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.

Potential side effects of currently available pharmacotherapies in male lower urinary tract symptoms suggestive of benign prostatic hyperplasia.

INTRODUCTION: The drug classes of α1-adrenoceptor antagonists, 5α-reductase inhibitors, and phosphodiesterase type 5 inhibitors are guideline-recommended treatments of lower urinary tract symptoms suggestive of benign prostatic hyperplasia; muscarinic receptor antagonists and ß3-adrenoceptor agonists are also recommended if storage symptoms are insufficiently addressed with one of the other three drug classes. AREAS COVERED: We provide a narrative review (no formalized literature searches performed) of the tolerability of these drug classes with emphasis on the more recently introduced medications, on combination treatment, and on more lately emerging risks. EXPERT OPINION/COMMENTARY: The tolerability profiles are distinct between drug classes but, with few exceptions, similar within a drug class. Within a drug, formulations with longer duration of action tend to have better tolerability. Efficacy gains using combination treatment at least partly come at a cost of lesser tolerability. Greater susceptibility to experience adverse events based on age, comorbidities, and comedications appears conceptually important but remains under-investigated in this therapeutic area.

Several classes of medicines are available to treat male lower urinary tract symptoms that are believed to result from an enlarged prostate. These include α₁-adrenoceptor antagonists (α-blockers), 5α-reductase inhibitors (ARI), and phosphodiesterase type 5 inhibitors (PDEI); muscarinic receptor antagonists and ß₃-adrenoceptor agonists are additionally used in men that have persisting storage symptoms upon treatment with the former three drug classes. Each drug class has a distinct tolerability profile. Within a drug class, medicines with a longer duration of action, either intrinsically or due to specific drug formulations, tend to have better tolerability. Men with greater age, comorbidities, and comedications may be at greater risk of experiencing side effects when medically treating their lower urinary tract symptoms. While combination of members of multiple drug classes may increase efficacy, this often comes at the price of experiencing more side effects. The relative benefit/risk ratio needs to be individually analyzed in each patient.

[Conservative and pharmacological treatment of benign prostatic hyperplasia : The German S2e-guideline 2023-part2]. / Konservative und medikamentöse Therapie des benignen Prostatasyndroms : Die deutsche S2e-Leitlinie 2023 ­ Teil 2.

BACKGROUND: Lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH, in German guidelines: benign prostatic syndrome [BPS]) is considered the most common disease of the lower urinary tract in men and can have a tremendous impact on the quality-of-life of affected patients. Conservative and pharmacological therapy of this disease are of great importance, both in improving LUTS and reducing progression-related complications. OBJECTIVES: Presentation of the conservative and pharmacological treatment options according to the current German S2e guideline on BPS. MATERIALS AND METHODS: Summary and overview of chapters 9 and 10 of the current German S2e guideline on BPS. RESULTS: In addition to a controlled watchful waiting for BPS patients without an absolute indication for prostate surgery, a variety of phytopharmacological formulations and synthetic drugs according to the symptomatology and clinical progress are available. Phytotherapy should, due to inconsistent study data, only be considered for mild to moderate symptoms. Synthetic drugs include alpha-blockers, 5α-reductase inhibitors, phosphodiesterase inhibitors, antimuscarinics and, more recently, the ß3-agonist mirabegron in the current guideline. In addition, various combination therapies are listed and evaluated according to their indications, effects and side effects. CONCLUSIONS: The current German S2e guideline on the diagnosis and treatment of BPS provides an evidence-based foundation for finding the best possible and most effective medication.

Progress in Functional Urology Reflected in Recent Papers in the Journal of Clinical Medicine.

Benign conditions of the lower urinary tract, including benign prostatic hyperplasia, overactive bladder syndrome, and stress urinary incontinence, are frequent in the general population. Despite their benign nature, they have major adverse effects on the quality of life of the afflicted patients and their partners. Despite major progress in the diagnosis and treatment of these conditions, improved understanding and management of these patients remain substantial medical needs. This editorial discusses some recent high-quality articles published in the Journal of Clinical Medicine on the understanding of the epidemiology, pathophysiology, diagnostic, and treatment of benign diseases of the lower urinary tract tissues such as the bladder and prostate.

[Diagnostic work-up of benign prostatic hyperplasia : The German S2e-guideline 2023 part 1]. / Diagnostik des benignen Prostatasyndroms : Die deutsche S2e-Leitlinie 2023 Teil 1.

BACKGROUND: Lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH; in German guidelines: benign prostatic syndrome [BPS]) is the most frequent urological disease in men and can result in a considerable deterioration of quality-of-life. BPS can be associated with LUTS, benign prostatic enlargement (BPE), and bladder outlet obstruction (BOO) or benign prostatic obstruction (BPO), respectively. The expert group on BPS of the German Society of Urology has re-evaluated the tests for the assessment of BPH and provides evidence-based recommendations. OBJECTIVES: Presentation and evidence-based rating of tests for the assessment of patients with BPS. MATERIALS AND METHODS: Summary and overview of chapters 5, 6, and 8 of the latest long version of the German S2e guideline on BPS. RESULTS: The diagnostic work-up should clarify (1) whether the complaints of the patient are caused by BPS, (2) how relevant the complaints are and whether treatment is necessary, (3) whether complications of the lower or upper urinary tract already exist, and (4) which treatment will be most suitable. Baseline assessment should be done in all BPS patients and include history, measurement of LUTS and quality-of-life, urinalysis, serum prostate-specific antigen, post-void residual, ultrasound of the lower urinary tract, including measurements of prostate volume, intravesical prostatic protrusion and detrusor wall thickness, and ultrasound of the upper urinary tract. Additional tests can follow when questions remain unanswered after baseline assessment. These optional tests include bladder diaries, uroflowmetry, serum creatinine, urethrocystoscopy, other noninvasive tests for the determination of BOO/BPO such as penile cuff test, condom catheter method and near-infrared spectroscopy, and other imagining tests such as X­ray and MRI investigations. CONCLUSIONS: The updated German S2e guideline summarizes evidence-based recommendations on the diagnostic work-up, including the assessment of the BPS components BPE, LUTS, and BOO/BPO.

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).

Are ß3 -adrenoceptor gene polymorphisms relevant for urology?

AIMS: ß3 -adrenoceptors (ARs) are an important drug target for the treatment of overactive bladder syndrome (OAB) and are under investigation for other indications. The human ß3 -AR gene is polymorphic; an exchange of amino acid tryptophan (Trp) for arginine (Arg) in position 64 of the receptor protein is the most frequent and best-studied polymorphism. A narrative review on the impact of ß3 -AR polymorphisms on urological disease and its treatment is presented. RESULTS: Two out of four studies have reported that the 64Arg allele was found more frequently in subjects with OAB than in healthy controls. A large study in a highly selective population (men undergoing prostatectomy for cancer treatment) did not confirm this. On the other hand, studies examining symptom severity typically found little difference between 64Arg and 64Trp carriers. In vitro studies with endogenously expressed ß3 -AR reported a decreased lipolytic response in human adipose tissue. Studies with heterologously expressed receptors sometimes found a decreased responsiveness to agonists including ß3 -AR agonists, but others did not confirm that. CONCLUSIONS: The overall evidence points to carriers of the 64Arg genotype expressing fewer and/or hypofunctional ß3 -ARs and being associated with the presence of OAB but such findings were only detected inconsistently. If this hypofunctionality exists, the consequences may be of insufficient magnitude to allow a robust detection. Only adequately powered studies comparing responses with a ß3 -AR agonist in 64Arg carriers versus wild-type patients can address this.

Personalised versus non-individualised case-based CME: A randomised pilot study.

The PinPoint Case Platform (PPCP) offers independent online case-based CME. To align with personal learning needs, a functionality of needs assessments ("QuickScan") was developed, directing users to follow personalised case journeys. A randomised study was conducted, comparing its effectiveness, time efficiency and user experience with a format of non-individualised case-based learning. Forty-two residents in urology from five European countries were randomly assigned to follow non-individualised case-based learning (control group) or a needs assessment plus personalised case journeys on different topics in prostate cancer. After performing a pre- and post-assessment, both groups showed a similar increase in test scores (Mann-Whitney U = 247; p = .113), but the time needed for completing the learning exercise was significantly lower in the group with the personalised approach (median: 45 vs 90 minutes; Mann-Whitney U = 97.5; p = .0141). The quality of the two learning methods was similarly well received by both groups. In conclusion, learners who followed personalised case journeys learned similarly effective but more time efficient than non-individualised case-based learners. Future studies should determine if these findings can be extrapolated to board-certified physicians following CME activities.

Established and emerging treatments for diabetes-associated lower urinary tract dysfunction.

Dysfunction of the lower urinary tract (LUT) including urinary bladder and urethra (and prostate in men) is one of the most frequent complications of diabetes and can manifest as overactive bladder, underactive bladder, urinary incontinence, and as aggravated symptoms of benign prostate hyperplasia. We have performed a selective literature search to review existing evidence on efficacy of classic medications for the treatment of LUT dysfunction in diabetic patients and animals, i.e., α1-adrenoceptor and muscarinic receptor antagonists, ß3-adrenoceptor agonists, and phosphodiesterase type 5 inhibitors. Generally, these agents appear to have comparable efficacy in patients and/or animals with and without diabetes. We also review effects of antidiabetic medications on LUT function. Such studies have largely been performed in animal models. In the streptozotocin-induced models of type 1 diabetes, insulin can prevent and reverse alterations of morphology, function, and gene expression patterns in bladder and prostate. Typical medications for the treatment of type 2 diabetes have been studied less often, and the reported findings are not yet sufficient to derive robust conclusions. Thereafter, we review animal studies with emerging medications perhaps targeting diabetes-associated LUT dysfunction. Data with myoinositol, daidzein, and with compounds that target oxidative stress, inflammation, Rac1, nerve growth factor, angiotensin II receptor, serotonin receptor, adenosine receptor, and soluble guanylyl cyclase are not conclusive yet, but some hold promise as potential treatments. Finally, we review nonpharmacological interventions in diabetic bladder dysfunction. These approaches are relatively new and give promising results in preclinical studies. In conclusion, the insulin data in rodent models of type 1 diabetes suggest that diabetes-associated LUT function can be mostly or partially reversed. However, we propose that considerable additional experimental and clinical studies are needed to target diabetes itself or pathophysiological changes induced by chronic hyperglycemia for the treatment of diabetic uropathy.

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.

[Medical treatment of male lower urinary tract symptoms: what's new?] / Medikamentöse Behandlung des benignen Prostatasyndroms: Was gibt's Neues?

Decades after the introduction of 5α-reductase inhibitors and α1-adrenoceptor antagonists, new data of practical relevance related to their desired and adverse effects continues to emerge. Some of these novel findings are to be taken seriously but are insufficiently established, for instance associations between drug use and depression or dementia. Multiple combination treatments have been tested. While combination treatment was often statistically superior to monotherapy, the difference was mostly in the range of 1 IPSS point, which raises doubts on the clinical relevance of the findings at the group level. The new evidence enables further personalisation of the treatment of male lower urinary tract dysfunction, but also makes individual risk-benefit considerations more complex.

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.

Impact of early vs. delayed initiation of dutasteride/tamsulosin combination therapy on the risk of acute urinary retention or BPH-related surgery in LUTS/BPH patients with moderate-to-severe symptoms at risk of disease progression.

PURPOSE: To evaluate the effect of delayed start of combination therapy (CT) with dutasteride 0.5 mg and tamsulosin 0.4 mg on the risk of acute urinary retention or benign prostatic hyperplasia (BPH)-related surgery (AUR/S) in patients with moderate-to-severe lower urinary tract symptoms (LUTS) at risk of disease progression. METHODS: Using a time-to-event model based on pooled data from 10,238 patients from Phase III/IV dutasteride trials, clinical trial simulations (CTS) were performed to assess the risk of AUR/S up to 48 months in moderate-to-severe LUTS/BPH patients following immediate and delayed start of CT for those not responding to tamsulosin monotherapy. Simulation scenarios (1300 subjects/arm) were investigated, including immediate start (reference) and alternative delayed start (six scenarios 1-24 months). AUR/S incidence was described by Kaplan-Meier survival curves and analysed using log-rank test. The cumulative incidence of events as well as the relative and attributable risks were summarised stratified by treatment. RESULTS: Survival curves for patients starting CT at month 1 and 3 did not differ from those who initiated CT immediately. By contrast, significant differences (p < 0.001) were observed when switch to CT occurs ≥ 6 months from the initial treatment. At month 48, AUR/S incidence was 4.6% vs 9.5%, 11.0% and 11.3% in patients receiving immediate CT vs. switchers after 6, 12 and 24 months, respectively. CONCLUSIONS: Start of CT before month 6 appears to significantly reduce the risk of AUR/S compared with delayed start by ≥ 6 months. This has implications for the treatment algorithm for men with LUTS/BPH at risk of disease progression.

Model-based meta-analysis of the time to first acute urinary retention or benign prostatic hyperplasia-related surgery in patients with moderate or severe symptoms.

AIMS: Combination therapy of 5α-reductase inhibitor and α-blocker is a guideline-endorsed therapeutic approach for patients with moderate-to-severe lower urinary tract symptoms or benign prostatic hyperplasia (LUTS/BPH) who are at risk of disease progression. We aimed to disentangle the contribution of clinical and demographic baseline characteristics affecting the risk of acute urinary retention or BPH-related surgery (AUR/S) from the effect of treatment with drugs showing symptomatic and disease-modifying properties. METHODS: A time-to-event model was developed using pooled data from patients (n = 10 238) enrolled into six clinical studies receiving placebo, tamsulosin, dutasteride or tamsulosin-dutasteride combination therapy. A parametric hazard function was used to describe the time to first AUR/S. Covariate model building included the assessment of relevant clinical and demographic factors on baseline hazard. Predictive performance was evaluated by graphical and statistical methods. RESULTS: An exponential hazard model best described the time to first AUR/S in this group of patients. Baseline International Prostate Symptom Score, prostate-specific antigen, prostate volume and maximum urine flow were identified as covariates with hazard ratio estimates of 1.04, 1.08, 1.01 and 0.91, respectively. Dutasteride monotherapy and tamsulosin-dutasteride combination therapy resulted in a significant reduction in the baseline hazard (56.8% and 66.4%, respectively). By contrast, the effect of tamsulosin did not differ from placebo. CONCLUSIONS: Our analysis showed the implications of disease-modifying properties of dutasteride and tamsulosin-dutasteride combination therapy for the risk of AUR/S. It also elucidated the contribution of different baseline characteristics to the risk of these events. The use of tamsulosin monotherapy (symptomatic treatment) has no impact on individual long-term risk.

Upregulation of ß3-adrenoceptors-a general marker of and protective mechanism against hypoxia?

ß3-Adrenoceptors exhibit a restricted expression pattern, particularly in humans. However, they have been found to be upregulated in various cancers and under several conditions associated with hypoperfusion such as congestive heart failure and diabetes for instance in the heart and other tissues. These conditions are frequently associated with hypoxia. Furthermore, direct induction of hypoxia has consistently been reported to cause upregulation of ß3-adrenoceptors across various tissues of multiple species including humans, rats, dogs, and fish. While a canonical hypoxia-response element in the promoter of the human ß3-adrenoceptor gene may play a role in this, no such sequence was found in rodent homologs. Moreover, not all upregulation of ß3-adrenoceptor protein is accompanied by increased expression of corresponding mRNA, indicating that the upregulation may involve factors other than transcriptional changes. We propose that upregulation of ß3-adrenoceptors at the mRNA and/or protein level is a general marker of hypoxic conditions. Moreover, it may be an additional pathway whereby cells and tissues adapt to reduced oxygen levels.

Is Dipstick Urinalysis Screening Beneficial in Men with Lower Urinary Tract Symptoms?

INTRODUCTION: Dipstick urinalysis is a widely used screening tool in the evaluation of men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). As limited data support the use of dipstick urinalysis, we have used data from three recently published studies to assess clinical outcomes in those who had dipstick urinalysis findings for blood, glucose, and/or leukocytes. METHODS: We analyzed data from three observational studies involving men interested in using over-the-counter tamsulosin: a self-selection study (SSS) and two actual-use studies of 8-week (AUS8) and 24-week (AUS24) durations. Subgroup analyses focused on pooled data from participants not using α-blockers or other prescription medication for LUTS suggestive of BPH (nonRx users) and who had urine dipstick findings. Data from participants using α-blockers (AUS8) or any prescription BPH medications (SSS and AUS24) are presented as reference. RESULTS: Overall, 2488 nonRx users underwent dipstick urinalysis and 680 (27.3%) had positive findings including traces of blood (332; 13.3%), glucose (259; 10.4%), and/or leukocytes (245; 9.8%). Among users of prescription medicines, 21.6% (37/171) in SSS, 27.4% (23/84) in AUS8, and 31.1% (47/151) in AUS24 had urine dipstick findings. The 200 dipstick-positive nonRx users in SSS underwent per protocol urological assessment: 26 (13.0%) had a newly diagnosed condition causing/contributing to urinary symptoms of which 2.9% were identified as medically important conditions. Among nonRx users with or without a dipstick finding, medically important conditions reported included prostate cancer (1.0% vs. 1.0%, respectively) and urolithiasis (1.0% vs. 0.3%, respectively). The proportion of men with dipstick urinalysis findings was similar between men who regularly visited their physician and those who did not. CONCLUSION: Dipstick urinalysis did not markedly increase the detection of undiagnosed medically important conditions that cause/contribute to urinary symptoms, suggesting that this test may not be a very effective screening tool for men with LUTS. FUNDING: Boehringer Ingelheim Pharmaceuticals, Inc.

Cognitive and mood side effects of lower urinary tract medication.

Introduction: Muscarinic receptor antagonists, 5α-reductase inhibitors and α1-adrenoceptor antagonists are frequently used drug classes for the treatment of lower urinary tract symptoms including those of overactive bladder syndrome and benign prostatic enlargement/benign prostatic obstruction. Areas covered: The authors review the evidence for adverse effects of these drug classes on cognitive function, mood and other functions of the central nervous system and discuss such effects against the evidence for mechanistic plausibility. Expert opinion: Muscarinic antagonists carry a risk for impaired cognition and other brain functions that differs quantitatively between compounds, being highest with oral formulations of oxybutynin. 5□-Reductase inhibitors can cause depressive symptoms even at low doses and starting several months after discontinuation of treatment. The evidence for α1-adrenoceptor antagonists and specifically tamsulosin to cause dementia is controversial and lacks mechanistic plausibility. We recommend that physicians treating patients with lower urinary tract symptoms carefully monitor mental status prior to prescribing and periodically thereafter.