Darolutamide: A Review in Metastatic Hormone-Sensitive Prostate Cancer.

Darolutamide (NUBEQA®) is an oral androgen receptor inhibitor (ARi) that is approved for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (ADT) and docetaxel. In a pivotal trial, darolutamide plus ADT and docetaxel was superior to placebo plus ADT and docetaxel in prolonging the primary endpoint of overall survival, with improvements also reported in most secondary endpoints. Treatment with darolutamide plus ADT and docetaxel was associated with a manageable tolerability profile. Furthermore, the adverse events reported with darolutamide plus ADT and docetaxel were generally consistent with the safety profiles previously reported for ADT and docetaxel. Darolutamide expands the availability of treatment options in mHSPC and may be useful as a treatment for high-volume disease (typically defined as ≥ 4 bone metastases with spread outside of the pelvis and vertebral column).

Prostate cancer is the second and fourth most diagnosed cancer in the USA and Europe, respectively. Distant metastases are detected in 8% of patients at initial presentation and are associated with poorer 5-year survival rates in comparison to patients with localised or regional disease. Historically, patients with metastatic hormone-sensitive prostate cancer (mHSPC) were treated with androgen deprivation therapy (ADT). More recently, patients have been treated with ADT plus either docetaxel or an androgen receptor inhibitor (ARi), or with a combination of an ARi, ADT and docetaxel. Darolutamide (NUBEQA^®) is an orally administered ARi which has been approved in combination with ADT and docetaxel for the treatment of mHSPC. In a clinical trial, darolutamide plus ADT and docetaxel was effective in prolonging the survival of patients in comparison with placebo plus ADT and docetaxel. Darolutamide plus ADT and docetaxel had a manageable tolerability profile and the adverse events reported with darolutamide plus ADT and docetaxel were consistent with those reported for ADT and docetaxel. Overall, darolutamide expands the availability of treatments for mHSPC and may be useful for patients with more severe disease.

Fezolinetant: First Approval.

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 signalling in the central nervous system is a non-hormonal strategy to modulate the activity of neurones that are associated with thermoregulation, thereby reducing the frequency and severity of VMS. Fezolinetant received its first approval in the USA in May 2023 for the treatment of moderate to severe VMS due to menopause. This article summarizes the milestones in the development of fezolinetant leading to this first approval in this indication.

Omaveloxolone: First Approval.

Omaveloxolone (SKYCLARYS™) is an orally active, small molecule semi-synthetic triterpenoid drug that increases antioxidant activity, which is being developed by Reata Pharmaceuticals, Inc. for the treatment of Friedreich's ataxia. In patients with Friedreich's ataxia, the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway is suppressed, which is associated with oxidative stress, mitochondrial dysfunction and damage to cells, including central and peripheral neurones. The Nrf2 pathway may be activated by omaveloxolone as it blocks the ubiquitination and degradation of Nrf2. Omaveloxolone was approved in February 2023 in the USA for the treatment of Friedreich's ataxia. This article summarizes the milestones in the development of omaveloxolone leading to this first approval for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older.

Nadofaragene Firadenovec: First Approval.

Nadofaragene firadenovec (nadofaragene firadenovec-vncg; Adstiladrin®) is a non-replicating adenoviral vector-based gene therapy developed by Ferring Pharmaceuticals for the treatment of high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC). Nadofaragene firadenovec constitutes vector DNA that encodes for interferon (IFN)-α2b and is the first approved gene therapy in bladder cancer. The production of IFN-α2b by transfected urothelial cells is associated with anticancer activity, including immunostimulatory, antiangiogenic and apoptotic effects. In December 2022, nadofaragene firadenovec received its first global approval in the USA for the treatment of high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumours in adults. This article summarizes the milestones in the development of nadofaragene firadenovec leading to this first approval for this indication.

Ublituximab: First Approval.

Ublituximab (ublituximab-xiiy; BRIUMVI™) is a glycoengineered anti-CD20 monoclonal antibody developed by TG Therapeutics, Inc. for the treatment of multiple sclerosis (MS). The mechanism of action of ublituximab involves the depletion of B cells via antibody-dependent cellular cytotoxicity, as B cells have a key role in the pathogenesis of MS. Ublituximab is the first anti-CD20 treatment that is administered twice-yearly as one hour infusions, following the initial doses. In December 2022, ublituximab received its first global approval in the USA for the treatment of adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. This article summarizes the milestones in the development of ublituximab leading to this first approval in this indication.

Antidepressants with anti-inflammatory properties may be useful in long COVID depression.

Long COVID, which is characterised by the presence of persistent symptoms following a COVID infection, may also cause long COVID depression (LCD). Although the risk factors for LCD are not directly characterised, prior mental health visits were associated with an increased risk for long COVID, whereas antidepressant use was not. Current evidence suggests that pro-inflammatory factors in the brain are linked to LCD, thus anti-inflammatory agents may be useful in mitigating LCD. Limited evidence suggests that selective serotonin reuptake inhibitors may also be effective in the treatment of LCD.

mRNA COVID-19 vaccines are well tolerated and myopericarditis is a rare adverse event following immunisation.

mRNA vaccines are considered to be important tools for the management of the COVID-19 pandemic. Although mRNA COVID-19 vaccines are well tolerated in most recipients, post-marketing data have highlighted an association between myocarditis and mRNA vaccines. Post-vaccine myocarditis (PVM) is most commonly reported in male adolescents receiving the second dose of an mRNA vaccine. However, the incidence of PVM is low and the risk of myocarditis should be kept in perspective. Cases of PVM are mostly mild in severity, and may be managed using existing myocarditis guidelines. The pathology of PVM is under investigation, and current data suggest that cross reactivity or hypersensitivity reactions may be involved. Globally, mRNA vaccines are generally recommended for use in children/adolescents, and delaying the administration of the second dose may reduce the risk of PVM.

Sotorasib: A Review in KRAS G12C Mutation-Positive Non-small Cell Lung Cancer.

Sotorasib (LUMAKRAS™ in the USA and LUMYKRAS™ in the EU) is an orally active, first-in-class G12C-mutant KRAS (KRASG12C) inhibitor. By binding irreversibly to KRASG12C, sotorasib inhibits downstream signalling pathways which are associated with cell growth and differentiation. Sotorasib is indicated for the treatment of adults with advanced, previously treated, KRAS G12C mutation-positive non-small cell lung cancer (NSCLC) in multiple countries, including the countries of the EU and the USA. A clinically relevant objective response rate was observed in patients with KRAS G12C mutation-positive NSCLC during the primary analysis and in an updated analysis of the phase I/II CodeBreaK 100 trial. Furthermore, a clinically relevant response duration was reported in updated analyses of the trial. Sotorasib has a manageable tolerability profile, with permitted dose modifications to manage toxicity. In summary, sotorasib is a promising KRASG12C inhibitor that increases the available treatment options for patients with KRAS G12C mutation-positive NSCLC who were previously treated with platinum-based chemotherapy and/or immunotherapy.

KRAS is a protein that is involved in cell signalling pathways, including those that are associated with cell growth and differentiation. KRAS mutations are detected in 23% of patients with non-small cell lung cancer (NSCLC), with the G12C mutation being the most common. G12C-mutant KRAS (KRAS^G12C) is kept in an activated state, which is associated with cancer. Sotorasib (LUMAKRAS™ in the USA and LUMYKRAS™ in the EU), which is taken orally once daily, is the first approved drug that inhibits KRAS^G12C; it permanently binds to KRAS^G12C and locks it in an inactivated state. Sotorasib is approved for adults who have advanced, previously treated, KRAS G12C mutation-positive NSCLC. In a clinical trial in patients with KRAS G12C mutation-positive NSCLC, a clinically relevant proportion of patients responded to sotorasib treatment. Furthermore, the duration of effectiveness with sotorasib was considered to be clinically relevant. Adverse reactions with sotorasib treatment were manageable; the dose may be decreased and/or sotorasib treatment may be temporarily stopped to manage adverse reactions. Overall, sotorasib is a promising treatment option for patients with KRAS G12C mutation-positive NSCLC who have received at least one prior systemic therapy.

Unusual complication after augmentation genioplasty: Odontogenic infection requiring implant removal.

Augmentation genioplasty is a common surgical procedure with extremely low infection rates. We present the case of a healthy middle-aged woman who experienced years of chronic infection after chin implantation due to an exposed mandibular canine root, which is exceedingly rare. Awareness of this potential complication may reduce patient morbidity.

Estetrol/Drospirenone: A Review in Oral Contraception.

Estetrol/drospirenone is a combined oral contraceptive (COC) with a plant-synthesised foetal oestrogen (estetrol) and a well-established progestin (drospirenone). In preclinical models, estetrol has lower binding affinity for the oestrogen receptor-α (ER-α) in contrast to estradiol and has antagonistic properties against membrane ER-α in several tissues, including the breast, while retaining agonistic activity on receptors located in the nucleus. The low oestrogenicity of estetrol may potentially contribute to reduced thrombotic risk. Estetrol/drospirenone was an effective contraceptive in phase II and III clinical trials, with regular and predictable bleeding cycles maintained in the majority of women. Estetrol/drospirenone was generally well-tolerated with metrorrhagia reported as the most common treatment-related adverse event, which is consistent with other COCs. Cases of migraines with aura (or severe migraines), deep vein thrombosis, hyperkalaemia and depression were rarely reported during the phase III trials. Overall, estetrol/drospirenone is an effective and generally well-tolerated COC, with a potentially reduced risk of thrombosis.

In 2019, an estimated 44% of women aged 15­49 years worldwide used modern contraception methods, and in these women using modern methods, 18% used an oral contraceptive. Estetrol/drospirenone is a combined oral contraceptive (COC) which uses estetrol, a plant-synthesised oestrogen naturally produced by the human foetal liver during pregnancy, in combination with drospirenone, a well-known progestin. Combined, these hormones suppress ovulation, which constitutes their primary mode of action in preventing pregnancy. As estetrol has weaker oestrogen-related effects, it may potentially reduce the risk for blood clots. Estetrol/drospirenone was an effective contraceptive in clinical trials, and most women had regular and predictable bleeding cycles. Metrorrhagia (i.e. abnormal bleeding) was the most commonly reported treatment-related adverse effect; however, this is a common issue with hormonal contraceptives. Cases of severe migraine headaches, deep vein thrombosis, high potassium levels or depression were rarely reported during clinical trials. Estetrol/drospirenone is an effective oral contraceptive, which may offer a contraceptive option with a lower risk for blood clots. However, further research is required to confirm the reduced risk of clotting.

Serplulimab: First Approval.

Serplulimab (®) is an intravenously administered anti-PD-1 antibody being developed by Shanghai Henlius Biotech, Inc. for the treatment of solid tumours. Anti-PD-1 immunotherapies, such as serplulimab, can stimulate immune responses by relieving PD-1-related immunosuppression. Serplulimab received its first approval on 25 Mar 2022 in China for the treatment of adult patients with advanced unresectable or metastatic microsatellite instability-high (MSI-H) solid tumours that have failed to respond to previous standard treatments. This article summarizes the milestones in the development of serplulimab leading to this first approval in the treatment of MSI-H solid tumours in adults.

Delafloxacin: A Review in Community-Acquired Pneumonia.

Delafloxacin (BAXDELA® in the USA; Quofenix® in the EU) is an anionic fluoroquinolone antibacterial that is approved for the treatment of community-acquired pneumonia (CAP) and acute bacterial skin and skin structure infections in adults. Delafloxacin demonstrated in vitro activity against Gram-positive and Gram-negative pathogens, including drug-resistant isolates. In a phase III trial in adults with CAP, delafloxacin was noninferior to moxifloxacin when assessed against FDA- and EMA-defined primary endpoints, with both fluoroquinolones achieving high treatment success rates. A prespecified subgroup analysis suggested that delafloxacin may be more efficacious than moxifloxacin in patients with a history of asthma or chronic obstructive pulmonary disease (COPD). Delafloxacin was generally well tolerated in patients with CAP, with most treatment-emergent adverse events graded as mild or moderate in severity. Fluoroquinolone-associated adverse events of special interest occurred infrequently, with no events of QT prolongation or phototoxicity reported with delafloxacin. Delafloxacin is an effective and generally well-tolerated treatment that increases the number of available treatments for CAP and, although further research is required, may be a useful option for patients with CAP and comorbid asthma or COPD.

Community-acquired pneumonia (CAP) can be caused by bacterial infection of the lungs, and is a common cause of infection-related deaths. As drug-resistant bacteria are becoming more common, new antibacterial drugs are needed. Delafloxacin (BAXDELA^® in the USA; Quofenix^® in the EU) is a fluoroquinolone antibacterial that inhibits bacterial enzymes required for DNA repair and replication. Delafloxacin kills a wide range of bacteria, including some drug-resistant variants. During a trial in adults with CAP, delafloxacin was as effective as moxifloxacin (also a fluoroquinolone antibacterial). Delafloxacin may be more effective than moxifloxacin in patients with a history of asthma or chronic obstructive pulmonary disease (COPD), although further research is needed. Most adverse events with delafloxacin were mild or moderate in severity, with diarrhoea being the most commonly occurring treatment-related adverse event (experienced by < 4% of recipients). Furthermore, the adverse effects of delafloxacin were generally consistent with those previously observed in patients with skin infections. Delafloxacin expands the range of treatments for CAP, and is potentially useful for patients with comorbid asthma or COPD.

Clazosentan: First Approval.

Clazosentan (PIVLAZ™) is a small molecule, endothelin (ET) A receptor-selective antagonist being developed by Idorsia Pharmaceuticals. ETA receptor inhibition by clazosentan decreases ET-related cerebral vasospasm, which may occur after an aneurysmal subarachnoid haemorrhage. Clazosentan has been approved in Japan for use in the prevention of cerebral vasospasm, vasospasm-related cerebral infarction and cerebral ischaemic symptoms after aneurysmal subarachnoid haemorrhage, following the results from the JapicCTI163369 and JapicCTI163368 phase III trials. This article summarises the milestones in the development of clazosentan leading to this first approval in this indication.

Liposomes with cyclodextrin channels and polyethyleneimine (PEI) improves cytoplasmic vaccine delivery and induces anti-cancer immune activity in mice.

Cancer vaccines have been developed as an additional method of treatment in the fight against cancer. However, an important barrier to an effective vaccine is the inefficient presentation of exogenous antigen by dendritic cells to cytotoxic CD8 T cells. In this study, DPPC liposomes were modified with channels and loaded with polyethyleneimine (PEI) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) to produce a vaccine carrier. The liposomes were designed to be pH responsive to facilitate delivery of antigens directly to the cytoplasm of antigen presenting cells, bypassing the cross-presentation pathway and improving cellular immune responses. The lysis of liposomes in acidic cell-free conditions was measured using a validated dynamic light scattering assay in order to gain an insight into the mechanism of PEI-mediated lysis. Dendritic cell stimulation and T cell proliferation was investigated in vitro and the potential of this formulation to stimulate a therapeutic anti-cancer immune response was examined in a murine melanoma model. The modified formulation stimulated T cell activation in vitro and induced a small but significant increase in survival in immunized mice. Overall, liposomes modified with PEI and channels successfully delivered antigen to the cytoplasm of dendritic cells, which subsequently led to the development of an appropriate immune response.

Recurrent Intramuscular Hemangioma (Infiltrating Angiolipoma) of the Lower Lip: A Case Report and Review of the Literature.

OBJECTIVE: To report a case of a recurrent intramuscular hemangioma (IMH) of the lower lip of a 68-year-old female and review the published literature to provide an overview of the presentation, diagnostic strategy, pathological classification, and management of these lesions within the oral cavity. METHODS: A case report was conducted by reviewing the documentation at a single institution. A systematic literature review on OVID MEDLINE and PubMed was performed using the MESH terms "intramuscular hemangioma" and "oral cavity," "tongue," "cheek," "buccal," "gingiva," and "lip." RESULTS: A 62-year-old female presented to our institution with a 2 × 2 × 1 cm IMH of the lower lip involving the surrounding orbicularis oris muscle. She underwent a submucosal resection and did well postoperatively. Six and a half years later, she represented to our institution with a new lower lip lesion in the area of her previous resection. Preoperative magnetic resonance imaging showed a new 10 × 11 mm lesion with a well circumscribed central component surrounded by ill-defined tissue. Preoperative angiography showed that the lesion was supplied by vessels branching off the left facial artery, which were embolized. She underwent wide-local excision (WLE) with bilateral advancement flaps and at her 2-month postoperative visit has not had recurrence. CONCLUSION: Only 39 cases of IMH in the oral cavity have been reported, with only 3 others occurring in the lower lip. Here we add the first case of an IMH of the oral cavity that recurred after primary WLE. The patient was successfully retreated with WLE. At a 3-month follow-up visit, she noted some incompetence with oral secretions and occasional tingling along the incision site but no evidence of recurrence.