Multiple Pharmaceutical Companies Research Articles

Hurdles and signposts on the road to virtual control groups-A case study illustrating the influence of anesthesia protocols on electrolyte levels in rats.

Introduction: Virtual Control Groups (VCGs) represent the concept of using historical control data from legacy animal studies to replace concurrent control group (CCG) animals. Based on the data curation and sharing activities of the Innovative Medicine Initiatives project eTRANSAFE (enhancing TRANSlational SAFEty Assessment through Integrative Knowledge Management) the ViCoG working group was established with the objectives of i) collecting suitable historical control data sets from preclinical toxicity studies, ii) evaluating statistical methodologies for building adequate and regulatory acceptable VCGs from historical control data, and iii) sharing those control-group data across multiple pharmaceutical companies. During the qualification process of VCGs a particular focus was put on the identification of hidden confounders in the data sets, which might impair the adequate matching of VCGs with the CCG. Methods: During our analyses we identified such a hidden confounder, namely, the choice of the anesthetic procedure used in animal experiments before blood withdrawal. Anesthesia using CO2 may elevate the levels of some electrolytes such as calcium in blood, while the use of isoflurane is known to lower these values. Identification of such hidden confounders is particularly important if the underlying experimental information (e.g., on the anesthetic procedure) is not routinely recorded in the standard raw data files, such as SEND (Standard for Exchange of Non-clinical Data). We therefore analyzed how the replacement of CCGs with VCGs would affect the reproducibility of treatment-related findings regarding electrolyte values (potassium, calcium, sodium, and phosphate). The analyses were performed using a legacy rat systemic toxicity study consisting of a control and three treatment groups conducted according to pertinent OECD guidelines. In the report of this study treatment-related hypercalcemia was reported. The rats in this study were anesthetized with isoflurane. Results: Replacing the CCGs with VCGs derived from studies comprising both anesthetics resulted in a shift of control electrolyte parameters. Instead of the originally reported hypercalcemia the use of VCG led to fallacious conclusions of no observed effect or hypocalcemia. Discussion: Our study highlights the importance of a rigorous statistical analysis including the detection and elimination of hidden confounders prior to the implementation of the VCG concept.

Descriptive study of the economic burden among patients with type 2 diabetes mellitus, chronic kidney disease, and chronic kidney disease and type 2 diabetes mellitus in a large US commercially insured population.

BACKGROUND: Chronic kidney disease (CKD) is a major public health concern that affects 37 million adults in the United States. It is well known that CKD presents a large economic burden, especially in the Medicare population. However, studies of the economic burden of CKD in younger populations are scarce. In particular, there is a gap in understanding how the presence of type 2 diabetes mellitus (T2DM) affects the burden of CKD in commercially insured populations. OBJECTIVE: To describe the economic and health care resource utilization (HCRU) burden of CKD within 3 patient groups (T2DM only, CKD only, and CKD and T2DM) aged 45-64 years overall and by Kidney Disease Improving Global Outcomes (KDIGO) CKD estimated glomerular filtration rate-based stage categories. METHODS: A descriptive, observational retrospective cohort study was conducted using administrative medical and pharmacy claims integrated with laboratory results data available in the HealthCore Integrated Research Database from January 1, 2017, to December 31, 2019. Three mutually exclusive groups of commercially insured patients aged 45-64 years were identified: T2DM only, CKD only, and CKD and T2DM. All-cause and disease-specific HCRU and costs in total, by medical and pharmacy benefits and across all places of service, were described for each of these groups 12 months after index date. For the CKD only and CKD and T2DM groups, costs were also described by KDIGO CKD stage. RESULTS: The CKD and T2DM group (n = 13,052) had numerically higher 12-month post-index all-cause and CKD/T2DM-related HCRU across all places of service. Mean 12-month all-cause costs for this group were $35,649, whereas costs for the CKD only group (n = 7,876) were $25,010 and costs for the T2DM only group (n = 120,364) were $16,121. Costs also tended to increase as CKD stage increased, with the greatest increases beginning at KDIGO stage 3b and higher. Mean 12-month all-cause costs for the CKD and T2DM group ranged from $29,993 to $41,222 for stages 1 to 3a and from $46,796 to $119,944 for stages 3b to 5. CONCLUSIONS: Commercially insured patients aged 45-64 years with CKD, especially those who also have T2DM, present a substantial burden in terms of elevated HCRU and costs. Costs tend to increase across KDIGO CKD stages and increase most rapidly at stage 3b and later. Therefore, there is an opportunity to reduce the burden of CKD in this population by investing in interventions to prevent or delay CKD disease progression. DISCLOSURES: HealthCore, Inc, received funding to perform this research, as well as funding from multiple pharmaceutical companies to perform various research studies outside of the submitted work. Mr Crowe and Dr Willey are employees of HealthCore, Inc., a wholly owned subsidiary of Elevance Health, Inc. Ms Chung was an employee of HealthCore, Inc., a wholly owned subsidiary of Elevance Health, Inc, at the time of study performance. Ms Chung and Dr Willey are shareholders of Elevance Health, Inc. Dr Kong, Dr Singh, Mr Farej, Dr Elliot, and Dr Williamson are employees of Bayer US, LLC. Dr Singh is a shareholder of Bayer US, LLC.

Organs‐on‐Chips: Trends and Challenges in Advanced Systems Integration

AbstractOrgan‐on‐chip platforms combined with high‐throughput sensing technology allow bridging gaps in information presented by 2D cultures modeled on static microphysiological systems. While these platforms do not aim to replicate whole organ systems with all physiological nuances, they try to mimic relevant structural, physiological, and functional features of organoids and tissues to best model disease and/or healthy states. The advent of this platform has not only challenged animal testing but has also presented the opportunity to acquire real‐time, high‐throughput data about the pathophysiology of disease progression by employing biosensors. Biosensors allow monitoring of the release of relevant biomarkers and metabolites as a result of physicochemical stress. It, therefore, helps conduct quick lead validation to achieve personalized medicine objectives. The organ‐on‐chip industry is currently embarking on an exponential growth trajectory. Multiple pharmaceutical and biotechnology companies are adopting this technology to enable quick patient‐specific data acquisition at substantially low costs.

INTERCOSTAL NERVE SCHWANNOMA IN THE LATERAL CHEST WALL: AN UNCOMMON OCCURENCE

INTERCOSTAL NERVE SCHWANNOMA IN THE LATERAL CHEST WALL: AN UNCOMMON OCCURENCE

Utilizing public and private sector data to build better machine learning models for the prediction of pharmacokinetic parameters

One solution to compensate for the shortage of publicly available data is to collect more quality-controlled data from the private sector through public-private partnerships. However, several issues must be resolved before implementing such a system. Here, we review the technical aspects of public-private partnerships using our initiative in Japan as an example. In particular, we focus on the procedure for collecting data from multiple private sector companies and building prediction models and discuss how merging public and private sector datasets will help to improve the chemical space coverage and prediction performance. Teaser: Japan's first public-private consortium in pharmacokinetics has incorporated data from multiple pharmaceutical companies to create useful predictive models.

Identification of β-Lactams Active against Mycobacterium tuberculosis by a Consortium of Pharmaceutical Companies and Academic Institutions.

Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of β-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories. We developed a higher order consortium within the TBDA in which four pharmaceutical companies (GlaxoSmithKline, Sanofi, MSD, and Lilly) collectively collaborated with screeners at Weill Cornell Medicine, the Infectious Disease Research Institute (IDRI), and the National Institute of Allergy and Infectious Diseases (NIAID), pharmacologists at Rutgers University, and medicinal chemists at the University of North Carolina to screen ∼8900 β-lactams, predominantly cephalosporins, and characterize active compounds. In a striking contrast to historical expectation, 18% of β-lactams screened were active against Mtb, many without a β-lactamase inhibitor. One potent cephaloporin was active in Mtb-infected mice. The steps outlined here can serve as a blueprint for multiparty, intra- and intersector collaboration in the development of anti-infective agents.

The EU Response to COVID-19: From Reactive Policies to Strategic Decision-Making.

The EU Response to COVID-19: From Reactive Policies to Strategic Decision-Making.

OP0101 RHEUMATOID ARTHRITIS DISEASE ACTIVITY OVER TIME AND SUBSEQUENT CARDIOVASCULAR RISKS.

Background:Rheumatoid arthritis (RA) patients have an increased risk of cardiovascular (CV) events not fully explained by traditional CV risk factors. The relationship between fluctuating inflammation due to RA disease activity and CV events is of interest.Objectives:To examine the influence of time-varying disease activity on the subsequent risks of CV disease.Methods:We followed patients from a large US registry of clinically diagnosed RA patients, starting at their first visit with a Clinical Disease Activity Index (CDAI) through the end of follow-up or first CV event. Exposure of interest was disease activity measured by categorical CDAI (high, moderate, low, and remission) averaged within each 6-month window. The outcome of interest was major adverse CV events (MACE) defined as non-fatal myocardial infarction, non-fatal stroke (excluding transient ischemic attacks), and CV death. For baseline confounders we considered age, gender, race, disease duration, Health Assessment Questionnaire, hypertension, diabetes, hyperlipidemia, family history of premature (age<50) CV events, and RF/ACPA seropositivity. For time-varying variables we considered tumor necrosis factor inhibitor (TNFi), non-TNFi biologic, methotrexate, oral glucocorticoid, non-steroidal anti-inflammatory drugs, statin, and aspirin use. We used the marginal structural model (MSM) framework to examine the impact of CDAI at each 6-month interval on MACE. We estimated time-varying hazard ratios (HRs) comparing high CDAI during follow-up to CDAI remission. Several predicted survival curves were constructed under different hypothetical CDAI scenarios, such as early and late transition to CDAI remission.Results:40,721 patients were eligible for our analyses. 77% were female and 84% were Caucasian. The mean age was 58 (SD 13) years with mean disease duration of 8.8 (median 5) years. Mean CDAI at their first registry visit was 14 (SD 13; remission 19%, low 31%, moderate 28%, and high 22%). Other baseline characteristics include: 41% current/former smokers, 31.5% with hypertension, 8.6% with diabetes, 18% with hyperlipidemia, and 52% seropositive. The average follow-up duration after baseline was 4.4 (median 3.3; max. 17.6) years. The crude event count of MACE was 1,050 events / 180,402 person-years.In the MSM analysis, the average HRs, assuming a constant HR, were 1.31 [0.90, 1.90] for low, 1.46 [1.01, 2.10] for moderate, and 1.43 [0.89, 2.31] for high CDAI disease activity categories during each 6-month interval. When approximating time-varying HR with linear trends, the highest estimates during the first 6 months of follow up were 1.61 [0.93, 2.77] for low CDAI, 1.97 [1.13, 3.43] for moderate CDAI, and 2.11 [1.13, 3.96] for high CDAI. These HRs gradually diminished during the follow up (Table). When we constructed hypothetical survival curves with transition to CDAI remission at different time points, earlier transition to CDAI remission was related to better event-free survival (Figure).Table 1.Time-varying hazard ratio estimates [95% confidence intervals] by duration in studyDisease activity measured by CDAIYearRemissionLowModerateHigh0.51.00 [ref]1.61 [0.93, 2.77]1.97 [1.13, 3.43]2.11 [1.13, 3.96]11.00 [ref]1.54 [0.97, 2.44]1.85 [1.17, 2.93]1.94 [1.13, 3.31]21.00 [ref]1.42 [1.00, 2.01]1.63 [1.16, 2.29]1.62 [1.04, 2.54]31.00 [ref]1.31 [0.90, 1.90]1.43 [0.97, 2.11]1.36 [0.80, 2.31]41.00 [ref]1.20 [0.72, 2.02]1.26 [0.72, 2.21]1.14 [0.55, 2.36]51.00 [ref]1.11 [0.54, 2.26]1.11 [0.51, 2.42]0.96 [0.36, 2.53]Figure 1.MACE-free survival curves under hypothetical CDAI scenariosConclusion:High and moderate CDAI were associated with higher hazard of MACE during the earlier period of follow-up, but the increased hazard diminished over time. In hypothetical senarios, earlier transition to CDAI remission would improve MACE free-survival.Acknowledgements:This study was sponsored by Corrona, LLC. Corrona is supported through contracted subscriptions with multiple pharmaceutical companies. The analysis was financially supported by Amgen Inc.Disclosure of Interests:Kazuki Yoshida Consultant of: OM1, Inc., Grant/research support from: Corrona, LLC., Hongshu Guan: None declared, Scott Stryker Shareholder of: Amgen, Inc., Employee of: Amgen, Inc., Elaine Karis Shareholder of: Amgen, Inc., Employee of: Amgen, Inc., Leslie Harrold Consultant of: AbbVie, Bristol-Myers Squibb, Genentech/Roche, Grant/research support from: Pfizer, Daniel Solomon Grant/research support from: DHS receives salary support from research contracts through Brigham and Women’s Hospital with Abbvie, Amgen, Corrona, Genentech and Janssen.

Healthcare Provider Attitudes toward the Newly Developed COVID-19 Vaccine: Cross-Sectional Study.

Background: During the long wait and the global anxiety for a vaccine against COVID-19, impressively high-safety and effective vaccines were invented by multiple pharmaceutical companies. Aim: We aimed to assess the attitudes of healthcare providers and evaluate their intention to advocate for the vaccine. Methods: This was a cross-sectional study conducted in a tertiary private hospital where an electronic survey was distributed among healthcare providers (HCPs). The survey contained two sections: socio-demographic characteristics and Likert-scale perception, with 72% internal consistency. Results: The response rate to the email survey was 37% (n = 236). In addition, 169 (71.6%) of respondents were women, with more than half (134, 56.8%) aged ≤35 years. A total of 110 (46.6%) had over 10 years of experience, and most of them were nurses (146, 62%). Univariate analysis revealed that older participants significantly accepted and advocated for the new vaccine more than the younger ones. In the multivariate analysis, men were significantly more likely than women to accept and advocate for the new vaccine, as were those with chronic illnesses. Participants with allergy were significantly less likely to accept the vaccine than others. odds ratio (OR) and p-values were 2.5, 0.003; 2.3, 0.04; and 0.4, 0.01, respectively. Conclusion: The acceptance rate for the newly-developed COVID-19 vaccines was average among HCPs. Sex, age, presence of chronic illnesses, and allergy were significant predictors of accepting the vaccine.

Targeting GSK3 and Associated Signaling Pathways Involved in Cancer.

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it was subsequently determined to have roles in multiple normal biochemical processes as well as various disease conditions. GSK-3 is sometimes referred to as a moonlighting protein due to the multiple substrates and processes which it controls. Frequently, when GSK-3 phosphorylates proteins, they are targeted for degradation. GSK-3 is often considered a component of the PI3K/PTEN/AKT/GSK-3/mTORC1 pathway as GSK-3 is frequently phosphorylated by AKT which regulates its inactivation. AKT is often active in human cancer and hence, GSK-3 is often inactivated. Moreover, GSK-3 also interacts with WNT/β-catenin signaling and β-catenin and other proteins in this pathway are targets of GSK-3. GSK-3 can modify NF-κB activity which is often expressed at high levels in cancer cells. Multiple pharmaceutical companies developed small molecule inhibitors to suppress GSK-3 activity. In addition, various natural products will modify GSK-3 activity. This review will focus on the effects of small molecule inhibitors and natural products on GSK-3 activity and provide examples where these compounds were effective in suppressing cancer growth.

Caplyta Receives FDA Approval For Schizophrenia

Back to table of contents Previous article Next article Clinical & ResearchFull AccessCaplyta Receives FDA Approval For SchizophreniaMark MoranMark MoranSearch for more papers by this authorPublished Online:6 Feb 2020https://doi.org/10.1176/appi.pn.2020.2a27AbstractThe drug acts on the brain through a mechanism different from many other second-generation antipsychotics, raising hopes that it might be a breakthrough in the treatment of schizophrenia.The Food and Drug Administration (FDA) in December approved Caplyta (lumateperone), an oral antipsychotic medication to treat schizophrenia in adults.According to the lumateperone label, the medication has been evaluated in 1,724 adult patients with schizophrenia exposed to one or more doses in placebo-controlled trials.The details of one of those trials appeared in JAMA Psychiatry last month. According to the paper, 450 patients were randomized to one of three daily treatments: 42 mg of lumateperone, 28 mg of lumateperone, or placebo.The primary endpoint was change in symptoms at 28 days as measured by the Positive and Negative Symptom Scale (PANSS). A secondary measure was the Clinical Global Impression of Severity (CGI-S) score, a seven-point clinician-rated scale of illness severity.William Carpenter, M.D., says that the effectiveness of lumateperone in treating patients with schizophrenia in real-world settings remains to be seen.Patients who took 42 mg of lumateperone (but not those who took 28 mg of lumateperone) experienced a statistically significant decrease in symptoms over the four-week trial compared with those taking placebo, as measured by PANSS. Patients who took either dose of the medication also experienced significant improvements on the CGI-S. The drug appears to be safe. Weight gain and other metabolic changes, cardiac problems, or problems with movement or motor coordination were similar in study participants.The study was supported by Intra-Cellular Therapies, which manufactures lumateperone.The agent has attracted some optimism as a possible breakthrough in schizophrenia treatment because it acts on glutamate receptors in the brain as well as dopamine and serotonin receptors. Many of the so-called “me-too” second-generation antipsychotics (SGAs) manufactured in recent years have acted on serotonin and dopamine only; experts agree that what is needed to make a dramatic improvement in the lives of people with schizophrenia are medications that work on the brain in entirely novel ways.In an editorial accompanying the study, Joshua Kantrowitz, M.D., of the Department of Psychiatry at Columbia University and the Nathan Kline Research Institute, expressed guarded optimism. “The relevance of an effective and potentially unique mechanism … could have an effect beyond lumateperone itself,” he wrote. “In recent years, multiple pharmaceutical companies have withdrawn from neuroscience research, and the success of lumateperone could spur additional research and development into novel mechanism research. After multiple high-profile failures, the field is risk averse. Thus, the stimulation of novel mechanism antipsychotic research could be as or more important than the role of lumateperone itself.”William Carpenter, M.D., editor of Schizophrenia Bulletin and chair of the Psychotic Disorders workgroup for DSM-5, has been especially critical of manufacturer claims about me-too drugs.“With so many me-too antipsychotic drugs available, is there reason to have higher expectations for lumateperone?” he asked. “It joins other drugs approved for schizophrenia in engaging dopaminergic pathways and appears to have a benign adverse effect profile. … While therapeutic advantages over current medications have not been reported, the mechanism simultaneously engaging dopaminergic, serotonergic, and glutamatergic networks is novel and merits further exploration.”The labeling for lumateperone includes a boxed warning noting that older patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death. The medication is not approved for the treatment of patients with dementia-related psychosis. ■“Efficacy and Safety of Lumateperone for Treatment of Schizophrenia: A Randomized Clinical Trial” is posted here. “The Potential Role of Lumateperone—Something Borrowed? Something New?” is posted here. ISSUES NewArchived

Repurposing anti-diabetic drugs for the treatment of Parkinson's disease: Rationale and clinical experience.

The most pressing need in Parkinson's disease (PD) clinical practice is to identify agents that might slow down, stop or reverse the neurodegenerative process of Parkinson's disease and therefore avoid the onset of the most disabling, dopa-refractory symptoms of the disease. These include dementia, speech and swallowing problems, poor balance and falling. To date, there have been no agents which have yet had robust trial data to confirm positive effects at slowing down the neurodegenerative disease process of PD. In this chapter we will review the reasons why there is growing interest in drugs currently licensed for the treatment of diabetes as agents which may slow down disease progression in PD, including a review of the published trials regarding exenatide, a GLP-1 receptor agonist licensed to treat type 2 diabetes, and recently shown to be associated with reduced severity of PD in a randomized, placebo controlled washout design trial of 60 patients treated for 48 weeks. This subject is now a major area of interest for multiple pharmaceutical companies hoping to bring GLP-1 receptor agonists forward as treatment options in PD.

PGI1 BAYESIAN NETWORK ANALYSIS OF MEDICARE PATIENTS WITH C-DIFF

Clostridium-difficile (c-diff) bacterium infect the large intestine causing symptoms ranging from pain and discomfort to diarrhea and life-threatening inflammation. While more than half a million Americans are impacted yearly, the most at risk are older adults or those with immune related disorders being treated with a biologic. From the 2014 Medicare MedPAR dataset, 70589 cases of c-diff were reported. A Bayesian network was utilized with primary nodes for surgery performed connected to length of stay (LOS) of 7+ days as well as death in hospital. Secondary nodes of a radiology test occurring, gender, and age of 80+ were included. Conditional probabilities were assessed and then updated when death was observed. LOS for c-diff was exponentially distributed where λ = 0.158. 66.08% of patients were female and 41.25% where 80+ years old. 2.145% of the c-diff patients died while in hospital, where 69.44% of those that died had surgery performed and 35.26% of those that survived had surgery. The median LOS was 7 days for those that died and 5 for those that survived, where 22% of those that did not have surgery and 49.2% that had surgery had a LOS of 7+ days. When death was observed, 52% of patients had a LOS of 7+ days and 71% had surgery, suggesting that surgery occurring is directly impacting both length of stay and death. 77% of those that had surgery had a radiology test performed, 63% were female, and 61% were 80+ years old. This analysis highlights the heavy hospital resource utilization of patients diagnosed with c-diff and the heavy burden of infection in the oldest age brackets of beneficiaries. Multiple pharmaceutical companies have c-diff vaccines in development that may help alleviate some of this burden. Results from this analysis highlight the unmet need in older Medicare patients.

Dancing with Deterrents: Understanding the Role of Abuse-Deterrent Opioid Formulations and Naloxone in Managing Cancer Pain.

Prescription opioids are commonly prescribed for the relief of many kinds of pain syndromes, including cancer pain. In order to combat the growing rates of abuse and misuse of prescription opioids, the Centers for Disease Control and Prevention, along with the U.S. Food and Drug Administration and multiple pharmaceutical companies, have implemented many risk mitigation strategies. Abuse-deterrent drug delivery technology and more consistent prescribing of the opioid antagonist, naloxone, are two of the mechanisms of reducing harm in patients on chronic opioid therapy. Abuse-deterrent technology is implemented into different commercially available opioid products with the intent of discouraging manipulation of the opioid or making the use of the manipulated opioid less appealing. Use of the opioid antagonist, naloxone, for reversal of intentional or unintentional opioid overdose is a safe and effective means to reduce potential risk in patients who are on opioids for pain management. These mechanisms have multiple advantages and limitations that influence their practical use specifically in patients with cancer pain. Patients with cancer pain have unique therapeutic needs and goals, and their balance of treatment risks and benefits differs from that of other kinds of chronic pain disorders. This article provides an overview of the advantages and limitations of these specific harm-reduction strategies and provides guidance on how to practically utilize them when caring for patients with cancer pain. IMPLICATIONS FOR PRACTICE: Treating cancer pain has important and unique considerations compared with other chronic, noncancer pain disorders. The use of risk mitigation strategies for opioid prescribing as promoted by the Centers for Disease Control and Prevention does not translate seamlessly to patients with cancer. It is crucial to be wary of the advantages and pitfalls of all risk mitigation strategies related to opioid use in patients with cancer pain. Careful examination of patient-specific risks and benefits should always be considered when implementing pharmacologic treatment and harm-reduction strategies for the management of cancer pain.

The ACTTION Guide to Clinical Trials of Pain Treatments: standing on the shoulders of giants.

The ACTTION Guide to Clinical Trials of Pain Treatments: standing on the shoulders of giants.

Health Plan Enrollment and Disenrollment of Individuals With and Without Established Chronic Disease in a U.S. Commercially Insured and Medicare Advantage Population.

Chronic disease is associated with increased health care resource utilization and costs. Effective development and implementation of health care management and clinical intervention programs require an understanding of health plan member enrollment and disenrollment behavior. To examine the health plan enrollment and disenrollment behavior of commercially insured and Medicare Advantage members with established chronic disease compared with matched members without the disease of interest, using data from a large national health insurer in the United States. This retrospective matched cohort study used administrative claims data from the HealthCore Integrated Research Database from January 1, 2006, to November 30, 2015, to identify adults with chronic disease (type 2 diabetes mellitus [T2DM], cardiovascular disease [CVD], chronic obstructive pulmonary disease [COPD], rheumatoid arthritis [RA], and breast cancer [BC]). Members with no established chronic disease (controls) were directly matched to members with established chronic disease (cases) on demographic characteristics. The earliest date on which members met the criteria for a given disease was defined as the index date. Controls had the same index date as the matched cases. All members had ≥ 12 months of continuous health plan enrollment before the index date. Outcomes included health plan member disenrollment and enrollment duration. Incidence rates per 1,000 member-years for member disenrollment were evaluated along with incidence rate ratios (relative risk) using a Poisson model. Time to disenrollment was analyzed by Cox proportional hazard models and Kaplan-Meier survival curves. Sensitivity analyses were conducted where death was included as a disenrollment event. 70,907 health plan members with BC (99.7% female, mean age 60.5 years); 28,883 members with COPD (52.3% female, mean age 66.7); 835,358 members with CVD (50.5% female, mean age 62.7 years); 210,936 members with T2DM (45.2% female, mean age 53.6 years); and 31,954 members with RA (72.0% female, mean age 55.5 years) were matched to controls and met the study criteria. The incidence rates of health plan disenrollment ranged from 155 to 192 members per 1,000 members per year. Compared with controls, members with chronic disease were 30%-40% less likely to disenroll from a health plan (P < 0.001 for all comparisons). Among those who disenrolled, enrollment duration ranged from 2.3 to 2.7 years among cases and 1.5 to 1.8 years among matched controls (P ≤ 0.001 for all comparisons). This real-world study demonstrated that members with chronic disease had a significantly lower rate of disenrollment and a longer duration of enrollment compared with matched controls and were continuously enrolled for almost a year longer than members without a diagnosed chronic disease. Understanding health plan enrollment and disenrollment behavior may provide a valuable context for determining the time frame for the effect of health care programs and initiatives. Funding for this study was provided by HealthCore, a wholly owned subsidiary of Anthem. Chung, Deshpande, Zolotarjova, Quimbo, and Willey are employees of HealthCore. Kern and Cochetti are former employees of HealthCore. Quimbo, Cochetti, and Willey are shareholders of Anthem. HealthCore receives funding from multiple pharmaceutical companies to perform various research studies outside of the submitted work. The preliminary results of this study were presented at AMCP Nexus 2015; March 26-29, 2015; Orlando, FL, and the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 2017 Conference; May 20-24, 2017; Boston, MA.

830P - Synthetic DNA immunotherapy in biochemically relapsed prostate cancer

Background: INO-5150 (PSA and PSMA) +/- INO-9012 (IL-12), a synthetic DNA immunotherapy, was assessed for safety, immunogenicity and efficacy in biochemically recurrent prostate cancer patients (pts). Methods: Phase I, open-label, multi-center study in the US included pts with rising PSA after surgery and/or RT, PSA doubling time (PSADT) >3 months (mos), testosterone >150 ng/dL and no concurrent ADT. Safety, immunogenicity and efficacy (PSA kinetics, PFS) were evaluated in 4 treatment arms of 15 pts each. Arms A: 2mg INO-5150, B: 8.5 mg INO-5150, C: 2mg INO-5150 + 1mg INO-9012 and D: 8.5mg INO-5150 + 1mg INO-9012. Pts received 4 IM doses of vaccine followed by electroporation on day 0, wks 3, 12 and 24 and were followed for 72 wks. Results: 50/61 (82%) pts completed all visits and treatments were well tolerated with no safety concerns. Median PFS for overall population [N = 61, baseline (D0) PSADT range (mos) 1.5-217.1, median 9.8] and for a subset of pts with D0 PSADT ≤12mos (N = 36) has not yet been reached (FU 3-19 mos). 86% of pts with D0 PSADT ≤12 mos were progression free through 19mos FU. 27 out of 36 (75%) pts with D0 PSADT≤ 12 mos had disease stabilization at wks 27 evidenced by significant improvement in log2PSA change over time (slope) and PSADT from D0 (Slope=0.19 declined to 0.1, PSADT=5.3 improved to 10.1 mos, p = <0.0001). This effect was maintained at wk 72 (Slope=0.09, PSADT=10.6, p = <0.0001). Immunogenicity was observed in 77% (47/61) of pts by multiple immunologic assessments. Patient immunogenicity to INO-5150 as determined by CD38 and Perforin + CD8 T cell immune reactivity correlated with attenuated % PSA rise compared to pts without reactivity (p = 0.05, n = 50). Conclusions: INO-5150 +/- INO-9012 was safe, well tolerated and immunogenic. Clinical efficacy was observed in the patients with D0 PSADT≤ 12 mos as evidenced by a significant dampening of log2PSA change over time and increased PSADT up to 72 weeks FU. Additional genomic analyses are ongoing to further elucidate the correlation of immunologic efficacy and clinical benefit. (NCT02514213). Clinical trial identification: FDA IND number 15870. Legal entity responsible for the study: Inovio Pharmaceuticals, Inc. Funding: Inovio Pharmaceuticals, Inc. Disclosure: N. Shore: Consulting or advisory role for multiple pharmaceutical companies. E.I. Heath: Consulting or advisory role and honoraria or funding received for multiple pharmaceutical companies. H. Cheng, Y. Whang: Funding received from multiple pharmaceutical companies. K. Bhatt, M. Morrow, T. McMullan, K. Kraynyak, J. Lee, B. Sacchetta, L. Liu, S. Rosencranz, I. Csiki, M.L. Bagarazzi: Employee of the pharmaceutical company sponsoring this research trial. S.T. Tagawa, R. Tutrone, J. Garcia, W. Kelly: Consulting or advisory role and funding received from multiple pharmaceutical companies. All other authors have declared no conflicts of interest.

Discovery of Small Molecule Therapeutics for Treatment of Chronic HBV Infection.

The chronic infection of hepatitis B virus (HBV) inflicts 250 million people worldwide representing a major public health threat. A significant subpopulation of patients eventually develop cirrhosis and hepatocellular carcinoma (HCC). Unfortunately, none of the current standard therapies for chronic hepatitis B (CHB) result in a satisfactory clinical cure rate. Driven by a highly unmet medical need, multiple pharmaceutical companies and research institutions have been engaged in drug discovery and development to improve the CHB functional cure rate, defined by sustainable viral suppression and HBsAg clearance after a finite treatment. This Review summarizes the recent advances in the discovery and development of novel anti-HBV small molecules. It is believed that an improved CHB functional cure rate may be accomplished via the combination of molecules with distinct MoAs. Thus, certain molecules may evolve into key components of a suitable combination therapy leading to superior outcome of clinical efficacy in the future.

Abstract 2607: The cBioPortal for Cancer Genomics: an open source platform for accessing and interpreting complex cancer genomics data in the era of precision medicine

Abstract The cBioPortal for Cancer Genomics is an open-access portal (http://cbioportal.org) that enables interactive, exploratory analysis of large-scale cancer genomics data. It integrates genomic and clinical data, and provides a suite of visualization and analysis options, including cohort and patient-level visualization, mutation visualization, survival analysis, enrichment analysis, and network analysis. The user interface is user-friendly, responsive, and makes genomic data easily accessible to translational scientists, biologists, and clinicians. The cBioPortal is a fully open source platform. All code is available on GitHub (https://github.com/cBioPortal/) under GNU Affero GPL license. The code base is maintained by multiple groups, including Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, Children’s Hospital of Philadelphia, Princess Margaret Cancer Centre, and The Hyve, an open source bioinformatics company based in the Netherlands. More than 30 academic centers as well as multiple pharmaceutical and biotech companies maintain private instances of the cBioPortal. This includes the recently launched cBioPortal instance at the NCI Genomic Data Commons (https://cbioportal.gdc.nci.nih.gov/), and two large cBioPortal instances hosting genomic and clinical data at MSK and DFCI, supporting the MSK-IMPACT and DFCI Profile projects, two of the largest clinical sequencing efforts in the world. Our multi-institutional software team has accelerated the progress of evolving the core architectural technologies and developing new features to keep pace with the rapidly advancing fields of cancer genomics and precision cancer medicine. For example, we have integrated multi-platform genomics data with extensive clinical data including patient demographics, treatment history, and survival data. We have also developed a patient-centric view that visualizes both clinical and genomic data with annotation from OncoKB knowledge base. In the next few years, the development team will focus on the following areas: (1) Implementing major architectural changes to ensure future scalability and performance. (2) New features to support precision medicine, including (i) improved integration of knowledge base annotation, (ii) enhanced visualization of patient timeline, drug response, and tumor evolution, (iii) new patient similarity metrics, (iv) improved support for immunogenomics and immunotherapy, and (v) new visualization and analysis features for understanding response to therapy. (3) New analysis and target discovery features for large cohorts, including (i) supporting user-defined virtual cohort by selecting samples from multiple studies, and (ii) comparison of genomic or clinical characteristics of two or more selected cohorts. (4) Expanding community outreach, user support and training, and documentation. Citation Format: Jianjiong Gao, Ersin Ciftci, Pichai Raman, Pieter Lukasse, Istemi Bahceci, Adam Abeshouse, Hsiao-Wei Chen, Ino de Bruijn, Benjamin Gross, Zachary Heins, Ritika Kundra, Aaron Lisman, Angelica Ochoa, Robert Sheridan, Onur Sumer, Yichao Sun, Jiaojiao Wang, Manda Wilson, Hongxin Zhang, James Xu, Andy Dufilie, Priti Kumari, James Lindsay, Anthony Cros, Karthik Kalletla, Fedde Schaeffer, Sander Tan, Sjoerd van Hagen, Jorge Reis-Filho, Kees van Bochove, Ugur Dogrusoz, Trevor Pugh, Adam Resnick, Chris Sander, Ethan Cerami, Nikolaus Schultz. The cBioPortal for Cancer Genomics: an open source platform for accessing and interpreting complex cancer genomics data in the era of precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2607. doi:10.1158/1538-7445.AM2017-2607

Designing Clinical Trials That Accept New Arms: An Example in Metastatic Breast Cancer.

Purpose The majority of randomized oncology trials are two-arm studies that test the efficacy of new therapies against a standard of care, thereby assigning a large proportion of patients to nonexperimental therapies. In contrast, multiarm studies efficiently share a common control arm while evaluating multiple experimental therapies. A major bottleneck for traditional multiarm trials is the requirement that all therapies-often drugs from different companies-have to be available at the same time when the trial starts. We evaluate the potential gains of a platform design-the rolling-arms design-that adds and removes arms on a rolling basis. Methods We define the rolling-arms design with the goal of minimizing the complexity of random assignment and data analyses of a platform trial. We then evaluate its potential advantages in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Multiple pharmaceutical companies currently test CDK4/6 inhibitors in combination with letrozole in independent two-arm trials. We conducted a simulation study to quantify the reduction in sample size, number of patients treated with the standard of care, and the average time to treatment discovery if these therapies had been tested in a rolling-arms trial. Results A rolling-arms platform design with two to five experimental treatments can reduce the overall sample size requirement by up to 30% compared with standard two-arm studies. It assigns up to 60% fewer patients to the control arm compared with five independent trials that test distinct treatments. Moreover, under realistic scenarios, effective experimental treatments are discovered up to 15 months earlier compared with separate two-arm trials. Conclusion The rolling-arms platform design is applicable to a broad variety of diseases, and under realistic scenarios, it is substantially more efficient than standard two-arm randomized trials.