Treosulfan (l-threitol-1,4-bis-methanesulfonate; dihydroxybusulfan) is a prodrug of a bifunctional alkylating cytotoxic agent that is approved for the treatment of ovarian carcinomas in a number of European countries. The antitumor activity of treosulfan has been shown in a variety of solid tumors. It is used for the treatment of all types of ovarian cancer, either supplementary to surgery or palliatively. Treosulfan is a prodrug that is converted nonenzymatically first to a mono-epoxide – (2S,3S)- 1,2-epoxy-3,4-butanediol-4-methanesulfonate – and then to a diepoxide – l-diepoxybutane, which is also a metabolite of butadiene – under physiological conditions. Such conversions are assumed to account for the alkylating and therapeutic activities of treosulfan.

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.

Durlobactam is a new member of the diazabicyclooctane class of beta-lactamase inhibitors with broad-spectrum activity against Ambler class A, C, and D serine beta-lactamases. Sulbactam is a first-generation beta-lactamase inhibitor with activity limited to a subset of class A enzymes that also has direct-acting antibacterial activity against Acinetobacter spp. The latter feature is due to sulbactam's ability to inhibit certain penicillin-binding proteins, essential enzymes involved in bacterial cell wall synthesis in this pathogen. Because sulbactam is also susceptible to cleavage by numerous beta-lactamases, its clinical utility for the treatment of contemporary Acinetobacter infections is quite limited. However, when combined with durlobactam, the activity of sulbactam is effectively restored against these notoriously multidrug-resistant strains. In May 2023, the FDA approved Innoviva’s antibiotic, sulbactam-durlobactam (Xacduro), for treatment in patients 18 years of age and older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible isolates of ABC.

Elacestrant (ER-306323 or RAD 1901 [6R)-6-(2-(N-(4-(2-(ethylamino)ethyl)benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol dihydrochloride]) is an estrogen receptor antagonist that binds to estrogen receptor-alpha (ERα). In ERpositive (ER ) HER2-negative (HER2-) breast cancer cells, elacestrant inhibited 17β-estradiol mediated cell proliferation at concentrations inducing degradation of ERα protein mediated through proteasomal pathway. Elacestrant demonstrated in vitro and in vivo antitumor activity including in ER HER2- breast cancer models resistant to fulvestrant and cyclin-dependent kinase 4/6 inhibitors and those harboring estrogen receptor 1 gene (ESR1) mutations. On January 27, 2023, the Food and Drug Administration (FDA) approved elacestrant (Orserdu, Stemline Therapeutics, Inc.) for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

Sparsentan (RE-021; BMS-346567; PS433540; DARA-a) is a novel candidate in development by Retrophin for the treatment of focal segmental glomerulosclerosis (FSGS), a serious kidney disorder that often leads to end-stage renal disease (ESRD). Sparsentan is a single molecule with antagonism of the endothelin type A receptor (ETAR) and the angiotensin II type 1 receptor (AT1R). Sparsentan has high affinity for both the ETAR (Ki= 12.8 nM) and the AT1R (Ki=0.36 nM), and greater than 500-fold selectivity for these receptors over the endothelin type B and angiotensin II subtype 2 receptors. Endothelin-1 and angiotensin II are thought to contribute to the pathogenesis of IgAN via the ETAR and AT1R, respectively. The US Food and Drug Administration gave accelerated approval on February 17 2023 to sparsentan (Filspari), the first non-immunosuppressive therapy labeled for treating adults with primary immunoglobulin A (IgA) nephropathy.

Leniolisib (JOENJA®) is an oral selective phosphoinositide 3-kinase-delta (PI3Kdelta) inhibitor being developed by Pharming Group NV in-licensed from Novartis for the treatment of immunodeficiency disorders. Leniolisib inhibits PI3K-delta by blocking the active binding site of PI3K-delta. In cell-free isolated enzyme assays, leniolisib was selective for PI3K-delta over PI3K-alpha (28-fold), PI3K-beta (43-fold), and PI3K-gamma (257-fold), as well as the broader kinome. In cell-based assays, leniolisib reduced pAKT pathway activity and inhibited proliferation and activation of B and T cell subsets. Gain-of-function variants in the gene encoding the p110-delta catalytic subunit or loss of function variants in the gene encoding the p85-alpha regulatory subunit each cause hyperactivity of PI3K-delta. Leniolisib inhibits the signalling pathways that lead to increased production of PIP3, hyperactivity of the downstream mTOR/AKT pathway, and to the dysregulation of B and T cells. In March 2023, leniolisib received its first approval for the treatment of activated PI3Kdelta syndrome (APDS) in adult and paediatric patients 12 years of age and older. Leniolisib is also under regulatory review in European Union for the treatment of APDS. Development of leniolisib for the treatment of Sjögren's syndrome has been discontinued.

Fezolinetant (VEOZAH™) is an oral, small molecule, neurokinin 3 receptor (NK3R) antagonist, which is being developed by Astellas Pharma Inc. for the treatment of moderate to severe vasomotor symptoms (VMS) or hot flashes due to menopause. Inhibiting NK3R-mediated signaling in the central nervous system is a non-hormonal strategy to modulate the activity of neurons that are associated with thermoregulation, thereby reducing the frequency and severity of VMS. VEOZAH is a neurokinin 3 (NK3) receptor antagonist that blocks neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron to modulate neuronal activity in the thermoregulatory center. Fezolinetant has a high affinity for the NK3 receptor (Ki value of 19.9 to 22.1 nmol/L), which is more than 450-fold higher than the binding affinity to NK1 or NK2 receptors. Fezolinetant received its first approval in the USA in May 2023 for the treatment of moderate to severe VMS due to menopause.

Lenacapavir (Sunlenca®) is a long-acting capsid inhibitor of human immunodeficiency virus type 1 (HIV-1) being developed by Gilead Sciences Inc. Lenacapavir is a multistage, selective inhibitor of HIV-1 capsid function that directly binds to the interface between capsid protein (p24) subunits in hexamers. Surface plasmon resonance sensorgrams showed dose-dependent and saturable binding of lenacapavir to cross-linked wild-type capsid hexamer with an equilibrium binding constant (KD) of 1.4 nM. Lenacapavir inhibits HIV-1 replication by interfering with multiple essential steps of the viral lifecycle, including capsid-mediated nuclear uptake of HIV-1 proviral DNA (by blocking nuclear import proteins binding to capsid), virus assembly and release (by interfering with Gag/Gag-Pol functioning, reducing production of capsid protein subunits), and capsid core formation (by disrupting the rate of capsid subunit association, leading to malformed capsids). It is available as an oral tablet and injectable solution, with the latter being a slow-release formulation to allow bi-annual subcutaneous administration. In August 2022, lenacapavir received its first approval in the EU for use in combination with other antiretroviral(s) in adults with multi-drug resistant HIV infection, for whom it is otherwise not possible to construct a suppressive anti-viral regimen. On December 22, 2022 the US Food and Drug Administration granted approval for Gilead Sciences’ Sunlenca (lenacapavir) plus other antiretroviral(s) to treat human immunodeficiency virus type 1 infection.

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.