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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]

We report a novel small-molecule screening approach that combines data augmentation and machine learning to identify Food and Drug Administration (FDA)-approved drugs interacting with the calcium pump (Sarcoplasmic reticulum Ca2+- ATPase, SERCA) from skeletal (SERCA1a) and cardiac (SERCA2a) muscle. This approach uses information about smallmolecule effectors to map and probe the chemical space of pharmacological targets, thus allowing to screen with high precision large databases of small molecules, including approved and investigational drugs. We chose SERCA because it plays a major role in the excitation-contraction-relaxation cycle in muscle and it represents a major target in both skeletal and cardiac muscle. The machine learning model predicted that SERCA1a and SERCA2a are pharmacological targets for seven statins, a group of FDA-approved 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors used in the clinic as lipid-lowering medications. We validated the machine learning predictions by using in vitro ATPase assays to show that several FDA-approved statins are partial inhibitors of SERCA1a and SERCA2a. Complementary atomistic simulations predict that these drugs bind to two different allosteric sites of the pump. Our findings suggest that SERCA-mediated Ca2+ transport may be targeted by some statins (e.g., atorvastatin), thus providing a molecular pathway to explain statinassociated toxicity reported in the literature. These studies show the applicability of data augmentation and machine learning-based screening as a general platform for the identification of off-target interactions and the applicability of this approach extends to drug discovery. [ABSTRACT FROM AUTHOR]

To explore the impact of previous treatment on the efficacy of investigational new drugs in registration trials for 1st line metastatic breast cancer (MBC). Thirteen US Food and Drug Administration (FDA) approved indications for 1st line MBC between 1/2000–12/2023 were identified and their supporting publications were searched in the ClinicalTrials.gov and Google Scholar. Where available, hazard ratios (HRs) and 95 % confidence intervals (CI) for overall-survival (OS) were pooled into meta-analysis and the difference in the magnitude of OS benefit between treatment naïve and previously treated patients was analyzed. There was no difference in the magnitude of OS benefit between treatment-naïve and previously treated patients (HR=0.72 versus 0.80,p for difference=0.25). In indications for triple-negative BC, treatment-naïve patients had higher magnitude of OS benefit compared to previously treated patients (HR=0.53 versus 0.81,p=0.03). In indications for luminal disease, the magnitude of benefit was comparable between the subgroups. In trials supporting 1st line therapy for TNBC the magnitude of benefit is significantly higher in treatment naïve compared to previously treated patients. Our findings may represent a previously unrecognized bias, potentially over-estimating the benefit of triple-negative BC new drugs. • Proportion of treatment-naïve patients in Metastatic Breast Cancer trials varies. • All FDA approved indications for 1st line MBC between 2000 and 23 were identified. • Meta-analysis to compare treatment-naïve to previously treated patients was done. • For triple negative disease indications, OS benefit is higher for treatment naïve. • For luminal disease indications, OS benefit is comparable between both subgroups. [ABSTRACT FROM AUTHOR]

Hospital exemption (HE) is a regulated pathway that allows the use of advanced therapy medicinal products (ATMPs) within the European Union (EU) under restrictive conditions overseen by national medicine agencies. In some EU countries, HE is granted for ATMPs with no demonstrated safety and efficacy; therefore, they are equivalent to investigational drugs. In other countries, HE is granted for ATMPs with demonstrated quality, safety and efficacy and for which centralized marketing authorization has not been requested. The Committee on the Ethics of Cell and Gene Therapy of the International Society for Cell & Gene Therapy reflects here on the ethical issues concerning HE application from the perspective of the patient, including risk–benefit balance, accessibility and transparency, while providing evidence that HE must not be regarded as a conduit for unproven and unethical ATMP-based interventions. Indeed, HE represents a legal instrument under which a patient's need for access to novel ATMPs is reconciled with ethics. Moreover, for some unmet medical needs, HE is the only pathway for accessing innovative ATMPs. Nonetheless, HE harmonization across EU Member States and limitations of ATMP use under the HE rule when similar products have already been granted centralized marketing authorization to avoid a parallel regulatory pathway are controversial issues whose political and economic consequences are beyond the scope of this review. Finally, the institution of an EU registry of HE applications and outcomes represents a priority to improve transparency, reduce patient risks, increase efficiency of health systems, facilitate company awareness of business opportunities and boost progressive entry of ATMPs into the therapeutic repertoire of health systems. [ABSTRACT FROM AUTHOR]

Intensive care unit (ICU) sedation with sevoflurane is associated with nephrogenic diabetes insipidus. Given that isoflurane is now licenced (in Europe) for ICU sedation and has Investigational New Drug status in the USA, evidence indicates that clinicians should stop using sevoflurane in this indication except in the context of clinical trials. [ABSTRACT FROM AUTHOR]

Investigational cell and gene-based therapies are subject to FDA oversight and applicable regulation, which includes the requirement for submission of an Investigational New Drug application (IND) prior to initiation of clinical investigations. Within an IND, nonclinical information is presented to demonstrate safety and activity for a first-in-human investigational product. Toxicology assessments of investigational cell and gene therapy products may utilize hybrid pharmacology-toxicology studies that are not required to comply with Good Laboratory Practices (GLP) regulation. Our academic institution has the expertise to perform nonclinical assessments without outsourcing activities to a GLP test facility. However, the FDA strongly recommends quality oversight of non-GLP studies and resulting reports by personnel independent of the conduct of the study. We are developing an independent review service to promote data quality and integrity of non-GLP studies. The Office of Research Regulatory Affairs at Nationwide Children's Hospital provides support for preparation of regulatory documents and guidance on emergent regulatory issues. Based on FDA recommendations regarding non-GLP study oversight, the need for a process for data quality assurance of IND enabling preclinical studies and reports was identified. This department is positioned to advocate for and contribute to development of a structure for an internal nonclinical data review service. The service will be available to researchers conducting non-GLP studies as a mechanism for independent review in order to promote data quality standards appropriate for regulatory submissions. Here we present the preparation and initial implementation of a structured independent nonclinical data review process at our academic institution. To standardize the process, minimum recommendations for review of study report and corresponding data resulting from nonclinical studies have been defined. The scope of data review includes risk-based independent peer review of nonclinical study reports, incorporating review of prospective protocols, data summaries, and source data verification. Briefly, our office has prepared standard operating procedures outlining the voluntary review process and communication with study leadership, template documentation that may be utilized to record roles and actions, and work instructions providing guidance to aid the peer reviewer in performance of review activities. [ABSTRACT FROM AUTHOR]

• We conducted a questionnaire on the regulatory guidelines for CTPs. • Respondents from India, China, Korea, Taiwan, and Japan participated. • Differences in answers result from different experiences and regulatory guidelines. • Continuous knowledge sharing and discussion will result in faster CTP approval. • We make suggestions for regulatory harmonization and optimization in Asia. Cell-based regenerative medicine is an innovative field that can potentially alter the overall survival and quality of life of patients with devastating diseases. Several cell therapy products (CTPs) have been approved within the last two decades, and more are under development. The establishment of an effective developmental strategy in accordance with the regulatory bodies of each country/region is crucial for fast delivery of each respective CTP. In particular, facilitating investigational new drug (IND) approval is important for accelerating the transition from non-clinical to clinical research/trial phases. Here the authors compared the non-clinical prerequisites for initiating clinical studies in five Asian countries/regions (India, China, Korea, Taiwan and Japan) from an industry viewpoint. The authors first identified the differences and tried to clarify the perspectives/considerations underpinning the different requirements. The authors' findings revealed that differences in regulations and development experiences, especially with CTPs, have led to clear differences in the non-clinical study package and its corresponding study design. By sharing experiences of the research and development of CTPs among Asian countries/regions and including not only industry but also regulatory authorities, we will be able to expedite cross-border IND approval and eventually contribute to the early delivery of innovative CTPs to many Asian patients. [ABSTRACT FROM AUTHOR]

Impaired dark adaptation (DA), a defect in the ability to adjust to dimly lit settings, is a universal hallmark of aging. However, the mechanisms responsible for impaired DA are poorly understood. Vitamin A byproducts, such as vitamin A dimers, are small molecules that form in the retina during the vitamin A cycle. We show that later in life, in the human eye, these byproducts reach levels commensurate with those of vitamin A. In mice, selectively inhibiting the formation of these byproducts, with the investigational drug C20D3-vitamin A, results in faster DA. In contrast, acutely increasing these ocular byproducts through exogenous delivery leads to slower DA, with otherwise preserved retinal function and morphology. Our findings reveal that vitamin A cycle byproducts alone are sufficient to cause delays in DA and suggest that they may contribute to universal age-related DA impairment. Our data further indicate that the age-related decline in DA may be tractable to pharmacological intervention by C20D3-vitamin A [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis is a chronic and progressive lung disease characterized by the accumulation of scar tissue in the lungs, which leads to impaired lung function and reduced quality of life. The prognosis for idiopathic pulmonary fibrosis (IPF), which is the most common form of pulmonary fibrosis, is generally poor. The median survival for patients with IPF is estimated to be around 3–5 years from the time of diagnosis. Currently, there are two approved drugs (Pirfenidone and Nintedanib) for the treatment of IPF. However, Pirfenidone and Nintedanib are not able to reverse or cure pulmonary fibrosis. There is a need for new pharmacological interventions that can slow or halt disease progression and cure pulmonary fibrosis. This review aims to provide an updated overview of current and future drug interventions for idiopathic pulmonary fibrosis, and to summarize possible targets of potential anti-pulmonary fibrosis drugs, providing theoretical support for further clinical combination therapy or the development of new drugs. [Display omitted] • Idiopathic pulmonary fibrosis remains a challenging disease with no effective cure. • New drugs and treatment strategies are urgently needed to improve the quality of life for patients with pulmonary fibrosis. • This systematic review evaluates the antifibrotic potential of non-antifibrotic agents and investigational drugs. [ABSTRACT FROM AUTHOR]

• Unlicensed umbilical cord blood units can be safely and effectively used for hematopoietic cell transplantation (HCT) in adult and pediatric patients. • Unlicensed umbilical cord blood expands access to racially/ethnically diverse patients in need of HCT. • Further studies are required to compared licensed and unlicensed umbilical cord blood HCT. Umbilical cord blood (UCB) transplantation (UCBT) is a curative procedure for patients with hematologic malignancies and genetic disorders and expands access to transplantation for non-Caucasian patients unable to find a fully matched unrelated donor. In 2011, the US Food and Drug Administration required that unrelated UCBT be performed using either licensed UCB or unlicensed UCB under the Investigational New Drug (IND) program. The National Marrow Donor Program manages an IND under which 2456 patients (1499 adults and 957 children, 564 with malignant diseases and 393 with nonmalignant diseases) underwent single or double UCBT between October 2011 and December 2016. The median patient age was 31 years (range, <1 to 81 years), and 50% of children and 36% of adults were non-Caucasian. The median time to neutrophil engraftment (ie, absolute neutrophil count ≥500/mm3) was 22 days for adults, 20 days for pediatric patients with malignant diseases, and 19 days for pediatric patients with nonmalignant diseases, with corresponding rates of engraftment at 42 days of 89%, 88%, and 90%. In these 3 groups of patients, the incidence of acute graft-versus-host disease (GVHD) grade II-IV was 35%, 32%, and 24%; the incidence of chronic GVHD was 24%, 26%, and 24%; and 1-year overall survival (OS) was 57%, 71%, and 79%, respectively. In multivariate analysis, younger age, lower Hematopoietic Cell Transplantation-Specific Comorbidity Index, early-stage chemotherapy-sensitive disease, and higher performance score were predictive of improved OS for adults. In a subset analysis of children with malignancies undergoing single UCBT, the use of either licensed UCB (n = 48) or unlicensed UCB (n = 382) was associated with similar engraftment and survival. The use of unlicensed UCB units is safe and effective and provides an important graft source for a diverse population. [ABSTRACT FROM AUTHOR]

Early-stage clinical evaluation of tinengotinib (TT-00420) demonstrated encouraging preliminary efficacies in multiple types of refractory cancers, including fibroblast growth factor receptors (FGFR) inhibitors relapsed cholangiocarcinoma (CCA), castrate-resistant prostate cancer (CRPC), and HR+/HER2- breast cancer and triple negative breast cancer (TNBC). To further evaluate drug-like properties of the drug candidate, it is imperative to understand its metabolism and pharmacokinetic properties. This manuscript presented the investigation results of in vitro permeability, plasma protein binding, metabolic stability, metabolite identification, and drug-drug interaction of tinengotinib. Preclinical ADME (absorption, distribution, excretion, and metabolism) studies in rats and dogs was also conducted using a radioactive labeled tinengotinib, [14C]tinengotinib. Tinengotinib was found to have high permeability and high plasma protein binding and equally distributed between blood and plasma. There were no unique metabolites in human liver microsomes and tinengotinib showed moderate hepatic clearance. Tinengotinib is neither a potential inhibitor nor an inducer of P450 enzymes at clinically relevant concentrations, and unlikely to cause drug-drug interactions when used in combination with other drugs mediated by a key transporter, either as victim or perpetrator. Taken together, tinengotinib demonstrated a minimal risk of clinically relevant drug-drug interactions. Tinengotinib showed good oral bioavailability and dose-dependent exposures in both rat and dog after oral administration. The total radioactivity was largely distributed in the gastrointestinal system and liver, and tinengotinib could not easily pass through the blood-brain barrier. The major drug-related component in rat and dog plasma was unchanged drug (>89 %) with primary route of elimination via feces (>93 % of the dose) and minor via renal excretion (<4 % of the dose). Tinengotinib metabolism is mediated largely by CYP3A4, with minor contributions from CYP2D6 and CYP2C8. Major metabolic pathways include oxidation, oxidative cleavage of the morpholine ring, glucuronide and glutathione conjugations. The overall preclinical pharmacokinetics profile supported the selection and development of tinengotinib as a clinical candidate. [Display omitted] [ABSTRACT FROM AUTHOR]

Among different strategies to develop novel therapies, drug repositioning (aka repurposing) aims at identifying new uses of an already approved or investigational drug. This approach has the advantages of availability of the extensive pre-existing knowledge of the drug's safety, pharmacology and toxicology, manufacturing and formulation. It provides advantages to the risk- versus -rewards trade-off as compared to the costly and time-consuming de novo drug discovery process. Clofazimine, a red-colored synthetic derivative of riminophenazines initially isolated from lichens, was first synthesized in the 1950 s, and passed through several phases of repositioning in its history as a drug. Being initially developed as an anti-tuberculosis treatment, it was repurposed for the treatment of leprosy, prior to re-repositioning for the treatment of multidrug-resistant tuberculosis and other infections. Since 1990 s, reports on the anticancer properties of clofazimine, both in vitro and in vivo , started to appear. Among the diverse mechanisms of action proposed, the activity of clofazimine as a specific inhibitor of the oncogenic Wnt signaling pathway has recently emerged as the promising targeting mechanism of the drug against breast, colon, liver, and other forms of cancer. Seventy years after the initial discovery, clofazimine's journey as a drug finding new applications continues, serving as a colorful illustration of drug repurposing in modern pharmacology. [Display omitted] • Clofazimine is a synthetic derivative of lichen-derived natural products. • Initially a drug candidate for tuberculosis, it was repositioned against leprosy. • New indications of clofazimine include multidrug-resistant tuberculosis and cancer. • Multiple mechanisms of action were proposed, including inhibition of Wnt signaling. • Clofazimine is a colorful example of drug repositioning / repurposing. [ABSTRACT FROM AUTHOR]

Curative therapies and other medicines considered "game-changing" in terms of health gain can be accompanied by high demand and high list prices that pose budget challenges to public and private payers and health systems-the so-called affordability issue. These challenges are exacerbated when longer term effectiveness, and thus value for money, is uncertain, but they can arise even when treatments are proven to be highly cost-effective at the time of launch. This commentary reviews innovative payment solutions proposed in the literature to address the affordability issue, including the use of credit markets and of staged payments linked to patient outcomes, and draws on discussions with payers in the United States and Europe on the feasibility or desirability of operationalizing any of the alternative financing and payment strategies that appear in the literature. This included a small number of semistructured interviews. We conclude that there is a mismatch between the enthusiasm in the academic literature for developing new approaches and the scepticism of payers that they can work or are necessary. For the foreseeable future, affordability pressures will continue to be handled by aggressive price bargaining, high co-pays (in systems in which this is possible), and restricting access to subgroups of patients. Of the mechanisms we explored, outcomes-based payments were of most interest to payers, but the costs associated with operating such schemes, together with implementation challenges, did not make them an attractive option for managing affordability. [ABSTRACT FROM AUTHOR]

There are three major assays that must be conducted in standard investigational new drug (IND) -enabling ototoxicity study designs: 1) functional acoustic threshold measurements (Auditory Brainstem Respsonse, ABR); 2) otohistopathology and 3) cytocochleograms. We provide evidence to demonstrate the unreliability of auditory threshold shifts (ABRs) to predict cochlear cell death and build a case for conducting full cochlea processing and cell count measurements from the complete cochlea from apex to base. [ABSTRACT FROM AUTHOR]

Hepatic veno-occlusive disease, or sinusoidal obstruction syndrome (VOD/SOS), is a serious and potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) or of chemotherapy regimens alone. Defibrotide is a complex mixture of single-stranded polydeoxyribonucleotides that is approved in the United States for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT and in the European Union, Israel, and South Korea for treating severe hepatic VOD/SOS post-HSCT. Defibrotide was previously available in the United States as an investigational drug through a treatment protocol (treatment IND) study. Interim results of that large, treatment IND study of patients with VOD/SOS and with or without multiorgan dysfunction (MOD; also known as multiorgan failure) are presented here. Defibrotide was administered i.v. at 6.25 mg/kg every 6 hours (25 mg/kg/day), with a recommended treatment duration of at least 21 days. Enrolled patients (n = 681) were diagnosed with VOD/SOS based on Baltimore or modified Seattle criteria or liver biopsy analysis. Among the 573 HSCT recipients, 288 (50.3%; 95% confidence interval [CI], 46.2% to 54.4%) were alive at day +100 post-HSCT. Day +100 survival for the pediatric (≤16 years) and adult (>16 years) subgroups was 54.5% (95% CI, 49.1% to 60.0%; n = 174 of 319) and 44.9% (95% CI, 38.8% to 51.0%; n = 114 of 254), respectively. In the MOD subgroup, 159 of 351 patients (45.3%; 95% CI, 40.1% to 50.5%) of patients were alive at day +100 post-HSCT. Treatment with defibrotide was generally well tolerated, and drug-related toxicities were consistent with previous studies. Adverse events were reported in 69.6% of safety-evaluable patients (399 of 573). Other than VOD/SOS and associated MOD symptoms, the most commonly reported treatment-emergent adverse event was hypotension (13.8%). Day +100 survival results observed in this trial were consistent with results seen in previous trials of defibrotide for VOD/SOS in adult and pediatric patients. These data support the potential benefit of defibrotide in treating a VOD/SOS patient population that includes those with and without MOD. [ABSTRACT FROM AUTHOR]

One-hundred percent perfluorohexyloctane (PFHO) is a water-free, preservative-free eye drop approved by the Food and Drug Administration in the United States for the treatment of dry eye disease. PFHO has shown relief of dry eye signs and symptoms in clinical trials and has potent antievaporative action in vitro. The objective of this study was to measure the level of oxygen in PFHO. T1 relaxation times (time taken for proton spins to translate from a random alignment to an alignment with the main magnetic field) for fluorine-19 in perfluorohexyloctane were measured using fluorine-19 nuclear magnetic resonance spectroscopy. The level of oxygen was interpolated from published data. The hydrogen-1 and fluorine-19 nuclear magnetic resonance spectra of PFHO were well resolved and the resonance assignments and intensities were as expected. The T1 values calculated for the CF 3 group resonance in the current study was 0.901 seconds and 1.12 seconds at 25 °C and 37 °C, respectively. The T1 values for the CF 2 group resonances increased by 17% to 24% with an increase in temperature from 25 °C to 37 °C. The mean (SD) partial pressure of oxygen in PFHO was calculated to be 257 (36) mm Hg and 270 (38) mm Hg at 25 °C and 37 °C, respectively. The current study confirms that PFHO contains a significant amount of oxygen, more so than that calculated for tears in equilibrium with air. Once instilled on the eye, PFHO is not expected to be a barrier to the oxygen necessary for a healthy cornea and may in fact deliver nonreactive oxygen to the cornea to facilitate healing in patients with dry eye disease. [ABSTRACT FROM AUTHOR]

The cardiovascular field is still searching for a treatment for abdominal aortic aneurysms (AAA). This inflammatory disease often goes undiagnosed until a late stage and associated rupture has a high mortality rate. No pharmacological treatment options are available. Three hallmark factors of AAA pathology include inflammation, extracellular matrix remodeling, and vascular smooth muscle dysfunction. Here we discuss drugs for AAA treatment that have been studied in clinical trials by examining the drug targets and data present for each drug's ability to regulate the aforementioned three hallmark pathways in AAA progression. Historically, drugs that were examined in interventional clinical trials for treatment of AAA were repurposed therapeutics. Novel treatments (biologics, small-molecule compounds etc.) have not been able to reach the clinic, stalling out in pre-clinical studies. Here we discuss the backgrounds of previous investigational drugs in hopes of better informing future development of potential therapeutics. Overall, the highlighted themes discussed here stress the importance of both centralized anti-inflammatory drug targets and rigor of translatability. Exceedingly few murine studies have examined an intervention-based drug treatment in halting further growth of an established AAA despite interventional treatment being the therapeutic approach taken to treat AAA in a clinical setting. Additionally, data suggest that a potentially successful drug target may be a central inflammatory biomarker. Specifically, one that can effectively modulate all three hallmark factors of AAA formation, not just inflammation. It is suggested that inhibiting PGE 2 formation with an mPGES-1 inhibitor is a leading drug target for AAA treatment to this end. [Display omitted] • A review of drugs from clinical trials treating abdominal aortic aneurysms (AAA). • Each drug's ability to alter three main pathways of AAA progression is discussed. • Very few of the drugs' preclinical studies used intervention-based treatment. • New anti-inflammatory drug targets are needed that can alter the three pathways. [ABSTRACT FROM AUTHOR]

Secondary pharmacology studies are a time-efficient and cost-effective method for determining the safety profile of a potential new drug before it enters human trials. The results of these multi-target screens are commonly submitted with Investigational New Drug (IND) applications, but there currently is little guidance on how such information is presented and which targets are chosen for testing. In this study, we expand on our previous analysis of secondary pharmacology reports by manually curating and analyzing all secondary pharmacology results received by the FDA received as part of an IND submission. A total of 1120 INDs submitted by 480 sponsors between 1999 and October 2020 were included in this study. The overall results were largely consistent with previous internal and external studies, showing that the most tested target in our set was the histamine 1 receptor (tested 938 times), the most hit target was sodium channel site 2 (hit 141 times), and the target with the highest hit percentage was the vesicular monoamine transporter 2 (hit 42.2% of the time). Additionally, this study demonstrated that improvements in the secondary pharmacology submission process, such as changes in formatting and nomenclature, could enhance the utility of these assays for regulatory review, including assisting with identifying the safety liabilities of a drug candidate early in development. This updated data set will allow FDA-industry collaborative working groups to continue developing the best methods for regulatory submission of secondary pharmacology data and evaluate the need for a standard target panel. [ABSTRACT FROM AUTHOR]

Background aims. A clinical research roadmap has been developed as a resource for researchers to identify critical areas and potential pitfalls when transitioning a cellular therapy product from the research laboratory, by means of an Investigational New Drug (IND) application, into early-phase clinical trials. The roadmap describes four key areas: basic and preclinical research, resource development, translational research and Good Manufacturing Practice (GMP) and IND assembly and submission. Methods. Basic and preclinical research identifies a new therapeutic concept and demonstrates its potential value with the use of a model of the relevant disease. During resource development, the appropriate specialists and the required expertise to bring this product into the clinic are identified (eg, researchers, regulatory specialists, GMP manufacturing staff, clinicians and clinical trials staff, etc). Additionally, the funds required to achieve this goal (or a plan to procure them) are identified. In the next phase, the plan to translate the research product into a clinical-grade therapeutic is developed. Finally regulatory approval to start the trial must be obtained. In the United States, this is done by filing an IND application with the Food and Drug Administration. Results. The National Heart, Lung and Blood Institute-funded Production Assistance for Cellular Therapies program has facilitated the transition of a variety of cellular therapy products from the laboratory into Phasel/2 trials. Conclusions. The five Production Assistance for Cellular Therapies facilities have assisted investigators by performing translational studies and GMP manufacturing to ensure that cellular products met release specifications and were manufactured safely, reproducibly and at the appropriate scale. The roadmap resulting from this experience is the focus of this article. [ABSTRACT FROM AUTHOR]

• Surrogate end points with accelerated approval have been widely used for approvals, with an increasing trend from 2019 to 2020 (32% vs. 51%). The approved doses usually were much higher (11-fold) than the lowest tested dose in first-in-human trials, while much closer (2-fold lower) to the highest dose tested in clinical trials. During 2020, the Food and Drug Administration approved 53 novel drugs. Biomarkers, surrogate endpoints and dosing regimens used in early and pivotal clinical stages are evaluated. Information on various efficacy end points of 2020 Food and Drug Administration approved novel drugs was gathered from the Drug Approvals and Databases page of the Food and Drug Administration website. Endpoint data from efficacy end points for the 2019 approved novel drugs by Tong and Wang are used as a comparison. Among the 53 drugs approved during 2020, 49 were for treatment of various diseases and 4 were for diagnostics. Twenty-five drug approvals (51%, relative to 49 drugs for treatment of diseases) were based on surrogate end points, consisting of 12 accelerated approvals and 13 regular approvals. There were 19 drug approvals for cancer treatments (39%, relative to 49 drugs for treatment of diseases). During 2019, there were 48 drugs approved. Forty-four were for treatment of various diseases and 4 were for diagnostics. Fourteen drug approvals (32%, relative to 44 drugs for treatment of diseases) were based on surrogate end points, consisting of 9 accelerated approvals and 5 regular approvals. There were 10 drug approvals for cancer treatments (23%, relative to 44 drugs for treatment of diseases). The approved doses were usually much closer to the highest dose tested in clinical trials (about 2-fold lower) compared with the lower dose tested in clinical trials (about 11-fold higher). Large and variable distances between the starting low dose in humans and the final approved doses indicate that finding the optimal dose in clinical trials is still a time-consuming and costly process. Further dose analysis for cancer drugs approved during 2020 showed that the distances between the starting dose in human beings and the final approved doses of cancer drugs were still large and variable, similar to distances in noncancer drugs. Stratification of drugs approved in 2020 by molecular weights shows that small molecular weights (<1000 Daltons) appeared to be smaller and less variable than those for drugs with large molecules (>1000 Daltons). (Curr Ther Res Clin Exp. 2022; 83:XXX–XXX) Surrogate end points with accelerated approval have been widely used for approvals, with an increasing trend from 2019 to 2020 (32% vs. 51%). The approved doses usually were much higher (10-fold) than the lowest tested dose in first-in-human trials, while much closer (2-fold lower) to the highest dose tested in clinical trials. [ABSTRACT FROM AUTHOR]

Abstract: Background: 2-Amino-2-[2-(4-octylphenyl)ethyl] propane-1,3-diol hydrochloride (FTY720) is a novel agent with protective effect on several markers of liver injury. It is a chemical substance derived by modifying myriocin from the ascomycete Isaria sinclairii. It has been reported that FTY720 is able to treat autoimmune encephalomyelitis, renal cancer, asthma, and multiple sclerosis. More potent clinical applications of FTY720 need to be investigated. Objective: The aim of this study was to evaluate the protective effect of FTY720 on several markers of experimental liver injury and to investigate the possible mechanism of action. Methods: Concanavalin A (Con A) at a dose of 15 mg/kg was intravenously. injected in mice, and 10 days before the Con A challenge, 1 mg/kg, 3 mg/kg, and 6 mg/kg of FTY720 were administered to mice. The liver injury was monitored biochemically by measuring serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and tumor necrosis factor-α (TNF-α) levels. TNF-α and nuclear factor-κB (NF-κB) in liver tissue were detected by Western blot analysis. Results: FTY720, when administered intragastrically for 10 days in mice with Con A–induced liver injury, dose-dependently reduced serum ALT and AST and TNF-α levels. The differences were statistically significant (P ≤ 0.05). It was also found that FTY720 decreases TNF-α and NF-κB protein expression in liver tissue. Conclusions: FTY720 is able to improve several markers of Con A–induced liver injury in mice, including serum ALT, serum AST, TNF-α, and NF-κB, which might be at least in part related to its ability to reduce TNF-α/NF-κB cascade activity. [Copyright &y& Elsevier]

Overactive bladder (OAB) is a common clinical condition for which current drug treatment comprises drugs blocking the cholinergic nerve supply, or augmenting the adrenergic nerve supply, to the detrusor muscle of the urinary bladder. Current treatments have drawbacks, including lack of efficacy and the development of adverse effects in some patients. Hence, new and better drugs for treating OAB will be clinically useful. This review is meant to provide information on drugs currently undergoing preclinical or clinical trials for the treatment of OAB published in journal articles or elsewhere. The cited articles were retrieved from PubMed and Google Scholar from January 1, 1990, to December 31, 2021. The search terms used were contraction or contractility, detrusor, inhibition, isolated or in vitro, in vivo, overactive bladder , and relaxant effect or relaxation. There are 4 classes of new drugs under various stages of development for the treatment of OAB. These are drugs acting on the autonomic nerve supply to the detrusor muscle of the urinary bladder that include the anticholinergics tarafenacin and afacifenacin and the β 3 adrenoceptor agonists solabegron and ritobegron; drugs acting on ion channels in the detrusor muscle (eg, potassium channel openers and calcium channel blockers), drugs acting on cellular enzymes like phosphodiesterase-5 inhibitors and Rho kinase inhibitors, and drugs acting on miscellaneous targets (eg, pregabalin and trimetazidine). Drugs currently used to treat OAB target only the cholinergic and adrenergic cellular signalling pathways. There are many other drugs under trial targeting other cellular pathways that may be useful for treating OAB. Their approval for clinical use might improve the treatment of patients with OAB. (Curr Ther Res Clin Exp. 2022; 83:XXX–XXX) [ABSTRACT FROM AUTHOR]

The nucleotide analogue remdesivir is an investigational drug for the treatment of human coronavirus infection. Remdesivir is a phosphoramidate prodrug and is known to target viral RNAdependent RNA polymerases. In this issue, Gordon et al. identify that remdesivir acts as a delayed RNA chain terminator for MERS-CoV polymerase complexes. [ABSTRACT FROM AUTHOR]

Secondary pharmacology studies are utilized by the pharmaceutical industry as a cost-efficient tool to identify potential safety liabilities of drugs before entering Phase 1 clinical trials. These studies are recommended by the Food and Drug Administration (FDA) as a part of the Investigational New Drug (IND) application. However, despite the utility of these assays, there is little guidance on which targets should be screened and which format should be used. Here, we evaluated 226 secondary pharmacology profiles obtained from close to 90 unique sponsors. The results indicated that the most tested target in our set was the GABA benzodiazepine receptor (tested 168 times), the most hit target was adenosine 3 (hit 24 times), and the target with the highest hit percentage was the quinone reductase 2 (NQO2) receptor (hit 29% of the time). The overall results were largely consistent with those observed in previous publications. However, this study also identified the need for improvement in the submission process of secondary pharmacology studies by industry, which could enhance their utility for regulatory purpose. FDA-industry collaborative working groups will utilize this data to determine the best methods for regulatory submission of these studies and evaluate the need for a standard target panel. [ABSTRACT FROM AUTHOR]

• Current status about incidence and mortality rate of breast cancer worldwide. • Risk factors of breast cancer. • Inflammatory consequence and molecular pathways of breast cancer. • Pathological and targeted facets of breast cancer. • Role of investigational drugs for treatment of breast cancer with clinical status. Cancer is a heterogeneous disease, occurs due to transcriptional changes in genetic and epigenetic including numerous genes and proteins. Worldwide, breast cancer (BC) is the life-threatening malignancies in women, is characterized by the occurrence of more than one molecular alteration. The incidence and mortality of BC are growing every day because of the adoption of western living standards, metropolitanization, and more life expectancy. Even though many modern approaches are available for the detection and treatment of BC, despite of these, it remains the topmost cause of death in women. This review highlights various approaches, including the importance of clinical, pathological, and molecular aspects of BC. Moreover, risk factors, biomarkers, immunotherapy, investigational drugs, and their role through tumor targets and immune systems have been discussed for management of BC. Furthermore, various targeting approaches for tumors through nanocarriers and their clinical trials have been elaborated in BC challenges and future perspectives. [ABSTRACT FROM AUTHOR]

In nonclinical toxicology the highest dose or exposure without test article-related adverse effects, known as the No Observed Adverse Effect Level (NOAEL), is a variable that may be determined. In safety pharmacology the vast majority of the endpoints measured are quantitative numeric functional endpoints such as changes in heart rate, blood pressure or respiratory frequency, endpoints that are usually not assessed using a defined framework of adversity. Therefore, we asked the question: is there a role for the NOAEL in safety pharmacology? To help answer this question, we conducted a survey via the Safety Pharmacology Society. We found that within safety pharmacology there is no formal definition of adversity and no guidance on defining NOAEL. We also found, perhaps unsurprisingly, there is no agreed rubric for using a NOAEL in safety pharmacology and we learned that the NOAEL is not a requirement in order to progress a new investigational drug through the regulatory process. Thus, a summary label such as NOAEL lacks nuance and disregards context in relation to the nature and the severity of the safety pharmacology findings. Consequently, defining 'adversity' and determining a NOAEL in safety pharmacology studies are not recommended since the range of functional endpoints investigated do not conform to a binary 'toxic/non-toxic' rubric. Focusing on describing test article-related effects on safety pharmacology endpoints, using reasoned arguments as part of an integrated risk assessment, will ensure that the clinical pharmacologists and regulatory bodies see a clear description of relevant findings at each dose or exposure level. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a deadly and uncurable disease characterized by remodeling of the pulmonary vasculature and increased pulmonary artery pressure. Angiotensin Converting Enzyme 2 (ACE2) and its product, angiotensin-(1–7) [ANG-(1-7)] were expressed in lettuce chloroplasts to facilitate affordable oral drug delivery. Lyophilized lettuce cells were stable up to 28 months at ambient temperature with proper folding, assembly of CTB-ACE2/ANG-(1-7) and functionality. When the antibiotic resistance gene was removed, Ang1-7 expression was stable in subsequent generations in marker-free transplastomic lines. Oral gavage of monocrotaline-induced PAH rats resulted in dose-dependent delivery of ANG-(1–7) and ACE2 in plasma/tissues and PAH development was attenuated with decreases in right ventricular (RV) hypertrophy, RV systolic pressure, total pulmonary resistance and pulmonary artery remodeling. Such attenuation correlated well with alterations in the transcription of Ang-(1–7) receptor MAS and angiotensin II receptor AGTRI as well as IL-1β and TGF-β1. Toxicology studies showed that both male and female rats tolerated ~10-fold ACE2/ANG-(1–7) higher than efficacy dose. Plant cell wall degrading enzymes enhanced plasma levels of orally delivered protein drug bioencapsulated within plant cells. Efficient attenuation of PAH with no toxicity augurs well for clinical advancement of the first oral protein therapy to prevent/treat underlying pathology for this disease. Image 1 [ABSTRACT FROM AUTHOR]

Cardiovascular disorders constitute the principal cause of deaths worldwide and will continue as the major disease-burden by the year 2060. A significant proportion of heart failures occur because of use and misuse of drugs and most of the investigational agents fail to achieve any clinical relevance. Here, we investigated rosuvastatin and retinoic acid for their "pharmacological pleiotropy" against high dose β-adrenergic agonist (isoproterenol)-induced acute myocardial insult. Rats were pretreated with rosuvastatin and/or retinoic acid for seven days and the myocardial injury was induced by administering isoproterenol on the seventh and eighth day. After induction, rats were anaesthetized for electrocardiography, then sacrificed and different samples were collected/stored for various downstream assays. Myocardial injury with isoproterenol resulted in increased cardiac mass, decreased R-wave amplitude, increased QRS and QT durations; elevated levels of cardiac markers like cTnI, CK-MB, ALT and AST; increased lipid peroxidation, protein carbonylation and tissue nitric oxide levels; decreased endogenous antioxidants like SOD, CAT, GR, GST, GPx and total antioxidant activity; increased inflammatory markers like TNF-α and IL-6; decreased the mRNA expression of Nrf2 and Bcl-2; increased the mRNA expression of Bax, eNOS and iNOS genes. Pretreatment with rosuvastatin and/or retinoic acid mitigated many of the above biochemical and pathological alterations. Our results demonstrate that rosuvastatin and retinoic acid exert cardioprotective effects and may act as potential agents in the prevention of β-adrenergic agonist-induced acute myocardial injury in rats. Cardioprotective potential of rosuvastatin and retinoic acid could be attributed to their influence on the redox pathways, immunomodulation, membrane stability, Nrf2 preservation, iNOS and Bax expression levels. Thus, they may act directly or indirectly at various steps, the breakpoints, in the pathophysiological cascade responsible for cardiac injury. Our study gives insights about the pharmacological pleiotropism of rosuvastatin and retinoic acid. Image 1 • Rosuvastatin and retinoic acid diminish myocardial injury induced by isoprenaline in rats. • Rosuvastatin and retinoic acid may show pleiotropic action. • Have antioxidant properties against isoprenaline-induced cardiac stress. • Mitigate inflammatory response induced by isoprenaline in cardiac tissue. • Affect various factors like TNF-α, Nrf2, Bax and iNOS. [ABSTRACT FROM AUTHOR]

Soft tissue sarcomas are rare tumors consisting of more than 50 histological subtypes. The rarity and diversity made it difficult to conduct studies for investigational new drugs. Doxorubicin remains the standard of care in metastatic soft tissue sarcoma and several investigational new drugs such as olaratumab failed to demonstrate additional benefit in combination with doxorubicin. Pazopanib, a multitargeted tyrosine kinase inhibitor, is the only drug approved for soft tissue sarcoma. In gastrointestinal stromal tumor (GIST) and dermatofibrosarcoma protuberans, molecular targeted agent and accompanying genetic alterations have been investigated and introduced into daily clinical practice. Recent advances in omics technologies such as next-generation sequence have focused on more precise approaches and enabled to investigate comprehensive mutational analyses for soft tissue sarcomas. New driver genes have been identified across the tumor types and one of the promising genetic alterations is NTRK fusion. NTRK fusion could be detected in less than 1% of sarcomas. TRK tyrosine kinases show high activity against NTRK fusion-positive tumors including soft tissue sarcomas. Multigene assay might have some role to detect such rare genetic alterations. GIST is one of a successful model of precision medicine. Imatinib, sunitinib, and regorafenib are currently available in Japan. Novel molecular targeted agents such as kit inhibitors and a HSP90 inhibitor are currently under development. [ABSTRACT FROM AUTHOR]

Soft tissue sarcomas are rare tumors consisting of more than 50 histological subtypes. The rarity and diversity made it difficult to conduct studies for investigational new drugs. Doxorubicin remains the standard of care in metastatic soft tissue sarcoma and several investigational new drugs such as olaratumab failed to demonstrate additional benefit in combination with doxorubicin. Pazopanib, a multitargeted tyrosine kinase inhibitor, is the only drug approved for soft tissue sarcoma. In gastrointestinal stromal tumor (GIST) and dermatofibrosarcoma protuberans, molecular targeted agent and accompanying genetic alterations have been investigated and introduced into daily clinical practice. Recent advances in omics technologies such as next-generation sequence have focused on more precise approaches and enabled to investigate comprehensive mutational analyses for soft tissue sarcomas. New driver genes have been identified across the tumor types and one of the promising genetic alterations is NTRK fusion. NTRK fusion could be detected in less than 1% of sarcomas. TRK tyrosine kinases show high activity against NTRK fusion-positive tumors including soft tissue sarcomas. Multigene assay might have some role to detect such rare genetic alterations. GIST is one of a successful model of precision medicine. Imatinib, sunitinib, and regorafenib are currently available in Japan. Novel molecular targeted agents such as kit inhibitors and a HSP90 inhibitor are currently under development. [ABSTRACT FROM AUTHOR]

The author reflects on the aspects of the U.S. Food and Drug Administration's advice (FDA) for cell and gene therapies (CGTs) clinical trials design. He cites the issues of the likely uncontrolled gene expression after DNA integration. He states that FDA's guidelines are descriptive and offer some guidance on integrating risk-benefit concerns into CGT trial design. The guidance includes various meetings an investigator should have with the FDA in developing an investigational new drug (IND).