Drugs For Other Indications Research Articles

Abstract 7574: Exploring the therapeutic potential of proteasome inhibitors in targeting SOX2-driven LUSC and SCLC

Abstract This study addresses the current lack of small molecules targeting SOX2, a pivotal protein in cancer, through an examination of the effectiveness of FDA-approved drugs and proteasome inhibitors. Building on prior research demonstrating the proteasome inhibitor CFZ's capacity to diminish the expression of ITGB4 and PXN in LUAD effectively, our investigation highlights CFZ and IXA as potent inhibitors at nanomolar concentrations. Notably, CFZ treatment enhances sensitivity to cisplatin by suppressing the expression of ITGB4 and the stemness-associated gene SOX2.At a mechanistic level, CFZ hinders histone acetylation at the SOX2 promoter site, leading to rapid and specific downregulation. RNA-seq analysis of COH2 cells treated with CFZ unveils substantial downregulation of genes related to transcription and DNA binding. Z score analysis further reveals a noteworthy inhibition of key transcription factors (TFs), including SOX2, NANOG, POU5F1, SALL4, and KLF4. This TF inhibition extends to neuroendocrine cell lines, identifying 16 overlapping targets of SOX2 associated with stemness. These findings suggest a potential therapeutic approach for targeting cisplatin-resistant cancer stem cells across various cancer types. Moreover, the study proposes a synergistic effect of cisplatin and CFZ in mitigating the growth of neuroendocrine phenotype, SCLC. Given the limited medical options currently available for this phenotype, this insight holds particular significance. In conclusion, our study unveils CFZ as a potent transcriptional suppressor of SOX2, providing a novel strategy to sensitize cisplatin-resistant cancer stem cells. The results underscore the interplay of genetic and non-genetic mechanisms in drug resistance, emphasizing the significance of repurposing drugs for other indications. Citation Format: Atish Mohanty, Linlin Guo, Sravani Ramisetty, Sharad Singhal, Erminia Massarelli, Prakash Kulkarni, Ravi Salgia. Exploring the therapeutic potential of proteasome inhibitors in targeting SOX2-driven LUSC and SCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7574.

Risk of dementia among antidepressant elderly users: A population-based cohort analysis in Spain

The use of antidepressants with anticholinergic effects has been associated with an increased risk of dementia. However, the results published are contradictory. The aim of the study is to compare the risk of developing dementia in elderly who were prescribed tricyclic antidepressants (TCA) versus those who were prescribed selective serotonin reuptake inhibitors (SSRIs) and other antidepressants (OA). A prospective population-based cohort study was performed using the Spanish Database for Pharmacoepidemiological Research in Primary Care (BIFAP) data (from 2005 to 2018). The cohort study included 62,928 patients age ≥ 60 without dementia and with antidepressant long-term monotherapy. Patients were divided into exposure antidepressant groups based on ATC system [TCA, SSRIs users and OAs users]. The risk of dementia was calculated by Cox regression models, providing hazard ratios (HR) and 95 % confidence intervals. The Kaplan-Meier model was used for survival analysis. Chi2 test was used as association test. The results showed SSRI users had higher dementia risk than TCA users (HR = 1.864; 95%CI = 1.624–2.140). Moreover, OA users had also significant risk of dementia (HR = 2.103; 95%CI = 1.818–2.431). Several limitations are the variation of the trend in the prescription of antidepressants, the small number of patients that use some antidepressants, the lack of information related to the dose, or socioeconomic characteristics, the use of antidepressant drugs for other indications, or the therapeutic compliance.Our findings showed that older users of SSRI and OA have more risk of developing dementia than TCA elderly users. However, additional studies would be needed.

Participant Recruitment From Low- and Middle-Income Countries for Pivotal Trials of Drugs Approved by the U.S. Food and Drug Administration : A Cross-Sectional Analysis.

Many participants in clinical trials supporting U.S. Food and Drug Administration (FDA) drug approvals are recruited from outside the United States, including from low- and middle-income countries (LMICs). Where participants are recruited for pivotal trials has implications for ethical research conduct and generalizability. To describe LMIC recruitment for pivotal trials of newly approved drugs for cancer, neurologic disease, and cardiovascular disease. Cross-sectional analysis. Pivotal trials of new cancer, cardiovascular, and neurologic drugs approved from 2012 to 2019 matched to ClinicalTrials.gov, FDA records, and publications. Host countries and available per country enrollments were extracted. The primary end point was the proportion of pivotal trials enrolling participants in LMICs. The secondary end point was the proportion of pivotal trial participants contributed by LMICs for each indication area. Data were obtained from 66 new drugs and 144 pivotal clinical trials. All cardiovascular approvals (12 drugs, 29 trials) and neurologic approvals (26 drugs, 54 trials) were analyzed, as well as a random sample of cancer approvals (28 of 85 drugs [33%]) matched to their pivotal trials (61 of 210 trials [29%]). Among the trials, 56% in cancer, 79% in cardiovascular disease, and 56% in neurology recruited from an LMIC. For multicountry trials, country-level enrollment figures were not available for 71 trials (55%). For those reporting per country enrollment, the percentage of participants recruited from LMICs was 8% for cancer trials, 36% for cardiovascular trials, and 17% for neurology trials. The study was limited to FDA-approved drugs in 3 areas, including a sample of cancer drugs. Pivotal trials of nonapproved drugs or drugs for other indications were not captured. Most pivotal trials for FDA-approved drugs recruit from LMICs. Publications and FDA documents generally do not provide country-level data on recruitment. None.

Compliance to guideline-recommended pharmacotherapy in patients with heart failure, 2014 to 2020

Abstract Background Poor drug adherence in heart failure (HF) is associated with increased morbidity and mortality. Aims We aimed to investigate compliance to European guidelines for treatment of HF in Norway by measuring initiation and persistence of inhibitors of the renin-angiotensin system (RASi), β-blockers (BB) and mineralocorticoid receptor antagonists (MRA). Methods We included all patients ≥18 years with a first hospital contact for HF registered in the Norwegian Patient Registry (NPR) between 2014–2020. Patients >80 years of age and patients that deceased within the first 30 days were excluded. The study population was linked to the Norwegian Prescription Database for longitudinal data on drug prescriptions. Dual HF therapy was defined as taking at least two recommended HF drug classes, triple HF therapy was defined as taking all three drug classes. To estimate initiation, we counted the days from index HF to the first HF prescription, dual HF therapy and triple HF therapy within the first 365 days. We repeated the analysis for drug-naive patients, as some patients receive HF drugs for other indications or based on a tentative HF diagnosis. Patients were considered persistent if they did not experience any treatment break of more than 30 days. We allowed for stockpiling up to a maximum of 60 days, except for when the dose changed or if patients switched medication within the same drug class. Initiation and persistence were calculated by the Kaplan-Meier method, followed to death or December 2020. Results Out of 54,899 patients, 75%, 69% and 21% initiated BB, RASi and MRA, respectively (Figure 1). 13% of the population did not receive any of the three drug groups. Dual HF therapy was prescribed to 61% of the patients and triple HF therapy to 16%. In drug-naive patients, a lower proportion received any HF-drug within the first year (BB, 61%; RASi, 55%; and MRA, 19%), however, a higher proportion was collected within the first 30 days (BB, 48%; RASi, 46%; and MRA, 11%). Among the patients initiating therapy, 72% were persistent on BB, 71% on RASi and 48% on MRA throughout the first year with prominent declines in persistence around 3 and 6 months after initiation (Figure 2). Two years after initiation, the proportions of patients on BB, RASi and MRA decreased to 58%, 57% and 31%, respectively. The 5-year persistence was 38%, 37% and 15%, respectively. Conclusion This study found poor treatment compliance to HF medications in a real-world population of HF patients with only 61% of patients initiating dual pharmacotherapy and only 16% received all three dug classes. Nearly half of the patients discontinued RASi and BB within 2 years. The results suggest that systematic efforts should be done to increase the proportion of patients on guideline recommended therapies. These efforts should be focused on early initiation of multiple drug therapies as well as to maintain patients on treatment over time. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Novartis Norway AS and The Norwegian Research Council

Identification of Drugs Associated with Lower Risk of Parkinson's Disease Using a Systematic Screening Approach in a Nationwide Nested Case-Control Study.

Drugs for other indications may be repurposable as disease-modifying drugs for Parkinson's disease (PD). A systematic hypothesis-free approach can enable identification of candidates for repurposing. We applied a hypothesis-free systematic approach to identify drugs associated with lower risk of PD to discover candidates with potential for repurposing as disease-modifying drugs for PD and to illustrate challenges in observational studies that simultaneously investigate multiple repurposing candidates. The Finnish Parkinson's disease study (FINPARK), a nationwide nested case-control study, was randomized to screening (10,183 cases, 67,849 controls) and replication (10,184 cases, 67,754 controls) samples, including cases diagnosed in 1998-2015. After screening all univariable associations of register-derived exposure to individual-drug, group- and subgroup level since 1995 (exposure ≥3 years before outcome, threshold P = 0.1), different exposure periods were used in confounder-adjusted replication analyses. In screening stage, the group-level (antipsoriatics and antigout preparations) and subgroup-level (cicatrizants, topical antipsoriatics, antigout preparations and mydriatics and cycloplegics) associations were mainly due to individual drugs. Seven other drugs (eg methotrexate, drugs for chronic obstructive pulmonary disease, COPD and/or asthma) were associated with lower risk. Associations of antigout preparations and antipsoriatics were replicated. COPD/asthma drugs, methotrexate and diabetes drugs were studied in separate, indication-restricted designs. The results reflect the known risk factors and the implied role of the immune system in PD pathogenesis and spurious associations. They underline the importance of controlling for confounding by indication, which is challenging to apply to systematic screening.

Genomic variants-driven drug repurposing for tuberculosis by utilizing the established bioinformatic-based approach

A major challenge in translating genomic variants of Tuberculosis (TB) into clinical implementation is to integrate the disease-associated variants and facilitate drug discovery through the concept of genomic-driven drug repurposing. Here, we utilized two established genomic databases, namely a Genome-Wide Association Study (GWAS) and a Phenome-Wide Association Study (PheWAS) to identify the genomic variants associated with TB disease and further utilize them for drug-targeted genes. We evaluated 3.425 genomic variants associated with TB disease which overlapped with 200 TB-associated genes. To prioritize the biological TB risk genes, we devised an in-silico pipeline and leveraged an established bioinformatics method based on six functional annotations (missense mutation, cis-eQTL, biological process, cellular component, molecular function, and KEGG molecular pathway analysis). Interestingly, based on the six functional annotations that we applied, we discovered that 14 biological TB risk genes are strongly linked to the deregulation of the biological TB risk genes. Hence, we demonstrated that 12 drug target genes overlapped with 40 drugs for other indications and further suggested that the drugs may be repurposed for the treatment of TB. We highlighted that CD44, CCR5, CXCR4, and C3 are highly promising proposed TB targets since they are connected to SELP and HLA-B, which are biological TB risk genes with high systemic scores on functional annotations. In sum, the current study shed light on the genomic variants involved in TB pathogenesis as the biological TB risk genes and provided empirical evidence that the genomics of TB may contribute to drug discovery.

Translating osteoarthritis genetics research: challenging times ahead.

The ultimate goal of molecular genetic studies of human diseases is to translate the discoveries for patient benefit. For diseases that lack licensed disease-modifying therapeutics, such as osteoarthritis (OA), the need is acute. OA is polygenic and affects older individuals, with a recent genome-wide study of over 800 000 individuals adding 52 novel association signals to those already reported on for this common arthritis. Many of the predicted effector genes of these signals encode proteins that are targets of drugs for other indications, highlighting repurposing opportunities. Here, the potential for OA genetic data to translate is discussed, including whether the developmental origin of OA will limit the application of genetic risk data for disease-modification purposes.

A brain proteomic signature of incipient Alzheimer's disease in young APOE ε4 carriers identifies novel drug targets.

Aptamer-based proteomics revealed differentially abundant proteins in Alzheimer’s disease (AD) brains in the Baltimore Longitudinal Study of Aging and Religious Orders Study (mean age, 89 ± 9 years). A subset of these proteins was also differentially abundant in the brains of young APOE ε4 carriers relative to noncarriers (mean age, 39 ± 6 years). Several of these proteins represent targets of approved and experimental drugs for other indications and were validated using orthogonal methods in independent human brain tissue samples as well as in transgenic AD models. Using cell culture–based phenotypic assays, we showed that drugs targeting the cytokine transducer STAT3 and the Src family tyrosine kinases, YES1 and FYN, rescued molecular phenotypes relevant to AD pathogenesis. Our findings may accelerate the development of effective interventions targeting the earliest molecular triggers of AD.

The Price of Progress: Cost, Access, and Adoption of Novel Cardiovascular Drugs in Clinical Practice.

Purpose of ReviewThe launch of new effective and safe cardiovascular drugs has produced large gains in health outcomes for several cardiovascular conditions. But this innovation comes at the cost of rapidly increasing pharmaceutical spending and high out-of-pocket costs.Recent FindingsIn the USA, manufacturers are able to set prices according to what the market will bear rather than value to patients or society, with a complicated system of discounts and rebates obscuring the final price borne by payors. Some of these costs are passed on to patients in the form of co-payments or co-insurance, making these effective but high-cost medications unaffordable for many patients. Orphan drugs developed to treat rare diseases—for which manufactures are presented substantial financial and regulatory benefits—are particularly problematic, as they typically enter the market at very high prices compared with drugs for other indications.SummarySystematic cost-effectiveness analyses from the healthcare sector or societal perspectives can help identify the value-based price of a medication at market entry as well as later in the lifecycle of the drug when more data on effectiveness and safety becomes available. Despite bipartisan support, legislative progress on drug pricing has been slow. Clinicians should know the cost of the drugs they prescribe frequently, use generics where feasible, and regularly discuss out-of-pocket costs with patients to pre-empt cost-related non-adherence.

COVID-19 and Cardiovascular Disease: Issues of Diagnosis and Treatment

COVID-19 affects not only the respiratory system, but also the cardiovascular system. The damage to the cardiovascular system in COVID-19 is multifactorial and several mechanisms are involved, including direct invasion, inflammation, thrombosis, autoantibody synthesis, and oxygen imbalance. The inflammation causes the release of cytokines, especially interleukin-6, and damage to cardiomyocytes. The overproduction of cytokines leads to an abnormal inflammatory response called a cytokine storm, which is believed to be the culprit in cardiovascular events in COVID-19 patients. Cardiovascular disease is common in patients with COVID-19, and these patients are at increased risk of morbidity and mortality. There is still no data on cardiac dysfunction due to myocardial damage in patients recovering from COVID-19. Most often, this is normal heart function after complete recovery. But often there are myocardial damage and an increased level of troponin as a marker of the severity of the disease associated with a cytokine storm, hypoxia, vasopressors and blood clotting disorders. It is important for every physician to make a differential diagnosis between decompensated heart failure complicated by pulmonary infection and COVID-19 infection. Monitoring and influencing myocardial injury is extremely important in critically ill patients. Treatment of COVID-19 patients with cardiovascular complications is mostly supportive. The role of pharmacological blocking of the reninangiotensin-aldosterone system in patients with cardiovascular disease and COVID-19 infection requires further research as the relationship appears to be very complex. To date, professional cardiological societies do not recommend canceling ACE inhibitors or agiotensin II receptor antagonists for patients taking these drugs for other indications. Special care should be taken about the potential cardiovascular side effects of the various therapies used to treat viral infections. When using them, daily monitoring of the QT interval on the ECG is proposed.

Поражение сердечно-сосудистой системы при COVID-19

COVID-19 affects not only the respiratory system, but also the cardiovascular system. The damage to the cardiovascular system in COVID-19 is multifactorial and several mechanisms are involved, including direct invasion, inflammation, thrombosis, autoantibody synthesis, and oxygen imbalance. The inflammation causes the release of cytokines, especially interleukin-6, and damage to cardiomyocytes. The overproduction of cytokines leads to an abnormal inflammatory response called a cytokine storm, which is believed to be the culprit in cardiovascular events in COVID-19 patients. Treatment of COVID-19 patients with cardiovascular complications is mostly supportive. The role of pharmacological blocking of the renin-angiotensin-aldosterone system in patients with cardiovascular disease and COVID-19 infection requires further research as the relationship appears to be very complex. To date, professional cardiological societies do not recommend canceling ACE inhibitors or agiotensin II receptor antagonists for patients taking these drugs for other indications. Special care should be taken about the potential cardiovascular side effects of the various therapies used to treat viral infections. When using them, daily monitoring of the QT interval on the ECG is proposed.

H2S as a Therapeutic Adjuvant Against COVID-19: Why and How?

H2S as a Therapeutic Adjuvant Against COVID-19: Why and How?

Model Amphipathic Peptide Coupled with Tacrine to Improve Its Antiproliferative Activity.

Drug repurposing and drug combination are two strategies that have been widely used to overcome the traditional development of new anticancer drugs. Several FDA-approved drugs for other indications have been tested and have demonstrated beneficial anticancer effects. In this connection, our research group recently reported that Tacrine, used to treat Alzheimer’s Disease, inhibits the growth of breast cancer MCF-7 cells both alone and in combination with a reference drug. In this view, we have now coupled Tacrine with the model amphipathic cell-penetrating peptide (CPP) MAP, to ascertain whether coupling of the CPP might enhance the drug’s antiproliferative properties. To this end, we synthesized MAP through solid-phase peptide synthesis, coupled it with Tacrine, and made a comparative evaluation of the parent drug, peptide, and the conjugate regarding their permeability across the blood-brain barrier (BBB), ability to inhibit acetylcholinesterase (AChE) in vitro, and antiproliferative activity on cancer cells. Both MAP and its Tacrine conjugate were highly toxic to MCF-7 and SH-SY5Y cells. In turn, BBB-permeability studies were inconclusive, and conjugation to the CPP led to a considerable loss of Tacrine function as an AChE inhibitor. Nonetheless, this work reinforces the potential of repurposing Tacrine for cancer and enhances the antiproliferative activity of this drug through its conjugation to a CPP.

Machine learning prediction of oncology drug targets based on protein and network properties

BackgroundThe selection and prioritization of drug targets is a central problem in drug discovery. Computational approaches can leverage the growing number of large-scale human genomics and proteomics data to make in-silico target identification, reducing the cost and the time needed.ResultsWe developed a machine learning approach to score proteins to generate a druggability score of novel targets. In our model we incorporated 70 protein features which included properties derived from the sequence, features characterizing protein functions as well as network properties derived from the protein-protein interaction network. The advantage of this approach is that it is unbiased and even less studied proteins with limited information about their function can score well as most of the features are independent of the accumulated literature. We build models on a training set which consist of targets with approved drugs and a negative set of non-drug targets. The machine learning techniques help to identify the most important combination of features differentiating validated targets from non-targets. We validated our predictions on an independent set of clinical trial drug targets, achieving a high accuracy characterized by an Area Under the Curve (AUC) of 0.89. Our most predictive features included biological function of proteins, network centrality measures, protein essentiality, tissue specificity, localization and solvent accessibility. Our predictions, based on a small set of 102 validated oncology targets, recovered the majority of known drug targets and identifies a novel set of proteins as drug target candidates.ConclusionsWe developed a machine learning approach to prioritize proteins according to their similarity to approved drug targets. We have shown that the method proposed is highly predictive on a validation dataset consisting of 277 targets of clinical trial drug confirming that our computational approach is an efficient and cost-effective tool for drug target discovery and prioritization. Our predictions were based on oncology targets and cancer relevant biological functions, resulting in significantly higher scores for targets of oncology clinical trial drugs compared to the scores of targets of trial drugs for other indications. Our approach can be used to make indication specific drug-target prediction by combining generic druggability features with indication specific biological functions.

Novel Drugs and Clinical Trial-Based Treatments Prolong Survival of Peripheral T-Cell Lymphomas (PTCL) Patients: Single Institution Retrospective Analysis

Introduction Peripheral T-cell lymphomas (PTCL) are a group of rare and heterogeneous diseases associated with unfavorable prognoses. Conventional chemotherapy has been the standard of care, but is considered marginally effective. This outcome has been attributed to the fact that most PTCL treatments are derived from the management of aggressive B-cell lymphomas. While relapse is common, subsequent line therapies are heterogeneous, and can include many lines of non-specific chemotherapy. Recently approved novel agents, such as pralatrexate and histone deacetylase (HDAC) inhibitors, and clinical trials however, tend to either not be used or used too late in the natural history of the disease. Herein, we compared the efficacy of chemotherapy and novel therapies, in first line, second line and third line, to identify factors that might influence the outcome of PTCL patients in a single institutional cohort. Methods A search of the electronic medical record and clinical trial databases from January 1, 1994 to May 31, 2019 was performed to identify patients with PTCL. Only patients 18 years and older with pathology-confirmed PTCL and complete clinical data were included. Due to substantially different disease characteristics, behavior, and treatment, we excluded patients with T/NK large granular lymphocytic leukemia and primary cutaneous T-cell lymphoma, with the exception of transformed mycosis fungoides. Overall survival (OS) was calculated from the time of diagnosis to death from any cause. Kaplan-Meier curves were generated and compared based on the log-rank test. Cox proportional hazard models were used to investigate the association by adjusting for the type of treatments and the lines of therapy. Statistical analyses were performed with SAS version 9.4. Results There were 213 patients (1.2 males:1 female) included in the analysis with a median age of diagnosis of 56.9 years (range 18.1-90.3). Front-line therapies typically consisted of chemotherapy, including CHOP, CHOEP, and EPOCH. The use of clinical trials and novel agents increased as patients progressed through multiple lines of therapy. Figure 1A showed that patients who achieved a CR with first line chemotherapy had a better overall survival than patients who did not (median 8.9 years vs 0.83 years, p<0.0001), with trends suggesting improvement in survival with novel combinations and single agents. Although limited by small numbers, patients with primary refractory or relapsed disease were generally given additional lines of chemotherapy, and the percentage of patients who achieved CR trended down more drastically (42% first line in Figure 1A, 16% second line in Figure 1D, 21% third line in Figure 1G) than patients who received novel combinations (50% first line in Figure 1B, 23% second line in Figure 1E, 30% third line in Figure 1H) or single agents (27% first line in Figure 1C, 40% second line in Figure 1F, 20% third line in Figure 1I). There were no significant differences in the frequency of radiotherapy or autologous stem cell transplantation over the study period. Our data demonstrate that exposure to novel agents (p=0.002) in Figure 2A and novel combinations (p=0.003) in Figure 2B, especially histone deacetylase inhibitors (HDACI, p=0.045) in Figure 2D, during the treatment course of PTCL patients, was associated with prolonged overall survival. Pralatrexate had a trend toward improving outcomes in the first ten years as shown in Figure 2C, but this was not statistically significant. Conclusions Clinical trials and novel therapies improve outcomes and should be considered earlier in the therapy of patients with PTCL. Patients who obtain CR early have the best overall survival. Our findings suggest that patients with R/R PTCL who fail chemotherapy should be enrolled in clinical trials or be given novel approved agents rather than repeated rounds of non-specific cytotoxic therapy. Disclosures Marchi: Spectrum Pharmaceuticals, Verastem Oncology: Research Funding. O'Connor:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADCT Therapeutics, Affimed, Agensys, Merck, Seattle Genetics, Spectrum, Trillium, and Verastem Oncology.: Research Funding; TG Therapeutics: Other: Travel Support, Research Funding. OffLabel Disclosure: Drugs that are approved for the treatment of patients with relapsed and refractory peripheral T-cell lymphoma, such as pralatrexate (a novel antifolate) and histone deacetylase inhibitors, were used in the front line setting when patients were not candidates for chemotherapy or enrolled in clinical trials. Outcomes are also described for non-FDA approved drugs used as monotherapy or in combination in clinical trials as well as FDA approved drugs for other indications used in clinical trials are described though not explicitly listed.

PNS181 SUBMISSIONS TO A NATIONAL HTA AGENCY IN IRELAND: DRUGS WITH DESIGNATED ORPHAN STATUS

In Ireland, the National Centre for Pharmacoeconomics (NCPE) examines the cost effectiveness of all new drugs for which reimbursement by the health payer is sought. Applicant companies make submissions to the NCPE for evaluation. We aim to determine the proportion of all drugs with European Medicines Agency (EMA) designated orphan status and marketing authorization (MA) that are submitted to the NCPE. We aim to evaluate the time from MA to submission to the NCPE. This was a retrospective review of publicly available websites. The number of drugs that had received EMA orphan designation (January 2009 to February 2019 inclusive) and subsequent MA was established. The percentage of these drugs that were subsequently subject to a NCPE submission was determined. Timelines for submission to the NCPE were examined. Outcomes were analyzed as a function of year of orphan designation and indication (‘cancer’ vs. ‘non-cancer’). Analyses were performed on Microsoft Excel and IBM SPSS Statistics (version 24.0). In total, 83 eligible drugs (i.e. held both EMA orphan designation and MA) were identified. Of these, 51 (61.4%) had been submitted to the NCPE. The mean time from MA to NCPE submission for all drugs was 21.1 months. The mean time ranged from 1 month to 22.1 months depending on the year of orphan designation. Those drugs for cancer were more likely to be submitted to the NCPE (vs. drugs for other indications); p=0.008; Chi-squared test. Not all drugs with EMA designated orphan status and MA are subject to a NCPE submission. As such, reimbursement is not sought in all instances. Timelines for submission to the NCPE vary depending on year of orphan designation. Drugs for cancer are more likely to be submitted to the NCPE (versus drugs for other indications).

Re-thinking Alzheimer's disease therapeutic targets using gene-based tests

BackgroundAlzheimer's disease (AD) is a devastating condition with no known effective drug treatments. Existing drugs only alleviate symptoms. Given repeated expensive drug failures, we assessed systematically whether approved and investigational AD drugs are targeting products of genes strongly associated with AD and whether these genes are targeted by existing drugs for other indications which could be re-purposed.MethodsWe identified genes strongly associated with late-onset AD from the loci of genetic variants associated with AD at genome-wide-significance and from a gene-based test applied to the most extensively genotyped late-onset AD case (n = 17,008)-control (n = 37,154) study, the International Genomics of Alzheimer's Project. We used three gene-to-drug cross-references, Kyoto Encyclopedia of Genes and Genomes, Drugbank and Drug Repurposing Hub, to identify genetically validated targets of AD drugs and any existing drugs or nutraceuticals targeting products of the genes strongly associated with late-onset AD.FindingsA total of 67 autosomal genes (forming 9 gene clusters) were identified as strongly associated with late-onset AD, 28 from the loci of single genetic variants, 51 from the gene-based test and 12 by both methods. Existing approved or investigational AD drugs did not target products of any of these 67 genes. Drugs for other indications targeted 11 of these genes, including immunosuppressive disease-modifying anti-rheumatic drugs targeting PTK2B gene products.InterpretationApproved and investigational AD drugs are not targeting products of genes strongly associated with late-onset AD. However, other drugs targeting products of these genes exist and could perhaps be re-purposing to combat late-onset AD after further scrutiny.

Abstract 4643: Drug-Target Explorer: An interactive tool for examining chemical-biological interactions

Abstract Background: Phenotypic high-throughput screens are often utilized in modern oncology drug discovery pipelines. Such screens are conducted with an array of molecules (panels of oncology drugs, drugs for other indications, and compounds with possibly unknown bioactivity), ultimately measuring a biological change within a disease model. For example, a screen might test drugs in NF1 wild-type and mutant cancer cell lines to find molecules that are selectively toxic to NF1 mutant cells. While these screens can yield valuable hits, they also present the challenge of identifying the target(s) that mediate the effect seen in the screen for several reasons. For example, many drugs have a polypharmacologic target profile making it hard to identify which targets are biologically relevant for a given drug. This can cause a single drug to be treated as a specific inhibitor of different targets by different researchers. Furthermore, some libraries contain molecules for which drug-target studies have never been conducted. To address these challenges, we developed an application that enables exploration of the chemical-biological interaction space. Methods: Data from ChEMBL, PubChem, DrugBank, and the Drug-Gene Interaction Database (DGIdb) for over 7000 small molecules were downloaded. Drug-target interaction data points as well as evidence to the contrary were quantified for each interaction. In addition, when quantitative data were obtained, median IC50s were calculated. Each molecule was annotated with a name and chemical structure, and every target was annotated with protein & gene identifiers. To enable exploration of this database, an interactive web interface was developed using the R Shiny platform and cheminformatics R packages (rcdk, fingerprint, webchem).Results: The app enables the end user with a specific query molecule to search a database of experimentally-derived drug-target interactions. The database can be queried using drug names or structures. A similarity parameter allows the user to expand their search to other structurally related molecules. The structure of the query molecule is compared to every database molecule, and structurally similar molecules and targets are presented in interactive tabular and network-based forms for in-depth exploration. The app also performs enrichment analysis on the target lists, and allows the user to evaluate structure-activity relationships for drug response data using publicly-available in vitro datasets. Finally, if a user has a target of interest, they can search for molecules that bind that target and explore the resulting data interactively. Conclusions: This app provides a multifunctional platform for exploring chemical space as it relates to biological targets, and may be useful at several steps along the oncology drug development pipeline including target discovery, structure-activity relationship, and lead identification studies. Citation Format: Robert J. Allaway, Sara J. Gosline, Marco Nievo, Salvatore La Rosa, Annette Bakker, Justin Guinney. Drug-Target Explorer: An interactive tool for examining chemical-biological interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4643.

Regulatory innovation for expansion of indications and pediatric drug development.

For regulatory approval of a new drug, the most preferred and reliable source of evidence would be randomized controlled trials (RCT). However, a great number of drugs, being developed as well as already marketed and being used, usually lack proper indications for children. It is imperative to develop properly evaluated drugs for children. And expanding the use of already approved drugs for other indications will benefit patients and the society. Nevertheless, to get an approval for expansion of indications, most often with off-label experiences, for drugs that have been approved or for the development of pediatric indications, either during or after completing the main drug development, conducting RCTs may not be the only, if not right, way to take. Extrapolation strategies and modelling & simulation for pediatric drug development are paving the road to the better approval scheme. Making the use of data sources other than RCT such as EHR and claims data in ways that improve the efficiency and validity of the results (e.g., randomized pragmatic trial and randomized registry trial) has been the topic of great interest all around the world. Regulatory authorities should adopt new methodologies for regulatory approval processes to adapt to the changes brought by increasing availability of big and real world data utilizing new tools of technological advancement.

Antiplatelet therapy and exodontia: far away from a definite conclusion

Dear Editor;We read a review article about antiplatelet therapy and dental management in your journal (1). Kumar concluded that patients taking dual antiplatelet therapy has an increased risk for post-operative bleeding complications.The focus question of this article contains many other smeller questions. We recently answered one of these questions in our study; one tooth extraction is safe in patients taking aspirin and clopidogrel during one year after percutaneous coronary intervention (PCI) with stenting (2). But many questions remained without answer. Is two teeth extraction safe in these patients? What about more than two teeth extraction or in patients taking other antiplatelet drugs for other indications? What about other dental interventions? For answering each of these specific questions we need to design a prospective original study, with enough sample size, and comparing the results with a matched control group.Also there are many confounders for bleeding after exodontia (e.g. dentist's skill, type of antiplatelet drug and its manufacturing company, indication and duration of taking antiplatelet therapy, number and kind of extracted teeth, and dentist's skill) (2, 3). Controlling these confounders needs prospective studies focusing on specific group of patients. For example, patients taking unique dose and type of antiplatelet drug for a unique indication and duration, undergoing unique dental intervention by unique dentist. Then this result could be compared with a group of healthy subjects undergoing same dental intervention by the same dentist. So we do not have enough evidences to make a definite conclusion about what we should do in case of dental intervention for patients taking antiplatelet therapy.