MGL-3196 is a first-in-class, orally administered, small-molecule, liver-directed, THR β-selective agonist. Preclinical, toxicology and Phase 1 clinical data suggest MGL-3196 has an attractive, differentiated profile as a potential treatment for non-alcoholic steatohepatitis (NASH) and dyslipidemias. THR-β selectivity also enhances the safety profile of MGL-3196, compared to non-selective agents. MGL-3196 has shown no suppression of the central thyroid axis, no THR-α effects on heart rate or bone, and no elevation of liver enzymes. These characteristics make MGL-3196 among the most promising molecules in development in this therapeutic area. MGL-3196 is in a Phase 2 clinical trial for the treatment of non-alcoholic steatohepatitis (NASH).

Fezolinetant (VEOZAH™) is an oral, small molecule, neurokinin 3 receptor (NK3R) antagonist, which is being developed by Astellas Pharma Inc. for the treatment of moderate to severe vasomotor symptoms (VMS) or hot flashes due to menopause. Inhibiting NK3R-mediated signaling in the central nervous system is a non-hormonal strategy to modulate the activity of neurons that are associated with thermoregulation, thereby reducing the frequency and severity of VMS. VEOZAH is a neurokinin 3 (NK3) receptor antagonist that blocks neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron to modulate neuronal activity in the thermoregulatory center. Fezolinetant has a high affinity for the NK3 receptor (Ki value of 19.9 to 22.1 nmol/L), which is more than 450-fold higher than the binding affinity to NK1 or NK2 receptors. Fezolinetant received its first approval in the USA in May 2023 for the treatment of moderate to severe VMS due to menopause.

Mitapivat (AG-348; PKM2 activator 1020) is a novel, first-in-class oral small molecule allosteric activator of the pyruvate kinase enzyme. Mitapivat has been shown to significantly upregulate both wild-type and numerous mutant forms of erythrocyte pyruvate kinase (PKR), increasing adenosine triphosphate (ATP) production and reducing levels of 2,3-diphosphoglycerate. Given this mechanism, mitapivat has been evaluated in clinical trials in a wide range of hereditary hemolytic anemias, including pyruvate kinase deficiency (PKD), sickle cell disease, and the thalassemias. Mitapivat was approved for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency in the United States in February 2022, and in the European Union in November 2022.

Voclosporin (Lupkynis™) is an oral calcineurin inhibitor immunosuppressant that is being developed by Aurinia Pharmaceuticals. Voclosporin is an analogue of cyclosporine with a modification at the amino acid-1 position. The drug has been designed to show improved potency against calcineurin inhibition and better metabolic stability than cyclosporine. Although the exact mechanism of voclosporin is not yet clear, it inhibits calcineurin, thereby blocking lymphocyte proliferation and T-cell mediated immune responses, as well as increasing podocyte integrity in the kidney. In January 2021, based on positive results from the pivotal phases II and III trials, oral voclosporin received its first approval in the USA for use in combination with a background immunosuppressive therapy regimen for adults with active lupus nephritis. Voclosporin is also being explored for the novel coronavirus disease 2019 (COVID-19) in kidney transplant recipients. Clinical evaluation of voclosporin for plaque psoriasis, coronary artery restenosis and rheumatoid arthritis has been discontinued and no recent development for prevention of renal transplant rejection has been identified since 2015.

Difelikefalin (Korsuva™) is a synthetic peptide agonist of the kappa opioid receptor being developed by Cara Therapeutics for the treatment of pruritus. In August 2021, intravenous difelikefalin was approved in the USA for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD) in adults undergoing haemodialysis. Difelikefalin selectively acts on kappa opioid receptors in peripheral tissues, which contribute to pruritis and nociception. The activation of opioid receptors in peripheral neurons and keratinocytes reduces afferent (sensory) impulses towards the central nervous system, decreasing pain signals. Activating kappa opioid receptors on immune cells, including monocytes and T lymphocytes, decreases the release of pro-inflammatory chemicals such as prostaglandins.

Finerenone (Kerendia®), a first-in-class, orally administered, selective, nonsteroidal mineralocorticoid receptor antagonist (MRA), is being developed by Bayer HealthCare Pharmaceuticals for the treatment of diabetic kidney disease (DKD) and heart failure (HF), including chronic HF (CHF). Finerenone blocks MR mediated sodium reabsorption and MR overactivation in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, and blood vessels) tissues. MR overactivation is thought to contribute to fibrosis and inflammation. Finerenone has a high potency and selectivity for the MR and has no relevant affinity for androgen, progesterone, estrogen, and glucocorticoid receptors. Finerenone has been approved in the USA to reduce the risk of sustained estimated glomerular filtration rate (eGFR) decline, end stage renal disease (ESRD), cardiovascular death, nonfatal myocardial infarction (MI), and hospitalization for HF in adults with chronic kidney disease (CKD) associated with type 2 diabetes (T2D). Finerenone is undergoing regulatory assessment in the EU and in China. A phase III trial is investigating finerenone in patients who have HF with preserved ejection fraction.

Cortexolone 17α-propionate (WINLEVI, BREEZULA) is a steroid belonging to the family of cortexolone derivatives. It is a topical and peripherally selective androgen antagonist. WINLEVI is used for the treatment of acne and has completed Phase II clinical trials and Phase III trials. BREEZULA is used for the treatment of androgenic alopecia and is currently undergoing a Phase II trial in the US.

Cedazuridine is a specific cytidine deaminase (CDA) inhibitor that was approved in combination with decitabine for the treatment of variable forms of myelodysplastic syndrome (MDS). It is known that decitabine is rapidly metabolized by CDA prior to reaching systemic circulation when administered orally. Thus, cedazuridine by inhibition of CDA increases systemic exposure of decitabine.

Vibegron is a selective beta 3 adrenergic receptor (β3AR) agonist that is being developed in Japan jointly by Kyorin Pharmaceutical Co., Ltd and Kissei Pharmaceutical Co., Ltd and in other regions worldwide (except in several other Asian countries) by Urovant Sciences for the treatment of overactive bladder (OAB). Vibegron potently activates human b3AR and increases cAMP levels, with an EC50 of 1.1 nM. Based on results from Japanese phase III trials, vibegron received approval in Japan in September 2018 for this indication. Vibegron, an active ingredient of Beova® Tablets, is a novel once-daily oral treatment for overactive bladder (OAB), acts selectively on the bladder's β3-adrenergic receptor, relaxes the bladder and enhances the urine collection, and consequently improves the symptoms of urgency, urinary frequency and urge urinary incontinence associated with OAB. On December 23, 2020 the FDA approved vibegron (Gemtesa) for the treatment of adult patients with overactive bladder (OAB) with symptoms of urge urinary incontinence (UUI), urgency, and urinary frequency.

ODM-201 (also known as BAY-1841788) is a non-steroidal antiandrogen, specifically, a full and high-affinity antagonist of the androgen receptor (AR), that is under development by Orion and Bayer HealthCare for the treatment of advanced, castration-resistant prostate cancer (CRPC). ODM-201 appears to negligibly cross the blood-brain-barrier. This is beneficial due to the reduced risk of seizures and other central side effects from off-target GABAA receptor inhibition that tends to occur in non-steroidal antiandrogens that are structurally similar to enzalutamide. Moreover, in accordance with its lack of central penetration, ODM-201 does not seem to increase testosterone levels in mice or humans, unlike other non-steroidal antiandrogens. Another advantage is that ODM-201 has been found to block the activity of all tested/well-known mutant ARs in prostate cancer, including the recently-identified clinically-relevant F876L mutation. ODM-201 has been studied in phase I and phase II clinical trials and has thus far been found to be effective and well-tolerated, with the most commonly reported side effects including fatigue, nausea, and diarrhea. No seizures have been observed.