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Distal renal tubular acidosis (dRTA) is characterized by a primary defect in proton secretion by α-intercalated cells of the collecting duct, leading to impaired urine acidification and resulting in metabolic acidosis, hypokalemia, and hypercalciuria. Inherited forms of dRTA are currently associated with variants in five genes (SLC4A1, ATP6V1B1, ATP6V0A4, FOXI1, and WDR72), each being associated with specific extra-renal manifestations. Acquired forms can result from autoimmune diseases or drug side effects. Classical complications include nephrolithiasis, nephrocalcinosis, reduced glomerular filtration rate (GFR), bone demineralization, and growth failure. Treatment focuses on correcting the acid–base imbalance through alkali supplementation (potassium, sodium, or magnesium bicarbonate or citrate) to reduce renal disease progression and promote normal growth and mineralization. Traditional treatments (alkali and potassium supplementation) often suffer from poor adherence due to frequent day and night administrations, gastrointestinal discomfort, and unpleasant taste. A novel investigational drug, ADV7103, which contains potassium citrate and potassium bicarbonate in an extended-release formulation, has recently been approved by the European Medicine Agency (EMA) for dRTA. Recent studies support its use as a first-line treatment, given its efficacy and safety profile. [ABSTRACT FROM AUTHOR]

Adavosertib (AZD1775) is a potent small‐molecule inhibitor of Wee1 kinase. This analysis utilized pharmacokinetic data from 8 Phase I/II studies of adavosertib to characterize the population pharmacokinetics of adavosertib in patients (n = 538) with solid tumors and evaluate the impact of covariates on exposure. A nonlinear mixed‐effects modeling approach was employed to estimate population and individual parameters from the clinical trial data. The model for time dependency of apparent clearance (CL) was developed in a stepwise manner and the final model validated by visual predictive checks (VPCs). Using an adavosertib dose of 300 mg once daily on a 5 days on/2 days off dosing schedule given 2 weeks out of a 3‐week cycle, simulation analyses evaluated the impact of covariates on the following exposure metrics at steady state: maximum concentration during a 21‐day cycle, area under the curve (AUC) during a 21‐day cycle, AUC during the second week of a treatment cycle, and AUC on day 12 of a treatment cycle. The final model was a linear 2‐compartment model with lag time into the dosing compartment and first‐order absorption into the central compartment, time‐varying CL, and random effects on all model parameters. VPCs and steady‐state observations confirmed that the final model satisfied all the requirements for reliable simulation of randomly sampled Phase I and II populations with different covariate characteristics. Simulation‐based analyses revealed that body weight, renal impairment status, and race were key factors determining the variability of drug‐exposure metrics. [ABSTRACT FROM AUTHOR]

Objective: Complications from diabetic foot wounds, including bacterial infection, ulceration and gangrene, are major causes of hospitalisation and are responsible for 85% of amputations in patients with diabetes. Given that orally administered investigational therapeutic Cytoreg (Cytorex de Venezuela SA, Venezuela), a defined aqueous mixture of hydrofluoric, hydrochloric, sulfuric, phosphoric, citric and oxalic acids, has been shown to increase levels of arterial blood oxygen in a Wistar rat model, oral and oral+topical Cytoreg were tested on patients with diabetic foot ulcers (DFUs) under a humanitarian, compassionate-use protocol. Method: All patients received oral Cytoreg (5.0 ml concentrate in fruit juice) for 30 days; half also received weekly wound washing with Cytoreg concentrate in isotonic saline (1:50 volume/volume) (oral+topical group). In addition to standard clinical observations, wounds were monitored against the Saint Elian checklist system for the diabetic foot. Results: A total of 10 patients took part in the study. Complete wound closure was observed in 4/5 patients in the oral+topical group; in the remaining patient, necrotic and fibrin tissues on the wound edges were eliminated. Half (2/4) of the patients receiving oral-only Cytoreg experienced complete wound closure; one patient in this group was removed prematurely because of an unrelated illness and was not replaced. During the study, no significant differences were observed between groups in either the oxygen saturation of the affected tissues or in insulin and glycaemia levels (p<0.05). Significant increases in arterial haemoglobin and arterial oxygen partial pressure (p<0.05) were observed, and significant decreases were measured in the levels of glycosylated haemoglobin, aspartate aminotransferase, glutamic-pyruvic transaminase, creatine and urea (p<0.05). Conclusion: The results of this study justify an expanded clinical study for the treatment of DFUs with Cytoreg. [ABSTRACT FROM AUTHOR]

Cedirogant is an inverse agonist of retinoic acid‐related orphan receptor gamma thymus developed for the treatment of chronic plaque psoriasis. Cedirogant induces cytochrome P450 (CYP) 3A4 while inhibiting P‐glycoprotein (P‐gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and OATP1B3 in vitro. Static drug–drug interactions (DDIs) predictions suggested possible clinical induction of CYP3A4, and inhibition of P‐gp, BCRP, and OATP1B1, leading to challenges in interpreting DDI studies between cedirogant and substrates of CYP3A, P‐gp, BCRP, and OATP1B1/3. Here the effects of cedirogant on the pharmacokinetics of two statin drugs were investigated in healthy participants. Coproporphyrin‐I (CP‐I), a selective endogenous OATP1B biomarker, was used to assess the impact of cedirogant on OATP1B. Cedirogant (375 mg once daily) increased rosuvastatin maximum plasma concentration (Cmax) and area under the plasma concentration curve (AUCtau) by 141% and 55%, respectively when co‐administered, whereas atorvastatin Cmax increased by 40% with no effect on its AUCtau compared with administration of rosuvastatin/atorvastatin alone. Cedirogant did not increase CP‐I exposures, indicating no clinical OATP1B inhibition. The increased rosuvastatin exposure and minimal change in atorvastatin exposure with co‐administration of cedirogant is attributed to BCRP inhibition and interplay between P‐gp/BCRP inhibition and CYP3A induction, respectively. Correlation analysis with data from two investigational drugs (glecaprevir and flubentylosin) demonstrated that OATP1B1 R‐value of > 1.5 and [Cmax,u]/[OATP1B1 IC50] of > 0.1 are associated with > 1.25‐fold increase in CP‐I Cmax ratio. This demonstrates the utility of CP‐I in disentangling mechanisms underlying a complex DDI involving multiple transporters and enzymes and proposes refined criteria for static OATP1B inhibition predictions. [ABSTRACT FROM AUTHOR]

Since the United States Food and Drug Administration (FDA) approved the first chimeric antigen receptor T-cell (CAR-T) therapy in 2017, it has marked a major breakthrough in cancer treatment, leading to a surge in global research and applications in this field. In recent years, China has made rapid progress, quickly catching up through heavy investment in CAR-T construction, preparation processes, and treatment strategies. China's CAR-T therapy market is driven by substantial pharmaceutical investment targeting its vast population, yet high therapy costs remain uncovered by basic medical insurance. In November 2023, FDA issued a warning about the risk of secondary cancers in patients undergoing CAR-T therapy, sparking global concern. In fact, the China National Medical Products Administration (NMPA) preemptively implemented a series of measures to address the safety concerns of CAR-T therapy, emphasizing the risk of secondary cancers and advising lifelong monitoring as part of the approval process for CAR-T products. Nevertheless, additional regulatory measures are needed to address emerging risks, particularly the threat of secondary cancers. The authors believe that raising the standards for Investigational New Drug (IND) approval and establishing a dynamic reporting and feedback system based on real-world data will strengthen regulatory oversight and support the sustainable growth of the CAR-T industry in China. [ABSTRACT FROM AUTHOR]

Phenylketonuria is an inherited condition characterised by neurotoxic accumulation of phenylalanine (Phe). APHENITY assessed the efficacy and safety of orally administered synthetic sepiapterin in children and adults with phenylketonuria. APHENITY was a phase 3, randomised, double-blind, placebo-controlled study performed at 34 clinics, hospitals, and university sites in 13 countries. Individuals of all ages with a clinical diagnosis of phenylketonuria were eligible for inclusion if they had a blood Phe concentration of 360 μmol/L or higher at study entry, whereas individuals with hyperphenylalaninaemia due to pathogenic variants in GCH1, PTS, QDPR, SPR , and PCBD1 , consistent with a diagnosis of primary BH 4 deficiency, were excluded. Part 1 was a 14-day open-label assessment of blood Phe concentration response to sepiapterin. In part 2, sepiapterin-responsive participants were randomly assigned (1:1) by a web-response system based on a block randomisation schedule (permuted block size of 2 and 4) to 6 weeks of sepiapterin (forced-dose escalation: 20, 40, and 60 mg/kg per day per consecutive 2-week period) or placebo. The investigational drug and placebo were identical in their appearance and delivery. Dried blood samples were collected for analysis of Phe concentration on days –1, 1 (before dose was administered), 5, 10, 14, 19, 24, 28, 33, 38, and 42 in part 2, either in-clinic or at home. The primary endpoint for part 2, mean change from baseline in blood Phe after 6 weeks, was assessed in the primary analysis set of participants with at least a 30% reduction in blood Phe concentration in part 1, who took at least one dose in part 2. Safety was evaluated in all participants receiving at least one dose of treatment. The completed study is registered at EudraCT (2021-000474-29) and ClinicalTrials.gov (NCT05099640). APHENITY was conducted between Sept 30, 2021, and April 3, 2023. 187 people were assessed for eligibility, of whom 157 were enrolled. In part 1, 156 participants were assessed or evaluated, of whom 114 (73%) were sepiapterin-responsive (ie, ≥15% reduction in blood Phe from baseline). In part 2, 98 participants (49 in the placebo group and 49 in the sepiapterin group) were in the primary analysis set. There was a significant reduction of blood Phe concentration after 6 weeks of sepiapterin (–63%, SD 20) compared with placebo (1%, 29; least squares mean change –395·9 μmol/L, SE 33·8; p<0·0001). Treatment-emergent adverse events were reported in 33 (59%) of 56 participants who received sepiapterin and 18 (33%) of 54 participants who received placebo. Most treatment-emergent adverse events were mild gastrointestinal events (11 [20%] of 56 participants who received sepiapterin and ten [19%] of 54 participants who received placebo) that resolved quickly. There were no deaths and no serious or severe adverse events. Sepiapterin is a promising oral therapy for individuals with phenylketonuria, was well tolerated, and resulted in significant and clinically meaningful reductions in blood Phe concentration in participants with varying disease severity. PTC Therapeutics. [ABSTRACT FROM AUTHOR]

With the International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) E17 guidelines in effect from 2018, the design of Asia‐inclusive multiregional clinical trials (MRCTs) has been streamlined, thereby enabling efficient simultaneous global development. Furthermore, with the recent regulatory reforms in China and its drug administration joining the ICH as a full regulatory member, early participation of China in the global clinical development of novel investigational drugs is now feasible. This would also allow for inclusion of the region in the geographic footprint of pivotal MRCTs leveraging principles of the ICH E5 and E17. Herein, we describe recent case examples of model‐informed Asia‐inclusive global clinical development in the EMD Serono portfolio, as applied to the ataxia telangiectasia and Rad3‐related inhibitors, tuvusertib and berzosertib (oncology), the toll‐like receptor 7/8 antagonist, enpatoran (autoimmune diseases), the mesenchymal–epithelial transition factor inhibitor tepotinib (oncology), and the antimetabolite cladribine (neuroimmunological disease). Through these case studies, we illustrate pragmatic approaches to ethnic sensitivity assessments and the application of a model‐informed drug development toolkit including population pharmacokinetic/pharmacodynamic modeling and pharmacometric disease progression modeling and simulation to enable early conduct of Asia‐inclusive MRCTs. These examples demonstrate the value of a Totality of Evidence approach where every patient's data matter for de‐risking ethnic sensitivity to inter‐population variations in drug‐ and disease‐related intrinsic and extrinsic factors, enabling inclusive global development strategies and timely evidence generation for characterizing benefit/risk of the proposed dosage in Asian populations. [ABSTRACT FROM AUTHOR]

The 17th Eilat Conference on New Antiepileptic Drugs and Devices took place in Madrid, Spain on May 5–8, 2024. As usual, the core part of the conference consisted of presentations on investigational drugs at various stages of development for epilepsy‐related indications. Summaries of information on compounds in preclinical or early clinical development are included in an accompanying publication (Part I). In this article, we provide summaries for five compounds in more advanced clinical development, i.e. compounds for which some information on antiseizure activity in individuals with epilepsy is available. These investigational treatments include azetukalner (XEN1101), a potent, KV7.2/7.3‐specific potassium channel opener in development for the treatment of focal seizures, generalized tonic–clonic seizures, and major depressive disorder; bexicaserin (LP352), a selective 5‐HT2C receptor superagonist in development for the treatment of seizures associated with developmental and epileptic encephalopathies; radiprodil, a selective negative allosteric modulator of NR2B subunit‐containing N‐methyl‐D‐aspartate glutamate receptors, in development for the treatment of seizures and behavior manifestations associated with disorders caused by gain‐of‐function mutations in the GRIN1, −2A, ‐2B, or ‐2D genes; soticlestat (TAK‐935), a selective inhibitor of cholesterol 24‐hydroxylase in development for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome; and STK‐001, an antisense oligonucleotide designed to upregulate Nav1.1 protein expression and improve outcomes in individuals with Dravet syndrome. The diversity in mechanisms of action of these agents illustrates different approaches being pursued in the discovery of novel treatments for seizures and epilepsy. For two of the compounds discussed in this report (azetukalner and soticlestat), clinical evidence of efficacy has already been obtained in a randomized placebo‐controlled adjunctive‐therapy trial. For the other compounds, adequately powered placebo‐controlled efficacy trials have not been completed to date. [ABSTRACT FROM AUTHOR]

Hypoparathyroidism is a disease characterized by inadequate or absent parathyroid hormone (PTH) levels. It manifests with hypocalcemia, hyperphosphatemia, and elevated urinary fractional excretion of calcium. The conventional therapy with calcium supplementation and active vitamin D analogs is limited by the pill burden, unstable calcium concentrations, and significant renal and bone complications. Hence, the development of replacement therapies utilizing PTH or PTH-related receptor modulators has emerged as a promising therapeutic avenue. rhPTH (1-84) (NATPARA®) is a once-daily injection of full-length recombinant human parathyroid hormone that was initially approved by the U.S. Food and Drug Administration(FDA) in 2015 for hypoparathyroidism. However, it was recalled from the U.S. market in 2019, and its production will cease globally by the end of 2024. TransCon™ PTH, known as palopegteriparatide, utilizes an innovative technology to provide a sustained release of PTH (1-34) prodrug. It has received approval from the European Medicines Agency and is currently undergoing FDA review. Eneboparatide is a PTH receptor 1 agonist, designed to stimulate a specific receptor configuration. Encaleret is a negative allosteric modulator of the calcium-sensing receptor and rescues the secretion of naive PTH inAutosomal Dominant Hypocalcemia type 1. MBX 2109 is an investigational once-weekly PTH prodrug that addresses thefrequent administration challenge. EB612, the tablet form of PTH(1-34), is the first oral hormone replacement treatment for hypoparathyroidism. Recent developments in the management of chronic hypoparathyroidism hold promise as a therapeutic approach to restore physiological function, manage symptoms, and prevent associated complications. [ABSTRACT FROM AUTHOR]

Introduction: Additional considerations are required for the benefit-risk assessment of new drugs or indications in the setting of (neo)adjuvant cancer treatment as compared to the metastatic/advanced setting, possibly leading to different decision patterns for the (neo)adjuvant versus the metastatic and advanced setting within a health authority but also among different health authorities. Methods: We analyzed regulatory decisions at the Swiss Agency for Therapeutic Products Swissmedic (SMC) for all oncology indications (mostly metastatic indications) and indications in the (neo)adjuvant setting and compared these to decisions taken by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA). Results: Comparing the positive and negative decisions within SMC between July 2017 and December 2021, the approval rates were with 66.7% lower for (neo)adjuvant indications versus 88.4% in the metastatic and advanced indications. While the approval rates for metastatic and advanced new active substances (NAS) applications were similar at SMC as compared to the EMA and the FDA, they were lower for (neo)adjuvant applications at SMC as compared to the EMA and the FDA. The underlying reason in all cases with divergent decisions at SMC as compared to EMA and FDA was that no overall survival benefit as compared to control arm has been observed in the submitted data package. Conclusion: Approval and consensus decision rates at SMC in comparison to EMA and FDA were lower for (neo)adjuvant indications but not for advanced and metastastic NAS oncology indications. [ABSTRACT FROM AUTHOR]

Purpose An investigational drug services (IDS) pharmacy plays a vital role in supporting clinical trial research by ensuring the safe and efficient management of investigational products. This article describes the implementation of an electronic project management software to improve an IDS pharmacy's study protocol work. The article describes the implementation of the software and how this approach addressed specific challenges, including project oversight, process standardization, documentation, reporting, accountability, and intrateam communication. Summary We describe an electronic project management software system used to streamline and standardize the work associated with study protocols. This software provides an organized and customizable workspace to manage tasks associated with each study protocol. The software automates task creation, tracks progress, and ensures comprehensive record keeping. Additionally, the software fosters effective communication within the team and offers real-time reporting to assess team productivity and progress. We have observed improved consistency, enhanced revenue, including approximately $18,000 in additional fee capture, and increased collaboration among pharmacy team members. Conclusion Implementing an electronic project management software has proven highly beneficial in the IDS pharmacy. The software has significantly improved workflow efficiency by addressing challenges in study protocol management. While initial setup and training required time and resources, the long-term benefits in project oversight, collaboration, and revenue capture justify the investment. An electronic project management software is a valuable tool in managing the complexity of study protocol activities and supports the pharmacy's crucial role in advancing clinical research. [ABSTRACT FROM AUTHOR]

Three medications are FDA approved in the US for treatment of Alcohol Use Disorder (AUD), and a few others are used off-label. Patient compliance and efficacy in the broader population are major hurdles for current AUD medications. As a consequence, there is an urgent need for improved pharmacotherapeutics to complement behavioral approaches. Here, we report pilot testing of a minocycline analog, 10-butylether minocycline (BEM, 10 mg/kg p.o.), in two female minipigs with free-choice drinking to intoxication for nearly two and a half years. Each pig met DSM-5 criteria for diagnosis of severe AUD, and BEM reduced both alcohol intake and preference. BEM is currently undergoing testing for approval as an Investigational New Drug by the FDA for AUD treatment. [ABSTRACT FROM AUTHOR]

Purpose: To report an incident of a breakthrough deep vein thrombosis (DVT) and potential example of a drug-drug interaction in a patient treated with edoxaban and rifabutin who was being treated for respiratory tuberculosis. Case: A 76-year-old male presented with anemia requiring transfusion and subsequent shortness of breath that was later diagnosed to be respiratory tuberculosis. He experienced a prolonged hospital stay due to persistently positive Mycobacterium tuberculosis respiratory samples and a complicated social situation that required continuous hospitalization for approximately five months. During his treatment the patient was transitioned from apixaban to edoxaban due to a drug-drug interaction with rifabutin. He subsequently had a DVT while on edoxaban after two months of therapy that would require him to transition to warfarin. Conclusion: This case represents an example of a potentially significant drug-drug interaction between edoxaban and rifabutin. Other direct oral anticoagulants (DOACs) exhibit a potential drug-drug interaction that limit their effectiveness when used with rifamycins. This report describes the first known case of a patient experiencing a DVT after prolonged edoxaban use in combination with rifabutin. Treatment with DOACs for patients taking concomitant cytochrome P450 (CYP) inducers such as rifabutin may be more complicated than previously believed. [ABSTRACT FROM AUTHOR]

Background: During the ongoing outbreak of clade II monkeypox virus (MPXV), many U.S. patients were prescribed tecovirimat, an antiviral drug that was made available under an expanded access Investigational New Drug (EA-IND) program. We evaluated EA-IND data to summarize characteristics of treated patients, outcomes, and serious adverse events (SAEs). Methods: We evaluated data from patients prescribed tecovirimat from May 29, 2022, through July 10, 2023. Baseline patient characteristics, clinical courses, and outcomes were evaluated via intake forms, outcome forms, and patient diaries. Data were summarized in aggregate by human immunodeficiency virus (HIV) status and by comorbidities of special interest. Reported SAEs were also compiled. Results: Tecovirimat was prescribed for over 7100 patients in the United States, most often for lesions in sensitive anatomical areas, such as certain anogenital lesions (83.5%; 5135 out of 6148 patients), and pain (52.5%; 3227 out of 6148 patients). The demographic and clinical characteristics mirrored those of patients worldwide. Among the 7181 patients with returned intake forms, 1626 also had returned outcome forms (22.6%). Many patients with severe immunocompromise (e.g., HIV with CD4 counts <200 cells/μl) received multiple courses of tecovirimat (43.1%; 22 out of 51 patients), including intravenously, and often experienced poor outcomes (35.3%; 18 out of 51 patients). Overall, 223 SAEs and 40 deaths were reported. Most SAEs were among patients who were severely immunocompromised, one of whom experienced hallucinations after tecovirimat was administered at twice the standard dose. Conclusions: Tecovirimat was used extensively. The returned EA-IND data suggest that life-threatening or protracted infections occurred in persons who were severely immunocompromised. SAEs were not commonly reported. The EA-IND data are not definitive; controlled clinical trial data are essential to elucidating if and how tecovirimat should be used. [ABSTRACT FROM AUTHOR]

Background and Objectives: Dovitinib (DVB) is a pan-tyrosine kinase inhibitor (TKI) that can be administered orally. In September 2023, the FDA granted Oncoheroes approval to proceed with an Investigational New Drug (IND) application for dovitinib. This application is intended for the treatment of relapsed or advanced juvenile solid tumors, namely, osteosarcoma. Materials and Methods: The target of the present study was to develop a rapid, green, accurate, and sensitive UHPLC-MS/MS method for measuring DVB levels in human liver microsomes (HLMs). The validations of the HLMs were performed via the established UHPLC-MS/MS approach, as stated in the US FDA reported guidelines for the standards of bioanalytical method validation protocol. The StarDrop in silico software package (version 6.6), which involves the DEREK and WhichP450 in silico modules, was used to check the DVB structure for hazardous alerts and metabolic instability. The DVB and encorafenib (EFB), internal standard, and chromatographic peaks were successfully separated using a reversed phase column (an Eclipse Plus Agilent C8 column) and an isocratic mobile phase. The production of DVB parent ions was accomplished by utilizing the positive ionization mode of an ESI source. The identification and measurement of DVB daughter ions were conducted using the MRM mode. Results: The inter-day accuracy and precision exhibited a spectrum of values in the range of −0.56% to 9.33%, while the intra-day accuracy and precision showcased a range of scores between 0.28% and 7.28%. The DVB calibration curve showed a linear relationship that ranged from 1 to 3000 ng/mL. The usefulness of the currently validated UHPLC-MS/MS method was approved by the lower limit of quantification (LLOQ) of 1 ng/mL. The AGREE findings demonstrate that the UHPLC-MS/MS method had a noteworthy degree of ecological greenness. The in vitro half-life (t1/2) and intrinsic clearance (Clint) of DVB were calculated to be 15.48 min and 52.39 mL/min/kg, respectively, which aligned with the findings from the WhichP450 software (version 6.6). Conclusions: Via the usage of in silico software, it has been observed that making small changes to the structure of the aryl piperazine ring and quinolinone moieties, or replacing these groups in the drug design process, shows potential for enhancing the metabolic safety and stability of newly developed derivatives compared to DVB. [ABSTRACT FROM AUTHOR]

In the last three decades, gene therapy has demonstrated significant progress. Over 700 active investigational new drug (IND) applications have been reported. Research on in utero gene therapy has advanced, but ethical and safety concerns persist. A novel approach under investigation is placental gene therapy, which holds promise for targeting diseases associated with placental dysfunction, such as fetal growth restriction (FGR) and preeclampsia. One of the underlying causes of placental insufficiency in these conditions is reduced placental growth factor-driven angiogenesis and endothelial cell dysfunction during fetal development. Studies have explored the overexpression of growth factor transgenes like IGF-1 to address FGR, yielding promising outcomes in animal models. Furthermore, intra-placental gene transfer, instead of systemic delivery of gene therapy vectors, has the potential to treat and cure these disorders. However, challenges and limitations akin to in utero gene therapy persist, including the risk of in utero infection, potential impairment of the mother's future fertility, the risk of germline integration, and possible off-target effects of gene transfer in the fetus or the mother. Consequently, additional research and deliberation within the scientific and medical communities are warranted to fully comprehend the potential benefits and risks of placental gene therapy. [ABSTRACT FROM AUTHOR]

Although decades of intensive drug discovery efforts to treat neurodegenerative disorders (NDs) have failed, around half a million patients in more than 2000 studies continue being tested, costing over USD 100 billion, despite the conclusion that even those drugs which have been approved have no better effect than a placebo. The US Food and Drug Administration (FDA) has established multiple programs to innovate the treatment of rare diseases, particularly NDs, providing millions of USD in funding primarily by encouraging novel clinical trials to account for issues related to study sizes and adopting multi-arm studies to account for patient dropouts. Instead, the FDA should focus on the primary reason for failure: the poor bioavailability of drugs reaching the brain (generally 0.1% at most) due to the blood–brain barrier (BBB). There are several solutions to enhance entry into the brain, and the FDA must require proof of significant entry into the brain as the prerequisite to approving Investigational New Drug (IND) applications. The FDA should also rely on factors other than biomarkers to confirm efficacy, as these are rarely relevant to clinical use. This study summarizes how the drugs used to treat NDs can be made effective and how the FDA should change its guidelines for IND approval of these drugs. [ABSTRACT FROM AUTHOR]

Mutant epidermal growth factor receptor (EGFR) signaling has emerged as a key cause of carcinogenesis and therapy resistance in non‐small cell lung cancer (NSCLC), which continues to pose a serious threat to world health. In this study, we aimed to elucidate the complex molecular pathways of EGFR‐mediated autophagy signaling in NSCLC. We identified naphtho[2,3‐a]pyrene, an anthraquinolone derivative, to be a promising investigational drug that targets EGFR‐mediated autophagy using a cellular model system. By utilizing systems biology, we developed a computational model that explained the signaling of EGFR‐mediated autophagy and identified critical crosstalk sites that could be inhibited therapeutically. As a lead compound, naphtho[2,3‐a]pyrene was confirmed by molecular docking experiments. It was found to be cytotoxic to NSCLC cells, impact migration, induce apoptosis, and arrest cell cycle, both on its own and when combined with standard drugs. The anticancer efficacy of naphtho[2,3‐a]pyrene was validated in vivo on CDX nude mice. It showed synergistic activity against NSCLC when coupled with gefitinib, chloroquine, and radiation. Altogether, our study highlights naphtho[2,3‐a]pyrene's therapeutic promise in NSCLC by focusing on EGFR‐mediated autophagy and providing a new strategy to fight drug resistance and tumor survival. [ABSTRACT FROM AUTHOR]

Background: Arginine deprivation therapy (ADT) hinders glioma cells' access to nutrients by reducing peripheral blood arginine, showing great efficacy in various studies, which suggests it as a potentially promising treatment for glioma. The aim of this systematic review was to explore the mechanism of ADT for gliomas, the therapeutic effect based on existing research, and possible combination therapies. Methods: We performed a systematic literature review of PubMed, ScienceDirect and Web of Science databases according to PRISMA guidelines, searching for articles on the efficacy of ADT in glioma. Results: We identified 17 studies among 786 search results, among which ADT therapy mainly based on Arginine free condition, Arginine Deiminase and Arginase, including three completed clinical trials. ADT therapy has shown promising results in vivo and in vitro, with its safety confirmed in clinical trials. In the early phase of treatment, glioblastoma (GBM) cells develop protective mechanisms of stress and autophagy, which eventually evolve into caspase dependent apoptosis or senescence, respectively. The immunosuppressive microenvironment is also altered by arginine depletion, such as the transformation of microglia into a pro-inflammatory phenotype and the activation of T-cells. Thus, ADT therapy demonstrates glioma-killing effect in the presence of a combination of mechanisms. In combination with various conventional therapies and investigational drugs such as radiotherapy, temozolomide (TMZ), cyclin-dependent kinase inhibitors (CDK) inhibitors and autophagy inducers, ADT therapy has been shown to be more effective. However, the phenomenon of drug resistance due to re-expression of ASS1 rather than stem cell remains to be investigated. Conclusion: Despite the paucity of studies in the literature, the available data demonstrate the therapeutic potential of arginine deprivation therapy for glioma and encourage further research, especially the exploration of its combination therapies and the extrapolation of what we know about the effects and mechanisms of ADT from other tumors to glioma. [ABSTRACT FROM AUTHOR]

Objective: To demonstrate the noninferiority of the novel hemostatic agent, Hemofence (BMI Korea Co., Ltd., thrombin cross-linked sodium hyaluronate gel matrix) compared to the established agent, Floseal Hemostatic Matrix (Baxter, thrombin-gelatin matrix) in achieving hemostasis for spinal surgeries, with secondary objectives to assess additional efficacy and safety. Methods: This clinical trial was a multicenter, randomized, subject-blinded, active-controlled, parallel-group, phase 3 study. Investigational drugs were administered to the first and second bleeding sites of each participant (or only to the first site if a second site was absent), evaluating hemostasis success rate within 10 minutes and the time to achieve hemostasis. Subsequent visits were conducted for safety assessments. For noninferiority test, a 97.5% one-sided confidence interval (CI) was used; the test group was deemed noninferior if the lower limit exceeded -10%. Results: This trial showed a 97.10% success rate in the test group and 96.05% in the control group for primary efficacy. The 95% CI (-4.90% to 7.44%) confirmed the test drug's noninferiority. Time to hemostasis showed no significant difference between groups. All adverse events, adverse drug reactions, and serious adverse events were statistically similar between groups (p=1.000, p=0.243, and p=0.966, respectively). Conclusion: A novel hemostatic agent, Hemofence, demonstrated an efficacy and safety profile comparable to that of Floseal. [ABSTRACT FROM AUTHOR]

While activating RET fusions are identified in various cancers, lung cancer represents the most common RET fusion-positive tumor. The clinical drug development of RET inhibitors in RET fusion-positive lung cancers naturally began after RET fusions were first identified in patient tumor samples in 2011, and thereafter paralleled drug development in RET fusion-positive thyroid cancers. Multikinase inhibitors were initially tested with limited efficacy and substantial toxicity. RET inhibitors were then designed with improved selectivity, central nervous system penetrance, and activity against RET fusions and most RET mutations, including resistance mutations. Owing their success to these rationally designed features, the first-generation selective RET tyrosine kinase inhibitors (TKIs) had higher response rates, more durable disease control, and an improved safety profile compared to the multikinase inhibitors. This led to lung and thyroid cancer, and later tumor-agnostic regulatory approvals. While next-generation RET TKIs were designed to abrogate uncommon on-target (e.g., solvent front mutation) resistance to selpercatinib and pralsetinib, many of these drugs lacked the selectivity of the first-generation TKIs, raising the question of what the future holds for drug development in RET-dependent cancers. [ABSTRACT FROM AUTHOR]

As the population ages, the demographic of adults aged 75 years and older in the U.S. is projected to grow to 45 million by 2050. Hypercholesterolemia is directly linked to atherosclerotic cardiovascular disease (ASCVD), which remains the leading cause of death in older adults. However, primary prevention of ASCVD through lipid-lowering agents remains unclear among older adults owing to limited involvement of older adults in current trials, lack of dedicated trials, and evidence primarily derived from secondary and retrospective analyses. Therefore, this article aims to (1) review key updates from the latest guidelines on treatment of hypercholesterolemia in older adults, (2) highlight limitations of the current ASCVD risk scores in the geriatric population, (3) present outcomes from key studies on the use of lipid-lowering agents and associated side effects, including a brief review of novel agents such as bempedoic acid, although very few adults over age 75 were included in these trial, and (4) finally, highlight upcoming dedicated trials of statins in older adults for the primary prevention of important geriatric outcomes as well as ASCVD. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma is a heterogenous hematological condition with a worldwide incidence of between 0.5–5 per 100,000. The standard front-line treatment algorithm suggests induction chemotherapy, early stem cell transplant in those eligible, followed by maintenance chemotherapy. Unfortunately, most people subsequently relapse and require salvage treatment. A wide array of options are available in the management of relapse/refractory multiple myeloma. Our review aims to describe the new, approved treatment modalities in this setting while describing data on the efficacy, tolerability, and nuances of each available option. Multiple myeloma is a heterogeneous condition characterized by the proliferation of monoclonal B-cells, for which there is currently no curative treatment available. Relapses are, unfortunately, common after first-line treatment. While the prognosis for relapsed refractory multiple myeloma is generally poor, advances in the treatment of relapsed or refractory multiple myeloma offer hope. However, the expansion of effective options in targeted treatment offers renewed optimism and hope that patients who fail on older therapies may respond to newer modalities, which are often used in combination. We review currently approved and novel investigational agents classified by mechanisms of action, efficacy, approved setting, and adverse events. We delve into future directions of treatment for relapsed/refractory multiple myeloma, reviewing novel agents and therapeutic targets for the future. [ABSTRACT FROM AUTHOR]

The European Medicines Agency adopted their Geriatric Medicines Strategy more than a decade ago. The strategy aims at elucidating the evidence basis for marketing authorization of new medicines which will be used in the older population, and at ensuring the appropriate communication of findings to the patient and healthcare provider. During the past decade new tools and data sources have emerged to support the strategy goals, and their use should be considered. Possible concrete actions are presented to improve the design of clinical trials, the data collection both pre‐ and post‐approval, the assessment of the findings, and the communication to assist informed prescription and safe medicine taking. Implementation and prioritization of these actions should be done from the perspective of addressing the needs of patients while maximizing efficient use of resources, with the aim of integrating geriatric aspects into routine medicines development and assessment. [ABSTRACT FROM AUTHOR]

Under‐representation of subgroups of the population in clinical trials has been and continues to be a problem despite goals of academia, industry, and government. Older adults are among the groups that are under‐represented in trials of medications that they are likely to receive once marketing approval has been received. Recent legislation that mandates that clinical trial participants be representative of patient population has been passed and creates hope that greater numbers of older adults will be enrolled in clinical trials and that they will be representative of "typical" geriatric patients. However, there is the need for collection of current data on disease prevalences with granularity as to age, gender, and race as well as geriatric co‐morbidities to assess the representativeness of clinical trial participants relative to patient populations. Consensus on definitions and collection of data relevant to geriatric patient populations are needed to evaluate effects of comorbidities, frailty, cognitive and physical function. There will also be a need for expansion of the geriatric research workforce, facilities for research both in academic centers but also in the community and long‐term care facilities, and for engagement with and involvement of communities that have been traditionally under‐represented to conduct clinical trials that enroll truly representative patient populations. [ABSTRACT FROM AUTHOR]

The article discusses the U.S. Food & Drug Administration's (FDA) guidelines and potential actions to enhance older adult drug evaluation as of September 2024. Topics covered include potential solutions to the underrepresentation of older adult patients in new drug therapy evaluation, and the possible safety deficiency due to lack of a subgroup's information that could disapprove a drug for market access. Also noted is the Consolidated Appropriations Act's support of patient representation.

The purpose of this overview was to perform an exploratory analysis of in‐house drug‐drug interaction (DDI) studies conducted with investigational drugs and oral midazolam to assess the value of measuring 1‐OH‐midazolam (1‐OHM) in such studies. The perpetrator effect of the investigational drugs on cytochrome P450 3A (CYP3A) was assessed by analyzing both midazolam and 1‐OHM in plasma and evaluating their pharmacokinetic parameters. Given the almost exclusive metabolism of the parent drug by CYP3A to the main metabolite 1‐OHM, an increase in midazolam and a decrease in 1‐OHM exposure in the case of CYP3A inhibition caused by a perpetrator drug would be expected. The opposite would be anticipated in the case of CYP3A induction. For this analysis, the perpetrator potential of eight different investigational drugs was incorporated. Among the 10 studies included, the identified CYP3A inhibitors (n = 4) and inducers (n = 1) were classified based on the data generated with midazolam per se, with 1‐OHM levels not contributing to the interpretation of the data as they did not corroborate the findings of the parent compound. Therefore, it was concluded that continued analysis of 1‐OHM in plasma may be questionable as it does not add value to the interpretation of the results when performing CYP3A DDI studies with an investigational drug as a perpetrator. [ABSTRACT FROM AUTHOR]

Summary: In severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab is unclear. We utilised a novel overlapping strategy in three patients with very-high fracture risk despite long-term denosumab which led to greater bone density improvements than previously reported with standard approaches. Larger confirmatory prospective studies are needed. Purpose/introduction: In patients with severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab has not been established. The ideal strategy would maximise gains in bone mineral density (BMD) with romosozumab and effectively mitigate the risk of rebound increased bone turnover when sequencing from denosumab. Limited studies exploring the sequence from denosumab to romosozumab report only modest-to-no improvement in BMD and inadequate suppression of rebound bone turnover. Methods: We describe three patients with severe osteoporosis and multiple fragility fractures despite long-term denosumab. A novel overlapping sequential treatment approach was utilised to maximise therapeutic benefit given these patients had a very high fracture risk. Romosozumab was commenced 3 months after the last denosumab dose. Instead of waiting until completion of romosozumab, denosumab was recommenced 6 months after commencing romosozumab in response to rising bone turnover markers. Results: Patients experienced a ~ 5–22% increase in lumbar spine BMD, and one patient had an 8% increase in total hip BMD after 12 months romosozumab. Serum bone turnover markers demonstrated an anabolic effect of romosozumab occurred despite overlapping treatment with denosumab. Recommencement of denosumab suppressed an increase in bone resorption in all cases. No new vertebral fractures occurred during this treatment. Conclusions: A novel overlapping sequential treatment approach between denosumab and romosozumab produced greater improvements in lumbar spine and hip BMD than previously reported with standard approaches. Larger prospective controlled studies are needed to confirm these findings and establish the optimal use of romosozumab in patients pre-treated with denosumab to maximise BMD gains and minimise fracture risk. [ABSTRACT FROM AUTHOR]

Purpose This project aimed to characterize the resources necessary for pharmacists to support the required steps for obtaining and handling investigational drugs outside of a study protocol in the individual patient and intermediate-size population Expanded Access Program (EAP) processes. The second aim was to characterize the types of EAP requests received. Summary This retrospective, single-center, observational study was performed by reviewing EAP requests initiated at Duke University Hospital (DUH) between August 1, 2017, and February 11, 2023. The annualized cost of unreimbursed EAP study services was projected to be approximately $196,500 at DUH for 2023. Of the 168 EAP requests submitted after the institutional policy requiring pharmacy and therapeutics (P&T) committee approval was established, 162 (96.4%) were approved by the P&T committee. Conclusion Given the lack of published information on a pharmacist-led workflow related to EAP services, this study sought to share DUH's process for managing EAP requests. As there is no mechanism for reimbursement of EAP services, they can be difficult to manage given the labor resources required. Further work is needed to recoup unreimbursed investigational drug service labor costs to ensure compassionate use programs can be implemented in a manner that is financially sustainable for a health system. [ABSTRACT FROM AUTHOR]

Maternal vaccination is a safe and effective means of preventing infection in pregnant women, their fetuses, and infants after birth. Several vaccines are routinely administered in pregnancy as a valuable part of prenatal care with supporting recommendations from national and international health organizations. Fears concerning vaccine safety in pregnancy are pervasive despite sufficient available safety data to support their use, leading to underutilization of maternal immunization. Despite this hesitancy, the field of maternal vaccination is evolving to include more vaccines in the routine prenatal vaccination schedule, including the new RSV vaccine. This review discusses the currently recommended vaccines in pregnancy, evidence for their use, and an overview of ongoing clinical trials investigating prospective vaccines for pregnant women. [ABSTRACT FROM AUTHOR]

In the absence of an efficacious vaccine, chemotherapy remains crucial to prevent and treat malaria. Given its key role in haemoglobin degradation, falcilysin constitutes an attractive target. Here, we reveal the mechanism of enzymatic inhibition of falcilysin by MK-4815, an investigational new drug with potent antimalarial activity. Using X-ray crystallography, we determine two binary complexes of falcilysin in a closed state, bound with peptide substrates from the haemoglobin α and β chains respectively. An antiparallel β-sheet is formed between the substrate and enzyme, accounting for sequence-independent recognition at positions P2 and P1. In contrast, numerous contacts favor tyrosine and phenylalanine at the P1' position of the substrate. Cryo-EM studies reveal a majority of unbound falcilysin molecules adopting an open conformation. Addition of MK-4815 shifts about two-thirds of falcilysin molecules to a closed state. These structures give atomic level pictures of the proteolytic cycle, in which falcilysin interconverts between a closed state conducive to proteolysis, and an open conformation amenable to substrate diffusion and products release. MK-4815 and quinolines bind to an allosteric pocket next to a hinge region of falcilysin and hinders this dynamic transition. These data should inform the design of potent inhibitors of falcilysin to combat malaria. The antimalarial drug MK-4815 shifts falcilysin to a closed state inhibiting its proteolytic cycle, which provides insights for designing potent falcilysin inhibitors to combat malaria. [ABSTRACT FROM AUTHOR]

Patients with psoriasis often take multiple medications due to comorbidities, raising concerns about drug–drug interactions (DDIs) during the development of new medicines. DDI risk assessments of a new small molecule showed risks of CYP3A4 autoinduction and being a sensitive CYP3A4 substrate. We conducted a real‐world evidence (RWE) claims analysis to assess the frequency of prescription claims for up to 12 months from the date of the initial psoriasis diagnosis for drugs that may interact with CYP3A4 substrates. We used 2013 to 2018 patient data from the US Merative MarketScan Research Database. Among patients diagnosed with psoriasis, less than 1% had a claim for a moderate/strong inducer, but up to 15% had a claim for moderate/strong inhibitor. Most prescriptions for CYP3A4 inhibitors or inducers included antibiotics and anticonvulsants. While CYP3A4 inducers were rarely used, those treated received more than >90 days treatment. Then, these RWE data were used to inform the early translational medicine strategy for the new investigational drug by strategically integrating DDI evaluations into a first‐in‐human healthy volunteer trial prior to studies in patients with psoriasis. The resulting DDI substudy showed that the investigational small molecule did not induce midazolam clearance but was sensitive to CYP3A inhibition, leading to the decision to exclude concomitant use of strong CYP3A4 inducers or inhibitors from clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is one of the most dangerous cancers affecting women, so animal models of breast cancer have been created, new drugs are constantly being sought, and new procedures are being developed to destroy tumor cells. As to this last aspect, the use of high-intensity focused ultrasound is promising. It is a non-invasive technique, but its availability is significantly limited due to such devices' costliness and lack of versatility. Therefore, this project aimed to construct a low-cost, compact HIFU for precise destruction of cancer cells in the region of interest and to test the efficacy of the shortened-duration ablation procedure in a rat model of implantable breast cancer. Our research is preclinical and may also be applicable in veterinary medicine. The HIFU ablation technique is limited by the long duration of the procedure, which results from the large difference between the size of the HIFU beam's focus and the tumor size. Ablation of large tumors requires treating them with a sequence of single HIFU beams, with a specific time interval in-between. The aim of this study was to evaluate the biological effects induced in a malignant solid tumor of the rat mammary gland, implanted in adult Wistar rats, during HIFU treatment according to a new ablation plan which allowed researchers to significantly shorten the duration of the procedure. We used a custom, automated, ultrasound imaging-guided HIFU ablation device. Tumors with a 1 mm thickness margin of healthy tissue were subjected to HIFU. Three days later, the animals were sacrificed, and the HIFU-treated tissues were harvested. The biological effects were studied, employing morphological, histological, immunohistochemical, and ultrastructural techniques. Massive cell death, hemorrhages, tissue loss, influx of immune cells, and induction of pro-inflammatory cytokines were observed in the HIFU-treated tumors. No damage to healthy tissues was observed in the area surrounding the safety margin. These results confirmed the efficacy of the proposed shortened duration of the HIFU ablation procedure and its potential for the treatment of solid tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: The current review summarizes the new potential treatment strategies for patients with early-stage non-small cell lung cancer with immunotherapy and targeted therapies and defines the current challenges for making treatment decisions with these approaches in daily practice. The recent advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint blockers (ICBs) in early-stage non-small cell lung cancer (NSCLC) has dramatically modified treatment strategies by improving the prognosis in this setting. Osimertinib and alectinib, both TKIs, have shown significant improvements in outcomes for patients with resected EGFR- and ALK-positive NSCLC, respectively, changing the standard of care in these subgroups. More recently, the LAURA trial showed the efficacy of osimertinib after chemoradiotherapy in patients with unresectable stage III NSCLC harboring EGFR mutations. Numerous trials are still ongoing to investigate neoadjuvant/perioperative TKIs in several oncogene-driven NSCLC. In addition, several ICBs have been tested and approved as adjuvant (atezolizumab and pembrolizumab), neoadjuvant (nivolumab), and perioperative treatments (pembrolizumab) for patients with resectable early-stage NSCLC. Despite these advances, many challenges remain regarding the use of TKIs and ICBs in this setting, including the optimal duration of adjuvant TKI or induction ICB therapy, the role of minimal residual disease to identify patients at high-risk of disease relapse and to guide adjuvant treatment decisions, and the role of adjuvant chemotherapy in resected oncogene-driven NSCLC. Furthermore, potential predictive biomarkers for efficacy are needed to eventually intensify the entire perioperative strategies. This review aims to summarize and discuss the available evidence, the ongoing trials, and the challenges associated with TKI- and ICB-based approaches in early-stage NSCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer can create a shield of suppressive innate immune cells that stop our body's natural defenses from tumors. VTX-0811 is a new drug that targets these cells and turns them from allies of cancer to fighters against it. Preclinical tests show that it works in the lab on human cells and tumors and is safe and efficacious in animals. The results are promising and pave the way for human trials to see if VTX-0811 can become a new powerful weapon against cancer. Omnipresent suppressive myeloid populations in the tumor microenvironment limit the efficacy of T-cell-directed immunotherapies, become more inhibitory after administration of T-cell checkpoint inhibitors, and are overall associated with worse survival of cancer patients. In early clinical trials, positive outcomes have been demonstrated for therapies aimed at repolarizing suppressive myeloid populations in the tumor microenvironment. We have previously described the key role of P-selectin glycoprotein ligand-1 (PSGL-1) in maintaining an inhibitory state of tumor-associated macrophages (TAMs), most of which express high levels of PSGL-1. Here we describe a novel, first-in-class humanized high-affinity monoclonal antibody VTX-0811 that repolarizes human macrophages from an M2-suppressive phenotype towards an M1 inflammatory phenotype, similar to siRNA-mediated knockdown of PSGL-1. VTX-0811 binds to PSGL-1 of human and cynomolgus macaque origins without inhibiting PSGL-1 interaction with P- and L-Selectins or VISTA. In multi-cellular assays and in patient-derived human tumor cultures, VTX-0811 leads to the induction of pro-inflammatory mediators. RNAseq data from VTX-0811 treated ex vivo tumor cultures and M2c macrophages show similar pathways being modulated, indicating that the mechanism of action translates from isolated macrophages to tumors. A chimeric version of VTX-0811, consisting of the parental murine antibody in a human IgG4 backbone, inhibits tumor growth in a humanized mouse model of cancer. VTX-0811 is exceptionally well tolerated in NHP toxicology assessment and is heading into clinical evaluation after successful IND clearance. [ABSTRACT FROM AUTHOR]

The reagent system based on the combined use of Et3SiH/I2 acts as an efficient N-glycosidation promoter for the synthesis of natural and sugar-modified nucleosides. An analysis of reaction stereoselectivity in the absence of C2-positioned stereodirecting groups revealed high selectivity with six-membered substrates, depending on the nucleophilic character of the nucleobase or based on anomerization reactions. The synthetic utility of the Et3SiH/I2-mediated N-glycosidation reaction was highlighted by its use in the synthesis of the investigational drug apricitabine. [ABSTRACT FROM AUTHOR]

Purpose Health-system pharmacists play a crucial role in monitoring the pharmaceutical pipeline to manage formularies, allocate resources, and optimize clinical programs for new therapies. This article aims to support pharmacists by providing periodic updates on new and anticipated novel drug approvals. Summary Selected drug approvals anticipated in the 12-month period covering the second quarter of 2024 through the first quarter of 2025 are reviewed. The analysis emphasizes drugs expected to have significant clinical and financial impact in hospitals and clinics, as selected from 52 novel drugs awaiting US Food and Drug Administration approval. New cellular and gene therapies for cancers continued to strengthen the pipeline, in addition to new drugs targeting previously untreatable conditions. Several novel drugs are being developed for rare and ultra-rare diseases such as hemophilia, Niemann-Pick disease type C, hereditary angioedema, and aromatic l -amino acid decarboxylase deficiency. Conclusion The current drug pipeline includes new drugs with various indications for cancers and rare diseases as well as diabetes, acute coronary syndrome, chronic skin disorder, and chronic obstructive pulmonary disease. [ABSTRACT FROM AUTHOR]

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare and progressive disease that causes progressive cough, exertional dyspnea, impaired quality of life, and death. Objectives: Bexotegrast (PLN-74809) is an oral, once-daily, investigational drug in development for the treatment of IPF. Methods: This Phase-2a multicenter, clinical trial randomized participants with IPF to receive, orally and once daily, bexotegrast at 40 mg, 80 mg, 160 mg, or 320 mg, or placebo, with or without background IPF therapy (pirfenidone or nintedanib), in an approximately 3:1 ratio in each bexotegrast dose cohort, for at least 12 weeks. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Exploratory efficacy endpoints included change from baseline in FVC, quantitative lung fibrosis (QLF) extent (%), and changes from baseline in fibrosis-related biomarkers. Measurements and Main Results: Bexotegrast was well tolerated, with similar rates of TEAEs in the pooled bexotegrast and placebo groups (62/89 [69.7%] and 21/31 [67.7%], respectively). Diarrhea was the most common TEAE; most participants with diarrhea also received nintedanib. Participants who were treated with bexotegrast experienced a reduction in FVC decline over 12 weeks compared with those who received placebo, with or without background therapy. A dose-dependent antifibrotic effect of bexotegrast was observed with QLF imaging, and a decrease in fibrosis-associated biomarkers was observed with bexotegrast versus placebo. Conclusions: Bexotegrast demonstrated a favorable safety and tolerability profile, up to 12 weeks for the doses studied. Exploratory analyses suggest an antifibrotic effect according to FVC, QLF imaging, and circulating levels of fibrosis biomarkers. Clinical trial registered with (NCT04396756). [ABSTRACT FROM AUTHOR]

Currently, cervical cancer (CC) is the fourth recorded widespread cancer among women globally. There are still many cases of metastatic or recurring disease discovered, despite the incidence and fatality rates declining due to screening identification and innovative treatment approaches. Palliative chemotherapy continues to be the standard of care for patients who are not contenders for curative therapies like surgery and radiotherapy. This article seeks to provide a thorough and current summary of therapies that have been looked into for the management of CC. The authors emphasize the ongoing trials while reviewing the findings of clinical research. Agents that use biological mechanisms to target different molecular pathways such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), poly ADP-ribosepolymerase (PARP), and epigenetic biological mechanisms epitomize and offer intriguing research prospects. [ABSTRACT FROM AUTHOR]

Advanced therapy medicinal products (ATMPs) are rapidly evolving to offer new treatment options. The scientific, technical, and clinical complexities subject drug regulatory authorizes to regulatory challenges. To advance the regulatory capacity for ATMPs, the National Medical Products Administration in China made changes to the drug regulatory system and developed regulatory science with the goal of addressing patient needs and encouraging innovation. This study aimed to systematically identify the regulatory evidence on ATMPs in China under the guidance of an overarching framework from the World Health Organization Global Benchmarking Tool. It was found that China's administrative authorities at all levels have issued a number of policy documents to promote the development of ATMPs, covering biopharmaceutical products research and development (n = 14), biopharmaceutical industry development (n = 9), high-quality development of medical institutions (n = 1), specific development plans/projects (n = 6) and specific regional development (n = 4). The legal and regulatory framework of ATMPs in China has been established and is subject to continuous adjustment in various aspects including regulations (n = 3), departmental rules or administrative normative documents (n = 22), and technical guidance (n = 15). As the regulatory reform continues, the drug review processes have been revised, and various technical standards have been launched, which aim to establish a regulatory approach that oversees the full life-cycle development of ATMPs in the country. The limited number of investigational new drug applications and approved ATMPs suggests a lag remains between the translation of advanced therapeutic technologies into clinically available medical products. To accelerate the translational research of ATMP in countries such as China, developing and adopting real-world evidence generated from clinical use in designated healthcare facilities to support scientific decision-making in ATMP regulation is warranted. The enhancement of regulatory capacity building and multi-stakeholder collaborations should also be encouraged to facilitate the timely evaluation of promising ATMPs to meet more patient needs. [ABSTRACT FROM AUTHOR]

Purpose This project compared the time to complete investigational prescription drug order verification by investigational drug service (IDS) pharmacists in an onsite vs offsite (hybrid) staffing model, evaluating the impact of remote work on verification time. Methods Parenteral IDS drug orders from August 2019 through June 2022 were analyzed. Electronic medical records were timestamped for each order, first verification, second verification, and medication administration. The project was divided into four 6-month time periods to allow for 2 independent comparisons of onsite vs hybrid staffing models. A survey was given retrospectively to IDS pharmacists for the last hybrid timeframe to assess work satisfaction and burnout. Results A total of 4,398 orders were evaluated. The time from order entry to first verification was 14 minutes (n = 1,248) during the first onsite time period compared to 13 minutes (n = 1,042) during the first hybrid period (P = 0.003). The time for order verification was similar between the second onsite and hybrid periods (12 minutes [n = 1,041] vs 10 minutes [n = 1,067], respectively; P < 0.0001). The staff satisfaction survey for the hybrid model showed high levels of job satisfaction and no self-reported burnout. Conclusion The remote hybrid staffing model did not result in a meaningful change in the time from order placement to medication administration within the IDS pharmacy. Hybrid staffing also resulted in greater job satisfaction among IDS pharmacists. This study highlights the benefits of implementing remote work practices in the pharmacy practice setting. [ABSTRACT FROM AUTHOR]

Myristoylation, the N-terminal addition of the fatty acid myristate to proteins, regulates membrane-bound signal transduction pathways important in cancer cell biology. This modification is catalyzed by two N-myristoyltransferases, NMT1 and NMT2. Zelenirstat is a first-in-class potent oral small molecule inhibitor of both NMT1 and NMT2 proteins. Patients with advanced solid tumors and relapsed/refractory (R/R) B-cell lymphomas were enrolled in an open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until progression or unacceptable toxicity. The endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD), pharmacokinetic parameters, and anticancer activity. Twenty-nine patients were enrolled (25 advanced solid tumor; 4 R/R B-cell lymphoma) and 24 were DLT-evaluable. Dosing ranged from 20 mg once daily (OD) to 210 mg OD without DLT, but gastrointestinal DLTS were seen in the 280 mg cohort. MTD and recommended phase 2 dose were 210 mg OD. Common adverse events were predominantly Gr ≤ 2 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked at 2 h with terminal half-lives averaging 10 h. Steady state was achieved by day 15, and higher doses achieved trough concentrations predicted to be therapeutic. Stable disease as best response was seen in eight (28%) patients. Progression-free survival and overall survival were significantly better in patients receiving 210 mg OD compared to those receiving lower doses. Zelenirstat is well-tolerated, achieves plasma exposures expected for efficacy, and shows early signs of anticancer activity. Further clinical development of zelenirstat is warranted. [ABSTRACT FROM AUTHOR]

Background: The management of pediatric dermatological conditions such as alopecia areata (AA), psoriasis, atopic dermatitis (AD), and hidradenitis suppurativa (HS) has significantly evolved with the introduction of biologics and small molecule targeted therapies. The advancement in understanding the immunopathogenesis of these chronic skin conditions has led to the development and approval of novel biologics and small molecule therapies. Initially approved by the United States Food and Drug Administration (FDA) for adults, most of these therapies are now being evaluated in clinical trials for safety and efficacy in adolescents and children, expanding new treatment options for pediatric patients. The role of the FDA in drug approval is multifaceted from drug inception, ensuring that research, data, and evidence show that the proposed drug is effective and safe for the intended use. Objective: The goal of this review article is to provide an overview of the recently FDA-approved and potential biologic and oral small molecule therapies in clinical trials for AA, psoriasis, AD, and HS in pediatric patients. Methods: The search for this review included keywords in ClinicalTrials.gov, PubMed, and Google Scholar for the latest research and clinical trials relevant to these conditions and treatments without the PRISMA methodology. Results: For pediatric AA, ritlecitinib is FDA-approved, while baricitinib and updacitinib are in phase 3 clinical trials for pediatric approval. The FDA-approved drugs for pediatric psoriasis include secukinumab, ustekinumab, ixekizumab, etanercept, and apremilast. Other phase 3 clinical trials for pediatric psoriasis include risankizumab, guselkumab, tildrakizumab, brodalumab, and deucravacitinib. For pediatric AD, the FDA-approved drugs are dupilumab, tralokinumab, abrocitinib, and upadacitinib, with many other drugs in phase 3 trials. Adalimumab is an FDA-approved biologic for pediatric HS, with various clinical trials ongoing for adults. The approved biologics and small molecule therapies had higher efficacy and improved safety profiles compared to traditional medications. Conclusions: With numerous ongoing trials, the success of these clinical trials could lead to their inclusion in treatment guidelines for these chronic skin conditions. Biologics and small molecule therapies offer new avenues for effective disease management, enabling personalized therapeutic interventions and improving pediatric health outcomes. [ABSTRACT FROM AUTHOR]

Despite the effectiveness of insulin injections in managing hyperglycemia in type 1 diabetes mellitus (T1DM), they fall short in addressing autoimmunity and regenerating damaged islets. This review aims to explore the potential and prospects of emerging treatment modalities for T1DM, including mesenchymal stem cells (MSCs), MSC-derived exosomes, gene therapy, islet allotransplantation, pancreatic islet cell transplantation, and teplizumab. We review emerging treatment modalities for T1DM, highlighting several promising strategies with varied mechanisms and outcomes. Mesenchymal stem cells demonstrate potential in modulating the immune response and preserving or restoring beta-cell function, although variability in sources and administration routes necessitates further standardization. Similarly, MSC-derived exosomes show promise in promoting beta-cell regeneration and immune regulation, supported by early-stage studies showing improved glucose homeostasis in animal models, albeit with limited clinical data. Gene therapy, utilizing techniques like CRISPR-Cas9, offers targeted correction of genetic defects and immune modulation; however, challenges in precise delivery and ensuring long-term safety persist. Islet allotransplantation and pancreatic islet cell transplantation have achieved some success in restoring insulin independence, yet challenges such as donor scarcity and immunosuppression-related complications remain significant. Teplizumab, an anti-CD3 monoclonal antibody, has demonstrated potential in delaying T1DM onset by modulating immune responses and preserving beta-cell function, with clinical trials indicating prolonged insulin production capability. Despite significant progress, standardization, long-term efficacy, and safety continue to pose challenges across these modalities. Conclusion: While these therapies demonstrate significant potential, challenges persist. Future research should prioritize optimizing these treatments and validating them through extensive clinical trials to enhance T1DM management and improve patient outcomes. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic-led worldwide healthcare crisis necessitates prompt societal, ecological, and medical efforts to stop or reduce the rising number of fatalities. Numerous mRNA based vaccines and vaccines for viral vectors have been licensed for use in emergencies which showed 90% to 95% efficacy in preventing SARS-CoV-2 infection. However, safety issues, vaccine reluctance, and skepticism remain major concerns for making mass vaccination a successful approach to treat COVID-19. Hence, alternative therapeutics is needed for eradicating the global burden of COVID-19 from developed and low-resource countries. Repurposing current medications and drug candidates could be a more viable option for treating SARS-CoV-2 as these therapies have previously passed a number of significant checkpoints for drug development and patient care. Besides vaccines, this review focused on the potential usage of alternative therapeutic agents including antiviral, antiparasitic, and antibacterial drugs, protease inhibitors, neuraminidase inhibitors, and monoclonal antibodies that are currently undergoing preclinical and clinical investigations to assess their effectiveness and safety in the treatment of COVID-19. Among the repurposed drugs, remdesivir is considered as the most promising agent, while favipiravir, molnupiravir, paxlovid, and lopinavir/ritonavir exhibited improved therapeutic effects in terms of elimination of viruses. However, the outcomes of treatment with oseltamivir, umifenovir, disulfiram, teicoplanin, and ivermectin were not significant. It is noteworthy that combining multiple drugs as therapy showcases impressive effectiveness in managing individuals with COVID-19. Tocilizumab is presently employed for the treatment of patients who exhibit COVID-19-related pneumonia. Numerous antiviral drugs such as galidesivir, griffithsin, and thapsigargin are under clinical trials which could be promising for treating COVID-19 individuals with severe symptoms. Supportive treatment for patients of COVID-19 may involve the use of corticosteroids, convalescent plasma, stem cells, pooled antibodies, vitamins, and natural substances. This study provides an updated progress in SARS-CoV-2 medications and a crucial guide for inventing novel interventions against COVID-19. [ABSTRACT FROM AUTHOR]

Purpose There are currently no consensus guidelines on establishing metrics for investigational drug services (IDS). Because of the complexity of research protocols, it remains difficult for sites to track pharmacy productivity and create a baseline for IDS growth within the institution, as well as to perform benchmarking with peer institutions. The goal of this study was to help establish practical guidance for IDS metrics and site utility as applicable. Methods This was a survey-based project conducted by the metrics subgroup of the Hematology/Oncology Pharmacy Association (HOPA) IDS special interest group (SIG), which was formed specifically for this analysis. Three surveys developed by the metrics subgroup were sent to members of the IDS HOPA SIG to gather metrics. The first survey included questions about what metrics IDS sites currently collect. The identified metrics were then condensed into categories. Through a consensus-based approach, standardized definitions were established and applied to future surveys. The 2 subsequent surveys sent to HOPA SIG members helped create a list of top recommended metrics that are recommended for every IDS site to track. Results A total of 3 surveys were sent to 75 recipients, with the response rate ranging from 24% to 38%. From these surveys and consensus with the metrics subgroup, 5 top recommended metrics were identified: (1) active protocols; (2) dispenses; (3) new clinical trials initiated; (4) patients treated; and (5) clinical interventions. Conclusion These recommended metrics should serve as guidance and allow for standardization to help ensure adequate resources are available for IDS pharmacy staff. These recommendations should serve as a basis for standardization and benchmarking with peer institutions. [ABSTRACT FROM AUTHOR]

All types of ginger have common fundamental components, although they possess distinct strengths and inclinations when it comes to effectiveness and medicinal applications. Fresh ginger possesses the ability to effectively stimulate movement within the body, alleviate the act of vomiting, induce sweating, and provide relief for external syndromes. Dried ginger possesses both defensive and stimulant characteristics, which effectively raise the internal temperature and enhance the Yang energy. Fresh ginger is more hydrating than dried ginger, highly skilled at heating the Middle-jiao, alleviating pain, halting bleeding, and managing diarrhea. Dried ginger possesses the ability to alleviate coldness when consumed in a heated form, as well as to alleviate diarrhea when consumed in a heated form. It thrives in warm conditions and has a tendency to revert back to its warm nature. The moisture content of baked ginger is inferior to that of dried ginger, but it is highly effective in alleviating pain, bleeding, and diarrhea by warming the Middle-jiao. Ginger charcoal and stir-fried charcoal, produced through carbonization, have excellent heat retention properties and are effective in warming meridians and stopping bleeding. The potency and ability to spread of roasted ginger is less intense compared to fresh ginger, and its moisture content is not as low as that of dried ginger. The medicinal characteristics of this substance are gentle, making it beneficial for alleviating vomiting in patients who are physically frail. Its primary mode of action is on the Middle-jiao. Nevertheless, the main chemical compositions of various traditional Chinese medicines are nearly identical due to their shared base element. Ginger, in particular, possesses a range of pharmacological activities including antioxidant, anti-inflammatory, anti-tumor, anti-bacterial, and anticoagulant properties. However, modern pharmacological research has not fully acknowledged the clinical medicinal value of ginger and consequently, fails to provide accurate guidance for clinical medication. This situation has a negative impact on the contemporary advancement of traditional Chinese medicine (TCM). The research on modernizing ginger is conducted by analyzing and considering the prospects. It is based on Traditional Chinese Medicine (TCM) theory and incorporates the comprehensive perspective of TCM philosophy. In order to modernize ginger, it is essential to have a proper knowledge of the concepts of "recognizing nature by efficacy, homology, and mutual expression of nature and efficacy" and "rationally utilizing modern drug research technology". By applying these principles, we can construct a bridge towards the advancement of ginger. [ABSTRACT FROM AUTHOR]

NAFLD, non-alcoholic fatty liver disease, is a liver condition in which it builds up too much fat which is not related to alcohol consumption. This review explores the evolution of treatment for NAFLD and its more serious version, non-alcoholic steatohepatitis (NASH). The American Association for the Study of Liver Disease (AASLD) has introduced new terminologies for these diseases in 1923. NAFLD is now called metabolic dysfunction-associated steatotic liver disease (MASLD) and NASH is called metabolic dysfunction-associated steatohepatitis (MASH). This study investigates different treatments for these conditions from lifestyle changes to innovative therapies. These conditions are usually treated through improved diet, increased physical activity and weight management as FDA has not yet approved any specific drugs for their treatment. Diabetes drugs are found helpful in treating NASH. Some recent advancements have led to precision medicine and customized innovative individual therapies. NASH is now treated by adopting different strategies. The first strategy aims to reduce excess liver fat. The second strategy fights inflammation, oxidative stress, and apoptosis. The third strategy targets metabolic endotoxemia and the gut microbiome. These emerging therapies show promise for slowing the progression of NASH-related disorders. [ABSTRACT FROM AUTHOR]

Background Adolescents and young adults frequently receive chemotherapy near death. We know less about the use of targeted agents and immunotherapy or trends over time. Methods We conducted a retrospective cohort study of 1836 adolescents and young adults with cancer who died between 2009 and 2019 after receiving care at 1 of 3 sites (Dana-Farber Cancer Institute, Kaiser Permanente Northern California, and Kaiser Permanente Southern California). We reviewed electronic health data and medical records to examine use of cancer-directed therapy in the last 90 days of life, including chemotherapy, targeted therapy, immunotherapy, and investigational drugs. Results Over the study period, 35% of adolescents and young adults received chemotherapy in the last 90 days of life; 24% received targeted therapy, 7% immunotherapy, and 5% investigational drugs. Additionally, 56% received at least 1 form of systemic cancer-directed therapy in the last 90 days of life. After adjustment for patient sex, race, ethnicity, age, site of care, diagnosis, and years from diagnosis to death, the proportion of adolescents and young adults receiving targeted therapy (odds ratio [OR] = 1.05 per year of death, 95% confidence interval [CI] = 1.02 to 1.10; P  = .006), immunotherapy (OR = 1.27, 95% CI = 1.18 to 1.38; P  < .0001), and any cancer-directed therapy (OR = 1.04, 95% CI = 1.01 to 1.08; P  = .01) in the last 90 days of life increased over time. Conclusions More than half of adolescents and young adults receive cancer therapy in the last 90 days of life, and use of novel agents such as targeted therapy and immunotherapy is increasing over time. Although some adolescents and young adults may wish to continue cancer therapy while living with advanced disease, efforts are needed to ensure that use of cancer-directed therapy meets preferences of adolescents and young adults approaching death. [ABSTRACT FROM AUTHOR]