A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2023.

With 54 new drugs and seven cellular and gene therapy products, the approvals by the US Food and Drug Administration (FDA) recovered 2023 from the 2022 dent back to the levels of 2020-2021. As in previous years of this annual review, we assign these new drugs to one of three levels of innovation: first drug against a condition ("first-in-indication"), first drug using a novel molecular mechanism ("first-in-class"), and "next-in-class," i.e., a drug using an already exploited molecular mechanism. We identify four (7%) "first-in-indication," 22 (36%) "first-in-class," and 35 (57%) "next-in-class" drugs. By treatment area, rare diseases (54%) and cancer drugs (23%) were once again the most prevalent (and partly overlapping) therapeutic areas. Other continuing trends were the use of accelerated regulatory approval pathways and the reliance on biopharmaceuticals (biologics). 2023 marks the approval of a first therapy based on CRISPR/Cas9 gene editing.

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2022.

While new drug approvals by the U.S. Food and Drug Administration (FDA) had remained stable or even increased in the first 2 years of the COVID-19 pandemic, the 37 newly approved drugs in 2022 are considerably less than the 53 and 50 new drugs approved in 2020 and 2021, respectively, and less than the rolling 10-year average of 43. As in previous years of this annual review, we assign these new drugs to one of three levels of innovation: first drug against a condition ("first-in-indication"), first drug using a novel molecular mechanism ("first-in-class"), and "next-in-class," i.e., a drug using an already exploited molecular mechanism. We identify two "first-in-indication" (ganaxolon and teplizumab), 20 (54%) "first-in-class," and 17 (46%) "next-in-class" drugs. By treatment area, rare diseases and cancer drugs were once again the most prevalent (partly overlapping) therapeutic areas. Other continuing trends were the use of accelerated regulatory approval pathways and the reliance on biopharmaceuticals (biologics).

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2021.

The second year of the COVID-19 pandemic had no adverse effect on the number of new drug approvals by the US Food and Drug Administration (FDA). Quite the contrary, with a total of 50 new drugs, 2021 belongs to the most successful FDA years. We assign these new drugs to one of three levels of innovation: (1) first drug against a condition ("first-in-indication"), (2) first drug using a novel molecular mechanism ("first-in-class"), and (3) "next-in-class", i.e., a drug using an already exploited molecular mechanism. We identify 21 first-in-class, 28 next-in-class, and only one first-in-indication drugs. By treatment area, the largest group is once again cancer drugs, many of which target specific genetic alterations. Every second drug approved in 2021 targets an orphan disease, half of them being cancers. Small molecules continue to dominate new drug approvals, followed by antibodies and non-antibody biopharmaceuticals. In 2021, the FDA continued to approve drugs without strong evidence of clinical effects, best exemplified by the aducanumab controversy.

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2020.

While the COVID-19 pandemic also affected the work of regulatory authorities, the US Food and Drug Administration approved a total of 53 new drugs in 2020, one of the highest numbers in the past decades. Most newly approved drugs related to oncology (34%) and neurology (15%). We discuss these new drugs by level of innovation they provide, i.e., first to treat a condition, first using a novel mechanisms of action, and "others." Six drugs were first in indication, 15 first using a novel mechanism of action, and 32 other. This includes many drugs for the treatment of orphan indications and some for the treatment of tropical diseases previously neglected for commercial reasons. Small molecules continue to dominate new drug approvals, followed by antibodies. Of note, newly approved drugs also included small-interfering RNAs and antisense oligonucleotides. These data show that the trend for declines in drug discovery and development has clearly been broken.

Nitric Oxide and S-Nitrosylation in Cardiac Regulation: G Protein-Coupled Receptor Kinase-2 and ß-Arrestins as Targets.

Cardiac diseases including heart failure (HF), are the leading cause of morbidity and mortality globally. Among the prominent characteristics of HF is the loss of ß-adrenoceptor (AR)-mediated inotropic reserve. This is primarily due to the derangements in myocardial regulatory signaling proteins, G protein-coupled receptor (GPCR) kinases (GRKs) and ß-arrestins (ß-Arr) that modulate ß-AR signal termination via receptor desensitization and downregulation. GRK2 and ß-Arr2 activities are elevated in the heart after injury/stress and participate in HF through receptor inactivation. These GPCR regulators are modulated profoundly by nitric oxide (NO) produced by NO synthase (NOS) enzymes through S-nitrosylation due to receptor-coupled NO generation. S-nitrosylation, which is NO-mediated modification of protein cysteine residues to generate an S-nitrosothiol (SNO), mediates many effects of NO independently from its canonical guanylyl cyclase/cGMP/protein kinase G signaling. Herein, we review the knowledge on the NO system in the heart and S-nitrosylation-dependent modifications of myocardial GPCR signaling components GRKs and ß-Arrs.

Role of the ß3-adrenergic receptor subtype in catecholamine-induced myocardial remodeling.

ß3-Adrenoceptors (AR) stimulate cardiac Na+/K+ pump in healthy hearts. ß3-ARs are upregulated by persistent sympathetic hyperactivity; however, their effect on Na+/K+ ATPase activity and ventricular function in this condition is still unknown. Here, we investigate preventive effects of additional ß3-AR activation (BRL) on Na+/K+ ATPase activity and in vivo hemodynamics in a model of noradrenaline-induced hypertrophy. Rats received NA or NA plus simultaneously administered BRL in vivo infusion for 14 days; their cardiac function was investigated by left ventricular pressure-volume analysis. Moreover, fibrosis and apoptosis were also assessed histologically. NA induced an hypertrophic pattern, as detected by morphological, histological, and biochemical markers. Additional BRL exposure reversed the hypertrophic pattern and restored Na+/K+ ATPase activity. NA treatment increased systolic function and depressed diastolic function (slowed relaxation). Additional BRL treatment reversed most NA-induced hemodynamic changes. NA decreased Na+/K+ pump α2 subunit expression selectively, a change also reversed by additional BRL treatment. Increasing ß3-AR stimulation may prevent the consequences of chronic NA exposure on Na+/K+ pump and in vivo hemodynamics. ß3-AR agonism may thus represent a new therapeutic strategy for pharmacological modulation of hypertrophy under conditions of chronically enhanced sympathetic activity.