Daniel A. Cohen

The 'Numbers Game' in The Pre-and Post-Sarbanes-Oxley Eras

We document a decline in the frequency of just meeting/beating analysts’ earnings expectations in the aftermath of the 2001-2002 accounting scandals and the passage of the 2002 Sarbanes-Oxley Act (SOX). The primary purpose of this study is to explain this observed pattern. We hypothesize and provide empirical evidence that the drop in the frequency of just meeting/beating is associated with both (1) a decline in the use of downward earnings expectations management and upward accrual-based earning management in the Post-SOX period relative to the preceding seven-year period and (2) an increase in upward real earnings management activities.

The ARPA internet protocol

Abstract A variety of computer networks are interconnected by gateway computers in the ARPA internetwork system. Processes on different networks may exchange messages with each other by means of an Internet Protocol which must be implemented in each subscriber (host) computer and in the gateways. The Internet Protocol is a relatively simple protocol that provides for the delivery of individual messages (datagrams) with high but not perfect reliability. This Internet Protocol does not replace the existing protocol in any network, but is used by processes to extend the range of communications. Messages in Internet Protocol are transmitted through any individual network by encapsulating them in that networks protocol. This paper presents an overview of the Internet Protocol and the operation of the gateway computers in the ARPA internet system.

In Vitro and In Vivo Antiviral Activity and Resistance Profile of the Hepatitis C Virus NS3/4A Protease Inhibitor ABT-450

ABSTRACT The development of direct-acting antiviral agents is a promising therapeutic advance in the treatment of hepatitis C virus (HCV) infection. However, rapid emergence of drug resistance can limit efficacy and lead to cross-resistance among members of the same drug class. ABT-450 is an efficacious inhibitor of HCV NS3/4A protease, with 50% effective concentration values of 1.0, 0.21, 5.3, 19, 0.09, and 0.69 nM against stable HCV replicons with NS3 protease from genotypes 1a, 1b, 2a, 3a, 4a, and 6a, respectively. In vitro, the most common amino acid variants selected by ABT-450 in genotype 1 were located in NS3 at positions 155, 156, and 168, with the D168Y variant conferring the highest level of resistance to ABT-450 in both genotype 1a and 1b replicons (219- and 337-fold, respectively). In a 3-day monotherapy study with HCV genotype 1-infected patients, ABT-450 was coadministered with ritonavir, a cytochrome P450 3A4 inhibitor shown previously to markedly increase peak, trough, and overall drug exposures of ABT-450. A mean maximum HCV RNA decline of 4.02 log10 was observed at the end of the 3-day dosing period across all doses. The most common variants selected in these patients were R155K and D168V in genotype 1a and D168V in genotype 1b. However, selection of resistant variants was significantly reduced at the highest ABT-450 dose compared to lower doses. These findings were informative for the subsequent evaluation of ABT-450 in combination with additional drug classes in clinical trials in HCV-infected patients. (Study M11-602 is registered at ClinicalTrials.gov under registration no. NCT01074008.)

The Sarbanes Oxley Act of 2002: Implications for Compensation Contracts and Managerial Risk-Taking

This paper investigates the effect of the Sarbanes-Oxley Act (hereafter, SOX) on the compensation structure and the risk-taking incentives of CEOs as revealed by their research and development expenses and capital expenditures. We hypothesize that firms will respond to the additional liability imposed by SOX on corporate executives by altering the mix of incentive compensation to fixed salary awarded to them in order to provide insurance. Consistent with this claim, we find that there was a significant decline in the ratio of incentive compensation to salary after the passage of SOX. We also hypothesize and find that there was a significant decline in research and development expenses and capital expenditures made by CEOs after the passage of SOX. This result is obtained after controlling for the effects of the economic environment and changes in compensation structure on CEOs’ action choices. We interpret the above as evidence of some of the potential costs of this new regulation.

Resistance Analysis of Baseline and Treatment-Emergent Variants in Hepatitis C Virus Genotype 1 in the AVIATOR Study with Paritaprevir-Ritonavir, Ombitasvir, and Dasabuvir

ABSTRACT AVIATOR, a phase 2 clinical trial, evaluated ritonavir-boosted paritaprevir (a protease inhibitor), ombitasvir (an NS5A inhibitor), and dasabuvir (a nonnucleoside polymerase inhibitor) (the three-drug [3D] regimen) with or without ribavirin (RBV) for 8, 12, or 24 weeks in 406 HCV genotype 1 (GT1)-infected patients. The rate of sustained virologic response 24 weeks after treatment ranged from 88% to 100% across the arms of the 3D regimen with or without RBV; 20 GT1a-infected patients and 1 GT1b-infected patient experienced virologic failure (5.2%). Baseline resistance-conferring variants in NS3 were rare. M28V in GT1a and Y93H in GT1b were the most prevalent preexisting variants in NS5A, and C316N in GT1b and S556G in both GT1a and GT1b were the most prevalent variants in NS5B. Interestingly, all the GT1a sequences encoding M28V in NS5A were from the United States, while GT1b sequences encoding C316N and S556G in NS5B were predominant in the European Union. Variants preexisting at baseline had no significant impact on treatment outcome. The most prevalent treatment-emergent resistance-associated variants (RAVs) in GT1a were R155K and D168V in NS3, M28T and Q30R in NS5A, and S556G in NS5B. The single GT1b-infected patient experiencing virologic failure had no RAVs in any target. A paritaprevir-ritonavir dose of 150/100 mg was more efficacious in suppressing R155K in NS3 than a 100/100-mg dose. In patients who failed after receiving 12 or more weeks of treatment, RAVs were selected in all 3 targets, while most patients who relapsed after 8 weeks of treatment did so without any detectable RAVs. Results from this study guided the selection of the optimal treatment regimen, treatment duration, and paritaprevir dose for further development of the 3D regimen. (This study has been registered at ClinicalTrials.gov under registration number NCT01464827.)

Sexual dysfunction is highly prevalent among men with chronic hepatitis C virus infection and negatively impacts health-related quality of life.

OBJECTIVES:Although sexual dysfunction has been reported in patients with hepatitis C virus (HCV) infection, little is known about this association. The aims of this study were to determine the prevalence of sexual dysfunction among men with chronic HCV infection and to evaluate the impact of sexual dysfunction on health-related quality of life (HRQOL).METHODS:We prospectively enrolled 112 HCV positive men and 239 HCV negative controls, and all patients completed validated questionnaires to assess sexual function (Brief Male Sexual Function Inventory [BMSFI]), depression (Beck Depression Inventory), and HRQOL (Medical Outcomes Study Short Form-36). The BMSFI assessed sexual drive, erection, ejaculation, sexual problem assessment, and overall sexual satisfaction.RESULTS:HCV positive men had significantly more sexual dysfunction than control subjects across all five domains of the BMFSI. In addition, HCV-infected men were significantly more likely than controls to not be sexually satisfied (53.6% vs 28.9%, p < 0.001) and this remained statistically significant after adjusting for age, race, and other potential confounding variables (OR = 3.36; 95% CI, 1.59–7.13). In the 241 individuals without depression, HCV positive men were significantly more likely to not be sexually satisfied as compared with control subjects (47.5% vs 11.0%, p < 0.001). HCV-infected men who were not sexually satisfied scored significantly worse in six of eight domains of HRQOL as compared with HCV-infected men who were sexually satisfied.CONCLUSIONS:Sexual dysfunction is highly prevalent in men with chronic HCV infection, is independent of depression, and is associated with a marked reduction in HRQOL.

Complications of gastrectomy following CPT-11-based neoadjuvant chemotherapy for gastric cancer

Potential benefits of neoadjuvant therapy for locally advanced gastric cancer include tumor downstaging and an increased R0 resection rate. Potential disadvantages include increased surgical complications. This study assesses postoperative morbidity and mortality by comparing patients undergoing gastrectomy with and without neoadjuvant chemotherapy. From October 1998 to July 2002, a total of 34 patients with locally advanced gastric cancer were placed on a phase II neoadjuvant chemotherapy protocol consisting of two cycles of CPT-11 (75 mg/m2) with cisplatin (25 mg/m2). Demographic, clinical, morbidity, and mortality data were compared for these patients (CHEMO) versus 85 patients undergoing gastrectomy without neoadjuvant chemotherapy (SURG). The CHEMO patients were more likely to be less than 70 years of age (P ≦ 0.01), have proximal tumors (P ≦ 0.01), and undergo proximal gastrectomy (P ≦ 0.025). Fifty-two percent of SURG patients had T3/T4 tumors compared to 19% of CHEMO patients, consistent with tumor downstaging. The R0 resection rate was similar (80%). Morbidity was 41% in CHEMO patients and 39% in SURG patients. There were five postoperative deaths (4.4%), two in the CHEMO group and three in the SURG group (P = NS). It was concluded that neoadjuvant chemotherapy with CPT-11 and cisplatin is not associated with increased postoperative morbidity compared to surgery alone. CPT-11-based neoadjuvant chemotherapy should be tested further in combined-modality treatment of gastric cancer.

HCV RNA assay sensitivity impacts the management of patients treated with direct-acting antivirals.

BACKGROUND Application of response-guided therapy (RGT) rules to the treatment of HCV infection with pegylated interferon-α2a and ribavirin, and direct-acting antivirals (DAAs) such as the NS3/4A protease inhibitors (PIs) boceprevir and telaprevir, relies on the determination of viral genotype and on-treatment HCV RNA level. Currently there are few data available regarding the clinical impact of the analytical differences that exist between different HCV RNA quantification assays on treatment decisions such as those involved in RGT. METHODS We sought to ascertain the concordance between two HCV RNA quantification assays, the Roche/High-Pure-System COBAS(®) TaqMan (CTM) version 2 and Abbott RealTime HCV (ART), and to understand the impact of different assay characteristics on treatment decisions. We evaluated 1,336 specimens collected from 74 patients enrolled in the Phase II CHAMPION-2 study of the investigational DAAs ABT-450 (an acylsulfonamide NS3/4A PI), ABT-072 and ABT-333 (both non-nucleoside NS5B polymerase inhibitors). RESULTS HCV RNA level results were highly correlated, but CTM values were higher than those from ART by an average of 0.46 log IU/ml. Use of ART HCV RNA level results led to a higher positive predictive value of week 4 viral load for the achievement of a sustained virological response 24 weeks after the end of treatment (100% versus 87% using the lower limit of detection as the threshold). CONCLUSIONS This study suggests that HCV viral load assay performance characteristics need to be taken into consideration when managing HCV patients with RGT. Further studies are required to determine whether a consensus HCV RNA level threshold can be established or whether HCV viral load assays with greater sensitivity can increase cure rates with RGT.

On protocol multiplexing

The notion of protocol multiplexing usually means the ability of a protocol to accommodate several instances of higher level protocols at the same time. In this paper we propose to extend this notion to allow sharing of messages, and packets, among several simultaneous communicating processes, which will increase the communication efficiency by reducing the total number of messages transmitted through the media. This paper discusses several aspects of multiplexing and the interaction of multiplexing with other protocol issues.

Drug-Drug Interactions between Sofosbuvir and Ombitasvir-Paritaprevir-Ritonavir with or without Dasabuvir

ABSTRACT The combination of ombitasvir (an NS5A inhibitor), paritaprevir (an NS3/4A inhibitor) coadministered with ritonavir (r), and dasabuvir (an NS5B nonnucleoside polymerase inhibitor), referred to as the 3D regimen, and the combination of ombitasvir-paritaprevir-r, referred to as the 2D regimen, have demonstrated high efficacy with and without ribavirin in hepatitis C virus (HCV)-infected subjects. These regimens have potential for coadministration with sofosbuvir (nucleoside NS5B inhibitor) in the treatment of HCV. This phase 1, drug-drug interaction, open-label, multiple-dose study enrolled 32 healthy subjects to receive the 3D or 2D regimen in combination with sofosbuvir. Doses of study drugs were as follows: ombitasvir-paritaprevir-r, 25/150/100 mg daily (QD); dasabuvir, 250 mg twice daily (BID); and sofosbuvir, 400 mg QD. Blood samples were collected on study days 7, 14, and 21 for evaluating drug interaction at steady state. The effect of the 3D and 2D regimens on the pharmacokinetics of sofosbuvir and its circulating metabolite GS-331007 and vice versa was assessed by a repeated-measures analysis. Exposures of the 3D and 2D regimens were similar (≤20% change) during coadministration with sofosbuvir and during administration alone. Sofosbuvir exposures were 61% to 112% higher with the 3D regimen and 64% to 93% higher with the 2D regimen than with sofosbuvir alone. GS-331007 total exposures were 27% and 32% higher with the 3D and 2D regimens, respectively, than with sofosbuvir alone. Increases in sofosbuvir and GS-331007 exposures likely resulted from breast cancer resistance protein (BCRP) and/or P glycoprotein (P-gp) transporter inhibition by paritaprevir and ritonavir. No subjects discontinued the study due to study drug-related adverse events. No dose adjustment is recommended for 3D, 2D, or sofosbuvir in clinical trials exploring the safety and efficacy of the combination. (This study has been registered at ClinicalTrials.gov under registration no. NCT02356562 and NCT02292719.)