Zavegepant is a third generation, small-molecule, calcitonin gene-related peptide (CGRP) receptor antagonist being developed by Pfizer, under a license from Bristol-Myers Squibb, for the prevention and treatment of chronic and episodic migraine. In March 2023, zavegepant nasal spray (ZAVZPRET™) received its first approval in the USA for the acute treatment of migraine with or without aura in adults, based on two randomized, double-blind, placebo-controlled studies. Clinical development of an oral formulation of zavegepant is currently underway.

Pirtobrutinib is a small molecule, noncovalent inhibitor of BTK. BTK is a signaling protein of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Pirtobrutinib binds to wild type BTK and BTK harboring C481 mutations, leading to inhibition of BTK kinase activity. In nonclinical studies, pirtobrutinib inhibited BTK-mediated B-cell CD69 expression and inhibited malignant B-cell proliferation. Pirtobrutinib showed dose-dependent anti-tumor activities in BTK wild type and BTK C481S mutant mouse xenograft models. On January 27, 2023, the Food and Drug Administration (FDA) granted accelerated approval to pirtobrutinib (Jaypirca, Eli Lilly and Company) for relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor.

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.

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.

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.

Trilaciclib (Cosela™) is a small-molecule, short-acting, inhibitor of cyclin-dependent kinases (CDK) 4 and 6 developed by G1 Therapeutics for its myeloprotection and potential antitumor efficacy and safety benefits in combination with cancer chemotherapy. CDKs govern cell cycle progression, and trilaciclib induces a transient, reversible G1 cell cycle arrest of proliferating haematopoietic stem and progenitor cells in bone marrow, thus protecting them from damage during chemotherapy. In February 2021, trilaciclib received its first approval in the USA to decrease the incidence of chemotherapy-induced myelosuppression in adult patients when administered prior to a platinum/etoposide-containing regimen or topotecan-containing regimen for extensive-stage small cell lung cancer (ES-SCLC). Clinical studies in breast cancer, colorectal cancer and small cell lung cancer are underway in several countries.

Lurbinectedin (PM-01183) - is a synthetic tetrahydropyrrolo [4, 3, 2-de]quinolin-8(1H)-one alkaloid analogue with potential antineoplastic activity. Lurbinectedin covalently binds to residues lying in the minor groove of DNA, which may result in delayed progression through S phase, cell cycle arrest in the G2/M phase and cell death. Lurbinectedin is a novel anticancer agent currently undergoing late-stage (Phase II /III) clinical evaluation in platinum-resistant ovarian, BRCA1/2-mutated breast and small-cell lung cancer. Lurbinectedin is structurally related to trabectedin and it inhibits active transcription and the DNA repair machinery in tumour cells.

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.

Pexidartinib (PLX3397) is a small-molecule receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Pexidartinib binds to and inhibits phosphorylation of stem cell factor receptor (KIT), colony-stimulating factor-1 receptor (CSF1R) and FMS-like tyrosine kinase 3 (FLT3), which may result in the inhibition of tumor cell proliferation and down-modulation of macrophages, osteoclasts and mast cells involved in the osteolytic metastatic disease. FDA has granted Breakthrough Therapy Designation to pexidartinib (PLX3397) for the treatment of tenosynovial giant cell tumor (TGCT) where surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. In addition to Breakthrough Therapy Designation, pexidartinib (PLX3397) has been granted Orphan Drug Designation by FDA for the treatment of pigmented villonodular synovitis (PVNS) and giant cell tumor of the tendon sheath (GCT-TS). It also has received Orphan Designation from the European Commission for the treatment of TGCT.