PF-04965842 is an orally administered selective Janus kinase 1 (JAK1) inhibitor. PF-04965842 is currently in clinical trials for the treatment of autoimmune diseases.

Tapinarof (also known as benvitimod, WB-1001; GSK-2894512), a therapeutic aryl hydrocarbon receptor agonist that selectively modulates the cytokine cascade deep under the skin, a process that rapidly decreases inflammations and skin plague. Tapinarof cream 1% (VTAMA®) is being developed by Dermavant Sciences Inc. (a subsidiary of Roivant Sciences Inc.) as a once-daily topical treatment for plaque psoriasis and atopic dermatitis. In May 2022, tapinarof cream 1% was approved in the USA for the topical treatment of plaque psoriasis in adults. Tapinarof cream 1% is also being investigated for the treatment of atopic dermatitis.

Oteseconazole (VIVJOA™) is an orally administered azole antifungal agent developed by Mycovia Pharmaceuticals for the treatment of fungal infections. It inhibits cytochrome P450 (CYP) 51, thereby affecting the formation and integrity of the fungal cell membrane, but has a low affinity for human CYP enzymes due to its tetrazole metal-binding group. Oteseconazole is the first agent to be approved (in April 2022) for recurrent vulvovaginal candidiasis (RVVC) in the USA, where it is indicated to reduce the incidence of RVVC in females with a history of RVVC who are NOT of reproductive potential. Clinical development for the treatment of onychomycosis, and invasive and opportunistic infections is ongoing.

Trofinetide (NNZ 2566), a proprietary small molecule analogue of glycine-proline-glutamate [Glypromate®], is being developed by Neuren Pharmaceuticals and Acadia Pharmaceuticals for the treatment of brain injuries, fragile X syndrome, Rett syndrome. Trofinetide is a synthetic analogue of a naturally occurring neurotrophic peptide derived from IGF-1, a growth factor produced by brain cells. In animal models, trofinetide exhibits a wide range of important effects including inhibiting neuroinflammation, normalizing the role of microglia and correcting deficits in synaptic function. Trofinetide was approved in March 2023 in the USA for the treatment of Rett syndrome in adult and pediatric patients 2 years of age and older.

Belzutifan (PT2977) is an orally active, small molecule inhibitor of hypoxia-inducible factor (HIF)-2alpha (HIF-2a). Upon oral administration, HIF-2alpha inhibitor PT2977 binds to and blocks the function of HIF-2alpha, thereby preventing HIF-2alpha heterodimerization and its subsequent binding to DNA. This results in decreased transcription and expression of HIF-2alpha downstream target genes, many of which regulate hypoxic signaling. This inhibits cell growth and survival of HIF-2alpha-expressing tumor cells. HIF-2alpha, the alpha subunit for the heterodimeric transcription factor HIF-2, is overexpressed in many cancers and promotes tumorigenesis.

Fosdenopterin (NulibryTM) is a synthetic cyclic pyranopterin monophosphate that is being developed by Origin Biosciences (a subsidiary of BridgeBio Pharma) for the treatment of molybdenum cofactor deficiency (MoCD) type A. Patients with MoCD Type A have mutations in the MOCS1 gene leading to deficient MOCS1A/B dependent synthesis of the intermediate substrate, cPMP. Substrate replacement therapy with NULIBRY provides an exogenous source of cPMP, which is converted to molybdopterin. Molybdopterin is then converted to molybdenum cofactor, which is needed for the activation of molybdenum-dependent enzymes, including sulfite oxidase (SOX), an enzyme that reduces levels of neurotoxic sulfites. Fosdenopterin was approved by the US FDA in February 2021 for use in reducing the risk of mortality in paediatric and adult patients with MoCD type A.

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.

Samidorphan, which was developed by Alkermes, is an opioid receptor antagonist that has been co-formulated with olanzapine into a single-dose oral tablet to mitigate the risk of weight gain while providing the therapeutic effect of olanzapine. In June 2021, the Food and Drug Administration (FDA) approved Lybalvi (olanzapine/samidorphan) for indications including treatment of adults with schizophrenia and/or bipolar I disorder (acute manic episodes or acute episodes with mixed features).

Fexinidazole is an antiparasitic drug, which is in the phase III of clinical trial for the treatment of Human African Trypanosomiasis, and in the phase II for the treatment Disease, Chagas and Visceral Leishmaniosis. However, for the Visceral Leishmaniosis, studies were terminated, due to lack of efficacy. Fexinidazole rapidly metabolized to two active metabolites, a sulfone and a sulfoxide, which prolong the pharmacological action of parent drug. These metabolites retaine trypanocidal activity but are less effective in nifurtimox-resistant lines, which can lead to the potential danger in the use of fexinidazole as a monotherapy.