.\u00a0T3\u00a0<\/span><\/span>binds to the\u00a0<\/span><\/span>THR<\/span>–<\/span>\u03b1 (mainly in\u00a0the\u00a0<\/span>heart and bone) and\u00a0–<\/span>\u03b2<\/span> (mainly in the liver) to regulate gene transcription. Population studies have shown associations between NAFLD and overt hypothyroidism, subclinical hypothyroidism and low thyroid hormone in the normal range.22\u201325 <\/sup><\/span>Patients with higher baseline TSH levels and no evidence of liver disease were more likely to develop NAFLD.26<\/sup><\/span>\u00a0In addition, the prevalence of NAFLD was\u00a0found to significantly\u00a0<\/span>increase<\/span>\u00a0as serum TSH level increased,\u00a0even<\/span>\u00a0after adjusting<\/span>\u00a0for age, gender and smoking status.23 <\/sup><\/span>Moreover, a recent systematic review and meta-analysis by Mantovani et al. <\/span><\/span>found <\/span>hypothyroidism to be significantly associated with the presence and severity of NAFLD.27<\/sup><\/span> Given the association between\u00a0<\/span>hypothyroidism and NAFLD, Bruinstroop\u00a0et al.<\/span> treated with\u00a0<\/span>T4\u00a0<\/span>20 Asian<\/span>\u00a0men<\/span>\u00a0who have normal thyroid gland function with\u00a0<\/span>T2<\/span>DM, euthyroidism<\/span>, hepatic steatosis on ultrasound and\u00a0alanine aminotransferase <\/span><\/span>levels\u00a0less than three\u00a0<\/span><\/span>times<\/span><\/span>\u00a0the upper limit of normalT4<\/span>;<\/span> dosing was titrated to achieve TSH levels 0.34<\/span><\/span><\/span><\/span><\/span>\u22121<\/span><\/span>.70<\/span> mIU\/L,<\/span>\u00a0<\/span>as<\/span>\u00a0the lowest prevalence of NAFLD was seen in those with TSH<\/span><<\/span>1.70\u00a0<\/span>mIU\/L<\/span><\/span><\/span>.28<\/sup><\/span>\u00a0Patients\u00a0<\/span>were then treated with\u00a0a\u00a0<\/span>maintenance dose\u00a0of\u00a0<\/span>thy<\/span>roxine for\u00a016<\/span>\u00a0weeks<\/span>. Reduction in hepatic steatosis was assessed using<\/span>\u00a0magnetic resonance imaging-derived proton density fat fraction (<\/span><\/span>MRI-PDFF)<\/span>. Overall, a\u00a0<\/span>12<\/span>%<\/span>\u00a0decrease in\u00a0intra<\/span>hepatic\u00a0<\/span>lipid content\u00a0<\/span>was observed, <\/span>with a\u00a023<\/span>%<\/span>\u00a0reduction in those over the age of 50\u00a0years<\/span>. However, in patients with subclinical hypothyroidism or euthyroidism, the beneficial effects of longer treatment with<\/span>\u00a0thyroid hormone<\/span>\u00a0<\/span><\/span>would need to be weighed against long-term clinical adverse effects,<\/span>\u00a0such as atrial tachycardia, arrhythmias and loss of bone density through\u00a0the effect of<\/span><\/span>\u00a0<\/span>THR-\u03b1<\/span><\/span>. As THR–<\/span>\u03b2<\/span>\u00a0is the predominant\u00a0iso<\/span>form in the liver, specific targeting may be a better approach.<\/p>\n

The<\/span>\u00a0effect\u00a0of thyroid hormones\u00a0<\/span>on autophagy, mitophagy, mitochondrial biogenesis and\u00a0\u03b2<\/span>-oxidation<\/h2>\n

Autophagy is a normal physiologic<\/span>\u00a0metabolic process wherein a cell consumes its own redundant or damaged organelles\u00a0to fuel<\/span>\u00a0regeneration of newer<\/span>\u00a0healthier organelles. T3<\/span>\u00a0<\/span><\/span>induces autophagy in the hepatoma cell line HepG2 in a dose-dependent manner and specifically promotes lipophagy,<\/span>\u00a0resulting in the delivery of additional internal free fatty acids to the mitochondria for\u00a0\u03b2<\/span>–<\/span>oxidation.29<\/sup><\/span> In addition, <\/span>T3 <\/span><\/span>promotes <\/span>mitochondrial oxidation due to\u00a0<\/span>a combination of mitophagy and mitochondrial biogenesis.30<\/sup><\/span>\u00a0Taken together, these results\u00a0show\u00a0<\/span>that\u00a0thyroid hormones<\/span>\u00a0can regulate lipid homeostasis via autophagy and help to explain how\u00a0thyroid hormones<\/span>\u00a0increase oxidative metabolism through effects on mitochondrial turnover and activity.<\/p>\n

Intrahepatic hypothyroidism as a driver of\u00a0non–<\/span>alcoholic steatohepatitis<\/span><\/h2>\n

In a mouse NASH model where mice were fed a Western diet with fructose for\u00a016<\/span>\u00a0weeks<\/span>, increased steatosis, inflammation and fibrosis were associated with a statistically significant decrease in intrahepatic\u00a0T4\u00a0<\/span>and\u00a0T3<\/span><\/span>.31<\/sup><\/span>\u00a0In addition, in a dietary mouse model of NASH, administration\u00a0of thyroid hormones\u00a0<\/span>decreased hepatic triglyceride content\u00a0(3.19\u00a0<\/span><\/span><\/span>\u00b1\u00a0<\/span>0<\/span>.68\u00a0mM\/g liver <\/span>versus <\/span>8.04\u00a0\u00b1 <\/span>0<\/span>.42\u00a0mM\/g<\/span>\u00a0liver) and hydroxyproline\u00a0(1.44<\/span><\/span>\u00a0\u00b1\u00a0<\/span>0<\/span>.07 mg\/g liver <\/span>versus<\/span>\u00a02.58\u00a0<\/span>\u00b1\u00a0<\/span>0<\/span>.30\u00a0mg\/g<\/span>\u00a0liver) compared with mice with untreated NASH.32<\/sup><\/span><\/span>\u00a0Moreover,\u00a0thyroid hormones\u00a0<\/span>restored autophagy and mitochondrial biogenesis to increase\u00a0\u03b2<\/span>-oxidation of fatty acids and reduced lipotoxicity, oxidative stress, hepatic inflammation and fibrosis.32<\/sup><\/span><\/p>\n

In the liver, deiodinase type\u00a01\u00a0(DIO1)<\/span><\/span><\/span>\u00a0converts the prohormone\u00a0T4\u00a0<\/span>to the bioactive hormone T3. Interestingly<\/span>,\u00a0in\u00a0<\/span>a model of\u00a0<\/span>early NASH<\/span>,\u00a0<\/span><\/span>DIO1<\/span>\u00a0levels and activity are increased suggesting\u00a0that there<\/span>\u00a0<\/span>is a<\/span>\u00a0<\/span>compensatory increase to handle excess lipids.31<\/sup><\/span>\u00a0However, low\u00a0<\/span><\/span>DIO1\u00a0<\/span>levels and activity have<\/span>\u00a0been observed in humans and rodents with advanced NASH,<\/span>33<\/sup><\/span>\u00a0and\u00a0<\/span><\/span>DIO1<\/span>\u00a0knockdown leads to increased intrahepatic lipid content.31<\/sup><\/span><\/p>\n

At the cellular level,\u00a0<\/span>in\u00a0both rodent and human\u00a0<\/span>healthy\u00a0<\/span>livers<\/span>,\u00a0<\/span>hepatocytes strongly expressed\u00a0<\/span>DIO<\/span>1<\/span><\/span>\u00a0and stromal cells weakly expressed DIO<\/span>3.33<\/sup><\/span>\u00a0Very little DIO<\/span>1\u00a0was<\/span>\u00a0detected in other non-parenchymal cells of the liver. During injury, hepatocyte expression of DIO<\/span>1 decreased, whereas stromal expression of DIO<\/span>3 increased, particularly in myofibroblasts.33<\/sup><\/span>\u00a0In patients, this was\u00a0also\u00a0<\/span>reflected by increased serum reverse T3 (<\/span>rT3)<\/span>. Moreover, the decreases in the free T3 to rT3 and free T4 to rT3 ratios distinguished advanced from mild fibrosis, even in individuals with similar serum levels of TSH and free T4.33<\/sup><\/span>\u00a0Therefore, it is thought that<\/span>\u00a0with chronic liver injury, intrahepatic thyroid hormone signall<\/span>ing\u00a0may be impaired; this impairment would <\/span>decrease <\/span>conversion of T4 by DIO1 to active T3 and increase conversion of T4 by DIO3 to inactive rT3, leading to the\u00a0<\/span>accumulation of lipotoxic species, stimulating a cycle of repetitive liver injury.33<\/sup><\/span>\u00a0Taken together, these findings<\/span>\u00a0suggest\u00a0that\u00a0<\/span>intrahepatic hypothyroidism may be a driver of NASH pathogenesis (Figure 2<\/span><\/em>).<\/p>\n

\"\"<\/p>\n

Specific\u00a0r<\/span>ole of\u00a0thyroid hormone receptor<\/span>–\u03b2<\/span>\u00a0in\u00a0h<\/span>epatic\u00a0l<\/span>ipid\u00a0m<\/span>etabolism<\/h2>\n

Hepatocytes\u00a0highly express\u00a0<\/span><\/span><\/span>THR-\u03b2<\/span>,<\/span>\u00a0which is responsible for\u00a0<\/span>regulating\u00a0<\/span>metabolic pathways that are impaired in NAFLD and NASH.34<\/sup><\/span>\u00a0Most hepatic fat is derived from free fatty acids released by adipocytes. In NASH,\u00a0\u03b2<\/span>-oxidation of hepatic lipids is decreased, resulting in lipotoxicity.35<\/sup><\/span>\u00a0Animal studies have shown that\u00a0the<\/span>\u00a0activation of THR-\u03b2<\/span>\u00a0plays an important role in reducing triglycerides\u00a0<\/span>and cholesterol.33,36 <\/sup><\/span>In cultured Hep<\/span>G2\u2013<\/span>TH<\/span>R–<\/span>\u03b2<\/span>\u00a0cells\u00a0of a mouse model<\/span>,\u00a0thyroid hormone\u00a0<\/span>treatment increased mitochondrial respiration and fatty acid oxidation under basal and\u00a0p<\/span>almitic\u00a0a<\/span>cid<\/span><\/span>-treated conditions\u00a0and<\/span>\u00a0decreased lipopolysaccharides and\u00a0palmitic acid<\/span><\/span>-stimulated inflammatory and fibrotic responses.32<\/sup><\/span>\u00a0Figure 3<\/span><\/em>\u00a0summarizes and highlights some of the hepatocyte pathways thought to be upregulated by THR-\u03b2\u00a0<\/span><\/span>agonists and most relevant to NASH.<\/p>\n

\"\"<\/p>\n

\n

It is hypothesized that\u00a0<\/span><\/span><\/span><\/span>THR–\u03b2<\/span><\/span>\u00a0agonists, such as<\/span>\u00a0r<\/span>esmetirom, activate THR-\u03b2<\/span>, an abundant nuclear hormone receptor found hepatocytes. It is hypothesized that\u00a0activating\u00a0<\/span>THR-\u03b2<\/span>\u00a0modulates several\u00a0<\/span>genes that promote uptake of\u00a0free fatty acids<\/span><\/span><\/span>\u00a0from both external sources (CPT1),<\/span>\u00a0as well as increased production and uptake of internal\u00a0free fatty acids\u00a0<\/span>from\u00a0de novo<\/em>\u00a0lipogenesis<\/span>\u00a0(ACC1, FAS) and lipophagy. Increased mitochondrial biogenesis (CPT1a,\u00a0<\/span>mcad, PDk4, UCP2) and mitophagy of unhealthy mitochondria increase capacity to handle and burn the increased flow of\u00a0free fatty acids<\/span>. While increased cholesterol is produced due to upregulation of HMGCoA reductase,\u00a0<\/span>bile acid synthesis increases\u00a0<\/span>through increased CYP7A1 and excretion,<\/span>\u00a0and\u00a0<\/span>LDL\u00a0uptake\u00a0<\/span>by the liver\u00a0increases\u00a0<\/span>by induction of\u00a0the\u00a0<\/span>LDL<\/span><\/span>-R<\/span>. As a result, fatty acid\u00a0\u03b2<\/span>-oxidation, mitochondrial biogenesis,\u00a0<\/em>de novo<\/em>\u00a0lipogenesis<\/span>, cholesterol and bile acid synthesis\u00a0all increase<\/span>, and\u00a0<\/span>LDL\u00a0<\/span>cholesterol levels\u00a0decrease<\/span>.\u00a0<\/span>SHBG,<\/span><\/span><\/span><\/span>\u00a0which transports androgens and\u00a0o<\/span>estrogens in blood and regulates their access to target tissues,<\/span>\u00a0is also a known downstream target of THR-\u03b2<\/span>\u00a0and may be a biomarker of target engagement.<\/p>\n<\/div>\n

In one study, p<\/span>atients with\u00a0THR-\u03b2<\/span><\/span>\u00a0mutations had<\/span>\u00a0increased liver fat\u00a0(<\/span>as assessed by c<\/span>ontrolled a<\/span>ttenuation p<\/span>arameters<\/span><\/span><\/span> using <\/span>t<\/span>ransient, e<\/span>lastography)<\/span>\u00a0compared\u00a0with\u00a0<\/span>their unaffected family members,<\/span>\u00a0while controlling for\u00a0body mass index<\/span>.37<\/sup><\/span>\u00a0All participants belonged to the same family, lived on the same small island and were,<\/span>\u00a0therefore,<\/span>\u00a0exposed to similar environmental conditions. No difference in insulin resistance was observed between the\u00a0two<\/span>\u00a0groups.\u00a0<\/span>Individuals with\u00a0<\/span>NASH\u00a0display<\/span>\u00a0low THR-\u03b2 <\/span>activity, which <\/span>exacerbates <\/span>mitochondrial dysfunction and lipotoxicity<\/span>.35<\/sup><\/span>\u00a0Given the role\u00a0played by<\/span>\u00a0THR-\u03b2<\/span>\u00a0signal<\/span>ling in liver metabolism,<\/span>\u00a0a strong rationale for developing<\/span>\u00a0THR–<\/span>\u03b2<\/span>-selective thyromimetics exists. Consequently, new molecules with a very high THR–<\/span>\u03b2<\/span>\u00a0affinity and hepatic selectivity have been developed\u00a0to treat\u00a0<\/span>lipid-associated hepatic disorders,\u00a0in\u00a0<\/span>particular NAFLD.<\/p>\n

Thyroid hormone receptor<\/span>–\u03b2<\/span>\u00a0agonists for the\u00a0t<\/span>reatment of\u00a0non–<\/span>alcoholic fatty liver disease<\/span>\/non–<\/span>alcoholic steatohepatitis<\/span><\/h2>\n

<\/span>For the treatment of NASH, a THR-\u03b2<\/span>\u00a0agonist\u00a0ideally<\/span>\u00a0needs to achieve\u00a0three<\/span>\u00a0goals: 1)\u00a0r<\/span>educed<\/span>\u00a0hepatic steatos<\/span>is, inflammation and fibrosis; 2)\u00a0l<\/span>iver specificity with no effect on the\u00a0h<\/span>ypothalamus-p<\/span>ituit<\/span>ary-t<\/span>hyroid\u00a0a<\/span>xis, which<\/span>\u00a0regulates<\/span>\u00a0serum thyroid levels; 3)\u00a0h<\/span>igh THR-\u03b2<\/span>\u00a0selectivity to limit off-target THR-\u03b1 effects on the bone\/cartilage and heart.<\/span><\/p>\n

<\/span><\/span>Sobetirome (GC-1) and\u00a0e<\/span>protirome (KB2115)\u00a0<\/span>were the first\u00a0THR-\u03b2<\/span><\/span>\u00a0agonists\u00a0<\/span>shown to reduce<\/span>\u00a0intrahepatic lipid content in\u00a0preclinical <\/span>models<\/span>.38,39<\/sup><\/span>\u00a0Despite\u00a0its<\/span>\u00a0favou<\/span>rable\u00a0lipid-lowering <\/span>effects, e<\/span>protirome development was halted in\u00a0p<\/span>hase\u00a0<\/span><\/span><\/span>III<\/span>\u00a0<\/span>because it caused<\/span>\u00a0<\/span>cartilage damage\u00a0<\/span>in dogs following chronic treatment.40<\/sup><\/span>\u00a0<\/span>In addition, liver toxicity was noted when patients with familial hypercholesterola<\/span>emia were treated after only\u00a06<\/span>\u00a0weeks<\/span>.34,40<\/sup><\/span><\/span> Sobetirome had<\/span>\u00a0beneficial effects on lipid profile by upregulating\u00a0low-density lipoprotein (<\/span>LDL)<\/span>\u00a0receptors on hepatocytes,<\/span> and reduced hepatic steat<\/span>osis in a\u00a0<\/span>rat<\/span>\u00a0model of NAFLD.\u00a0<\/span>Despite these favou<\/span>rable\u00a0results<\/span>, funding limited its advancement\u00a0to<\/span> p<\/span>hase\u00a0<\/span>I<\/span>,<\/span><\/span><\/span>\u00a0along with some experimental observations of hyperglyca<\/span>emia and insulin resistance.41 <\/sup><\/span>Interestingly, Sob-AM2, a methyl amide derivative of s<\/span>obetirome, which has greater\u00a0central nervous system\u00a0<\/span>penetration,<\/span> is being investigated <\/span>for treating <\/span>d<\/span>emyeli<\/span>nating diseases\u00a0in preclinical models<\/span>.42<\/sup><\/span>\u00a0<\/span><\/span><\/span>Novel 4\u2019<\/span>–a<\/span>mino-b<\/span>enzyl-p<\/span>henoxyacetic\u00a0a<\/span>cid\u00a0t<\/span>hyromimetics IS25 and the prodrug TG68 showed<\/span> promise in preclinical <\/span>testing,<\/span>\u00a0and additional\u00a0in vivo<\/em><\/span>\u00a0studies will be needed to determine\u00a0their<\/span>\u00a0potential for\u00a0treating<\/span> <\/span>NAFLD and <\/span>NASH.34 <\/sup><\/span><\/span>A novel g<\/span>lucagon\/T3 hybrid molecule,<\/span>\u00a0which is meant to have both the anti-lipid effects of glucagon along with the positive energy effects of T3,<\/span>\u00a0has recently been developed.43<\/sup><\/span>\u00a0P<\/span>reclinical<\/span>\u00a0models using this molecule in obese mice\u00a0found\u00a0<\/span>decreased<\/span>\u00a0serum lipids, decreased adipose mass, reversal of NASH, reduced atherosclerotic plaque accumulation and improved glucose metabolism,<\/span>\u00a0a<\/span><\/span>while avoiding <\/span><\/span>thyrotoxicosis and the hyperglyca<\/span>emic effects of glucagon.43<\/sup><\/span>\u00a0Although\u00a0<\/span>additional studies are\u00a0still\u00a0<\/span>needed to advance the molecule,<\/span>\u00a0it is notable that\u00a0<\/span>this approach does not rely on isoform selectivity\u00a0to produce\u00a0<\/span>its beneficial effects.<\/p>\n

The THR-\u03b2<\/span>\u00a0agonists\u00a0that are\u00a0<\/span>furthest along in development for the treatment of NASH are\u00a0r<\/span>esmetirom (MGL-3196), VK2809 (<\/span>MB0<\/span>7811<\/span>), <\/span>ASC-41 and TERN 501. VK2809 is a prodrug activated by cytochrome P4503A (<\/span>CYP3A)<\/span> in the liver and is being investigated for the treatment of NASH with F2\/F3 fibrosis in a phase\u00a0<\/span>II<\/span>b clinical trial\u00a0<\/span>(ClinicalTrials.gov identifier:\u00a0<\/span>NCT04173065),44<\/sup><\/span>\u00a0<\/span>and TERN-501 is\u00a0being investigated<\/span><\/span><\/span>\u00a0<\/span>for\u00a0the<\/span>\u00a0treatment of NASH\u00a0in a phase II<\/span>a <\/span>(ClinicalTrials.gov identifier:\u00a0<\/span>NCT05415722).45<\/sup><\/span>\u00a0ASC-4, also a prodrug metabolized by CYP3A, is\u00a0being investigat<\/span>ed <\/span>in a <\/span>phase\u00a0<\/span><\/span><\/span><\/span>II<\/span>\u00a0trial\u00a0<\/span>and\u00a0is\u00a0<\/span>limited to China (ClinicalTrials.gov identifier:\u00a0<\/span>NCT05118360).46<\/sup><\/span>\u00a0C<\/span>ompleted and on–<\/span>going trials with other THR-\u03b2<\/span>\u00a0agonists are summarized in\u00a0Table 2<\/span><\/em>.47\u201351<\/sup><\/span>\u00a0Data shown for all agents, with the exception of\u00a0r<\/span>esmetirom, are derived from presentations at international meetings or results presented on company websites and,<\/span>\u00a0thus,<\/span>\u00a0have not been subject to peer\u00a0<\/span>review.<\/p>\n

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Summary of p<\/span>re-clinical d<\/span><\/span><\/span>ata for resmetirom<\/span>\u00a0<\/span><\/h1>\n

<\/span>Resmetirom\u00a0<\/span>i<\/span>s an investigational liver-directed agonist of\u00a0<\/span>THR<\/span>\u00a0that\u00a0is\u00a0<\/span><\/span>28<\/span>\u00a0times<\/span>\u00a0more selective<\/span>\u00a0for THR-\u03b2<\/span>\u00a0<\/span>over\u00a0<\/span>THR-\u03b1.<\/span>52<\/sup><\/span>\u00a0In vitro <\/em><\/span>studies have\u00a0<\/span>demonstrated<\/span>\u00a0resmetirom<\/span><\/span>\u2019s preferential use of the\u00a0organic anion transporting polypeptides<\/span>\u00a0<\/span>1B1 receptor for hepatocyte uptake and stronger activation of THR–<\/span>\u03b2<\/span>.53,54 <\/sup><\/span>Moreover, o<\/span>xygen c<\/span>onsumption\u00a0r<\/span>ate<\/span>\u00a0<\/span>studies<\/span>\u00a0<\/span>found\u00a0<\/span>that both T3 and resmetirom<\/span><\/span>\u00a0increased basal and maximal respiration<\/span><\/span>, <\/span>accompanied by an increase in\u00a0the\u00a0<\/span>production\u00a0of\u00a0<\/span>adenosine triphosphate,<\/span>\u00a0<\/span><\/span>reflecting<\/span>\u00a0higher oxidation of substrates.53 <\/sup><\/span>While it is known that increased hepatic THR-\u03b2<\/span>\u00a0agonism increases the level of hepatic\u00a0DIO1<\/span>,55,56 <\/sup><\/span>additional\u00a0in vitro<\/em><\/span>\u00a0and\u00a0in vivo<\/em><\/span>\u00a0data suggest that\u00a0resmetirom<\/span><\/span>\u00a0upregulates\u00a0the\u00a0<\/span>expression of DIO1,<\/span>\u00a0<\/span>supporting its role not only\u00a0<\/span>as a thyr<\/span>omimetic but also\u00a0in<\/span> potentially increasing the <\/span>conversion of T4 to T3.54<\/sup><\/span>\u00a0Al<\/span>t<\/span>hough not definitive,<\/span>\u00a0the\u00a0<\/span>low serum T4\u00a0detected\u00a0<\/span>in patients treated with\u00a0resmetirom<\/span><\/span><\/span>\u00a0indirectly suggests this mechanism may be relevant.53<\/sup><\/span><\/p>\n

Given its specificity for THR–<\/span>\u03b2<\/span>\u00a0and its impact on lipophagy, mitophagy, mitogenesis and\u00a0\u03b2<\/span>–<\/span>oxidation within hepatocytes,\u00a0resmetirom<\/span><\/span>\u00a0is an appealing agent for\u00a0treating\u00a0<\/span>NASH.<\/p>\n

Summary of completed clinical trial data<\/span><\/span><\/span><\/h1>\n

The first–<\/span>in-human data\u00a0on\u00a0<\/span>resmetirom<\/span><\/span>\u00a0in healthy volunteers ca<\/span>me from a single-centre<\/span>, randomized, double-blind, placebo-controlled, ascending–<\/span>dose study in\u00a072<\/span>\u00a0subjects<\/span>\u00a0to assess\u00a0its\u00a0<\/span>safety and pharmacokinetics (ClinicalTrials.gov identifier: NCT01367873)\u00a0<\/span>and a\u00a02<\/span>-week multiple–<\/span>dose study\u00a0<\/span>(<\/span>5<\/span><\/span><\/span>\u2013<\/span>200\u00a0<\/span><\/span>mg<\/span>) in 48 healthy participants with mildly elevated\u00a0<\/span>LDL<\/span>\u00a0(><\/span><\/span>110<\/span>\u00a0mg\/dL<\/span>) to assess its<\/span>\u00a0safety, pharmacokinetics, impact on thyroid axis hormones and\u00a0LDL cholesterol (<\/span>LDL-C)<\/span>\u00a0lowering\u00a0effects\u00a0<\/span>(ClinicalTrials.gov identifier: NCT01519531)<\/span>.57<\/sup><\/span>\u00a0Resmetirom was tolerated well at all doses,<\/span>\u00a0and no dose-related adverse events\u00a0or\u00a0<\/span>changes in electrocardiogram<\/span>\u00a0findings, vital\u00a0<\/span>signs<\/span> or liver enzyme levels<\/span>\u00a0were reported.\u00a0<\/span>C<\/span>ompared\u00a0with\u00a0<\/span>placebo,\u00a0patients receiving r<\/span>esmetirom displayed a<\/span><\/span>\u00a0<\/span>reduction\u00a0of up to 30%\u00a0<\/span>in LDL-C,\u00a028% in\u00a0<\/span>non-high-density lipoprotein–<\/span>cholesterol<\/span><\/span>,\u00a024% for in\u00a0<\/span>a<\/span>polipoprotein B and\u00a060<\/span>%<\/span>\u00a0in triglycerides\u00a0compared with those receiving placebo<\/span><\/span>. At the\u00a0<\/span><\/span><\/span>highest dose\u00a0(200 mg<\/span>), there was a significant (p<\/span><\/em><\/span><<\/span>0.0001<\/span>) reversible reduction of\u00a0<\/span>approximately\u00a0<\/span>20<\/span>%<\/span> in the level of prohormone free T4 compared with\u00a0<\/span>placebo;<\/span>57 <\/sup><\/span><\/span>this\u00a0<\/span>could theoretically be explained by increased hepatic metabolism of T4 by\u00a0DIO1,\u00a0<\/span>but has not yet been proven.55 <\/sup><\/span>No impact ,on the central thyroid axis was observed,<\/span>\u00a0as reflected by\u00a0the lack of\u00a0<\/span>change in\u00a0TSH<\/span> or free T3 levels. In conclusion, in\u00a0<\/span>this\u00a02<\/span>-week study,\u00a0r<\/span>esmetirom was well\u00a0<\/span>tolerated and demonstrated favou<\/span>rable effects on lipid metabolism\u00a0<\/span>in healthy volunteers with mild elevation in LDL<\/span>-C<\/span>.57 <\/sup><\/span>Given\u00a0that\u00a0<\/span>cardiovascular disease is the leading cause of death in patients with NASH, the favou<\/span>rable cardiometabolic profile of resmetirom <\/span>and <\/span>the preclinical<\/span>\u00a0data for intrahepatic thyr<\/span>oidism as a driver of lipotoxicity in NASH<\/span>,\u00a0resmetirom<\/span>\u00a0was advanced to\u00a0p<\/span>hase\u00a0<\/span><\/span>II<\/span>\/III<\/span>\u00a0trials in patients with NASH.<\/p>\n

The first seminal clinical trial was a\u00a036<\/span>–<\/span>week,<\/span><\/span>\u00a0phase\u00a0<\/span><\/span><\/span>II<\/span>,<\/span>\u00a0serial liver biopsy study (ClinicalTrials.gov identifier: <\/span>NCT02912260) in patients with biopsy–<\/span>confirmed NASH (fibrosis stages\u00a01<\/span>\u2013<\/span>3<\/span>), with a\u00a0NAFLD\u00a0<\/span>a<\/span>ctivity\u00a0s<\/span>core (<\/span><\/span>NAS)<\/span>\u00a0<\/span>\u22654<\/span>\u00a0and hepatic fat fraction of\u00a0<\/span>\u2265<\/span><\/span>10%<\/span>\u00a0at baseline when assessed by\u00a0<\/span>MRI-PDFF.47<\/sup><\/span>\u00a0<\/span>The NAS comprises <\/span>three <\/span>components: <\/span>steatosis\u00a0(<\/span>0\u2013<\/span><\/span><\/span><\/span>3)<\/span><\/span>,<\/span>\u00a0ballooning\u00a0(<\/span>0\u2013<\/span><\/span><\/span><\/span>2) <\/span><\/span>and <\/span>inflammation\u00a0(<\/span>0\u2013<\/span><\/span><\/span><\/span>3)<\/span>.\u00a0<\/span>The maximum <\/span>NAS is 8, <\/span><\/span>and patients had to have a score\u00a0<\/span>\u2265<\/span><\/span>4<\/span>\u00a0with the requirement of ballooning for inclusion.<\/p>\n

Patients were randomly assigned to receive\u00a0either\u00a0<\/span>r<\/span>esmetirom\u00a080<\/span>\u00a0mg<\/span>\u00a0or placebo orally once\u00a0<\/span>a\u00a0<\/span>day.<\/span>\u00a0S<\/span>erial hepatic fat measurements were obtained at\u00a0W<\/span>eeks 12 and 36, and a second liver biopsy was obtained at\u00a0<\/span>W<\/span>eek 36\u00a0<\/span>(<\/span>Figure 4<\/em><\/span>;\u00a0the\u00a0<\/span>36<\/span>–<\/span>week<\/span>\u00a0main study).47<\/sup><\/span>\u00a0The primary goal of this study was to determine whether\u00a0resmetirom<\/span>\u00a0could effectively reduce the burden of lipotoxic lipids that may be driving liver injury. Therefore, the primary endpoint was\u00a0a\u00a0<\/span>relative change in MRI-PDFF fat quantification at 12<\/span>\u00a0weeks<\/span> in patients\u00a0<\/span>on resmetirom<\/span>\u00a0compared\u00a0with <\/span>placebo. Key secondary endpoints included the proportion of patients who <\/span>had <\/span>achieved a\u00a0<\/span><\/span>reduction in hepatic fat\u00a0of\u00a0\u226530%<\/span><\/span>\u00a0at 12 and\u00a036 <\/span>weeks<\/span>\u00a0on MRI-PDFF,<\/span> and critical liver biopsy assessments evaluating <\/span>significant improvements <\/span>in NASH and fibrosis as dictated by the\u00a0<\/span>FDA. Reduction in ballooning and inflammation are critical,<\/span>\u00a0as a simple reduction in steatosis in isolation could result in a\u00a0<\/span>2<\/span>–<\/span>point reduction in NAS wit<\/span>hout any impact on the more relevant features of ballooning and inflammation.<\/p>\n

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At\u00a0W<\/span>eek 12 of treatment,\u00a0patients treated with\u00a0<\/span>r<\/span>esmetirom (n<\/span>=<\/span>78<\/span>) demonstrated both a relative reduction (-32.9%<\/span>\u00a0versus<\/span>\u00a0<\/span>–<\/span>10.4<\/span>%<\/span>) and an absolute reduction\u00a0(-7.0%<\/span>\u00a0versus<\/span>\u00a0<\/span>–<\/span>2.7<\/span>%<\/span>) of hepatic fat compared with\u00a0patients on\u00a0<\/span>placebo (n<\/span>=<\/span>38<\/span>;\u00a0p<\/span><\/em><\/span><<\/span>0<\/span>.<\/span>0001). At\u00a0W<\/span>eek 36,\u00a0patients treated with\u00a0<\/span>r<\/span>esmetirom (n<\/span>=<\/span>74<\/span>) showed\u00a0both\u00a0<\/span>a statistically significant relative (–<\/span>37.3<\/span>%<\/span>\u00a0versus<\/span>\u00a0<\/span>–<\/span>8.9<\/span>%<\/span>) and absolute\u00a0(-8.2%<\/span>\u00a0versus<\/span>\u00a0<\/span>–<\/span>2.8<\/span>%<\/span>) reduction in hepatic fat\u00a0compared with\u00a0patients on\u00a0<\/span>placebo (n=34; p<0.0001)\u00a0<\/span>(Table 3<\/span><\/em>).<\/span>47<\/sup><\/span>\u00a0Furthermore,\u00a0<\/span>r<\/span>esmetirom\u00a0seemed to produce<\/span>\u00a0statistically significant reductions in a number of secondary and exploratory endpoints,<\/span>\u00a0including liver enzymes, multiple lipoproteins and atherogenic lipids (Table 4<\/span><\/em>).47<\/sup><\/span>\u00a0rT3 levels were also significantly reduced\u00a0in resmetirom-treated patients<\/span>,<\/span> suggesting an impact on intrahepatic metabolism of T4 towards<\/span><\/span>\u00a0active T3, possibly due to increased DIO1 activity. Resmetirom exposure was assessed by\u00a0W<\/span>eek 2\u00a0through pharmacokinetic<\/span>\u00a0<\/span>studies,<\/span>\u00a0and dose adjustments were made at\u00a0W<\/span>eek\u00a04<\/span><\/span>\u00a0by an unblinded monitor.\u00a0<\/span><\/span><\/span><\/span><\/span><\/span><\/span><\/span><\/span><\/span>A<\/span>s\u00a0sex hormone\u00a0<\/span>binding globulin (SHBG)\u00a0<\/span>is a known downstream target of THR–<\/span>\u03b2<\/span>\u00a0agonism in the liver, it was assessed as a potential surrogate marker of target engagement and hepatic exposure to\u00a0r<\/span>esmetirom,\u00a0with<\/span>\u00a0a<\/span>\u00a0<\/span>high SHBG group<\/span>\u00a0defined as\u00a0<\/span>a\u00a0<\/span>\u2265<\/span><\/span>75%<\/span>\u00a0and\u00a0\u2265<\/span><\/span><\/span><\/span>88<\/span>%<\/span>\u00a0increase\u00a0in SHBG concentration\u00a0<\/span>from baseline\u00a0to<\/span>\u00a0W<\/span>eek 12 and 36, respectively. Therefore, secondary\u00a0and<\/span>\u00a0<\/span>exploratory endpoints were broken down by exposure level and SHB<\/span>G response.<\/p>\n

\"\"<\/p>\n

\"\"<\/p>\n

<\/span><\/span><\/span><\/span><\/span><\/span><\/span>A<\/span>lthough\u00a0<\/span><\/span>there was not a<\/span>\u00a0significant difference in\u00a0the number of\u00a0<\/span>patients\u00a0<\/span>achieving\u00a0<\/span><\/span><\/span>\u2265<\/span>1<\/span>\u00a0stage improvement in fibrosis\u00a0on resmetirom <\/span>compared with placebo\u00a0at the Week 36 liver biopsy<\/span><\/span><\/span>, several key observations were made in assessing the <\/span>impact of r<\/span>esmetirom <\/span>on NASH and predictors of response.\u00a0<\/span><\/span><\/span>Specifically,\u00a0<\/span>t<\/span>he proportion of patients with a 2-point reduction in NAS\u00a0and<\/span> at least a 1-point reduction in either ballooning or inflammation <\/span>at\u00a0<\/span>the\u00a0<\/span><\/span>Week 36<\/span>\u00a0biopsy was significantly greater in the resmetirom group compared\u00a0with the <\/span>placebo group <\/span>but<\/span>\u00a0only in certain subgroups\u00a0of patients<\/span>, including<\/span>\u00a0those who had\u00a0<<\/span>5%<\/span>\u00a0weight<\/span>\u00a0loss (p<\/span><\/em><\/span>=<\/span>0.017<\/span>), those with high\u00a0r<\/span>esmetirom exposure (p<\/span><\/em><\/span>=<\/span>0.021<\/span>) and those who were MRI–<\/span>PDFF responders by\u00a0W<\/span>eek 12 (p<\/span><\/em><\/span>=<\/span>0063<\/span>). This last finding suggests that early reduction in hepatic fat could predict\u00a0who is<\/span>\u00a0likely to have a response\u00a0by<\/span>\u00a0the\u00a0<\/span><\/span>Week 36<\/span>\u00a0liver biopsy. Indeed<\/span>, of the\u00a046<\/span>\u00a0patients<\/span>\u00a0in the\u00a0r<\/span>esmetirom group who were MRI-PDFF responders at\u00a0W<\/span>eek 12,\u00a018 (<\/span>39<\/span>%)<\/span><\/span>\u00a0<\/span><\/em><\/span><\/span><\/span>achieved NASH resolution\u00a0(p<\/em><\/span>=<\/span>0.0013<\/span>),<\/span><\/span>\u00a0defined as\u00a0a<\/span> ballooning score of 0, inflammation of 0\u2013<\/span><\/span><\/span>1 <\/span>with a\u00a0<\/span><\/span>\u2265<\/span><\/span>2<\/span>\u00a0point reduction in NAS score. Change in absolute NAS was not significantly<\/span>\u00a0different between groups but did show a difference in those with<\/span>\u00a0high exposure<\/span>, high SHBG and\u00a0<\/span>Week 12<\/span>\u00a0MRI-PDFF response (Table 5<\/span><\/em>).47<\/sup><\/span>\u00a0The authors suggested<\/span>\u00a0that thyroid hormone–<\/span>responsive protein SHBG may serve as a biomarker\u00a0for\u00a0<\/span>monitoring<\/span>\u00a0compliance and optimizing<\/span>\u00a0dosing.\u00a0<\/span>There was no difference in\u00a0<\/span>p<\/span>atients<\/span>\u00a0who achieved <\/span>NASH resolution with no worsening of fibro<\/span>sis, except in\u00a0a\u00a0<\/span>subgroup analysis\u00a0of\u00a0<\/span>those<\/span><\/span><\/span><\/span><\/span>\u00a0with\u00a0<\/span><<\/span>9.5%<\/span>\u00a0weight<\/span>\u00a0loss\u00a0and<\/span>\u00a0MRI-PDFF response, defined as >30% reduction of MRI-PDFF at\u00a0W<\/span>eek 12.<\/span><\/p>\n

\"\"<\/p>\n

Overall,<\/span>\u00a0this study met its primary endpoint of MRI-PDFF reduction at<\/span>\u00a0W<\/span>eek<\/span>\u00a012<\/span>. Moreover,\u00a0r<\/span>esmetirom responders with\u00a0a\u00a0<\/span>30<\/span>%<\/span>\u00a0<\/span>MRI-<\/span>PDFF\u00a0<\/span>reduction at\u00a0<\/span>W<\/span>eek 12 had higher rates of NASH resolution (37<\/span>%)\u00a0<\/span>at<\/span>\u00a0the\u00a0<\/span><\/span>Week\u00a0<\/span>36 liver biopsy compared\u00a0with\u00a0<\/span>non-responders (4<\/span>%) along with\u00a0a\u00a0<\/span>reduction\u00a0i<\/span>n liver enzymes and fibrosis biomarkers,<\/span>\u00a0suggesting that early\u00a0<\/span>MRI-<\/span>PDFF\u00a0<\/span>response may predict future NASH resolution and anti-fibrotic effect. In patients treated with\u00a0r<\/span>esmetirom, a higher incidence of mild diarrho<\/span>ea and nausea was reported; <\/span>however,<\/span>\u00a0most adverse events were mild, self-limiting<\/span>\u00a0and balanced between the two groups studied. There were no reports of adverse events related to THR-\u03b1 activity, such as\u00a0<\/span>changes in\u00a0<\/span>bone mineral density\u00a0based on dual-energy X-ray absorptiometry (DEXA) scan<\/span><\/span><\/span><\/span>, thyroid axis suppression or cardiovascular adverse events.47<\/sup><\/span><\/p>\n

At the end of the main\u00a036<\/span>–<\/span>week,<\/span><\/span>\u00a0phase\u00a0<\/span><\/span><\/span>II<\/span>\u00a0<\/span>study, a\u00a036<\/span>–<\/span>week,<\/span><\/span>\u00a0active–<\/span>treatment,<\/span>\u00a0open-label extension<\/span>\u00a0(OLE<\/span>) study was conducted in\u00a031 <\/span>patients<\/span> with persistently mild to markedly elevated liver enzymes (Figure 4<\/span><\/em>).58<\/sup><\/span> All OLE study endpoints were exploratory. The main efficacy outcome was absolute and relative reductions in MRI-PDFF at W<\/span>eek 36. At\u00a0W<\/span>eek 36, patients treated with\u00a0r<\/span>esmetirom 80 mg <\/span>or 100<\/span>\u00a0mg<\/span>\u00a0demonstrated a mean absolute reduction in MRI-PDFF of\u00a0<\/span><\/span>–<\/span>11.1<\/span>%<\/span>\u00a0(standard error\u00a01.5<\/span>%<\/span>;\u00a0p<\/span><\/em><\/span><<\/span>0.0001<\/span>) and mean relative reduction of\u00a0<\/span><\/span>–<\/span>52.3<\/span>%<\/span>\u00a0(standard error <\/span>4.4%,\u00a0p<\/span><\/em><\/span><<\/span>0.0001<\/span>). Interestingly, the\u00a0c<\/span>ontrolled att<\/span>enuation parameter<\/span><\/span><\/span>\u00a0score,<\/span>\u00a0which is commonly used to assess steatosis with\u00a0FibroScan\u00ae<\/sup><\/span><\/span>\u00a0(Echosens, Paris, France)<\/span><\/span>,<\/span>\u00a0did not correlate with changes in MRI-PDFF,<\/span>\u00a0suggesting that it may not be a reliable assessment of steatosis reduction in response to treatment. Other key outcomes,<\/span>\u00a0including\u00a0<\/span><\/span>liver enzymes, lipid profiles and markers of fibrogenesis,<\/span>\u00a0were favou<\/span>rably reduced and\u00a0are\u00a0<\/span>shown in\u00a0Table 6<\/span><\/em>.58<\/sup><\/span>\u00a0While no repeat liver biopsy was\u00a0conducted\u00a0<\/span>at the end of the OLE\u00a0study<\/span>, several markers of fibrogenesis were assessed. Of particular interest\u00a0were\u00a0<\/span>PRO-C3 and C3M levels, which had not been initially analys<\/span>ed in the main\u00a036<\/span>–<\/span>week<\/span>\u00a0study. PRO<\/span>-C3 reflects\u00a0the\u00a0<\/span>production of the pro-peptide (N-terminal pro-collagen) of type III collagen and is thought to be a biomarker of new collagen production by activated stellate cells or fibrogenesis. On the other hand, C3M is the\u00a0matrix metallopeptidase 9<\/span><\/span>–<\/span>mediated degradation product of type III collagen and,<\/span>\u00a0thus,<\/span>\u00a0reflects fibrinolysis.\u00a0Therefore, t<\/span>he PRO-C3\/C3M\u00a0ratio\u00a0<\/span>is thought to reflect net fibrosis production.59<\/sup><\/span>\u00a0<\/span>In\u00a0the\u00a0<\/span>post\u00a0<\/span>hoc<\/em>\u00a0analysis from the main study, the PRO-C3\/C3M\u00a0ratio\u00a0<\/span>significantly correlated with fibrosis stage (p<\/span><\/em><\/span>=<\/span>0.001<\/span>) and ballooning (p<\/span><\/em><\/span>=<\/span>0.003<\/span>) on liver biopsy. It did not correlate with other NAS components.<\/span><\/span>58<\/sup><\/span><\/span>\u00a0<\/span>During the OLE study, similar to the main study,\u00a0<\/span>PRO-C3, a\u00a0neo-epitope pro-peptide of type III collagen formation<\/span>,<\/span><\/span><\/span>\u00a0was reduced significantly with\u00a0r<\/span>esmetirom treatment (p<\/span><\/em><\/span>=<\/span>0.0005<\/span>),<\/span>\u00a0and C3M increased such that\u00a0the\u00a0<\/span>PRO-C3\/C3M ratio decreased significantly with treatment\u00a0<\/span>(p<\/span><\/em><\/span><<\/span>0.0001<\/span>).58<\/sup><\/span>\u00a0Consistent with these changes, l<\/span>iver stiffness\u00a0calculated using vibration–<\/span>controlled transient elastography\u00a0<\/span><\/span><\/span><\/span><\/span>on FibroS<\/span>can\u00ae<\/sup><\/span><\/span>\u00a0<\/span>showed statistically significant\u00a0(p=0.015<\/span>)<\/span><\/span>\u00a0improvement<\/span>\u00a0during the\u00a036<\/span>–<\/span>week<\/span>\u00a0OLE study and may serve as a convenient point–<\/span>of–<\/span>care assessment for treatment effects in a real-world setting.60<\/sup><\/span>\u00a0In terms of impact on the thyroid axis, treatment with\u00a0r<\/span>esmetirom significantly reduced serum rT3 and increased the\u00a0<\/span>free\u00a0<\/span>T3<\/span>\/rT3\u00a0ratio<\/span>. The extent to which this reflects a correction in hepatic thyroid activity is not clear,<\/span>\u00a0but is postulated. While no effect on TSH was observed,\u00a0free\u00a0<\/span>T3 did increase by<\/span>\u00a04<\/span>%,<\/span>\u00a0<\/span><\/span>which requires further monitoring<\/span>\u00a0in\u00a0a\u00a0<\/span>longer–<\/span>term follow-up. Overall, results from the\u00a036<\/span>–<\/span>week<\/span>\u00a0phase\u00a0<\/span><\/span>II<\/span>\u00a0study and\u00a0the<\/span>\u00a036<\/span>–<\/span>week<\/span>\u00a0OLE study demonstrated safety and efficacy, informed dosing, and suggested<\/span>\u00a0the potential role of non–<\/span>invasive assessments in\u00a0evaluating<\/span>\u00a0response to\u00a0r<\/span>esmetirom, further influencing\u00a0use<\/span>\u00a0in the phase\u00a0<\/span>III<\/span>\u00a0<\/span>NASH study MAESTRO-NASH (ClinicalTrials.gov identifier:\u00a0<\/span>NCT03900429).47,58,61<\/sup><\/span>\u00a0Interestingly, using data from the main study, those\u00a0with a\u00a0\u226530% reduction in<\/span><\/span>\u00a0fat\u00a0on<\/span>\u00a0MRI-PDFF\u00a0<\/span><\/span><\/span>by\u00a0W<\/span>eek 12\u00a0were\u00a0<\/span>independently associated with greater improvements in\u00a0<\/span>p<\/span>hysical\u00a0f<\/span>unctioning and P<\/span>hysical C<\/span>omponent S<\/span>ummary scores at\u00a0W<\/span>eek 36 (p<\/span><\/em><\/span><o<\/span><\/span>.05<\/span>).62<\/sup><\/span>\u00a0Patients with improvement in NASH and fibrosis on liver biopsy also showed improvement in components of\u00a0h<\/span>eal<\/span>th-r<\/span>elated\u00a0q<\/span>uality of\u00a0<\/span>l<\/span>ife.<\/span>47<\/sup><\/span><\/span><\/span><\/span><\/span>\u00a0Whether this improvement is seen in longer-term studies remains to be evaluated, but these results are encouraging as the regulatory agencies want to\u00a0en<\/span>sure that any therapy makes a patient function and feel better.<\/p>\n

 <\/p>\n

Posi<\/span>tive\u00a0p<\/span>hase\u00a0III<\/span>\u00a0<\/span>results for\u00a0n<\/span>on-thyroid hormone receptor<\/span>–\u03b2<\/span>\u00a0agonists in the treatment of\u00a0non–<\/span>alcoholic steatohepatitis<\/span><\/span>:\u00a0o<\/span><\/span><\/span>beticholic acid<\/h2>\n

While the focus of this review is on\u00a0r<\/span>esmetirom,\u00a0o<\/span>beticholic\u00a0a<\/span>cid (OCA<\/span>) has also demonstrated positive phase\u00a0III<\/span>\u00a0<\/span>results for NASH. OCA is a bile\u00a0<\/span>acid analogue<\/span>\u00a0that works by activating the farnesoid X receptor\u00a0<\/span>and\u00a0received FDA<\/span>\u00a0approval<\/span>\u00a0for the treatment of patients with\u00a0primary biliary cholangitis<\/span><\/span>\u00a0in\u00a02016<\/span><\/span>.63<\/sup><\/span>\u00a0In a large, multicentre<\/span>, phase\u00a0<\/span><\/span>II<\/span>b clinical trial,\u00a0patients who received <\/span>OCA\u00a0(<\/span>25<\/span>\u00a0mg\/day<\/span>)<\/span>\u00a0demonstrated improved steatohepatitis and fibrosis over\u00a072<\/span>\u00a0weeks<\/span><\/span>.64<\/sup><\/span>\u00a0In the phase\u00a0<\/span><\/span><\/span>III<\/span>\u00a0<\/span>clinical trial, OCA significantly improved fibrosis and NASH disease activity among patients with NASH.65<\/sup><\/span>\u00a0Due to its mechanism of action, OCA inhibits the synthesis of bile acids from cholesterol and thus results in a mild increase in cholesterol and\u00a0the\u00a0<\/span>incidence of gallstones in patients on therapy. Pruritis is a common side effect that can cause <\/span>therapy discontinuations\u00a0<\/span>in about\u00a010<\/span>%<\/span>\u00a0of patients.\u00a0An\u00a0<\/span>o<\/span>n–<\/span>going phase\u00a0<\/span><\/span><\/span><\/span>III<\/span>\u00a0<\/span>study<\/span>\u00a0<\/span>is\u00a0<\/span>assessing the long-term efficacy and safety of OCA (ClinicalTrials.gov identifier:<\/span> <\/span>NCT02548351) and\u00a0is\u00a0<\/span>under review by the FDA.66<\/sup><\/span>\u00a0It is possible that OCA will be the first approved therapy for NASH,<\/span>\u00a0with submission of\u00a0r<\/span>esmetirom data to the FDA to follow.<\/p>\n

Future directions and anticipated focus of new clinical trialsFuture Directions and Anticipated Focus of New Clinical Trials<\/span><\/span><\/h2>\n

Based on its safety, tolerability and efficacy\u00a0as\u00a0<\/span>reflected by non–<\/span>invasive assessments,\u00a0r<\/span>esmetirom has established itself as a leader in the crowded field of\u00a0<\/span>potential\u00a0<\/span><\/span>NASH therapeutics.\u00a0<\/span>While not yet published and thus not discussed extensively,\u00a052<\/span>–<\/span>week<\/span>\u00a0serial biopsy data including\u00a0950<\/span>\u00a0patients<\/span>\u00a0from\u00a0the\u00a0<\/span>MAESTRO-NASH\u00a0trial\u00a0<\/span>were<\/span>\u00a0released publicly in top–<\/span>line clinical results at the end of\u00a02022<\/span><\/span>.67<\/sup><\/span>\u00a0Both primary outcomes were met with 1) NASH resolution (ballooning of 0, inflammation of\u00a00\u2013<\/span><\/span><\/span>1)<\/span>\u00a0and\u00a0<\/span>\u2265<\/span>2<\/span>-point NAS reduction,<\/span>\u00a0with no worsening of fibrosis (p<\/span><\/em><\/span><<\/span>0.0001<\/span>\u00a0at both doses),<\/span>\u00a0and 2)\u00a0f<\/span>ibrosis improvement by at least one stage,<\/span>\u00a0with no worsening of NAS (p<\/span><\/em><\/span>=<\/span>0.0002<\/span>\u00a0and\u00a0p<\/span><\/span><\/span><<\/span>0.0001<\/span>\u00a0at 80\u00a0mg\u00a0<\/span>and\u00a0100<\/span>\u00a0mg<\/span>, respectively). We await\u00a0a<\/span>\u00a0formal peer-reviewed<\/span>\u00a0publication and\u00a0<\/span>Subpart H\u00a0(Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses<\/span>)\u00a0<\/span><\/span><\/span>filing\u00a0with<\/span>\u00a0<\/span>the FDA. While the MAESTRO-NAFLD-<\/span>OLE\u00a0study\u00a0<\/span>focuses on\u00a0the\u00a0<\/span>safety and tolerability of an additional\u00a052<\/span>\u00a0weeks<\/span>\u00a0of\u00a0r<\/span>esmetirom exposure, the extensive secondary and exploratory endpoints provided invaluable information on the monitoring of drug response using various non–<\/span>invasive assessments of steatosis and more importantly\u00a0<\/span>fibrosis<\/span>.58<\/sup><\/span><\/p>\n

Thus far,<\/span>\u00a0no clinical trials have demonstrated efficacy\u00a0<\/span>of resmetirom<\/span>\u00a0<\/span>in a cirrhotic population, largely because they have focused on\u00a0reducing<\/span>\u00a0fibrosis by one stage on liver biopsy as a primary endpoint,<\/span>\u00a0or have enrolled patients with too advanced\u00a0a\u00a0<\/span>disease. For a cirrhosis<\/span>\u00a0trial, clinical endpoints\u00a0represent<\/span>\u00a0the most critical assessment of efficacy.\u00a0The\u00a0<\/span>MAESTRO-NASH-OUTCOMES trial <\/span>(ClinicalTrials.gov identifier<\/span> <\/span>NCT05500222) will be enrolling\u00a0patients with\u00a0<\/span>early\u00a0<\/span>Child-Pugh class<\/span>\u00a0A\u00a0<\/span>cirrhosis\u00a0<\/span>(score\u00a0of<\/span>\u00a05\u2013<\/span><\/span><\/span>6)<\/span>\u00a0and,<\/span> through a rigorous <\/span>adjudication process,<\/span><\/span>\u00a0define\u00a0<\/span>clinical events with a composite clinical endpoint\u00a0that\u00a0<\/span>includes hepatic decompensation events,\u00a0Model for End-stage Liver Disease\u00a0score\u00a0<\/span><\/span><\/span>\u2265<\/span>15<\/span>, liver transplant and all-cause mortality.68<\/sup><\/span>\u00a0Ultimately,\u00a0it is improvement in clinical outcomes that<\/span>\u00a0<\/span>will move\u00a0<\/span>both the FDA and payors.<\/p>\n

The path to NASH therapeutics reaching the market has been challenging. Early optimism was tempered by numerous failed trials. However, optimism\u00a0has been<\/span>\u00a0renewed with\u00a0the\u00a0<\/span>promising data\u00a0collected<\/span>\u00a0for\u00a0r<\/span>esmetirom. Its safety profile,<\/span>\u00a0coupled with potential efficacy that will be determined in upcoming data from phase\u00a0<\/span><\/span><\/span>III<\/span>\u00a0<\/span>trials,<\/span>\u00a0positions<\/span>\u00a0it as a leader in a crowded field of candidate therapeutics.<\/p>\n","protected":false},"excerpt":{"rendered":"

Non–alcoholic fatty liver disease (NAFLD) encompasses a spectrum of fatty liver diseases, including non–alcoholic fatty liver\u00a0(NAFL)\u00a0and non–alcoholic steatohepatitis (NASH).1\u00a0NAFLD is associated with\u00a0metabolic\u00a0disorders,\u00a0including obesity, hypertension, dyslipidaemia, type\u00a02\u00a0diabetes mellitus (T2DM), hypothyroidism and metabolic syndrome.2\u00a0The diagnosis of NAFLD requires\u00a0\u22655%\u00a0histologic or imaging evidence of hepatic steatosis,\u00a0with\u00a0exclusion of secondary causes of\u00a0hepatic steatosis, such as significant alcohol consumption, hereditary disorders and […]<\/p>\n","protected":false},"author":77788,"featured_media":20802,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_relevanssi_hide_post":"","_relevanssi_hide_content":"","_relevanssi_pin_for_all":"","_relevanssi_pin_keywords":"","_relevanssi_unpin_keywords":"","_relevanssi_related_keywords":"","_relevanssi_related_include_ids":"","_relevanssi_related_exclude_ids":"","_relevanssi_related_no_append":"","_relevanssi_related_not_related":"","_relevanssi_related_posts":"","_relevanssi_noindex_reason":"","rank_math_lock_modified_date":false,"footnotes":""},"categories":[1],"tags":[],"class_list":["post-49407","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-uncategorized","vocabulary_1-liver-disorders","journal-touchreviews-in-endocrinology"],"acf":[],"_links":{"self":[{"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/posts\/49407"}],"collection":[{"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/users\/77788"}],"replies":[{"embeddable":true,"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/comments?post=49407"}],"version-history":[{"count":61,"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/posts\/49407\/revisions"}],"predecessor-version":[{"id":52057,"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/posts\/49407\/revisions\/52057"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/media\/20802"}],"wp:attachment":[{"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/media?parent=49407"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/categories?post=49407"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.touchendocrinology.com\/wp-json\/wp\/v2\/tags?post=49407"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}