The dihydrochloride salt of nolatrexed, a water-soluble lipophilic quinazoline folate analog with antineoplastic activity. Nolatrexed occupies the folate binding site of thymidylate synthase, resulting in inhibition of thymidylate synthase activity and thymine nucleotide synthesis with subsequent inhibition of DNA replication, DNA damage, S-phase cell cycle arrest, and caspase-dependent apoptosis. This agent also exhibits radiosensitizing activity. Orphan designation of nolatrexed was granted in the Unites States of America for treatment of hepatocellular carcinoma.

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.

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.

Selisistat (EX 527) was discovered by Elixir scientists as a selective human SIRT1 inhibitor and exhibits >200-fold selectivity against SIRT2 and SIRT3. Human SIRT1 is an enzyme that deacetylates the p53 tumor suppressor protein and has been suggested to modulate p53-dependent functions including DNA damage-induced cell death. It was shown that drug was highly safe in toxicology studies. Selisistat passed Phase II clinical trials to treat Huntington’s disease, but that study was discontinued.

Beloranib (also known as ZGN-433 or CKD-732), a fumagillin anticancer drug that initially was developed by CKD Pharmaceuticals for the treatment of solid tumors. Beloranib is a potent inhibitor of methionine aminopeptidase 2 (MetAP2), an enzyme that modulates the activity of key cellular processes that control metabolism. This drug was studied for the treatment of Prader-Willi syndrome and obesity caused by hypothalamic injury, including craniopharyngioma-associated obesity and severe obesity in the general population. European Commission has granted orphan drug designation for beloranib for the treatment of craniopharyngioma, a rare form of benign brain tumor and for the treatment of Prader-Willi syndrome. Beloran participated in phase III clinical trials to evaluate efficacy and safety in obese adolescent and adult subjects with Prader-Willi Syndrome, but these studies were terminated. In 2016, Zafgen, the company developed the drug, based on discussions with the regulatory authority and review of obstacles, costs and development timelines to gain marketing approval for beloranib, has decided to discontinue further development of the drug.

Linsitinib is an inhibitor of the insulin receptor and the insulin-like growth factor 1 receptor, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell apoptosis. Linsitinib is in phase II clinical trials for the treatment of metastatic prostate carcinoma, gastrointestinal stromal tumors and other cancers. Common adverse events included fatigue, nausea hyperglycaemia and anorexia.