Verucerfont (formerly GSK561679), a corticotropin releasing factor (CRF) receptor 1 antagonist, is being developed by GlaxoSmithKline under the license from Neurocrine Biosciences, for the treatment of post-traumatic stress disorder and congenital adrenal hyperplasia (CAH). Verucerfont is a potent, selective CRF1 receptor antagonist (IC50 for CRF1, CRF2, and CRF-BP ~ 6.1, >1000 and >1000 nM, respectively), and is orally available and brain penetrant. Verucerfont is in phase II clinical trials for the treatment of post-traumatic stress disorder or alcoholism. The compound was also in trials for the treatment of classic congenital adrenal hyperplasia (CAH). However, this research has been discontinued. In 2015, orphan drug designation was received in U.S. for the indication.

Mocetinostat is an rationally designed, orally available, Class 1-selective, small molecule, 2-aminobenzamide HDAC inhibitor with potential antineoplastic activity. Mocetinostat binds to and inhibits Class 1 isoforms of HDAC, specifically HDAC 1, 2 and 3, which may result in epigenetic changes in tumor cells and so tumor cell death; although the exact mechanism has yet to be defined, tumor cell death may occur through the induction of apoptosis, differentiation, cell cycle arrest, inhibition of DNA repair, upregulation of tumor suppressors, down regulation of growth factors, oxidative stress, and autophagy, among others. It is undergoing clinical trials for treatment of various cancers including bladder cancer, diffuse large B cell lymphoma, follicular lymphoma, myelodysplastic syndromes, non-small cell lung cancer. Fatigue, weight loss or anorexia were most common treatment-related adverse events.

PBI 4050, a synthetic analog of a medium-chain fatty acid that displays agonist and antagonist ligand affinity toward GPR40 and GPR84, that was developed for managing inflammatory and fibrosis-related diseases. In addition, PBI-4050 may exert antifibrotic activity in the liver through a novel mechanism of action involving modulation of intracellular ATP levels and the LKB1/AMPK/mTOR pathway in stellate cells. This drug participated in clinical trials for the treatment of acute lung injury, cystic fibrosis, diabetic nephropathies; idiopathic pulmonary fibrosis; metabolic syndrome; scleroderma; type 2 diabetes mellitus. Besides, this drug has granted a Rare Pediatric Disease Designation for the treatment of Alström syndrome (AS). PBI-4050 was also previously granted Orphan Drug Designation by the FDA and the EMA for the treatments of AS and idiopathic pulmonary fibrosis (IPF) as well as PIM (Promising Innovative Medicine) designation by the Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of IPF and AS. The FDA grants Rare Pediatric Disease Designations for serious or life-threatening diseases wherein the serious or life-threatening manifestations primarily affect individuals aged from birth to 18 years, including age groups, often called neonates, infants, children, and adolescents. Now Prometic Life Sciences plans to file investigational new drug application for pivotal phase III trial for Alstrom's syndrome in the second half of 2019.

Soraprazan (remofuscin), a potassium-competitive acid blocker (P-CAB; formerly called an acid pump antagonist [APA]), is being developed by Katairo GmbH for the treatment of Stargardt's disease and dry age-related macular degeneration (AMD). Clinical development is underway for Stargardt's disease and dry age-related macular degeneration in the Netherlands and Germany. On 13 November 2013, orphan designation was granted by the European Commission to Katairo GmbH, Germany, for soraprazan for the treatment of Stargardt’s disease. Soraprazan is a a highly potent reversible, and fast-acting inhibitor of gastric H,K-ATPase. Soraprazan shows immediate inhibition of acid secretion in various in vitro models and in vivo and was found to be more than 2000-fold selective for H,K-ATPase over Na,K- and Ca-ATPases.

EC-18 (now known as mosedipimod), a synthetic copy of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) that was developed by Enzychem Lifescience for oral administration for the treatment of immune and inflammatory related diseases, including psoriasis, rheumatoid arthritis, asthma, atopic dermatitis, and sepsis. The US Food and Drug Administration (FDA) has granted Orphan Drug Designation to EC-18 for the treatment of Acute Radiation Syndrome (ARS) and for the for the neutropenia treatment. Besides, the EC-18 is participating in phase II clinical trials to investigate the efficacy and safety of the agent for chemoradiation-induced oral mucositis and chemotherapy-induced neutropenia. This drug has a multimodal mechanism of action. It stimulates calcium influx into T lymphocytes and increases the production of various cytokines. In addition, EC-18 enhances the cytolytic activity of natural killer (NK) cells and suppresses the expression of the transmembrane protein tumor cell toll-like receptor 4 (TLR-4) on cancer cells, thus suppresses tumor cell proliferation.

Emeramide or Irminix® (N,N'-bis(2-mercaptoethyl)isophthalamide (NBMI)) is a lipid-soluble thiol-redox antioxidant and heavy metal chelator. Orphan Drug Designation has been granted for the prevention and treatment of mercury toxicity in the EU and USA. Phase 1 and Phase 2a clinical studies have been performed and found Irminix® to be effective and safe with no adverse effects. A Phase 2a clinical trial for the treatment of chronic obstructive pulmonary disease has been completed in summer of 2018 and found Irminix® to be safe with no adverse effects.

Livoletide (AZP-531) is an analog of unacylated ghrelin, a naturally occurring hormone that is thought to counteract the effects of acylated ghrelin. The drug was designed to improve glycaemic control and reduce weight. Livoletide participated in pivotal phase 2b/3 clinical study for the treatment of Prader-Willi syndrome. In addition, the drug was studied in patients with type 2 diabetes mellitus (T2D). Its pharmacokinetic profile, suitable for once daily dosing, and metabolic effects support further clinical development for T2D.

Oglufanide, an angiogenesis inhibitor, an immunomodulator, that originally was developed and registered in Russia under the brand name timogen. Oglufanide inhibits vascular endothelial growth factor (VEGF), which may inhibit angiogenesis. This agent has also been reported to stimulate the immune response to hepatitis C virus and intracellular bacterial infections. Oglufanide was studied in the USA for the treatment of cancer, and in September 2001, it was granted Orphan Drug designation for the treatment of ovarian cancer. In addition, in Australia this drug was involved in phase II clinical trial for the treatment of hepatitis C. Oglufanide is also participated in phase III trials for patients with Kaposi's sarcoma, however, this study was discontinued.