Upadacitinib (ABT-494) is a Janus kinase 1 (JAK1) inhibitor currently being developed by AbbVie for the treatment of rheumatoid arthritis (RA), Crohn’s disease, ulcerative colitis, atopic dermatitis, and psoriatic arthritis. It is also being investigated as a potential treatment for people with active ankylosing spondylitis (AS). Currently, upadacitinib is being evaluatedin six global phase III studies in RA and twophase III studies in psoriatic arthritis (PsA), inaddition to phase II studies in Crohn’s disease and atopicdermatitis and a combined phase II/III study inulcerative colitis. Upadacitinib is a potent and selective Janus kinase (JAK) 1 inhibitor with an IC50 of 43 nM.

ADX-N05, originally discovered by SK Holdings, is a selective dopamine and norepinephrine reuptake inhibitor (DNRI). ADX-N05 (Solriamfetol, sold under the brand name Sunosi) is approved in the US and is under regulatory review in the EU to improve wakefulness in adult patients with hypersomnia associated with narcolepsy or obstructive sleep apnoea.The US FDA has approved solriamfetol (Sunosi, Jazz Pharmaceuticals) for the treatment of excessive daytime sleepiness in adults with narcolepsy or obstructive sleep apnea.The dual-acting dopamine and norepinephrine reuptake inhibitor is approved for narcolepsy in once-daily 75 mg and 150 mg doses, and in obstructive sleep apnea in once-daily 37.5 mg, 75 mg, and 150 mg doses.

Allopregnanolone is a neurosteroid metabolite of progesterone. It is an allosteric modulator of inhibitory γ-aminobutyric acid (GABA-A) receptors on neural stem cells and other cell types in the brain. Allopregnanolone has effects similar to those of other positive allosteric modulators of the GABA action at GABAA receptor such as the benzodiazepines, including anxiolytic, sedative, and anticonvulsant activity. A solution of allopregnanolone, SAGE-547 is an intravenous allosteric modulator of both synaptic and extrasynaptic γ-aminobutyric acid type A (GABAA)receptors. It's believed that allopregnanolone is effective as an anticonvulsant when prolonged seizure activity has become resistant to benzodiazepine treatment. Under the names brexanolone and SAGE-547, allopregnanolone is under development by SAGE Therapeutics as an intravenously administered drug for the treatment of super-refractory status epilepticus, postpartum depression, and essential tremor. Allopregnanolone is in phase III trials for the treatment of super-refractory status epilepticus (SRSE) and postpartum depression.

Alpelisib (BYL719) is a PI3Kα-selective inhibitor. PI3K-AKT-mTOR pathway is frequently activated in cancer, therefore investigational PI3K inhibitor alpelisib is considered to be effective as an anticancer agent and has been in clinical development by Novartis. Alpelisib have demonstrated activity in preclinical models of solid tumors and had favorable tolerability profiles, with the most common adverse events consistent with “on-target” inhibition of PI3K in early clinical studies. There are ongoing clinical trials of alpelisib in a range of cancer types, including breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and glioblastoma multiforme. Combination therapy with other chemo therapeutics may be preferable.

Ubrogepant, a small molecule drug, is being developed by Merck & Co for the treatment of migraine. The calcitonin gene-related peptide receptor (CGRP) antagonist is administered orally as a film coated tablet. Ubrogepant is a competitive antagonist with high affinity, potency, and selectivity for the human CGRP receptor. In the four clinical studies (ACHIEVE I, ACHIEVE II, UBR-MD-04 and 3110-105-002) ubrogepant demonstrated efficacy, safety and tolerability in the acute treatment of migraine among a broad patient population, including those who had an insufficient response to a triptan or those patients in whom triptans were contraindicated, as well as in patients who had moderate to severe CV risk profile.

Tenapanor is an inhibitor of the sodium-proton (Na(+)/H(+)) exchanger NHE3 and reduces sodium absorption in the GI tract, thus increasing intestinal fluid. Ardelyx has completed Phase 3 development of tenapanor for the treatment of irritable bowel syndrome with constipation (IBS-C) and submitted a new drug application to the U.S. Food and Drug Administration for the treatment of patients with IBS-C. In addition, tenapanor successfully completed phase III clinical trial for the treatment of hyperphosphatemia in people with end-stage renal disease who are on dialysis and RDX013, a potassium secretagogue program for the potential treatment of high potassium, or hyperkalemia, a problem among certain patients with kidney and/or heart disease.

Pretomanid (PA-824) is an experimental anti-tuberculosis drug. Pretomanid is a bicyclic nitroimidazole-like molecule with a very complex mechanism of action. It is active against both replicating and hypoxic, non-replicating Mycobacterium tuberculosis. As a potential TB therapy, it has many attractive characteristics - most notably its novel mechanism of action, its activity in vitro against all tested drug-resistant clinical isolates, and its activity as both a potent bactericidal and a sterilizing agent in mice. In addition, the compound shows no evidence of mutagenicity in a standard battery of genotoxicity studies, no significant cytochrome P450 interactions, and no significant activity against a broad range of Gram-positive and Gram-negative bacteria. This compound has been developed by TB Alliance and is a potential cornerstone of future TB and drug-resistant TB treatment regimens. It is currently undergoing Phase III clinical trials.

Fedratinib (SAR-302503, TG-101348) is a selective small-molecule inhibitor of Janus kinase-2. Fedratinib demonstrated therapeutic efficacy in a murine model of myeloproliferative disease. Sanofi was developing Fedratinib for the treatment of myeloproliferative diseases and solid tumors. The clinical development of fedratinib was terminated after reports of Wernicke's encephalopathy in myelofibrosis patients.

Trifarotene is a novel first-in-class fourth-generation topical retinoid. It is a potent and selective RAR gamma-agonist. In multiple mouse models, trifarotene exhibited superior comedolytic, anti-inflammatory and depigmenting activity compared with other topical retinoids. In this 52-week study, trifarotene was safe, well-tolerated and effective in moderate facial and truncal acne. Trifarotene is in phase II clinical trial for the treatment of ichthyosis.

Siponimod (BAF312) is a dual agonist at the sphingosine-1 phosphate receptors, S1PR1 and S1PR5. The S1P receptor is commonly found on the surface of specific cells residing in the central nervous system (CNS), that are responsible for causing CNS damage that drives loss of function in secondary progressive multiple sclerosis (SPMS). Siponimod (BAF312) enters the brain and by binding to these specific receptors, may prevent the activation of these harmful cells, helping to reduce the loss of physical and cognitive function associated with SPMS.