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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]

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]

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]

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]

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]

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]

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]

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]

Despite >1 in 5 children taking prescription drugs in the United States, offlabel drug use is common. To increase the study of drugs in children, regulatory bodies have enacted legislation to incentivize and require pediatric drug studies. As a result of this legislation, novel trial approaches, and an increase in personnel with pediatric expertise, there have been numerous advancements in pediatric drug development. With this review, we aim to highlight developments in pediatric pharmacology over the past 6 years for the most common disease processes that may be treated pharmacologically by the pediatric primary care provider. Using information extracted from label changes between 2018 and 2023, the published literature, and Clinicaltrials.gov, we discuss advances across multiple therapeutic areas relevant to the pediatric primary care provider, including asthma, obesity and related disorders, mental health disorders, infections, and dermatologic conditions. We highlight instances in which new drugs have been developed on the basis of a deeper mechanistic understanding of illness and instances in which labels have been expanded in older drugs on the basis of newly available data. We then consider additional factors that affect pediatric drug use, including cost and nonpharmacologic therapies. Although there is work to be done, efforts focused on pediatric-specific drug development will increase the availability of evidence-based, labeled guidance for commonly prescribed drugs and improve outcomes through the safe and effective use of drugs in children. [ABSTRACT FROM AUTHOR]

Firsocostat is an oral, liver‐targeted inhibitor of acetyl‐coenzyme A carboxylase in development for the treatment of metabolic dysfunction‐associated steatohepatitis. Hepatic organic anion transporting polypeptides play a significant role in the disposition of firsocostat with minimal contributions from uridine diphospho‐glucuronosyltransferase and cytochrome P450 3A enzymes. This phase 1 study evaluated the pharmacokinetics and safety of firsocostat in participants with mild, moderate, or severe hepatic impairment. Participants with stable mild, moderate, or severe hepatic impairment (Child–Pugh A, B, or C, respectively [n = 10 per cohort]) and healthy matched controls with normal hepatic function (n = 10 per cohort) received a single oral dose of firsocostat (20 mg for mild and moderate hepatic impairment; 5 mg for severe hepatic impairment) with intensive pharmacokinetic sampling over 96 h. Safety was monitored throughout the study. Firsocostat plasma exposure (AUCinf) was 83%, 8.7‐fold, and 30‐fold higher in participants with mild, moderate, and severe hepatic impairment, respectively, relative to matched controls. Firsocostat was generally well tolerated, and all reported adverse events were mild in nature. Dose adjustment is not necessary for the administration of firsocostat in patients with mild hepatic impairment. However, based on the observed increases in firsocostat exposure, dose adjustment should be considered for patients with moderate or severe hepatic impairment, and additional safety and efficacy data from future clinical trials will further inform dose adjustment. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite significant advancements, acute myeloid leukemia (AML) still remains characterized by a dismal prognosis in too many patients, and oftentimes, a cure can be achieved only after allogeneic hematopoietic stem cell transplantation (allo-HSCT), a procedure hampered by severe treatment-related complications. Despite this, new technologies have made it possible to harness the activity of the immune system against AML and use it as a new form of therapy, and intense research in the field has been made in recent years. This review aims to summarize the main concepts and strategies under study, considered from the point of view of the practicing hematologist, with special interest in the underlying biological principles and on treatment safety and efficacy. It will hopefully provide physicians, as well as the curious enthusiasts, with an updated, critically assessed description of immunotherapy as part of a more precise oncology approach to the treatment of AML. The potential of the immune system to eradicate leukemic cells has been consistently demonstrated by the Graft vs. Leukemia effect occurring after allo-HSCT and in the context of donor leukocyte infusions. Various immunotherapeutic approaches, ranging from the use of antibodies, antibody–drug conjugates, bispecific T-cell engagers, chimeric antigen receptor (CAR) T-cells, and therapeutic infusions of NK cells, are thus currently being tested with promising, yet conflicting, results. This review will concentrate on various types of immunotherapies in preclinical and clinical development, from the point of view of a clinical hematologist. The most promising therapies for clinical translation are the use of bispecific T-cell engagers and CAR-T cells aimed at lineage-restricted antigens, where overall responses (ORR) ranging from 20 to 40% can be achieved in a small series of heavily pretreated patients affected by refractory or relapsing leukemia. Toxicity consists mainly in the occurrence of cytokine-release syndrome, which is mostly manageable with step-up dosing, the early use of cytokine-blocking agents and corticosteroids, and myelosuppression. Various cytokine-enhanced natural killer products are also being tested, mainly as allogeneic off-the-shelf therapies, with a good tolerability profile and promising results (ORR: 20–37.5% in small trials). The in vivo activation of T lymphocytes and NK cells via the inhibition of their immune checkpoints also yielded interesting, yet limited, results (ORR: 33–59%) but with an increased risk of severe Graft vs. Host disease in transplanted patients. Therefore, there are still several hurdles to overcome before the widespread clinical use of these novel compounds. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite considerable progress in cancer research and treatment, cancer continues to be a major health challenge, often requiring invasive treatments with substantial side effects. Immuno-therapy, which targets the immune system's PD-1/PD-L1 pathway, represents a promising alternative. This critical pathway allows cancer cells to avoid immune destruction by inhibiting T-cells. Our study employs computational techniques to develop inhibitors that block the PD-L1 pathway, specifically in the acidic environment of tumors. By analyzing around 10,000 natural compounds, we identified a potential pH-selective inhibitor that shows greater effectiveness in the acidic conditions typical of cancerous tissues. This research suggests a novel approach for experimental groups to explore, focusing on developing targeted, pH-dependent inhibitors that could mark a significant step in enhancing the precision and effectiveness of immunotherapy treatments, potentially revolutionizing cancer therapy. Immunotherapy, particularly targeting the PD-1/PD-L1 pathway, holds promise in cancer treatment by regulating the immune response and preventing cancer cells from evading immune destruction. Nonetheless, this approach poses a risk of unwanted immune system activation against healthy cells. To minimize this risk, our study proposes a strategy based on selective targeting of the PD-L1 pathway within the acidic microenvironment of tumors. We employed in silico methods, such as virtual screening, molecular mechanics, and molecular dynamics simulations, analyzing approximately 10,000 natural compounds from the MolPort database to find potential hits with the desired properties. The simulations were conducted under two pH conditions (pH = 7.4 and 5.5) to mimic the environments of healthy and cancerous cells. The compound MolPort-001-742-690 emerged as a promising pH-selective inhibitor, showing a significant affinity for PD-L1 in acidic conditions and lower toxicity compared to known inhibitors like BMS-202 and LP23. A detailed 1000 ns molecular dynamics simulation confirmed the stability of the inhibitor-PD-L1 complex under acidic conditions. This research highlights the potential of using in silico techniques to discover novel pH-selective inhibitors, which, after experimental validation, may enhance the precision and reduce the toxicity of immunotherapies, offering a transformative approach to cancer treatment. [ABSTRACT FROM AUTHOR]

Introduction: On-treatment excursions of liver laboratory test values in clinical trials involving subjects with underlying liver disease are relevant for the efficacy and safety assessment of drug products and biologics. Existing visualization and analysis tools do not efficiently provide an integrated view of these excursions when baseline liver tests are abnormal. Objective: The aim of this study was to develop a composite plot that enables visualization of on-treatment changes in liver test results both as multiples of the upper limit of normal defined by each laboratory's reference population (×ULN) and multiples of the subjects' baseline (×BLN) values. Methods: The composite plot approach combines biochemical evaluation for drug-induced severe hepatotoxicity (eDISH) plots sequentially applied to subjects' baseline and peak on-treatment liver test results normalized by ULN and integrates them into a four-panel shift plot of peak on-treatment values normalized by BLN. Results: The composite plot enabled efficient assessment of improvement in liver test values during treatment compared with pretreatment in subjects treated with the investigational drug (or the natural history of placebo-treated subjects) and identified outlier subjects for potential drug-induced liver injury. Conclusion: For studies in subjects with abnormal baseline values, the composite plot has potential application in the assessment of beneficial and concerning on-treatment modifications in liver test values in reference to the individual subject's baseline and population threshold values. [ABSTRACT FROM AUTHOR]

Purpose: An expanded access clinical trials (EACTs) provides exceptional patient access to investigational new drugs for life-threatening diseases for which no effective treatment exists. Based on public information, we have studied EACTs since 2016, when the EACT system was launched in Japan. In this study, we investigated the reality of EACTs by interviewing pharmaceutical companies and clarifying how they view them. Patients and Methods: We conducted semi-structured interviews with 10 pharmaceutical companies developing new drugs. This study aims to clarify the status of EACTs, so we selected pharmaceutical companies that develop innovative drugs for which they may perform EACTs (however, experience in conducting EACTs was optional). Results: All those surveyed were aware of EACTs. Twelve access clinical trials were conducted, and the EACT implementation rate for pivotal clinical trials was 2.5%. The most common reason for implementing an EACT was "requests from physicians and medical institutions" (nine companies, 90.0%), and the most common reason for not implementing an EACT was "the applicability of the system" (five companies). Improvements to EACTs were identified by eight companies (80.0%); financial assistance by six companies (60.0%); reducing the scope of data to be collected and simplifying the procedure by six companies (60.0%). Seven companies (70.0%) responded that a Single Patient Investigational New Drug Application should be conducted, suggesting that the system should be revised. Conclusion: An interview survey of ten pharmaceutical companies developing new drugs in Japan regarding expanded access clinical trials indicated that there were issues with the system. Many wished to improve the system by establishing a single patient access system, supporting resources, and simplifying procedures. Based on our interviews with 10 Japanese pharmaceutical companies, it was found that the system needed to be improved by introducing a single patient access system, providing supporting resources, and simplifying procedures. In Japan, about eight years have passed since EACT was established, and it appears a revision of the EACT legislation is due. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic inflammatory condition that significantly affects the quality of life of both patients and their families or caregivers. Recently, treatment for moderate-to-severe AD were limited to conventional immunosuppressive therapies. However, currently, with the approval of biologic treatments and oral small molecules in the past decade, the effective and safe management of patients with AD is possible. Despite these advancements, challenges and unmet needs in clinical practice remain. This includes patients who do not respond well to or cannot tolerate existing treatment options and inadequate therapies that can modify the disease course. This review aimed to provide an overview of the current treatment approach for AD, highlight the current challenges in treatment, and discuss the rationale for novel treatment options and emerging evidence on systemic treatment options for AD. [ABSTRACT FROM AUTHOR]

While randomized, placebo‐controlled, double‐blinded clinical studies are the gold standard for evaluating the efficacy of investigational drugs, the use of placebo in children with achondroplasia should be limited because it provides no clinical benefit while exhausting study participants' treatment window. Recifercept is an investigational drug for treating children with achondroplasia aged 2–10 years. An alternative efficacy evaluation method, instead of a placebo control arm, was employed in the phase II study. Prior to participating in the phase II study, participants completed a natural history (NH) study. Based on the NH data, a multi‐variate linear mixed effects natural disease course model of three anthropometric end points (standing height, sitting height, and arm span) was developed. The model was validated using published growth charts of children with achondroplasia. Subsequently, the model was used to simulate the natural growth trajectories (without any treatment) of the three anthropometric end points for the individuals enrolled in the phase II study. To quantify the efficacy of recifercept, the simulations were compared with the observations post‐recifercept treatment in the phase II study. For all the tested doses of recifercept, at the individual level, the observations were comparable to the simulations at 6 and 12 months post‐recifercept treatment, suggesting no treatment effect. The results contributed to the decision of terminating recifercept clinical development. This work delivers a framework that could eliminate the need for placebo in clinical trials yet provide sufficient evidence for evaluating the efficacy of an investigational drug. [ABSTRACT FROM AUTHOR]

Introduction: Pharmaceutical regulation on a global scale is a complex process, with regulatory bodies overseeing various aspects, including licensing, registration, manufacturing, marketing, and labeling. Among these, the USFDA plays a crucial role in upholding public health. The pharmaceutical industry contributes significantly to well-being by developing and distributing therapeutic agents. The journey of evaluating new pharmaceuticals involves meticulous examination through several phases, from safety and efficacy assessments to toxicity evaluation. Drug approval involves submitting New Drug Applications (NDAs) to regulatory agencies like the USFDA and EMA. However, disparities in durations contribute to the phenomenon known as "drug lag." This lag refers to delays in a pharmaceutical product's availability in one market compared to another. Addressing this issue is crucial, given its impact on patient access to treatments. Method: This study aims to analyze the extent of drug lag, focusing on newly approved oncology targeted therapies in Saudi Arabia, the United States, and the European Union. Data for cancer treatments authorized by the USFDA, EMA, and SFDA from January 1, 1997, to December 31, 2022, were collected from regulatory agency websites. The data sources included authorization letters, prescription information, and evaluation documents. We conducted a comparative assessment of drug lag for approved oncology targeted therapies between Saudi Arabia, the US, and the EU. Result: Our analysis identified 135 newly approved oncology-targeted drugs within the specified timeframe. Of these, 71 received approval in all three regions, while disparities were evident in others. The USFDA consistently had the highest number of approved drugs, with 98.5% of drugs initially approved there. In contrast, Saudi Arabia had the lowest number of approved drugs and a significantly longer median drug lag, indicating substantial delays in drug availability. Conclusion: This study highlights the significance of mitigating drug lag to enhance global healthcare outcomes and patient access to innovative therapies. Further research and collaborative efforts are essential to bridging these disparities and promoting equitable healthcare worldwide. [ABSTRACT FROM AUTHOR]

In June 2021, FDA released a Draft Guidance on Sponsor Responsibilities for IND Safety Reporting and cited components of a recommended Safety Surveillance Plan (SSP). To meet the expectations of the 2021 FDA guidance, sponsors should document their plan for aggregate safety assessment. The Drug Information Association-American Statistical Association Interdisciplinary Safety Evaluation scientific working group has proposed an Aggregate Safety Assessment Plan (ASAP) that addresses this recommendation. The 2021 FDA guidance also discusses potential strategies for unblinded review of safety data from ongoing studies by an independent Assessment Entity, which could occur via planned periodic evaluations or "triggered" reviews based on blinded data assessments. The Assessment Entity reviewing unblinded data makes recommendations as to whether the threshold has been met for submission of an aggregate IND safety report. In this paper, we discuss how the ASAP supports IND aggregate safety reporting decisions, including elements to be included in a proposed SSP appendix to the ASAP. In addition, the authors advocate for the benefits of developing a charter (or specific section of the Data Monitoring Committee charter, if applicable) that describes the responsibilities and conduct of the Assessment Entity. With these components in place, study sponsors will meet the objective of having clearly defined processes for the monitoring of clinical trial safety data in aggregate and making IND safety reporting decisions. [ABSTRACT FROM AUTHOR]

Tecovirimat is the first-line antiviral treatment recommended for severe mpox or for persons with mpox who are at risk for severe disease; tecovirimat is available in the United States under an expanded access investigational new drug (IND) protocol. During the 2022-2023 mpox outbreak, local U.S. health jurisdictions facilitated access to tecovirimat. In June 2022, Los Angeles County (LAC) rapidly developed strategies for tecovirimat distribution using existing medical countermeasure distribution networks established by the Public Health Emergency Preparedness Program and the Hospital Preparedness Program, creating a hub and spoke distribution network consisting of 44 hub facilities serving 456 satellite sites across LAC. IND patient intake forms were analyzed to describe mpox patients treated with tecovirimat. Tecovirimat treatment data were matched with case surveillance data to calculate time from specimen collection to patients receiving tecovirimat. Among 2,281 patients with mpox in LAC, 735 (32%) received tecovirimat during June 2022-January 2023. Among treated patients, approximately two thirds (508; 69%) received treatment through community clinics and pharmacies. The median interval from specimen collection to treatment was 2 days (IQR = 0-5 days). Local data collection and analysis helped to minimize gaps in treatment access and facilitated network performance monitoring. During public health emergencies, medical countermeasures can be rapidly deployed across a large jurisdiction using existing distribution networks, including clinics and pharmacies. [ABSTRACT FROM AUTHOR]

Activating mutations of FLT3 contribute to deregulated hematopoietic stem and progenitor cell (HSC/Ps) growth and survival in patients with acute myeloid leukemia (AML), leading to poor overall survival. AML patients treated with investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop resistance to these drugs. Development of resistance is largely due to acquisition of cooccurring mutations and activation of additional survival pathways, as well as emergence of additional FLT3 mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options available. We have identified 2 novel nicotinamide-based FLT3 inhibitors (HSN608 and HSN748) that target FLT3 mutations at subnanomolar concentrations and are potently effective against drug-resistant secondary mutations of FLT3. These compounds show antileukemic activity against FLT3ITD in drug-resistant AML, relapsed/refractory AML, and in AML bearing a combination of epigenetic mutations of TET2 along with FLT3ITD. We demonstrate that HSN748 outperformed the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3ITD in vivo. [ABSTRACT FROM AUTHOR]

Simple Summary: Diffuse large B cell lymphoma is the most common type of B cell neoplasm, and can be cured by traditional chemoimmunotherapy in 60–70% of cases. Relapsed/refractory patients usually have a dismal prognosis and most of them finally succumb to lymphoma. In the last decade, several new innovative therapies have been approved against DLBCL, targeting both surface antigens and the intracellular pathways of neoplastic B cells. Compared to standard chemotherapy, new monoclonal antibodies and engineered T cells have shown an increased response rate, progression-free survival and overall survival, but, on the other side of the coin, patients have been experiencing new kinds of toxicities, previously unknown, that clinicians have been learning to manage. Here, we review new drugs that are already approved or under investigation for DLBCL and the corresponding molecular target on lymphoma cells. Since the introduction of rituximab in the late 1990s, significant progress has been made in advancing targeted therapies for B cell lymphomas, improving patients' chance of being cured and clinicians' therapeutic armamentarium. A better understanding of disease biology and pathogenic pathways, coupled with refinements in immunophenotypic and molecular diagnostics, have been instrumental in these achievements. While traditional chemotherapy remains fundamental in most cases, concerns surrounding chemorefractoriness and cumulative toxicities, particularly the depletion of the hemopoietic reserve, underscore the imperative for personalized treatment approaches. Integrating targeted agents, notably monoclonal antibodies, alongside chemotherapy has yielded heightened response rates and prolonged survival. A notable paradigm shift is underway with innovative-targeted therapies replacing cytotoxic drugs, challenging conventional salvage strategies like stem cell transplantation. This review examines the landscape of emerging targets for lymphoma cells and explores innovative therapies for diffuse large B cell lymphoma (DLBCL). From Chimeric Antigen Receptor-T cells to more potent monoclonal antibodies, antibody–drug conjugates, bispecific antibodies, checkpoint inhibitors, and small molecules targeting intracellular pathways, each modality offers promising avenues for therapeutic advancement. This review aims to furnish insights into their potential implications for the future of DLBCL treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is a long-term inflammatory skin disease. A novel herbal formula containing nine Chinese herbal medicines, named Inflammation Skin Disease Formula (ISDF), has been prescribed in clinics for decades. Aims: To investigate the efficacy and action mechanisms of ISDF on psoriasis using imiquimod (IMQ) and Interleukin-23 (IL-23)-induced models in mice and reveal the pharmacokinetics profile of ISDF in rats. Methods: Topical administration of IMQ and intradermal injection with IL-23 respectively induced skin lesions like psoriasis on the dorsal area of Balb/c and C57 mice. The mice's body weight, skin thickness, and psoriasis area and severity index (PASI) were assessed weekly. SD rats were used in the pharmacokinetics study and the contents of berberine and baicalin were determined. Results: The PASI scores and epidermal thickness of mice were markedly decreased after ISDF treatment in both models. ISDF treatment significantly decreased the contents of IL-17A and IL-22 in the serum of IMQ- and IL-23-treated mice. Importantly, ISDF markedly downregulated IL-4, IL-6, IL-1β, and tumor necrosis factor α (TNF-α) gene expression, and the phosphorylation of NF-κB p65, JNK, ERKs and MAPK p38 in IMQ-treated mice. The protein phosphorylation of Jak1, Jak2, Tyk2 and Stat3 was significantly mitigated in the ISDF-treated groups. The absorption of baicalin and berberine of ISDF through the gastrointestinal tract of rats was limited, and their distribution and metabolism in rats were also very slow, which suggested ISDF could be used in the long-term application. Conclusions: ISDF has a strong anti-psoriatic therapeutic effect on mouse models induced with psoriasis through IMQ and IL-23, which is achieved by inhibiting the activation of the Jak/Stat3-activated IL-23/Th17 axis and the downstream NF-κB signalling and MAPK signalling pathways. ISDF holds great potential to be a therapy for psoriasis and should be further developed for this purpose. [ABSTRACT FROM AUTHOR]

Background: Currently, the treatment and prevention of migraine remain highly challenging. Mendelian randomization (MR) has been widely used to explore novel therapeutic targets. Therefore, we performed a systematic druggable genome-wide MR to explore the potential therapeutic targets for migraine. Methods: We obtained data on druggable genes and screened for genes within brain expression quantitative trait locis (eQTLs) and blood eQTLs, which were then subjected to two-sample MR analysis and colocalization analysis with migraine genome-wide association studies data to identify genes highly associated with migraine. In addition, phenome-wide research, enrichment analysis, protein network construction, drug prediction, and molecular docking were performed to provide valuable guidance for the development of more effective and targeted therapeutic drugs. Results: We identified 21 druggable genes significantly associated with migraine (BRPF3, CBFB, CDK4, CHD4, DDIT4, EP300, EPHA5, FGFRL1, FXN, HMGCR, HVCN1, KCNK5, MRGPRE, NLGN2, NR1D1, PLXNB1, TGFB1, TGFB3, THRA, TLN1 and TP53), two of which were significant in both blood and brain (HMGCR and TGFB3). The results of phenome-wide research showed that HMGCR was highly correlated with low-density lipoprotein, and TGFB3 was primarily associated with insulin-like growth factor 1 levels. Conclusions: This study utilized MR and colocalization analysis to identify 21 potential drug targets for migraine, two of which were significant in both blood and brain. These findings provide promising leads for more effective migraine treatments, potentially reducing drug development costs. [ABSTRACT FROM AUTHOR]

Background: Paclitaxel administration is considered a keystone in the management of many types of cancers. However, paclitaxel chemotherapy often leads to peripheral neuropathy which is the most prominent adverse effect that reduces the patient's quality of life and demands dose reduction leading to decreased disease curing. Paclitaxel induces peripheral neuropathy through disruption of microtubules, distorted function of ion channels, axonal degeneration, and inflammatory events. So far, there is no standard medication to prevent the incidence of paclitaxel-induced peripheral neuropathy (PIPN). Main body: Numerous preclinical studies in rats and rodents showed that several therapeutic agents have neuroprotective mechanisms and reduce the incidence of PIPN, proving their effectiveness in the prevention of PIPN in animal models. Different mechanisms, such as reduction of the expression of inflammatory mediators, quenching of reactive oxygen species, prevention of neuronal damage, and other mechanisms, have been explored. Moreover, many clinical trials have further established the neuroprotective effect of several investigational drugs on PIPN. Twenty preclinical studies of pharmacological interventions were reviewed for their preventive effect on neuropathy. These medications targeted cannabinoid receptors, oxidative stress, inflammatory response, and ion channels. Additionally, 25 clinical studies with pharmacological preventive interventions of PIPN have been reviewed, of which only 10 showed preventive action in PIPN. Conclusion: Prevention of PIPN is currently considered an emergent field of research. This review highlights the potential interventions and presents recent findings from both preclinical and clinical studies on the significant prevention of PIPN to help in effective decision-making. However, further well-designed research is required to ascertain recommendations for clinical practice. [ABSTRACT FROM AUTHOR]

The article offers information on the 31st Conference on Retroviruses and Opportunistic Infections (CROI 2024) held in Denver, Colorado. Topics include strategies to prevent cardiovascular disease in people living with HIV, new oral drugs for HIV treatment, and community-based interventions for managing severe hypertension in Kenya and Uganda.