A Nonrandomized Phase 2 Trial of EG-Mirotin, a Novel, First-in-class, Subcutaneously Delivered Peptide Drug for Non-Proliferative Diabetic Retinopathy

ABSTRACTBackgroundEG-Mirotin, which includes an active ingredient; EGT022, targeting Non-Proliferative Diabetic Retinopathy (NPDR), the early stage of retinopathy. EG-Mirotin is a drug that is used before capillary damage progresses to an irreversible stage. Safety and efficacy of EG-Mirotin were investigated in subjects with Type 1 or 2 diabetes and NPDR with the degree from moderate to severe.MethodsSubjects (n=10, 20 eyes) satisfying the selection criteria through the screening test were administered EG-Mirotin once a day (3 mg in 1.5 ml of sterile saline) for 5 days, 5 times in total, and were evaluated of the Ischemic index changes and safety. End-of-study (EOS) is performed approximately 8 weeks ± 1 (57 days ± 7) from the first dose.ResultsA total of 4 Treatment Emergent Adverse Events (TEAE) were observed in 2 subjects out of 10 (20.00%) who received the investigational drug. Among them, no subjects were reported experiencing a TEAE related to the investigational drug. All injections were well tolerated (3 mg in 1.5 ml of sterile saline) with no dose-limiting adverse events, deaths, serious adverse events. The overall average percent change in ischemic index at each evaluation point compared to baseline was statistically significant (Greenhouse-Geisser F=9.456, p=0.004 for the main effect of time), and a larger change was observed when the baseline ischemic index value was high (Greenhouse-Geisser F=10.946, p=0.002 for the time*group interaction).ConclusionsEG-Mirotin was well tolerated and found to reverse the ischemia and leakage of capillaries in the retina caused by diabetes.

Motives and risk perceptions of participants in a phase 1 trial for Hepatitis C Virus investigational therapy in pregnancy

Limited research has been done among pregnant people participating in investigational drug trials. To enhance the ethical understanding of pregnant people’s perspectives on research participation, we sought to describe motives and risk perceptions of participants in a phase 1 trial of ledipasvir/sofosbuvir (LDV/SOF) treatment for chronic Hepatitis C virus (HCV) during pregnancy. Pregnant people with chronic HCV infection enrolled in an open-label, phase 1 study of LDV/SOF participated in semi-structured, in-depth interviews to explore their reasons for participation and experiences within the study. Pregnant people took 12 weeks of LDV/SOF and were interviewed at enrollment and at the end of study. We recorded the interviews, transcribed them verbatim, coded them using NVivo software, and performed inductive thematic analysis. Nine women completed the study yielding 18 interview transcripts. We identified two themes regarding motives and one regarding risk perception. Motives—(1) Women conceptualized study participation as part of the caregiving role they associate with motherhood; participating was viewed as an act of caregiving for their infants, their families, themselves, and other pregnant women with chronic HCV. (2) Women also noted that they faced multiple barriers to treatment prior to pregnancy that created a desire to receive therapy through trial participation. Risk perception—(3) Women acknowledged personal and fetal risk associated with participation. Acceptance of risk was influenced by women’s concepts of motherhood, preexisting knowledge of HCV and medical research, family members, intimate partners, or by the study design. Women enrolled in a phase 1 trial for chronic HCV therapy during pregnancy acknowledged risks of participation and were motivated by hopes for fetal and personal benefit and by lack of prenatal access to treatment. Ethical inclusion of pregnant people in research should acknowledge structural factors that contribute to vulnerability and data deficiencies for treatment in pregnancy.

654 Fragility of functional/symptomatic endpoints to assess the efficacy of drugs for pulmonary arterial hypertension

Aims Drugs for pulmonary arterial hypertension (PAH) have historically been evaluated for their efficacy in improving functional capacity and decreasing symptoms. However, these measures of treatment effect are approximate and subject to substantial variability, and therapeutic choices based on them may be aleatory. Methods and results We reviewed the articles reporting the results of phase 3 PAH randomized controlled trials (RCTs) and calculated the fragility index (FI) for the outcomes exploring functional capacity and symptoms. The FI corresponds to the number of events that need to be added to the arm with the smallest number of events to make a significant result non-significant: the lower the FI, the fragile the trial with respect to the endpoint examined. For RCTs with non-significant results, we calculated the FI as the number of events that need to be removed from the investigational drug (ID) group to reach a P-value <0.05. When possible, we also computed the FI for PAH hospitalization. Data about the rate of functional/symptomatic improvement were available for 22 (63%) of 35 RCTs (Table). The ID was superior to placebo or comparator with P < 0.05 in 10 (45%) of these 22 studies. The median FI was 2 [interquartile range (IQR): 6.5], with 4 RCTs having a FI = 1 and only 2 > 10 (Table). For the 12 RCTs in which the effect of the ID was neutral (P > 0.05), the median FI was 6 (IQR 4.25) (Table). The hospitalization FI was determined for 17 (77%) of the 22 RCTs and was overall higher than the one for the functional/symptomatic outcome (median 6, IQR 8). Conclusions Accessible information about the effects of PAH drugs on functional capacity and/or symptoms is published for 6 in 10 RCTs, in which very few events in one arm could have flipped the results from non-significant to significant or, more remarkably, from significant to non-significant. The evidence supporting the reduction of PAH hospitalizations as a treatment goal appears to be more robust.

ASSESSMENT OF ANTITOXIC AND ANTI-INFECTIOUS ACTIONS OF THE EXPERIMENTAL PREPARATION

In the course of the research, the antitoxic and anti-infectious effects of the developed drug were determined on white mice and white rats. To assess the antitoxic effect in the experiment on white rats, cadmium damage was modeled, followed by taking into account the antidote activity. An increase in the survival rate of animals receiving the drug was found – 60 % versus 40 % in the control, higher hematological indicators: the content of hemoglobin, erythrocytes and leukocytes in the blood of experimental animals was higher than similar control values, respectively, by 3.8, 15.3 and 16,4 %. The anti-infectious effect of the feed additive was determined during the experiment on infecting white mice with the causative agent of Escherichiosis – E. coli (strain "KB-1"). It was found that the introduction of the study drug into the diet of infected animals smoothed the clinical picture of the infectious process, had a hemoprotective effect: the content of erythrocytes, leukocytes, neutrophils, lymphocytes, neutrophils in the blood of experimental animals exceeded the control values, respectively, by 2.5, 13.6, 16, 7, 14.3, 28.6 %. The results of the investigated subject showed that the investigational drug has a well-pronounced antitoxic and anti-infectious effect.

Challenges with Conducting an Investigational Drug Study in Older Adults in Nursing Homes During a Pandemic

In the early months of the pandemic, SARS-CoV-2 infected nursing home residents in explosive and deadly outbreaks. Nursing home residents disproportionately accounted for over 40% of COVID-19 mortality nationally. This national emergency drove scientific and public health experts to develop and implement administrative, clinical, and research programs to limit the pandemic’s impact, especially for high-risk individuals, such as those hospitalized or living in nursing homes. Nursing home policies, prompted by the Centers for Medicare & Medicaid Services (CMS) and the Centers for Disease Control and Prevention (CDC) guidance, severely restricted access beginning in March 2020 in an effort to limit disease exposure. In July 2020 we began the process to conduct an investigational SARS-CoV-2 post exposure prophylaxis study of nursing home residents, incorporating FDA guidance developed for conducting investigational drug trials in the context of COVID-19. Our research teams adapted our nursing home engagement, resident consenting and research data collection strategies accordingly. We remotely screened residents living in any of 28 nursing homes for eligibility to participate, ultimately consenting and randomizing individuals in 11 facilities. Of the 2,683 nursing home residents 65 years or older we screened, 48 (1.8%) agreed to consent individually or through proxy, most often a legally authorized representative. We will describe our research methods, with emphasis on how we addressed challenges presented due to performing all research tasks remotely and identify strategies that can qualitatively improve the remote nursing home research experience.

National Comprehensive Cancer Network investigational drug service consensus recommendations

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Gene Expression Profiles in Sporadic ALS Fibroblasts Define Disease Subtypes and The Metabolic Effects of the Investigational Drug EH301

Background: Majority of ALS cases are sporadic (sALS), as they lack defined genetic causes. Metabolic alterations shared between the nervous system and skin fibroblasts have emerged in ALS. Recently, we found that a subgroup of sALS fibroblasts (sALS1) is characterized by metabolic profiles (metabotype) distinct from other sALS cases (sALS2) and controls, suggesting that metabolic therapies could be effective in sALS. The metabolic modulators nicotinamide riboside and pterostilbene (EH301) are under clinical development for the treatment of ALS. Here, we studied the metabolome and transcriptome of sALS cells to understand the molecular bases of sALS metabotypes and the impact of EH301.Methods: Six fibroblast cell lines (3 male and 3 female subjects of similar ages) were used for each group (sALS1, sALS2, and controls). Metabolomics and transcriptomics were investigated at baseline and after EH301 treatment. Differential gene expression (DEGs) and metabolite abundance were assessed by a Wald Test and ANOVA, respectively, with FDR correction, and pathway analyses were performed. EH301 protection against metabolic stress was tested by thiol depletion. Weighted gene co-expression network analysis (WGCNA) was used to investigate the association of metabolic and clinical features and was also performed on the Answer ALS dataset from induced motor neurons (iMN). A machine learning model based on DEGs was tested as a sALS disease progression predictor. Results: We found that the sALS1 transcriptome is distinct from sALS2 and that EH301 modifies gene expression differently in sALS1, sALS2, and controls. Furthermore, EH301 had strong protective effects against metabolic stress, which is linked to anti-inflammatory and antioxidant pathways. WGCNA revealed that ALS functional rating scale and metabotypes are associated with gene modules enriched for cell cycle, immunity, autophagy, and metabolism terms, which are modified by EH301. Meta-analysis of publicly available transcriptomics data from iMNs confirmed functional associations of genes correlated with disease traits. A small subset of genes differentially expressed in sALS fibroblasts could be used in a machine learning model to predict disease progression.Conclusions: Multi-omics analyses of patient-derived fibroblasts highlighted differential metabolic and transcriptomic profiles in sALS metabotypes, which translate into differential responses to the investigational drug EH301.

Evaluation of drug cost avoidance resulting from conduct of cancer clinical trials in a community-based oncology practice.

66 Background: Aim: To prospectively evaluate cost avoidance during routine conduct of cancer clinical trials in a community based integrated delivery network (IDN) consisting of a health services provider group, a health insurance plan and a hospital system. Only 2%–7% of adult cancer patients participate in clinical trials nationwide [1]. Inadequate funding and concerns about financial viability have been identified as factors that impede clinical trial accrual in the community oncology setting. ‘Cost-avoidance’, defined as dollars that would have been spent to purchase medications but were not spent because of study-related interventions [3] has been proposed as one mechanism to overcome this. Methods: Anti-cancer and hematology drugs provided by intergroup as well as pharmaceutical industry-based trial sponsors to patients enrolled in oncology clinical research were tabulated. Analysis of cost avoidance was restricted to patients covered by the IDNs health plan. Additionally, drugs provided by the trial sponsor were included in the analysis only if they represented a normal standard of care for the disease state. Cost avoidance was defined as the net ingredient cost of the drugs that would have been spent by the health plan for patient care if drugs provided by trial sponsors were not available. Results: Between January 2020 and April 2021, 25 patients covered by the IDN were recruited into clinical trials. Cost savings resulted from 7 targeted and immuno-oncology medications. Net cost avoidance in 2020 was $1,229,798 while that in 2021 till date has been $892,783. The realized cost savings has allowed recruitment of additional clinical research staff as well as expansion of clinical research to rural regional sites served by the IDN. Conclusions: Anticancer drugs provided free of charge by clinical trial sponsors render significant cost savings, ensuring viability and even expansion of oncology clinical research in community based IDNs. References: National Health Expenditure Data. 2018, U.S. Centers for Medicare & Medicaid Services: Baltimore, MD 21244. McDonagh MS, M.S., Naden E., Costs and savings of investigational drug services. American Journal of Health-Systems Pharmacy, 2000. 57: p. 40-43.[Table: see text]