Aramchol (arachidyl amido cholanoic acid; Galmed) is a conjugate of cholic acid and arachidic acid, and belongs to the synthetic fatty acid bile acid conjugates (FABACs) family. Aramchol inhibits the liver enzyme stearoyl-CoA desaturase 1 inhibitor (SCD1), and as a result fatty acid synthesis is reduced while fatty acid oxidation is increased. Additionally, Aramchol has hypocholesterolemic effects due to the upregulation of ATP-binding cassette transporter 1 (ABCA1). Ultimately, Aramchol causes incomplete SCD inhibition while also being anti-atherogenic.
Ocaliva (obeticholic acid; Intercept Pharmaceuticals) is a selective farnesoid X receptor (FXR) agonist. FXR is a nuclear bile acid receptor involved in the regulation of bile acids, lipids, and possibly glucose. Ocaliva is a derivative of chenodeoxycholic acid, the endogenous FXR agonist found naturally in human bile acid. By activating FXR, Ocaliva improves insulin sensitivity and inhibits lipogenesis, which reduces fat buildup in the liver and results in decreased inflammation. Ocaliva has also been linked to weight loss. Ocaliva is currently approved in the US and EU for primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA.
Elafibranor (Genfit) is an oral peroxisome proliferator-activated receptor (PPAR) alpha-delta dual agonist. The medication activates PPAR-alpha and PPAR-delta, which control gene expression. Stimulating these receptors increases insulin sensitivity and fatty acid oxidation, which results in a reduction of fat buildup in the liver and leads to a decrease in fibrosis and inflammation.
FXR is a nuclear receptor that regulates bile acid metabolism and signaling. Activation of the receptor inhibits bile acid synthesis from cholesterol via cytochrome P450 7A1 and increases bile acid conjugation, transport, and excretion. This protects the liver from the potentially harmful effects caused during bile acid accumulation. Tropifexor (Novartis/Pfizer) is a novel, highly potent, non-bile acid FXR agonist. It has demonstrated potent activity in rodent Parkinson’s disease models by measuring the induction of FXR target genes in tissues.
Selonsertib (Gilead) is a small molecule that inhibits apoptosis signal-regulating kinase 1 (ASK1). ASK1 has been shown to promote inflammation, apoptosis, and fibrosis in settings of oxidative stress. Non-alcoholic steatohepatitis (NASH) increases oxidative stress and ASK1 activation, so by inhibiting ASK1, selonsertib has been shown to decrease inflammation and fibrosis in patients with NASH.
Resmetirom (Madrigal Pharmaceuticals) is a thyroid hormone receptor (THR) β-selective agonist which selectively targets receptors in the liver. The THR is involved in the regulation of metabolism, cholesterol, and triglycerides, as well as the pathological buildup of fat in the liver. The high liver specificity of resmetirom aims to avoid adverse events associated with THR activation outside the liver.
Firsocostat (Gilead) is an acetyl-CoA carboxylase (ACC) allosteric inhibitor which binds to the biotin carboxylase domain of ACC with high potency and selectivity. Firsocostat inhibits both isoforms (ACC1 and ACC2) of ACC, which results in the reduction of the production of malonyl-CoA carboxylase, therefore reducing a key substrate for fatty acid synthesis. This also reduces the inhibitory effect of malonyl-CoA on the carnitine palmitoyltransferase 1 (CPT-1), which is the rate-limiting step in β-oxidation and leads to an increase in the breakdown of free fatty acids.
Emricasan (Conatus/Novartis) is a small molecule which inhibits pan-caspases. These enzymes are key modulators of apoptosis and inflammation, and chronically elevated apoptosis is often present in liver disease, which leads to the accumulation of apoptotic cells and the release of apoptotic bodies. These end products of apoptosis are engulfed by surrounding tissues which promote disease pathology and inflammation.
Dovato ([dolutegravir + lamivudine]; ViiV Healthcare) is a single-tablet regimen approved in the US for the treatment of HIV-1 infection in patients who are treatment-naïve. It is also being developed in the EU for the treatment of HIV-1 infection in patients who are treatment-naïve (with an approval decision expected by Q3 2019), as well as for patients who are virologically suppressed (US/Japan/EU).
Biktarvy ([bictegravir + emtricitabine + tenofovir alafenamide (TAF)]; Gilead) is an single-tablet regimen (STR) approved for the treatment of HIV-1 infection. It is a co-formulation of Gilead’s novel integrase strand transfer inhibitor (INSTI) bictegravir, and the marketed drug Descovy, which is a fixed-dose combination (FDC) of the nucleoside reverse transcriptase inhibitors (NRTIs) emtricitabine and TAF.
Juluca ([dolutegravir + rilpivirine]; ViiV Healthcare/Johnson & Johnson) is a single-tablet regimen approved in the US for the treatment of patients infected with HIV-1 who have achieved viral suppression.
Odefsey ([rilpivirine + emtricitabine + tenofovir alafenamide (TAF)]; Gilead/Johnson & Johnson) is a single-tablet regimen approved in the US and five major EU markets (France, Germany, Italy, Spain, and the UK) for the treatment of HIV-1 infection. Odefsey contains Gilead’s nucleos(t)ide reverse transcriptase inhibitors (NRTIs) TAF and Emtriva (emtricitabine), and Johnson & Johnson’s non-nucleoside reverse transcriptase inhibitor Edurant (rilpivirine; Johnson & Johnson).
Symtuza ([darunavir + cobicistat + emtricitabine + tenofovir alafenamide (TAF)]; Johnson & Johnson) is a once-daily single-tablet regimen (STR) combination of the protease inhibitor (PI) Prezista, the two nucleos(t)ide reverse transcriptase inhibitors (NRTIs), Emtriva (emtricitabine; Gilead) and TAF (Gilead), and the boosting agent Tybost (cobicistat; Gilead). Symtuza is the first STR containing a PI.
Truvada ([emtricitabine + tenofovir disoproxil fumarate (TDF)]; Gilead/Japan Tobacco) is a once-daily, fixed-dose combination of two of Gilead’s marketed nucleoside reverse transcriptase inhibitors (NRTIs):
Cabotegravir is an integrase strand transfer inhibitor analog of Tivicay (dolutegravir; ViiV Healthcare), and rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI), branded as Edurant (Johnson & Johnson).
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