Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant, and selective inhibitor of mutant IDH1. Olutasidenib was designed to reduce R-2-HG and revert pathologic epigenetic modifications that impair cellular differentiation to restore regulatory enzyme function. In patients with AML, susceptible IDH1 mutations are defined as those leading to increased levels of 2-hydroxyglutarate (2-HG) in the leukemia cells and where efficacy is predicted by 1) clinically meaningful remissions with the recommended dose of olutasidenib and/or 2) inhibition of mutant IDH1 enzymatic activity at concentrations of olutasidenib sustainable at the recommended dosage according to validated methods. The most common of such mutations in patients with AML are R132H and R132C substitutions. In vitro, olutasidenib inhibited mutated IDH1 R132H, R132L, R132S, R132G, and R132C proteins; wild-type IDH1 or mutated IDH2 proteins were not inhibited. Olutasidenib inhibition of mutant IDH1 led to decreased 2-HG levels in vitro and in in vivo xenograft models. On December 1, 2022, the FDA approved olutasidenib (brand name Rezlidhia) capsules for adult patients with relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation as detected by an FDA-approved test.

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.

Maralixibat (Livmarli™) is a potent, apical, sodium‐dependent, bile acid transporter competitive inhibitor with minimal systemic absorption being developed by Mirum Pharmaceuticals for the treatment of rare cholestatic liver diseases including Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC) and biliary atresia. Maralixibat received its first approval on 29 September 2021, in the USA, for use in the treatment of cholestatic pruritus in patients with ALGS 1 year of age and older. Maralixibat is also under regulatory review for ALGS in Europe, and clinical development for cholestatic liver disorders including ALGS in patients under 1 year of age, PFIC and biliary atresia is continuing in several other countries. This article summarises the milestones in the development of maralixibat leading to this first approval for ALGS.

Ibrexafungerp (BREXAFEMME®) is an orally active triterpenoid antifungal drug being developed by SCYNEXIS, Inc. for the treatment of fungal infections. The inhibition of β-1,3-D glucan synthetase by ibrexafungerp compromises the integrity of fungal cell walls. Ibrexafungerp has been recently approved for the treatment of vulvovaginal candidiasis (VVC), and it is the first novel antifungal drug class to be approved in more than 20 years. Food and Drug Administration's decision was based on positive results from two pivotal phase III studies in which oral ibrexafungerp proved both safe and effective in patients with vulvovaginal candidiasis. Development for the treatment of recurrent VVC and invasive fungal infections is ongoing.

Cabotegravir is an investigational drug that is being studied for the treatment and prevention of HIV infection. Cabotegravir belongs to a class (group) of HIV drugs called integrase inhibitors. Integrase inhibitors block an HIV enzyme called integrase. (An enzyme is a protein that starts or increases the speed of a chemical reaction.) By blocking integrase, integrase inhibitors prevent HIV from multiplying and can reduce the amount of HIV in the body. Cabotegravir does not require boosting with an additional drug. Two forms of cabotegravir are being studied: tablets that are taken by mouth (known as oral cabotegravir or oral CAB) and a long-acting injectable form that is injected into the muscle (known as cabotegravir LA or CAB LA; LA stands for "long-acting"). (A long-acting drug formulation works over a long period of time. Using this type of drug might mean that the drug could be taken less often, making a treatment or prevention regimen simpler to take.) Cabotegravir is in Phase-III clinical trials for HIV infections.

Remimazolam is an intravenous benzodiazepine sedative-hypnotic with rapid onset and offset of action. This compound undergoes organ-independent metabolism to an inactive metabolite. Like other benzodiazepines, remimazolam can be reversed with flumazenil to rapidly terminate sedation and anesthesia. Phase I and II clinical trials have shown that remimazolam is safe and effective when used for procedural sedation. Phase III clinical trials have been completed investigating efficacy and safety in patients undergoing bronchoscopy and colonoscopy. The developer of this drug has suggested that intensive care unit sedation (beyond 24 hours) could be another possible indication for further development, since it is unlikely that prolonged infusions or higher doses of remimazolam would result in accumulation and extended effect.

Fostemsavir (BMS-663068) is an investigational attachment inhibitor with a unique mechanism of action. It is a prodrug of temsavir, which binds to HIV envelope glycoprotein 120 (gp120), thereby preventing viral attachment to the host CD4 cell surface receptor. In the absence of effective binding of HIV gp120 with the host CD4 receptor, HIV does not enter the host cell. Because fostemsavir has a novel mechanism of action, the drug should have full activity against HIV strains that have developed resistance to other classes of antiretroviral medications. In a phase 2b study of treatment-experienced individuals, fostemsavir appeared to be well tolerated. Phase 3 studies are ongoing.

Berotralstat (ORLADEYO™; BCX7353) is an orally administered kallikrein inhibitor, which has been developed by BioCryst Pharmaceuticals for hereditary angioedema (HAE). The inhibition of kallikrein by berotralstat decreases the production of bradykinin, which prevents the localised tissue oedema that occurs during attacks of HAE. Berotralstat has been approved in the USA, and subsequently in Japan, for prophylaxis to prevent attacks of HAE in adults and paediatric patients aged 12 years or older.

Osilodrostat (INN, USAN) (developmental code name LCI-699) is an orally active, non-steroidal corticosteroid biosynthesis inhibitor which is under development by Novartis for the treatment of Cushing's syndrome and pituitary ACTH hypersecretion (a specific subtype of Cushing's syndrome). Osilodrostat specifically acts as a potent and selective inhibitor of aldosterone synthase (CYP11B2) and at higher dosages of 11β-hydroxylase (CYP11B1). Osilodrostat decreases plasma and urinary aldosterone levels and rapidly corrects hypokalemia, in patients with primary aldosteronism and hypertension. At doses ≥1 mg o.d. Osilodrostat markedly increases 11-deoxycortisol plasma levels and blunts ACTH-stimulated cortisol release in ≈20% of patients, consistent with the inhibition of CYP11B1. In patients with resistant hypertension, Osilodrostat produces a non-significant reduction in blood pressure, possibly due to the increase in 11-deoxycortisol levels and the stimulation of the hypothalamic-pituitary-adrenal feedback axis. Because of the lack of selectivity, poor antihypertensive effect, and short half-life, the development of Osilodrostat as antihypertensive was halted. As of 2017, Osilodrostat is in phase III and phase II clinical trials for the treatment of pituitary ACTH hypersecretion and Cushing's syndrome, respectively.

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.